Susan Hiniker

All Publications

• 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

• Automating the Treatment Planning Process for Volumetric Modulated Arc Therapy Craniospinal Irradiation (VMAT-CSI). Practical radiation oncology Romero, I. O., Simiele, E. A., Lozko, Y., Severyn, Y., Skinner, L. B., Yang, Y., Wang, J. Y., Xing, L., Gibbs, I., Hiniker, S. M., Kovalchuk, N. 2023

  Abstract

  The purpose of this work is to develop a method to automate the treatment planning process of craniospinal irradiation (CSI) using volumetric modulated arc therapy (VMAT).Two scripts were developed using the Eclipse Scripting Application Programming Interface (ESAPI) to perform auto-plan preparation and optimization. Ten patients (age, 5-44 years) previously treated at our institution with low dose VMAT-CSI (prescription of 12 Gy) prior to total body irradiation were selected to evaluate the efficacy of the proposed auto-planning process. Paired t-tests compared the dosimetric indices of the auto-plans to the manually generated clinical plans. All plans were normalized to 95% of PTV coverage with the prescription dose. Two physicians and one physicist were asked to evaluate the manual plans and auto-plans of each patient in a blinded retrospective review and to indicate clinical acceptability and which plans were preferred for treatment.Compared to the manual CSI plans, the auto plans obtained significant reductions in Dmean to the parotids, submandibular glands, larynx, thyroid, and significant reduction in the plan PTV Dmax and D0.03cc. The standard deviation range of the dosimetric parameters was greatly reduced for auto plans (range, 0.1-1.3 Gy) relative to manual plans (range, 0.4-5.9 Gy) indicating better plan consistency. Among the ten patients, the auto-plans were preferred over the manual plans 90% of the time by the reviewing experts. The required time for auto-planning was approximately 1 hour compared to estimated 4 or more hours for manual planning.Reductions in planning time without sacrifices in plan quality were obtained using the auto-planning process compared with manual planning. Variation in plan quality was also reduced. The auto-planning scripts will be made freely available to other institutions and clinics.

  View details for DOI 10.1016/j.prro.2023.11.014

  View details for PubMedID 38048988

• Treatment Course and Outcomes of Intracranial Teratomas in Pediatric Patients: A Retrospective 15-Year Case Series Study. Pediatric neurosurgery Wu, A., Jin, M. C., Vogel, H., Hiniker, S., Campen, C., Prolo, L. M., Grant, G. A. 2023; 58 (6): 429-438

  Abstract

  There is no standard treatment paradigm for intracranial teratomas, a rare subset of primary intracranial non-germinomatous germ cell tumors (NGGCT), which comprise less than 1% of pediatric brain tumors. This case series retrospectively analyzes treatment and outcomes of pediatric intracranial teratomas from a single institution.Authors reviewed a comprehensive pathology database at Stanford's Lucile Packard Children's Hospital for intracranial teratomas in pediatric patients treated from 2006 to 2021; their demographics, treatment, and clinical course were analyzed.Among 14 patients, median follow-up time was 4.6 years and mean age at diagnosis was 10.5 years. Ten had elevated tumor markers and underwent chemotherapy as initial treatment for NGGCT. Ultimately, these patients all required surgery for progressive or residual disease. Two patients did not undergo radiation. After biopsy or resection, 8 patients had pure mature teratoma, five had mixed germ cell tumor with teratoma component, and one had immature teratoma. The patient with immature teratoma died during chemotherapy from septic shock. No patients experienced recurrence. Common sequelae were endocrine (42.8%) and eye movement (50.0%) abnormalities.We highlight the variable treatment course and outcome for pediatric patients with intracranial teratomas. Elevated tumor markers at presentation, along with imaging findings, favor chemotherapy initiation for presumed NGGCT. Resection of residual tumor is recommended even if tumor markers return to normal. Prognosis remains excellent; no patients had recurrence with a median follow-up of 4.6 years.

  View details for DOI 10.1159/000534721

  View details for PubMedID 37879310

• Patterns of local recurrence and risk of skin recurrence in soft tissue sarcomas after surgical resection. Practical radiation oncology Ewongwo, A., Oladipo, E. D., Hui, C., Avedian, R. S., Steffner, R. J., Mohler, D. G., Kalbasi, A., Chin, A. L., Million, L., Hiniker, S. M., Moding, E. J. 2023

  Abstract

  Although there is a theoretical risk of skin seeding during surgical resection of soft tissues sarcomas (STSs), current consensus guidelines recommend against routine use of bolus during RT. However, the risk of skin recurrence has not been systematically assessed. We aimed to assess the patterns of local recurrence (LR) in patients with STS treated with surgery with or without RT.We performed a retrospective analysis of adults with STSs evaluated at our institution between 2007-2021. For patients who developed LR, the depth was evaluated. Progression free survival (PFS) and overall survival (OS) were analyzed from time of first LR using Kaplan-Meier method. Cumulative incidence of distant metastasis (CIDM) was calculated with competing risk analysis from date of LR.Of the 206 patients evaluated, 20 had LR (9.7%). Among patients with LR, five patients (25.0%) were treated with surgery alone and 15 patients (75.0%) with surgery and RT. In patients treated with RT, 46.7% had pre-operative RT, 53.3% had post operative RT, and bolus was used in 46.7%. Surgical margins were close (<1mm) in 4 patients (20.0%) and positive in 10 patients (50.0%). LR occurred in the deep subfascial tissue in 9 patients (45%), subcutaneous tissue in 10 patients (50.0%), and skin in 1 patient (5.0%). The patient with a skin recurrence was treated with surgery alone and the tumor involved the skin at presentation. In patients treated with RT, LR occurred within RT field in 13 patients (86.7%). At 1 year after LR, PFS was 70.3%, OS was 81.7%, and CIDM was 5.9%.Skin recurrences were rare after surgical resection of STSs, and only occurred in a tumor that involved the skin at initial presentation. These findings support current recommendations against routine use of bolus in STSs not involving the skin at presentation.

  View details for DOI 10.1016/j.prro.2023.09.006

  View details for PubMedID 37804883

• 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

• Effect of Testicular Boost in Children With Leukemia Receiving Total Body Irradiation and Stem Cell Transplant: A Single-Institution Experience. Advances in radiation oncology Blomain, E. S., Jiang, A., Donaldson, S. S., Agarwal, R., Bertaina, A., Shyr, D., Eisenberg, M. L., Hoppe, R. T., Hiniker, S. M., Oh, J. 2023; 8 (1): 101071

  Abstract

  Children with leukemia who receive fractionated total body irradiation (fTBI) with 12 to 13.2 Gy as part of conditioning for hematopoietic stem cell transplant are frequently treated with an additional 4 Gy testicular boost to reduce the risk of testicular relapse. While institutional practices vary, limited data exists regarding whether the 4-Gy testicular boost reduces the risk of relapse and whether it causes toxicity beyond that imparted by TBI. This study compared the survival and endocrine outcomes among the patients who were treated with and without a testicular boost as part of fTBI from 1990 to 2019 at our center.We retrospectively reviewed charts of male children with leukemia treated with fTBI as part of a conditioning regimen for stem cell transplant from 1990 to 2019. Reported outcomes included progression-free survival, testicular relapse rate, and overall survival. Gonadal dysfunction and fertility were assessed by comparing the rate of abnormally low testosterone or high luteinizing hormone or follicular stimulating hormone, number of offspring, fertility service use, and abnormal sperm count in the subsequent follow-up period between the testicular boost and nonboost subset.Ninety-three male patients (63 acute lymphoblastic leukemia, 30 acute myeloid leukemia) with a median age of 9 years (range, 1-22) and follow-up of 3.3 years were included. In addition to 12- to 13.2-Gy fTBI, 51 male patients (54%) received a testicular boost to 4 Gy. There was 1 testicular relapse in the boost subset and none in the nonboost subset. Five-year progression-free survival for the boost and nonboost subset was 74% and 66%, respectively (P = .31). On multivariable analysis, boost was not associated with improved relapse-free survival or overall survival. More patients in the boost subset (35 of 51, 69%) had abnormal serum gonadal blood work compared with the nonboost subset (18 of 42, 43%) (P = .03).Omission of testicular boost may be associated with comparable oncologic but improved gonadal endocrine outcomes and should be further studied.

  View details for DOI 10.1016/j.adro.2022.101071

  View details for PubMedID 36483061

  View details for PubMedCentralID PMC9723295

• FUNCTIONAL AND TOXICITY OUTCOMES OF RADIATION THERAPY FOR DUPUYTREN'S CONTRACTURE Oh, J., Wang, Y., Hiniker, S. ELSEVIER IRELAND LTD. 2023: S98

  View details for Web of Science ID 001133676400224

• OUTCOMES OF PEDIATRIC AND ADOLESCENT PATIENTS WITH METASTATIC SARCOMA TREATED WITH SURGICAL RESECTION OR STEREOTACTIC ABLATIVE RADIATION THERAPY Oh, J., Gutkin, P., Wang, Y., Donaldson, S., Steffner, R., Bruzoni, M., Avedian, R., Spunt, S., Pribnow, A., Hiniker, S. ELSEVIER IRELAND LTD. 2023: S98

  View details for Web of Science ID 001133676400225

• Improved organ sparing using auto-planned Stanford volumetric modulated arc therapy for total body irradiation technique. Pediatric blood & cancer Ngo, N., Blomain, E. S., Simiele, E., Romero, I., Hoppe, R. T., Hiniker, S. M., Kovalchuk, N. 2023: e30589

  Abstract

  To evaluate dosimetric differences between auto-planned volumetric modulated arc therapy (VMAT) total body irradiation (TBI) technique and two-dimensional radiotherapy using anterior-posterial/posterio-anterial beams (2D AP/PA) TBI technique.Ten pediatric patients treated with VMAT-TBI on Varian c-arm linac were included in this study. VMAT-TBI plans were generated using our in-house developed and publicly shared auto-planning scripts. For each VMAT-TBI plan, a 2D AP/PA plan was created replicating the institution's clinical setup with the patient positioned at extended source to skin distance (SSD) with a compensator to account for differences in patient thickness, 50% transmission daily lung blocks, and electron chest wall boosts prescribed to 50% of the photon prescription. Clinically relevant metrics were analyzed and compared between the VMAT and 2D plans.All VMAT-TBI plans achieved planned target volume (PTV) D90% ≥ 100% of prescription. VMAT-TBI PTV D90% significantly increased (7.1% ± 2.9%, p < .001) compared to the 2D technique, whereas no differences were observed in global Dmax (p < .2) and PTV V110% (p < .4). Compared to the 2D plans, significant decreases in the Dmean to the lungs (-25.6% ± 11.5%, p < .001) and lungs-1 cm (-34.1% ± 10.1%, p < .001) were observed with the VMAT plans. The VMAT technique also enabled decrease of dose to other organs: kidneys Dmean (-32.5% ± 5.0%, p < .001) and lenses Dmax (-5.3% ± 8.1%, p = .03); and in addition, for 2 Gy prescription: testes/ovaries Dmean (-41.5% ± 11.5%, p < .001), brain Dmean (-22.6% ± 5.4%, p = .002), and thyroid Dmean (-18.2% ± 16.0%, p = .03).Superior lung sparing with improved target coverage and similar global Dmax were observed with the VMAT plans as compared to 2D plans. In addition, VMAT-TBI plans provided greater dose reductions in gonads, kidneys, brain, thyroid, and lenses.

  View details for DOI 10.1002/pbc.30589

  View details for PubMedID 37486149

• Central Endocrine Complications Among Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review. International journal of radiation oncology, biology, physics Wheeler, G., Grassberger, C., Samers, J., Dwyer, M., Wiltshire, K., Daly, P., Alvarez, B., Campbell, B. A., Kerr, A. J., Kron, T., Duane, F. K., Zacharin, M., Downie, P., Kyriakou, E., Ronckers, C. M., Constine, L. S., Hiniker, S. M. 2023

  Abstract

  PURPOSE: Children who receive cranial radiation therapy (RT) as a component of treatment for malignancy are often at risk of long-term central endocrine toxicity secondary to radiation to the hypothalamic-pituitary axis (HPA). A comprehensive analysis was performed of central endocrine late effects in survivors of childhood cancer treated with RT as part of the Pediatric Normal Tissue Effects in the Clinic (PENTEC) consortium.METHODS AND MATERIALS: A systematic review of the risk of RT-related central endocrine effects was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A total of 4629 publications were identified, of which 16 met criteria for inclusion in dose modeling analysis, with a total of 570 patients in 19 cohorts. Eighteen cohorts reported outcomes for growth hormone deficiency (GHD), 7 reported outcomes for central hypothyroidism (HT), and 6 reported outcomes for adrenocorticotropic hormone (ACTH) deficiency.RESULTS: Normal tissue complication probability modeling for GHD (18 cohorts, 545 patients) yielded D50=24.9 Gy (95% CI, 20.9-28.0) and gamma50=0.5 (95% CI, 0.27-0.78). The normal tissue complication probability model fit for whole brain irradiation in children with a median age of >5 years indicated a 20% risk of GHD for patients who receive a mean dose of 21 Gy in 2-Gy fractions to the HPA. For HT, among 7 cohorts (250 patients), D50=39 Gy (95% CI, 34.1-53.2) and gamma50=0.81 (95% CI, 0.46-1.35), with a 20% risk of HT in children who receive a mean dose of 22 Gy in 2-Gy fractions to the HPA. For ACTH deficiency (6 cohorts, 230 patients), D50=61 Gy (95% CI, 44.7-119.4) and gamma50=0.76 (95% CI, 0.5-1.19); there is a 20% risk of ACTH deficiency in children who receive a mean dose of 34 Gy in 2-Gy fractions to the HPA.CONCLUSIONS: RT dose to the HPA increases the risk of central endocrine toxicity, including GHD, HT, and ACTH deficiency. In some clinical situations, these toxicities may be difficult to avoid, and counseling of patients and families with respect to anticipated outcomes is important.

  View details for DOI 10.1016/j.ijrobp.2023.04.024

  View details for PubMedID 37269265

• Successful treatment of orbital Langerhans cell histiocytosis with stereotactic radiosurgery: A case report and literature review. Clinical case reports Etter, E., Bosse, B., Wang, Y. P., Hiniker, S., Oh, J. 2023; 11 (6): e7506

  Abstract

  Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasm arising from the proliferation of pathologic Langerhans cells. LCH has a spectrum of presentations predominantly affecting male pediatric patients. As LCH is a relatively uncommon diagnosis, there is no standard of care for treatment of the disease and treatment is based largely on clinical judgment, lesion characteristics, and symptoms at presentation. Here we present a case of unifocal, isolated orbital LCH in a 19-year-old young man treated initially with surgical resection. Follow-up imaging 2months later demonstrated significant regrowth of the mass and no other sites of disease. The recurrent orbital disease was treated with stereotactic radiosurgery (SRS) to 7 Gy in one fraction. Near complete resolution of the mass was achieved with no recurrence after 1.5years of follow-up. SRS for treatment of orbital LCH is a novel treatment not previously described in the literature which may provide benefit in select cases.

  View details for DOI 10.1002/ccr3.7506

  View details for PubMedID 37346879

• Feasibility of the Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) system for anesthesia avoidance in pediatric patients: A multicenter trial. International journal of radiation oncology, biology, physics Gutkin, P. M., Skinner, L., Jiang, A., Donaldson, S. S., Loo, B. W., Oh, J., Wang, Y. P., von Eyben, R., Snyder, J., Bredfeldt, J. S., Breneman, J. C., Constine, L. S., Faught, A. M., Haas-Kogan, D., Holmes, J. A., Krasin, M., Ccls, C. L., Marcus, K. J., Maxim, P. G., Iii, S. M., Murphy, B., Palmer, J. D., Perkins, S. M., Shen, C. J., Terezakis, S., Bush, K., Hiniker, S. M. 2023

  Abstract

  The AVATAR system was the first published radiotherapy (RT) compatible system to reduce the need for pediatric anesthesia through video-based distraction. We evaluate the feasibility of AVATAR implementation and effects on anesthesia use, quality of life (QoL), and anxiety in a multicenter pediatric trial.Pediatric patients 3-10 years of age preparing to undergo RT at 10 institutions were prospectively enrolled. Children able to undergo at least one fraction of RT using AVATAR without anesthesia were considered successful (S). Patients requiring anesthesia for their entire treatment course were non-successful (NS). PedsQL3.0 Cancer Module survey (PedsQL) assessed QoL and was administered to the patient and guardian at RT simulation, midway through RT, and final treatment. The modified Yale Preoperative Assessment Survey Short Form (mYPAS) assessed anxiety and was performed at the same three timepoints. Success was evaluated using Chi-square test. PedsQL and mYPAS scores were assessed using mixed effects models with time points evaluated as fixed effects and a random intercept on the subject.Eighty-one children were included; median age was 7 years. AVATAR was successful at all 10 institutions and with photon and proton RT. There were 63 (78%) S patients; anesthesia was avoided for a median of 20 fractions per patient. Success differed by age (p=0.04) and private versus public insurance (p<0.001). Both patient (p=0.008) and parent (p=0.006) PedsQL scores significantly improved over the course of RT for patients ages 5-7. Anxiety in the treatment room decreased for both S and NS patients over RT course (p<0.001), by age (p<0.001) and by S versus NS patients (p<0.001).In this 10-center prospective trial, anesthesia avoidance with AVATAR was 78% in children age 3-10 years, higher than among age-matched historical controls (49%, p<0.001). AVATAR implementation is feasible across multiple institutions and should be further studied and made available to patients who may benefit from video-based distraction.

  View details for DOI 10.1016/j.ijrobp.2023.03.063

  View details for PubMedID 37001762

• Rhabdomyosarcoma with isolated lung metastases: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Pediatric blood & cancer Vasquez, J. C., Luo, L. Y., Hiniker, S. M., Rhee, D. S., Dasgupta, R., Chen, S., Weigel, B. J., Xue, W., Venkatramani, R., Arndt, C. A. 2023: e30293

  Abstract

  To determine outcomes of children with rhabdomyosarcoma (RMS) with isolated lung metastases.Data were analyzed for 428 patients with metastatic RMS treated on COG protocols. Categorical variables were compared using Chi-square or Fisher's exact tests. Event-free survival (EFS) and overall survival (OS) were estimated using Kaplan-Meier method and compared using the log-rank test.Compared with patients with other metastatic sites (n = 373), patients with lung-only metastases (n = 55) were more likely to be <10 years of age, have embryonal histology (embryonal rhabdomyosarcoma), have N0 disease, and less likely to have primary extremity tumors. Lung-only patients had significantly better survival outcomes than patients with all other sites of metastatic disease (p < .0001) with 5-year EFS of 48.1 versus 18.8% and 5-year OS of 64.1 versus 26.9%. Patients with lung-only metastases, and those with a single extrapulmonary site of metastasis, had better survival compared with patients with two or more sites of metastatic disease (p < .0001). In patients with ERMS and lung-only metastases, there was no significant difference in survival between patients ≥10 years and 1-9 years (5-year EFS: 58.3 vs. 68.2%, 5-year OS: 66.7 vs. 67.7%).With aggressive treatment, patients with ERMS and lung-only metastatic disease have superior EFS and OS compared with patients with other sites of metastatic disease, even when older than 10 years of age. Consideration should be given to including patients ≥10 years with ERMS and lung-only metastases in the same group as those <10 years in future risk stratification algorithms.

  View details for DOI 10.1002/pbc.30293

  View details for PubMedID 36916768

• Efficacy and Safety of Stereotactic Body Radiation Therapy for Pediatric Malignancies: The LITE-SABR Systematic Review and Meta-Analysis. Advances in radiation oncology Singh, R., Valluri, A., Didwania, P., Lehrer, E. J., Baliga, S., Hiniker, S., Braunstein, S. E., Murphy, E. S., Lazarev, S., Tinkle, C., Terezakis, S., Palmer, J. D. 2023; 8 (2): 101123

  Abstract

  Purpose: Limited data are currently available on clinical outcomes after stereotactic body radiation therapy (SBRT) for pediatric and adolescent and young adult (AYA) patients with cancer. We aimed to perform a systematic review and study-level meta-analysis to characterize associated local control (LC), progression-free survival (PFS), overall survival, and toxicity after SBRT.Methods and Materials: Relevant studies were queried using a Population, Intervention, Control, Outcomes, Study Design (PICOS)/Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)/Meta-analysis of Observational Studies in Epidemiology (MOOSE) selection criteria. Primary outcomes were 1-year and 2-year LC as well as incidence of acute and late grade 3 to 5 toxicities, with secondary outcomes of 1-year overall survival and 1-year PFS. Outcome effect sizes were estimated with weighted random effects meta-analyses. Mixed-effects weighted regression models were performed to examine potential correlations between biologically effective dose (BED10), LC, and toxicity incidence.Results: Across 9 published studies, we identified 142 pediatric and AYA patients with 217 lesions that were treated with SBRT. Estimated 1-year and 2-year LC rates were 83.5% (95% confidence interval, 70.9%-96.2%) and 74.0% (95% CI, 64.6%-83.4%), respectively, with an estimated acute and late grade 3 to 5 toxicity rate of 2.9% (95% CI, 0.4%-5.4%; all grade 3). The estimated 1-year OS and PFS rates were 75.4% (95% CI, 54.5%-96.3%) and 27.1% (95% CI, 17.3%-37.0%), respectively. On meta-regression, higher BED10 was correlated with improved 2-year LC with every 10 Gy10 increase in BED10 associated with a 5% improvement in 2-year LC (P=.02) in sarcoma-predominant cohorts.Conclusions: SBRT provided durable LC for pediatric and AYA patients with cancer with minimal severe toxicities. Dose escalation may result in improved LC for sarcoma-predominant cohorts without a subsequent increase in toxicity. However, further investigations with patient-level data and prospective inquiries are indicated to better define the role of SBRT based on patient and tumor-specific characteristics.

  View details for DOI 10.1016/j.adro.2022.101123

  View details for PubMedID 36845622

• Investigating and modeling positron emission tomography factors associated with large cell transformation from low-grade lymphomas. EJHaem Obeid, J. P., Hiniker, S. M., Schroers-Martin, J., Guo, H. H., No, H. J., Moding, E. J., Advani, R. H., Alizadeh, A. A., Hoppe, R. T., Binkley, M. S. 2023; 4 (1): 90-99

  Abstract

  Low-grade lymphomas have a 1%-3% annual risk of transformation to a high-grade histology, and prognostic factors remain undefined. We set to investigate the role of positron emission tomography (PET) metrics in identification of transformation in a retrospective case-control series of patients matched by histology and follow-up time. We measured PET parameters including maximum standard uptake value (SUV-max) and total lesion glycolysis (TLG), and developed a PET feature and lactate dehydrogenase (LDH)-based model to identify transformation status within discovery and validation cohorts. For our discovery cohort, we identified 53 patients with transformation and 53 controls with a similar distribution of follicular lymphoma (FL). Time to transformation and control follow-up time was similar. We observed a significant incremental increase in SUV-max and TLG between control, pretransformation and post-transformation groups (P < 0.05). By multivariable analysis, we identified a significant interaction between SUV-max and TLG such that SUV-max had highest significance for low volume cases (P = 0.04). We developed a scoring model incorporating SUV-max, TLG, and serum LDH with improved identification of transformation (area under the curve [AUC] = 0.91). Our model performed similarly for our validation cohort of 23 patients (AUC = 0.90). With external and prospective validation, our scoring model may provide a specific and noninvasive tool for risk stratification for patients with low-grade lymphoma.

  View details for DOI 10.1002/jha2.615

  View details for PubMedID 36819184

  View details for PubMedCentralID PMC9928791

• Effect of Testicular Boost in Children With Leukemia Receiving Total Body Irradiation and Stem Cell Transplant: A Single-Institution Experience ADVANCES IN RADIATION ONCOLOGY Blomain, E. S., Jiang, A., Donaldson, S. S., Agarwal, R., Bertaina, A., Shyr, D., Eisenberg, M. L., Hoppe, R. T., Hiniker, S. M., Oh, J. 2023; 8 (1)

  View details for DOI 10.1016/j.adro.2022.101071

  View details for Web of Science ID 000876956000001

• Comment on: Metastatic rhabdomyosarcoma: Evidence of the impact of radiotherapy on survival. A retrospective single-center experience. Pediatric blood & cancer Crane, J. N., Donaldson, S. S., Spunt, S. L., Hiniker, S. M. 2022: e30111

  View details for DOI 10.1002/pbc.30111

  View details for PubMedID 36495537

• Long-term Outcomes of Diffuse or Recurrent Tenosynovial Giant Cell Tumor Treated with Postoperative External Beam Radiation Therapy. Practical radiation oncology Baniel, C., Yoo, C. H., Jiang, A., von Eyben, R., Mohler, D. G., Ganjoo, K., Bui, N., Donaldson, S. S., Million, L., Rijn, M. v., Moon Oh, J., Hiniker, S. M. 2022

  Abstract

  PURPOSE: Tenosynovial giant cell tumor (TGCT) is a rare proliferative disorder of synovial membrane that previously was known as pigmented villonodular synovitis (PVNS). Primary treatment involves surgical resection, however, complete removal of all disease involvement is difficult to achieve. Radiation may be useful to reduce the risk of recurrence. We report and update our institutional experience treating diffuse and recurrent TGCT with postsurgical external beam radiation therapy.METHODS AND MATERIALS: We performed a retrospective chart review of 30 patients with TGCT from 2003-2019 treated with radiation therapy. Each patient was evaluated for demographics, radiation treatment parameters, surgical management, complications, and outcome.RESULTS: With mean follow-up of 82 months (range 3-211), 24 patients (80%) who underwent surgery followed by radiation therapy did not experience any further relapse, and all 30 patients achieved local control (100%) with additional salvage therapy following radiotherapy. The most common site of disease was the knee (n=22, 73%), followed by the ankle (n=5, 16%) and the hand (n=3, 10%). Seven patients (24%) presented at time of initial diagnosis while 23 (76%) presented with recurrent disease following surgical resection, with an average of 2.6 surgical procedures prior to radiotherapy. Following resection, 18/30 patients (67%) demonstrated residual TGCT by imaging. The median radiotherapy dose delivered was 36 Gy (range, 34-36 Gy) in 1.8-2.5 Gy/fractions over 4 weeks. In the assessment of post-treatment joint function, 26 sites (86%) exhibited excellent or good function, 2 (7%) fair, and 2 poor (7%) as determined by our scoring system. There were no cases of radiation-associated malignancy.CONCLUSIONS: Among patients with diffuse or recurrent TGCT, postsurgical external beam radiation therapy provided excellent local control and good functional status, with minimal treatment-related complications. Post-surgical radiation therapy is a well-tolerated noninvasive treatment that should be considered following maximal cytoreductive resection to prevent disease progression and recurrence.

  View details for DOI 10.1016/j.prro.2022.11.004

  View details for PubMedID 36460182

• Investigating Metabolic Response after CAR-T Therapy and Bridging Radiotherapy for Relapsed/Refractory B-Cell Lymphoma Marar, M., Hiniker, S., Hoppe, R., Binkley, M. AMER SOC HEMATOLOGY. 2022: 12786-12787

  View details for DOI 10.1182/blood-2022-165302

  View details for Web of Science ID 000893230305405

• Stereotactic radiosurgery for recurrent pediatric brain tumors: clinical outcomes and toxicity. Neurosurgical focus Wang, E., Gutkin, P. M., Oh, J., Pollom, E., Soltys, S. G., Grant, G. A., Prolo, L. M., Chang, S., Li, G., Fisher, P. G., Partap, S., Campen, C. J., Gibbs, I. C., Hiniker, S. M. 2022; 53 (5): E2

  Abstract

  Recurrence of brain tumors in children after the initial course of treatment remains a problem. This study evaluated the efficacy and safety of reirradiation using stereotactic radiosurgery (SRS) in patients with recurrent pediatric primary brain tumors.This IRB-approved retrospective review included pediatric patients with recurrent primary brain tumors treated at Stanford University from 2000 to 2019 using frameless SRS. Time to local failure (LF) and distant intracranial failure (DIF) were measured from the date of SRS and analyzed using competing risk analysis. Overall survival (OS) and progression-free survival (PFS) were analyzed with the Kaplan-Meier method.In total, 37 patients aged 2-24 years (median age 11 years at recurrence) were treated for 48 intracranial tumors. Ependymoma (38%) and medulloblastoma (22%) were the most common tumor types. The median (range) single fraction equivalent dose of SRS was 16.4 (12-24) Gy. The median (range) follow-up time was 22.9 (1.5-190) months. The median OS of all patients was 36.8 months. Eight of 40 (20%) lesions with follow-up imaging locally recurred. The 2-year cumulative incidence of LF after reirradiation with SRS was 12.8% (95% CI 4.6%-25.4%). The 2-year cumulative incidence of DIF was 25.3% (95% CI 12.9%-39.8%). The median PFS was 18 months (95% CI 8.9-44). Five (10.4%) patients developed toxicities potentially attributed to SRS, including cognitive effects and necrosis.Reirradiation using SRS for recurrent pediatric brain tumors appears safe with good local control. Innovations that improve overall disease control should continue because survival outcomes after relapse remain poor.

  View details for DOI 10.3171/2022.8.FOCUS22361

  View details for PubMedID 36321285

• CHARACTERISTICS AND OUTCOMES OF PATIENTS WITH RHABDOMYOSARCOMA WITH ISOLATED LUNG METASTASES: A REPORT FROM THE SOFT TISSUE SARCOMA COMMITTEE OF THE CHILDREN'S ONCOLOGY GROUP Vasquez, J., Luo, L., Hiniker, S., Rhee, D., Dasgupta, R., Chen, S., Weigel, B., Xue, W., Venkatramani, R., Arndt, C. WILEY. 2022

  View details for Web of Science ID 000859203900290

• Time to resolution of iodine-123 metaiodobenzylguanidine (123 I-MIBG) avidity and local control outcomes for high-risk neuroblastoma following radiation therapy. Journal of medical imaging and radiation oncology Oh, J., Gutkin, P., Wang, Y. P., Sandhu, N., Majzner, R. G., Nadel, H., Shimada, H., Lansinger, O., von Eyben, R., Donaldson, S., Bruzoni, M., Sodji, Q. H., Hiniker, S. M. 2022

  Abstract

  INTRODUCTION: 123 I-MIBG scan is used in neuroblastoma (NB) to monitor treatment response. Time to resolution of 123 I-MIBG avidity after radiation therapy (RT) is unknown. We sought to determine time to resolution of 123 I-MIBG avidity after RT and local failure (LF) rate.METHODS: We performed a retrospective review of children with high-risk NB who underwent 123 I-MIBG scans pre- and post-RT from 2003 to 2019. Time from RT to resolution of 123 I-MIBG activity was analysed. LF and cumulative incidence of local progression (CILP) after RT stratified by site, presence of residual disease and use of boost RT were determined.RESULTS: Forty-two patients with median age 3.9years (1.9-4.7years) were included, with median follow-up time 3.9years (1.4-6.9). Eighty-six lesions were treated with RT to median dose of 21.6Gy. Eighteen of 86 lesions were evaluable for time to resolution of MIBG avidity after RT, with median resolution time of 78days (36-208). No LF occurred among 26 patients who received RT to primary sites after GTR, versus 4/12 (25%) patients treated with residual primary disease. 2-year CILP was 19% (12% primary disease 25% metastatic disease (P=0.18)). 2-year CILP for non-residual primary, residual primary, non-residual metastatic and residual metastatic lesions was 0%, 42%, 11% and 30% respectively (P=0.01) and for boosted and non-boosted residual lesions was 29% and 35% (P=0.44).CONCLUSION: Median time to MIBG resolution after RT was 78days. Primary lesions without residual disease had excellent local control. LF rate was higher after RT for residual disease, with no benefit for boost RT.

  View details for DOI 10.1111/1754-9485.13487

  View details for PubMedID 36300562

• Outcomes of Pediatric and Adolescent Patients with Metastatic Sarcoma Treated with Surgical Resection or Stereotactic Ablative Radiation Therapy (SABR) Oh, J., Gutkin, P., Donaldson, S., Steffner, R., Bruzoni, M., Avedian, R., Spunt, S., Pribnow, A., Hiniker, S. LIPPINCOTT WILLIAMS & WILKINS. 2022: S42

  View details for Web of Science ID 000847787800089

• Analysis of Metabolic Tumor Volume in Patients Undergoing Radiotherapy Prior to or After CAR-T Therapy for Relapsed/refractory Aggressive B Cell Lymphoma Marar, M., Hiniker, S., Hoppe, R., Binkley, M. LIPPINCOTT WILLIAMS & WILKINS. 2022: S12-S13

  View details for Web of Science ID 000847787800028

• Comparison of treatment cost and quality-of-life impact of thyroid eye disease therapies Shah, S., Lu, T., Yu, M., Hiniker, S., Dosiou, C., Kossler, A. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2022

  View details for Web of Science ID 000844437005105

• Local control outcomes using stereotactic body radiotherapy or surgical resection for metastatic sarcoma. International journal of radiation oncology, biology, physics Gutkin, P. M., von Eyben, R., Chin, A., Donaldson, S. S., Oh, J., Jiang, A., Ganjoo, K. N., Avedian, R. S., Bruzoni, M., Steffner, R. J., Moding, E. J., Hiniker, S. M. 2022

  Abstract

  Traditional management of metastatic sarcoma primarily relies on systemic therapy, with surgery often used for tumor control. We analyzed the rates of recurrence, overall survival, and treatment complications in patients undergoing either surgical resection or stereotactic body radiotherapy (SBRT) for metastatic sarcoma of the bone and/or soft tissue.The records of patients with metastatic sarcoma between 2009-2020 were reviewed. Local recurrence (LR) was defined as tumor growth or recurrence at the tumor site. Cumulative local recurrence incidence was analyzed accounting for the competing risk of death, and groups were compared using the Gray test. Overall survival (OS) was assessed using the Kaplan Meier method and log-rank test. Hazard ratios were determined using Cox proportional test.A total of 525 metastatic lesions in 217 patients were analyzed. Mean age was 57 years (range 4-88). The lung was the predominant site treated (50%), followed by intra-abdominal (13%), and soft-tissue (11%). Two-year cumulative incidences of LR for surgery and SBRT were 14.8% (95% confidence interval [CI], 11.6-18.5) and 1.7% (95% CI, 0.1-8.2), respectively (p=0.003). LR occurred in 72/437 (16.5%) tumors treated with surgery and 2/88 (2.3%) tumors treated with SBRT. Adjusted hazard ratio for LR of lesions treated surgically was 11.5 (p=0.026) when controlled for tumor size and tumor site. Median OS was 29.8 months (95% CI, 25.6-40.9). There were 47 surgical complications of a total of 275 procedures (18%). Of 58 radiation treatment courses, radiation-related toxicity was reported during the treatment of 7 lesions (12%), and none were higher than grade 2.We observed excellent local control among patients selected for treatment with SBRT for metastatic sarcoma, with no evidence of increase in LR following SBRT when compared to surgical management. Further investigation is necessary to better define the most appropriate local control strategies for metastatic sarcoma.

  View details for DOI 10.1016/j.ijrobp.2022.05.017

  View details for PubMedID 35643255

• Volumetric modulated arc therapy total body irradiation in pediatric and adolescent/young adult patients undergoing stem cell transplantation: Early outcomes and toxicities. Pediatric blood & cancer Marquez, C., Hui, C., Simiele, E., Blomain, E., Oh, J., Bertaina, A., Klein, O., Shyr, D., Jiang, A., Hoppe, R. T., Kovalchuk, N., Hiniker, S. M. 2022: e29689

  Abstract

  INTRODUCTION: Total body irradiation (TBI) is an important component of many conditioning regimens for hematopoietic stem cell transplantation (HSCT), most commonly used in pediatric and adolescent/young adult (AYA) patients. We aimed to evaluate outcomes and toxicities among pediatric and AYA patients treated with TBI utilizing volumetric modulated arc therapy total body irradiation (VMAT-TBI).METHODS: We reviewed pediatric and AYA patients treated with VMAT-TBI at our institution from 2019 to 2021. Data on patient and disease characteristics, treatment details, outcomes and toxicities were collected. Overall survival (OS) and relapse-free survival (RFS) were analyzed using the Kaplan-Meier method.RESULTS: Among 38 patients, 16 (42.1%) were treated with myeloablative regimens and 22 (57.9%) with nonmyeloablative regimens. Median age was 7.2 years (range: 1-27) and median follow-up was 8.7 months (range: 1-21). Lungs Dmean was 7.3 ± 0.3Gy for myeloablative regimens (range: 6.8-7.8). Kidneys were spared to average mean dose of 71.4 ± 4.8% of prescription dose. Gonadal sparing was achieved for patients treated for nonmalignant diseases to Dmean of 0.7 ± 0.1Gy. No patient experienced primary graft failure; one (2.6%) experienced secondary graft failure. The most common grade 1-2 acute toxicities were nausea (68.4%) and fatigue (55.3%). Mucositis was the most common grade 3-4 acute toxicity, affecting 39.5% of patients. There were no cases of pneumonitis or nephrotoxicity attributable to TBI.CONCLUSION: VMAT-TBI offers increased ability to spare organs at risk in pediatric and AYA patients undergoing HSCT, with a favorable acute/subacute toxicity profile and excellent disease control.

  View details for DOI 10.1002/pbc.29689

  View details for PubMedID 35373904

• Detection of Recurrence After Thoracic Stereotactic Ablative Radiotherapy Using FDG-PET-CT. Clinical lung cancer Sodji, Q. H., Harris, J. P., Quon, A., Modlin, L. A., Lau, B., Jiang, A., Trakul, N., Maxim, P. G., Diehn, M., Loo, B. W., Hiniker, S. M. 2022

  Abstract

  INTRODUCTION/BACKGROUND: Differentiating local recurrence (LR) from post-treatment changes following stereotactic ablative radiotherapy (SABR) for thoracic tumors is challenging. We sought to evaluate the performance of FDG-PET-CT in distinguishing recurrence from post-radiation changes in patients with stage I-II non-small cell lung cancer (NSCLC) treated with SABR.MATERIALS AND METHODS: We performed a retrospective review of patients with stage I-II NSCLC treated with SABR and subsequently followed with surveillance FDG-PET-CT scans from 2004 to 2014. The radiology reports were coded as 0 or 1 if minimally or substantially concerning for LR, respectively, and correlated with outcome. Prognostic factors for false-positive FDG-PET-CT were assessed using logistic regression models.RESULTS: We identified 145 patients meeting inclusion criteria for the retrospective analysis. Amongst the 39 (26.9%) patients with FDG-PET-CT scans concerning for LR 3 to 24 months after treatment, 14 were confirmed to have LR. Thus, the positive predictive value (PPV) of FDG-PET-CT in identifying LR was 36% (14/39). Factors associated with a false-positive scan included concerning FDG-PET-CT at the earliest post-treatment time point (3 months) (odds ratio 0.67, P= .04) and older age (odds ratio 2.3, P= .02).CONCLUSION: Our analysis indicates that the PPV of a concerning FDG-PET-CT after SABR for early-stage NSCLC is relatively low, especially at early post-treatment timepoints, but accuracy is improving over time with institutional experience.

  View details for DOI 10.1016/j.cllc.2022.01.006

  View details for PubMedID 35246393

• The Stanford VMAT TBI Technique. Practical radiation oncology Kovalchuk, N., Simiele, E., Skinner, L., Yang, Y., Howell, N., Lewis, J., Hui, C., Blomain, E. S., Hoppe, R. T., Hiniker, S. M. 2022

  Abstract

  In this work, we describe the technical aspects of the XXX VMAT TBI technique, compare it to other VMAT TBI techniques, and share our initial experience.From September 2019 to August 2021, 35 patients were treated with VMAT TBI at our institution. Treatment planning was performed using in-house developed automated planning scripts. Organ sparing depended on the regimen: myeloablative (lungs, kidneys, and lenses); non-myeloablative with benign disease (lungs, kidneys, lenses, gonads, brain, and thyroid). Quality assurance was performed using EPID portal dosimetry and Mobius3D. Robustness was evaluated for the first ten patients by performing local and global isocenter shifts of 5 mm. Treatment was delivered using IGRT for every isocenter and every fraction. In-vivo measurements were performed on the matchline between the VMAT and AP/PA fields and on the testes for the first fraction.The lungs, lungs-1cm, and kidneys Dmean were consistently spared to 57.6±4.4%, 40.7±5.5%, and 70.0±9.9% of the prescription dose, respectively. Gonadal sparing (Dmean=0.69±0.13 Gy) was performed for all patients with benign disease. The average PTV D1cc was 120.7±6.4% for all patients. The average Gamma passing rate for the VMAT plans was 98.1±1.6% (criteria of 3%/2mm). Minimal differences were observed between Mobius3D- and EclipseAAA-calculated PTV Dmean (0.0±0.3%) and lungs Dmean (-2.5±1.2%). Robustness evaluation showed that the PTV Dmax and lungs Dmean are insensitive to small positioning deviations between the VMAT isocenters (1.1±2.4% and 1.2±1.0%, respectively). The average matchline dose measurement indicated patient setup was reproducible (96.1±4.5% relative to prescription dose). Treatment time, including patient setup and beam-on, was 47.5±9.5 min.The XXX VMAT TBI technique, from simulation to treatment delivery, was presented and compared to other VMAT TBI techniques. Together with publicly shared autoplanning scripts, our technique may provide the gateway for wider adaptation of this technology and the possibility of multi-institutional studies in the cooperative group setting.

  View details for DOI 10.1016/j.prro.2021.12.007

  View details for PubMedID 35182803

• Radiation Therapy without Anesthesia for a 2-Year Old Child using Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR). Practical radiation oncology Prasad, R. N., Baliga, S., Banner, J., Cadieux, C., Centnar, A., Degnan, M., Depinet, M., Ewing, A., Hobbs, N., Jiang, A. L., Manring, I., Perlow, H. K., Rock, A., Skinner, L. B., Tenney, L., Walls, V., Hiniker, S. M., Palmer, J. D. 1800

  Abstract

  Radiation therapy (RT) is essential to managing many pediatric malignancies, but can be anxiety, fear, and discomfort provoking for children due to prolonged treatment time, extended course, and restrictive immobilization. Patients under 10 years frequently require daily general anesthesia (GA), which is resource intensive, expensive, potentially toxic, and anxiety/fear provoking. The Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR), a video streaming device, has been proposed as an alternative to anesthesia in patients aged 3-10. A pilot study evaluating the efficacy of this novel innovation is accruing, but patients under 3 are ineligible. We simulated a 2-year-old with Stage IV Wilms tumor for bilateral whole lung and left flank irradiation without GA. Using the AVATAR, we attempted to deliver RT to this patient without sedation. Patient anxiety at the time of simulation and at the beginning, middle, and end of the treatment course was characterized using the validated Modified Yale Preoperative Anxiety Score (mYPAS) measurement tool. Although the patient tolerated CT simulation without GA or AVATAR use, his mYPAS of 14/18 indicated significant anxiety. Using the AVATAR, all treatments were delivered without GA; mYPAS scores were 5, 4 (lowest possible), and 4 at the first, mid-course and final treatments, indicating no significant anxiety and a decrease from pre-AVATAR baseline. Without GA, the package time to deliver RT decreased by 66% from 90 to 30 minutes. In summary, we describe an expanded, previously unreported indication for the AVATAR by demonstrating the feasibility of this anesthesia-reducing/omitting approach in appropriate younger patients currently excluded from ongoing trials. The financial and quality of life benefits (including decreased stress, anxiety, toxicity, cost, and appointment time) of AVATAR utilization may be extendable to a younger patient population than previously thought. In older children, prospective validation is ongoing, but additional study in patients under 3 is needed.

  View details for DOI 10.1016/j.prro.2021.12.009

  View details for PubMedID 34971793

• Multidisciplinary management of newly diagnosed pediatric large cell neuroendocrine carcinoma of the lung causing hemoptysis. Pediatric blood & cancer Marquez, C. P., Violari, E. G., Sodji, Q., Jiang, A. L., Donaldson, S. S., Josephs, S., Hiniker, S. M. 2021: e29182

  View details for DOI 10.1002/pbc.29182

  View details for PubMedID 34125484

• Rhabdomyosarcoma. Pediatric blood & cancer Yechieli, R. L., Mandeville, H. C., Hiniker, S. M., Bernier-Chastagner, V., McGovern, S., Scarzello, G., Wolden, S., Cameron, A., Breneman, J., Fajardo, R. D., Donaldson, S. S. 2021; 68 Suppl 2: e28254

  Abstract

  Rhabdomyosarcoma is a heterogeneous disease both in presentation and histology. Improvements in a multimodality therapy resulted in the improved overall survival for patients with a low-risk and intermediate-risk disease but not for patients with a metastatic disease. We reviewed and contrasted the North American and European practice patterns, though ultimately the principles of staging, surgery, radiation therapy, and chemotherapy are similar in both Children's Oncology Group and International Society of Paediatric Oncology treatment approaches. Efforts are underway to investigate improved local control rates in higher risk patients using radiation dose escalation strategies, and delayed primary excision in select cases. The prognostic significance of imaging-based chemotherapy response, proton therapy, novel biomarkers, and targeted drugs will be determined in upcoming clinical trials.

  View details for DOI 10.1002/pbc.28254

  View details for PubMedID 33818882

• Low-Dose Total Skin Electron Beam Therapy Combined With Mogamulizumab for Refractory Mycosis Fungoides and Sezary Syndrome. Advances in radiation oncology Fong, S., Hong, E. K., Khodadoust, M. S., Li, S., Hoppe, R. T., Kim, Y. H., Hiniker, S. M. 2021; 6 (3): 100629

  Abstract

  Purpose: Management of patients with refractory mycosis fungoides and Sezary syndrome (SS) is often challenging, as available therapies lack durable response and consistent activity across disease compartments. Combining low-dose total skin electron beam therapy (LD-TSEBT) upfront with mogamulizumab could optimize the clinical outcome of these patients. LD-TSEBT is effective in clearing skin disease, and mogamulizumab is an antitumor immunotherapy with long-term tolerability, suggesting its potential as a maintenance therapy after maximal response. We examine the combination regimen in patients with SS who were previously treated.Methods and Materials: Two patients with SS were treated with combination LD-TSEBT and mogamulizumab. Both patients received mogamulizumab 1 mg/kg weekly * 4 and then bi-weekly; LD-TSEBT (12 Gy) was initiated within 2 days of starting mogamulizumab and given over 2-3 weeks. Safety and clinical response were evaluated.Results: Total skin electron beam therapy plus mogamulizumab (TSE-Moga) was well-tolerated without any unanticipated adverse events. Patient 1 (T4N2bM0B2) was a 63-year-old woman with 4 prior systemic therapies; time to global response with TSE-Moga was 9 weeks. Patient 2 (T4NxM0B2) was a 75-year-old man with 5 prior systemic therapies; time to global response was 4 weeks. Both patients lacked global response to their prior therapies but achieved global complete response (blood and skin) with TSE-Moga. After a follow-up of 72 weeks and 43 weeks, respectively, global complete response continued.Conclusions: TSE-Moga demonstrated excellent tolerability and promising clinical activity with ongoing global complete responses in 2 patients with refractory SS. This encouraging experience supports our ongoing clinical trial evaluating the efficacy and safety of TSE-Moga in mycosis fungoides and SS.

  View details for DOI 10.1016/j.adro.2020.11.014

  View details for PubMedID 33748543

• Radiation Therapy for Primary Cutaneous Gamma Delta Lymphoma Prior to Stem Cell Transplantation. Cancer investigation Wu, Y. F., Skinner, L., Lewis, J., Khodadoust, M. S., Kim, Y. H., Kwong, B. Y., Weng, W., Hoppe, R. T., Sodji, Q., Hui, C., Kastelowitz, N., Fernandez-Pol, S., Hiniker, S. M. 2021: 1–11

  Abstract

  We present a patient with widespread PCGD-TCL of the bilateral arms and legs, who underwent radiotherapy with 34Gy in 17 fractions using circumferential VMAT and 3-D printed bolus to the 4 extremities prior to planned stem cell transplant, who was then found to have progression in the liver, lung, and skin, followed by drastic regression of all in and out-of-field lesions on imaging 1.5months later. The cause of regression may be related to a radiation-induced abscopal effect from the immunomodulatory effects of radiation, or related to immune reactivation in the setting of cessation of systemic immunosuppressive agents.

  View details for DOI 10.1080/07357907.2021.1919696

  View details for PubMedID 33899635

• Excellent Outcome for Pediatric Patients With High-Risk Hodgkin Lymphoma Treated With Brentuximab Vedotin and Risk-Adapted Residual Node Radiation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Metzger, M. L., Link, M. P., Billett, A. L., Flerlage, J., Lucas, J. T., Mandrell, B. N., Ehrhardt, M. J., Bhakta, N., Yock, T. I., Friedmann, A. M., de Alarcon, P., Luna-Fineman, S., Larsen, E., Kaste, S. C., Shulkin, B., Lu, Z., Li, C., Hiniker, S. M., Donaldson, S. S., Hudson, M. M., Krasin, M. J. 2021: JCO2003286

  Abstract

  PURPOSE: Brentuximab vedotin, an effective anti-CD30 antibody-drug conjugate approved for use in adults with classical Hodgkin lymphoma (HL), was introduced in this frontline trial to reduce prescribed radiation in children and adolescents with classical HL.METHODS: Open-label, single-arm, multicenter trial for patients (age ≤ 18 years) with stage IIB, IIIB, or IV classical HL was conducted. Brentuximab vedotin replaced each vincristine in the OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) regimen according to GPOH-HD2002 treatment group 3 (TG3); two cycles of AEPA and four cycles of CAPDac. Residual node radiotherapy (25.5 Gy) was given at the end of all chemotherapy only to nodal sites that did not achieve a complete response (CR) at the early response assessment (ERA) after two cycles of therapy. Primary objectives were to evaluate the safety and efficacy (complete remission at ERA) of this combination and the 3-year event-free (EFS) and overall survival (OS). The trials are registered at ClinicalTrials.gov identifier: NCT01920932.RESULTS: Of the 77 patients enrolled in the study, 27 (35%) achieved complete remission at ERA and were spared radiation. Patients who were irradiated received radiation to individual residual nodal tissue. At a median follow-up of 3.4 years, the 3-year EFS was 97.4% (SE 2.3%) and the OS was 98.7% (SE 1.6%). One irradiated patient experienced disease progression at the end of therapy and now remains disease free more than 6 years following salvage therapy, and one unexpected death occurred. Only 4% of patients experienced grade 3 neuropathy.CONCLUSION: The integration of brentuximab vedotin in the frontline treatment of pediatric high-risk HL is highly tolerable, facilitated significant reduction in radiation exposure, and yielded excellent outcomes.

  View details for DOI 10.1200/JCO.20.03286

  View details for PubMedID 33826362

• Multimodality treatment including whole pleura radiation therapy for DICER1-associated pediatric pleuropulmonary blastoma. Pediatric blood & cancer Hui, C., Shin, D. H., Wakeling, A., Donaldson, S. S., Hazard, F. K., Rangaswami, A., Hiniker, S. M. 2021: e29004

  Abstract

  Limited data are available regarding radiation therapy in pediatric pleuropulmonary blastoma (PPB). We report the case of a 3-year-old girl with type II PPB successfully treated with trimodality therapy including multiagent chemotherapy, resection, and whole pleura radiation therapy. While longer follow-up is required to confirm ultimate local tumor control and long-term post-treatment sequelae, currently 3.5years following therapy, she is well, without recurrent disease or observable toxicity. The goal of this report is to add our experience to the literature regarding PPB, its management, and treatment, as prospective randomized controlled trials are not feasible due to the rarity of this disease.

  View details for DOI 10.1002/pbc.29004

  View details for PubMedID 33751747

• Use of Audiovisual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) for Anesthesia Avoidance in a Pediatric Patient With Down Syndrome. Advances in radiation oncology Gutkin, P. M., Donaldson, S. S., Skinner, L., Callejas, M., Cimino, J., Lore, J., Bush, K., Hiniker, S. M. 2021; 6 (2): 100637

  View details for DOI 10.1016/j.adro.2020.100637

  View details for PubMedID 33732961

• Stage I-II diffuse large B-cell lymphoma treated with rituximab and chemotherapy with or without radiotherapy. Leukemia & lymphoma Binkley, M. S., Hiniker, S. M., Younes, S., Yoo, C., Wignarajah, A., Jin, M., Guo, H. H., Gupta, N. K., Natkunam, Y., Advani, R. H., Hoppe, R. T. 2021: 1–15

  Abstract

  We set to identify prognostic factors in a retrospective cohort of consecutive patients with stage I-II diffuse large B-cell lymphoma treated with rituximab-chemotherapy with or without radiotherapy from 2001 through 2017 at our institution. We identified 143 patients with median follow-up of 7.7years. The majority were male (59.4%), had stage II (53.1%), had stage-modified IPI 0-1 (smIPI, 58.1%), and had non-bulky disease (<7cm, 68.5%). 99 patients (69.2%) received rituximab-chemotherapy followed by radiotherapy, and 44 patients (30.8%) received rituximab-chemotherapy alone. The 5-year progression-free survival (PFS) and overall survival (OS) were 81.2% and 88.9%, respectively. The 5-year PFS for those with smIPI 0-1 versus 2-4 was 89.5% versus 69.7%, respectively (P=0.005). Bulky disease (≥7cm) was associated with worse PFS and OS on univariable and multivariable analyses (P<0.05). Patients with smIPI 0-1 without bulky disease have excellent outcomes. However, patients with smIPI 2-4 or bulky disease have a high risk of progression.

  View details for DOI 10.1080/10428194.2021.1876859

  View details for PubMedID 33622155

• Financial Toxicity in Patients with Brain and Spine Metastases. World neurosurgery Koenig, J. L., Sandhu, N. n., Sborov, K. n., Sabolch, A. n., Usoz, M. n., Li, G. n., Gephart, M. H., Chang, S. n., Hiniker, S. n., Soltys, S. G., Pollom, E. L. 2021

  Abstract

  Financial toxicity associated with cancer treatment has a deleterious impact on patient outcomes but has not been well-characterized among patients with metastatic cancers. We characterize the extent of financial toxicity among this population and identify factors associated with financial toxicity.We prospectively surveyed adult patients with brain and spine metastases who received radiosurgery at a large academic medical center between January 2018 and December 2019. Financial toxicity was measured with the Personal Financial Wellness (PFW) Scale.In total, 93 patients were included with a median survival of 17.7 months. Most patients had private insurance (47%) or Medicare with supplemental insurance (42%) while 11% of patients were uninsured or insured by Medicaid/Medicare/Veterans Affairs. 60% of patients were primary income earners of which 52% had dependents. The median PFW score was 7.0 (interquartile range, 5.1-9.1) with financial toxicity reported in 23 (25%) patients. After adjusting for age and education level, private insurance (OR 0.28; p=0.080) was associated with a lower likelihood of financial toxicity. At least one emergency department visit (OR 3.87; p=0.024) and a cancer-related change in employment status (OR 3.63; p=0.036) were associated with greater likelihood of reporting financial toxicity.Most poor prognosis cancer patients with brain and spine metastases treated at a tertiary center are primary income earners and experience financial toxicity. Further studies are warranted to assess the longitudinal impact of financial toxicity in patients with metastatic cancer, particularly those with at least one emergency department visit and a cancer-related change in employment status.

  View details for DOI 10.1016/j.wneu.2021.04.103

  View details for PubMedID 33940276

• Wilms Tumor (Nephroblastoma), Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Balis, F., Green, D. M., Anderson, C., Cook, S., Dhillon, J., Gow, K., Hiniker, S., Jasty-Rao, R., Lin, C., Lovvorn, H., MacEwan, I., Martinez-Agosto, J., Mullen, E., Murphy, E. S., Ranalli, M., Rhee, D., Rokitka, D., Tracy, E. L., Vern-Gross, T., Walsh, M. F., Walz, A., Wickiser, J., Zapala, M., Berardi, R. A., Hughes, M. 2021; 19 (8): 945-977

  Abstract

  The NCCN Guidelines for Wilms Tumor focus on the screening, diagnosis, staging, treatment, and management of Wilms tumor (WT, also known as nephroblastoma). WT is the most common primary renal tumor in children. Five-year survival is more than 90% for children with all stages of favorable histology WT who receive appropriate treatment. All patients with WT should be managed by a multidisciplinary team with experience in managing renal tumors; consulting a pediatric oncologist is strongly encouraged. Treatment of WT includes surgery, neoadjuvant or adjuvant chemotherapy, and radiation therapy (RT) if needed. Careful use of available therapies is necessary to maximize cure and minimize long-term toxicities. This article discusses the NCCN Guidelines recommendations for favorable histology WT.

  View details for DOI 10.6004/jnccn.2021.0037

  View details for PubMedID 34416707

• Pediatric Hodgkin Lymphoma, Version 3.2021. Journal of the National Comprehensive Cancer Network : JNCCN Flerlage, J. E., Hiniker, S. M., Armenian, S., Benya, E. C., Bobbey, A. J., Chang, V., Cooper, S., Coulter, D. W., Cuglievan, B., Hoppe, B. S., Isenalumhe, L., Kelly, K., Kersun, L., Lamble, A. J., Larrier, N. A., Magee, J., Oduro, K., Pacheco, M., Price, A. P., Roberts, K. B., Smith, C. M., Sohani, A. R., Trovillion, E. M., Walling, E., Xavier, A. C., Burns, J. L., Campbell, M. 2021; 19 (6): 733-754

  Abstract

  Hodgkin lymphoma (HL) is a highly curable form of cancer, and current treatment regimens are focused on improving treatment efficacy while decreasing the risk of late effects of treatment. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for pediatric HL provide recommendations on the workup, diagnostic evaluation, and treatment of classic HL, including principles of pathology, imaging, staging, systemic therapy, and radiation therapy. This portion of the NCCN Guidelines focuses on the management of pediatric classic HL in the upfront and relapsed/refractory settings.

  View details for DOI 10.6004/jnccn.2021.0027

  View details for PubMedID 34214968

• Use of cardiac radiation therapy as bridging therapy to CAR-T for relapsed pediatric B-cell acute lymphoblastic leukemia. Pediatric blood & cancer Marquez, C. P., Montiel-Esparza, R., Hui, C., Schultz, L. M., Davis, K. L., Hoppe, R. T., Donaldson, S. S., Ramakrishna, S., Hiniker, S. M. 2020: e28870

  Abstract

  The use of radiotherapy as bridging therapy to chimeric antigen receptor T-cell therapy (CAR-T) in pre-B acute lymphoblastic leukemia (B-ALL) has been minimally explored. Here, we present a boy with B-ALL who relapsed after allogeneic bone marrow transplant with disseminated disease, including significant symptomatic cardiovascular and gastrointestinal (GI) involvement. The cardiac and GI leukemic infiltrates were successfully treated with bridging radiation therapy (BRT) prior to CAR-T infusion. Using this approach, he successfully tolerated CAR-T with no evidence of disease or sequelae on 3-month follow-up. This is the first reported case of safe and effective delivery of cardiac BRT in B-ALL.

  View details for DOI 10.1002/pbc.28870

  View details for PubMedID 33355997

• Paraneoplastic Neurologic Symptoms in a Pediatric Patient with Hodgkin Lymphoma. Cancer investigation Baniel, C. C., Donaldson, S. S., Aftandilian, C., Hiniker, S. M. 2020: 1–7

  Abstract

  Neurological paraneoplastic syndromes are exceedingly rare, and often difficult to recognize clinically. Paraneoplastic achalasia is a condition characterized by new onset dysphagia that is unrelated to tumor burden, most often due to the development of auto-immune antibodies targeting esophageal tissue. Due to the rarity of this condition, diagnosis is often delayed, leading to increased time to treatment. Here we report a case of a rare paraneoplastic achalasia in a female child with EBV+Hodgkin lymphoma, review literature describing paraneoplastic achalasia, and discuss treatment strategies for improving clinical outcome in these patients.

  View details for DOI 10.1080/07357907.2020.1852412

  View details for PubMedID 33191790

• A multi-institutional phase 2 trial of stereotactic body radiotherapy in the treatment of bone metastases in pediatric and young adult patients with sarcoma. Cancer Elledge, C. R., Krasin, M. J., Ladra, M. M., Alcorn, S. R., Han, P., Gibbs, I. C., Hiniker, S. M., Laack, N. N., Terezakis, S. A. 2020

  Abstract

  BACKGROUND: Metastasectomy is standard of care for pediatric patients with metastatic sarcoma with limited disease. For patients with unresectable disease, stereotactic body radiotherapy (SBRT) may serve as an alternative. Herein, the authors report the results of a prospective, multi-institutional phase 2 trial of SBRT in children and young adults with metastatic sarcoma.METHODS: Patients aged >3 years and ≤40 years with unresected, osseous metastatic nonrhabdomyosarcoma sarcomas of soft tissue and bone were eligible. Patients received SBRT to a dose of 40 Gray (Gy) in 5 fractions. Local control (LC), progression-free survival (PFS), and overall survival (OS) were calculated using the Kaplan-Meier method.RESULTS: Fourteen patients with a median age of 17 years (range, 4-25 years) were treated to 37 distinct metastatic lesions. With a median follow-up of 6.8 months (30.5 months in surviving patients), the Kaplan-Meier patient-specific and lesion-specific LC rates at 6 months were 89% and 95%, respectively. The median PFS was 6 months and the median OS was 24 months. In a post hoc analysis, PFS (median, 9.3 months vs 3.7 months; log-rank P = .03) and OS (median not reached vs 12.7 months; log-rank P = .02) were improved when all known sites of metastatic disease were consolidated with SBRT compared with partial consolidation. SBRT was well tolerated, with 2 patients experiencing grade 3 toxicities.CONCLUSIONS: SBRT achieved high rates of LC in pediatric patients with inoperable metastatic nonrhabdomyosarcoma sarcomas of soft tissue and bone. These results suggest that the ability to achieve total consolidation of metastatic disease with SBRT is associated with improved PFS and OS.

  View details for DOI 10.1002/cncr.33306

  View details for PubMedID 33170960

• Durability of response in metastatic melanoma patients after combined treatment with radiation therapy and ipilimumab. Melanoma management Sodji, Q. H., Gutkin, P. M., Swetter, S. M., Reddy, S. A., Hiniker, S. M., Knox, S. J. 2020; 7 (1): MMT36

  Abstract

  Aim: We previously reported a prospective trial evaluating the safety and efficacy of combining ipilimumab and radiation therapy in patients with metastatic melanoma. Herein, we provide a long-term update on patients with complete response (CR) or partial response (PR).Patients & methods: We continued to follow these patients with serial imaging including computed tomography, PET or MRI.Results: Two of the three patients with CR are still alive and without evidence of melanoma but with chronic treatment-induced hypophysitis. The third patient died of hepatocellular carcinoma, but with no evidence of melanoma. Among the three patients with PR, two achieved CR after pembrolizumab monotherapy.Conclusion: This long-term follow up reveals the striking durability of the CRs, which appears to correlate with a grade 2-3 hypophysitis.

  View details for DOI 10.2217/mmt-2019-0020

  View details for PubMedID 32399174

• Impact of Audio-Visual Assisted Therapeutic Ambience in Radiotherapy (AVATAR) on Anesthesia Use, Payer Charges, and Treatment Time in Pediatric Patients. Practical radiation oncology Balazy, K. E., Gutkin, P. M., Skinner, L., von Eyben, R., Fowler, T., Pinkham, D. W., Rodriguez, S., Maxim, P. G., Donaldson, S. S., Loo, B. W., Bush, K., Hiniker, S. M. 2020

  Abstract

  PURPOSE: Pediatric radiotherapy requires optimal immobilization that often necessitates daily anesthesia. To decrease anesthesia use, we implemented a novel XXX system which projects video onto a radiolucent screen within the child's line of vision to provide attentional diversion. We investigated its reduction on anesthesia use, payer charges, and treatment time, as well as its impact on radiation delivery.METHODS AND MATERIALS: A 6-year retrospective analysis was performed among children undergoing radiotherapy (n=224), 3 years before and 3 after introduction of XXX. The frequency of anesthesia use before and after XXX implementation, as well as radiotherapy treatment times were compared. The number of spared anesthesia treatments allowed for a charge to payer analysis. To document lack of surface dose perturbation by XXX, a phantom craniospinal treatment course was delivered both with and without XXX. Additionally, an ion chamber course was delivered to document changes to dose at depth.RESULTS: More children were able to avoid anesthesia use entirely in the post-XXX cohort, compared to the pre-XXX cohort (73.2% vs 63.4%, p=0.03) and fewer required anesthesia for each treatment (18.8% vs 33%; p = 0.03). XXX introduction reduced anesthesia use for all ages studied. Treatment time per session was reduced by 38% using XXX compared to anesthesia. There were 326 fewer anesthesia sessions delivered over three years after XXX was introduced, with an estimated savings of > $500,000. OSLDs revealed a small increase in dose of 0.8%-9.5% with XXX, while the use of a thermomolded face mask increased skin dose as much as 58%.CONCLUSIONS: XXX introduction decreased anesthesia use in children undergoing radiotherapy; more avoided anesthesia entirely, and fewer needed it for every treatment. This resulted in a reduction in treatment time, and savings of nearly $550,000 in approximately 3 years, with minimal perturbation of radiotherapy dose delivery.

  View details for DOI 10.1016/j.prro.2019.12.009

  View details for PubMedID 31935524

• Impact of Proton Radiotherapy on Treatment Timing in Pediatric and Adult Patients with Central Nervous System Tumors Neuro-Oncology Practice Jin, M. C., Shi, S., Wu, A., Sandhu, N., Xiang, M., Soltys, S. G., Hiniker, S., Li, G., Pollom, E. L. 2020

  View details for DOI 10.1093/nop/npaa034

• Improving the Pediatric Patient Experience During Radiation Therapy - A Children's Oncology Group Study. International journal of radiation oncology, biology, physics Holt, D. E., Hiniker, S. M., Kalapurakal, J. A., Breneman, J. C., Shiao, J. C., Boik, N. n., Cooper, B. T., Dorn, P. L., Hall, M. D., Logie, N. n., Lucas, J. T., MacEwan, I. J., Olson, A. C., Palmer, J. D., Patel, S. n., Pater, L. E., Surgener, S. n., Tsang, D. S., Vogel, J. H., Wojcik, A. n., Wu, C. C., Milgrom, S. A. 2020

  Abstract

  Treatment with radiation therapy (RT) can cause anxiety and distress for pediatric patients and their families. Radiation oncology teams have developed strategies to reduce the negative psychological impact. This survey study aimed to characterize these methods.A 37-item questionnaire was sent to all radiation oncology members of the Children's Oncology Group to explore strategies to improve the pediatric patient experience. The Wilcoxon rank-sum test was used to assess factors associated with use of anesthesia for older children.Surveys were completed by 106 individuals from 84/210 institutions (40%). Respondents included 89 radiation oncologists and 17 supportive staff. Sixty-one percent of centers treated ≤50 children per year. Respondents described heterogenous interventions. The median age at which most children no longer required anesthesia was 6-years-old (range: ≤3-years-old to ≥ 8-years-old). Routine anesthesia use at an older age was associated with physicians' lack of awareness of these strategies (p=.04) and <10 years of pediatric radiation oncology experience (p=.04). Fifty-two percent of respondents reported anesthesia use added >45 minutes in the radiation oncology department daily. Twenty-six percent of respondents planned to implement new strategies, with 65% focusing on video-based distraction therapy and/or augmented reality/virtual reality.Many strategies are used to improve children's experience during RT. Lack of awareness of these interventions is a barrier to their implementation and is associated with increased anesthesia use. This study aims to disseminate these methods with the goal of raising awareness, facilitating implementation, and, ultimately, improving the experience of pediatric cancer patients and their caregivers.

  View details for DOI 10.1016/j.ijrobp.2020.09.002

  View details for PubMedID 32931864

• A preliminary report of gonadal-sparing TBI using a VMAT technique. Practical radiation oncology Blomain, E. S., Kovalchuk, N. n., Neilsen, E. n., Skinner, L. n., Hoppe, R. T., Hiniker, S. M. 2020

  Abstract

  Reproductive toxicity is common following total body irradiation and has major quality of life implications for patients. In that context, this is the first report of gonadal-sparing VMAT TBI, successfully delivered in a boy and a girl with aplastic anemia. Both patients' VMAT TBI plans demonstrated improved gonadal sparing versus simulated conventional 2D approach (mean testes dose 0.45 Gy VMAT versus 0.72 Gy 2D; mean ovary dose 0.64 Gy VMAT versus 1.47 Gy 2D). PTV coverage was also improved for both cases with the VMAT plan versus conventional 2D plan (2 Gy D90% versus 1.9 Gy D90%, respectively). Given these dosimetric advantages, the present study can serve as a proof-of-concept for further prospective studies evaluating this technique for wider applications in populations receiving TBI.

  View details for DOI 10.1016/j.prro.2020.07.006

  View details for PubMedID 32795616

• Patterns of Care and Age-Specific Impact of Extent of Resection and Adjuvant Radiotherapy in Pediatric Pineoblastoma. Neurosurgery Jin, M. C., Prolo, L. M., Wu, A. n., Azad, T. D., Shi, S. n., Rodrigues, A. J., Soltys, S. G., Pollom, E. L., Li, G. n., Hiniker, S. M., Grant, G. A. 2020

  Abstract

  Pediatric pineoblastomas are highly aggressive tumors that portend poor outcomes despite multimodal management. Controversy remains regarding optimal disease management.To evaluate patterns of care and optimal clinical management of pediatric pineoblastoma.A total of 211 pediatric (age 0-17 yr) histologically confirmed pineoblastoma patients diagnosed between 2004 and 2015 were queried from the National Cancer Database. Wilcoxon rank-sum statistics and chi-squared analyses were used to compare continuous and categorical variables, respectively. Univariable and multivariable Cox regressions were used to evaluate prognostic impact of covariates. Propensity-score matching was used to balance baseline characteristics.Older patients (age ≥ 4 yr) experienced improved overall survival compared to younger patients (age < 4 yr) (hazard ratio [HR] = 0.41; 95% CI 0.25-0.66). Older patients (adjusted odds ratio [aOR] = 5.21; 95% CI 2.61-10.78) and those residing in high-income regions (aOR = 3.16; 95% CI 1.21-8.61) received radiotherapy more frequently. Radiotherapy was independently associated with improved survival in older (adjusted HR [aHR] = 0.31; 95% CI 0.12-0.87) but not younger (aHR = 0.64; 95% CI 0.20-1.90) patients. The benefits of radiotherapy were more pronounced in patients receiving surgery than in those not receiving surgery (aHR [surgical patients] = 0.23; 95% CI 0.08-0.65; aHR [nonsurgical patients] = 0.46; 95% CI 0.22-0.97). Older patients experienced improved outcomes associated with aggressive resection (P = .041); extent of resection was not associated with survival in younger patients (P = .880).Aggressive tumor resection was associated with improved survival only in older pediatric patients. Radiotherapy was more effective in patients receiving surgery. Age-stratified approaches might allow for improved disease management of pediatric pineoblastoma.

  View details for DOI 10.1093/neuros/nyaa023

  View details for PubMedID 32110805

• The prognostic significance of anaplasia in childhood rhabdomyosarcoma: A report from the Children's Oncology Group. European journal of cancer (Oxford, England : 1990) Shenoy, A. n., Alvarez, E. n., Chi, Y. Y., Li, M. n., Shern, J. F., Khan, J. n., Hiniker, S. M., Granberg, C. F., Hawkins, D. S., Parham, D. M., Teot, L. A., Rudzinski, E. R. 2020; 143: 127–33

  Abstract

  Established prognostic indicators in rhabdomyosarcoma (RMS), the most common childhood soft tissue sarcoma, include several clinicopathologic features. Among pathologic features, anaplasia has been suggested as a potential prognostic indicator, but the clinical significance of anaplasia remains unclear.Patients enrolled on one of five recent Children's Oncology Group clinical trials for RMS (D9602, n = 357; D9802, n = 80; D9803, n = 462; ARST0331, n = 335; and ARST0531, n = 414) with prospective central pathology review were included in this study. Clinicopathologic variables including demographic information, risk group, histologic subtype, and anaplasia were recorded along with overall survival (OS) and failure-free survival (FFS) with failure defined by recurrence, progression, or death. The log-rank test was used to compare OS and FFS.Anaplasia was more common in embryonal RMS (27% of all embryonal RMS) than other subtypes of RMS (11% for alveolar RMS, 7% for botryoid RMS, 11% for spindle cell RMS). On multivariate analyses, anaplasia was not an independent prognostic factor in RMS (OS:hazard ratio (HR) = 1.12, p = 0.43; FFS:HR = 1.07, p = 0.56) across all subtypes or within embryonal RMS only (OS:HR = 1.41, p = 0.078; FFS:HR = 1.25, p = 0.16). Among tumors with TP53 mutations, 69% had anaplasia, while only 24% of tumors with anaplasia had a tumoral TP53 mutation.Anaplasia is not an independent indicator of adverse outcomes in RMS. Emerging information on the prognostic significance of TP53 mutations raises the possibility that anaplasia may be a surrogate marker of TP53 mutations in some cases. Tumoral TP53 mutation status may be investigated as a prognostic indicator in future studies.

  View details for DOI 10.1016/j.ejca.2020.10.018

  View details for PubMedID 33302115

• 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

• Successful Full-term Pregnancies After High-dose Pelvic Radiotherapy for Ewing Sarcoma: A Case Report. Journal of pediatric hematology/oncology Gutkin, P. M., Chen, E. L., Miller, C. J., Donaldson, S. S., Kovalchuk, N., Callejas, M. J., Hiniker, S. M. 2019

  Abstract

  Survivors of childhood cancer are at risk of long-term sequelae that arise as a consequence of cancer treatment. Radiation and chemotherapy treatment in pediatric female patients can have detrimental impacts on fertility, particularly in those with pelvic tumor involvement. We report 2 successful natural full-term pregnancies with vaginal delivery in a woman 12 years after biopsy, irradiation (55.5Gy), and multi-agent chemotherapy for treatment of pelvic Ewing sarcoma. Both children were born healthy, with no complications in pregnancy or delivery. Fertility preservation and risk assessment following chemotherapy/radiation therapy is evolving, providing new data to effectively counsel and treat young women.

  View details for DOI 10.1097/MPH.0000000000001581

  View details for PubMedID 31415018

• Successful Use of Frameless Stereotactic Radiosurgery for Treatment of Recurrent Brain Metastases in an 18 Month Old Child. The International journal of neuroscience Rahimy, E., Chuang, C., Spunt, S. L., Mahaney, K., Donaldson, S. S., Gibbs, I. C., Soltys, S. G., Pollom, E., Hiniker, S. M. 2019: 1–6

  Abstract

  There are very few reported cases of stereotactic radiosurgery delivered in children under 3 years of age. We report an 18 month old boy with metastatic recurrence of undifferentiated round cell sarcoma to the brain which was treated with chemotherapy, resection, and robotic frameless stereotactic radiosurgery (SRS). Frameless SRS was delivered without technical difficulties, acute adverse events, or clinical sequelae 1.5 months post-radiation. Longer term follow-up will be needed to evaluate local tumor control and effects on neurocognitive development, endocrine function, and growth. This report adds to the literature of the few reported cases of successfully attempted SRS in very young children.

  View details for DOI 10.1080/00207454.2019.1655015

  View details for PubMedID 31401906

• Treatment and outcomes in classic Hodgkin lymphoma post-transplant lymphoproliferative disorder in children PEDIATRIC BLOOD & CANCER Twist, C. J., Hiniker, S. M., Gratzinger, D., Gutkin, P. M., Merriott, D. J., Iagaru, A., Link, M. P., Donaldson, S. S. 2019; 66 (8)

  View details for DOI 10.1002/pbc.27803

  View details for Web of Science ID 000472549200013

• Volumetric Modulated Arc Therapy and 3-Dimensional Printed Bolus in the Treatment of Refractory Primary Cutaneous Gamma Delta Lymphoma of the Bilateral Legs PRACTICAL RADIATION ONCOLOGY Obeid, J., Gutkin, P. M., Lewis, J., Skinner, L., Wang, E. B., Khodadoust, M. S., Kim, Y. H., Weng, W., Hoppe, R. T., Hiniker, S. M. 2019; 9 (4): 220–25

  View details for DOI 10.1016/j.prro.2019.02.016

  View details for Web of Science ID 000472574100020

• Low-dose Total Skin Electron Beam Therapy for Refractory Cutaneous CD30 Positive Lymphoproliferative Disorders. The Journal of dermatological treatment Panjwani, N., Yoo, C. H., Wang, E., Khodadoust, M. S., Kim, Y. H., Hoppe, R. T., Hiniker, S. M. 2019: 1–5

  Abstract

  We describe a case of a 48-year-old woman with a refractory cutaneous CD30 positive lymphoproliferative disorder treated successfully with total skin electron beam radiotherapy (TSEBT).

  View details for DOI 10.1080/09546634.2019.1628913

  View details for PubMedID 31179774

• FLT-PET-CT for the Detection of Disease Recurrence After Stereotactic Ablative Radiotherapy or Hyperfractionation for Thoracic Malignancy: A Prospective Pilot Study FRONTIERS IN ONCOLOGY Hiniker, S. M., Sodji, Q., Quon, A., Gutkin, P. M., Arksey, N., Graves, E. E., Chin, F. T., Maxim, P. G., Diehn, M., Loo, B. W. 2019; 9

  View details for DOI 10.3389/fonc.2019.00467

  View details for Web of Science ID 000470114000001

• FLT-PET-CT for the Detection of Disease Recurrence After Stereotactic Ablative Radiotherapy or Hyperfractionation for Thoracic Malignancy: A Prospective Pilot Study. Frontiers in oncology Hiniker, S. M., Sodji, Q., Quon, A., Gutkin, P. M., Arksey, N., Graves, E. E., Chin, F. T., Maxim, P. G., Diehn, M., Loo, B. W. 2019; 9: 467

  Abstract

  Differentiating local recurrence from post-treatment changes on PET scans following stereotactic ablative radiotherapy (SABR) or hyperfractionation for lung tumors is challenging. We performed a prospective pilot study of 3-deoxy-3-[18F]-fluorothymidine (FLT)-PET-CT in patients with equivocal post-radiation FDG-PET-CT to assess disease recurrence. Methods: We prospectively enrolled 10 patients, 9 treated with SABR and 1 with hyperfractionated external beam radiotherapy for thoracic malignancy with subsequent equivocal follow-up FDG-PET-CT, to undergo FLT-PET-CT prior to biopsy or serial imaging. FLT-PET scans were interpreted by a radiologist with experience in reading FLT-PET-CT and blinded to the results of any subsequent biopsy or imaging. Results: Of the 10 patients enrolled, 8 were evaluable after FLT-PET-CT. Based on the FLT-PET-CT, a blinded radiologist accurately predicted disease recurrence vs. inflammatory changes in 7 patients (87.5%). The combination of higher lesion SUVmax and higher ratio of lesion SUVmax to SUVmax of mediastinal blood pool was indicative of recurrence. Qualitative assessment of increased degree of focality of the lesion also appears to be indicative of disease recurrence. Conclusion: Adjunctive FLT-PET-CT imaging can complement FDG-PET-CT scan in distinguishing post-treatment radiation changes from disease recurrence in thoracic malignancies. These findings support the investigation of FLT-PET-CT in a larger prospective study.

  View details for DOI 10.3389/fonc.2019.00467

  View details for PubMedID 31214507

  View details for PubMedCentralID PMC6555304

• Treatment and outcomes in classic Hodgkin lymphoma post-transplant lymphoproliferative disorder in children. Pediatric blood & cancer Twist, C. J., Hiniker, S. M., Gratzinger, D., Gutkin, P. M., Merriott, D. J., Iagaru, A., Link, M. P., Donaldson, S. S. 2019: e27803

  Abstract

  Classic Hodgkin lymphoma post-transplant lymphoproliferative disorder (HL-PTLD) has been rarely reported in children, with limited data available to guide treatment decisions. We report a retrospective review of five children diagnosed with classic HL-PTLD following solid organ transplant between 2007 and 2013 at Stanford University. Patients were treated with Stanford V chemotherapy and involved field radiation therapy. With a median follow-up of 7.2 years (range, 4.7-10.5 years) since diagnosis, all patients remain in remission from HL-PTLD and free from graft failure. In this series, combined modality therapy with risk-adapted chemotherapy and radiation therapy was a successful strategy for the treatment of classic HL-PTLD.

  View details for PubMedID 31062898

• Volumetric modulated arc therapy and 3-dimensional printed bolus in the treatment of refractory primary cutaneous gamma delta lymphoma of the bilateral legs. Practical radiation oncology Obeid, J., Gutkin, P. M., Lewis, J., Skinner, L., Wang, E. B., Khodadoust, M. S., Kim, Y. H., Weng, W., Hoppe, R. T., Hiniker, S. M. 2019

  Abstract

  Patients with extensive dermal and subcutaneous disease present a technical challenge for treatment with radiation therapy (RT). Volumetric arc therapy (VMAT) can effectively treat disease on circumferential surfaces while minimizing dose to the core structures. However, treatment of extensive areas of the bilateral lower extremities with this technique has not been previously reported. Here we report the successful treatment of a patient with primary cutaneous gamma-delta T-cell lymphoma of the bilateral legs using VMAT and a custom 3-dimensional printed bolus. This approach is applicable for the treatment of cutaneous malignancies of the lower extremities.

  View details for PubMedID 30836188

• Stereotactic Radiosurgery for Pediatric and Adult Intracranial and Spinal Ependymomas. Stereotactic and functional neurosurgery Shi, S. n., Jin, M. C., Koenig, J. n., Gibbs, I. C., Soltys, S. G., Chang, S. D., Li, G. n., Hayden Gephart, M. n., Hiniker, S. M., Pollom, E. L. 2019: 1–6

  Abstract

  We report efficacy and toxicity outcomes with stereotactic radiosurgery (SRS) for intracranial and spinal ependymoma.We analyzed adult and pediatric patients with newly diagnosed or recurrent intracranial or spinal ependymoma lesions treated with SRS at our institution. Following SRS, local failure (LF) was defined as failure within or adjacent to the SRS target volume, while distant failure (DF) was defined as failure outside of the SRS target volume. Time to LF and DF was analyzed using competing risk analysis with death as a competing risk.Overall survival (OS) was calculated from the date of first SRS to the date of death or censored at the date of last follow-up using the Kaplan-Meier method.Twenty-one patients underwent SRS to 40 intracranial (n = 30) or spinal (n = 10) ependymoma lesions between 2007 and 2018, most commonly with 18 or 20 Gy in 1 fraction. Median follow-up for all patients after first SRS treatment was 54 months (range 2-157). The 1-year, 2-year, and 5-year rates of survival among patients with initial intracranial ependymoma were 86, 74, and 52%, respectively. The 2-year cumulative incidences of LF and DF after SRS among intracranial ependymoma patients were 25% (95% CI 11-43) and 42% (95% CI 22-60), respectively. No spinal ependymoma patient experienced LF, DF, or death within 2 years of SRS. Three patients had adverse radiation effects.SRS is a viable treatment option for intracranial and spinal ependymoma with excellent local control and acceptable toxicity.

  View details for DOI 10.1159/000502653

  View details for PubMedID 31590165

• Central Nervous System Relapse After Stem Cell Transplantation in Adolescents and Young Adults with Acute Lymphoblastic Leukemia: A Single-Institution Experience. Journal of adolescent and young adult oncology Kozak, M. M., Yoo, C. H., Gutkin, P. M., von Eyben, R. n., Agarwal, R. n., Donaldson, S. S., Muffly, L. n., Hiniker, S. M. 2019

  Abstract

  Purpose: To evaluate outcomes and central nervous system (CNS) relapse in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL), who underwent total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (allo-SCT). Methods: A total of 136 AYA patients with ALL who received TBI before allo-SCT between 1998 and 2018 were reviewed. Twenty patients received cranial radiation in their initial treatment before conditioning for transplant and were excluded. Competing risk analysis was used to estimate the cumulative incidence of relapse. Kaplan-Meier and log-rank tests were used to calculate overall survival (OS) and to identify factors predictive of relapse. OS and time to relapse were calculated from date of allo-SCT. Results: One hundred sixteen patients were included in the analysis. Median age was 27 years and median follow-up time was 42 months. Twenty-six patients suffered a disease relapse and 49 died, 26 of posttransplantation complications. The median time to relapse was 7 months and the 5-year OS was 60%. Seven patients had a CNS relapse: 4 of 20 patients (25%) with pre-SCT CNS disease had a post-allo-SCT CNS relapse compared to 3 of 97 (3.1%) without pre-SCT CNS disease. Median time to CNS relapse was 7 months. Patients with post-SCT CNS relapse had median OS of 19 months. Conclusions: AYA patients with CNS disease who undergo an allo-SCT have a high rate of CNS relapse. The addition of additional CNS-directed therapy to transplant protocols warrants further investigation.

  View details for DOI 10.1089/jayao.2019.0121

  View details for PubMedID 31747341

• Cost Analysis of Audiovisual-Assisted Therapeutic Ambiance in Radiation Therapy (AVATAR) Aided Omission of Anesthesia in Radiation for Pediatric Malignancies. Practical radiation oncology McClelland, S. n., Overton, K. W., Overshiner, B. n., Bush, K. n., Loo, B. W., Skinner, L. B., Watson, G. A., Holmes, J. A., Hiniker, S. M., Maxim, P. G. 2019

  View details for DOI 10.1016/j.prro.2019.09.011

  View details for PubMedID 31574319

• Outcomes for pediatric patients with osteosarcoma treated with palliative radiotherapy. Pediatric blood & cancer Chen, E. L., Yoo, C. H., Gutkin, P. M., Merriott, D. J., Avedian, R. S., Steffner, R. J., Spunt, S. L., Pribnow, A. K., Million, L. n., Donaldson, S. S., Hiniker, S. M. 2019: e27967

  Abstract

  Few studies have addressed the efficacy of palliative radiotherapy (RT) for pediatric osteosarcoma (OS), a disease generally considered to be radioresistant. We describe symptom relief, local control, and toxicity associated with palliative RT among children with OS.Patients diagnosed with OS at age 18 and under and treated with RT for palliation of symptomatic metastases or local recurrence at the primary site from 1997 to 2017 were included. We retrospectively reviewed details of RT, symptom improvement, local control, survival, and toxicity.Thirty-two courses of palliative RT were given to 20 patients with symptomatic metastatic and/or locally recurrent primary disease. The median equivalent dose in 2 Gy fractions (EQD2) was 40.0 Gy (range, 20.0-60.4). The median number of fractions per course was 15 (range, 5-39). Symptom improvement occurred in 24 (75%) courses of RT at a median time of 15.5 days (range, 3-43). In nine courses (37.5%), symptoms recurred after a median duration of symptom relief of 140 days (range, 1-882). Higher EQD2 correlated with longer duration of response (r = 0.39, P = 0.0003). Imaging revealed local failure in 3 of 14 courses followed with surveillance imaging studies (21.4%). The median time to progression was 12.9 months (range, 4.4-21.8). The median follow-up time following the first course of palliative RT was 17.5 months (range, 1.74-102.24), and median time to overall survival was 19.4 months. Toxicity was mild, with grade 2 toxicity occurring in one course (3.1%).RT is an effective method of symptom palliation for patients with recurrent or metastatic OS, with higher delivered dose correlating with longer symptom relief and with little associated toxicity.

  View details for DOI 10.1002/pbc.27967

  View details for PubMedID 31407520

• Prognostic Significance of P16 Expression and P53 Expression in Primary Vaginal Cancer. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists Nwachukwu, C. R., Harris, J. P., Chin, A. n., Von Eyben, R. n., Giaretta, S. n., Shaffer, J. L., Hiniker, S. M., Kapp, D. S., Folkins, A. K., Kidd, E. A. 2019; 38 (6): 588–96

  Abstract

  To evaluate the correlation between p16 expression and clinical outcomes in patients with primary vaginal cancer treated with definitive radiotherapy. P16 immunohistochemical was performed on 25 patient samples and recorded from pathology reports in 7 patients. P53 immunohistochemical was performed on 3 p16-negative samples. Baseline characteristics were compared using the Fisher exact test. Outcomes were compared using log-rank tests, and cox proportional hazards models. Survival and recurrence analysis was performed with the Kaplan-Meier method and cumulative incidence estimates. P16 expression was positive in 29 patients and negative in 3 patients. Two of the p16-negative tumors showed positive expression of p53. The median overall survival, progression-free survival and 2-yr cumulative incidence of recurrence were 66 mo [95% confidence interval (CI), 31-96], 34 mo (95% CI, 21-86), and 19% (95% CI, 7%-34%), respectively. P16-positive tumors had higher median overall survival and progression-free survival compared with p16-negative tumors (82 vs. 31 mo, P=0.02 and 35 vs 16 mo, P=0.04, respectively). The 2-yr cumulative incidence of recurrence was 14% for p16-positive tumors compared with 67% for p16-negative tumors (P=0.07). On univariable analysis, p16-negative status, age older than 65, and advanced stage were associated with inferior overall survival. P16 negativity is an independent predictor of inferior overall survival. P16-positive vaginal cancers have a better prognosis and decreased incidence of recurrence compared with p16-negative tumors. These prognostic findings associated with p16-negative vaginal cancers will need to be confirmed in larger patient cohorts.

  View details for DOI 10.1097/PGP.0000000000000568

  View details for PubMedID 31593028

• Contemporary management of metastatic soft tissue sarcoma. Current problems in cancer Bui, N. Q., Wang, D. S., Hiniker, S. M. 2019

  Abstract

  Soft tissue sarcoma (STS) is a rare, heterogeneous cancer that can have high rates of distant metastases. Optimal treatment planning requires detailed knowledge of distinct sarcoma histologies as well as the wide array of therapeutic options through surgical, medical, radiation, and interventional oncology. In this review article, we discuss the contemporary management of metastatic STS and the underlying data behind these recommendations. All patients with metastatic STS should be discussed in a multidisciplinary tumor board at an experienced sarcoma center. For patients with oligometastatic disease, there should be strong consideration for definitive local therapy such as surgical resection, stereotactic body radiation therapy, or ablative procedures. In cases with widespread metastases, cytotoxic chemotherapy represents the standard treatment for STS patients with traditional chemotherapies, such as anthracyclines, gemcitabine/docetaxel, ifosfamide, and dacarbazine, still being the most commonly used drugs today. The recent approvals of trabectedin, eribulin, and pazopanib have expanded the therapeutic armamentarium for metastatic STS. Histology-directed treatment is crucial for certain subtypes of STS which are highly sensitive to targeted therapy and relatively insensitive to chemotherapy. Despite the significant progress that has been made in metastatic STS in the past decade, overall prognosis is poor and there is a critical need for novel therapeutics.

  View details for DOI 10.1016/j.currproblcancer.2019.06.005

  View details for PubMedID 31248634

• Complete Response of Metastatic Melanoma to Local Radiation and Immunotherapy: 6.5 Year Follow-Up. Cureus Gutkin, P. M., Hiniker, S. M., Swetter, S. M., Reddy, S. A., Knox, S. J. 2018; 10 (12): e3723

  Abstract

  The combined use of immunotherapy and radiation therapy is emerging as a potentially effective treatment for patients with immunogenic tumors such as melanoma; however, evidence for long-term treatment outcomes is lacking. Herein, we summarize our previously described case study of a patient with metastatic melanoma treated with two cycles of ipilimumab, followed by stereotactic body radiotherapy to two of seven liver metastases, with two additional cycles of ipilimumab. In the longest follow-up to date, we report a successful treatment outcome at 6.5 years. Our patient remains in complete remission, with no evidence of disease or recurrence 6.5 years after treatment. He continues to manage chronic hypophysitis developed secondary to immunotherapy and has developed osteopenia from prolonged systemic glucocorticoid use. The use of radiotherapy in combination with targeted immune therapy appears to be an effective treatment strategy, with long-lasting efficacy.

  View details for PubMedID 30788205

• Prognostic Significance of P16 Expression and P53 Expression in Primary Vaginal Cancer. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists Nwachukwu, C. R., Harris, J. P., Chin, A., Von Eyben, R., Giaretta, S., Shaffer, J. L., Hiniker, S. M., Kapp, D. S., Folkins, A. K., Kidd, E. A. 2018

  Abstract

  To evaluate the correlation between p16 expression and clinical outcomes in patients with primary vaginal cancer treated with definitive radiotherapy. P16 immunohistochemical was performed on 25 patient samples and recorded from pathology reports in 7 patients. P53 immunohistochemical was performed on 3 p16-negative samples. Baseline characteristics were compared using the Fisher exact test. Outcomes were compared using log-rank tests, and cox proportional hazards models. Survival and recurrence analysis was performed with the Kaplan-Meier method and cumulative incidence estimates. P16 expression was positive in 29 patients and negative in 3 patients. Two of the p16-negative tumors showed positive expression of p53. The median overall survival, progression-free survival and 2-yr cumulative incidence of recurrence were 66mo [95% confidence interval (CI), 31-96], 34mo (95% CI, 21-86), and 19% (95% CI, 7%-34%), respectively. P16-positive tumors had higher median overall survival and progression-free survival compared with p16-negative tumors (82 vs. 31mo, P=0.02 and 35 vs 16mo, P=0.04, respectively). The 2-yr cumulative incidence of recurrence was 14% for p16-positive tumors compared with 67% for p16-negative tumors (P=0.07). On univariable analysis, p16-negative status, age older than 65, and advanced stage were associated with inferior overall survival. P16 negativity is an independent predictor of inferior overall survival. P16-positive vaginal cancers have a better prognosis and decreased incidence of recurrence compared with p16-negative tumors. These prognostic findings associated with p16-negative vaginal cancers will need to be confirmed in larger patient cohorts.

  View details for PubMedID 30516621

• Orthotopic Liver Transplantation After Stereotactic Body Radiotherapy for Pediatric Hepatocellular Carcinoma with Central Biliary Obstruction and Nodal Involvement. Cureus Chen, E., Rangaswami, A., Esquivel, C. O., Concepcion, W., Lungren, M., Thakor, A. S., Yoo, C. H., Donaldson, S. S., Hiniker, S. M. 2018; 10 (10): e3499

  Abstract

  Here we describe the case of a 10-year-old boy with a history of chronic hepatitis B who was diagnosed with hepatocellular carcinoma (HCC) with a large central hepatic mass and metastatic disease in a celiac lymph node. His tumor wasunresectable, due to location and lack of clear margins, and he could not receive chemotherapy due to elevated bilirubin. He was treated with stereotactic body radiotherapy (SBRT) to the primary site and involved nodal region. After completing radiotherapy, his total bilirubin level fell below 1.0 mg/dL, allowing him to begin systemic therapy with cisplatinand doxorubicin.At threemonths after SBRT, his bilirubin was 0.1 mg/dL, alpha-fetoprotein (AFP) was 88 ng/mL, and imaging demonstrated a decrease in tumor size (total volume 28.7 cc), with no evidence of local or distant disease progression.He then developed distant disease within the liver, but his disease remained controlled at the primary site and nodes that had been treated with SBRT.He underwent orthotopic liver transplantation (OLT) with an uneventful operative course and remains with no evidence of disease at sevenmonths after OLT. This is one of the first reported cases of successful downstaging of pediatric HCC with nodal involvement to allow for OLT, and it argues for consideration of similar patients for OLT.

  View details for PubMedID 30648040

• Survival Impact of Postoperative Radiotherapy Timing in Pediatric and Adolescent Medulloblastoma. Neuro-oncology Chin, A. L., Moding, E. J., Donaldson, S. S., Gibbs, I. C., Soltys, S. G., Hiniker, S. M., Pollom, E. L. 2018

  Abstract

  Radiation therapy (RT) remains a critical component of multimodality treatment for medulloblastoma. Traditionally, clinicians strive to start RT within 4-5 weeks of surgery, but the optimal timing after surgery remains unclear.Using the National Cancer Database, we identified pediatric and adolescent patients with medulloblastoma treated with curative-intent surgery, RT, and chemotherapy. Factors associated with early or delayed RT were identified using Pearson chi-squared tests. Overall survival (OS) differences based on RT timing were compared using the Kaplan-Meier estimator with log-rank tests. Patient, tumor, and treatment characteristics associated with OS were analyzed with univariate and multivariate Cox proportional hazard models.Among the 1338 patients analyzed, early RT (defined as initiation ≤3 weeks after surgery) was associated with younger age, M1-3 disease, and subtotal resection. Patients who initiated RT early had decreased five-year OS compared with patients who initiated RT 3.1-4, 4.1-5, or >5 weeks after surgery (72.5%, 80.5%, 79.4%, and 77.8%, respectively; p=0.019), but there was no significant difference in OS among the latter three groups (p=0.788). On multivariate analysis, early RT versus the 3.1-4-week interval was significantly associated with poorer OS (adjusted HR 1.72; 95% CI 1.19-2.48; p=0.004), while time to RT of >5 weeks but within 90 days of surgery did not adversely impact OS (p=0.563).In this large national database analysis, delaying RT within 90 days of surgery was not associated with inferior outcomes. Although clinical judgment remains paramount, postoperative RT timing should allow for healing and the development of an optimal treatment plan.

  View details for PubMedID 29309676

• Post-treatment surveillance imaging in lymphoma SEMINARS IN ONCOLOGY Hiniker, S. M., Hoppe, R. T. 2017; 44 (5): 310–22

  Abstract

  Appropriate post-treatment management of patients with lymphoma has been controversial, with imaging frequently performed as post-treatment surveillance. The goal of post-treatment imaging is to identify relapse prior to clinical symptoms, when the burden of disease is lower and the possibility of effective salvage therapy and cure are greater. However, little data exist to support the performance of surveillance imaging after completion of treatment, with the vast majority of studies suggesting there is no clinical benefit to surveillance imaging in asymptomatic patients. Ongoing efforts seek to identify a subset of patients with a higher risk of relapse that might benefit from surveillance imaging, though financial and other costs associated with imaging are non-negligible and must be considered. Here we summarize the current data regarding post-treatment surveillance imaging in lymphoma.

  View details for PubMedID 29580433

• Stereotactic body radiotherapy for pediatric hepatocellular carcinoma with central biliary obstruction PEDIATRIC BLOOD & CANCER Hiniker, S. M., Rangaswami, A., Lungren, M. P., Thakor, A. S., Concepcion, W., Balazy, K. E., Kovalchuk, N., Donaldson, S. S. 2017; 64 (6)

  Abstract

  Here, we present the case of a pediatric patient with newly diagnosed hepatocellular carcinoma causing central biliary obstruction and persistently elevated bilirubin of 3.0-4.3 mg/dl despite placement of bilateral internal-external biliary drains. The tumor was not resectable, and the patient was not a candidate for liver transplant due to nodal disease, for chemotherapy due to hyperbilirubinemia, or for local therapies aside from stereotactic body radiotherapy (SBRT). In this report, we discuss the successful use of SBRT in the management of this patient, and its role in allowing the patient to become a candidate for additional therapies.

  View details for DOI 10.1002/pbc.26330

  View details for PubMedID 28436210

• Chemoradiation impairs normal developmental cortical thinning in medulloblastoma. Journal of neuro-oncology Kundu, P., Li, M. D., Durkee, B. Y., Hiniker, S. M., Bush, K., von Eyben, R., Monje, M. L., Yeom, K. W., Donaldson, S. S., Gibbs, I. C. 2017

  Abstract

  Medulloblastoma patients are treated with surgery, radiation and chemotherapy. Radiation dose to the temporal lobe may be associated with neurocognitive sequelae. Longitudinal changes of temporal lobe cortical thickness may result from neurodevelopmental processes such as synaptic pruning. This study applies longitudinal image analysis to compare developmental change in cortical thickness in medulloblastoma (MB) patients who were treated by combined modality therapy to that of cerebellar juvenile pilocytic astrocytoma (JPA) patients who were treated by surgery alone. We hypothesized that the rates of developmental change in cortical thickness would differ between these two groups. This retrospective cohort study assessed changes in cortical thickness over time between MB and JPA patients. High-resolution magnetic resonance (MR) images of 14 MB and 7 JPA subjects were processed to measure cortical thickness of bilateral temporal lobe substructures. A linear mixed effects model was used to identify differences in substructure longitudinal changes in cortical thickness. The left temporal lobe exhibited overall increased cortical thickness in MB patients relative to JPA patients who showed overall cortical thinning (mean annual cortical thickness change: MB 0.14 mm/year versus JPA -0.018 mm/year across all substructures), particularly in the inferior temporal lobe substructures (p < 0.0001). The cortical thickness change of the right temporal lobe substructures exhibited similar, though attenuated trends (p = 0.002). MB patients exhibit overall increased cortical thickness rather than cortical thinning as seen in JPA patients and as expected in normal cortical development. These observations are possibly due to chemoradiation induced-disruption of normal neuronal mechanisms. Longitudinal image analysis may identify early biomarkers for neurocognitive function with routine imaging.

  View details for DOI 10.1007/s11060-017-2453-5

  View details for PubMedID 28534154

• Very high-energy electron (VHEE) beams in radiation therapy; Treatment plan comparison between VHEE, VMAT, and PPBS. Medical physics Schüler, E., Eriksson, K., Hynning, E., Hancock, S. L., Hiniker, S. M., Bazalova-Carter, M., Wong, T., Le, Q., Loo, B. W., Maxim, P. G. 2017

  Abstract

  The aim of this study was to evaluate the performance of very high-energy electron beams (VHEE) in comparison to clinically derived treatment plans generated with volumetric modulated arc therapy (VMAT) and proton pencil beam scanning (PPBS) technology. We developed a custom optimization script that could be applied automatically across modalities to eliminate operator bias during IMRT optimization.Four clinical cases were selected (prostate cancer, lung cancer, pediatric brain tumor, and head and neck cancer (HNC)). The VHEE beams were calculated in the EGSnrc/DOSXYZnrc Monte Carlo code for 100 and 200 MeV beams. Treatment plans with VHEE, VMAT, and PPBS were optimized in a research version of RayStation using an in-house developed script to minimize operator bias between the different techniques.The in-house developed script generated similar or superior plans to the clinically used plans. In the comparisons between the modalities, the integral dose was lowest for the PPBS-generated plans in all cases. For the prostate case, the 200 MeV VHEE plan showed reduced integral dose and reduced organ at risk (OAR) dose compared to the VMAT plan. For all other cases, both the 100 and the 200 MeV VHEE plans were superior to the VMAT plans, and the VHEE plans showed better conformity and lower spinal cord dose in the pediatric brain case and lower brain stem dose in the HNC case when compared to the PPBS plan.The automated optimization developed in this study generated similar or superior plans as compared to the clinically used plan and represents an unbiased approach to compare treatment plans generated for different modalities. In the present study, we also show that VHEE plans are similar or superior to VMAT plans with reduced mean OAR dose and increased target conformity for a variety of clinical cases, and VHEE plans can even achieve reductions in OAR doses compared to PPBS plans for shallow targets. With increased VHEE energy, better conformity and even higher reductions in mean OAR doses are achieved. On the whole, VHEE was intermediate between photon VMAT and PPBS for OAR sparing.

  View details for DOI 10.1002/mp.12233

  View details for PubMedID 28339108

• Initial clinical outcomes of audiovisual-assisted therapeutic ambience in radiation therapy (AVATAR). Practical radiation oncology Hiniker, S. M., Bush, K., Fowler, T., White, E. C., Rodriguez, S., Maxim, P. G., Donaldson, S. S., Loo, B. W. 2017

  Abstract

  Radiation therapy is an important component of treatment for many childhood cancers. Depending upon the age and maturity of the child, pediatric radiation therapy often requires general anesthesia for immobilization, position reproducibility, and daily treatment delivery. We designed and clinically implemented a radiation therapy-compatible audiovisual system that allows children to watch streaming video during treatment, with the goal of reducing the need for daily anesthesia through immersion in video.We designed an audiovisual-assisted therapeutic ambience in radiation therapy (AVATAR) system using a digital media player with wireless streaming and pico projector, and a radiolucent display screen positioned within the child's field of view to him or her with sufficient entertainment and distraction for the duration of serial treatments without the need for daily anesthesia. We piloted this system in 25 pediatric patients between the ages of 3 and 12 years. We calculated the number of fractions of radiation for which this system was used successfully and anesthesia avoided and compared it with the anesthesia rates reported in the literature for children of this age.Twenty-three of 25 patients (92%) were able to complete the prescribed course of radiation therapy without anesthesia using the AVATAR system, with a total of 441 fractions of treatment administered when using AVATAR. The median age of patients successfully treated with this approach was 6 years. Seven of the 23 patients were initially treated with daily anesthesia and were successfully transitioned to use of the AVATAR system. Patients and families reported an improved treatment experience with the use of the AVATAR system compared with anesthesia.The AVATAR system enables a high proportion of children to undergo radiation therapy without anesthesia compared with reported anesthesia rates, justifying continued development and clinical investigation of this technique.

  View details for DOI 10.1016/j.prro.2017.01.007

  View details for PubMedID 28242188

• Phase I Trial: SABR and Ipilimumab-Letter. Clinical cancer research : an official journal of the American Association for Cancer Research Hiniker, S. M., Reddy, S. A., Swetter, S. M., Knox, S. J. 2017; 23 (1): 320

  View details for PubMedID 28049160

• Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance CANCER DISCOVERY Jeong, Y., Hoang, N. T., Lovejoy, A., Stehr, H., Newman, A. M., Gentles, A. J., Kong, W., Diana Truong, D., Martin, S., Chaudhuri, A., Heiser, D., Zhou, L., Say, C., Carter, J. N., Hiniker, S. M., Loo, B. W., West, R. B., Beachy, P., Alizadeh, A. A., Diehn, M. 2017; 7 (1): 86-101

  Abstract

  Lung squamous cell carcinoma (LSCC) pathogenesis remains incompletely understood, and biomarkers predicting treatment response remain lacking. Here, we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal, suggesting that mutations in these genes lead to expansion of mutant stem cell clones. Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histologic and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model. Deletion of Keap1 promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT). KEAP1/NRF2 mutation status predicted risk of local recurrence after RT in patients with non-small lung cancer (NSCLC) and could be noninvasively identified in circulating tumor DNA. Thus, KEAP1/NRF2 mutations could serve as predictive biomarkers for personalization of therapeutic strategies for NSCLCs.We developed an LSCC mouse model involving Trp53 and Keap1, which are frequently mutated in human LSCCs. In this model, ABSCs are the cell of origin of these tumors. KEAP1/NRF2 mutations increase radioresistance and predict local tumor recurrence in radiotherapy patients. Our findings are of potential clinical relevance and could lead to personalized treatment strategies for tumors with KEAP1/NRF2 mutations. Cancer Discov; 7(1); 86-101. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1.

  View details for DOI 10.1158/2159-8290.CD-16-0127

  View details for Web of Science ID 000396017700024

  View details for PubMedCentralID PMC5222718

• A Prospective Clinical Trial Combining Radiation Therapy With Systemic Immunotherapy in Metastatic Melanoma. International journal of radiation oncology, biology, physics Hiniker, S. M., Reddy, S. A., Maecker, H. T., Subrahmanyam, P. B., Rosenberg-Hasson, Y., Swetter, S. M., Saha, S., Shura, L., Knox, S. J. 2016; 96 (3): 578-588

  Abstract

  Local radiation therapy (RT) combined with systemic anti-cytotoxic T-lymphocyte-associated protein-4 immunotherapy may enhance induction of systemic antimelanoma immune responses. The primary objective of the present trial was to assess the safety and efficacy of combining ipilimumab with RT in patients with stage IV melanoma. The secondary objectives included laboratory assessment of induction of antimelanoma immune responses.In our prospective clinical trial, 22 patients with stage IV melanoma were treated with palliative RT and ipilimumab for 4 cycles. RT to 1 to 2 disease sites was initiated within 5 days after starting ipilimumab. Patients had ≥1 nonirradiated metastasis measuring ≥1.5 cm available for response assessment. Tumor imaging studies were obtained at baseline, 2 to 4 weeks after cycle 4 of ipilimumab, and every 3 months until progression. Laboratory immune response parameters were measured before and during treatment.Combination therapy was well-tolerated without unexpected toxicities. Eleven patients (50.0%) experienced clinical benefit from therapy, including complete and partial responses and stable disease at median follow-up of 55 weeks. Three patients (27.3%) achieved an ongoing systemic complete response at a median follow-up of 55 weeks (range 32-65), and 3 (27.3%) had an initial partial response for a median of 40 weeks. Analysis of immune response data suggested a relationship between elevated CD8-activated T-cells and response.This is the second prospective clinical trial of treatment of metastatic melanoma using the combination of RT and systemic immunotherapy and the first using this sequence of therapy. The results from the present trial demonstrate that a subset of patients may benefit from combination therapy, arguing for continued clinical investigation of the use of RT combined with immunotherapy, including programmed cell death 1 inhibitors, which might have the potential to be even more effective in combination with RT.

  View details for DOI 10.1016/j.ijrobp.2016.07.005

  View details for PubMedID 27681753

• Role of KEAP1/NRF2 and TP53 Mutations in Lung Squamous Cell Carcinoma Development and Radiation Resistance. Cancer discovery Jeong, Y., Hoang, N. T., Lovejoy, A., Stehr, H., Newman, A. M., Gentles, A. J., Kong, W., Truong, D., Martin, S., Chaudhuri, A., Heiser, D., Zhou, L., Say, C., Carter, J. N., Hiniker, S. M., Loo, B. W., West, R. B., Beachy, P., Alizadeh, A. A., Diehn, M. 2016

  Abstract

  Lung squamous cell carcinoma (LSCC) pathogenesis remains incompletely understood, and biomarkers predicting treatment response remain lacking. Here, we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal, suggesting that mutations in these genes lead to expansion of mutant stem cell clones. Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histologic and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model. Deletion of Keap1 promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT). KEAP1/NRF2 mutation status predicted risk of local recurrence after RT in patients with non-small lung cancer (NSCLC) and could be noninvasively identified in circulating tumor DNA. Thus, KEAP1/NRF2 mutations could serve as predictive biomarkers for personalization of therapeutic strategies for NSCLCs.We developed an LSCC mouse model involving Trp53 and Keap1, which are frequently mutated in human LSCCs. In this model, ABSCs are the cell of origin of these tumors. KEAP1/NRF2 mutations increase radioresistance and predict local tumor recurrence in radiotherapy patients. Our findings are of potential clinical relevance and could lead to personalized treatment strategies for tumors with KEAP1/NRF2 mutations. Cancer Discov; 7(1); 86-101. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1.

  View details for PubMedID 27663899

• Partial orbit irradiation achieves excellent outcomes for primary orbital lymphoma. Practical radiation oncology Binkley, M. S., Hiniker, S. M., Donaldson, S. S., Hoppe, R. T. 2016; 6 (4): 255-261

  Abstract

  Primary radiation therapy (RT) achieves excellent local control and overall survival when treating localized orbital lymphoma. However, evidence supporting irradiation of partial orbit volumes to spare nearby critical structures is lacking. We sought to investigate outcomes for patients with localized orbital lymphoma treated with partial orbit irradiation.We retrospectively reviewed patients with orbital lymphoma treated with RT at our institution who met our inclusion criteria: biopsy-confirmed, low-grade lymphoma, localized disease, partial orbit treatment volumes, and follow-up >3months. The Kaplan-Meier method was used to measure overall survival (OS), and the cumulative incidence function adjusted for the competing risk of death was used to measure local failure (LF), contralateral orbit recurrence (COR), and progression. Patient characteristics were compared with outcomes using Fisher exact test for dichotomous variables and Wilcoxon rank-sum test for continuous variables.Thirty-two patients meeting inclusion criteria were identified with median follow-up of 45.8months (range, 3.6-171.9). The majority had stage IEA disease; their sites included conjunctiva (n=20) and retrobulbar or lacrimal gland (n=12). Median partial orbit RT dose was 30.6Gy (range, 22.5-36). Five-year OS was 100%. Five-year cumulative incidence of LF, COR, and overall disease progression was 5.3%, 5.9%, and 21.4%, respectively. Five-year cumulative incidence of LF was 8.3% for conjunctival disease versus 0.0% for retrobulbar or lacrimal gland involvement (P=.15). No significant association was observed between the outcomes of LF, COR, or progression and pretreatment characteristics. Acute and late toxicity included grade 2 periorbital edema (n=3, 9.4%), dry eye (n=3, 9.4%), retinal vascular disorder (n=1, 3.1%), conjunctivitis (n=2, 6.3%), and grade 3 cataract (n=1, 3.1%).Use of partial orbit irradiation in treating low-grade, localized orbital lymphoma achieves excellent survival with low rates of LF, COR, or progression.

  View details for DOI 10.1016/j.prro.2015.11.013

  View details for PubMedID 26935235

• Dose-Response Modeling of the Visual Pathway Tolerance to Single-Fraction and Hypofractionated Stereotactic Radiosurgery. Seminars in radiation oncology Hiniker, S. M., Modlin, L. A., Choi, C. Y., Atalar, B., Seiger, K., Binkley, M. S., Harris, J. P., Liao, Y. J., Fischbein, N., Wang, L., Ho, A., Lo, A., Chang, S. D., Harsh, G. R., Gibbs, I. C., Hancock, S. L., Li, G., Adler, J. R., Soltys, S. G. 2016; 26 (2): 97-104

  Abstract

  Patients with tumors adjacent to the optic nerves and chiasm are frequently not candidates for single-fraction stereotactic radiosurgery (SRS) due to concern for radiation-induced optic neuropathy. However, these patients have been successfully treated with hypofractionated SRS over 2-5 days, though dose constraints have not yet been well defined. We reviewed the literature on optic tolerance to radiation and constructed a dose-response model for visual pathway tolerance to SRS delivered in 1-5 fractions. We analyzed optic nerve and chiasm dose-volume histogram (DVH) data from perioptic tumors, defined as those within 3mm of the optic nerves or chiasm, treated with SRS from 2000-2013 at our institution. Tumors with subsequent local progression were excluded from the primary analysis of vision outcome. A total of 262 evaluable cases (26 with malignant and 236 with benign tumors) with visual field and clinical outcomes were analyzed. Median patient follow-up was 37 months (range: 2-142 months). The median number of fractions was 3 (1 fraction n = 47, 2 fraction n = 28, 3 fraction n = 111, 4 fraction n = 10, and 5 fraction n = 66); doses were converted to 3-fraction equivalent doses with the linear quadratic model using α/β = 2Gy prior to modeling. Optic structure dose parameters analyzed included Dmin, Dmedian, Dmean, Dmax, V30Gy, V25Gy, V20Gy, V15Gy, V10Gy, V5Gy, D50%, D10%, D5%, D1%, D1cc, D0.50cc, D0.25cc, D0.20cc, D0.10cc, D0.05cc, D0.03cc. From the plan DVHs, a maximum-likelihood parameter fitting of the probit dose-response model was performed using DVH Evaluator software. The 68% CIs, corresponding to one standard deviation, were calculated using the profile likelihood method. Of the 262 analyzed, 2 (0.8%) patients experienced common terminology criteria for adverse events grade 4 vision loss in one eye, defined as vision of 20/200 or worse in the affected eye. One of these patients had received 2 previous courses of radiotherapy to the optic structures. Both cases were meningiomas treated with 25Gy in 5 fractions, with a 3-fraction equivalent optic nerve Dmax of 19.2 and 22.2Gy. Fitting these data to a probit dose-response model enabled risk estimates to be made for these previously unvalidated optic pathway constraints: the Dmax limits of 12Gy in 1 fraction from QUANTEC, 19.5Gy in 3 fractions from Timmerman 2008, and 25Gy in 5 fractions from AAPM Task Group 101 all had less than 1% risk. In 262 patients with perioptic tumors treated with SRS, we found a risk of optic complications of less than 1%. These data support previously unvalidated estimates as safe guidelines, which may in fact underestimate the tolerance of the optic structures, particularly in patients without prior radiation. Further investigation would refine the estimated normal tissue complication probability for SRS near the optic apparatus.

  View details for DOI 10.1016/j.semradonc.2015.11.008

  View details for PubMedID 27000505

• Dose-Response Modeling of the Visual Pathway Tolerance to Single-Fraction and Hypofractionated Stereotactic Radiosurgery SEMINARS IN RADIATION ONCOLOGY Hiniker, S. M., Modlin, L. A., Choi, C. Y., Atalar, B., Seiger, K., Binkley, M. S., Harris, J. P., Liao, Y. J., Fischbein, N., Wang, L., Ho, A., Lo, A., Chang, S. D., Harsh, G. R., Gibbs, I. C., Hancock, S. L., Li, G., Adler, J. R., Soltys, S. G. 2016; 26 (2): 97-104

  Abstract

  Patients with tumors adjacent to the optic nerves and chiasm are frequently not candidates for single-fraction stereotactic radiosurgery (SRS) due to concern for radiation-induced optic neuropathy. However, these patients have been successfully treated with hypofractionated SRS over 2-5 days, though dose constraints have not yet been well defined. We reviewed the literature on optic tolerance to radiation and constructed a dose-response model for visual pathway tolerance to SRS delivered in 1-5 fractions. We analyzed optic nerve and chiasm dose-volume histogram (DVH) data from perioptic tumors, defined as those within 3mm of the optic nerves or chiasm, treated with SRS from 2000-2013 at our institution. Tumors with subsequent local progression were excluded from the primary analysis of vision outcome. A total of 262 evaluable cases (26 with malignant and 236 with benign tumors) with visual field and clinical outcomes were analyzed. Median patient follow-up was 37 months (range: 2-142 months). The median number of fractions was 3 (1 fraction n = 47, 2 fraction n = 28, 3 fraction n = 111, 4 fraction n = 10, and 5 fraction n = 66); doses were converted to 3-fraction equivalent doses with the linear quadratic model using α/β = 2Gy prior to modeling. Optic structure dose parameters analyzed included Dmin, Dmedian, Dmean, Dmax, V30Gy, V25Gy, V20Gy, V15Gy, V10Gy, V5Gy, D50%, D10%, D5%, D1%, D1cc, D0.50cc, D0.25cc, D0.20cc, D0.10cc, D0.05cc, D0.03cc. From the plan DVHs, a maximum-likelihood parameter fitting of the probit dose-response model was performed using DVH Evaluator software. The 68% CIs, corresponding to one standard deviation, were calculated using the profile likelihood method. Of the 262 analyzed, 2 (0.8%) patients experienced common terminology criteria for adverse events grade 4 vision loss in one eye, defined as vision of 20/200 or worse in the affected eye. One of these patients had received 2 previous courses of radiotherapy to the optic structures. Both cases were meningiomas treated with 25Gy in 5 fractions, with a 3-fraction equivalent optic nerve Dmax of 19.2 and 22.2Gy. Fitting these data to a probit dose-response model enabled risk estimates to be made for these previously unvalidated optic pathway constraints: the Dmax limits of 12Gy in 1 fraction from QUANTEC, 19.5Gy in 3 fractions from Timmerman 2008, and 25Gy in 5 fractions from AAPM Task Group 101 all had less than 1% risk. In 262 patients with perioptic tumors treated with SRS, we found a risk of optic complications of less than 1%. These data support previously unvalidated estimates as safe guidelines, which may in fact underestimate the tolerance of the optic structures, particularly in patients without prior radiation. Further investigation would refine the estimated normal tissue complication probability for SRS near the optic apparatus.

  View details for DOI 10.1016/j.semradonc.2015.11.008

  View details for Web of Science ID 000373242700003

• Dosimetric Factors and Toxicity in Highly Conformal Thoracic Reirradiation. International journal of radiation oncology, biology, physics Binkley, M. S., Hiniker, S. M., Chaudhuri, A., Maxim, P. G., Diehn, M., Loo, B. W., Shultz, D. B. 2016; 94 (4): 808-815

  Abstract

  We determined cumulative dose to critical structures, rates of toxicity, and outcomes following thoracic reirradiation.We retrospectively reviewed our institutional database for patients treated between 2008 and 2014, who received thoracic reirradiation with overlap of 25% prescribed isodose lines. Patients received courses of hyperfractionated (n=5), hypofractionated (n=5), conventionally fractionated (n=21), or stereotactic ablative radiation therapy (n=51). Doses to critical structures were converted to biologically effective dose, expressed as 2 Gy per fraction equivalent dose (EQD2; α/β = 2 for spinal cord; α/β = 3 for other critical structures).We identified 82 courses (44 for retreatment) in 38 patients reirradiated at a median 16 months (range: 1-71 months) following initial RT. Median follow-up was 17 months (range: 3-57 months). Twelve- and 24-month overall survival rates were 79.6% and 57.3%, respectively. Eighteen patients received reirradiation for locoregionally recurrent non-small cell lung cancer with 12-month rates of local failure and regional recurrence and distant metastases rates of 13.5%, 8.1%, and 15.6%, respectively. Critical structures receiving ≥75 Gy EQD2 included spinal cord (1 cm(3); n=1), esophagus (1 cm(3); n=10), trachea (1 cm(3); n=11), heart (1 cm(3); n=9), aorta (1 cm(3); n=16), superior vena cava (1 cm(3); n=12), brachial plexus (0.2 cm(3); n=2), vagus nerve (0.2 cm(3); n=7), sympathetic trunk (0.2 cm(3); n=4), chest wall (30 cm(3); n=12), and proximal bronchial tree (1 cm(3); n=17). Cumulative dose-volume (D cm(3)) toxicity following reirradiation data included esophagitis grade ≥2 (n=3, D1 cm(3) range: 41.0-100.6 Gy), chest wall grade ≥2 (n=4; D30 cm(3) range: 35.0-117.2 Gy), lung grade 2 (n=7; V20combined-lung range: 4.7%-21.7%), vocal cord paralysis (n=2; vagus nerve D0.2 cm(3) range: 207.5-302.2 Gy), brachial plexopathy (n=1; D0.2 cm(3) = 242.5 Gy), and Horner's syndrome (n=1; sympathetic trunk D0.2 cm(3) = 130.8 Gy). No grade ≥4 toxicity was observed.Overlapping courses of reirradiation can be safely delivered with acceptable toxicity. Some toxicities occurred acutely at doses considered safe for a single course of therapy (esophagus). We observed rib fracture, brachial plexopathy, and Horner's syndrome for patients receiving high cumulative doses to corresponding critical structures.

  View details for DOI 10.1016/j.ijrobp.2015.12.007

  View details for PubMedID 26831903

• A single-institution retrospective analysis of outcomes for stage I-II primary mediastinal large B-cell lymphoma treated with immunochemotherapy with or without radiotherapy LEUKEMIA & LYMPHOMA Binkley, M. S., Hiniker, S. M., Wu, S., Natkunam, Y., Mittra, E. S., Advani, R. H., Hoppe, R. T. 2016; 57 (3): 604-608

  Abstract

  As the optimal treatment for primary mediastinal large B-cell lymphoma (PMBCL) remains undefined, we evaluated outcomes of patients treated with standard and dose-intense rituximab-chemotherapy (R-CT) with and without radiotherapy (RT). We retrospectively identified 28 patients with stage I-II PMBCL in our lymphoma database, re-reviewed pathology slides and scored interim or post-chemotherapy PET/CTs using the Deauville scale. Fourteen patients received RT (36-45 Gy) preceded by either six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or 12 weeks of rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin (R-VACOP-B) with median follow-up of 94 months. Fourteen patients received 4-8 cycles of dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide and rituximab (DA-EPOCH-R) with median follow-up of 38 months; one of these received RT (36 Gy) due to post-chemotherapy PET/CT Deauville score 4. Following R-CT and RT or DA-EPOCH-R, 5-year and 3-year FFP and OS were both 100%. Both R-CHOP/R-VACOP-B with RT and DA-EPOCH-R demonstrate excellent outcomes.

  View details for DOI 10.3109/10428194.2015.1067700

  View details for Web of Science ID 000372499800016

• Predictors of clinical response to immunotherapy with or without radiotherapy JOURNAL OF RADIATION ONCOLOGY Hiniker, S. M., Maecker, H. T., Knox, S. J. 2015; 4 (4): 339–45

  View details for DOI 10.1007/s13566-015-0219-2

  View details for Web of Science ID 000218779400004

• Value of Surveillance Studies for Patients With Stage I to II Diffuse Large B-Cell Lymphoma in the Rituximab Era. International journal of radiation oncology, biology, physics Hiniker, S. M., Pollom, E. L., Khodadoust, M. S., Kozak, M. M., Xu, G., Quon, A., Advani, R. H., Hoppe, R. T. 2015; 92 (1): 99-106

  Abstract

  The role of surveillance studies in limited-stage diffuse large B-cell lymphoma (DLBCL) in the rituximab era has not been well defined. We sought to evaluate the use of imaging (computed tomography [CT] and positron emission tomography [PET]-CT) scans and lactate dehydrogenase (LDH) in surveillance of patients with stage I to II DLBCL.A retrospective analysis was performed of patients who received definitive treatment between 2000 and 2013.One hundred sixty-two consecutive patients with stage I to II DLBCL were treated with chemotherapy +/- rituximab, radiation, or combined modality therapy. The 5-year rates of overall survival (OS) and freedom from progression (FFP) were 81.2% and 80.8%, respectively. Of the 162 patients, 124 (77%) were followed up with at least 1 surveillance PET scan beyond end-of-treatment scans; of those, 94 of 124 (76%) achieved a complete metabolic response on PET scan after completion of chemotherapy, and this was associated with superior FFP (P=.01, HR=0.3) and OS (P=.01, HR 0.3). Eighteen patients experienced relapse after initial response to therapy. Nine relapses were initially suspected by surveillance imaging studies (8 PET, 1 CT), and 9 were suspected clinically (5 by patient-reported symptoms and 4 by symptoms and physical examination). No relapses were detected by surveillance LDH. The median duration from initiation of treatment to relapse was 14.3 months among patients with relapses suspected by imaging, and 59.8 months among patients with relapses suspected clinically (P=.077). There was no significant difference in OS from date of first therapy or OS after relapse between patients whose relapse was suspected by imaging versus clinically. Thirteen of 18 patients underwent successful salvage therapy after relapse.A complete response on PET scan immediately after initial chemotherapy is associated with superior FFP and OS in stage I to II DLBCL. The use of PET scans as posttreatment surveillance is not associated with a survival advantage. LDH is not a sensitive marker for relapse. Our results argue for limiting the use of posttreatment surveillance in patients with limited-stage DLBCL.

  View details for DOI 10.1016/j.ijrobp.2015.01.039

  View details for PubMedID 25863757

• Predictors of clinical response to immunotherapy with or without radiotherapy. Journal of radiation oncology Hiniker, S. M., Maecker, H. T., Knox, S. J. 2015; 4: 339-345

  Abstract

  Success with recent immunotherapies has resulted in previously unattainable response rates, as well as durable responses in diseases with historically poor prognoses. The combination of radiation therapy and immunotherapy has been a recent area of active investigation, with exciting results in a subset of patients. However, patient characteristics predictive of probable benefit from therapy and clinically meaningful biomarkers indicative of the early development of an antitumor immune response have yet to be identified. What is needed is a better way to predict which patients are likely to benefit from therapy, which would allow those patients unlikely to benefit from immunotherapy to be spared potentially futile therapies, thereby avoiding unnecessary risks of toxicity and costly treatment. Here, we summarize the early data on predictors of clinical response to immunotherapy, and to immunotherapy in combination with radiation.

  View details for PubMedID 26709361

• Recent advances in understanding and managing rhabdomyosarcoma. F1000prime reports Hiniker, S. M., Donaldson, S. S. 2015; 7: 59-?

  Abstract

  Rhabdomyosarcoma is the most common childhood soft tissue sarcoma and the fourth most common pediatric solid tumor. For most patients, treatment consists of a multimodality approach, including chemotherapy, surgery, and/or radiotherapy. To guide treatment, patients with rhabdomyosarcoma are risk stratified based on a number of factors. These factors include clinical group, which depends largely on the extent of resection and nodal involvement, and stage, which takes into account tumor size, invasion, nodal involvement, and disease site. Histology of the tumor and age at diagnosis are also factored into risk stratification. Recent advances in understanding the biology of the disease have allowed for the further sub-classification of rhabdomyosarcoma. In addition, elucidation of additional clinical features associated with poor prognosis has allowed for better understanding of risk and provides more clarity regarding those patients who require more intensive therapy. Many areas of active investigation are ongoing, including the following: further delineation of the biological underpinnings of the various disease subtypes with the possibility of molecularly targeted therapy; a better understanding of clinical risk factors, including the evaluation and management of potentially involved lymph nodes; determination of the appropriate role of post-treatment imaging and assessment of response to therapy; and incorporation of advanced radiotherapeutic techniques, including conformal intensity-modulated photon and proton therapy.

  View details for DOI 10.12703/P7-59

  View details for PubMedID 26097732

  View details for PubMedCentralID PMC4447051

• Immunotherapy and radiation. Seminars in oncology Hiniker, S. M., Knox, S. J. 2014; 41 (6): 702-713

  Abstract

  Radiation therapy and immunotherapy are both well-established treatments for malignant disease. Radiotherapy has long been utilized for purposes of providing local tumor control, and the recent success with novel immunomodulatory agents has brought immunotherapy into the forefront of clinical practice for the treatment of many tumor types. Although radiotherapy has traditionally been thought to mediate tumor regression through direct cytotoxic effects, it is now known that radiation also alters the local tumor microenvironment with effects on both the local and systemic anti-tumor immune response. There is growing evidence that the rational integration of the immunomodulatory effects of radiotherapy with the expanding armamentarium of clinically approved immunotherapeutics can yield potent anti-tumor responses exceeding the benefit of either therapy alone. Here we summarize current approaches to the combination of immunotherapy with radiation therapy.

  View details for DOI 10.1053/j.seminoncol.2014.09.019

  View details for PubMedID 25499631

• Value of surveillance studies for patients (pts) with stage I-II diffuse large B-cell lymphoma (DLBCL) in the rituximab (R) era. Hiniker, S. M., Pollom, E. L., Khodadoust, M. S., Kozak, M. M., Advani, R. H., Hoppe, R. T. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613204223

• Survival and neurocognitive outcomes after cranial or craniospinal irradiation plus total-body irradiation before stem cell transplantation in pediatric leukemia patients with central nervous system involvement. International journal of radiation oncology, biology, physics Hiniker, S. M., Agarwal, R., Modlin, L. A., Gray, C. C., Harris, J. P., Million, L., Kiamanesh, E. F., Donaldson, S. S. 2014; 89 (1): 67-74

  Abstract

  To evaluate survival and neurocognitive outcomes in pediatric acute lymphoblastic leukemia (ALL) patients with central nervous system (CNS) involvement treated according to an institutional protocol with stem cell transplantation (SCT) and a component of craniospinal irradiation (CSI) in addition to total-body irradiation (TBI) as preparative regimen.Forty-one pediatric ALL patients underwent SCT with TBI and received additional cranial irradiation or CSI because of CNS leukemic involvement. Prospective neurocognitive testing was performed before and after SCT in a subset of patients. Cox regression models were used to determine associations of patient and disease characteristics and treatment methods with outcomes.All patients received a cranial radiation boost; median total cranial dose was 24 Gy. Eighteen patients (44%) received a spinal boost; median total spinal dose for these patients was 18 Gy. Five-year disease-free survival (DFS) for all patients was 67%. Those receiving CSI had a trend toward superior DFS compared with those receiving a cranial boost alone (hazard ratio 3.23, P=.14). Patients with isolated CNS disease before SCT had a trend toward superior DFS (hazard ratio 3.64, P=.11, 5-year DFS 74%) compared with those with combined CNS and bone marrow disease (5-year DFS 59%). Neurocognitive testing revealed a mean post-SCT overall intelligence quotient of 103.7 at 4.4 years. Relative deficiencies in processing speed and/or working memory were noted in 6 of 16 tested patients (38%). Pre- and post-SCT neurocognitive testing revealed no significant change in intelligence quotient (mean increase +4.7 points). At a mean of 12.5 years after transplant, 11 of 13 long-term survivors (85%) had completed at least some coursework at a 2- or 4-year college.The addition of CSI to TBI before SCT in pediatric ALL with CNS involvement is effective and well-tolerated. Craniospinal irradiation plus TBI is worthy of further protocol investigation in children with CNS leukemia.

  View details for DOI 10.1016/j.ijrobp.2014.01.056

  View details for PubMedID 24725690

• ALARA: In Radiation Oncology and Diagnostic Imaging Alike ONCOLOGY-NEW YORK Hiniker, S. M., Donaldson, S. S. 2014; 28 (3): 247-248

  View details for Web of Science ID 000333550900014

  View details for PubMedID 24855734

• Survival and Neurocognitive Outcomes Following Cranial or Craniospinal Irradiation Plus Total Body Irradiation Prior to Transplantation in Children with CNS Leukemia Hiniker, S. M., Agarwal, R., Modlin, L. A., Harris, J. P., Kiamanesh, E. E., Million, L., Gray, C. C., Donaldson, S. S. ELSEVIER SCIENCE INC. 2014: S170–S171

  View details for DOI 10.1016/j.bbmt.2013.12.277

  View details for Web of Science ID 000331155400254

• Re-irradiation with stereotactic body radiation therapy as a novel treatment option for isolated local recurrence of pancreatic cancer after multimodality therapy: experience from two institutions. Journal of gastrointestinal oncology Wild, A. T., Hiniker, S. M., Chang, D. T., Tran, P. T., Khashab, M. A., Limaye, M. R., Laheru, D. A., Le, D. T., Kumar, R., Pai, J. S., Hargens, B., Sharabi, A. B., Shin, E. J., Zheng, L., Pawlik, T. M., Wolfgang, C. L., Koong, A. C., Herman, J. M. 2013; 4 (4): 343-351

  Abstract

  Limited treatment options exist for isolated local recurrence of pancreatic ductal adenocarcinoma (PDA) following surgical resection accompanied by neoadjuvant or adjuvant chemoradiation therapy (CRT). While select patients are eligible for re-resection, recurrent lesions are often unresectable. Stereotactic body radiation therapy (SBRT) represents a possible minimally invasive treatment option for these patients, although published data in this setting are currently lacking. This study examines the safety, efficacy, and palliative capacity of re-irradiation with SBRT for isolated local PDA recurrence. All patients undergoing SBRT at two academic centers from 2008-2012 were retrospectively reviewed to identify those who received re-irradiation with SBRT for isolated local recurrence or progression of PDA after previous conventionally fractionated CRT. Information regarding demographics, clinicopathologic characteristics, therapies received, survival, symptom palliation, and toxicity was obtained from patient charts. Kaplan-Meier statistics were used to analyze survival and the log-rank test was used to compare survival among patient subgroups. Eighteen patients were identified. Fifteen had previously undergone resection with neoadjuvant or adjuvant CRT, while 3 received definitive CRT for locally advanced disease. Median CRT dose was 50.4 Gy [interquartile range (IQR), 45.0-50.4 Gy] in 28 fractions. All patients subsequently received gemcitabine-based maintenance chemotherapy, but developed isolated local disease recurrence or progression without evidence of distant metastasis. Locally recurrent or progressive disease was treated with SBRT to a median dose of 25.0 Gy (range, 20.0-27.0 Gy) in 5 fractions. Median survival from SBRT was 8.8 months (95% CI, 1.2-16.4 months). Despite having similar clinicopathologic disease characteristics, patients who experienced local progression greater than vs. less than 9 months after surgery/definitive CRT demonstrated superior median survival (11.3 vs. 3.4 months; P=0.019) and progression-free survival (10.6 vs. 3.2 months; P=0.030) after SBRT. Rates of freedom from local progression at 6 and 12 months after SBRT were 78% (14 of 18 patients) and 62% (5 of 8 patients), respectively. Effective symptom palliation was achieved in 4 of 7 patients (57%) who reported symptoms of abdominal or back pain prior to SBRT. Five patients (28%) experienced grade 2 acute toxicity; none experienced grade ≥3 acute toxicity. One patient (6%) experienced grade 3 late toxicity in the form of small bowel obstruction. In conclusion, re-irradiation with hypofractionated SBRT in this salvage scenario appears to be a safe and reasonable option for palliation of isolated local PDA recurrence or progression following previous conventional CRT. Patients with a progression-free interval of greater than 9 months prior to isolated local recurrence or progression may be most suitable for re-irradiation with SBRT, as they appear to have a better prognosis with survival that is long enough for local control to be of potential benefit.

  View details for DOI 10.3978/j.issn.2078-6891.2013.044

  View details for PubMedID 24294505

  View details for PubMedCentralID PMC3819776

• Primary squamous cell carcinoma of the vagina: Prognostic factors, treatment patterns, and outcomes. Gynecologic oncology Hiniker, S. M., Roux, A., Murphy, J. D., Harris, J. P., Tran, P. T., Kapp, D. S., Kidd, E. A. 2013; 131 (2): 380-385

  Abstract

  Primary squamous cell carcinoma (SCCA) of the vagina is a rare malignancy with limited data to guide treatment. We evaluated prognostic factors and outcomes for patients with primary vaginal SCCA treated with definitive radiation therapy at a single institution.A retrospective analysis was performed on patients treated for primary vaginal SCCA from 1959 to 2011.Ninety-one patients with primary vaginal SCCA were treated with definitive radiation therapy. Thirty-eight patients had FIGO stage I, 28 stage II, 13 stage III, and 12 stage IV disease. The mean total dose was 70.1Gy. Two-year overall survival (OS), locoregional control rate (LRC), and distant metastasis-free survival by stage were, respectively: stage I: 96.2%, 80.6%, 87.5%; stage II: 92.3%, 64.7%, 84.6%; stage III: 66.6%, 44.4%, 50.0%; and stage IV: 25.0%, 14.3%, 25.0%. Treatment with total dose over 70Gy was associated with improved OS (p=0.0956) and LRC (p=0.055). There was a significant difference in median dose received by patients who developed grade 3/4 toxicity compared to those who did not (82.9Gy versus 70.0Gy, p=0.0019). None of the 10 patients treated with IMRT experienced locoregional recurrence or grade 3/4 toxicity. Tumor size larger than 4cm was associated with worse OS (p=0.0034) and LRC (p=0.006).Our analysis suggests that the optimal dose for definitive treatment of SCCA of the vagina lies between 70 and 80Gy. Treatment with IMRT may allow for dose escalation with reduced toxicity and excellent LRC. Tumor size over 4cm is associated with inferior outcomes and may require additional treatment modalities.

  View details for DOI 10.1016/j.ygyno.2013.08.012

  View details for PubMedID 23954572

• Sporadic versus Radiation-Associated Angiosarcoma: A Comparative Clinicopathologic and Molecular Analysis of 48 Cases. Sarcoma Hung, J., Hiniker, S. M., Lucas, D. R., Griffith, K. A., McHugh, J. B., Meirovitz, A., Thomas, D. G., Chugh, R., Herman, J. M. 2013; 2013: 798403-?

  Abstract

  Angiosarcomas are aggressive tumors of vascular endothelial origin, occurring sporadically or in association with prior radiotherapy. We compared clinicopathologic and biologic features of sporadic angiosarcomas (SA) and radiation-associated angiosarcomas (RAA). Methods. From a University of Michigan institutional database, 37 SA and 11 RAA were identified. Tissue microarrays were stained for p53, Ki-67, and hTERT. DNA was evaluated for TP53 and ATM mutations. Results. Mean latency between radiotherapy and diagnosis of RAA was 11.9 years: 6.7 years for breast RAA versus 20.9 years for nonbreast RAA (P = 0.148). Survival after diagnosis did not significantly differ between SA and RAA (P = 0.590). Patients with nonbreast RAA had shorter overall survival than patients with breast RAA (P = 0.03). The majority of SA (86.5%) and RAA (77.8%) were classified as high-grade sarcomas (P = 0.609). RAA were more likely to have well-defined vasoformative areas (55.6% versus 27%, P = 0.127). Most breast SA were parenchymal in origin (80%), while most breast RAA were cutaneous in origin (80%). TMA analysis showed p53 overexpression in 25.7% of SA and 0% RAA, high Ki-67 in 35.3% of SA and 44.4% RAA, and hTERT expression in 100% of SA and RAA. TP53 mutations were detected in 13.5% of SA and 11.1% RAA. ATM mutations were not detected in either SA or RAA. Conclusions. SA and RAA are similar in histology, immunohistochemical markers, and DNA mutation profiles and share similar prognosis. Breast RAA have a shorter latency period compared to nonbreast RAA and a significantly longer survival.

  View details for DOI 10.1155/2013/798403

  View details for PubMedID 24082817

• A Systemic Complete Response of Metastatic Melanoma to Local Radiation and Immunotherapy TRANSLATIONAL ONCOLOGY Hiniker, S. M., Chen, D. S., Reddy, S., Chang, D. T., Jones, J. C., Mollick, J. A., Swetter, S. M., Knox, S. J. 2012; 5 (6): 404-407

  Abstract

  Melanoma is a relatively immunogenic tumor, in which infiltration of melanoma cells by T lymphocytes is associated with a better clinical prognosis. We hypothesized that radiation-induced cell death may provide additional stimulation of an anti-tumor immune response in the setting of anti-CTLA-4 treatment.In a pilot melanoma patient, we prospectively tested this hypothesis. We treated the patient with two cycles of ipilimumab, followed by stereotactic ablative radiotherapy to two of seven hepatic metastases, and two additional cycles of ipilimumab.Subsequent positron emission tomography-computed tomography scan indicated that all metastases, including unirradiated liver lesions and an unirradiated axillary lesion, had completely resolved, consistent with a complete response by RECIST.The use of radiotherapy in combination with targeted immunotherapy as a noninvasive in vivo tumor vaccine strategy appears to be a promising method of enhancing the induction of systemic immune responses and anti-tumor effect.

  View details for DOI 10.1593/tlo.12280

  View details for PubMedID 23323154

• Wild-type EGFR Is Stabilized by Direct Interaction with HSP90 in Cancer Cells and Tumors NEOPLASIA Ahsan, A., Ramanand, S. G., Whitehead, C., Hiniker, S. M., Rehemtulla, A., Pratt, W. B., Jolly, S., Gouveia, C., Kristy Truong, K., Van Waes, C., Ray, D., Lawrence, T. S., Nyati, M. K. 2012; 14 (8): 670-?

  Abstract

  The epidermal growth factor receptor (EGFR) has been targeted for inhibition using tyrosine kinase inhibitors and monoclonal antibodies, with improvement in outcome in subsets of patients with head and neck, lung, and colorectal carcinomas. We have previously found that EGFR stability plays a key role in cell survival after chemotherapy and radiotherapy. Heat shock protein 90 (HSP90) is known to stabilize mutant EGFR and ErbB2, but its role in cancers with wild-type (WT) WT-EGFR is unclear. In this report, we demonstrate that fully mature, membrane-bound WT-EGFR interacts with HSP90 independent of ErbB2. Further, the HSP90 inhibitors geldanamycin (GA) and AT13387 cause a decrease in WT-EGFR in cultured head and neck cancer cells. This decrease results from a significantly reduced half-life of WT-EGFR. WT-EGFR was also lost in head and neck xenograft specimens after treatment with AT13387 under conditions that inhibited tumor growth and prolonged survival of the mice. Our findings demonstrate that WT-EGFR is a client protein of HSP90 and that their interaction is critical for maintaining both the stability of the receptor as well as the growth of EGFR-dependent cancers. Furthermore, these findings support the search for specific agents that disrupt HSP90's ability to act as an EGFR chaperone.

  View details for DOI 10.1593/neo.12986

  View details for Web of Science ID 000308490500001

  View details for PubMedID 22952420

• Abscopal Effect in a Patient with Melanoma NEW ENGLAND JOURNAL OF MEDICINE Hiniker, S. M., Chen, D. S., Knox, S. J. 2012; 366 (21): 2035-2035

  View details for Web of Science ID 000304353000021

  View details for PubMedID 22621637

• Role of Epidermal Growth Factor Receptor Degradation in Cisplatin-Induced Cytotoxicity in Head and Neck Cancer CANCER RESEARCH Ahsan, A., Hiniker, S. M., Ramanand, S. G., Nyati, S., Hegde, A., Helman, A., Menawat, R., Bhojani, M. S., Lawrence, T. S., Nyati, M. K. 2010; 70 (7): 2862-2869

  Abstract

  Cisplatin and its analogues are the most commonly used agents in the treatment of head and neck squamous cell carcinoma. In this study, we investigated a possible role of epidermal growth factor (EGF) receptor (EGFR) phosphorylation and degradation in cisplatin-induced cytotoxicity. Cisplatin treatment led to an increase in initial EGFR phosphorylation at Y1045, the binding site of ubiquitin ligase, Casitas B-lineage lymphoma (c-Cbl), followed by ubiquitination in the relatively cisplatin-sensitive cell lines. However, cisplatin-resistant cell lines underwent minimal EGFR phosphorylation at the Y1045 site and minimal ubiquitination. We found that EGFR degradation in response to cisplatin was highly correlated with cytotoxicity in seven head and neck cancer cell lines. Pretreatment with EGF enhanced cisplatin-induced EGFR degradation and cytotoxicity, whereas erlotinib pretreatment blocked EGFR phosphorylation, degradation, and cisplatin-induced cytotoxicity. Expression of a mutant Y1045F EGFR, which is relatively resistant to c-Cbl-mediated degradation, in Chinese hamster ovary cells and the UMSCC11B human head and neck cancer cell line protected EGFR from cisplatin-induced degradation and enhanced cell survival compared with wild-type (WT) EGFR. Transfection of WT c-Cbl enhanced EGFR degradation and cisplatin-induced cytotoxicity compared with control vector. These results show that cisplatin-induced EGFR phosphorylation and subsequent ubiquitination and degradation is an important determinant of cisplatin sensitivity. Our findings suggest that treatment with an EGFR inhibitor before cisplatin would be antagonistic, as EGFR inhibition would protect EGFR from cisplatin-mediated phosphorylation and subsequent ubiquitination and degradation, which may explain the negative results of several recent clinical trials. Furthermore, they suggest that EGFR degradation is worth exploring as an early biomarker of response and as a target to improve outcome.

  View details for DOI 10.1158/0008-5472.CAN-09-4294

  View details for Web of Science ID 000278486000031

  View details for PubMedID 20215522

• Role of Cell Cycle in Epidermal Growth Factor Receptor Inhibitor-Mediated Radiosensitization CANCER RESEARCH Ahsan, A., Hiniker, S. M., Davis, M. A., Lawrence, T. S., Nyati, M. K. 2009; 69 (12): 5108-5114

  Abstract

  Epidermal growth factor receptor (EGFR) inhibitors are increasingly used in combination with radiotherapy in the treatment of various EGFR-overexpressing cancers. However, little is known about the effects of cell cycle status on EGFR inhibitor-mediated radiosensitization. Using EGFR-overexpressing A431 and UMSCC-1 cells in culture, we found that radiation activated the EGFR and extracellular signal-regulated kinase pathways in quiescent cells, leading to progression of cells from G(1) to S, but this activation and progression did not occur in proliferating cells. Inhibition of this activation blocked S-phase progression and protected quiescent cells from radiation-induced death. To determine if these effects were caused by EGFR expression, we transfected Chinese hamster ovary (CHO) cells, which lack EGFR expression, with EGFR expression vector. EGFR expressed in CHO cells also became activated in quiescent cells but not in proliferating cells after irradiation. Moreover, quiescent cells expressing EGFR underwent increased radiation-induced clonogenic death compared with both proliferating CHO cells expressing EGFR and quiescent wild-type CHO cells. Our data show that radiation-induced enhancement of cell death in quiescent cells involves activation of the EGFR and extracellular signal-regulated kinase pathways. Furthermore, they suggest that EGFR inhibitors may protect quiescent tumor cells, whereas radiosensitization of proliferating cells may be caused by downstream effects such as cell cycle redistribution. These findings emphasize the need for careful scheduling of treatment with the combination of EGFR inhibitors and radiation and suggest that EGFR inhibitors might best be given after radiation in order to optimize clinical outcome.

  View details for DOI 10.1158/0008-5472.CAN-09-0466

  View details for Web of Science ID 000267506400025

  View details for PubMedID 19509222

• Radiotherapy using a water bath in the treatment of Bowen's disease of the digit RADIOTHERAPY AND ONCOLOGY Herman, J. M., Pierce, L. J., Sandler, H. M., Griffith, K. A., Jabbari, S., Hiniker, S. M., Johnson, T. M. 2008; 88 (3): 398-402

  Abstract

  Bowen's disease (BD), a form of squamous cell carcinoma in situ, can transform into invasive squamous cell carcinoma and should be treated aggressively. Although standard treatment for BD is electrodessication and curettage, radiotherapy (RT) can be used for those patients who are poor surgical candidates or when surgery could result in a poor cosmetic and functional outcome. Surgical treatment of BD of the digit can result in poor function and sometimes amputation. Here, we report our experience using a unique water bath technique to treat BD of the digit.This retrospective review evaluates the outcomes and toxicity of nine consecutive patients with BD of the digit treated with RT between 1999 and 2004. Fourteen digit lesions were immersed in a water bath and treated with photon irradiation. The median radiation dose delivered was 50Gy (range 25-66Gy) in 2.5Gy fractions (range 2-3Gy).The median age of the patients treated was 77 years (range 29-87 years). Three patients (33%) had more than one digit treated. With a median follow-up of 25 months (range 0.4-52 months), all 14 digit lesions are locally controlled. The majority of lesions demonstrated mild to moderate erythema, desquamation, or edema (grade 1-2) acutely following RT which resolved within one month of treatment. Two digits (14%) developed ulcers (grade 4) which healed following RT. The only long-term toxicity was decreased sensation and strength in one patient who had three circumferential lesions. This toxicity was limited and did not appear to influence the patient's daily activities (grade 2).These preliminary results demonstrate high rates of tumor control with minimal morbidity following definitive RT in the treatment of BD of the digit, and suggest that RT may be a viable treatment alternative to surgery for selected lesions. Through a multidisciplinary assessment, treatment of BD of the digit can be individualized to optimize patient care.

  View details for DOI 10.1016/j.radonc.2008.05.025

  View details for Web of Science ID 000260203800013

  View details for PubMedID 18571754

• Effects of cerivastatin withdrawal on statin persistence. Annals of pharmacotherapy Reaume, K. T., Erickson, S. R., Dorsch, M. P., Dunham, N. L., Hiniker, S. M., Prabhakar, N., Kline-Rogers, E. M., Eagle, K. A. 2008; 42 (7): 956-961

  Abstract

  Medication-taking behavior is influenced by many factors, as described by the Health Belief Model. Information on withdrawals of drugs from the market may be an example of negative external stimuli that might influence patients' decisions to persist with long-term drug therapy.To evaluate the association between the withdrawal of cerivastatin from the market and persistence in taking all other statins in patients who recently experienced acute coronary syndrome (ACS).Patients from a large ACS registry who responded to questions about medication use during a postdischarge telephone survey between November 2000 and February 2002 were categorized into 3 groups: pre- (November 1, 2000-April 30, 2001), peri- (May 1, 2001-August 31, 2001), and post- (September 1, 2001-February 28, 2002) cerivastatin withdrawal periods. Patients were considered persistent if, at the time of the survey, they continued to take study medication that had been prescribed at discharge. Persistence with angiotensin-converting enzyme inhibitors, aspirin, and beta-blockers was also assessed to determine whether changes in statin persistence were unique to the class or related to other medication issues that affected all classes. The Kruskal-Wallis test, with post hoc Mann-Whitney U test, was used to analyze the differences in persistence between the groups. All comparisons were considered statistically significant at p less than 0.05.There were no significant differences in patient characteristics between study groups. Persistence with statins decreased during the periwithdrawal period (88.4% pre vs 76.7% peri) and rebounded in the postwithdrawal period (90.8%; p = 0.007). There were no significant differences in persistence with the other drug classes.The temporary decline in statin persistence appeared to be associated with the withdrawal of cerivastatin, while persistence with the other study medications remained constant. Clinicians need to understand the potential effect of factors such as media attention surrounding a drug's withdrawal on patients' medication-taking behavior.

  View details for DOI 10.1345/aph.1K575

  View details for PubMedID 18523235