Michael A Arnold, MD, PhD, FCAP

All Publications

• Therapy-related mutational signatures in subsequent neoplasms among survivors of childhood cancer. Cancer discovery Brady, S. W., Arnold, M. A., Wang, M., Alsallaq, R., Dong, L., Khan, M. A., Yang, W., Stratton, K. L., Liu, W., Chen, Y., Plyler, E., Steele, J. A., Powers, B. B., Rosenfeld, D., Edmonson, M. N., Feng, Y., Terekhanova, N. V., Hagiwara, K., Arunachalam, S., Mulder, H. L., Srivastava, D. K., Rusch, M., Nolan, V. G., McDonald, A., Sapkota, Y., Gramatges, M. M., Turcotte, L. M., Im, C., Howell, R. M., Easton, J., Ma, X., Wang, Z., Leisenring, W. M., Conces, M., Neglia, J. P., Yasui, Y., Bhatia, S., Ellison, D. W., Zhang, J., Armstrong, G. T. 2026

  Abstract

  Childhood cancer survivors have heightened risk of developing subsequent neoplasms (SNs) related to therapy. We analyzed whole-genome, exome and RNA sequencing of 200 breast, meningioma, and thyroid SNs, which developed a median of 26.4 years after childhood cancer, among 160 survivors. Meningioma and thyroid SNs were enriched for driver gene rearrangements compared to de novo tumors, including NF2-disrupting alterations and kinase fusions potentially induced by radiation. Radiation correlated with increased insertion-deletion signature ID5. Nitrogen mustard treatment correlated with elevated "flat" signature SBS5 in breast and meningioma SNs; in vitro, these agents caused an unresolved flat signature associated with multiple flat COSMIC signatures. In meningioma, platinum therapy correlated with NF2 splice-site variants. Analysis of 19 multi-sample survivors revealed intrapatient heterogeneity in meningioma, including clonally independent tumors. These results demonstrate the long-term impact of childhood cancer treatment on the genomes of SNs developing in adulthood, which may guide SN treatment and prevention.

  View details for DOI 10.1158/2159-8290.CD-25-0231

  View details for PubMedID 42001506

• Pathology podcasts: a growing educational tool ACADEMIC PATHOLOGY Mohamed, S., Schukow, C. P., Worthy, J., Strenk, D., Jackson, N. R., Loghavi, S., Jiang, X., Bellizzi, A. M., Arnold, M. A. 2025; 12 (4): 100227

  Abstract

  Podcasts serve as an easy, affordable, and on-the-go experience for listeners of all types, particularly those casually broaching a new subject they are interested in learning more about. Podcasting as a tool for pathology education has had a growing reach for several years, and has gained traction as an academic work product for medical education, promoting journals and articles, and attracting trainees to pathology. Yet, there is sparse academic literature reviewing the topic. In this article, we aim to provide a qualitative synthesis of peer-reviewed and other online sources, with objectives including introducing podcasting, reviewing its role in medical education, and exploring issues unique to pathology. National podcasting trends, advantages, and limitations of podcasts in pathology will be covered. Additionally, a comprehensive list of pathology podcasts, quantitative analysis of select podcast downloads, and practical steps for pathologists interested in creating their own podcasts will also be provided.

  View details for DOI 10.1016/j.acpath.2025.100227

  View details for Web of Science ID 001612022600001

  View details for PubMedID 41357136

  View details for PubMedCentralID PMC12677045

• Basal cell carcinoma risk prediction in survivors of childhood cancer JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Im, C., Boull, C., Lu, Z., Liao, K., Hasan, H., Xu, L., Sapkota, Y., Howell, R. M., Arnold, M. A., Conces, M. R., Housten, A. J., Gebauer, J., Langer, T., Teepen, J. C., Kremer, L. C. M., Constine, L. S., Yasui, Y., Hudson, M. M., Ness, K. K., Armstrong, G. T., Neglia, J. P., Yuan, Y., Turcotte, L. M. 2025; 117 (11): 2352-2361

  Abstract

  Survivors of childhood cancer face excess risk of developing basal cell carcinoma. Age-specific basal cell carcinoma risk prediction models for survivors may support targeted screening recommendations.We developed models predicting basal cell carcinoma risk by ages 40 and 50 years featuring detailed cancer treatment predictors, utilizing statistical and machine-learning algorithms and data from 23 166 five-year survivors in the Childhood Cancer Survivor Study, a multi-institutional retrospective cohort study. Selected models were externally validated in 5314 survivors in the St Jude Lifetime Cohort. Model discrimination and precision were evaluated using the area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC) and benchmarked against the current Children's Oncology Group Long-Term Follow-Up Guidelines (COG LTFU, v6.0) for skin cancer screening.By ages 40 and 50 years, basal cell carcinoma cumulative incidence was 5% and 15% in the Childhood Cancer Survivor Study and 7% and 21% in the St Jude Lifetime Cohort, respectively. The XGBoost algorithm-based models with treatment dose-specific predictors performed best, showing good external discrimination (age 40 years: AUROC = 0.75; age 50 years: AUROC = 0.76) and precision (age 40 years: AUPRC = 0.20; age 50 years: AUPRC = 0.52), outperforming COG LTFU Guideline-directed risk stratification (age 40 years: AUROC = 0.65; age 50 years: AUROC = 0.62; age 40 years: AUPRC = 0.09; age 50 years: AUPRC = 0.26; P < .01). These novel models reclassified 37% of survivors with COG-recommended skin cancer screening as low risk by age 40 years and 29% of survivors without COG-recommended screening as moderate or high risk by age 50 years, suggesting these recommendations overestimate risk in younger survivors and miss relevant predictors (eg, attained age, chemotherapy).In this study, we present validated basal cell carcinoma risk prediction models for childhood cancer survivors that outperform current practice guidelines. The associated online risk calculator can inform risk- and age-based screening recommendations.

  View details for DOI 10.1093/jnci/djaf228

  View details for Web of Science ID 001579095000001

  View details for PubMedID 40833927

  View details for PubMedCentralID PMC12574208

• MyoD is essential in rhabdomyosarcoma by promoting survival through differentiation and CYLD ISCIENCE Oles, A. R., Yu, P. Y., Udeme, A., Sharma, S., Londhe, P., Pryce, B. R., Talbert, E. E., Hill, E. M., Miranda, C. J., Kaspar, B. K., Arnold, M. A., Hyland, J., London, C. A., Houghton, P. J., Wang, D. J., Roberts, R. D., Guttridge, D. C. 2025; 28 (8): 113149

  Abstract

  Rhabdomyosarcoma (RMS) is the most common soft tissue cancer among children, characterized by a skeletal muscle lineage that is impaired from undergoing terminal differentiation. NF-κB is constitutively active in cancer cells and plays a critical role in cell survival. Although NF-κB is also activated in RMS, surprisingly, we find that these tumors are far less dependent on NF-κB for their survival. Instead, RMS cells survive, paradoxically, by being partially differentiated under the control of the myogenic transcription factor MyoD. Loss of MyoD, or cellular reprogramming, dedifferentiates RMS tumor cells and sensitizes their death under stress. MyoD enhances RMS survival by regulating DNA methyltransferases, which in turn suppresses the tumor suppressor and pro-apoptotic gene CYLD. From these findings, we propose that MyoD acts as an oncogene in RMS by enhancing survival through pro-differentiation and anti-cell death activities.

  View details for DOI 10.1016/j.isci.2025.113149

  View details for Web of Science ID 001544722000001

  View details for PubMedID 40799389

  View details for PubMedCentralID PMC12341531

• The impact of genetic ancestry on survival outcomes in pediatric rhabdomyosarcoma: A report from the Children's Oncology Group HUMAN GENETICS AND GENOMICS ADVANCES Onwuka, E. A., Magyar, C. L., Martin-Giacalone, B. A., Scheurer, M. E., Marquez-Do, D. A., Zobeck, M., Atkinson, E. G., Rudzinski, E. R., Arnold, M. A., Barkauskas, D. A., Hall, D., Khan, J., Shern, J. F., Scheet, P., Crompton, B., Linardic, C. M., Hawkins, D. S., Venkatramani, R., Mirabello, L., Huff, C. D., Richard, M. A., Lupo, P. J. 2025; 6 (3): 100466

  Abstract

  Emerging evidence suggests genetic ancestry may influence childhood cancer outcomes, but its impact on pediatric rhabdomyosarcoma (RMS) is unknown. We explored genetic ancestry's impact on survival among children with RMS. This multi-center observational cohort study is a secondary analysis of previously collected biobanking, genomic, and clinical data. The study included 920 individuals with newly diagnosed RMS under 40 years of age enrolled from 2005 to 2017 under the COG soft tissue sarcoma biobanking protocol D9902. The primary endpoints were (1) event-free survival (EFS), defined as the time from study enrollment to tumor recurrence/progression, secondary malignancy, or death from any cause; and (2) overall survival (OS), defined as the time from study enrollment to death from any cause. Genetic ancestry was estimated using Grafpop software, and Cox regression assessed the association between genetic ancestry and EFS and OS, considering RMS overall, by fusion status, and by histological subtype. Covariates included sex, age at diagnosis, tumor stage, and histology, except during stratified analyses. In embryonal RMS and PAX3/7:FOXO1 fusion-negative RMS, individuals with South Asian or Asian-Pacific Islander ancestry showed worse EFS (hazard ratio [HR] 2.06, 95% confidence interval [CI] 1.07-3.97, p = 0.03 and HR 2.01, 95% CI 1.07-3.76, p = 0.03, respectively) and OS (HR 2.30, 95% CI 1.09-4.84, p = 0.03 and HR 2.33, 95% CI 1.15-4.70, p = 0.020, respectively) compared to those with primarily European genetic ancestry. These findings suggest that genetic ancestry influences survival outcomes within RMS subtypes, and further understanding may improve precision-medicine-based efforts.

  View details for DOI 10.1016/j.xhgg.2025.100466

  View details for Web of Science ID 001521802700001

  View details for PubMedID 40495382

  View details for PubMedCentralID PMC12256324

• Body Mass Index, Physical Activity, and Subsequent Neoplasm Risk Among Childhood Cancer Survivors JAMA ONCOLOGY Joffe, L., Mirzaei, S., Bhatia, S., Darji, H., Ness, K. K., Onerup, A., Ladas, E. J., Im, C., Lupo, P. J., Oeffinger, K. C., Friedman, D., Howell, R. M., Conces, M. R., Arnold, M. A., Armstrong, G. T., Neglia, J. P., Yasui, Y., Kadan-Lottick, N. S., Turcotte, L. M. 2025; 11 (8): 835-845

  Abstract

  High body mass index (BMI) and low physical activity levels are risk factors for adult-onset cancers. Limited data exist on their relationship with subsequent neoplasms among childhood cancer survivors.To evaluate associations between time-varying BMI/physical activity and subsequent neoplasm risk among childhood cancer survivors.This retrospective cohort analysis included 5-year childhood cancer survivors diagnosed younger than 21 years of age between 1970 and 1999, enrolled in the Childhood Cancer Survivor Study (CCSS), with follow-up through September 2019 at pediatric tertiary care hospitals in the US and Canada. The data analysis was performed between March 2021 and July 2024.Self-reported time-varying BMI and maximum reported physical activity (metabolic equivalent of task h/wk [MET-h/wk]) before any subsequent neoplasm development; first assessed at cohort entry and up to 6 times thereafter.Cumulative incidence by physical activity level and relative rates (RRs) by physical activity and time-varying BMI categories, adjusted for demographic and clinical variables, were estimated for any, subtype (hematologic, solid organ, central nervous system [CNS], skin), and specific (breast, thyroid, colorectal, meningioma) subsequent neoplasms using piecewise exponential models.Of 25 658 enrolled CCSS participants, 22 716 had BMI data before subsequent neoplasm development and met eligibility criteria for this study (46.3% female; median [range] attained age, 33.7 [5.7-67.3 years]). Among 22 716 survivors, 2554 subsequent neoplasms occurred among 2156 individuals (56.7% female; median [range] age at subsequent neoplasm diagnosis, 37.4 [13.7-63.3] years). Survivors reporting lower physical activity had higher 30-year subsequent neoplasm cumulative incidence: 18.6% (95% CI, 17.0-20.3) for 0 MET-h/wk vs 10.9% (95% CI, 9.9-12.1) for 15-21 MET-h/wk. Obese BMI was associated with increased incidence rates of solid organ (RR, 1.22; 95% CI, 1.01-1.46), CNS (RR, 1.47; 95% CI, 1.12-1.95), and skin (RR, 1.30; 95% CI, 1.13-1.50) subsequent neoplasms. Higher physical activity (15-21 MET-h/wk) demonstrated a protective association for any (RR, 0.61; 95% CI, 0.53-0.71), solid organ (RR, 0.65; 95% CI, 0.52-0.83), CNS (RR, 0.50; 95% CI, 0.35-0.70), and skin (RR, 0.72; 95% CI, 0.60-0.86) subsequent neoplasms. BMI and physical activity were specifically associated with subsequent meningiomas and thyroid carcinomas, but not with breast or colorectal cancers, nor hematologic subsequent neoplasms.Among childhood cancer survivors in this cohort study, obesity was associated with an increased risk for multiple subsequent neoplasm types, while higher physical activity was associated with reduced subsequent neoplasm risk. Lifestyle interventions should be considered in future subsequent neoplasm prevention research.

  View details for DOI 10.1001/jamaoncol.2025.1340

  View details for Web of Science ID 001504017200001

  View details for PubMedID 40471634

  View details for PubMedCentralID PMC12142476

• Treatment, toxicity, and mortality after subsequent breast cancer in female survivors of childhood cancer NATURE COMMUNICATIONS Im, C., Hasan, H., Stene, E., Monick, S., Rader, R. K., Sheade, J., Wolfe, H., Lu, Z., Spector, L. G., Mcdonald, A. J., Nolan, V., Arnold, M. A., Conces, M. R., Moskowitz, C. S., Henderson, T. O., Robison, L. L., Armstrong, G. T., Yasui, Y., Nanda, R., Oeffinger, K. C., Neglia, J. P., Blaes, A., Turcotte, L. M. 2025; 16 (1): 3088

  Abstract

  Childhood cancer survivors, particularly those who received chest radiotherapy, are at high risk for developing subsequent breast cancer. Minimizing long-term toxicity risks associated with additional radiotherapy and chemotherapy is a priority, but therapeutic tradeoffs have not been comprehensively characterized and their impact on survival is unknown. In this study, 431 female childhood cancer survivors with subsequent breast cancer from a multicenter retrospective cohort study were evaluated. Compared with one-to-one matched females with first primary breast cancer, survivors are as likely to be prescribed guideline-concordant treatment (N = 344 pairs; survivors: 94%, controls: 93%), but more frequently undergo mastectomy (survivors: 81%, controls: 60%) and are less likely to be treated with anthracyclines (survivors: 47%, controls: 66%) or radiotherapy (survivors: 18%, controls: 61%). Despite this, survivors have nearly 3.5-fold (95% CI = 2.17-5.57) greater mortality risk. Here, we show survivors with subsequent breast cancer face excess mortality despite therapeutic tradeoffs and require specialized treatment guidelines.

  View details for DOI 10.1038/s41467-025-58434-w

  View details for Web of Science ID 001456731600013

  View details for PubMedID 40164623

  View details for PubMedCentralID PMC11958683

• Nonorbital, Nonparameningeal Head and Neck Rhabdomyosarcoma: A Report From the Children's Oncology Group PEDIATRIC BLOOD & CANCER Aye, J. M., Xue, W., Gao, Z., Ladra, M., Indelicato, D. J., Sheyn, A., Dasgupta, R., Arnold, M. A., Shenoy, A., Linardic, C. M., Venkatramani, R. 2025; 72 (6): e31673

  Abstract

  Rhabdomyosarcoma (RMS) is the most common pediatric head and neck soft-tissue sarcoma. Intergroup Rhabdomyosarcoma Study I-IV demonstrated that patients with alveolar RMS (ARMS), Group III disease, or clinically involved regional lymph nodes had a worse prognosis. The outcomes and prognostic features of patients with nonorbital, nonparameningeal head and neck (NONPHN) RMS treated in subsequent Children's Oncology Group (COG) trials have not been reported.Patients enrolled in COG low-risk (D9602 or ARST0331), intermediate-risk (D9803 or ARST0531), and high-risk (D9802, ARST0431, or ARST08P1) trials were included. All patients received chemotherapy. Those with Group I (completely resected) ARMS and those with Group II (microscopic residual) or Group III (macroscopic residual) RMS received 36-50.4 Gy adjuvant radiotherapy (RT).One hundred seventy-two patients with NONPHN RMS were treated across the seven trials. Most patients had cheek primaries (30%), Group II (38%) or Group III (34%) disease, no clinical or radiological evidence of nodal involvement (N0, 80%), and received RT (70%). The median follow-up was 7.7 years. Five-year event-free survival and overall survival were 70.8% and 83.7%, respectively. The regional failure rate for patients with N0 disease was 2%.Outcomes for patients with NONPHN RMS were similar to contemporary studies. Despite lower RT target volumes on the ARST-series versus the D-series protocols, patients with Group III tumors maintained comparable outcomes. Low regional failure rates suggested that sentinel lymph node sampling in patients with N0 disease and elective nodal RT in patients with ARMS and N0 disease are not necessary.

  View details for DOI 10.1002/pbc.31673

  View details for Web of Science ID 001447512600001

  View details for PubMedID 40108481

  View details for PubMedCentralID PMC12165632

• Loss of H3K27me3 Is Not Specific to Malignant Triton Tumor: Immunohistochemical Analysis of 23 Cases of Embryonal Rhabdomyosarcoma. Archives of pathology & laboratory medicine Warmke, L. M., Davis, J. L., Al-Ibraheemi, A., Arnold, M., Tan, S., Shenoy, A., Surrey, L. F., Parham, D. M., Rudzinski, E. R. 2025

  Abstract

  Malignant peripheral nerve sheath tumor (MPNST) is a rare, often high-grade sarcoma. A small subset of MPNST shows evidence of heterologous rhabdomyoblastic differentiation, also known as malignant triton tumor (MTT). Immunohistochemical loss of histone 3 lysine 27 trimethylation (H3K27me3) has previously been described as a reliable marker for both MPNST and MTT.To assess the loss of H3K27me3 as a potential tool for discriminating MTT from embryonal rhabdomyosarcoma (ERMS).We studied the immunohistochemical expression of H3K27me3 in 23 pediatric cases of confirmed ERMS. Of the 23 patients, 21 were male and 2 were female, with an age range of 2 months to 18 years (median, 5 years). Most of the tumors arose in the paratesticular soft tissue (n = 14), with other locations including the pelvis (n = 3), thigh (n = 2), abdomen (n = 1), orbit (n = 1), prostate gland (n = 1), and parotid gland (n = 1). All cases had characteristic morphologic features of ERMS.By immunohistochemistry, all tested cases expressed desmin (18 of 18), myogenin (20 of 20), and MyoD1 (5 of 5). More than half of the cases (12 of 23; 52%) showed loss (nuclear absence) of H3K27me3, defined as staining in less than 5% of the tumor cells. The remaining cases demonstrated some degree of partial staining with H3K27me3, ranging from 5 to 40% of the tumor cells. No significant correlation between H3K27me3 expression and clinicopathologic features was identified.Loss of H3K27me3 frequently occurs in ERMS (52%) and is not reliable in distinguishing ERMS from MTT.

  View details for DOI 10.5858/arpa.2024-0199-OA

  View details for PubMedID 39957203

• Temporal trends of subsequent central nervous system malignancies among survivors of childhood cancer JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Galvin, R. T., Chen, Y., Yuan, Y., Cooney, T., Howell, R., Smith, S., Arnold, M. A., Conces, M., Leisenring, W., Armstrong, G. T., Neglia, J. P., Turcotte, L. M. 2025; 117 (5): 1036-1045

  Abstract

  It is not known whether temporal changes in childhood cancer therapy have reduced risk of subsequent malignant neoplasms of the central nervous system (CNS), a frequently fatal late effect of cancer therapy.Five-year survivors of primary childhood cancers diagnosed between 1970 and 1999 in the Childhood Cancer Survivor Study with CNS subsequent malignant neoplasms were identified. Cumulative incidence rates and standardized incidence ratios were compared among survivors diagnosed between 1970-1979 (n = 6223), 1980-1989 (n = 9680), and 1990-1999 (n = 8999). Multivariable models assessed risk factors for CNS subsequent malignant neoplasms.A total of 157 CNS subsequent malignant neoplasms (1970s, 52; 1980s, 63; 1990s, 42) were identified, excluding meningiomas, which were most often malignant gliomas. The proportion of survivors receiving any cranial radiotherapy exposure was reduced over time (1970s, 77.0%; 1980s, 54.3%; 1990s, 33.9%), while the proportion receiving more than 35 Gy cranial radiotherapy showed a smaller reduction (11.4%, 10.8%, and 8.5%, respectively). Twenty-year cumulative incidence and standardized incidence ratios for CNS subsequent malignant neoplasms by treatment decade were 0.32% (95% confidence interval = 0.18% to 0.46%) and 6.6 (95% CI = 5.0 to 8.7); 0.55% (95% CI = 0.41% to 0.70%) and 8.3 (95% CI = 6.6 to 10.4); and 0.43% (95% CI = 0.31% to 0.55%) and 9.2 (95% CI = 7.0 to 12.0), respectively, with no statistically significant decreases between eras. Multivariable analyses showed increased risk for cranial radiotherapy dose levels more than 10 Gy and for primary diagnoses of medulloblastoma and/or primitive neuro-ectodermal tumor (hazard ratio [HR] = 18.7, 95% CI = 9.2 to 37.9) and astrocytoma (HR = 10.1, 95% CI = 5.3 to 19.5). Three-year cumulative incidence of death after CNS subsequent malignant neoplasms, by treatment decade, were 76%, 74%, and 73%, respectively.CNS subsequent malignant neoplasm incidence has not decreased despite fewer survivors exposed to CNS-directed radiotherapy. CNS subsequent malignant neoplasm remains a substantial source of mortality for affected patients.

  View details for DOI 10.1093/jnci/djaf005

  View details for Web of Science ID 001415741300001

  View details for PubMedID 39792043

  View details for PubMedCentralID PMC12058266

• Keratinocyte carcinomas in survivors of childhood cancer: A report from the childhood cancer survivor study JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Boull, C., Chen, Y., Im, C., Geller, A., Sapkota, Y., Bates, J. E., Howell, R., Arnold, M. A., Conces, M., Constine, L. S., Robison, L., Yasui, Y., Armstrong, G. T., Neglia, J. P., Turcotte, L. M. 2024; 91 (6): 1125-1135

  Abstract

  Childhood cancer survivors (CCS) are at increased risk for keratinocyte carcinomas (KC) however, the long-term incidence of single and multiple KC is not well established.Identify risk factors and quantify KC cumulative incidence and multiple-incidence burden in CCS.KC were identified among Childhood Cancer Survivor Study participants, a cohort of 5-year cancer survivors diagnosed <21 years of age between 1970 and 1999 in North America. Cumulative incidence was estimated and multivariable models assessed relative rates of KC associated with survivor and treatment characteristics.Among 25,658 participants, 1446 developed 5363 KC (93.5% basal cell carcinoma, 6.7% squamous cell carcinoma; mean age 37.0 years (range 7.3-67.4), mean latency 25.7 years; 95.3% White and 88.4% with radiotherapy). Mean lesion count was 3.7 with 26.1% experiencing ≥4. Radiotherapy imparted a 4.5-fold increase in the rate of any KC and 9.4-fold increase in the rate of ≥4 KC. Allogeneic and autologous hematopoietic cell transplant were associated with a 3.4- and 2.3-fold increased rate of KC, respectively.Participant self-reporting of some data including race without skin phototype and past medical history may have impacted analysis.The burden of KC in CCS remains high, but predictable risk factors should guide screening.

  View details for DOI 10.1016/j.jaad.2024.07.1520

  View details for Web of Science ID 001363043500001

  View details for PubMedID 39182687

  View details for PubMedCentralID PMC11602347

• Late subsequent leukemia after childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS) CANCER MEDICINE Ghosh, T., Hyun, G., Dhaduk, R., Conces, M., Arnold, M. A., Howell, R. M., Henderson, T. O., Mcdonald, A., Robison, L. L., Yasui, Y., Ness, K. K., Armstrong, G. T., Neglia, J. P., Turcotte, L. M. 2024; 13 (20): e70086

  Abstract

  Subsequent short-latency leukemias are well-described among survivors of childhood cancer. However, late (5-14.9 years from diagnosis, LL) and very late (≥15 years from diagnosis, VLL) subsequent leukemias have not been well studied. We assessed risk factors, prevalence, and outcomes for LL and VLL in the Childhood Cancer Survivor Study cohort.Subsequent leukemias, among 25,656 five-year survivors, were self-reported and confirmed by pathology review. Standardized incidence ratios (SIR) and cumulative incidences were calculated, and relative risks (RR) were estimated using Cox regression for exposures.Seventy-seven survivors developed subsequent leukemia, 49 survivors with LL (median time from diagnosis 7.8 years, range 5.0-14.5 years) and 28 with VLL (median time from diagnosis 25.4 years, range 15.9-42.8 years), with a cumulative incidence of 0.23% (95% CI 0.18%-0.30%) 20 years from diagnosis for all subsequent leukemias. The most common leukemia subtypes were acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia. Compared to the general population, survivors were at increased risk, for developing LL (SIR 9.3, 95% CI 7.0-12.1) and VLL (SIR 5.9, 95% CI 3.9-8.4). In multivariable relative risk analyses, cumulative epipodophyllotoxin dose >4000 mg/m2 was associated with increased risk for LL and VLL (RR 4.5, 95% CI 2.0-9.9).In this large series of late subsequent leukemias, survivors of childhood cancer are at increased risk, with no evidence of plateau over time. We observed most risk among survivors who received high cumulative doses of epipodophyllotoxins. Ongoing consideration for this late effect should continue beyond 10 years.

  View details for DOI 10.1002/cam4.70086

  View details for Web of Science ID 001337968400001

  View details for PubMedID 39431920

  View details for PubMedCentralID PMC11492532

• Children and young adults with newly diagnosed rhabdomyosarcoma metastatic to bone treated on Children's Oncology Group studies. Pediatric blood & cancer Schloemer, N. J., Xue, W., Qumseya, A., Luo, L. Y., Hiniker, S. M., Lautz, T. B., Rhee, D. S., Arnold, M. A., Venkatramani, R. 2024: e31200

  Abstract

  Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Despite bone metastases being present in 5% of patients at diagnosis, there are limited studies examining these outcomes. We sought to define the prognostic factors, clinical courses, and outcomes of children treated on Children's Oncology Group (COG) clinical trials with RMS metastatic to bone at diagnosis.We performed a retrospective analysis of patients diagnosed with bone metastatic RMS enrolled on COG RMS clinical trials (D9802, D9803, ARST0431, or ARST08P1) between 1997 and 2013.RMS metastatic to bone was identified in 154 patients at a median age of 14.9 years at diagnosis. Fifty-eight percent of patients were male, 90% had metastases at additional sites, 74% had alveolar histology, and extremity was the most common primary site (31%). Eighty-six percent of patients (n = 133) received radiation therapy. The 3- and 5-year event-free survival (EFS) was 15.4% and 14.5%, respectively. The 3- and 5-year overall survival (OS) was 30.4% and 18.0%, respectively. We identified alveolar histology, FOXO1 fusion presence, unfavorable primary location, higher Oberlin score, and lack of radiation as poor prognostic characteristics for both EFS and OS in univariate analysis. Lack of radiation was not significant when excluding patients with events prior to 20 weeks.This study is the largest analysis of patients with bone metastatic RMS, and defines the poor overall outcomes and negative prognostic factors for these patients. They may be eligible for therapy deintensification for improved quality of life or pursuit of novel treatments/approaches, which are desperately needed.

  View details for DOI 10.1002/pbc.31200

  View details for PubMedID 39016936

• Natural Histories and Disease Complications in a Cohort of 151 Children With Gastric or Duodenal Eosinophilia AMERICAN JOURNAL OF GASTROENTEROLOGY Quinn, L. A., Burger, C., Nguyen, B., Arnold, M. A., Menard-Katcher, C., Pan, Z., Furuta, G. T., Bauer, M. E. 2024; 119 (7): 1298-1308

  Abstract

  Eosinophilic gastritis (EoG) and duodenitis (EoD) are rare conditions that are poorly understood. Our aim was to describe the natural history of children with varying degrees of gastric or duodenal eosinophilia with respect to disease complications and histologic and endoscopic longitudinal trajectories.The electronic medical record at a tertiary children's hospital was queried to identify patients with EoG, EoD, or EoG + EoD who were cared for between January 2010 and 2022. Multiple logistic regression was performed to explore associations between baseline features and persistence/recurrence of eosinophilia or complications remote from diagnosis.We identified 151 patients: 92 with EoG, 24 with EoD, 12 with EoG + EoD, and 23 with tissue eosinophilia but did not meet histologic criteria for EoG or EoD (low grade). The average age at diagnosis was 10.6 years, and average follow-up was 5.8 years. Twenty-five percent of patients with EoG or EoD had persistence/recurrence of eosinophilia; this was associated with increases in the EoG Endoscopic Reference Score (adjusted odds ratio [aOR] 1.34, confidence interval [CI] 1.03-1.74) on diagnostic endoscopy. Eighteen percent suffered from disease complications, and development of late complications was associated with presenting with a complication (aOR 9.63, CI 1.09-85.20), severity of duodenal endoscopic abnormalities (aOR 8.74, CI 1.67-45.60), and increases in the EoG Endoscopic Reference Score (aOR 1.70, CI 1.11-2.63).Patients with gastric and duodenal eosinophilia should be followed closely to monitor for recurrence and complications, especially those presenting with endoscopic abnormalities or complications.

  View details for DOI 10.14309/ajg.0000000000002644

  View details for Web of Science ID 001267591700018

  View details for PubMedID 38174865

  View details for PubMedCentralID PMC11222049

• Addition of temsirolimus to chemotherapy in children, adolescents, and young adults with intermediate-risk rhabdomyosarcoma (ARST1431): a randomised, open-label, phase 3 trial from the Children's Oncology Group LANCET ONCOLOGY Gupta, A. A., Xue, W., Harrison, D. J., Hawkins, D. S., Dasgupta, R., Wolden, S., Shulkin, B., Qumseya, A., Routh, J. C., MacDonald, T., Feinberg, S., Crompton, B., Rudzinski, E. R., Arnold, M., Venkatramani, R. 2024; 25 (7): 912-921

  Abstract

  The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic FOXO1 fusion-positive disease. Temsirolimus in combination with chemotherapy has shown promising activity in patients with relapsed or refractory rhabdomyosarcoma. We aimed to compare event-free survival in patients with intermediate-risk rhabdomyosarcoma treated with vincristine, actinomycin, and cyclophosphamide alternating with vincristine and irinotecan (VAC/VI) combined with temsirolimus followed by maintenance therapy versus VAC/VI alone with maintenance therapy.ARST1431 was a randomised, open-label, phase 3 trial conducted across 210 institutions in Australia, Canada, New Zealand, and the USA. Eligible patients were those aged 40 years or younger with non-metastatic FOXO1-positive rhabdomyosarcoma or unresected FOXO1-negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had FOXO1-negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV FOXO1-negative disease with distant metastases. Eligible patients had to have a Lansky performance status score of 50 or higher if 16 years or younger and a Karnofsky performance status score of 50 or higher if older than 16 years; all patients were previously untreated. Patients were randomised (1:1) in blocks of four and stratified by histology, stage, and group. Patients received intravenous VAC/VI chemotherapy with a cyclophosphamide dose of 1·2 g/m2 per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m2 or 0·5 mg/kg per dose for those who weighed less than 10 kg. The total duration of therapy was 42 weeks followed by 6 months of maintenance therapy with oral cyclophosphamide plus intravenous vinorelbine for all patients. Temsirolimus was withheld during radiotherapy and for 2 weeks before any major surgical procedure. The primary endpoint was 3-year event-free survival. Data were analysed with a revised intention-to-treat approach. The study is registered with ClinicalTrials.gov (NCT02567435) and is complete.Between May 23, 2016, and Jan 1, 2022, 325 patients were enrolled. In 297 evaluable patients (148 assigned to VAC/VI alone and 149 assigned to VAC/VI with temsirolimus), the median age was 6·3 years (IQR 3·0-11·3); 33 (11%) patients were aged 18 years or older; 179 (60%) of 297 were male. 113 (77%) of 148 patients were FOXO1 negative in the VAC/VI group, and 108 (73%) of 149 were FOXO1 negative in the VAC/VI with temsirolimus group. With a median follow-up of 3·6 years (IQR 2·8-4·5), 3-year event-free survival did not differ significantly between the two groups (64·8% [95% CI 55·5-74·1] in the VAC/VI group vs 66·8% [57·5-76·2] in the VAC/VI plus temsirolimus group (hazard ratio 0·86 [95% CI 0·58-1·26]; log-rank p=0·44). The most common grade 3-4 adverse events were anaemia (62 events in 60 [41%] of 148 patients in the VAC/VI group vs 89 events in 87 [58%] of 149 patients in the VAC/VI with temsirolimus group), lymphopenia (83 events in 65 [44%] vs 99 events in 71 [48%]), neutropenia (160 events in 99 [67%] vs 164 events in 105 [70%]), and leukopenia (121 events in 86 [58%] vs 132 events in 93 [62%]). There was one treatment-related death in the VAC/VI with temsirolimus group, categorised as not otherwise specified.Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their FOXO1 translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population.The Children's Oncology Group (supported by the US National Cancer Institute, US National Institutes of Health).

  View details for DOI 10.1016/S1470-2045(24)00255-9

  View details for Web of Science ID 001260864300001

  View details for PubMedID 38936378

  View details for PubMedCentralID PMC11550893

• Virtual Pathology Elective, Real Education The PathElective.com Experience as a Model for Novel Pathology Pedagogy and a Primer for Curricular Evolution ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Lilley, C. M., Arnold, C. A., Arnold, M. A., Booth, A. L., Gardner, J. M., Jiang, X., Loghavi, S., Mirza, K. M. 2024; 148 (5): 595-602

  Abstract

  PathElective.com was created in response to the pandemic's restrictions on interactions with trainees, and since has been incorporated into many training programs worldwide, serving as a unique means of delivering high-quality pathology and laboratory medical education at multiple levels of training.To analyze student usage, performance, and satisfaction to provide insight into the effectiveness of virtual education to guide curricular evolution.Squarespace (Squarespace, Inc) was used for website development and to collect website analytics. Students were assessed before and after course participation using a dual-form crossover quiz design. Quiz data were anonymous and analyzed with a paired t test to account for varying student backgrounds. A novel analysis was performed aimed at examining the attrition rate of students across multiple modules.During the study period (May 1, 2020 to October 31, 2021), PathElective.com received 577 483 page views, 126 180 visits, 59 928 unique visitors, and 10 278 registered users who earned 15 305 certificates. A total of 7338 premodule and postmodule quiz pairs were analyzed. The overall average increase in score was 13.83% (P = .02). All but 5 of the 56 courses experienced a statistically significant increase in score. All courses received median scores of Very Satisfied/Satisfied in all 6 assessment domains. Aggregate attrition data revealed a unique, negative polynomial relationship (R2 = 0.656).PathElective.com is a free, effective means of enhancing anatomic/clinical pathology training in medical education. These analyses offer a unique perspective on the online user experience and could guide the development of future online medical education resources.

  View details for DOI 10.5858/arpa.2022-0259-OA

  View details for Web of Science ID 001216666900002

  View details for PubMedID 37638521

• Polygenic risk scores, radiation treatment exposures and subsequent cancer risk in childhood cancer survivors. Nature medicine Gibson, T. M., Karyadi, D. M., Hartley, S. W., Arnold, M. A., Berrington de Gonzalez, A., Conces, M. R., Howell, R. M., Kapoor, V., Leisenring, W. M., Neglia, J. P., Sampson, J. N., Turcotte, L. M., Chanock, S. J., Armstrong, G. T., Morton, L. M. 2024; 30 (3): 690-698

  Abstract

  Survivors of childhood cancer are at increased risk for subsequent cancers attributable to the late effects of radiotherapy and other treatment exposures; thus, further understanding of the impact of genetic predisposition on risk is needed. Combining genotype data for 11,220 5-year survivors from the Childhood Cancer Survivor Study and the St Jude Lifetime Cohort, we found that cancer-specific polygenic risk scores (PRSs) derived from general population, genome-wide association study, cancer loci identified survivors of European ancestry at increased risk of subsequent basal cell carcinoma (odds ratio per s.d. of the PRS: OR=1.37, 95% confidence interval (CI)=1.29-1.46), female breast cancer (OR=1.42, 95% CI=1.27-1.58), thyroid cancer (OR=1.48, 95% CI=1.31-1.67), squamous cell carcinoma (OR=1.20, 95% CI=1.00-1.44) and melanoma (OR=1.60, 95% CI=1.31-1.96); however, the association for colorectal cancer was not significant (OR=1.19, 95% CI=0.94-1.52). An investigation of joint associations between PRSs and radiotherapy found more than additive increased risks of basal cell carcinoma, and breast and thyroid cancers. For survivors with radiotherapy exposure, the cumulative incidence of subsequent cancer by age 50years was increased for those with high versus low PRS. These findings suggest a degree of shared genetic etiology for these malignancy types in the general population and survivors, which remains evident in the context of strong radiotherapy-related risk.

  View details for DOI 10.1038/s41591-024-02837-7

  View details for PubMedID 38454124

• Adolescents and young adults with rhabdomyosarcoma: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Pediatric blood & cancer Harrison, D. J., Qumseya, A., Xue, W., Arnold, M., Lautz, T. B., Hiniker, S. M., Thomas, S. M., Venkatramani, R., Weiss, A. R., Mascarenhas, L. 2024: e30847

  Abstract

  The impact of established prognostic factors on survival outcomes for childhood rhabdomyosarcoma (RMS) have not been well described in the adolescent and young adult (AYA) RMS patient population.This is a retrospective analysis of patients with newly diagnosed RMS enrolled between 1997 and 2016 on seven previously reported Children's Oncology Group (COG) clinical trials. Demographics, clinical features, treatment details, and outcome data were collected. Five-year event-free survival (EFS) and overall survival (OS) were estimated for patients diagnosed at age 15-39 years and those diagnosed under age 15 years using the Kaplan-Meier method. Log-rank test was used to compare prognostic factors for EFS and OS. Factors significant in the univariable analysis were included in a Cox proportional hazards regression model. Nonsignificant covariates were removed from the multiple regression model.Total 2151 patients including 402 AYAs were analyzed. AYAs were more likely to present with primary tumors ≥5 cm in size, metastatic disease, alveolar histology, and have FOXO1 fusions compared to children. Five-year EFS for the AYA cohort was 44.2% versus 67% for children (p < .001), and 5-year OS was 52% for the AYA cohort versus 78% for children (p < .001). Multivariable analysis revealed tumor site, size and invasiveness, clinical group, and histology were prognostic in AYAs.AYAs with RMS have a poorer prognosis compared to younger children due to multiple factors. Further research focused on AYAs to better understand RMS biology and improve treatments is critical to improve survival.

  View details for DOI 10.1002/pbc.30847

  View details for PubMedID 38282125

• Histological transitional zone pull-through in Hirschsprung disease. Postoperative functional results and current recommendations BOLETIN MEDICO DEL HOSPITAL INFANTIL DE MEXICO Torre, L., Dominguez, A., Arnold, M., Lovell, M., Martinez, D., Bischoff, A., Wehrli, L. 2023; 80 (6): 331-338

  Abstract

  Surgeons create a neorectum to repair patients with Hirschsprung's disease (HD), which should be formed from a normoganglionic bowel. However, the neorectum is occasionally created with a transition zone (TZ) bowel. A neorectum created with a TZ has been postulated as a cause of postoperative enterocolitis or constipation. This study compares the incidence of enterocolitis and constipation in patients with TZ neorectum and normoganglionic bowel.We conducted a retrospective review of patients with rectosigmoid HD who underwent primary pull-through. Patients were divided into normoganglionic neorectum (NNR) and TZ neorectum. The diagnosis was based on the final histopathologic report of the proximal margin. The incidence of enterocolitis and constipation was compared between these two groups.A total of 98 HD patients were analyzed. Seventy-one patients fulfilled the inclusion criteria. 65 (92%) had a NNR, and six patients (8%) had a TZ neorectum. From these patients, 42 (59%) presented with enterocolitis or constipation. However, there was no significant difference between both groups.The present study showed no difference in the incidence of enterocolitis or postoperative constipation in HD patients with normoganglionic or TZ neorectum. These results suggest that TZ neorectum does not cause postoperative obstructive symptoms.

  View details for DOI 10.24875/BMHIM.23000050

  View details for Web of Science ID 001131543100008

  View details for PubMedID 38150718

• ALK-Rearranged Epithelioid Mesenchymal Neoplasm: Expanding the Spectrum of Tyrosine KinaseeAltered Mesenchymal Tumors MODERN PATHOLOGY Gestrich, C. K., Davis, J. L., Biederman, L., John, I., Alaggio, R., Giovannoni, I., Arnold, M. A., Shenoy, A., Tchakarov, A., Al-Ibraheemi, A. 2023; 36 (12): 100334

  Abstract

  The anaplastic lymphoma kinase (ALK) gene encodes a receptor tyrosine kinase, and fusions involving this gene have been reported in a variety of mesenchymal neoplasms. ALK-altered tumors with epithelioid morphology have been described in epithelioid inflammatory myofibroblastic sarcoma and epithelioid fibrous histiocytoma. Herein, we describe the clinicopathologic features of 7 ALK-rearranged mesenchymal tumors with epithelioid morphology occurring predominately in the pediatric population. Tumors occurred in 4 females and 3 males with an age ranging from 1 month to 28 years. Five tumors were superficial and solitary, while 1 presented with multiple peritoneal/omental nodules, and 1 presented as a large mediastinal mass. Morphologically, all tumors comprised epithelioid cells arranged in sheets, anastomosing cords, or small clusters embedded in a myxohyaline stroma. The cells had slightly variably sized ovoid nuclei with moderately prominent nucleoli and abundant eosinophilic cytoplasm. Four cases had sparse mitotic figures without necrosis. The remaining 3 tumors (2 deep and 1 superficial) had more than 10 mitoses per 10 high-power fields as well as foci of necrosis. ALK fusions were identified in all cases. The fusion partners included HMBOX1 (n = 1), VCL (n = 1), PRRC2B (n = 1), MYH10 (n = 1), STRN (n = 1), and EML4 (n = 2). One tumor recurred locally 2 years after initial resection; 1 patient had widely metastatic disease (mediastinal tumor). At the time of last follow-up (n = 6), 4 patients were alive without evidence of disease, 1 died due to complications of therapy (peritoneal tumor), and 1 was alive with disease. Our findings expand the spectrum of ALK-rearranged mesenchymal tumors. Our cases predominately occurred in older children and mainly exhibited epithelioid to round cell morphology, as opposed to spindle cell morphology. We also show that tumors in a deep location with higher-grade features follow a more aggressive clinical course.

  View details for DOI 10.1016/j.modpat.2023.100334

  View details for Web of Science ID 001099141200001

  View details for PubMedID 37726067

• Prognosis of children and young adults with newly diagnosed rhabdomyosarcoma metastatic to bone marrow treated on Children's Oncology Group studies. Pediatric blood & cancer Schloemer, N. J., Xue, W., Qumseya, A., Luo, L. Y., Hiniker, S. M., Lautz, T. B., Rhee, D. S., Arnold, M. A., Venkatramani, R. 2023: e30701

  Abstract

  Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Metastatic disease occurs in 16% of all RMS cases and has a poor prognosis. There are limited studies examining the outcomes specific to patients with RMS metastatic to bone marrow despite an incidence of 6% at diagnosis. Our study aims to document the outcomes, prognostic factors, and clinical courses of children presenting with RMS metastatic to bone marrow treated on Children's Oncology Group (COG) cooperative trials.We performed a retrospective analysis of the patients diagnosed with RMS metastatic to bone marrow between 1997 and 2013 enrolled on one of four COG RMS clinical trials of D9802, D9803, ARST0431, and ARST08P1.We identified 179 cases with RMS metastatic to bone marrow. Patients had a median age of 14.8 years, 58% were male, predominantly alveolar histology (76%), extremity was the most common primary site (32%), and 87% had metastatic disease to additional sites; 83% (n = 149) received radiation as a treatment modality. The 3- and 5-year event-free survival was 9.4% and 8.2%, respectively. The 3- and 5-year overall survival was 26.1% and 12.6%, respectively. Age ≥10 years, alveolar histology, FOXO1 fusion presence, unfavorable primary location, higher Oberlin score, and lack of radiation were identified as poor prognostic/predictive characteristics.This study represents the largest analysis of RMS metastatic to bone marrow, defining the poor prognostic outcome for these patients. These patients may be eligible for therapy deintensification or early pursuit of novel treatments/approaches that are desperately needed.

  View details for DOI 10.1002/pbc.30701

  View details for PubMedID 37783659

• Polygenic Risk and Chemotherapy-Related Subsequent Malignancies in Childhood Cancer Survivors: A Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study Report JOURNAL OF CLINICAL ONCOLOGY Im, C., Sharafeldin, N., Yuan, Y., Wang, Z., Sapkota, Y., Lu, Z., Spector, L. G., Howell, R. M., Arnold, M. A., Hudson, M. M., Ness, K. K., Robison, L. L., Bhatia, S., Armstrong, G. T., Neglia, J. P., Yasui, Y., Turcotte, L. M. 2023; 41 (27): 4381-+

  Abstract

  Chemotherapeutic exposures are associated with subsequent malignant neoplasm (SMN) risk. The role of genetic susceptibility in chemotherapy-related SMNs should be defined as use of radiation therapy (RT) decreases.SMNs among long-term childhood cancer survivors of European (EUR; N = 9,895) and African (AFR; N = 718) genetic ancestry from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study were evaluated. An externally validated 179-variant polygenic risk score (PRS) associated with pleiotropic adult cancer risk from the UK Biobank Study (N > 400,000) was computed for each survivor. SMN cumulative incidence comparing top and bottom PRS quintiles was estimated, along with hazard ratios (HRs) from proportional hazards models.A total of 1,594 survivors developed SMNs, with basal cell carcinomas (n = 822), breast cancers (n = 235), and thyroid cancers (n = 221) being the most frequent. Although SMN risk associations with the PRS were extremely modest in RT-exposed EUR survivors (HR, 1.22; P = .048; n = 4,630), the increase in 30-year SMN cumulative incidence and HRs comparing top and bottom PRS quintiles was statistically significant among nonirradiated EUR survivors (n = 4,322) treated with alkylating agents (17% v 6%; HR, 2.46; P < .01), anthracyclines (20% v 8%; HR, 2.86; P < .001), epipodophyllotoxins (23% v 1%; HR, 12.20; P < .001), or platinums (46% v 7%; HR, 8.58; P < .01). This PRS also significantly modified epipodophyllotoxin-related SMN risk among nonirradiated AFR survivors (n = 414; P < .01). Improvements in prediction attributable to the PRS were greatest for epipodophyllotoxin-exposed (AUC, 0.71 v 0.63) and platinum-exposed (AUC,0.68 v 0.58) survivors.A pleiotropic cancer PRS has strong potential for improving SMN clinical risk stratification among nonirradiated survivors treated with specific chemotherapies. A polygenic risk screening approach may be a valuable complement to an early screening strategy on the basis of treatments and rare cancer-susceptibility mutations.

  View details for DOI 10.1200/JCO.23.00428

  View details for Web of Science ID 001074767700008

  View details for PubMedID 37459583

  View details for PubMedCentralID PMC10522108

• Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer NATURE MEDICINE Wang, Y., Ronckers, C. M., van Leeuwen, F. E., Moskowitz, C. S., Leisenring, W., Armstrong, G. T., de Vathaire, F., Hudson, M. M., Kuehni, C. E., Arnold, M. A., Demoor-Goldschmidt, C., Green, D. M., Henderson, T. O., Howell, R. M., Ehrhardt, M. J., Neglia, J. P., Oeffinger, K. C., van der Pal, H. J. H., Robison, L. L., Schaapveld, M., Turcotte, L. M., Waespe, N., Haddy, N., Diallo, I., Baker, K., de Gonzalez, A., Conces, M. R., Constine, L. S., Hawkins, M., Loonen, J. J., Louwerens, M., Janssens, G. O., Mellemkjaer, L., Reulen, R., Winther, J. F., Kremer, L. C. M., Teepen, J. C., Intl Consortium Pooled Studies 2023; 29 (9): 2268-+

  Abstract

  Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m-2: 1.24, 95% confidence interval (CI): 1.18-1.31), with more than twofold increased risk for survivors treated with ≥200 mg m-2 cumulative doxorubicin dose versus no doxorubicin (HR: 2.50 for 200-299 mg m-2, HR: 2.33 for 300-399 mg m-2 and HR: 2.78 for ≥400 mg m-2). For daunorubicin, the associations were not statistically significant. Epirubicin was associated with increased SBC risk (yes/no, HR: 3.25, 95% CI: 1.59-6.63). For patients treated with or without chest irradiation, HRs per 100 mg m-2 of doxorubicin were 1.11 (95% CI: 1.02-1.21) and 1.26 (95% CI: 1.17-1.36), respectively. Our findings support that early initiation of SBC surveillance may be reasonable for survivors who received ≥200 mg m-2 cumulative doxorubicin dose and should be considered in SBC surveillance guidelines for survivors and future treatment protocols.

  View details for DOI 10.1038/s41591-023-02514-1

  View details for Web of Science ID 001066460900002

  View details for PubMedID 37696934

  View details for PubMedCentralID PMC10504074

• The Pathologic Diagnosis of Pediatric Soft Tissue Tumors in the Era of Molecular Medicine: The Sarcoma Pediatric Pathology Research Interest Group Perspective. Archives of pathology & laboratory medicine Black, J. O., Al-Ibraheemi, A., Arnold, M. A., Coffin, C. M., Davis, J. L., Parham, D. M., Rudzinski, E. R., Shenoy, A., Surrey, L. F., Tan, S. Y., Spunt, S. L. 2023

  Abstract

  Pediatric soft tissue tumors are one of the areas of pediatric pathology that frequently generate consult requests. Evolving classification systems, ancillary testing methods, new treatment options, research enrollment opportunities, and tissue archival processes create additional complexity in handling these unique specimens. Pathologists are at the heart of this critical decision-making, balancing responsibilities to consider expediency, accessibility, and cost-effectiveness of ancillary testing during pathologic examination and reporting.To provide a practical approach to handling pediatric soft tissue tumor specimens, including volume considerations, immunohistochemical staining panel recommendations, genetic and molecular testing approaches, and other processes that impact the quality and efficiency of tumor tissue triage.The World Health Organization Classification of Soft Tissue and Bone Tumors, 5th edition, other recent literature investigating tissue handling, and the collective clinical experience of the group are used in this manuscript.Pediatric soft tissue tumors can be difficult to diagnose, and evaluation can be improved by adopting a thoughtful, algorithmic approach to maximize available tissue and minimize time to diagnosis.

  View details for DOI 10.5858/arpa.2022-0364-RA

  View details for PubMedID 37196343

• Survival of patients with orbital and eyelid rhabdomyosarcoma treated on Children's Oncology Group studies from 1997 to 2013: A report from the Children's Oncology Group CANCER Metts, J., Xue, W., Gao, Z., Ermoian, R., Bradley, J. A., Arnold, M. A., Dasgupta, R., Venkatramani, R., Walterhouse, D. 2023; 129 (11): 1735-1743

  Abstract

  Orbital rhabdomyosarcoma (ORMS) commonly presents as low-risk disease (stage 1, group I-III, embryonal RMS) with excellent outcome. Long-term follow-up of patients with low-risk ORMS and outcomes of less common subgroups of ORMS treated on recent Children's Oncology Group (COG) trials have not been reported.Patients with ORMS enrolled on COG trials from 1997 to 2013 were identified. Demographic information and disease characteristics were collected. Outcomes were determined for the following subgroups: 1) low-risk ORMS, 2) resected (group I/II) low-risk ORMS, 3) non-low-risk ORMS, and 4) recurrent ORMS. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan-Meier method. ResultsThe authors identified 218 patients with ORMS. Most tumors were embryonal/botryoid (n = 169; 77.5%), <5 cm (n = 213; 97.7%), group III (n = 170; 78.0%), and without lymph node involvement (N0; n = 215; 98.6%). For 192 patients with low-risk ORMS, the 10-year EFS and OS rates were 85.5% (95% confidence interval [CI], 77.0%-94.0%) and 95.6% (95% CI, 90.8%-100.0%), respectively. Those with group I/II low-risk ORMS (n = 5 in group I; n = 39 in group IIA) had 10-year EFS and OS rates of 88.0% (95% CI, 72.6%-100.0%) and 97.6% (95% CI, 90.0%-100.0%), respectively. Twenty-six patients with non-low-risk ORMS had 5-year EFS and OS rates of 88.5% (95% CI, 75.6%-100.0%) and 95.8% (95% CI, 87.7%-100.0%), respectively. For patients with recurrent ORMS, the 10-year OS rate from the time of recurrence was 69.4% (95% CI, 50.0%-88.8%).Patients with ORMS had favorable long-term survival outcomes on COG studies from 1997 to 2013, including those who had both low-risk and non-low-risk disease. A significant proportion of patients with recurrent ORMS may achieve long-term survival.

  View details for DOI 10.1002/cncr.34723

  View details for Web of Science ID 000941540100001

  View details for PubMedID 36857314

  View details for PubMedCentralID PMC10288338

• Cohort profile: Risk and risk factors for female breast cancer after treatment for childhood and adolescent cancer: an internationally pooled cohort BMJ OPEN Wang, Y., Kremer, L. C. M., van Leeuwen, F. E., Armstrong, G. T., Leisenring, W., de Vathaire, F., Hudson, M. M., Kuehni, C. E., Arnold, M. A., Haddy, N., Demoor-Goldschmidt, C., Diallo, I., Howell, R. M., Ehrhardt, M. J., Moskowitz, C. S., Neglia, J. P., van der Pal, H. J. H., Robison, L. L., Schaapveld, M., Turcotte, L. M., Waespe, N., Ronckers, C. M., Teepen, J. C., Int Consortium Pooled Studies Subs 2022; 12 (11): e065910

  Abstract

  The International Consortium for Pooled Studies on Subsequent Malignancies after Childhood and Adolescent Cancer was established in 2018 to address gaps in knowledge of risk and risk factors for breast cancer subsequent to childhood/adolescent cancer by pooling individual patient data from seven cohorts. Initially, the pooled cohort will focus on three clinically relevant questions regarding treatment-related subsequent breast cancer risk in female survivors, which are the risk related to low-dose radiotherapy exposure to the chest, specific chemotherapy agents and attained age.The consortium database includes pooled data on 21 892 female survivors from seven cohorts in North America and Europe with a primary cancer diagnosis at <21 years of age, and survival ≥5 years from diagnosis.This is a newly established pooled study. The cohort profile summarised the data collected from each included cohort, including childhood cancer diagnosis information and treatment details (ie, radiotherapy fields and cumulative doses, and chemotherapy agents and cumulative doses for each agent). Included cohorts' follow-up started 1951-1981 and ended 2013-2021, respectively, for a median follow-up duration of 24.3 (IQR 18.0-32.8) years since primary cancer diagnosis. The median age at primary cancer diagnosis was 5.4 (IQR 2.5-11.9) years. And the median attained age at last follow-up was 32.2 (IQR 24.0-40.4) years. In all, 4240 (19.4%) survivors were treated with radiotherapy to the chest and 9308 (42.5%) with anthracyclines. At the end of the follow-up, 835 females developed a first subsequent breast cancer, including 635 invasive breast cancer only, 184 carcinomas in situ only (172 ductal carcinomas in situ and 12 lobular carcinomas in situ), and 16 with both an invasive and in situ diagnosis at the same moment. The cumulative incidences of subsequent breast cancer (both invasive and in situ) 25 and 35 years after primary cancer diagnosis were 2.2% and 6.2%, respectively.The consortium is intended to serve as a model and robust source of childhood/adolescent cancer survivor data for elucidating other knowledge gaps on subsequent breast cancer risk, and risk of other subsequent malignancies (including data on males) in the future.

  View details for DOI 10.1136/bmjopen-2022-065910

  View details for Web of Science ID 000884914500011

  View details for PubMedID 36344003

  View details for PubMedCentralID PMC9644351

• Association of Changes in Cancer Therapy Over 3 Decades With Risk of Subsequent Breast Cancer Among Female Childhood Cancer Survivors A Report From the Childhood Cancer Survivor Study (CCSS) JAMA ONCOLOGY Henderson, T. O., Liu, Q., Turcotte, L. M., Neglia, J. P., Leisenring, W., Hodgson, D., Diller, L., Kenney, L., Morton, L., de Gonzalez, A., Arnold, M., Bhatia, S., Howell, R. M., Smith, S. A., Robison, L. L., Armstrong, G. T., Oeffinger, K. C., Yasui, Y., Moskowitz, C. S. 2022; 8 (12): 1765-1774

  Abstract

  Breast cancer is the most common invasive subsequent malignant disease in childhood cancer survivors, though limited data exist on changes in breast cancer rates as primary cancer treatments have evolved.To quantify the association between temporal changes in cancer treatment over 3 decades and subsequent breast cancer risk.Retrospective cohort study of 5-year cancer survivors diagnosed when younger than 21 years between 1970 and 1999, with follow-up through December 5, 2020.Radiation and chemotherapy dose changes over time.Breast cancer cumulative incidence rates and age-specific standardized incidence ratios (SIRs) compared across treatment decades (1970-1999). Piecewise exponential models estimated invasive breast cancer and ductal carcinoma in situ (DCIS) risk and associations with treatment exposures, adjusted for age at childhood cancer diagnosis and attained age.Among 11 550 female survivors (median age, 34.2 years; range 5.6-66.8 years), 489 developed 583 breast cancers: 427 invasive, 156 DCIS. Cumulative incidence was 8.1% (95% CI, 7.3%-9.0%) by age 45 years. An increased breast cancer risk (SIR, 6.6; 95% CI, 6.1-7.2) was observed for survivors compared with the age-sex-calendar-year-matched general population. Changes in therapy by decade included reduced rates of chest (34% in the 1970s, 22% in the 1980s, and 17% in the 1990s) and pelvic radiotherapy (26%, 17%, and 13% respectively) and increased rates of anthracycline chemotherapy exposures (30%, 51%, and 64%, respectively). Adjusting for age and age at diagnosis, the invasive breast cancer rate decreased 18% every 5 years of primary cancer diagnosis era (rate ratio [RR], 0.82; 95% CI, 0.74-0.90). When accounting for chest radiotherapy exposure, the decline attenuated to an 11% decrease every 5 years (RR, 0.89; 95% CI, 0.81-0.99). When additionally adjusted for anthracycline dose and pelvic radiotherapy, the decline every 5 years increased to 14% (RR, 0.86; 95% CI, 0.77-0.96). Although SIRs of DCIS generally increased over time, there were no statistically significant changes in incidence.Invasive breast cancer rates in childhood cancer survivors have declined with time, especially in those younger than 40 years. This appears largely associated with the reduced use of chest radiation therapy, but was tempered by concurrent changes in other therapies.

  View details for DOI 10.1001/jamaoncol.2022.4649

  View details for Web of Science ID 000867876100003

  View details for PubMedID 36227603

  View details for PubMedCentralID PMC9562103

• Esophageal remodeling in eosinophilic esophagitis: Relationships to luminal captured biomarkers of inflammation and periostin JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Muir, A. B., Ackerman, S. J., Pan, Z., Benitez, A., Burger, C., Spergel, J. M., Furuta, G. T., Rothman, J., Wilkins, B. J., Arnold, M. A., Dolinsky, L., Grozdanovic, M., Menard-Katcher, C. 2022; 150 (3): 649-+

  Abstract

  Esophageal remodeling is a factor in disease progression and symptom severity for patients with eosinophilic esophagitis (EoE). Remodeling can begin early in children, resulting in stricture and food impaction. Detection of esophageal remodeling often depends on endoscopy and is appreciated only in its later stages.We sought to determine whether luminal eosinophil-associated and remodeling proteins captured by the esophageal string test (EST) correlate with measures of esophageal remodeling and biomarkers of the epithelial-mesenchymal transition (EMT).Patients with EoE (7-18 years old) were enrolled from 2 pediatric hospitals. Participants performed the EST and underwent endoscopy. Histology, distensibility measured by endoluminal functional lumen imaging probe, and symptoms were assessed. Protein quantitation by ELISA was performed on mucosal biopsy and EST samples. Tissue sections were evaluated for EMT. Outcome measures were summarized, and Spearman ρ was used to assess bivariate correlations.Forty patients (68% male) were enrolled (mean age, 12.5 years). Twenty-four (60%) had active disease (≥15 eosinophils per high-power field). EST-captured eotaxin-3, major basic protein 1, EDN, eosinophil peroxidase, and Charcot-Leyden crystal protein/galectin-10 showed significant correlations with peak eosinophils per high-power field (ρ 0.53-0.68, P < .001). Luminal proteins positively correlated with endoscopic features and markers of EMT, and negatively with esophageal distensibility. Periostin was captured by the EST and correlated with eosinophil density, basal zone hyperplasia, endoscopic appearance, and markers of EMT.Luminal markers of esophageal remodeling in addition to biomarkers of eosinophilic inflammation correlate with epithelial and functional remodeling in EoE.

  View details for DOI 10.1016/j.jaci.2022.03.022

  View details for Web of Science ID 000897541700023

  View details for PubMedID 35405206

  View details for PubMedCentralID PMC10367933

• Selective Immunoreactivity for WT1 Carboxy-Terminus Distinguishes Desmoplastic Small Round Cell Tumor From its Histologic Mimics PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Wong, Y., Buckley, K., Iwenofu, O., Singhi, A., Kahwash, S. B., Arnold, C. A., Tan, G., Arnold, M. A. 2022; 25 (5): 504-510

  Abstract

  Desmoplastic small round cell tumor (DSRCT) is an aggressive pediatric round cell sarcoma containing a characteristic EWSR1-WT1 gene fusion. In the absence of genetic data, distinguishing DSRCT from other small round cell tumors of childhood can be problematic due to overlapping histologic and immunohistochemical features. We studied the utility of immunohistochemistry with antibodies targeting both the amino-terminal and carboxy-terminal regions of the Wilms tumor-1 (WT1) protein in differentiating these groups of tumors. The study cohort included 33 cases of genetically confirmed pediatric round cell tumors (10 DSRCTs, 12 Wilms tumors, 10 Ewing sarcomas, and 1 CIC-rearranged sarcoma). Immunoreactivities and immunolocalization of both the WT1 amino-terminus and carboxy-terminus were scored and documented. All DSRCTs displayed selective reactivity for only the WT1 carboxy-terminus (10/10), while dual immunoreactivity for both the WT1 carboxy-terminus (12/12) and amino-terminus antibodies (12/12) were characteristic of Wilms tumors. CIC-rearranged sarcoma showed variable WT1 nuclear immunopositivity (1/1, 1/1) and Ewing sarcomas were consistently WT1-negative for both the WT1 amino-terminus (0/10) and carboxy-terminus (0/10). Dual WT1 amino-terminus and carboxy-terminus immunohistochemistry remains a helpful diagnostic tool in discriminating intraabdominal small round cell tumors, which serves as an adjunct to the genetic information in preventing misdiagnosis.

  View details for DOI 10.1177/10935266221088151

  View details for Web of Science ID 000791010600001

  View details for PubMedID 35488420

• Congenital spindle cell rhabdomyosarcoma: An international cooperative analysis EUROPEAN JOURNAL OF CANCER Whittle, S., Venkatramani, R., Schoenstein, A., Pack, S. D., Alaggio, R., Vokuhl, C., Rudzinski, E. R., Wulf, A., Zin, A., Gruver, J. R., Arnold, M. A., Merks, J. H. M., Hettmer, S., Koscielniak, E., Barr, F. G., Hawkins, D. S., Bisogno, G., Sparber-Sauer, M. 2022; 168: 56-64

  Abstract

  Spindle cell rhabdomyosarcoma (RMS) is a rare variant of RMS accounting for up to 10% of cases in infants. In older children and adults, spindle cell RMS is associated with MYOD1 mutations and a poor prognosis. In infants, it is associated with recurring fusions involving NCOA2 and VGLL2. Reports in the literature suggest a favorable prognosis for this subset, however, little is known about treatment and outcome data of infants with spindle cell RMS.Characteristics, treatment, and outcome of an international cohort of 40 patients aged ≤ 12 months with spindle cell RMS treated from 1997 to 2018 were evaluated.Localized disease (LD) was diagnosed in 39 patients. The median age at diagnosis was 2.5 months (range 0-12 months). Expert pathologic review confirmed the diagnosis of spindle cell RMS in all patients. Among 26 tumors that had molecular evaluation, 13 had rearrangements of NCOA and/or VGLL. Multimodal treatment of infants with LD included conventional (age adjusted) chemotherapy (n = 37), resection (n = 31) and radiotherapy (RT) (n = 5, brachytherapy in 3). Complete remission was achieved in 37/39 patients. Progressive disease occurred in two infants, relapsed disease in three. Microscopically complete surgical resection was associated with five-year event-free survival (EFS) and overall survival (OS) of 100%. Two patients with tumors ≤ 5 cm were treated with microscopically complete resection only and were alive 1 and 4.2 years after diagnosis. The 5-year EFS and OS for infants with LD were 86% (±11; CI 95%) and 91% (±9; CI 95%), respectively. One patient had metastatic disease (NCOA fusion positive) with primary tumor in head and neck and brain metastases. This patient died despite chemotherapy and delayed resection of the primary tumor due to respiratory failure secondary to cytomegalovirus infection 1.2 years after diagnosis.Infants with spindle cell RMS have an excellent prognosis. Multimodal treatment including microscopically complete resection of the tumor is strongly recommended.

  View details for DOI 10.1016/j.ejca.2022.03.022

  View details for Web of Science ID 000819787600007

  View details for PubMedID 35452896

  View details for PubMedCentralID PMC9123806

• Cytotoxic T-Lymphocyte-Associated Antigen 4 Haploinsufficiency Mimics Difficult-to-Treat Inflammatory Bowel Disease CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Constant, B. D., Dutmer, C. M., Arnold, M. A., Hall, C., Abbott, J. K., de Zoeten, E. F. 2022; 20 (4): E696-E702

  View details for DOI 10.1016/j.cgh.2021.05.001

  View details for Web of Science ID 000820753600005

  View details for PubMedID 33965572

  View details for PubMedCentralID PMC8572315

• Short NK- and Naive T-Cell Telomere Length Is Associated with Thyroid Cancer in Childhood Cancer Survivors: A Report from the Childhood Cancer Survivor Study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Man, T., Aubert, G., Richard, M. A., LeJeune, W., Hariri, E., Goltsova, T., Gaikwad, A., Chen, Y., Whitton, J., Leisenring, W. M., Arnold, M. A., Neglia, J. P., Yasui, Y., Robison, L. L., Armstrong, G. T., Bhatia, S., Gramatges, M. M. 2022; 31 (2): 453-460

  Abstract

  Survivors of childhood cancer are at risk for therapy-related subsequent malignant neoplasms (SMN), including thyroid SMN. Telomere length (TL) is associated with cancer risk, but the relationship between TL and SMN risk among survivors is less clear.We conducted a nested, matched case-control study of radiation-exposed 15-year+ adult survivors of childhood cancer with thyroid SMN (cases) and without SMN (controls). Forty-six cases were matched to 46 controls by primary diagnosis, chemotherapy (yes/no), radiation field, and follow-up duration. Lymphocyte TL (LTL) was measured by telomere flow-FISH cytometry using blood samples banked at a mean of 38.9 years (cases), 39.2 years (controls). Genetic variation in telomere genes was assessed by whole genome sequencing. Point estimates for LTL <10th percentile were determined for cases and controls.Cases had shorter median LTL than controls in three out of four leukocyte subsets. Cases were more likely to have NK cell LTL <10th percentile (P = 0.01), and 2.8-fold more likely to have naïve T-cell LTL <10th percentile than controls (CI, 1.07-8.78). Five out of 15 cases with a rare indel or missense variant had naïve T-cell LTL <10th percentile, compared with one out of eight controls.Long-term survivors have shorter than expected LTL, a finding that is more pronounced among survivors with thyroid SMN.The long-term impact of childhood cancer treatment on immune function is poorly understood. Our findings support immune function studies in larger survivor cohorts to assess long-term deficits in adaptive and innate immunity that may underlie SMN risk.

  View details for DOI 10.1158/1055-9965.EPI-21-0791

  View details for Web of Science ID 000753323800001

  View details for PubMedID 34782395

  View details for PubMedCentralID PMC8825729

• Polygenic Risk Score Improves Risk Stratification and Prediction of Subsequent Thyroid Cancer after Childhood Cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Song, N., Liu, Q., Wilson, C. L., Sapkota, Y., Ehrhardt, M. J., Gibson, T. M., Morton, L. M., Chanock, S. J., Neglia, J. P., Arnold, M. A., Michael, J., Gout, A. M., Mulder, H. L., Easton, J., Bhatia, S., Armstrong, G. T., Zhang, J., Delaney, A., Hudson, M. M., Robison, L. L., Yasui, Y., Wang, Z. 2021; 30 (11): 2096-2104

  Abstract

  Subsequent thyroid cancer (STC) is one of the most common malignancies in childhood cancer survivors. We aimed to evaluate the polygenic contributions to STC risk and potential utility in improving risk prediction.A polygenic risk score (PRS) was calculated from 12 independent SNPs associated with thyroid cancer risk in the general population. Associations between PRS and STC risk were evaluated among survivors from St. Jude Lifetime Cohort (SJLIFE) and were replicated in survivors from Childhood Cancer Survivor Study (CCSS). A risk prediction model integrating the PRS and clinical factors, initially developed in SJLIFE, and its performance were validated in CCSS.Among 2,370 SJLIFE survivors with a median follow-up of 28.8 [interquartile range (IQR) = 21.9-36.1] years, 65 (2.7%) developed STC. Among them, the standardized PRS was associated with an increased rate of STC [relative rate (RR) = 1.57; 95% confidence interval (CI) = 1.24-1.98; P < 0.001]. Similar associations were replicated in 6,416 CCSS survivors, among whom 121 (1.9%) developed STC during median follow-up of 28.9 (IQR = 22.6-34.6) years (RR = 1.52; 95% CI = 1.25-1.83; P < 0.001). A risk prediction model integrating the PRS with clinical factors showed better performance than the model considering only clinical factors in SJLIFE (P = 0.004, AUC = 83.2% vs. 82.1%, at age 40), which was further validated in CCSS (P = 0.010, AUC = 72.9% vs. 70.6%).Integration of the PRS with clinical factors provided a statistically significant improvement in risk prediction of STC, although the magnitude of improvement was modest.PRS improves risk stratification and prediction of STC, suggesting its potential utility for optimizing screening strategies in survivorship care.

  View details for DOI 10.1158/1055-9965.EPI-21-0448

  View details for Web of Science ID 000713822200014

  View details for PubMedID 34465587

  View details for PubMedCentralID PMC8568663

• Subsequent malignant neoplasms in the childhood cancer survivor study: Occurrence of cancer types in which human papillomavirus is an established etiologic risk factor CANCER Henderson, T. O., Fowler, B. W., Hamann, H. A., Nathan, P. C., Whitton, J., Leisenring, W. M., Oeffinger, K. C., Neglia, J. P., Turcotte, L. M., Arnold, M. A., Conces, M. R., Howell, R. M., Robison, L. L., Armstrong, G. T., Alexander, K. A. 2022; 128 (2): 373-382

  Abstract

  Human papillomavirus (HPV)-associated subsequent malignant neoplasms (SMNHPV ) in childhood cancer survivors are poorly understood.The cumulative risk of SMNHPV was assessed among 24,363 Childhood Cancer Survivor Study participants. Standardized incidence ratios (SIRs) and absolute excess risk were calculated using age-matched, sex-matched, and calendar year rates from the Surveillance, Epidemiology, and End Results program. Poisson regression models identified SMNHPV risk factors, evaluating relative SIRs (rSIR) and 95% confidence intervals (95% CIs).In total, 46 survivors developed an SMNHPV (median age, 31 years [range, 10-56 years]; median time from primary cancer, 21 years [range, 9-35 years]). SMNHPV sites included oropharynx (N = 44), anorectum (N = 6), uterine cervix (N = 2), and vulva (N = 2). The 33-year cumulative incidence was 0.3% (95% CI, 0.2%-0.4%), and the SIR was nearly 3-fold that of the general population (SIR, 2.86; 95% CI, 2.05-4.00). Female survivors were not at increased risk of cervical or vulvar cancers compared with the general population. All survivors had an elevated risk of oropharyngeal SMNHPV (males: SIR, 4.06; 95% CI, 2.37-6.97; females: SIR, 8.44; 95% CI 4.88-14.61) and anorectal SMNHPV (males: SIR, 13.56; 95% CI, 5.09-36.13; females: SIR, 9.15; 95% CI, 2.29-36.61). Males (vs females: rSIR, 1.99; 95% CI, 1.00-3.94); head, neck, and pelvic radiotherapy doses >3000 centigray (vs none: rSIR, 2.35; 95% CI, 1.11-4.97); and cisplatin-equivalent doses >400 mg/m2 (vs none: rSIR, 4.51; 95% CI, 1.78-11.43) were associated with increased SMNHPV SIRs in multivariable analysis.Childhood cancer survivors are at increased risk for SMN in sites susceptible to HPV-associated malignancies. Further research examining HPV in the etiology of SMN and the promotion of HPV vaccination and surveillance guidelines for SMNHPV in cancer survivors is warranted.

  View details for DOI 10.1002/cncr.33922

  View details for Web of Science ID 000703180400001

  View details for PubMedID 34606625

  View details for PubMedCentralID PMC8738100

• Is the appendix a good organ to diagnose total colonic aganglionosis? PEDIATRIC SURGERY INTERNATIONAL Reppucci, M. L., Arnold, M. A., Lovell, M., Santos-Jasso, K., Ketzer, J., Pena, A., de la Torre, L., Bischoff, A. 2022; 38 (1): 25-30

  Abstract

  The use of the appendix for diagnosis of Total Colonic Aganglionosis (TCA) remains controversial. This study aimed to categorize the presence of ganglion cells in the appendix and determine its reliability as a histological specimen for the diagnosis of TCA.This was a combined retrospective and prospective study. Permanent histological specimens of normal appendices removed during appendectomy for malrotation or falsely presumed appendicitis, and from patients with short segment Hirschsprung's disease (HD) or TCA were included. Permanent specimens of the appendix tip from Malone procedures were prospectively collected. All specimens were independently reviewed by two experienced pathologists in a standardized manner to assess for the presence of ganglion cells.A total of 112 appendices were evaluated. Nine came from patients with a diagnosis of TCA, and five from patients with HD. Ganglion cells were present in all specimens from patients with diagnoses other than TCA and were absent in all specimens from patients with TCA.In the correct clinical setting, the absence of ganglion cells in the appendix can allow for a reliable diagnosis of TCA.

  View details for DOI 10.1007/s00383-021-05023-9

  View details for Web of Science ID 000698549900001

  View details for PubMedID 34554294

  View details for PubMedCentralID 5117267

• Development and Validation of a Breast Cancer Risk Prediction Model for Childhood Cancer Survivors Treated With Chest Radiation: A Report From the Childhood Cancer Survivor Study and the Dutch Hodgkin Late Effects and LATER Cohorts JOURNAL OF CLINICAL ONCOLOGY Moskowitz, C. S., Ronckers, C. M., Chou, J. F., Smith, S. A., Friedman, D., Barnea, D., Kok, J. L., de Vries, S., Wolden, S. L., Henderson, T. O., Van der Pal, H. J. H., Kremer, L. C. M., Neglia, J. P., Turcotte, L. M., Howell, R. M., Arnold, M. A., Schaapveld, M., Aleman, B., Janus, C., Versluys, B., Leisenring, W., Sklar, C. A., Begg, C. B., Pike, M. C., Armstrong, G. T., Robison, L. L., van Leeuwen, F. E., Oeffinger, K. C., Childhood Canc Survivor Study Grp, Dutch Later Dutch Hodgkin Lymphom 2021; 39 (27): 3012-+

  Abstract

  Women treated with chest radiation for childhood cancer have one of the highest risks of breast cancer. Models producing personalized breast cancer risk estimates applicable to this population do not exist. We sought to develop and validate a breast cancer risk prediction model for childhood cancer survivors treated with chest radiation incorporating treatment-related factors, family history, and reproductive factors.Analyses were based on multinational cohorts of female 5-year survivors of cancer diagnosed younger than age 21 years and treated with chest radiation. Model derivation was based on 1,120 participants in the Childhood Cancer Survivor Study diagnosed between 1970 and 1986, with median attained age 42 years (range 20-64) and 242 with breast cancer. Model validation included 1,027 participants from three cohorts, with median age 32 years (range 20-66) and 105 with breast cancer.The model included current age, chest radiation field, whether chest radiation was delivered within 1 year of menarche, anthracycline exposure, age at menopause, and history of a first-degree relative with breast cancer. Ten-year risk estimates ranged from 2% to 23% for 30-year-old women (area under the curve, 0.63; 95% CI, 0.50 to 0.73) and from 5% to 34% for 40-year-old women (area under the curve, 0.67; 95% CI, 0.54 to 0.84). The highest risks were among premenopausal women older than age 40 years treated with mantle field radiation within a year of menarche who had a first-degree relative with breast cancer. It showed good calibration with an expected-to-observed ratio of the number of breast cancers of 0.92 (95% CI, 0.74 to 1.16).Breast cancer risk varies among childhood cancer survivors treated with chest radiation. Accurate risk prediction may aid in refining surveillance, counseling, and preventive strategies in this population.

  View details for DOI 10.1200/JCO.20.02244

  View details for Web of Science ID 000708091800006

  View details for PubMedID 34048292

  View details for PubMedCentralID PMC9384912

• Comprehensive molecular characterization of pediatric radiation-induced high-grade glioma NATURE COMMUNICATIONS DeSisto, J., Lucas, J. T., Xu, K., Donson, A., Lin, T., Sanford, B., Wu, G., Tran, Q. T., Hedges, D., Hsu, C., Armstrong, G. T., Arnold, M., Bhatia, S., Flannery, P., Lemma, R., Hardie, L., Schueller, U., Venkataraman, S., Hoffman, L. M., Dorris, K., Levy, J., Hankinson, T. C., Handler, M., Liu, A. K., Foreman, N., Vibhakar, R., Jones, K., Allen, S., Zhang, J., Baker, S. J., Merchant, T. E., Orr, B. A., Green, A. L. 2021; 12 (1): 5531

  Abstract

  Radiation-induced high-grade gliomas (RIGs) are an incurable late complication of cranial radiation therapy. We performed DNA methylation profiling, RNA-seq, and DNA sequencing on 32 RIG tumors and an in vitro drug screen in two RIG cell lines. We report that based on DNA methylation, RIGs cluster primarily with the pediatric receptor tyrosine kinase I high-grade glioma subtype. Common copy-number alterations include Chromosome (Ch.) 1p loss/1q gain, and Ch. 13q and Ch. 14q loss; focal alterations include PDGFRA and CDK4 gain and CDKN2A and BCOR loss. Transcriptomically, RIGs comprise a stem-like subgroup with lesser mutation burden and Ch. 1p loss and a pro-inflammatory subgroup with greater mutation burden and depleted DNA repair gene expression. Chromothripsis in several RIG samples is associated with extrachromosomal circular DNA-mediated amplification of PDGFRA and CDK4. Drug screening suggests microtubule inhibitors/stabilizers, DNA-damaging agents, MEK inhibition, and, in the inflammatory subgroup, proteasome inhibitors, as potentially effective therapies.

  View details for DOI 10.1038/s41467-021-25709-x

  View details for Web of Science ID 000698606100015

  View details for PubMedID 34545084

  View details for PubMedCentralID PMC8452624

• MYOD1 as a prognostic indicator in rhabdomyosarcoma PEDIATRIC BLOOD & CANCER Ahmed, A. A., Habeebu, S., Farooqi, M. S., Gamis, A. S., Gonzalez, E., Flatt, T., Sherman, A., Surrey, L., Arnold, M. A., Conces, M., Koo, S., Dioufa, N., Barr, F. G., Tsokos, M. G. 2021; 68 (9): e29085

  Abstract

  Rhabdomyosarcoma (RMS) is characterized by the expression of the myogenic regulatory protein MYOD1. Histologic types include alveolar, embryonal (ERMS), and spindle cell sclerosing RMS (SRMS). SRMS harbors MYOD1 mutations in a subset of adult cases in association with poor prognosis.To study the level of MYOD1 protein expression and its clinical significance, we have analyzed variable numbers of pediatric (<18 years of age) and adult (age range ≥18 to 35 years) ERMS and SRMS cases for presence or absence of MYOD1 immunoreactivity in correlation with clinical outcome and MYOD1 L122R mutations.Lack of MYOD1 immunoreactivity, identified in 23.8% of nonalveolar RMS (non-ARMS) cases, was more prevalent in SRMS (44%) than ERMS (17.2%) and was significantly associated with low overall survival and unfavorable tumor sites (p < .05). Lack of MYOD1 immunoreactivity was not associated with MYOD1 L122R mutations, which were identified in 3/37 (8%) cases including only two of 31 (6.5%) pediatric cases, one of 11 or 9% pediatric SRMS, and one case of infant ERMS.These studies highlight the prognostic role of MYOD1 in non-ARMS. Lack of MYOD1 immunoreactivity is associated with poor prognosis in ERMS and SRMS. MYOD1 gene mutations are generally infrequent in pediatric RMS. Although mutations are predominant in SRMS, they may exceptionally occur in infantile ERMS.

  View details for DOI 10.1002/pbc.29085

  View details for Web of Science ID 000645186300001

  View details for PubMedID 33913590

  View details for PubMedCentralID PMC9907363

• The Implementation and Effectiveness of PathElective.com ACADEMIC PATHOLOGY Lilley, C. M., Arnold, C. A., Arnold, M., Booth, A. L., Gardner, J. M., ''Sara'' Jiang, X., Loghavi, S., Mirza, K. M. 2021; 8: 23742895211006829

  Abstract

  The COVID-19 pandemic put most in-person pathology electives on-hold as departments adapted to changes in education and patient care. To address the subsequent void in pathology education, we created a free, virtual, modular, and high-quality pathology elective website. Website traffic from June 1, 2020, to October 1, 2020, was monitored using the built-in analyses on Squarespace. Twitter engagement was analyzed using Twitter analytics and the Symplur Social Graph Score. A voluntary satisfaction survey was sent to all PathElective users and results were analyzed. During this time, the site saw 25 467 unique visitors, over 34 988 visits, 181 302 page views, and 4449 subscriptions from 99 countries. Countries with the highest traffic are the United States (14 682), India (5210), and the Philippines (2195). PathElective's Twitter social graph score increased from 63.59 to 89.3 with the addition of 1637 followers. Data from surveyed users (n = 177) show most to be pathology residents (41%). Most subscribers (89%) are committed to a career in pathology. The majority heard of the website via Twitter (55%). Almost half of those surveyed engaged with the PathTwitter community on Twitter and of those who participated, 99% found that interaction useful. In all survey questions surrounding satisfaction and usefulness, a large majority of the users were either satisfied or very satisfied. PathElective is a novel pathology elective that offers a unique opportunity to educate medical students and residents from around the globe and demonstrates high effectiveness and satisfaction among users.

  View details for DOI 10.1177/23742895211006829

  View details for Web of Science ID 000639192200001

  View details for PubMedID 33884295

  View details for PubMedCentralID PMC8040569

• Suboptimal outcome for patients with biliary rhabdomyosarcoma treated on low-risk clinical trials: A report from the Children's Oncology Group PEDIATRIC BLOOD & CANCER Aye, J. M., Xue, W., Palmer, J. D., Walterhouse, D. O., Arnold, M. A., Heaton, T. E., Venkatramani, R. 2021; 68 (4): e28914

  Abstract

  Biliary rhabdomyosarcoma (RMS) is the most common biliary tumor in children. The biliary tract is classified as a favorable primary site. Therefore, patients with localized biliary RMS were included in two consecutive low-risk studies, D9602 and ARST0331, by the Children's Oncology Group (COG). The outcome for these patients treated with low-risk therapy has not been reported.Patients with biliary RMS enrolled on COG low-risk trials D9602 or ARST0331 were analyzed. All patients received systemic chemotherapy and those with Group II (microscopic residual) or Group III (macroscopic residual) disease received 36-50.4 Gy adjuvant radiotherapy (RT). Delayed primary excision (DPE) was allowed on both studies.Seventeen patients with biliary RMS were treated on D9602 (n = 7) or ARST0331 (n = 10). Median age was 3.5 years (range 1.7-10.3). Ten (59%) patients had tumors >5 cm and 14 (82%) had Group III disease. Fifteen (88%) patients received RT. The 5-year event-free survival (EFS) and overall survival (OS) were 70.6% (95% confidence interval [CI]: 46.9-94.3%) and 76.5% (95% CI: 54.6-98.4%), respectively. The majority of patients (80%) who received RT did not have disease recurrence while both patients who did not receive RT had local relapse. Five (36%) of 14 patients with Group III disease underwent DPE; two experienced a local relapse. In the nine patients without DPE, two developed local relapse.Patients with localized biliary RMS treated on low-risk studies had suboptimal outcomes. These patients may benefit from therapy on intermediate-risk studies.

  View details for DOI 10.1002/pbc.28914

  View details for Web of Science ID 000611903300001

  View details for PubMedID 33501771

  View details for PubMedCentralID PMC8765674

• Neovagina stricture complicated by high-grade dysplasia in a patient with history of cloaca and ulcerative colitis: a case report and review of the literature PEDIATRIC SURGERY INTERNATIONAL Alaniz, V. I., Wilcox, D. T., Arnold, M., Bodmer, J. L., de la Torre, L., Pena, A., Bischoff, A. 2021; 37 (4): 491-494

  Abstract

  Vaginoplasty with colon is a common technique for vaginal replacement in patients with cloaca. Malignancy in the neovagina is a rare outcome and typically presents decades after reconstruction. We present a case of an adolescent female with history of cloaca, ulcerative colitis, and high-grade dysplasia of the sigmoid neovagina.

  View details for DOI 10.1007/s00383-020-04838-2

  View details for Web of Science ID 000607330100002

  View details for PubMedID 33433664

  View details for PubMedCentralID 1293553

• Neurons populating the rectal extrinsic nerves in humans express neuronal and Schwann cell markers NEUROGASTROENTEROLOGY AND MOTILITY Woods, C., Kapur, R. P., Bischoff, A., Lovell, M., Arnold, M., Pena, A., Flockton, A., Sharkey, K. A., Belkind-Gerson, J. 2021; 33 (7): e14074

  Abstract

  In mice, Schwann cell (SC) progenitors give rise to autonomic ganglion cells and migrate into the gut to become enteric neurons. It is unknown whether SC progenitors have a similar fate in humans. In search of evidence for human SC-derived neurogenesis in the gastrointestinal (GI) tract, we studied the rectums from cadaveric controls and children with anorectal malformations (ARM).We analyzed distal rectal tissue taken at autopsy from 10 children with normal GI tracts and resected rectal specimens in 48 cases of ARM. Of these specimens, 6 had neurons within the extrinsic rectal innervation. These were further investigated with immunohistochemistry for neuronal and SC/glial markers.Perirectal tissue from control and ARM contained GLUT1-positive extrinsic nerves, many containing neurons. SC/glial markers (SOX10, CDH19, and PLP1) were expressed by glia in the enteric nervous system and perirectal nerves, while MPZ predominated only in glia of perirectal nerves, in both control and ARM. Neurons in perirectal nerves were 61% larger in ARM samples and co-expressed SOX10 (81%), PLP1 (73%), and CDH19 (56%). In ARM, cytoplasmic SOX10 was co-expressed with neuronal antigens in ~57% of submucosal and myenteric neurons, vs. ~3% in control. Furthermore, intrinsic gut neurons in ARM specimens co-expressed PLP1 (18%) and CDH19 (18%); however, neuronal co-expression of PLP1 and CDH19 was rarely (<2%) observed in controls.Dual expression of glial and neuronal markers in rectal and perirectal neurons support a model of Schwann cell-derived neurogenesis in the innervation of the human GI tract.

  View details for DOI 10.1111/nmo.14074

  View details for Web of Science ID 000603673800001

  View details for PubMedID 33382200

• Genetic Characterization of Pediatric Sarcomas by Targeted RNA Sequencing JOURNAL OF MOLECULAR DIAGNOSTICS Avenarius, M. R., Miller, C. R., Arnold, M. A., Koo, S., Roberts, R., Hobby, M., Grossman, T., Moyer, Y., Wilson, R. K., Mardis, E. R., Gastier-Foster, J. M., Pfau, R. B. 2020; 22 (10): 1238-1245

  Abstract

  Somatic variants, primarily fusion genes and single-nucleotide variants (SNVs) or insertions/deletions (indels), are prevalent among sarcomas. In many cases, accurate diagnosis of these tumors incorporates genetic findings that may also carry prognostic or therapeutic significance. Using the anchored multiplex PCR-based FusionPlex system, a custom RNA sequencing panel was developed that simultaneously detects fusion genes, SNVs, and indels in 112 genes found to be recurrently mutated in solid tumors. Using this assay, a retrospective analysis was conducted to identify somatic variants that may have assisted with classifying a cohort of 90 previously uncharacterized primarily pediatric sarcoma specimens. In total, somatic variants were identified in 45.5% (41/90) of the samples tested, including 22 cases with fusion genes and 19 cases with SNVs or indels. In addition, two of these findings represent novel alterations: a WHSC1L1/NCOA2 fusion and a novel in-frame deletion in the NRAS gene (NM_002524: c.174_176delAGC p.Ala59del). These sequencing results, taken in context with the available clinical data, indicate a potential change in the initial diagnosis, prognosis, or management in 27 of the 90 cases. This study presents a custom RNA sequencing assay that detects fusion genes and SNVs in tandem and has the ability to identify novel fusion partners. These features highlight the advantages associated with utilizing anchored multiplex PCR technology for the rapid and highly sensitive detection of somatic variants.

  View details for DOI 10.1016/j.jmoldx.2020.07.004

  View details for Web of Science ID 000575777800003

  View details for PubMedID 32745614

  View details for PubMedCentralID PMC7538815

• Subsequent Neoplasm Risk Associated With Rare Variants in DNA Damage Response and Clinical Radiation Sensitivity Syndrome Genes in the Childhood Cancer Survivor Study JCO PRECISION ONCOLOGY Morton, L. M., Karyadi, D. M., Hartley, S. W., Frone, M. N., Sampson, J. N., Howell, R. M., Neglia, J. P., Arnold, M. A., Hicks, B. D., Jones, K., Zhu, B., Dagnall, C. L., Karlins, E., Yeager, M. S., Leisenring, W. M., Yasui, Y., Turcotte, L. M., Smith, S. A., Weathers, R. E., Miller, J., Sigel, B. S., Merino, D. M., de Gonzalez, A., Bhatia, S., Robison, L. L., Tucker, M. A., Armstrong, G. T., Chanock, S. J. 2020; 4: 926-936

  Abstract

  Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown.We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records. We identified patients who developed SN types previously reported to be related to radiotherapy (RT-SNs; eg, basal cell carcinoma [BCC], breast cancer, meningioma, thyroid cancer, sarcoma) and matched controls (sex, childhood cancer type/diagnosis, age, SN location, radiation dose, survival). Conditional logistic regression assessed SN risk associated with potentially protein-damaging rare variants (SnpEff, ClinVar) in 476 DNA damage response or radiation sensitivity genes with exact permutation-based P values using a Bonferroni-corrected significance threshold of P < 8.06 × 10-5.Among 5,105 childhood cancer survivors of European descent, 1,108 (21.7%) developed at least 1 RT-SN. Out-of-field RT-SN risk, excluding BCC, was associated with homologous recombination repair (HRR) gene variants (patient cases, 23.2%; controls, 10.8%; odds ratio [OR], 2.6; 95% CI, 1.7 to 3.9; P = 4.79 × 10-5), most notably but nonsignificantly for FANCM (patient cases, 4.0%; matched controls, 0.6%; P = 9.64 × 10-5). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; P = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with EXO1 variants (patient cases, 1.8%; controls, 0.4%; P = 3.31 × 10-5), another gene implicated in DNA double-strand break repair.In this large-scale discovery study, we identified novel associations between RT-SN risk after childhood cancer and potentially protein-damaging rare variants in genes involved in DNA double-strand break repair, particularly HRR. With replication, these results could affect screening recommendations for childhood cancer survivors and risk-benefit assessments of treatment approaches.

  View details for DOI 10.1200/PO.20.00141

  View details for Web of Science ID 000615674800001

  View details for PubMedID 32923912

  View details for PubMedCentralID PMC7469586

• Renal Tumors in Children and Young Adults Older Than 5 Years of Age JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Mansfield, S. A., Lamb, M. G., Stanek, J. R., Arnold, M. A., Ranalli, M., Aldrink, J. H. 2020; 42 (4): 287-291

  Abstract

  Renal masses are most common in children between ages 1 to 3 years, with less known about renal tumors in older children and young adults. The aim of this study was to review the presentation, demographics, histology, and outcomes in patients over 5 years of age with renal tumors compared with younger children. 111 renal tumors were diagnosed in patients 5 years of age and older (median, 7 y; range, 5 to 31 y) between 1950 and 2017 at a single institution. Wilms tumor (WT) was the most common histology in 84 patients (75%), followed by renal cell carcinoma in 12 patients (10.7%). Abdominal pain was the most common presenting symptom (46%) followed by hematuria (28.8%), and a palpable abdominal mass (24.3%). For WT, older children more commonly presented with advanced-stage disease (stages 3 and 4) than younger children (57.7% vs. 11.5%; P<0.001). Event-free survival (EFS) and overall survival (OS) for favorable histology WT were not different between younger and older children (OS, P=0.43; EFS, P=0.46). In this cohort, older children more frequently present with variable signs and symptoms, less common histopathologies although WT was still most frequent, and more advanced-stage disease compared with younger cohorts, but without differences in EFS or OS.

  View details for DOI 10.1097/MPH.0000000000001593

  View details for Web of Science ID 000529959600025

  View details for PubMedID 31524665

• The genomic landscape of undifferentiated embryonal sarcoma of the liver is typified by C19MC structural rearrangement and overexpression combined with <i>TP53</i> mutation or loss PLOS GENETICS Setty, B. A., Jinesh, G. G., Arnold, M., Pettersson, F., Cheng, C., Cen, L., Yoder, S. J., Teer, J. K., Flores, E. R., Reed, D. R., Brohl, A. S. 2020; 16 (4): e1008642

  Abstract

  Undifferentiated embryonal sarcoma of the liver (UESL) is a rare and aggressive malignancy. Though the molecular underpinnings of this cancer have been largely unexplored, recurrent chromosomal breakpoints affecting a noncoding region on chr19q13, which includes the chromosome 19 microRNA cluster (C19MC), have been reported in several cases. We performed comprehensive molecular profiling on samples from 14 patients diagnosed with UESL. Congruent with prior reports, we identified structural variants in chr19q13 in 10 of 13 evaluable tumors. From whole transcriptome sequencing, we observed striking expressional activity of the entire C19MC region. Concordantly, in 7 of 7 samples undergoing miRNAseq, we observed hyperexpression of the miRNAs within this cluster to levels >100 fold compared to matched normal tissue or a non-C19MC amplified cancer cell line. Concurrent TP53 mutation or copy number loss was identified in all evaluable tumors with evidence of C19MC overexpression. We find that C19MC miRNAs exhibit significant negative correlation to TP53 regulatory miRNAs and K-Ras regulatory miRNAs. Using RNA-seq we identified that pathways relevant to cellular differentiation as well as mRNA translation machinery are transcriptionally enriched in UESL. In summary, utilizing a combination of next-generation sequencing and high-density arrays we identify the combination of C19MC hyperexpression via chromosomal structural event with TP53 mutation or loss as highly recurrent genomic features of UESL.

  View details for DOI 10.1371/journal.pgen.1008642

  View details for Web of Science ID 000531363700005

  View details for PubMedID 32310940

  View details for PubMedCentralID PMC7192511

• Genetic variation in <i>POT1</i> and risk of thyroid subsequent malignant neoplasm: A report from the Childhood Cancer Survivor Study PLOS ONE Richard, M. A., Lupo, P. J., Morton, L. M., Yasui, Y. A., Sapkota, Y. A., Arnold, M. A., Aubert, G., Neglia, J. P., Turcotte, L. M., Leisenring, W. M., Sampson, J. N., Chanock, S. J., Hudson, M. M., Armstrong, G. T., Robison, L. L., Bhatia, S., Gramatges, M. 2020; 15 (2): e0228887

  Abstract

  Telomere length is associated with risk for thyroid subsequent malignant neoplasm in survivors of childhood cancer. Here, we investigated associations between thyroid subsequent malignant neoplasm and inherited variation in telomere maintenance genes.We used RegulomeDB to annotate the functional impact of variants mapping to 14 telomere maintenance genes among 5,066 five-or-more year survivors who participate in the Childhood Cancer Survivor Study (CCSS) and who are longitudinally followed for incidence of subsequent cancers. Hazard ratios for thyroid subsequent malignant neoplasm were calculated for 60 putatively functional variants with minor allele frequency ≥1% in or near telomere maintenance genes. Functional impact was further assessed by measuring telomere length in leukocyte subsets.The minor allele at Protection of Telomeres-1 (POT1) rs58722976 was associated with increased risk for thyroid subsequent malignant neoplasm (adjusted HR = 6.1, 95% CI: 2.4, 15.5, P = 0.0001; Fisher's exact P = 0.001). This imputed SNP was present in three out of 110 survivors who developed thyroid cancer vs. 14 out of 4,956 survivors who did not develop thyroid cancer. In a subset of 83 survivors with leukocyte telomere length data available, this variant was associated with longer telomeres in B lymphocytes (P = 0.004).Using a functional variant approach, we identified and confirmed an association between a low frequency intronic regulatory POT1 variant and thyroid subsequent malignant neoplasm in survivors of childhood cancer. These results suggest that intronic variation in POT1 may affect key protein binding interactions that impact telomere maintenance and genomic integrity.

  View details for DOI 10.1371/journal.pone.0228887

  View details for Web of Science ID 000534629400051

  View details for PubMedID 32040538

  View details for PubMedCentralID PMC7010302

• Comparison of Radiation Dose Reconstruction Methods to Investigate Late Adverse Effects of Radiotherapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study RADIATION RESEARCH Schonfeld, S. J., Howell, R. M., Smith, S. A., Neglia, J. P., Turcotte, L. M., Arnold, M. A., Inskip, P. D., Oeffinger, K. C., Moskowitz, C. S., Henderson, T. O., Leisenring, W. M., Gibson, T. M., de Gonzalez, A., Sampson, J. N., Chanock, S. J., Tucker, M. A., Bhatia, S., Robison, L. L., Armstrong, G. T., Morton, L. M. 2020; 193 (2): 95-106

  Abstract

  Quantification of radiation dose to normal tissue during radiotherapy is critical for assessing risk for radiotherapy-related late effects, including subsequent neoplasms (SNs). Case-control studies of SNs typically reconstruct absorbed radiation dose to the specific SN location using individual treatment parameters. A simplified method estimates the maximum prescribed target dose to the body region in which the SN arises. We compared doses and risk estimates from these methods using data from case-control studies of subsequent brain tumors (64 cases, 244 controls) and breast cancer (94 cases, 358 controls) nested within the Childhood Cancer Survivor Study (≥5-year survivors of childhood cancer diagnosed 1970-1986). The weighted kappa statistic [95% confidence interval (CI)] evaluating agreement between categorical (>0-9.9/10-19.9/20-29.9/≥30 Gy) body-region and tumor location-specific doses was 0.95 (0.91-0.98) for brain and 0.76 (0.69-0.82) for breast. The body-region and location-specific doses were assigned to the same dose category for a smaller proportion of patients treated with fields delivering a heterogeneous dose across the tissue of interest (e.g., partial brain field = 57.1%; mantle field = 61.3%) than patients treated with fields delivering a more homogeneous dose (e.g., whole brain field = 100%). Excess odds ratios per Gy (95% CI) from conditional logistic regression were 1.25 (0.33-6.33) and 1.20 (0.31-6.14) for brain tumors and 0.21 (0.05-0.77) and 0.10 (0.02-0.44) for breast cancer, using location-specific and body-region doses, respectively. We observed that body-region doses can approximate location-specific doses when the tissue of interest is clearly in the radiation field or outside the treated body region. Agreement is lower when there is greater ambiguity of SN location relative to the treatment field.

  View details for DOI 10.1667/RR15308.1

  View details for Web of Science ID 000518792700001

  View details for PubMedID 31794291

  View details for PubMedCentralID PMC7063664

• Survival outcomes of patients with localized FOXO1 fusion-positive rhabdomyosarcoma treated on recent clinical trials: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Cancer Heske, C. M., Chi, Y. Y., Venkatramani, R. n., Li, M. n., Arnold, M. A., Dasgupta, R. n., Hiniker, S. M., Hawkins, D. S., Mascarenhas, L. n. 2020

  Abstract

  The objective of this analysis was to evaluate the clinical factors influencing survival outcomes in patients with localized (clinical group I-III), FOXO1 fusion-positive rhabdomyosarcoma (RMS).Patients with confirmed FOXO1 fusion-positive RMS who were enrolled on 3 completed clinical trials for localized RMS were included in the analytic cohort. Outcomes were analyzed using the Kaplan-Meier method to estimate event-free survival (EFS) and overall survival (OS), and the curves were compared using the log-rank test. A Cox proportional hazards regression model was used to perform multivariate analysis of prognostic factors that were significant in the univariate analysis.The estimated 4-year EFS and OS of 269 patients with localized, FOXO1 fusion-positive RMS was 53% (95% CI, 47%-59%) and 69% (95% CI, 63%-74%), respectively. Univariate analysis revealed that several known favorable clinical characteristics, including age at diagnosis between 1 and 9 years, complete surgical resection, tumor size ≤5 cm, favorable tumor site, absence of lymph node involvement, confinement to the anatomic site of origin, and PAX7-FOXO1 fusion, were associated with improved outcomes. Multivariate analysis identified older age (≥10 years) and large tumor size (>5 cm) as independent, adverse prognostic factors for EFS within this population, and patients who had both adverse features experienced substantially inferior outcomes.Patients with localized, FOXO1 fusion-positive RMS can be further risk stratified based on clinical features at diagnosis, and older patients with large primary tumors have the poorest prognosis.

  View details for DOI 10.1002/cncr.33334

  View details for PubMedID 33216382

• Young-Onset Ischemic Colitis: A Condition of Elusive Etiology Frequently Associated With Immune Dysregulation INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY Byrnes, K., Khararjian, A., Mannan, A. R., Arnold, M., Voltaggio, L. 2020; 28 (4): 361-366

  Abstract

  Ischemic colitis (IC) associates with older age, hypertension, and heart disease, among others. Young-onset IC is rare. We aimed to delineate clinical characteristics of young patients (<40 years) with IC. Cases from 1984 to 2017 were re-reviewed. Of the 60 cases available, 52% (n = 31) had histologic features of IC. Fifty-five percent were female with a mean age of 32 (range = 14-40) years. Fifty-eight percent (n = 18) were resections. The most common presentations were diarrhea and abdominal pain. Three teenagers had IC associated with prior surgery, volvulus, and constipation. In the 21- to 40-year group, 43% (n = 12) lacked clinical associations. A second subset (n = 6, 21%) had histories of immune dysregulation (lupus, dermatomyositis, vasculitis) and poorly controlled HIV/AIDS (n = 5, 18%). Smoking and cocaine were endorsed by 1 and 2 patients, respectively. One patient had premature atherosclerosis while another had HMG Co-A lyase deficiency. Vasculitis was identified in 22% of the resections and in none of the biopsies. Nineteen percent of patients died (n = 6) from complications of IC, all treated surgically, including 1 patient previously misdiagnosed as ulcerative colitis; 2 patients died of unrelated causes. While rare before 20 years of age, IC in teenagers relates to mechanical issues and is rare in children. Associations in young adults include immune dysregulation, cocaine and cigarette use, and premature atherosclerosis. Our retrospective cohort had a surgical mortality rate within the range reported by others, highlighting the importance of accurate diagnosis in young individuals.

  View details for DOI 10.1177/1066896919894671

  View details for Web of Science ID 000506742400001

  View details for PubMedID 31870209

• Association of Breast Cancer Risk After Childhood Cancer With Radiation Dose to the Breast and Anthracycline Use A Report From the Childhood Cancer Survivor Study JAMA PEDIATRICS Veiga, L. H., Curtis, R. E., Morton, L. M., Withrow, D. R., Howell, R. M., Smith, S. A., Weathers, R. E., Oeffinger, K. C., Moskowitz, C. S., Henderson, T. O., Arnold, M. A., Gibson, T. M., Leisenring, W. M., Neglia, J. P., Turcotte, L. M., Whitton, J. A., Robison, L. L., Armstrong, G. T., Inskip, P. D., Berrington de Gonzalez, A. 2019; 173 (12): 1171-1179

  Abstract

  Chest irradiation for childhood cancer is associated with increases in breast cancer risk. Growing evidence suggests that anthracyclines increase this risk, but the outcome of combined anthracycline use and radiotherapy has not been studied.To evaluate breast cancer risk in childhood cancer survivors following radiotherapy and chemotherapy and assess whether risks varied by estrogen receptor (ER) status.In a North American hospital-based nested case-control study, a retrospective cohort of 14 358 five-year survivors of childhood cancer, diagnosed from 1970 to 1986 and followed up through December 31, 2016, was analyzed. Cases (n = 271) were defined as women with subsequent breast cancer. Controls (n = 1044) were matched 4:1 to cases by age at first cancer and duration of follow-up (± 2 years). Data analysis was conducted from September 2017 to July 2018.Radiation dose to breast tumor site and ovaries and cumulative chemotherapy doses, including anthracyclines and alkylating agents.Odds ratios (ORs) for subsequent breast cancer by ER status.A total of 271 women served as breast cancer cases (median age at first cancer diagnosis, 15 years [range, 3-20]; median age at breast cancer diagnosis, 39 years [range, 20-57]): 201 invasive (113 ER positive [ER+], 41 ER negative [ER-], and 47 unknown) and 70 in situ breast cancers. The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5-6.5) and was similar for ER+ (OR per 10 Gy, 5.5; 95% CI, 2.8-12.6) and ER- (OR per 10 Gy, 4.8; 95% CI, 1.7-22.3) cancers. For women who received ovarian doses less than 1 Gy, the OR per 10 Gy to the breast was higher (OR, 6.8; 95% CI, 3.9-12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0-6.4). The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m2, 1.23; 95% CI, 1.09-1.39; P < .01 for trend), and was 1.49 (95% CI, 1.21-1.83) for ER+ cancer vs 1.10 (95% CI, 0.84-1.45) for ER- cancers (P value for heterogeneity = .47). There was an additive interaction between radiotherapy and anthracycline treatment (P = .04) with the OR for the combined association between anthracycline therapy and breast radiation dose of 10 Gy or more (compared with 0 to less than 1 Gy) of 19.1 (95% CI, 7.6-48.0) vs 9.6 (95% CI, 4.4-20.7) without anthracycline use.This study provides the first evidence to date that the combination of anthracyclines and radiotherapy may increase breast cancer risks compared with use of neither treatment with a similar radiation dose response for ER+ and ER- cancers and possibly higher anthracycline risks for ER+ cancers. These results might help inform surveillance guidelines for childhood cancer survivors.

  View details for DOI 10.1001/jamapediatrics.2019.3807

  View details for Web of Science ID 000505183100011

  View details for PubMedID 31657853

  View details for PubMedCentralID PMC6820042

• Subsequent Neoplasms After a Primary Tumor in Individuals With Neurofibromatosis Type 1 JOURNAL OF CLINICAL ONCOLOGY Bhatia, S., Chen, Y., Wong, F., Hageman, L., Smith, K., Korf, B., Cannon, A., Leidy, D. J., Paz, A., Andress, J. E., Friedman, G. K., Metrock, K., Neglia, J. P., Arnold, M., Turcotte, L. M., de Blank, P., Leisenring, W., Armstrong, G. T., Robison, L. L., Clapp, D., Shannon, K., Nakamura, J. L., Fisher, M. J. 2019; 37 (32): 3050-+

  Abstract

  Fundamental gaps in knowledge regarding the risk of subsequent neoplasms (SNs) in children with pathogenic neurofibromatosis type 1 (NF1) variants exposed to radiation and/or alkylator chemotherapy have limited the use of these agents.We addressed these gaps by determining the SN risk in 167 NF1-affected versus 1,541 non-NF1-affected 5-year childhood cancer survivors from the Childhood Cancer Survivor Study and 176 nonoverlapping NF1-affected individuals with primary tumors from University of Alabama at Birmingham and Children's Hospital of Philadelphia exposed to radiation and/or chemotherapy. Proportional subdistribution hazards multivariable regression analysis was used to examine risk factors, adjusting for type and age at primary tumor diagnosis and therapeutic exposures.In the Childhood Cancer Survivor Study cohort, the 20-year cumulative incidence of SNs in NF1 childhood cancer survivors was 7.3%, compared with 2.9% in the non-NF1 childhood cancer survivors (P = .003), yielding a 2.4-fold higher risk of SN (95% CI, 1.3 to 4.3; P = .005) in the NF1-affected individuals. In the University of Alabama at Birmingham and Children's Hospital of Philadelphia cohort, among NF1-affected individuals with a primary tumor, the risk of SNs was 2.8-fold higher in patients with irradiated NF1 (95% CI, 1.3 to 6.0; P = .009). In contrast, the risk of SNs was not significantly elevated after exposure to alkylating agents (hazard ratio, 1.27; 95% CI, 0.3 to 3.0; P = .9).Children with NF1 who develop a primary tumor are at increased risk of SN when compared with non-NF1 childhood cancer survivors. Among NF1-affected children with a primary tumor, therapeutic radiation, but not alkylating agents, confer an increased risk of SNs. These findings can inform evidence-based clinical management of primary tumors in NF1-affected children.

  View details for DOI 10.1200/JCO.19.00114

  View details for Web of Science ID 000498075300011

  View details for PubMedID 31532722

  View details for PubMedCentralID PMC6839906

• GD2-directed CAR-T cells in combination with HGF-targeted neutralizing antibody (AMG102) prevent primary tumor growth and metastasis in Ewing sarcoma INTERNATIONAL JOURNAL OF CANCER Charan, M., Dravid, P., Cam, M., Audino, A., Gross, A. C., Arnold, M. A., Roberts, R. D., Cripe, T. P., Pertsemlidis, A., Houghton, P. J., Cam, H. 2020; 146 (11): 3184-3195

  Abstract

  Ewing sarcoma (EWS) is the second most common and aggressive type of metastatic bone tumor in adolescents and young adults. There is unmet medical need to develop and test novel pharmacological targets and novel therapies to treat EWS. Here, we found that EWS expresses high levels of a p53 isoform, delta133p53. We further determined that aberrant expression of delta133p53 induced HGF secretion resulting in tumor growth and metastasis. Thereafter, we evaluated targeting EWS tumors with HGF receptor neutralizing antibody (AMG102) in preclinical studies. Surprisingly, we found that targeting EWS tumors with HGF receptor neutralizing antibody (AMG102) in combination with GD2-specific, CAR-reengineered T-cell therapy synergistically inhibited primary tumor growth and establishment of metastatic disease in preclinical models. Furthermore, our data suggested that AMG102 treatment alone might increase leukocyte infiltration including efficient CAR-T access into tumor mass and thereby improves its antitumor activity. Together, our findings warrant the development of novel CAR-T-cell therapies that incorporate HGF receptor neutralizing antibody to improve therapeutic potency, not only in EWS but also in tumors with aberrant activation of the HGF/c-MET pathway.

  View details for DOI 10.1002/ijc.32743

  View details for Web of Science ID 000494622000001

  View details for PubMedID 31621900

  View details for PubMedCentralID PMC7440656

• Guidelines for synoptic reporting of surgery and pathology in Hirschsprung disease JOURNAL OF PEDIATRIC SURGERY Veras, L. V., Arnold, M., Avansino, J. R., Bove, K., Cowles, R. A., Durham, M. M., Goldstein, A. M., Krishnan, C., Langer, J. C., Levitt, M., Monforte-Munoz, H., Rabah, R., Reyes-Mugica, M., Rollins, M. D., Kapur, R. P., Gosain, A., Amer Pediat Surgical Assoc Hirschs 2019; 54 (10): 2017-2023

  Abstract

  Synoptic, or standardized, reporting of surgery and pathology reports has been widely adopted in surgical oncology. Patients with Hirschsprung disease may experience morbidity related to surgical factors or underlying pathology and often undergo multiple operations. Our aim is to improve the postoperative outcome and care of patients with Hirschsprung disease by proposing a standardized set of data that should be included in every surgery and pathology report.Members of the American Pediatric Surgical Association Hirschsprung Disease Interest Group and experts in pediatric pathology of Hirschsprung disease participated in group discussions, performed literature review and arrived at expert consensus guidelines for surgery and pathology reporting.The importance of accurate operative and pathologic reports and the implications of inadequate documentation in patients with Hirschsprung disease are discussed and guidelines for standardizing these reports are provided.Adherence to the principles of reporting for operations and surgical pathology may improve outcomes for Hirschsprung disease patients and will facilitate identification of correlations among morphology, function, genetics and outcomes, which are required to improve the overall management of these patients.V.

  View details for DOI 10.1016/j.jpedsurg.2019.03.010

  View details for Web of Science ID 000493899400009

  View details for PubMedID 30935730

• Infra-anastomotic Innervation of Residual Aganglionic Distal Rectum After Pull-through Surgery for Hirschsprung Disease PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Kapur, R. P., Arnold, M. A., Conces, M. R. 2019; 22 (5): 420-430

  Abstract

  Descending neurons are important for intestinal reflex activities, including the recto-anal inhibitory reflex involved in normal defecation. Pull-through surgery for Hirschsprung disease results in the anastomosis of ganglionic bowel to native aganglionic rectum just superior to the internal anal sphincter, which potentially could allow for physiologically significant infra-anastomotic innervation.The density and distribution of intramuscular neuronal nitric oxide synthase (nNOS)- and mucosal calretinin-immunoreactive nerves were evaluated proximal and distal to the anastomosis in redo resection specimens after pull-through surgery for Hirschsprung disease. The findings were compared with data collected from cadaveric controls with no history of dysmotility and the distal aganglionic segments of primary rectal resections from patients with Hirschsprung disease.Native aganglionic rectum of Hirschsprung patients lacks the normal lush intramuscular nNOS- and mucosal calretinin-immunoreactive nerves present in normal bowel. In post-pull-through resection specimens obtained more than 7 months after pull-through surgery, nNOS- and calretinin-positive innervation is at least partially restored for variable distances up to 10 to 12 mm inferior to the anastomosis, respectively.Innervation of infra-anastomotic muscularis propria and mucosa in the aganglionic distal rectum occurs to a variable degree after pull-through surgery for Hirschsprung disease and may contribute to individual differences in postoperative obstructive symptoms. Strategies to enhance infra-anastomotic innervation may improve clinical outcome.

  View details for DOI 10.1177/1093526619837788

  View details for Web of Science ID 000486008400004

  View details for PubMedID 30915893

• Multifocal Appendiceal Carcinoid Tumor in an Adolescent: A Case Report and Review of the Literature JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Rinehardt, H., Ranalli, M., Diefenbach, K. A., Arnold, M. A., Espinosa Morazan, A., Aldrink, J. H. 2019; 41 (7): 568-570

  Abstract

  Appendiceal carcinoid tumors in children and adolescents are rare. This report describes a case of a multifocal appendiceal carcinoid tumor identified incidentally following appendectomy in an adolescent. In this report, we describe the staging process and surgical management for focal and locally invasive appendiceal carcinoid tumors and highlight the rarity of multifocality in this location. The diagnostic and pathologic challenges for this case are presented.

  View details for DOI 10.1097/MPH.0000000000001331

  View details for Web of Science ID 000489633800026

  View details for PubMedID 31569174

• Genome-Wide Association Study in Irradiated Childhood Cancer Survivors Identifies HTR2A for Subsequent Basal Cell Carcinoma JOURNAL OF INVESTIGATIVE DERMATOLOGY Sapkota, Y., Turcotte, L. M., Ehrhardt, M. J., Howell, R. M., Arnold, M. A., Wilson, C. L., Leisenring, W., Wang, Z., Sampson, J., Dagnall, C. L., Karlins, E., Li, S., Hicks, B. D., Weathers, R., Smith, S. A., Shelton, K., Liu, Q., Tucker, M. A., Chanock, S. J., Zhang, J., Hudson, M. M., Neglia, J. P., Armstrong, G. T., Robison, L. L., Morton, L. M., Bhatia, S., Yasui, Y. 2019; 139 (9): 2042-+

  View details for DOI 10.1016/j.jid.2019.02.029

  View details for Web of Science ID 000482187300027

  View details for PubMedID 30910758

• Mortality After Breast Cancer Among Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study JOURNAL OF CLINICAL ONCOLOGY Moskowitz, C. S., Chou, J. F., Neglia, J. P., Partridge, A. H., Howell, R. M., Diller, L. R., Friedman, D., Barnea, D., Morton, L. M., Turcotte, L. M., Arnold, M. A., Leisenring, W. M., Armstrong, G. T., Robison, L. L., Oeffinger, K. C., Henderson, T. O. 2019; 37 (24): 2120-+

  Abstract

  Female survivors of childhood cancer have a high risk of subsequent breast cancer. We describe the ensuing risk for mortality and additional breast cancers.Female participants in the Childhood Cancer Survivor Study, a cohort of 5-year survivors of cancer diagnosed between 1970 and 1986 before age 21 years, and subsequently diagnosed with breast cancer (n = 274; median age at breast cancer diagnosis, 38 years; range, 20 to 58 years) were matched to a control group (n = 1,095) with de novo breast cancer. Hazard ratios (HRs) and 95% CIs were estimated from cause-specific proportional hazards models.Ninety-two childhood cancer survivors died, 49 as a result of breast cancer. Overall survival after breast cancer was 73% by 10 years. Subsequent risk of death as a result of any cause was higher among childhood cancer survivors than among controls (HR, 2.2; 95% CI, 1.7 to 3.0) and remained elevated after adjusting for breast cancer treatment (HR, 2.4; 95% CI, 1.7 to 3.2). Although breast cancer-specific mortality was modestly elevated among childhood cancer survivors (HR, 1.3; 95% CI, 0.9 to 2.0), survivors were five times more likely to die as a result of other health-related causes, including other subsequent malignant neoplasms and cardiovascular or pulmonary disease (HR, 5.5; 95% CI, 3.4 to 9.0). The cumulative incidence of a second asynchronous breast cancer also was elevated significantly compared with controls (P < .001).Mortality after breast cancer was higher in childhood cancer survivors than in women with de novo breast cancer. This increased mortality reflects the burden of comorbidity and highlights the need for risk-reducing interventions.

  View details for DOI 10.1200/JCO.18.02219

  View details for Web of Science ID 000484327400004

  View details for PubMedID 31260644

  View details for PubMedCentralID PMC6698921

• Remodeling of Rectal Innervation After Pullthrough Surgery for Hirschsprung Disease: Relevance to Criteria for the Determination of Retained Transition Zone PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Kapur, R. P., Arnold, M. A., Conces, M. R., Ambartsumyan, L., Avansino, J., Levitt, M., Wood, R., Mast, K. J. 2019; 22 (4): 292-303

  Abstract

  After pullthrough surgery for Hirschsprung disease (HSCR), Glut1-positive submucosal nerve hypertrophy is used to diagnose retained transition zone in the neorectum. We hypothesized that pelvic nerves, severed during pullthrough surgery, sprout into the neorectum to mimic transition zone.The density (nerves/100x field) and maximum diameter of Glut1-positive submucosal nerves were measured in biopsies and redo resections from 20 patients with post-pullthrough obstructive symptoms. Their original and/or redo resections excluded unequivocal features of transition zone (myenteric hypoganglionosis or partial circumferential aganglionosis) in 17. Postoperative values were compared with control data from 28 cadaveric and 6 surgical non-HSCR specimens, and 14 primary HSCR resections. When possible, nerves were tracked from attached native pelvic soft tissue or aganglionic rectal cuff into the pulled-through colon.Glut1-positive submucosal nerves were not present in the 11 colons of non-HSCR infants less than 1 year of age, except sparsely in the rectum. In 17 older non-HSCR controls, occasional Glut1-positive nerves were observed in prerectal colon and were larger and more numerous in the rectum. In redo resections, Glut1-positive submucosal innervation in post-pullthrough specimens did not differ significantly from age-appropriate non-HSCR rectal controls and pelvic Glut1-positive nerves were never observed to penetrate the pulled-through colon. However, the density and caliber of Glut1-positive nerves in the neorectums were significantly greater than expected based on the prerectal location from which the pulled-through bowel originated.Submucosal innervation in post-pullthrough specimens does not support the hypothesis that native pelvic nerves innervate the neorectum, but suggests remodeling occurs to establish the age-appropriate density and caliber of rectal Glut1-positive innervation. The latter should not be interpreted as transition zone pullthrough in a rectal biopsy from a previously done pullthrough.

  View details for DOI 10.1177/1093526618817658

  View details for Web of Science ID 000474909000003

  View details for PubMedID 30541422

• Telomere Length-Associated Genetic Variants and the Risk of Thyroid Cancer in Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study (CCSS) CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Gramatges, M. M., Morton, L. M., Yasui, Y., Arnold, M. A., Neglia, J. P., Leisenring, W. M., Machiela, M. J., Dagnall, C. L., Chanock, S. J., Armstrong, G. T., Robison, L. L., Bhatia, S., Lupo, P. J. 2019; 28 (2): 417-419

  Abstract

  Given the inverse relationship described previously between telomere content and thyroid subsequent malignant neoplasm (thyroid SMN) in survivors of childhood cancer, we investigated the relationship between known genetic determinants of leukocyte telomere length (LTL) and thyroid SMN among survivors.Leveraging data from a large, genotyped survivor cohort, the Childhood Cancer Survivor Study, we used a well-described genetic risk score method to estimate the HR for thyroid SMN among 5,324 genotyped survivors.We identified 118 survivors with thyroid SMN and 5,206 without thyroid SMN. No association between genetically estimated LTL and risk for thyroid SMN was identified.Our results suggest that variation in common SNPs influencing LTL is not strongly associated with risk for thyroid SMN in survivors of childhood cancer.The previously observed inverse relationship between LTL and thyroid SMN risk in survivors of childhood cancer may be related to alternative molecular mechanisms and warrants further study.

  View details for DOI 10.1158/1055-9965.EPI-18-0972

  View details for Web of Science ID 000465321600021

  View details for PubMedID 30377209

  View details for PubMedCentralID PMC6363878

• Immune profiles of desmoplastic small round cell tumor and synovial sarcoma suggest different immunotherapeutic susceptibility upfront compared to relapse specimens PEDIATRIC BLOOD & CANCER Wedekind, M., Haworth, K. B., Arnold, M., Stanek, J. R., Lee, D., Cripe, T. P. 2018; 65 (11): e27313

  Abstract

  Desmoplastic small round cell tumor (DSRCT) and synovial sarcoma are rare tumors with dismal outcomes requiring new therapeutic strategies. Immunotherapies have shown promise in several cancer types, but have not been evaluated in DSRCT and synovial sarcoma. Because the immune microenvironment can provide indications of the inflammatory nature of tumors, immunohistochemical staining is able to assess the tumor immune infiltrates in both tumor types.Using tissue microarrays of DSRCT and synovial sarcoma tumor samples, we detected tumoral HLA-A/B/C, beta-2-microglobulin(B2M), and PD-L1 expression, and quantified tumor-infiltrating lymphocytes expressing CD4, CD8, CD56, CD45RO, or FOXP3 by immunohistochemistry. We used staining intensity on a scale of 0-3 and percentage of tumor stained to determine HLA, B2M, and PD-L1 scores. We calculated the cytotoxic T lymphocyte (CTL) target score as HLA score × B2M score/100.In diagnostic samples, we found high HLA and CTL target scores and low PD-L1 expression with decreased scores in recurrence for both tumor types. We found an increase in CD56+ natural killer cells in DSRCT samples from diagnosis to recurrence.We found similar immunostimulatory profiles in DSRCT and synovial sarcoma. Our findings suggest that DSRCT and synovial sarcoma may be amenable to immunotherapies, albeit there was significant heterogeneity. Interestingly, HLA and CTL target scores decreased at recurrence, possibly reflecting immunoevasion. Our findings suggest both tumor types may be amendable to CTL-based therapies at diagnosis but less so at relapse. Our results support further investigation into the prognostic and predictive value of these findings in a larger dataset.

  View details for DOI 10.1002/pbc.27313

  View details for Web of Science ID 000445194700018

  View details for PubMedID 30015384

• IL-6 and CXCL8 mediate osteosarcoma-lung interactions critical to metastasis JCI INSIGHT Gross, A. C., Cam, H., Phelps, D. A., Saraf, A. J., Bid, H. K., Cam, M., London, C. A., Winget, S. A., Arnold, M. A., Brandolini, L., Mo, X., Hinckley, J. M., Houghton, P. J., Roberts, R. D. 2018; 3 (16)

  Abstract

  Osteosarcoma (OS), a malignant tumor of bone, kills through aggressive metastatic spread almost exclusively to the lung. Mechanisms driving this tropism for lung tissue remain unknown, though likely invoke specific interactions between tumor cells and other cells within the lung metastatic niche. Aberrant overexpression of ΔNp63 in OS cells directly drives production of IL-6 and CXCL8. All these factors were expressed at higher levels in OS lung metastases than in matched primary tumors from the same patients. Expression in cell lines correlated strongly with lung colonization efficiency in murine xenograft models. Lentivirus-mediated expression endowed poorly metastatic OS cells with increased metastatic capacity. Disruption of IL-6 and CXCL8 signaling using genetic or pharmaceutical inhibitors had minimal effects on tumor cell proliferation in vitro or in vivo, but combination treatment inhibited metastasis across multiple models of metastatic OS. Strong interactions occurred between OS cells and both primary bronchial epithelial cells and bronchial smooth muscle cells that drove feed-forward amplification of IL-6 and CXCL8 production. These results identify IL-6 and CXCL8 as primary mediators of OS lung tropism and suggest pleiotropic, redundant mechanisms by which they might effect metastasis. Combination therapy studies demonstrate proof of concept for targeting these tumor-lung interactions to affect metastatic disease.

  View details for DOI 10.1172/jci.insight.99791

  View details for Web of Science ID 000442534200005

  View details for PubMedID 30135299

  View details for PubMedCentralID PMC6141177

• Histology, fusion status, and outcome in metastatic rhabdomyosarcoma: A report from the Children's Oncology Group PEDIATRIC BLOOD & CANCER Rudzinski, E. R., Anderson, J. R., Chi, Y., Gastier-Foster, J. M., Astbury, C., Barr, F. G., Skapek, S. X., Hawkins, D. S., Weigel, B. J., Pappo, A., Meyer, W. H., Arnold, M. A., Teot, L. A., Parham, D. M. 2017; 64 (12)

  Abstract

  Distinguishing alveolar rhabdomyosarcoma (ARMS) from embryonal rhabdomyosarcoma (ERMS) has historically been of prognostic and therapeutic importance. However, classification has been complicated by shifting histologic criteria required for an ARMS diagnosis. Children's Oncology Group (COG) studies after IRS-IV, which included the height of this diagnostic shift, showed both an increased number of ARMS and an increase in the proportion of fusion-negative ARMS. Following diagnostic standardization and histologic re-review of ARMS cases enrolled during this era, analysis of low-risk (D9602) and intermediate-risk (D9803) rhabdomyosarcoma (RMS) studies showed that fusion status rather than histology best predicts prognosis for patients with RMS. This analysis remains to be completed for patients with high-risk RMS.We re-reviewed cases on high-risk COG studies D9802 and ARST0431 with an enrollment diagnosis of ARMS. We compared the event-free survival (EFS) and overall survival by histology, PAX-FOXO1 fusion, and clinical risk factors (Oberlin score) for patients with metastatic RMS using the log-rank test.Histology re-review resulted in reclassification as ERMS for 12% of D9802 cases and 5% of ARST0431 cases. Fusion-negative RMS had a superior EFS to fusion-positive RMS; however, poorer outcome for metastatic RMS was most related to clinical risk factors including age, primary site, and number of metastatic sites.In contrast to low- or intermediate-risk RMS, in metastatic RMS, clinical risk factors have the most impact on patient outcome. PAX-FOXO1 fusion is more common in patients with a high Oberlin score, but fusion status is not an independent biomarker of prognosis.

  View details for DOI 10.1002/pbc.26645

  View details for Web of Science ID 000413372700011

  View details for PubMedID 28521080

  View details for PubMedCentralID PMC5647228

• If You Are Not on Social Media, Here's What You're Missing! #DoTheThing ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Freitag, C., Arnold, M. A., Gardner, J. M., Arnold, C. A. 2017; 141 (11): 1567-1576

  View details for DOI 10.5858/arpa.2016-0612-SA

  View details for Web of Science ID 000417031100017

  View details for PubMedID 28380306

• Immune profiling of NF1-associated tumors reveals histologic subtype distinctions and heterogeneity: implications for immunotherapy ONCOTARGET Haworth, K. B., Arnold, M. A., Pierson, C. R., Choi, K., Yeager, N. D., Ratner, N., Roberts, R. D., Finlay, J. L., Cripe, T. P. 2017; 8 (47): 82037-82048

  Abstract

  Successful treatment of neurofibromatosis type 1 (NF1)-associated tumors poses a significant clinical challenge. While the primary underlying genetic defect driving RAS signaling is well described, recent evidence suggests immune dysfunction contributes to tumor pathogenesis and malignant transformation. As immunologic characterizations, prognostic and predictive of immunotherapeutic clinical response in other cancers, are not fully described for benign and malignant NF1-related tumors, we sought to define their immunologic profiles. We determined the expression of human leukocyte antigen (HLA)-A/-B/-C, β-2-microglobulin (B2M), and T cell inhibitory ligands PD-L1 and CTLA-4 by microarray gene analysis and flow cytometry. We examined HLA-A/-B/-C, B2M, and PD-L1 expression on thirty-six NF1-associated tumor samples by immunohistochemistry, and correlated these with tumoral CD4+, CD8+, FOXP3+, CD56+, and CD45RO+ lymphocytic infiltrates. We evaluated several tumors from a single patient, observing trends of increasing immunogenicity over time, even with disease progression. We observed similarly immunogenic profiles for malignant peripheral nerve sheath tumors (MPNST) and nodular and plexiform neurofibromas, contrasting with diffuse neurofibromas. These studies suggest that while immunotherapies may offer some benefit for MPNST and nodular and plexiform neurofibromas, tumor heterogeneity might pose a significant clinical challenge to this novel therapeutic approach.

  View details for DOI 10.18632/oncotarget.18301

  View details for Web of Science ID 000412683900034

  View details for PubMedID 29137242

  View details for PubMedCentralID PMC5669868

• Crospovidone and Microcrystalline Cellulose A <i>Novel Description of Pharmaceutical Fillers in the Gastrointestinal Tract</i> AMERICAN JOURNAL OF SURGICAL PATHOLOGY Shaddy, S. M., Arnold, M. A., Shilo, K., Frankel, W. L., Harzman, A. E., Stanich, P. P., Singhi, A. D., Yearsley, M. M., Arnold, C. A. 2017; 41 (4): 564-569

  Abstract

  Crospovidone and microcrystalline cellulose (MCC) are pharmaceutical fillers well known in the pulmonary pathology literature. Fillers are inactive substances incorporated into medications to facilitate drug delivery. By examining 545 consecutive gastrointestinal surgical specimens from 302 patients between September 11, 2015 and October 23, 2015, we identified the fillers in 29 specimens from 26 patients. The control group consisted of an equal number of consecutive site-matched specimens collected during this same time. Pertinent clinicopathologic data were analyzed, and 1 case was subject to special stains. To confirm the histologic diagnosis, a variety of fillers and medications common to the patients were processed. The fillers were found in 9% of all patients, and there were no specific clinicopathologic associations. In the gastrointestinal tract, crospovidone is nonbirefringent and has a coral shape with each segment composed of a pink core and purple coat; MCC is brightly birefringent with matchstick shape and clear color. Identical material was seen in the processed crospovidone and MCC powders, as well as oxycodone-acetaminophen and omeprazole tablets. In summary, crospovidone and MCC are common, biologically inert, and they are most often seen in the small bowel. Their presence outside of the luminal bowel may serve as a surrogate marker for perforation. Awareness of their morphology is important to distinguish fillers from parasites, calcifications, and other medications, particularly those linked to mucosal injury. We report the unique histomorphologic profile of these fillers as a helpful diagnostic aide, and caution that the fillers have slightly divergent features when compared with those described in the lung.

  View details for DOI 10.1097/PAS.0000000000000790

  View details for Web of Science ID 000397829600016

  View details for PubMedID 28009603

• Renal Tumors in Children Younger Than 12 Months of Age: A 65-Year Single Institution Review JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Lamb, M. G., Aldrink, J. H., O'Brien, S. H., Yin, H., Arnold, M. A., Ranalli, M. A. 2017; 39 (2): 103-107

  Abstract

  Wilms tumor (WT) is the most prevalent pediatric renal tumor and most commonly occurs between ages 1 and 5 years. Data are lacking on children younger than 12 months with renal tumors. The cancer registry at the authors' institution was queried to identify patients 12 months and younger with renal masses. Demographics, clinical presentation, histopathology, stage, and survival outcomes were reviewed. The most common presenting symptoms included an asymptomatic abdominal mass (73%) and hematuria (9%). Histopathology revealed WT in 73% of patients, mesoblastic nephroma in 20%. Of those infants younger than 1 month of age, mesoblastic nephroma was the most common histopathology (68%). The 5-year overall survival (OS) was 93%, and 5-year event-free survival (EFS) was 93% for the entire group. For patients with WT, 5-year OS was 88% and 5-year EFS was 83%. Outcomes for congenital mesoblastic nephroma were excellent with 5-year OS and EFS of 100%. Reasons for good prognosis may be multifactorial and may include frequent well child checks in the first year of life and favorable histology. Patients in this age group are more likely to be classified as very low risk and may be treated with surgical resection alone.

  View details for DOI 10.1097/MPH.0000000000000698

  View details for Web of Science ID 000394572000019

  View details for PubMedID 27820132

• Temporal Trends in Treatment and Subsequent Neoplasm Risk Among 5-Year Survivors of Childhood Cancer, 1970-2015 JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Turcotte, L. M., Liu, Q., Yasui, Y., Arnold, M. A., Hammond, S., Howell, R. M., Smith, S. A., Weathers, R. E., Henderson, T. O., Gibson, T. M., Leisenring, W., Armstrong, G. T., Robison, L. L., Neglia, J. P. 2017; 317 (8): 814-824

  Abstract

  Cancer treatments are associated with subsequent neoplasms in survivors of childhood cancer. It is unknown whether temporal changes in therapy are associated with changes in subsequent neoplasm risk.To quantify the association between temporal changes in treatment dosing and subsequent neoplasm risk.Retrospective, multicenter cohort study of 5-year cancer survivors diagnosed before age 21 years from pediatric tertiary hospitals in the United States and Canada between 1970-1999, with follow-up through December 2015.Radiation and chemotherapy dose changes over time.Subsequent neoplasm 15-year cumulative incidence, cumulative burden, and standardized incidence ratios for subsequent malignancies, compared by treatment decade. Multivariable models assessed relative rates (RRs) of subsequent neoplasms by 5-year increments, adjusting for demographic and clinical characteristics. Mediation analyses assessed whether changes in rates of subsequent neoplasms over time were mediated by treatment variable modifications.Among 23 603 survivors of childhood cancer (mean age at diagnosis, 7.7 years; 46% female) the most common initial diagnoses were acute lymphoblastic leukemia, Hodgkin lymphoma, and astrocytoma. During a mean follow-up of 20.5 years (374 638 person-years at risk), 1639 survivors experienced 3115 subsequent neoplasms, including 1026 malignancies, 233 benign meningiomas, and 1856 nonmelanoma skin cancers. The most common subsequent malignancies were breast and thyroid cancers. Proportions of individuals receiving radiation decreased (77% for 1970s vs 33% for 1990s), as did median dose (30 Gy [interquartile range, 24-44] for 1970s vs 26 Gy [interquartile range, 18-45] for 1990s). Fifteen-year cumulative incidence of subsequent malignancies decreased by decade of diagnosis (2.1% [95% CI, 1.7%-2.4%] for 1970s, 1.7% [95% CI, 1.5%-2.0%] for 1980s, 1.3% [95% CI, 1.1%-1.5%] for 1990s). Reference absolute rates per 1000 person-years were 1.12 (95% CI, 0.84-1.57) for subsequent malignancies, 0.16 (95% CI, 0.06-0.41) for meningiomas, and 1.71 (95% CI, 0.88-3.33) for nonmelanoma skin cancers for survivors with reference characteristics (no chemotherapy, splenectomy, or radiation therapy; male; attained age 28 years). Standardized incidence ratios declined for subsequent malignancies over treatment decades, with advancing attained age. Relative rates declined with each 5-year increment for subsequent malignancies (RR, 0.87 [95% CI, 0.82-0.93]; P < .001), meningiomas (RR, 0.85 [95% CI, 0.75-0.97]; P = .03), and nonmelanoma skin cancers (RR, 0.75 [95% CI, 0.67-0.84]; P < .001). Radiation dose changes were associated with reduced risk for subsequent malignancies, meningiomas, and nonmelanoma skin cancers.Among survivors of childhood cancer, the risk of subsequent malignancies at 15 years after initial cancer diagnosis remained increased for those diagnosed in the 1990s, although the risk was lower compared with those diagnosed in the 1970s. This lower risk was associated with reduction in therapeutic radiation dose.

  View details for DOI 10.1001/jama.2017.0693

  View details for Web of Science ID 000395505600019

  View details for PubMedID 28245323

  View details for PubMedCentralID PMC5473951

• Molecular diagnostics in the management of rhabdomyosarcoma EXPERT REVIEW OF MOLECULAR DIAGNOSTICS Arnold, M. A., Barr, F. G. 2017; 17 (2): 189-194

  Abstract

  A classification of rhabdomyosarcoma (RMS) with prognostic relevance has primarily relied on clinical features and histologic classification as either embryonal or alveolar RMS. The PAX3-FOXO1 and PAX7-FOXO1 gene fusions occur in 80% of cases with the alveolar subtype and are more predictive of outcome than histologic classification. Identifying additional molecular hallmarks that further subclassify RMS is an active area of research. Areas Covered: The authors review the current state of the PAX3-FOXO1 and PAX7-FOXO1 fusions as prognostic biomarkers. Emerging biomarkers, including mRNA expression profiling, MYOD1 mutations, RAS pathway mutations and gene fusions involving NCOA2 or VGLL2 are also reviewed. Expert commentary: Strategies for modifying RMS risk stratification based on molecular biomarkers are emerging with the potential to transform the clinical management of RMS, ultimately improving patient outcomes by tailoring therapy to predicted patient risk and identifying targets for novel therapies.

  View details for DOI 10.1080/14737159.2017.1275965

  View details for Web of Science ID 000393890300010

  View details for PubMedID 28058850

  View details for PubMedCentralID PMC5657295

• Challenges to "Classic" Esophageal Candidiasis AMERICAN JOURNAL OF CLINICAL PATHOLOGY Alsomali, M. I., Arnold, M. A., Frankel, W. L., Graham, R. P., Hart, P. A., Lam-Himlin, D. M., Naini, B. V., Voltaggio, L., Arnold, C. A. 2017; 147 (1): 33-42

  Abstract

  We undertook the first case control study of histologically confirmed esophageal candidiasis (EC).A computer search from July 2012 through February 2015 identified 1,011 esophageal specimens, including 40 cases of EC and 20 controls.The EC incidence was 5.2%; it was associated with immunosuppression and endoscopic white plaques and breaks. Smoking was a predisposing factor, and alcohol was protective. EC had no unique symptoms, and 54% of endoscopic reports did not suspect EC. Important histologic clues included superficial and detached fragments of desquamated and hyper-pink parakeratosis, acute inflammation, intraepithelial lymphocytosis, dead keratinocytes, and bacterial overgrowth. Thirty percent had no neutrophilic infiltrate. Pseudohyphae were seen on H&E in 92.5% (n = 37/40). "Upfront" periodic acid-Schiff with diastase (PAS/D) on all esophageal specimens would have generated $68,333.49 in patient charges. Our targeted PAS/D strategy resulted in $13,044.87 in patient charges (cost saving = 80.9%, $55,288.62).We describe the typical morphology of EC and recommend limiting PAS/D to cases where the organisms are not readily identifiable on H&E and with at least one of the following: (1) ulcer, (2) suspicious morphology, and/or (3) clinical impression of EC.

  View details for DOI 10.1093/AJCP/AQW210

  View details for Web of Science ID 000397091400004

  View details for PubMedID 28158394

• A Strategy for <i>Helicobacter</i> llimanmanneckelegcchsetralisthru Utilization in Pediatric-emetics AMERICAN JOURNAL OF CLINICAL PATHOLOGY Conces, M. R., Arnold, C. A., Baker, P. B., Carter, C. M., Fung, B., Prasad, V., Arnold, M. A. 2016; 146 (5): 611-617

  Abstract

  Recent studies in adults have examined the utility of immunohistochemistry (IHC) in detecting Helicobacter in gastric biopsy specimens and reached differing conclusions. Dedicated cost-benefit analysis of Helicobacter IHC in pediatric gastric biopsy specimens has not been performed.From 1,955 pediatric gastric biopsies in a 1-year period, we identified 63 Helicobacter -positive and 120 Helicobacter -negative biopsy specimens. All cases were scored according to the Updated Sydney System for the severity of inflammation.We observed that pediatric Helicobacter infection was significantly associated with germinal center formation, active inflammation, oxyntic mucosa with moderate to severe chronic inflammation, and antral mucosa with any chronic inflammation, exclusive of mild and superficial chronic inflammation. At least one associated pattern was seen in each Helicobacter -positive biopsy specimen. In comparison with adults, pediatric Helicobacter -positive biopsy specimens are more likely to lack acute inflammation and more likely to show moderate to marked chronic inflammation.We recommend performing Helicobacter IHC on pediatric gastric biopsy specimens with any of the above inflammatory patterns. This approach can sensitively identify pediatric patients with Helicobacter gastritis, limit IHC staining to approximately 30% of all gastric biopsy specimens, and reduce costs by up to $55,306.90 per 1,000 biopsy specimens.

  View details for DOI 10.1093/AJCP/AQW149

  View details for Web of Science ID 000389389800013

  View details for PubMedID 28430952

• Histology, Fusion Status, and Outcome in Alveolar Rhabdomyosarcoma With Low-Risk Clinical Features: A Report From the Children's Oncology Group PEDIATRIC BLOOD & CANCER Arnold, M. A., Anderson, J. R., Gastier-Foster, J. M., Barr, F. G., Skapek, S. X., Hawkins, D. S., Raney, R., Parham, D. M., Teot, L. A., Rudzinski, E. R., Walterhouse, D. O. 2016; 63 (4): 634-639

  Abstract

  Distinguishing alveolar rhabdomyosarcoma (ARMS) from embryonal rhabdomyosarcoma (ERMS) is of prognostic and therapeutic importance. Criteria for classifying these entities evolved significantly from 1995 to 2013. ARMS is associated with inferior outcome; therefore, patients with alveolar histology have generally been excluded from low-risk therapy. However, patients with ARMS and low-risk stage and group (Stage 1, Group I/II/orbit III; or Stage 2/3, Group I/II) were eligible for the Children's Oncology Group (COG) low-risk rhabdomyosarcoma (RMS) study D9602 from 1997 to 1999. The characteristics and outcomes of these patients have not been previously reported, and the histology of these cases has not been reviewed using current criteria.We re-reviewed cases that were classified as ARMS on D9602 using current histologic criteria, determined PAX3/PAX7-FOXO1 fusion status, and compared these data with outcome for this unique group of patients.Thirty-eight patients with ARMS were enrolled onto D9602. Only one-third of cases with slides available for re-review (11/33) remained classified as ARMS by current histologic criteria. Most cases were reclassified as ERMS (17/33, 51.5%). Cases that remained classified as ARMS were typically fusion-positive (8/11, 73%), therefore current classification results in a similar rate of fusion-positive ARMS for all clinical risk groups. In conjunction with data from COG intermediate-risk treatment protocol D9803, our data demonstrate excellent outcomes for fusion-negative ARMS with otherwise low-risk clinical features.Patients with fusion-positive RMS with low-risk clinical features should be classified and treated as intermediate risk, while patients with fusion-negative ARMS could be appropriately treated with reduced intensity therapy.

  View details for DOI 10.1002/pbc.25862

  View details for Web of Science ID 000370497100011

  View details for PubMedID 26756883

  View details for PubMedCentralID PMC4755849

• Characterization of MHC Class I and-2-Microglobulin Expression in Pediatric Solid Malignancies to Guide Selection of Immune-Based Therapeutic Trials PEDIATRIC BLOOD & CANCER Haworth, K. B., Arnold, M. A., Pierson, C. R., Leddon, J. L., Kurmashev, D. K., Swain, H. M., Hutzen, B. J., Roberts, R. D., Cripe, T. P. 2016; 63 (4): 618-626

  Abstract

  Over 10,000 US children are diagnosed with cancer yearly. Though outcomes have improved by optimizing conventional therapies, recent immunotherapeutic successes in adult cancers are emerging. Cytotoxic T lymphocytes (CTLs) are the primary executioners of adaptive antitumor immunity and require antigenic presentation in the context of major histocompatibility complex (MHC) class I and the associated β-2-microglobulin (B2M). Loss of MHC I expression is a common immune escape mechanism in adult malignancies, but pediatric cancers have not been thoroughly characterized. The essential nature of MHC I expression in CTL-mediated cell death may dictate the success of immunotherapies, which rely on eliciting an adaptive response.We queried pediatric tumor microarray databases for MHC I and B2M gene expression. We detected MHC I in pediatric tumor cell lines by flow cytometry and characterized MHC I and B2M expression in patient samples by immunohistochemistry. To determine whether therapeutic approaches might enhance MHC I expression in selected models in vitro, we tested effects of exposure to IFN-γ and histone deacetylase inhibitors.Pediatric tumors overall, as well as samples within select individual tumor subtypes, exhibit wide ranges of MHC I and B2M gene and protein expression. For most cell lines tested, MHC I was inducible in vitro.MHC I and B2M expression vary among pediatric tumor types and should be evaluated as potential biomarkers, which might identify patients most likely to benefit from MHC I dependent immunotherapies. Modulation of MHC I expression may be a promising mechanism for enhancing MHC I dependent immunotherapeutic efficacy.

  View details for DOI 10.1002/pbc.25842

  View details for Web of Science ID 000370497100009

  View details for PubMedID 26575538

• Neuroblastomas vary widely in their sensitivities to herpes simplex virotherapy unrelated to virus receptors and susceptibility GENE THERAPY Wang, P., Swain, H. M., Kunkler, A. L., Chen, C., Hutzen, B. J., Arnold, M. A., Streby, K. A., Collins, M. H., Dipasquale, B., Stanek, J. R., Conner, J., van Kuppevelt, T. H., Glorioso, J. C., Grandi, P., Cripe, T. P. 2016; 23 (2): 135-143

  Abstract

  Although most high-risk neuroblastomas are responsive to chemotherapy, relapse is common and long-term survival is < 40%, underscoring the need for more effective treatments. We evaluated the responsiveness of 12 neuroblastoma cell lines to the Δγ134.5 attenuated oncolytic herpes simplex virus (oHSV), Seprehvir (HSV1716), which is currently used in pediatric phase I trials. We found that entry of Seprehvir in neuroblastoma cells is independent of the expression of nectin-1 and the sum of all four known major HSV entry receptors. We observed varying levels of sensitivity and permissivity to Seprehvir, suggesting that the cellular anti-viral response, not virus entry, is the key determinant of efficacy with this virus. In vivo, we found significant anti-tumor efficacy following Seprehvir treatment, which ranged from 6/10 complete responses in the CHP-134 model to a mild prolonged median survival in the SK-N-AS model. Taken together, these data suggest that anti-tumor efficacy cannot be solely predicted based on in vitro response. Whether or not this discordance holds true for other viruses or tumor types is unknown. Our results also suggest that profiling the expression of known viral entry receptors on neuroblastoma cells may not be entirely predictive of their susceptibility to Seprehvir therapy.

  View details for DOI 10.1038/gt.2015.105

  View details for Web of Science ID 000369549500003

  View details for PubMedID 26583803

  View details for PubMedCentralID PMC4742391

• Neutropenic Enterocolitis <i>New Insights Into a Deadly Entity</i> AMERICAN JOURNAL OF SURGICAL PATHOLOGY Sachak, T., Arnold, M. A., Naini, B. V., Graham, R. P., Shah, S. S., Cruise, M., Park, J. Y., Clark, L., Lamps, L., Frankel, W. L., Theodoropoulos, N., Arnold, C. A. 2015; 39 (12): 1635-1642

  Abstract

  Neutropenic enterocolitis (NE) is a deadly ileocecal-based disease seen in patients with a recent history of chemotherapy. As histology is not included in the current diagnostic criteria, the pathologic features of NE are poorly understood. We undertook a multi-institutional study of NE, and report helpful clinical clues, such as immunosuppression (n=20/20), recent chemotherapy (n=17/18), neutropenia (n=16/18) gastrointestinal symptoms (n=19/19), abnormal imaging studies of the cecum/right colon (n=11/14), and positive microbiological studies (n=13/15). Fever (n=9/15) and sepsis (n=8/16) were also common. Pathologically, the cecum/right colon was always involved (n=17/17), but findings were identified in other bowel segments as well. NE lesions consisted of patchy necrosis (n=18/20), infiltrating organisms (n=17/20), hemorrhage (n=15/20), ulcer (n=15/19), edema (n=15/20), and depletion of inflammatory cells (n=15/20). Seventy-nine percent (n=15/19) of patients with histologically confirmed NE died: 47% (n=7/15) of these deaths were attributed to NE and the remainder to the patients' underlying conditions. Importantly, we observed a clinical diagnostic discordancy rate of 35% (n=9/26): 15% (n=3/20) of histologically confirmed NE were clinically unsuspected, and 26% (n=6/23) of clinically suspected NE represented a different disease process. Alternative diagnoses included unspecified colitis, infection, graft-versus-host disease, relapsed malignancy, mycophenolate injury, appendicitis, and ischemia. The causes of death in patients with NE mimics included unrecognized appendicitis and unrecognized graft-versus-host disease. To improve diagnostic accuracy, we propose that histology be required for a diagnosis of "definitive NE," with other clinically suspicious cases reported as "suspicious for NE" until all other possible diagnoses have been reasonably excluded.

  View details for DOI 10.1097/PAS.0000000000000517

  View details for Web of Science ID 000365627200004

  View details for PubMedID 26414225

• Initial testing (stage 1) of the tubulin binding agent nanoparticle albumin-bound (<i>nab</i>) paclitaxel (Abraxane<SUP>®</SUP>) by the Pediatric Preclinical Testing Program (PPTP) PEDIATRIC BLOOD & CANCER Houghton, P. J., Kurmasheva, R. T., Kolb, E., Gorlick, R., Maris, J. M., Wu, J., Tong, Z., Arnold, M. A., Chatterjee, M., Williams, T. M., Smith, M. A. 2015; 62 (7): 1214-1221

  Abstract

  Nanoparticle albumin-bound paclitaxel (nab-paclitaxel, Abraxane(®)) is FDA approved for the treatment of several adult cancers. Antimitotic agents are essential components for curative therapy of pediatric solid tumors, although taxanes have shown limited activity. Because of the novel formulation, nab-paclitaxel was evaluated against a limited series of Pediatric Preclinical Testing Program (PPTP) solid tumors.Nab-paclitaxel was tested against a limited subset of PPTP solid tumor xenograft models at a dose of 50 mg/kg using a q4d × 3 schedule intravenously.Nab-paclitaxel was well tolerated in vivo, producing maximum weight loss of approximately 10% with recovery to baseline weight in the week following the third dose. All 20 xenograft models tested were considered evaluable for efficacy. Nab-paclitaxel induced statistically significant differences in event-free survival (EFS) distribution compared to control in 19 of 20 (95%) of the solid tumors. Objective responses were observed in 12 of 20 (60%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in 5 of 8 Ewing sarcoma models and 6 of 8 rhabdomyosarcomas. There were no objective regressions in either neuroblastoma (n = 2) or osteosarcoma (n = 2) xenograft panels. At the dose tested, systemic exposures of nab-paclitaxel in mice were somewhat greater than those tolerated in humans.The high level of activity observed against the rhabdomyosarcoma and Ewing sarcoma PPTP preclinical models makes nab-paclitaxel an interesting agent to consider for pediatric evaluation.

  View details for DOI 10.1002/pbc.25474

  View details for Web of Science ID 000354541600021

  View details for PubMedID 25809532

  View details for PubMedCentralID PMC4563818

• The oncogenic role of the cochaperone Sgt1 ONCOGENESIS Ogi, H., Sakuraba, Y., Kitagawa, R., Xiao, L., Shen, C., Cynthia, M. A., Ohta, S., Arnold, M. A., Ramirez, N., Houghton, P. J., Kitagawa, K. 2015; 4: e149

  Abstract

  Sgt1/Sugt1, a cochaperone of Hsp90, is involved in several cellular activities including Cullin E3 ubiqutin ligase activity. The high level of Sgt1 expression in colorectal and gastric tumors suggests that Sgt1 is involved in tumorigenesis. Here, we report that Sgt1 is overexpressed in colon, breast and lung tumor tissues and in Ewing sarcoma and rhabdomyosarcoma xenografts. We also found that Sgt1 heterozygous knockout resulted in suppressed Hras-mediated transformation in vitro and tumor formation in p53(-/-) mouse embryonic fibroblast cells and significantly increased survival of p53(-/-) mice. Moreover, depletion of Sgt1 inhibited the growth of Ewing sarcoma and rhabdomyosarcoma cells and destabilized EWS-FLI1 and PAX3-FOXO1 oncogenic fusion proteins, respectively, which are required for cellular growth. Our results suggest that Sgt1 contributes to cancer development by stabilizing oncoproteins and that Sgt1 is a potential therapeutic target.

  View details for DOI 10.1038/oncsis.2015.12

  View details for Web of Science ID 000355332600001

  View details for PubMedID 25985210

  View details for PubMedCentralID PMC4450263

• The Bethesda System for Reporting Thyroid Cytopathology Is Applicable to Frozen Section Diagnosis in Children PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Arnold, M. A., Nicol, K. K. 2015; 18 (2): 139-145

  Abstract

  The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) offers standardized and widely understood diagnostic categories for reporting thyroid cytology diagnoses. We compared the utility of TBSRTC categories in pediatric cytology diagnoses and pediatric intraoperative frozen section diagnoses. We examined the experience of our primary and referral care center over a 20-year period. This included 182 thyroidectomy patients who underwent 64 preoperative fine-needle aspirations and 91 intraoperative frozen section evaluations, including 38 patients evaluated sequentially by each method. All diagnoses were retrospectively reclassified into TBSRTC categories and correlated with the final thyroidectomy diagnoses. For each sampling method, malignant final diagnoses were observed at similar frequencies to rates predicted by TBSRTC. Malignant final diagnoses following fine-needle aspiration or frozen section diagnoses in TBSRTC categories other than malignant or suspicious for malignancy most often resulted from difficulty in detecting papillary carcinoma, including difficulty detecting the nuclear characteristics of papillary carcinoma in frozen sections. The limitations of needle biopsy and frozen section evaluations differ, yet serial utilization of these procedures was rarely informative. Based on the experience of our institution, classification of cytology and frozen section diagnosis by TBSRTC predicts a risk of malignancy similar to the guidance offered by TBSRTC. We recommend including a TBSRTC category when reporting either thyroid cytology or frozen section diagnoses in children.

  View details for DOI 10.2350/14-08-1542-OA.1

  View details for Web of Science ID 000353068800009

  View details for PubMedID 25625563

• The College of American Pathologists Guidelines for Whole Slide Imaging Validation Are Feasible for Pediatric Pathology: A Pediatric Pathology Practice Experience PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Arnold, M. A., Chenever, E., Baker, P. B., Boue, D. R., Fung, B., Hammond, S., Hendrickson, B. W., Kahwash, S. B., Pierson, C. R., Prasad, V., Nicol, K. K., Barr, T. 2015; 18 (2): 109-116

  Abstract

  Whole slide imaging (WSI) is rapidly transforming educational and diagnostic pathology services. Recently, the College of American Pathologists Pathology and Laboratory Quality Center (CAP-PLQC) published recommended guidelines for validating diagnostic WSI. We prospectively evaluated the guidelines to determine their utility in validating pediatric surgical pathology and cytopathology specimens. Our validation included varied pediatric specimen types, including complex or less common diagnoses, in accordance with the guidelines. We completed WSI review of 60 surgical pathology cases and attempted WSI review of 21 cytopathology cases. For surgical pathology cases, WSI diagnoses were highly concordant with glass slide diagnoses; a discordant diagnosis was observed in 1 of 60 cases (98.3% concordance). We found that nucleated red blood cells and eosinophilic granular bodies represented specific challenges to WSI review of pediatric specimens. Cytology specimens were more frequently discordant or failed for technical reasons, with overall concordance of 66.7%. Review of pediatric cytopathology specimens will likely require image capture in multiple focal planes. This study is the first to specifically evaluate WSI review for pediatric specimens and demonstrates that specimens representing the spectrum of pediatric surgical pathology practice can be reviewed using WSI. Our application of the proposed CAP-PLQC guidelines to pediatric surgical pathology specimens is, to our knowledge, the first prospective implementation of the CAP-PLQC guidelines.

  View details for DOI 10.2350/14-07-1523-OA.1

  View details for Web of Science ID 000353068800005

  View details for PubMedID 25387255

• Oncolytic HSV virotherapy in murine sarcomas differentially triggers an antitumor T-cell response in the absence of virus permissivity MOLECULAR THERAPY-ONCOLYTICS Leddon, J. L., Chen, C., Currier, M. A., Wang, P., Jung, F. A., Denton, N. L., Cripe, K. M., Haworth, K. B., Arnold, M. A., Gross, A. C., Eubank, T. D., Goins, W. F., Glorioso, J. C., Cohen, J. B., Grandi, P., Hildeman, D. A., Cripe, T. P. 2015; 2: 14010

  Abstract

  Multiple studies have indicated that in addition to direct oncolysis, virotherapy promotes an antitumor cytotoxic T cell response important for efficacy. To study this phenomenon further, we tested three syngeneic murine sarcoma models that displayed varied degrees of permissiveness to oncolytic herpes simplex virus replication and cytotoxicity in vitro, with the most permissive being comparable to some human sarcoma tumor lines. The in vivo antitumor effect ranged from no or modest response to complete tumor regression and protection from tumor rechallenge. The in vitro permissiveness to viral oncolysis was not predictive of the in vivo antitumor effect, as all three tumors showed intact interferon signaling and minimal permissiveness to virus in vivo. Tumor shrinkage was T-cell mediated with a tumor-specific antigen response required for maximal antitumor activity. Further analysis of the innate and adaptive immune microenvironment revealed potential correlates of susceptibility and resistance, including favorable and unfavorable cytokine profiles, differential composition of intratumoral myeloid cells, and baseline differences in tumor cell immunogenicity and tumor-infiltrating T-cell subsets. It is likely that a more complete understanding of the interplay between the immunologic immune microenvironment and virus infection will be necessary to fully leverage the antitumor effects of this therapeutic platform.

  View details for DOI 10.1038/mto.2014.10

  View details for Web of Science ID 000389432300001

  View details for PubMedID 27119100

  View details for PubMedCentralID PMC4782947

• Gastrointestinal Tract-derived Pulse Granulomata Clues to an Underrecognized Pseudotumor AMERICAN JOURNAL OF SURGICAL PATHOLOGY Nowacki, N. B., Arnold, M. A., Frankel, W. L., Harzman, A., Limketkai, B. N., Yearsley, M. M., Arnold, C. A. 2015; 39 (1): 84-92

  Abstract

  Pulse granulomata (PG) in the lung and oral pathology literature are presumed due to food (pulse) introduced by mucosal injury. Herein, we report the largest series of PG in the gastrointestinal tract (GIT): 22 resections were prospectively collected from 17 patients (8 men, range=28 to 85 y). All patients had a history of intestinal injury/disease: diverticulitis, fistula, adenocarcinoma, perforation, ulcerative colitis, appendicitis, anastomotic site leak, and/or stent leak. Nine of 22 specimens were designated "masses"; most of these were clinically concerning for neoplasia. Sites of involvement included the small and large intestine, appendix, liver, gallbladder, mesentery, omentum, peritoneum, cervix, ovary, and skin. PG were typically nodular (21/22) and multifocal (15/22); most involved the external surface of the bowel (20/22), and they ranged in size from 1.5 to 100 mm. Histologically, they contained variable amounts of hyaline ribbons and rings, inflammation, foreign body giant cells, calcifications, and food; larger lesions displayed circumferential stellate fibrosis (12/22). We describe 3 morphologic variants: hyaline predominant (mimicking amyloid), cellular predominant (mimicking spindle cell neoplasms), and sclerosing mesenteritis-like. All patients are alive and well at the time of follow-up. Histologically processed legumes showed similar structures as those identified in PG, providing support for an entrapped food origin. In summary, we detail important clinicopathologic clues, describe the PG morphologic spectrum, and demonstrate how to distinguish PG from their mimics. Although PG can present as clinically concerning masses, we conclude that they are pseudotumors arising secondary to entrapped food introduced through mucosal trauma, similar to their lung and oral counterparts.

  View details for Web of Science ID 000346768600009

  View details for PubMedID 25118813

• Gastrointestinal Tract-derived Pulse Granulomata <i>Clues to an Underrecognized Pseudotumor</i> AMERICAN JOURNAL OF SURGICAL PATHOLOGY Nowacki, N. B., Arnold, M. A., Frankel, W. L., Harzman, A., Limketkai, B. N., Yearsley, M. M., Arnold, C. A. 2015; 39 (1): 84-92

  Abstract

  Pulse granulomata (PG) in the lung and oral pathology literature are presumed due to food (pulse) introduced by mucosal injury. Herein, we report the largest series of PG in the gastrointestinal tract (GIT): 22 resections were prospectively collected from 17 patients (8 men, range=28 to 85 y). All patients had a history of intestinal injury/disease: diverticulitis, fistula, adenocarcinoma, perforation, ulcerative colitis, appendicitis, anastomotic site leak, and/or stent leak. Nine of 22 specimens were designated "masses"; most of these were clinically concerning for neoplasia. Sites of involvement included the small and large intestine, appendix, liver, gallbladder, mesentery, omentum, peritoneum, cervix, ovary, and skin. PG were typically nodular (21/22) and multifocal (15/22); most involved the external surface of the bowel (20/22), and they ranged in size from 1.5 to 100 mm. Histologically, they contained variable amounts of hyaline ribbons and rings, inflammation, foreign body giant cells, calcifications, and food; larger lesions displayed circumferential stellate fibrosis (12/22). We describe 3 morphologic variants: hyaline predominant (mimicking amyloid), cellular predominant (mimicking spindle cell neoplasms), and sclerosing mesenteritis-like. All patients are alive and well at the time of follow-up. Histologically processed legumes showed similar structures as those identified in PG, providing support for an entrapped food origin. In summary, we detail important clinicopathologic clues, describe the PG morphologic spectrum, and demonstrate how to distinguish PG from their mimics. Although PG can present as clinically concerning masses, we conclude that they are pseudotumors arising secondary to entrapped food introduced through mucosal trauma, similar to their lung and oral counterparts.

  View details for Web of Science ID 000346768600009

  View details for PubMedID 25118813

• Colesevelam and Colestipol <i>Novel Medication Resins in the Gastrointestinal</i> AMERICAN JOURNAL OF SURGICAL PATHOLOGY Arnold, M. A., Swanson, B. J., Crowder, C. D., Frankel, W. L., Lam-Himlin, D., Singhi, A. D., Stanich, P. P., Arnold, C. A. 2014; 38 (11): 1530-1537

  Abstract

  We report the morphologic description of the bile acid sequestrants (BAS) colesevelam and colestipol, as well as the largest series of cholestyramine. Histologically similar medication resins from 4 institutions were prospectively collected over 1 year (26 specimens, 15 patients). Comorbidities included hyperlipidemia (4/15), hypertension (4/15), inflammatory bowel disease (4/15), coronary artery disease (3/15), diarrhea (7/15), hypothyroidism (2/15), and ischemic bowel (1/15). Sites of involvement included the esophagus (1/26), stomach (1/26), small intestine (1/26), ileocecal valve (1/26), and colorectum (22/26). Associated histologic diagnoses included normal (8/26), chronic mucosal injury (11/26), acute inflammation (9/26), erosion/ulceration (6/26), and cytomegalovirus (2/26). The BAS resins were histologically indistinguishable from each other; they were all eosinophilic on hematoxylin and eosin (H&E) and lacked internal "fish-scales." To validate these observations, respective medications were submitted for histologic processing; the processed medications were identical to those in the patient specimens. Rare, irregular "fracture" lines presented diagnostic pitfalls by mimicking the true "fish-scales" of Kayexalate and sevelamer. Clues to the correct identification of BAS include recognition that the "fracture" lines were subtle, irregular, and restricted to large fragments or thick sections, likely representing a processing artifact. Moreover, Kayexalate is violet on H&E and black on acid fast bacillus, and sevelamer characteristically displays a 2-tone color on H&E and is magenta on acid fast bacillus. An association with inflammatory injury was seen (15/26). We believe that the BAS are innocent bystanders in complicated patients, although we cannot exclude their ability to cause mucosal injury in specific settings.

  View details for Web of Science ID 000343880200010

  View details for PubMedID 24921636

• Diagnostic Pitfalls of Differentiating Desmoplastic Small Round Cell Tumor (DSRCT) From Wilms Tumor (WT): Overlapping Morphologic and Immunohistochemical Features. American journal of surgical pathology Arnold, M. A., Schoenfield, L., Limketkai, B. N., Arnold, C. A. 2014; 38 (9): 1220-1226

  Abstract

  Desmoplastic small round cell tumor (DSRCT) and blastemal-predominant Wilms tumor (WT) share overlapping histologic features, yet accurate distinction is critical because of differing prognosis and treatment. We encountered a neck mass in a young adult with a concomitant abdominal mass. The neck mass was initially concerning for DSRCT on the basis of the poorly differentiated morphology, desmoplastic stroma, and immunoreactivity for desmin and cytokeratin. However, focal triphasic elements and glomeruloid bodies were identified on deeper sections, WT1 immunoreactivity was seen with antibodies to both the amino-terminus and carboxy-terminus, and EWSR1-WT1 rearrangement studies were negative, supporting the ultimate diagnosis of WT. On the basis of the overlapping histologic features of DSRCT and blastemal-predominant WT, we undertook a comparison study of desmin and cytokeratin reactivity patterns. We found that, whereas desmin reactivity was more frequent in DSRCT (11 of 12) than in WT blastema (11 of 22, P=0.024), dot-like perinuclear reactivity was seen with equal frequency in desmin-reactive DSRCT (10 of 11) and WT blastema (10 of 11), illustrating an important diagnostic pitfall. Moreover, we demonstrate coexpression of desmin and cytokeratin in both DSRCT (9 of 12) and WT blastema (11 of 22). Importantly, although dot-like desmin reactivity and coexpression of desmin and cytokeratin are historically associated with DSRCT, we demonstrate that these features can be seen in either DSRCT or blastemal-predominant WT. In these challenging cases, detection of an EWSR1-WT1 rearrangement and selective WT1 carboxy-terminus immunoreactivity (characteristic of DSRCT) or dual immunoreactivity for the WT1 amino-terminus and carboxy-terminus (characteristic of WT) remain the most discriminating diagnostic tools.

  View details for DOI 10.1097/PAS.0000000000000231

  View details for PubMedID 24832162

• Primary Subcutaneous Spindle Cell Ewing Sarcoma with Strong S100 Expression and <i>EWSR1</i>-<i>FLI1</i> Fusion: A Case Report PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Arnold, M. A., Ballester, L. Y., Pack, S. D., Abdullaev, Z., Merchant, M., Tsokos, M. G. 2014; 17 (4): 302-307

  Abstract

  Ewing sarcoma is described classically as a small, round cell tumor of bone and soft tissue in children and young adults. Ewing sarcoma most often is characterized by a fusion of the Ewing sarcoma breakpoint region 1 (EWSR1) and the Friend leukemia virus integration 1 (FLI1) genes, forming an EWSR1-FLI1 fusion transcript. We report an exceptional case of primary subcutaneous Ewing sarcoma in a 16-year-old female composed entirely of spindle cells with focal fascicular growth and exhibiting strong, diffuse immunohistochemical reactivity for S100, unlike classic Ewing sarcoma. However, reverse transcription-polymerase chain reaction (RT-PCR) analysis confirmed the presence of a rare variant of the EWSR1-FLI1 fusion transcript, featuring fusion of EWSR1 exon 10 to FLI1 exon 6. To our knowledge, the combined histologic, molecular, and clinical features have not been reported previously in Ewing sarcoma, and raise a broad differential diagnosis emphasizing the importance of molecular techniques in the diagnosis of this tumor.

  View details for DOI 10.2350/14-03-1454-CR.1

  View details for Web of Science ID 000342383300009

  View details for PubMedID 24735198

• Thoracolumbar spinal vascular malformation as a rare cause of isolated intraventricular hemorrhage Case report JOURNAL OF NEUROSURGERY-PEDIATRICS Marlin, E. S., Entwistle, J. J., Arnold, M. A., Pierson, C. R., Governale, L. S. 2014; 14 (1): 12-15

  Abstract

  Spinal vascular malformations are rare vascular lesions that most frequently present with back pain, radiculopathy, and/or myelopathy. Neurological decline is typically secondary to progressive radiculopathy, myelopathy, venous thrombosis, and stroke. Few case reports have described thoracolumbar spinal vascular malformations that present with both subarachnoid and intraventricular hemorrhage. This is the first reported case of a thoracolumbar spinal vascular malformation presenting with isolated intraventricular hemorrhage on initial imaging followed by acute and fatal rehemorrhage.

  View details for DOI 10.3171/2014.3.PEDS13565

  View details for Web of Science ID 000337935500002

  View details for PubMedID 24784978

• Cribriform Neuroepithelial Tumor Arising in the Lateral Ventricle PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Arnold, M. A., Stallings-Archer, K., Marlin, E., Grondin, R., Olshefski, R., Biegel, J. A., Pierson, C. R. 2013; 16 (4): 301-307

  Abstract

  Cribriform neuroepithelial tumor (CRINET) is a recently recognized central nervous system neoplasm that arises in the ventricles of young children and is characterized by primitive, non-rhabdoid SMARCB1-deficient cells with prominent cribriform architecture. We report a 14-month-old male who presented with signs of increased intracranial pressure. Neuroimaging revealed a large solid and cystic mass in the lateral ventricle. Tumor cells were small, primitive appearing, and arranged in cribriform and trabecular patterns with interspersed solid cellular areas. Rhabdoid cells were absent. Immunohistochemical staining showed no SMARCB1 (INI11, BAF47, hSNF5) expression and strong epithelial membrane antigen (EMA) immunoreactivity along luminal surfaces. Electron microscopy showed epithelial characteristics, including abundant basal lamina. Genetic analysis of the tumor revealed deletion of 1 SMARCB1 allele, while the other contained an intronic point mutation predicted to disrupt splicing. This case further illustrates the distinct histopathologic and molecular genetic features of CRINET and identifies distinctive ultrastructural features.

  View details for DOI 10.2350/12-12-1287-CR.1

  View details for Web of Science ID 000323264500008

  View details for PubMedID 23495723

• Diffuse intestinal ganglioneuromatosis in a child JOURNAL OF PEDIATRIC SURGERY Matthews, M. A. B., Adler, B. H., Arnold, M. A., Kumar, S., Carvalho, R., Besner, G. E. 2013; 48 (5): 1129-1133

  Abstract

  A 7 year old male with a history of congenital neutropenia and growth hormone deficiency presented with abdominal pain, fevers, and diarrhea. Imaging and endoscopy revealed significant inflammation of the ascending colon with stenosis at the level of the hepatic flexure. A right hemicolectomy was performed, and pathologic findings were consistent with diffuse intestinal ganglioneuromatosis. Due to recurrent mass effect at the intestinal anastomotic site detected radiologically, a second intestinal resection was performed 7 months later. Genetic testing was negative for mutations in the RET protooncogene, NF1 and PTEN tumor suppressor genes. We report a case of diffuse intestinal ganglioneuromatosis in a child with congenital neutropenia.

  View details for DOI 10.1016/j.jpedsurg.2013.03.066

  View details for Web of Science ID 000320372100047

  View details for PubMedID 23701793

  View details for PubMedCentralID PMC4076949

• A unique pattern of INI1 immunohistochemistry distinguishes synovial sarcoma from its histologic mimics HUMAN PATHOLOGY Arnold, M. A., Arnold, C. A., Li, G., Chae, U., El-Etriby, R., Lee, C., Tsokos, M. 2013; 44 (5): 881-887

  Abstract

  The absence of INI1 (SMARCB1, hSNF5, BAF47) immunohistochemical reactivity is a central feature of malignant rhabdoid tumor, renal medullary carcinoma, and epithelioid sarcoma. We characterized INI1 immunoreactivity in synovial sarcoma (49 cases) in comparison with its closest histologic mimics (68 cases). We observed a unique pattern of decreased INI1 immunoreactivity with a high specificity (100%) and sensitivity (86%) for synovial sarcoma and particular sensitivity for poorly differentiated subtypes of synovial sarcoma (94%; 16/17 cases). Decreased INI1 immunoreactivity was not seen in any of the other lesions we examined, including 14 cases of Ewing sarcoma and 22 cases of malignant peripheral nerve sheath tumor. Furthermore, decreased INI1 immunoreactivity is distinct from the complete absence of INI1 immunoreactivity seen in malignant rhabdoid tumor or other INI1-negative neoplasms. We propose that this distinct INI1 immunohistochemical pattern serves as a useful diagnostic tool to provide preliminary results before molecular test results are available, especially in cases of poorly differentiated synovial sarcoma and in cases where limited material precludes confirmatory molecular studies. Awareness of this unique pattern is critical to avoid misinterpreting decreased INI1 immunoreactivity as a complete absence of INI1 and, consequently, misdiagnosing synovial sarcoma as an INI1-negative neoplasm.

  View details for DOI 10.1016/j.humpath.2012.08.014

  View details for Web of Science ID 000318201400025

  View details for PubMedID 23245672

• Pegylated siRNA-loaded calcium phosphate nanoparticle-driven amplification of cancer cell internalization <i>in vivo</i> BIOMATERIALS Tobin, L. A., Xie, Y., Tsokos, M., Chung, S. I., Merz, A. A., Arnold, M. A., Li, G., Malech, H. L., Kwong, K. F. 2013; 34 (12): 2980-2990

  Abstract

  The cell membrane is a critical barrier to effective delivery for many therapeutics, including those which are nanoparticle-based. Improving nanoparticle transport across the cell membrane remains a fundamental challenge. Cancer cells preferentially internalized pegylated calcium phosphate nanoparticles over normal epithelial cells. Furthermore, non-cytotoxic levels of doxorubicin markedly amplified this difference by increasing free unbound caveolin-1 and resulted in enhanced caveolin-mediated nanoparticle endocytosis in cancer cells. Engineered pegylated siRNA-loaded triple-shell calcium phosphate nanoconstructs incorporating ultra-low levels of doxorubicin recapitulated these effects and delivered increased numbers of siRNA into cancer cells with target-specific results. Systemic administration of nanoparticles in vivo demonstrated highly preferential entry into tumors, little bystander organ biodistribution, and significant tumor growth arrest. In conclusion, siRNA-loaded calcium phosphate nanoparticles incorporating non-cytotoxic amounts of doxorubicin markedly enhances nanoparticle internalization and results in increased payload delivery with concomitant on-target effects.

  View details for DOI 10.1016/j.biomaterials.2013.01.046

  View details for Web of Science ID 000316038900013

  View details for PubMedID 23369215

  View details for PubMedCentralID PMC3633203

• The cutting edge of serrated polyps: a practical guide to approaching and managing serrated colon polyps GASTROINTESTINAL ENDOSCOPY Limketkai, B. N., Lam-Himlin, D., Arnold, C. A., Arnold, M. A. 2013; 77 (3): 360-375

  View details for DOI 10.1016/j.gie.2012.11.013

  View details for Web of Science ID 000314831000005

  View details for PubMedID 23410696

• Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C BLOOD Schwieger, M., Schueler, A., Forster, M., Engelmann, A., Arnold, M. A., Delwel, R., Valk, P. J., Loehler, J., Slany, R. K., Olson, E. N., Stocking, C. 2009; 114 (12): 2476-2488

  Abstract

  Acute myelogenous leukemia is driven by leukemic stem cells (LSCs) generated by mutations that confer (or maintain) self-renewal potential coupled to an aberrant differentiation program. Using retroviral mutagenesis, we identified genes that generate LSCs in collaboration with genetic disruption of the gene encoding interferon response factor 8 (Irf8), which induces a myeloproliferation in vivo. Among the targeted genes, we identified Mef2c, encoding a MCM1-agamous-deficiens-serum response factor transcription factor, and confirmed that overexpression induced a myelomonocytic leukemia in cooperation with Irf8 deficiency. Strikingly, several of the genes identified in our screen have been reported to be up-regulated in the mixed-lineage leukemia (MLL) subtype. High MEF2C expression levels were confirmed in acute myelogenous leukemia patient samples with MLL gene disruptions, prompting an investigation of the causal interplay. Using a conditional mouse strain, we demonstrated that Mef2c deficiency does not impair the establishment or maintenance of LSCs generated in vitro by MLL/ENL fusion proteins; however, its loss led to compromised homing and invasiveness of the tumor cells. Mef2c-dependent targets included several genes encoding matrix metalloproteinases and chemokine ligands and receptors, providing a mechanistic link to increased homing and motility. Thus, MEF2C up-regulation may be responsible for the aggressive nature of this leukemia subtype.

  View details for DOI 10.1182/blood-2008-05-158196

  View details for Web of Science ID 000269925000016

  View details for PubMedID 19584403

• Unsuspected, disseminated coccidioidomycosis without maternofetal morbidity diagnosed by placental examination: Case report and review of the literature CLINICAL INFECTIOUS DISEASES Arnold, C. A., Rakheja, D., Arnold, M. A., Peters, J. M., Fernandes, N. J., Quintanilla, N. M., Weinberg, A. G., Revell, P., Cavuoti, D. C. 2008; 46 (11): E119-E123

  Abstract

  Historically, untreated disseminated coccidioidomycosis during pregnancy was thought to be associated with 100% maternal fatality and 50% fetal mortality and was the leading cause of maternal deaths in areas of endemicity. As recently as 1995, therapeutic abortions and early deliveries were advocated in certain contexts. This report describes an unrecognized case of disseminated coccidioidomycosis diagnosed at the time of placental examination in a woman who completed her pregnancy without significant maternofetal complications. This case suggests that abortion and early delivery may not be necessary, because the possibility of an uncomplicated pregnancy exists. It is likely that other similar cases exist but remain underreported or underdiagnosed because of the mild, nondescript nature of the illness and low clinical suspicion. Although this mother and infant had good clinical outcomes, thorough travel histories and consideration of the associated travel-related diseases are important because of the possibility of serious, potentially avoidable clinical consequences.

  View details for DOI 10.1086/588047

  View details for Web of Science ID 000255606700035

  View details for PubMedID 18426374

• The MADS transcription factor Mef2c is a pivotal modulator of myeloid cell fate BLOOD Schueler, A., Schwieger, M., Engelmann, A., Weber, K., Horn, S., Mueller, U., Arnold, M. A., Olson, E. N., Stocking, C. 2008; 111 (9): 4532-4541

  Abstract

  Mef2c is a MADS (MCM1-agamous-deficient serum response factor) transcription factor best known for its role in muscle and cardiovascular development. A causal role of up-regulated MEF2C expression in myelomonocytic acute myeloid leukemia (AML) has recently been demonstrated. Due to the pronounced monocytic component observed in Mef2c-induced AML, this study was designed to assess the importance of Mef2c in normal myeloid differentiation. Analysis of bone marrow (BM) cells manipulated to constitutively express Mef2c demonstrated increased monopoiesis at the expense of granulopoiesis, whereas BM isolated from Mef2c(Delta/-) mice showed reduced levels of monocytic differentiation in response to cytokines. Mechanistic studies showed that loss of Mef2c expression correlated with reduced levels of transcripts encoding c-Jun, but not PU.1, C/EBPalpha, or JunB transcription factors. Inhibiting Jun expression by short-interfering RNA impaired Mef2c-mediated inhibition of granulocyte development. Moreover, retroviral expression of c-Jun in BM cells promoted monocytic differentiation. The ability of Mef2c to modulate cell-fate decisions between monocyte and granulocyte differentiation, coupled with its functional sensitivity to extracellular stimuli, demonstrate an important role in immunity--and, consistent with findings of other myeloid transcription factors, a target of oncogenic lesions in AML.

  View details for DOI 10.1182/blood-2007-10-116343

  View details for Web of Science ID 000255387400021

  View details for PubMedID 18326819

• Regulation of skeletal muscle sarcomere integrity and postnatal muscle function by <i>Mef2c</i> MOLECULAR AND CELLULAR BIOLOGY Potthoff, M. J., Arnold, M. A., McAnally, J., Richardson, J. A., Bassel-Duby, R., Olson, E. N. 2007; 27 (23): 8143-8151

  Abstract

  Myocyte enhancer factor 2 (MEF2) transcription factors cooperate with the MyoD family of basic helix-loop-helix (bHLH) transcription factors to drive skeletal muscle development during embryogenesis, but little is known about the potential functions of MEF2 factors in postnatal skeletal muscle. Here we show that skeletal muscle-specific deletion of Mef2c in mice results in disorganized myofibers and perinatal lethality. In contrast, neither Mef2a nor Mef2d is required for normal skeletal muscle development in vivo. Skeletal muscle deficient in Mef2c differentiates and forms normal myofibers during embryogenesis, but myofibers rapidly deteriorate after birth due to disorganized sarcomeres and a loss of integrity of the M line. Microarray analysis of Mef2c null muscles identified several muscle structural genes that depend on MEF2C, including those encoding the M-line-specific proteins myomesin and M protein. We show that MEF2C directly regulates myomesin gene transcription and that loss of Mef2c in skeletal muscle results in improper sarcomere organization. These results reveal a key role for Mef2c in maintenance of sarcomere integrity and postnatal maturation of skeletal muscle.

  View details for DOI 10.1128/MCB.01187-07

  View details for Web of Science ID 000251527100010

  View details for PubMedID 17875930

  View details for PubMedCentralID PMC2169182

• Histone deacetylase degradation and MEF2 activation promote the formation of slow-twitch myofibers JOURNAL OF CLINICAL INVESTIGATION Potthoff, M. J., Wu, H., Arnold, M. A., Shelton, J. M., Backs, J., McAnally, J., Richardson, J. A., Bassel-Duby, R., Olson, E. N. 2007; 117 (9): 2459-2467

  Abstract

  Skeletal muscle is composed of heterogeneous myofibers with distinctive rates of contraction, metabolic properties, and susceptibility to fatigue. We show that class II histone deacetylase (HDAC) proteins, which function as transcriptional repressors of the myocyte enhancer factor 2 (MEF2) transcription factor, fail to accumulate in the soleus, a slow muscle, compared with fast muscles (e.g., white vastus lateralis). Accordingly, pharmacological blockade of proteasome function specifically increases expression of class II HDAC proteins in the soleus in vivo. Using gain- and loss-of-function approaches in mice, we discovered that class II HDAC proteins suppress the formation of slow twitch, oxidative myofibers through the repression of MEF2 activity. Conversely, expression of a hyperactive form of MEF2 in skeletal muscle of transgenic mice promotes the formation of slow fibers and enhances running endurance, enabling mice to run almost twice the distance of WT littermates. Thus, the selective degradation of class II HDACs in slow skeletal muscle provides a mechanism for enhancing physical performance and resistance to fatigue by augmenting the transcriptional activity of MEF2. These findings provide what we believe are new insights into the molecular basis of skeletal muscle function and have important implications for possible therapeutic interventions into muscular diseases.

  View details for DOI 10.1172/JCI31960

  View details for Web of Science ID 000249384600017

  View details for PubMedID 17786239

  View details for PubMedCentralID PMC1957540

• MEF2C transcription factor controls chondrocyte hypertrophy and bone development DEVELOPMENTAL CELL Arnold, M. A., Kim, Y., Czubryt, M. P., Phan, D., McAnally, J., Qi, X., Shelton, J. M., Richardson, J. A., Bassel-Duby, R., Olson, E. N. 2007; 12 (3): 377-389

  Abstract

  Chondrocyte hypertrophy is essential for endochondral bone development. Unexpectedly, we discovered that MEF2C, a transcription factor that regulates muscle and cardiovascular development, controls bone development by activating the gene program for chondrocyte hypertrophy. Genetic deletion of Mef2c or expression of a dominant-negative MEF2C mutant in endochondral cartilage impairs hypertrophy, cartilage angiogenesis, ossification, and longitudinal bone growth in mice. Conversely, a superactivating form of MEF2C causes precocious chondrocyte hypertrophy, ossification of growth plates, and dwarfism. Endochondral bone formation is exquisitely sensitive to the balance between MEF2C and the corepressor histone deacetylase 4 (HDAC4), such that bone deficiency of Mef2c mutant mice can be rescued by an Hdac4 mutation, and ectopic ossification in Hdac4 null mice can be diminished by a heterozygous Mef2c mutation. These findings reveal unexpected commonalities in the mechanisms governing muscle, cardiovascular, and bone development with respect to their regulation by MEF2 and class II HDACs.

  View details for DOI 10.1016/j.devcel.2007.02.004

  View details for Web of Science ID 000245291400010

  View details for PubMedID 17336904

• Regulation of HDAC9 gene expression by MEF2 establishes a negative-feedback loop in the transcriptional circuitry of muscle differentiation MOLECULAR AND CELLULAR BIOLOGY Haberland, M., Arnold, M. A., McAnally, J., Phan, D., Kim, Y., Olson, E. N. 2007; 27 (2): 518-525

  Abstract

  Skeletal muscle development is controlled by the myocyte enhancer factor (MEF2) and myogenic basic helix-loop-helix (bHLH) families of transcription factors, which associate and synergistically activate muscle gene expression. Muscle differentiation is further reinforced by positive-feedback loops in which myogenic bHLH proteins activate their own expression and the expression of MEF2, while MEF2 stimulates expression of myogenic bHLH genes and the Mef2c gene. Here we describe a myogenic negative-feedback loop that consists of MEF2 proteins and the transcriptional repressor histone deacetylase 9 (HDAC9). We show that the HDAC9 gene is a direct transcriptional target of MEF2 in vitro and in vivo. HDAC9 can associate with MEF2 proteins and suppress their transcriptional activity. The transcriptional repressor HDAC9 thus forms a negative-feedback loop in the transcriptional circuitry of muscle differentiation.

  View details for DOI 10.1128/MCB.01415-06

  View details for Web of Science ID 000243353500009

  View details for PubMedID 17101791

  View details for PubMedCentralID PMC1800816

• PRISM/PRDM6, a transcriptional repressor that promotes the proliferative gene program in smooth muscle cells MOLECULAR AND CELLULAR BIOLOGY Davis, C. A., Haberland, M., Arnold, M. A., Sutherland, L. B., McDonald, O. G., Richardson, J. A., Childs, G., Harris, S., Owens, G. K., Olson, E. N. 2006; 26 (7): 2626-2636

  Abstract

  Smooth muscle cells (SMCs) display remarkable phenotypic diversity and plasticity and can readily switch between proliferative and differentiated states in response to extracellular cues. In an effort to identify novel transcriptional regulators of smooth muscle phenotypes, we compared the gene expression profiles of arterial and venous SMCs by microarray-based transcriptional profiling. Among numerous genes displaying distinct expression patterns in these two SMC types, we discovered an expressed sequence tag encoding a previously uncharacterized zinc finger protein belonging to the PRDM (PRDI-BF1 and RIZ homology domain) family of chromatin-remodeling proteins and named it PRISM (PR domain in smooth muscle). PRISM is expressed in a variety of smooth muscle-containing tissues and displays especially robust expression in the cardiac outflow tract and descending aorta during embryogenesis. PRISM is localized to the nucleus and contains an amino-terminal PR domain and four Krüppel-like zinc fingers at the carboxy terminus. We show that PRISM acts as a transcriptional repressor by interacting with class I histone deacetylases and the G9a histone methyltransferase, thereby identifying PRISM as a novel SMC-restricted epigenetic regulator. Overexpression of PRISM in cultured primary SMCs induces genes associated with the proliferative smooth muscle phenotype while repressing regulators of differentiation, including myocardin and GATA-6. Conversely, small interfering RNA-mediated knockdown of PRISM slows cell growth and induces myocardin, GATA-6, and markers of SMC differentiation. We conclude that PRISM acts as a novel epigenetic regulator of SMC phenotypic plasticity by suppressing differentiation and maintaining the proliferative potential of vascular SMCs.

  View details for DOI 10.1128/MCB.26.7.2626-2636.2006

  View details for Web of Science ID 000236312200015

  View details for PubMedID 16537907

  View details for PubMedCentralID PMC1430312

• Myospryn is a direct transcriptional target for MEF2A that encodes a striated muscle, α-actinin-interacting, costamere-localized protein JOURNAL OF BIOLOGICAL CHEMISTRY Durham, J. T., Brand, O. M., Arnold, M., Reynolds, J. G., Muthukumar, L., Weiler, H., Richardson, J. A., Naya, F. J. 2006; 281 (10): 6841-6849

  Abstract

  The full repertoire of proteins that comprise the striated muscle Z-disc and peripheral structures, such as the costamere, have yet to be discovered. Recent studies suggest that this elaborate protein network, which acts as a structural and signaling center for striated muscle, harbors factors that function as mechanosensors to ensure coordinated contractile activity. Mutations in genes whose products reside in this region often result in skeletal and cardio myopathies, demonstrating the importance of this macromolecular complex in muscle structure and function. Here, we describe the characterization of a direct, downstream target gene for the MEF2A transcription factor encoding a large, muscle-specific protein that localizes to the costamere in striated muscle. This gene, called myospryn, was identified by microarray analysis as a transcript down-regulated in MEF2A knock-out mice. MEF2A knock-out mice develop cardiac failure during the perinatal period with mutant hearts exhibiting several cardiac abnormalities including myofibrillar disarray. Myospryn is the mouse ortholog of a partial human cDNA of unknown function named cardiomyopathy-associated gene 5 (CMYA5). Myospryn is expressed as a single, large transcript of approximately 12 kilobases in adult heart and skeletal muscle with an open reading frame of 3739 amino acids. This protein, belonging to the tripartite motif superfamily of proteins, contains a B-box coiled-coil (BBC), two fibronectin type III (FN3) repeats, and SPRY domains and interacts with the sarcomeric Z-disc protein, alpha-actinin-2. Our findings demonstrate that myospryn functions directly downstream of MEF2A at the costamere in striated muscle potentially playing a role in myofibrillogenesis.

  View details for DOI 10.1074/jbc.M510499200

  View details for Web of Science ID 000236030800082

  View details for PubMedID 16407236

• Centronuclear myopathy in mice lacking a novel muscle-specific protein kinase transcriptionally regulated by MEF2 GENES & DEVELOPMENT Nakagawa, O., Arnold, M., Nakagawa, M., Hamada, H., Shelton, J. M., Kusano, H., Harris, T. M., Childs, G., Campbell, K. P., Richardson, J. A., Nishino, Olson, E. N. 2005; 19 (17): 2066-2077

  Abstract

  Myocyte enhancer factor 2 (MEF2) plays essential roles in transcriptional control of muscle development. However, signaling pathways acting downstream of MEF2 are largely unknown. Here, we performed a microarray analysis using Mef2c-null mouse embryos and identified a novel MEF2-regulated gene encoding a muscle-specific protein kinase, Srpk3, belonging to the serine arginine protein kinase (SRPK) family, which phosphorylates serine/arginine repeat-containing proteins. The Srpk3 gene is specifically expressed in the heart and skeletal muscle from embryogenesis to adulthood and is controlled by a muscle-specific enhancer directly regulated by MEF2. Srpk3-null mice display a new entity of type 2 fiber-specific myopathy with a marked increase in centrally placed nuclei; while transgenic mice overexpressing Srpk3 in skeletal muscle show severe myofiber degeneration and early lethality. We conclude that normal muscle growth and homeostasis require MEF2-dependent signaling by Srpk3.

  View details for DOI 10.1101/gad.1338705

  View details for Web of Science ID 000231630100011

  View details for PubMedID 16140986

  View details for PubMedCentralID PMC1199576