Oliver Dorigo, M.D., Ph.D.

All Publications

• Macrophage-derived CCL23 upregulates expression of T-cell exhaustion markers in ovarian cancer. British journal of cancer Kamat, K., Krishnan, V., Dorigo, O. 2022

  Abstract

  BACKGROUND: Macrophages are an important component of the tumour immune microenvironment (TME) and can promote tumour growth and metastasis. Macrophage-secreted chemokine-ligand-23 (CCL23) induces ovarian cancer cell migration via chemokine-receptor 1 (CCR1). However, the effect of CCL23 on other immune cells in the TME is unknown.METHODS: CCL23 levels were measured by ELISA. The expression of surface markers in exhaustion assays was quantified by flow cytometry. Signalling pathways were identified by phosphokinase array and validated by western blot.RESULTS: Ascites from patients with high-grade serous ovarian cancer (HGSC) contain high levels of CCL23. Similarly, significantly higher CCL23 levels were found in plasma from HGSC patients compared to healthy individuals. RNA-seq analysis of ovarian cancer tissues from TCGA showed that expression of CCL23 correlated with the presence of macrophages. In tissues with high levels of CCL23 and macrophage content, the fraction of CD8+T cells expressing exhaustion markers CTLA-4 and PD-1 were significantly higher compared to low-level CCL23 tissues. In vitro, CCL23 induced upregulation of immune checkpoint proteins on CD8+T cells, including CTLA-4, TIGIT, TIM-3 and LAG-3 via phosphorylation of GSK3beta in CD8+T cells.CONCLUSIONS: Our data suggest that CCL23 produced by macrophages contributes to the immune-suppressive TME in ovarian cancer by inducing an exhausted T-cell phenotype.

  View details for DOI 10.1038/s41416-022-01887-3

  View details for PubMedID 35750747

• Omental macrophages secrete chemokine ligands that promote ovarian cancer colonization of the omentum via CCR1. Communications biology Krishnan, V., Tallapragada, S., Schaar, B., Kamat, K., Chanana, A. M., Zhang, Y., Patel, S., Parkash, V., Rinker-Schaeffer, C., Folkins, A. K., Rankin, E. B., Dorigo, O. 2020; 3 (1): 524

  Abstract

  The omentum is the most common site of ovarian cancer metastasis. Immune cell clusters called milky spots are found throughout the omentum. It is however unknown if these immune cells contribute to ovarian cancer metastasis. Here we report that omental macrophages promote the migration and colonization of ovarian cancer cells to the omentum through the secretion of chemokine ligands that interact with chemokine receptor 1 (CCR1). We found that depletion of macrophages reduces ovarian cancer colonization of the omentum. RNA-sequencing of macrophages isolated from mouse omentum and mesenteric adipose tissue revealed a specific enrichment of chemokine ligandCCL6 in omental macrophages. CCL6 and the human homolog CCL23 were both necessary and sufficient to promote ovarian cancer migration by activating ERK1/2 and PI3K pathways. Importantly, inhibition of CCR1 reduced ovarian cancer colonization. These findings demonstrate a critical mechanism of omental macrophage induced colonization by ovarian cancer cells via CCR1 signaling.

  View details for DOI 10.1038/s42003-020-01246-z

  View details for PubMedID 32963283

• Aberrant nuclear β-catenin distribution does not prognosticate recurrences of endometrioid endometrial cancers - A retrospective single-institutional study. Gynecologic oncology Beshar, I., Moon, A. S., Darji, H., Liu, C., Jennings, M. T., Dorigo, O., Litkouhi, B., Diver, E. J., Karam, A. K., Howitt, B. E., Renz, M. 2023; 179: 85-90

  Abstract

  Aberrant β-catenin distribution has been theorized as a predictive biomarker for recurrence in early stage, low grade endometrioid endometrial cancer.This retrospective single-institution cohort study reviewed 410 patients with endometrial cancer from May 2018 to May 2022. Only endometrioid histology was included. Demographic and clinicopathological data were collected from the medical records. Univariate and multivariate logistic regressions, and sensitivity analyses for early stage, low grade and no specific molecular profile (NSMP) tumors were performed.297 patients were included for analysis. Most patients were over 60 years old, White, and with a BMI >30 and early stage low grade disease. Aberrant β-catenin distribution was found in 135 patients (45.5%) and wild type membranous β-catenin distribution in 162 (54.5%). While TP53 mutation correlated with endometrial cancer recurrence in this cohort (OR = 4.78), aberrant β-catenin distribution did not correlate in the overall population (OR = 0.75), the early stage low grade cancers (OR = 0.84), or the NSMP group (OR = 1.41) on univariate or multivariate analysis. No correlation between β-catenin distribution and local (OR = 0.61) or distant recurrences (OR = 0.90) was detected.Aberrant β-catenin distribution did not significantly correlate with recurrence in endometrioid endometrial cancer, nor in the early stage, low grade and NSMP sub-cohorts.

  View details for DOI 10.1016/j.ygyno.2023.10.025

  View details for PubMedID 37944330

• Does lymph node assessment change the prognostic significance of substantial LVSI and p53 status in endometrial endometrioid carcinoma? Gynecologic oncology Hui, C., Mendoza, M. G., von Eyben, R., Dorigo, O., Litkouhi, B., Renz, M., Karam, A., Hammer, P. M., Howitt, B. E., Kidd, E. 2023; 177: 150-156

  Abstract

  The PORTEC-2 update suggested that substantial lymphovascular space invasion (LVSI) and abnormal p53 expression (p53abnl) predict for poorer outcomes and that these patients should be treated with external beam radiation therapy (EBRT). We aim to determine if patients with these risk factors who undergo a lymph node (LN) assessment show similar outcomes.We retrospectively reviewed 126 patients with FIGO 2009 stage IA grade 3, stage IB grade 1-2, and stage IIIC (positive LN but no other stage II/III risk factors) endometrioid endometrial cancer who underwent LN assessment. Local (LR), regional recurrences (RR), and distant metastases were analyzed using competing risk methods, and overall survival (OS) was analyzed using Kaplan-Meier.Median follow-up time was 37.2 months. OS was significantly different between patients with and without p53abnl expression (16.7% versus 3.1% deceased), and between patients with and without LVSI (11.1% versus 1.5% deceased; p < 0.01 for both). The 2-year cumulative incidence of LR for patients with p53abnl versus wild type p53 and LVSI versus no LVSI was 11.1% (95% CI 0-25.6) versus 2.2% (95% CI 0-5.25; p = 0.04), and 11.4% (95% CI 2.0-20.9) versus 0%, respectively (p < 0.01). The 2-year cumulative RR in patients with LVSI versus no LVSI was 6.9% (95% CI 0-14.4) versus 0% (p = 0.05). No patients who completed pelvic RT experienced an in-field recurrence.Despite LN assessment, patients with high-intermediate risk early-stage or stage IIIC (with positive lymph nodes only but no other stage II or III risk factors) endometrial cancer with p53abnl expression and/or LVSI have worse outcomes. These patients may derive benefit from intensification with EBRT to improve local and pelvic control.

  View details for DOI 10.1016/j.ygyno.2023.09.001

  View details for PubMedID 37696217

• Adjuvant radiation therapy in early-stage endometrial cancer with abnormal beta-catenin expression is associated with improved local control. Gynecologic oncology Hui, C., Mendoza, M. G., Snyder, J., Dorigo, O., Litkouhi, B., Renz, M., Karam, A., Devereaux, K., Howitt, B. E., Kidd, E. A. 2023; 174: 42-48

  Abstract

  Emerging data suggests that abnormal (nuclear) β-catenin expression in some settings is associated with poorer outcomes. Our study aimed to verify the significance of abnormal β-catenin expression in early-stage endometrial cancer patients and determine if adjuvant radiation therapy (RT) improves local control.We identified 213 patients with FIGO 2018 stage I-II endometrioid endometrial cancer who underwent surgery from 2009 to 2021 with β-catenin expression assessed. Vaginal, regional, and distant recurrences were analyzed using competing risk methods, and overall survival was analyzed using Kaplan-Meier.Median follow up was 53.2 months; 6.9% experienced vaginal, 8.2% regional, and 7.4% distant recurrence. For the entire cohort, abnormal β-catenin expression was significantly associated with vaginal recurrence and remained significant on multivariate analysis (p = 0.03). There were 114 patients in the no specific molecular profile (NSMP) subgroup, and abnormal β-catenin expression was present in 46.5%. In the NSMP subgroup, abnormal β-catenin expression was associated with increased rates of vaginal recurrence (p = 0.06). Abnormal β-catenin expression in the NSMP subgroup was significant on multivariate analysis for vaginal recurrence (p = 0.04). RT significantly decreased vaginal recurrences in the entire cohort in patients with abnormal β-catenin expression (0%) versus wild type expression (17.5%; p = 0.03). In the NSMP subgroup 0% of patients who received RT versus 20.9% of patients who did not receive RT experienced a vaginal recurrence (p = 0.03).Use of adjuvant RT for stage I-II NSMP endometrial cancer with abnormal β-catenin expression improved local control. RT should be considered in these patients to decrease risk of vaginal recurrences.

  View details for DOI 10.1016/j.ygyno.2023.04.018

  View details for PubMedID 37149904

• Maveropepimut-S, a DPX-based immune-educating therapy, shows promising and durable clinical benefit in patients with recurrent ovarian cancer, a phase 2 trial. Clinical cancer research : an official journal of the American Association for Cancer Research Dorigo, O., Oza, A. M., Pejovic, T., Ghatage, P., Ghamande, S., Provencher, D., MacDonald, L. D., Torrey, H., Kaliaperumal, V., Ebrahimizadeh, W., Hirsch, H. A., Bramhecha, Y., Villella, J., Fiset, S. 2023

  Abstract

  Patients with platinum resistant ovarian cancer (OvCa) respond poorly to existing therapies. Hence there is a need for more effective treatments.The DeCidE1 trial is a multicenter, randomized, open-label, single-arm phase 2 study to evaluate the safety and effectiveness of maveropepimut-S (MVP-S) with cyclophosphamide (CPA) in patients with recurrent ovarian cancer. Median follow-up for evaluable subjects was 4.4 months. Data were collected from March 2019 to June 2021. Subjects received two injections of 0.25 mL MVP-S 3 weeks apart, followed by one 0.1 mL doses, every 8 weeks up to progression. Oral CPA, 50 mg twice daily, was administered in repeating weekly on and off cycles.Twenty-two patients were enrolled. Median age was 58 years (38-78 years). Among the evaluable population, ORR was 21% (90% CI, 7.5%-41.9%), with a DCR of 63% (90% CI, 41.8%-81.3%), including 4 (21%) patients with partial responses, 8 (42%) stable disease, and 7 (37%) progressive disease. The ORRs were consistent across subgroups based on platinum-sensitivity, and DCR was higher in the platinum-resistant subpopulation. Four stable disease patients maintained clinical benefit up to 25 months. Most treatment related adverse events (TRAEs) were grade 1 and 2 (87% of unique events). Most common AEs were injection site reactions. Eight subjects reported grade 3 and no grade 4 AEs. Survivin-specific T cell responses were observed in treated patients with clinical benefit.MVP-S with intermittent low-dose CPA is well-tolerated, with clinical benefit for patients with recurrent OvCa. Observed responses are irrespective of the platinum status.

  View details for DOI 10.1158/1078-0432.CCR-22-2595

  View details for PubMedID 37126016

• Monocytes - A Promising New TRAIL in Ovarian Cancer Cell Therapy. Clinical cancer research : an official journal of the American Association for Cancer Research Chow, S., Dorigo, O. 2022

  Abstract

  Adoptive cell transfer of interferon (IFN)-activated monocytes administered intraperitoneally to patients with platinum-resistant ovarian cancer demonstrated anti-tumor effects and acceptable tolerability. The exposure of monocytes to IFNalpha and IFNgamma upregulated TRAIL, which triggered caspase 8 and direct cell-to-cell contact-dependent apoptosis of ovarian cancer cells.

  View details for DOI 10.1158/1078-0432.CCR-22-2877

  View details for PubMedID 36383129

• ASO Visual Abstract: Impact of BRCA Mutation Status on Tumor Dissemination Pattern, Surgical Outcome, and Patient Survival in Primary and Recurrent High-Grade Serous Ovarian Cancer (HGSOC). A Multicenter, Retrospective Study of the Ovarian Cancer Therapy-Innovative Models Prolong Survival (OCTIPS) Consortium. Annals of surgical oncology Glajzer, J., Castillo-Tong, D. C., Richter, R., Vergote, I., Kulbe, H., Vanderstichele, A., Ruscito, I., Trillsch, F., Mustea, A., Kreuzinger, C., Gourley, C., Gabra, H., Taube, E. T., Dorigo, O., Horst, D., Keunecke, C., Baum, J., Angelotti, T., Sehouli, J., Braicu, E. I. 2022

  View details for DOI 10.1245/s10434-022-12681-z

  View details for PubMedID 36335272

• Impact of BRCA Mutation Status on Tumor Dissemination Pattern, Surgical Outcome and Patient Survival in Primary and Recurrent High-Grade Serous Ovarian Cancer: A Multicenter Retrospective Study by the Ovarian Cancer Therapy-Innovative Models Prolong Survival (OCTIPS)Consortium. Annals of surgical oncology Glajzer, J., Castillo-Tong, D. C., Richter, R., Vergote, I., Kulbe, H., Vanderstichele, A., Ruscito, I., Trillsch, F., Mustea, A., Kreuzinger, C., Gourley, C., Gabra, H., Taube, E. T., Dorigo, O., Horst, D., Keunecke, C., Baum, J., Angelotti, T., Sehouli, J., Braicu, E. I. 2022

  Abstract

  BACKGROUND: This study seeks to evaluate the impact of breast cancer (BRCA) gene status on tumor dissemination pattern, surgical outcome and survival in a multicenter cohort of paired primary ovarian cancer (pOC) and recurrent ovarian cancer (rOC).PATIENTS AND METHODS: Medical records and follow-up data from 190 patients were gathered retrospectively. All patients had surgery at pOC and at least one further rOC surgery at four European high-volume centers. Patients were divided into one cohort with confirmed mutation for BRCA1 and/or BRCA2 (BRCAmut) and a second cohort with BRCA wild type or unknown (BRCAwt). Patterns of tumor presentation, surgical outcome and survival data were analyzed between the two groups.RESULTS: Patients with BRCAmut disease were on average 4 years younger and had significantly more tumor involvement upon diagnosis. Patients with BRCAmut disease showed higher debulking rates at all stages. Multivariate analysis showed that only patient age had significant predictive value for complete tumor resection in pOC. At rOC, however, only BRCAmut status significantly correlated with optimal debulking. Patients with BRCAmut disease showed significantly prolonged overall survival (OS) by 24.3 months. Progression-free survival (PFS) was prolonged in the BRCAmut group at all stages as well, reaching statistical significance during recurrence.CONCLUSIONS: Patients with BRCAmut disease showed a more aggressive course of disease with earlier onset and more extensive tumor dissemination at pOC. However, surgical outcome and OS were significantly better in patients with BRCAmut disease compared with patients with BRCAwt disease. We therefore propose to consider BRCAmut status in regard to patient selection for cytoreductive surgery, especially in rOC.

  View details for DOI 10.1245/s10434-022-12459-3

  View details for PubMedID 36085390

• Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup. The Lancet. Oncology Vergote, I., Gonzalez-Martin, A., Lorusso, D., Gourley, C., Mirza, M. R., Kurtz, J., Okamoto, A., Moore, K., Kridelka, F., McNeish, I., Reuss, A., Votan, B., du Bois, A., Mahner, S., Ray-Coquard, I., Kohn, E. C., Berek, J. S., Tan, D. S., Colombo, N., Zang, R., Concin, N., O'Donnell, D., Rauh-Hain, A., Herrington, C. S., Marth, C., Poveda, A., Fujiwara, K., Stuart, G. C., Oza, A. M., Bookman, M. A., participants of the 6th Gynecologic Cancer InterGroup (GCIG) Ovarian Cancer Consensus Conference on Clinical Research, Mahner, S., Reuss, A., du Bois, A., Grimm, C., Marth, C., Berger, R., Concin, N., Chang, T., Ochiai, K., Gebski, V., Davis, A., Beale, P., Vergote, I., Kridelka, F., Denys, H., Vandecaveye, V., Cancido Dos Reis, F. J., Del Pilar Estevez Diz, M., Stuart, G., MacKay, H., Carey, M., Cibula, D., Dundr Path, P., Dorigo, O., Berek, J., O'Donnell, D., Saadeh, A., Boere, I., Lok, C., Coronado, P., Ottevanger, N., Tan, D. S., Ng, J., Gonzalez Martin, A., Oaknin, A., Poveda, A., Perez Fidalgo, A., Rauh-Hain, A., Lu, K., Lopez-Zavala, C., Gomez-Garcia, E. M., Ray-Coquard, I., Paoletti, X., Kurtz, J., Joly, F., Votan, B., Bookman, M., Moore, K., Arend, R., Fujiwara, K., Fujiwara, H., Hasegawa, K., Bruchim, I., Tsoref, D., Oda, K., Okamoto, A., Enomoto, T., Michel, D., Kim, H., Lee, J., Mukhopadhyay, A., Katsaros, D., Colombo, N., Pignata, S., Lorusso, D., Scambia, G., Kohn, E., Lee, J., McNeish, I., Nicum, S., Farrelly, L., Sehouli, J., Keller, M., Braicu, E., Bjorge, L., Mirza, M. R., Auranen, A., Welch, S., Oza, A. M., Heinzelmann, V., Gourley, C., Roxburgh, P., Herrington, C. S., Glasspool, R., Zang, R., Zhu, J. 2022; 23 (8): e374-e384

  Abstract

  The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer.

  View details for DOI 10.1016/S1470-2045(22)00139-5

  View details for PubMedID 35901833

• Technetium Tc 99m tilmanocept fails to detect sentinel lymph nodes in endometrial cancer. Gynecologic oncology reports Reddy, R. A., Moon, A. S., Chow, S., Heilbroner, L., Howitt, B., Diver, E., Dorigo, O., Litkouhi, B., Renz, M., Karam, A. 2022; 43: 101054

  Abstract

  Technetium Tc 99m tilmanocept is a synthetic radiotracer specifically designed for sentinel lymph node (SLN) mapping that has been FDA-approved in breast cancer, melanoma, and head and neck cancer. No published studies exist for the use of this radiotracer in endometrial cancer.The primary objective was to determine the detection rate of bilateral SLNs in endometrial cancer with the concurrent use of technetium Tc 99m tilmanocept and ICG.An open-label, single cohort, prospective feasibility study was conducted with participants receiving preoperative cervical injections of technetium Tc 99m tilmanocept followed by subsequent imaging and SPECT/CT. Intraoperative ICG injections were administered for all patients with near-infrared imaging used to visualize lymphatic vessels and nodes. A laparoscopic gamma counter was used to detect radioactive SLN intraoperatively.All six evaluated patients had FIGO grade 1 or 2 endometrioid histology. Stage IA/IB were in 33% and 66% of patients, respectively. Tilmanocept did not map any SLN in the first six patients but instead showed retention of the tracer in the cervical stroma, leading to study discontinuation for futility. ICG mapped bilateral SLN in all patients with the most common location being the external iliac region, followed by the obturator and common iliac areas. All patients had CD206 positive staining throughout the full wall thickness of ectocervix, transformation zone, endocervix, and lymphatic vessels. No patients experienced adverse events.Technetium Tc 99m tilmanocept did not detect SLN in early stage endometrial cancers and is unlikely to improve bilateral detection rate compared to ICG alone. ICG remains a standard technique for SLN detection in low stage, low grade endometrial cancer.

  View details for DOI 10.1016/j.gore.2022.101054

  View details for PubMedID 35958955

  View details for PubMedCentralID PMC9361318

• Predictive biomarker for surgical outcome in patients with advanced primary high-grade serous ovarian cancer. Are we there yet? An analysis of the prospective biobank for ovarian cancer. Gynecologic oncology Keunecke, C., Kulbe, H., Dreher, F., Taube, E. T., Chekerov, R., Horst, D., Hummel, M., Kessler, T., Pietzner, K., Kassuhn, W., Heitz, F., Muallem, M. Z., Lang, S. M., Vergote, I., Dorigo, O., Lammert, H., du Bois, A., Angelotti, T., Fotopoulou, C., Sehouli, J., Braicu, E. I. 2022

  Abstract

  BACKGROUND: High-grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer and is associated with high mortality rates. Surgical outcome is one of the most important prognostic factors. There are no valid biomarkers to identify which patients may benefit from a primary debulking approach.OBJECTIVE: Our study aimed to discover and validate a predictive panel for surgical outcome of residual tumor mass after first-line debulking surgery.STUDY DESIGN: Firstly, "In silico" analysis of publicly available datasets identified 200 genes as predictors for surgical outcome. The top selected genes were then validated using the novel Nanostring method, which was applied for the first time for this particular research objective. 225 primary ovarian cancer patients with well annotated clinical data and a complete debulking rate of 60% were compiled for a clinical cohort. The 14 best rated genes were then validated through the cohort, using immunohistochemistry testing. Lastly, we used our biomarker expression data to predict the presence of miliary carcinomatosis patterns.RESULTS: The Nanostring analysis identified 37 genes differentially expressed between optimal and suboptimal debulked patients (p < 0.05). The immunohistochemistry validated the top 14 genes, reaching an AUC O0.650. The analysis for the prediction of miliary carcinomatosis patterns reached an AUC of O0.797.CONCLUSION: The tissue-based biomarkers in our analysis could not reliably predict post-operative residual tumor. Patient and non-patient-associated co-factors, surgical skills, and center experience remain the main determining factors when considering the surgical outcome at primary debulking in high-grade serous ovarian cancer patients.

  View details for DOI 10.1016/j.ygyno.2022.06.010

  View details for PubMedID 35738917

• Revealing the human mucinome. Nature communications Malaker, S. A., Riley, N. M., Shon, D. J., Pedram, K., Krishnan, V., Dorigo, O., Bertozzi, C. R. 2022; 13 (1): 3542

  Abstract

  Mucin domains are densely O-glycosylated modular protein domains found in various extracellular and transmembrane proteins. Mucin-domain glycoproteins play important roles in many human diseases, such as cancer and cystic fibrosis, but the scope of the mucinome remains poorly defined. Recently, we characterized a bacterial O-glycoprotease, StcE, and demonstrated that an inactive point mutant retains binding selectivity for mucin-domain glycoproteins. In this work, we leverage inactive StcE to selectively enrich and identify mucin-domain glycoproteins from complex samples like cell lysate and crude ovarian cancer patient ascites fluid. Our enrichment strategy is further aided by an algorithm to assign confidence to mucin-domain glycoprotein identifications. This mucinomics platform facilitates detection of hundreds of glycopeptides from mucin domains and highly overlapping populations of mucin-domain glycoproteins from ovarian cancer patients. Ultimately, we demonstrate our mucinomics approach can reveal key molecular signatures of cancer from in vitro and ex vivo sources.

  View details for DOI 10.1038/s41467-022-31062-4

  View details for PubMedID 35725833

• A phase 1 open label, first in human trial to study safety and tolerability of NK-T cells combined with vvDD: An accelerated dose escalation in multiple tumor types. Dorigo, O., Contag, P., Moser, J., Patel, S., Frohlich, M. W. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000892509502098

• Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet (London, England) Gershenson, D. M., Miller, A., Brady, W. E., Paul, J., Carty, K., Rodgers, W., Millan, D., Coleman, R. L., Moore, K. N., Banerjee, S., Connolly, K., Secord, A. A., O'Malley, D. M., Dorigo, O., Gaillard, S., Gabra, H., Slomovitz, B., Hanjani, P., Farley, J., Churchman, M., Ewing, A., Hollis, R. L., Herrington, C. S., Huang, H. Q., Wenzel, L., Gourley, C. 2022; 399 (10324): 541-553

  Abstract

  BACKGROUND: Low-grade serous carcinoma of the ovary or peritoneum is characterised by MAPK pathway aberrations and its reduced sensitivity to chemotherapy relative to high-grade serous carcinoma. We compared the MEK inhibitor trametinib to physician's choice standard of care in patients with recurrent low-grade serous carcinoma.METHODS: This international, randomised, open-label, multicentre, phase 2/3 trial was done at 84 hospitals in the USA and UK. Eligible patients were aged 18 years or older with recurrent low-grade serous carcinoma and measurable disease, as defined by Response Evaluation Criteria In Solid Tumors version 1.1, had received at least one platinum-based regimen, but not all five standard-of-care drugs, and had received an unlimited number of previous regimens. Patients with serous borderline tumours or tumours containing low-grade serous and high-grade serous carcinoma were excluded. Eligible patients were randomly assigned (1:1) to receive either oral trametinib 2 mg once daily (trametinib group) or one of five standard-of-care treatment options (standard-of-care group): intravenous paclitaxel 80 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; intravenous pegylated liposomal doxorubicin 40-50 mg/m2 by body surface area once every 4 weeks; intravenous topotecan 4 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; oral letrozole 2·5 mg once daily; or oral tamoxifen 20 mg twice daily. Randomisation was stratified by geographical region (USA or UK), number of previous regimens (1, 2, or ≥3), performance status (0 or 1), and planned standard-of-care regimen. The primary endpoint was investigator-assessed progression-free survival while receiving randomised therapy, as assessed by imaging at baseline, once every 8 weeks for 15 months, and then once every 3 months thereafter, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02101788, and is active but not recruiting.FINDINGS: Between Feb 27, 2014, and April 10, 2018, 260 patients were enrolled and randomly assigned to the trametinib group (n=130) or the standard-of-care group (n=130). At the primary analysis, there were 217 progression-free survival events (101 [78%] in the trametinib group and 116 [89%] in the standard-of-care group). Median progression-free survival in the trametinib group was 13·0 months (95% CI 9·9-15·0) compared with 7·2 months (5·6-9·9) in the standard-of-care group (hazard ratio 0·48 [95% CI 0·36-0·64]; p<0·0001). The most frequent grade 3 or 4 adverse events in the trametinib group were skin rash (17 [13%] of 128), anaemia (16 [13%]), hypertension (15 [12%]), diarrhoea (13 [10%]), nausea (12 [9%]), and fatigue (ten [8%]). The most frequent grade 3 or 4 adverse events in the standard-of-care group were abdominal pain (22 [17%]), nausea (14 [11%]), anaemia (12 [10%]), and vomiting (ten [8%]). There were no treatment-related deaths.INTERPRETATION: Trametinib represents a new standard-of-care option for patients with recurrent low-grade serous carcinoma.FUNDING: NRG Oncology, Cancer Research UK, Target Ovarian Cancer, and Novartis.

  View details for DOI 10.1016/S0140-6736(21)02175-9

  View details for PubMedID 35123694

• Cell-based immunotherapies in gynecologic cancers. Current opinion in obstetrics & gynecology Lang, S. M., Dorigo, O. 1800; 34 (1): 10-14

  Abstract

  PURPOSE OF REVIEW: This review provides an update on recent developments in cell-based immunotherapy in gynecologic cancers.RECENT FINDINGS: Chimeric antigen receptor (CAR) technology has made significant progress allowing now for not only expressing CARs on T-cells, but also on other immune effector cells, such as natural killer cells and macrophages. Cell-based vaccines have started to show promising results in clinical trials.SUMMARY: Cell-based immunotherapies in gynecologic cancers continue to evolve with promising clinical efficacy in select patients.

  View details for DOI 10.1097/GCO.0000000000000760

  View details for PubMedID 34967809

• Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial LANCET Gershenson, D. M., Miller, A., Brady, W. E., Paul, J., Carty, K., Rodgers, W., Millan, D., Coleman, R. L., Moore, K. N., Banerjee, S., Connolly, K., Secord, A., O'Malley, D. M., Dorigo, O., Gaillard, S., Gabra, H., Slomovitz, B., Hanjani, P., Farley, J., Churchman, M., Ewing, A., Hollis, R. L., Herrington, C., Huang, H. Q., Wenzel, L., Gourley, C. 2022; 399 (10324): 541-553

  View details for Web of Science ID 000811944600001

• Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial LANCET Gershenson, D. M., Miller, A., Brady, W. E., Paul, J., Carty, K., Rodgers, W., Millan, D., Coleman, R. L., Moore, K. N., Banerjee, S., Connolly, K., Secord, A., O'Malley, D. M., Dorigo, O., Gaillard, S., Gabra, H., Slomovitz, B., Hanjani, P., Farley, J., Churchman, M., Ewing, A., Hollis, R. L., Herrington, C., Huang, H. Q., Wenzel, L., Gourley, C. 2022; 399 (10324): 541-553

  View details for Web of Science ID 000755144500027

• Evidence-Based Clinical Practice Guidelines for Extramammary Paget Disease. JAMA oncology Kibbi, N., Owen, J. L., Worley, B., Wang, J. X., Harikumar, V., Downing, M. B., Aasi, S. Z., Aung, P. P., Barker, C. A., Bolotin, D., Bordeaux, J. S., Cartee, T. V., Chandra, S., Cho, N. L., Choi, J. N., Chung, K. Y., Cliby, W. A., Dorigo, O., Eisen, D. B., Fujisawa, Y., Golda, N., Halfdanarson, T. R., Iavazzo, C., Jiang, S. I., Kanitakis, J., Khan, A., Kim, J. Y., Kuzel, T. M., Lawrence, N., Leitao, M. M., MacLean, A. B., Maher, I. A., Mittal, B. B., Nehal, K. S., Ozog, D. M., Pettaway, C. A., Ross, J. S., Rossi, A. M., Servaes, S., Solomon, M. J., Thomas, V. D., Tolia, M., Voelzke, B. B., Waldman, A., Wong, M. K., Zhou, Y., Arai, N., Brackett, A., Ibrahim, S. A., Kang, B. Y., Poon, E., Alam, M. 2022

  Abstract

  Extramammary Paget disease (EMPD) is a frequently recurring malignant neoplasm with metastatic potential that presents in older adults on the genital, perianal, and axillary skin. Extramammary Paget disease can precede or occur along with internal malignant neoplasms.To develop recommendations for the care of adults with EMPD.A systematic review of the literature on EMPD from January 1990 to September 18, 2019, was conducted using MEDLINE, Embase, Web of Science Core Collection, and Cochrane Libraries. Analysis included 483 studies. A multidisciplinary expert panel evaluation of the findings led to the development of clinical care recommendations for EMPD.The key findings were as follows: (1) Multiple skin biopsies, including those of any nodular areas, are critical for diagnosis. (2) Malignant neoplasm screening appropriate for age and anatomical site should be performed at baseline to distinguish between primary and secondary EMPD. (3) Routine use of sentinel lymph node biopsy or lymph node dissection is not recommended. (4) For intraepidermal EMPD, surgical and nonsurgical treatments may be used depending on patient and tumor characteristics, although cure rates may be superior with surgical approaches. For invasive EMPD, surgical resection with curative intent is preferred. (5) Patients with unresectable intraepidermal EMPD or patients who are medically unable to undergo surgery may receive nonsurgical treatments, including radiotherapy, imiquimod, photodynamic therapy, carbon dioxide laser therapy, or other modalities. (6) Distant metastatic disease may be treated with chemotherapy or individualized targeted approaches. (7) Close follow-up to monitor for recurrence is recommended for at least the first 5 years.Clinical practice guidelines for EMPD provide guidance regarding recommended diagnostic approaches, differentiation between invasive and noninvasive disease, and use of surgical vs nonsurgical treatments. Prospective registries may further improve our understanding of the natural history of the disease in primary vs secondary EMPD, clarify features of high-risk tumors, and identify superior management approaches.

  View details for DOI 10.1001/jamaoncol.2021.7148

  View details for PubMedID 35050310

• Abdominopelvic FLASH Irradiation Improves PD-1 Immune Checkpoint Inhibition in Preclinical Models of Ovarian Cancer. Molecular cancer therapeutics Eggold, J. T., Chow, S., Melemenidis, S., Wang, J., Natarajan, S., Loo, P. E., Manjappa, R., Viswanathan, V., Kidd, E. A., Engleman, E., Dorigo, O., Loo, B. W., Rankin, E. B. 2021

  Abstract

  Treatment of advanced ovarian cancer using PD-1/PD-L1 immune checkpoint blockade shows promise, however current clinical trials are limited by modest response rates. Radiation therapy has been shown to synergize with PD-1/PD-L1 blockade in some cancers but has not been utilized in advanced ovarian cancer due to toxicity associated with conventional abdominopelvic irradiation. While ultra-high dose rate (FLASH) irradiation has emerged as a strategy to reduce radiation-induced toxicity, the immunomodulatory properties of FLASH irradiation remain unknown. Here we demonstrate that single high dose abdominopelvic FLASH irradiation promoted intestinal regeneration and maintained tumor control in a preclinical mouse model of ovarian cancer. Reduced tumor burden in conventional and FLASH treated mice was associated with an early decrease in intratumoral regulatory T cells and a late increase in cytolytic CD8+ T cells. Compared to conventional irradiation, FLASH irradiation increased intratumoral T cell infiltration at early timepoints. Moreover, FLASH irradiation maintained the ability to increase intratumoral CD8+ T cell infiltration and enhance the efficacy of alphaPD-1 therapy in preclinical models of ovarian cancer. These data highlight the potential for FLASH irradiation to improve the therapeutic efficacy of checkpoint inhibition in the treatment of ovarian cancer.

  View details for DOI 10.1158/1535-7163.MCT-21-0358

  View details for PubMedID 34866044

• IDENTIFICATION OF POTENTIAL RESPONSE PREDICTORS TO MAVEROPEPIMUT-S (DPX-SURVIVAC), A NOVEL T CELL ACTIVATING IMMUNOTHERAPY, IN PATIENTS WITH ADVANCED RECURRENT OVARIAN CANCER Dorigo, O., Ebrahimizadeh, W., Kennedy, B., MacDonald, L., Fiset, S., Villella, J., Amit, O., Pejovic, T., Ghatage, P., Ghamande, S., Provencher, D., Bramhecha, Y. BMJ PUBLISHING GROUP. 2021: A380

  View details for DOI 10.1136/jitc-2021-SITC2021.353

  View details for Web of Science ID 000774877500342

• Phase II Trial Evaluating Efficacy of a Fitbit Program for Improving the Health of Endometrial Cancer Survivors Rahimy, E., Usoz, M., von Eyben, R., Fujimoto, D., Watanabe, D., Karam, A., Jairam-Thodla, A., Mills, M., Dorigo, O., Diver, E., Teng, N., English, D., Kidd, E. LIPPINCOTT WILLIAMS & WILKINS. 2021: S13

  View details for Web of Science ID 000701779700022

• Cancer-associated mesothelial cells promote ovarian cancer chemoresistance through paracrine osteopontin signaling. The Journal of clinical investigation Qian, J., LeSavage, B. L., Hubka, K. M., Ma, C., Natarajan, S., Eggold, J. T., Xiao, Y., Fuh, K. C., Krishnan, V., Enejder, A., Heilshorn, S. C., Dorigo, O., Rankin, E. B. 2021; 131 (16)

  Abstract

  Ovarian cancer is the leading cause of gynecological malignancy-related deaths, due to its widespread intraperitoneal metastases and acquired chemoresistance. Mesothelial cells are an important cellular component of the ovarian cancer microenvironment that promote metastasis. However, their role in chemoresistance is unclear. Here, we investigated whether cancer-associated mesothelial cells promote ovarian cancer chemoresistance and stemness in vitro and in vivo. We found that osteopontin is a key secreted factor that drives mesothelial-mediated ovarian cancer chemoresistance and stemness. Osteopontin is a secreted glycoprotein that is clinically associated with poor prognosis and chemoresistance in ovarian cancer. Mechanistically, ovarian cancer cells induced osteopontin expression and secretion by mesothelial cells through TGF-beta signaling. Osteopontin facilitated ovarian cancer cell chemoresistance via the activation of the CD44 receptor, PI3K/AKT signaling, and ABC drug efflux transporter activity. Importantly, therapeutic inhibition of osteopontin markedly improved the efficacy of cisplatin in both human and mouse ovarian tumor xenografts. Collectively, our results highlight mesothelial cells as a key driver of ovarian cancer chemoresistance and suggest that therapeutic targeting of osteopontin may be an effective strategy for enhancing platinum sensitivity in ovarian cancer.

  View details for DOI 10.1172/JCI146186

  View details for PubMedID 34396988

• Classification of molecular subtypes of high-grade serous ovarian cancer by MALDI-Imaging. Kassuhn, W., Klein, O., Darb-Esfahani, S., Lammert, H., Handzik, S., Taube, E. T., Schmitt, W. D., Dorigo, O., Horst, D., Keunecke, C., Dreher, F., George, J., Bowtell, D., Hummel, M., Sehouli, J., Bluethgen, N., Kulbe, H., Braicu, E. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.e17544

  View details for Web of Science ID 000708120303022

• Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2). Nature communications Swisher, E. M., Kwan, T. T., Oza, A. M., Tinker, A. V., Ray-Coquard, I., Oaknin, A., Coleman, R. L., Aghajanian, C., Konecny, G. E., O'Malley, D. M., Leary, A., Provencher, D., Welch, S., Chen, L., Wahner Hendrickson, A. E., Ma, L., Ghatage, P., Kristeleit, R. S., Dorigo, O., Musafer, A., Kaufmann, S. H., Elvin, J. A., Lin, D. I., Chambers, S. K., Dominy, E., Vo, L., Goble, S., Maloney, L., Giordano, H., Harding, T., Dobrovic, A., Scott, C. L., Lin, K. K., McNeish, I. A. 2021; 12 (1): 2487

  Abstract

  ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity.

  View details for DOI 10.1038/s41467-021-22582-6

  View details for PubMedID 33941784

• Long-term efficacy of megestrol acetate and tamoxifen in a recurrent adult granulosa cell tumor of the ovary. Gynecologic oncology reports Moon, A. S., Dorigo, O. 2021; 36: 100770

  Abstract

  Recurrent, non-resectable ovarian granulosa cell tumor has no standard treatment.Estrogen/progesterone receptor signaling regulates granulosa cell tumor growth.Granulosa cell tumor responds well to alternating megestrol and tamoxifen therapy.

  View details for DOI 10.1016/j.gore.2021.100770

  View details for PubMedID 34013014

• Classification of Molecular Subtypes of High-Grade Serous Ovarian Cancer by MALDI-Imaging. Cancers Kassuhn, W., Klein, O., Darb-Esfahani, S., Lammert, H., Handzik, S., Taube, E. T., Schmitt, W. D., Keunecke, C., Horst, D., Dreher, F., George, J., Bowtell, D. D., Dorigo, O., Hummel, M., Sehouli, J., Bluthgen, N., Kulbe, H., Braicu, E. I. 2021; 13 (7)

  Abstract

  Despite the correlation of clinical outcome and molecular subtypes of high-grade serous ovarian cancer (HGSOC), contemporary gene expression signatures have not been implemented in clinical practice to stratify patients for targeted therapy. Hence, we aimed to examine the potential of unsupervised matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) to stratify patients who might benefit from targeted therapeutic strategies. Molecular subtyping of paraffin-embedded tissue samples from 279 HGSOC patients was performed by NanoString analysis (ground truth labeling). Next, we applied MALDI-IMS paired with machine-learning algorithms to identify distinct mass profiles on the same paraffin-embedded tissue sections and distinguish HGSOC subtypes by proteomic signature. Finally, we devised a novel approach to annotate spectra of stromal origin. We elucidated a MALDI-derived proteomic signature (135 peptides) able to classify HGSOC subtypes. Random forest classifiers achieved an area under the curve (AUC) of 0.983. Furthermore, we demonstrated that the exclusion of stroma-associated spectra provides tangible improvements to classification quality (AUC = 0.988). Moreover, novel MALDI-based stroma annotation achieved near-perfect classifications (AUC = 0.999). Here, we present a concept integrating MALDI-IMS with machine-learning algorithms to classify patients according to distinct molecular subtypes of HGSOC. This has great potential to assign patients for personalized treatment.

  View details for DOI 10.3390/cancers13071512

  View details for PubMedID 33806030

• Prospective molecular classification of endometrial carcinomas: institutional implementation, practice, and clinical experience. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Devereaux, K. A., Weiel, J. J., Pors, J., Steiner, D. F., Ho, C., Charu, V., Suarez, C. J., Renz, M., Diver, E., Karam, A., Litkouhi, B., Dorigo, O., Kidd, E. A., Yang, E. J., Folkins, A. K., Longacre, T. A., Howitt, B. E. 2021

  Abstract

  The comprehensive genomic analysis of endometrial carcinoma (EC) by The Cancer Genome Atlas (TCGA) led to the discovery of four distinct and prognostically significant molecular subgroups. Molecular classification has the potential to improve risk-stratification when integrated with clinicopathologic features and has recently been included in national and international patient management EC guidelines. Thus, the adoption of molecular classification into routine pathologic and clinical practice is likely to grow significantly in the upcoming years. Establishing an efficient and standardized workflow for performing molecular classification on ECs, and reporting both the molecular and histologic findings in an integrative manner, is imperative. Here we describe our effort to implement rapid and routine molecular classification on all ECs diagnosed at our institution. To this effect, we performed immunohistochemistry as a surrogate marker for identifying genetic and/or epigenetic alterations in DNA mismatch repair (e.g., MLH1, PMS2, MSH6, MSH2), and TP53 genes. In addition, we have developed and employed a single-gene POLE SNaPshot assay, which is a rapid and analytically sensitive method for detecting select POLE exonuclease domain mutations (EDMs). We report our molecular testing workflow and integrative reporting system as well as the clinicopathologic and molecular features of 310 ECs that underwent routine molecular classification at our institution. The 310 ECs were molecularly classified as follows: 15 (5%) POLE mutant (POLEmut), 79 (25%) mismatch repair-deficient (MMRd), 135 (44%) no specific molecular profile (NSMP), and 81 (26%) p53 abnormal (p53abnl). This work provides an initial framework for implementing routine molecular classification of ECs.

  View details for DOI 10.1038/s41379-021-00963-y

  View details for PubMedID 34743187

• Phase II trial evaluating efficacy of a Fitbit program for improving the health of endometrial cancer survivors. Gynecologic oncology Rahimy, E. n., Usoz, M. n., von Eyben, R. n., Fujimoto, D. n., Watanabe, D. n., Karam, A. n., Jairam-Thodla, A. n., Mills, M. n., Dorigo, O. n., Diver, E. J., Teng, N. n., English, D. n., Kidd, E. n. 2021

  Abstract

  Despite the favorable prognosis of early stage endometrial cancer, mortality from cardiovascular disease is high. We aimed to evaluate the efficacy of a Fitbit program to improve physical activity in endometrial cancer survivors.Eligible patients were diagnosed with stage IA-IIIA endometrial adenocarcinoma, ≥3 months out from treatment. Participants received a Fitbit Alta and were randomized to receive communication via telephone or electronic methods (email/text). Communication was every two weeks for two months, then once during months four and five. Average daily steps were assessed weekly for nine months.The 46 analyzable patients demonstrated a baseline of 5641 median daily average steps. Average steps increased by 22% at 6 months but decreased to baseline by nine months. Baseline activity level (daily steps and walks per week) was the greatest predictor of activity level. Only the telephone intervention participants demonstrated increased activity level at several timepoints, although not maintained by nine months. BMI was unchanged. There was mild improvement in physical and social well-being in those with low baseline well-being (p = 0.009 and 0.014, respectively), regardless of intervention group. Emotional well-being correlated with step count (p = 0.005).Activity level was low and mildly improved on the Fitbit program with the telephone intervention, but effects did not persist by study completion. The program had the greatest impact on a select group of telephone intervention patients with high baseline walking frequency and low baseline step count. Others may require more intense intervention to promote more robust/persistent lifestyle changes.

  View details for DOI 10.1016/j.ygyno.2021.01.033

  View details for PubMedID 33551199

• Cell-based immunotherapy in gynecologic malignancies. Current opinion in obstetrics & gynecology Kamat, K., Krishnan, V., Berek, J. S., Dorigo, O. 2020

  Abstract

  PURPOSE OF REVIEW: To provide an update on cell-based immunotherapies in solid tumors particularly in gynecological cancers.RECENT FINDINGS: Recent clinical trial results demonstrate safety and tolerability of different cell therapies in gynecological cancers. Novel approaches, such as harnessing the cells of the innate immune system are also under investigation in a phase I trial.SUMMARY: Cell-based therapies are gaining widespread attention as evidenced by the increasing number of clinical trials encompassing both, innate and adaptive cells to target gynecological cancers. A majority of these therapeutic approaches are well tolerated and show promising results in early trials.

  View details for DOI 10.1097/GCO.0000000000000676

  View details for PubMedID 33278077

• An enzymatic toolkit for selective proteolysis, detection, and visualization of mucin-domain glycoproteins Shon, D., Malaker, S. A., Pedram, K., Yang, E., Krishnan, V., Dorigo, O., Bertozzi, C. R. OXFORD UNIV PRESS INC. 2020: 1111–12

  View details for Web of Science ID 000606577100192

• Development of Therapeutic Vaccines for Ovarian Cancer. Vaccines Chow, S., Berek, J. S., Dorigo, O. 2020; 8 (4)

  Abstract

  Ovarian cancer remains the deadliest of all gynecologic malignancies. Our expanding knowledge of ovarian cancer immunology has allowed the development of therapies that generate systemic anti-tumor immune responses. Current immunotherapeutic strategies include immune checkpoint blockade, cellular therapies, and cancer vaccines. Vaccine-based therapies are designed to induce both adaptive and innate immune responses directed against ovarian cancer associated antigens. Tumor-specific effector cells, in particular cytotoxic T cells, are activated to recognize and eliminate ovarian cancer cells. Vaccines for ovarian cancer have been studied in various clinical trials over the last three decades. Despite evidence of vaccine-induced humoral and cellular immune responses, the majority of vaccines have not shown significant anti-tumor efficacy. Recently, improved vaccine development using dendritic cells or synthetic platforms for antigen presentation have shown promising clinical benefits in patients with ovarian cancer. In this review, we provide an overview of therapeutic vaccine development in ovarian cancer, discuss proposed mechanisms of action, and summarize the current clinical experience.

  View details for DOI 10.3390/vaccines8040657

  View details for PubMedID 33167428

• FLASH irradiation enhances the therapeutic index of abdominal radiotherapy in mice Natarajan, S., Levy, K., Wang, J., Chow, S., Eggold, J., Loo, P., Manjappa, R., Lartey, F. M., Schuler, E., Skinner, L., Rafat, M., Ko, R., Kim, A., Al Rawi, D., von Eyben, R., Dorigo, O., Casey, K. M., Graves, E. E., Bush, K., Yu, A. S., Koong, A. C., Maxim, P. G., Loo, B. W., Rankin, E. B. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7445.AM2020-5351

  View details for Web of Science ID 000590059306341

• Total abdominal ultra-rapid FLASH irradiation enhances the efficacy of PD-1 inhibition in preclinical models of ovarian cancer Chow, S., Eggold, J. T., Levy, K., Wang, J., Manjappa, R., Breitkreutz, D. Y., Yu, A. S., Bush, K., Dorigo, O., Loo, B. W., Rankin, E. B. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7445.AM2020-5357

  View details for Web of Science ID 000590059306346

• Minimally Invasive Surgery for Gynecologic Cancers-A Cautionary Tale. JAMA oncology Karam, A., Dorigo, O. 2020

  View details for DOI 10.1001/jamaoncol.2020.1617

  View details for PubMedID 32525507

• Incorporating Parp-inhibitors in Primary and Recurrent Ovarian Cancer: A Meta-analysis of 12 phase II/III randomized controlled trials. Cancer treatment reviews Ruscito, I., Bellati, F., Ray-Coquard, I., Mirza, M. R., du Bois, A., Gasparri, M. L., Costanzi, F., De Marco, M. P., Nuti, M., Caserta, D., Pignata, S., Dorigo, O., Sehouli, J., Braicu, E. I. 2020; 87: 102040

  Abstract

  BACKGROUND: The second decade of 2000s is witnessing a new ovarian cancer (OC) paradigm shift thanks to the results recently obtained by a new class of targeted agents: the Poly(ADP-ribose)polymerase (PARP)-Inhibitors (PARPi). Aim of this meta-analysis is to analyze available results obtained with PARPi, administered alone or in combination with chemo- and/or target-therapies in terms of efficacy and safety for the treatment of recurrent and primary advanced OC.METHODS: On December 2019, all published phase II/III randomized clinical studies were systematically searched using the terms "[Parp-Inhibitor] AND [ovar*]". Twelve phase II/III randomized controlled trials were identified, with a total number of 5171 patients included.RESULTS: Results demonstrated that PARPi account for a significant improvement of PFS in both recurrent and primary OC setting, independently from their administration schedule and independently from patients' BRCA mutational status. Moreover, patients harboring a Homologous Recombination Deficiency (HRD) positive testing primary or recurrent OC progress significantly later after PARPi administration/association. Results also reported that PARPi increase the occurrence of severe (G3-G4) anemia. Furthermore, severe fatigue occurred more frequently among patients subjected to PARPi combined with chemotherapy and to PARPi plus Bevacizumab. Finally, a significant increase in severe high blood pressure occurrence was observed when PARPi was added to antiangiogenetics, compared to PARPi alone but a significant decrease in G3-G4 hypertension occurrence was found in PARPi plus bevacizumab users compared to Bevacizumab alone.CONCLUSIONS: PARPi are a valid option for the treatment of both primary and relapsed OC patients, with a relative low incidence of severe side effects.

  View details for DOI 10.1016/j.ctrv.2020.102040

  View details for PubMedID 32485510

• Infiltration of tumor by T cells following treatment with DPX-Survivac and intermittent low dose cyclophosphamide (CPA) leads to clinical responses in advanced recurrent ovarian cancer (OvCa). Dorigo, O., MacDonald, L., Schindler, J., Bramhecha, Y., Torrey, H., Kaliaperumal, V., Hrytsenko, O., Dirk, B., Patterson, K., Stanford, M., Fiset, S. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368302499

• DPX-Survivac, a novel T-cell immunotherapy, to induce robust T-cell responses in advanced ovarian cancer Dorigo, O., Fiset, S., MacDonald, L., Bramhecha, Y., Hrytsenko, O., Dirk, B., Rosu, G., Stanford, M. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000529994300011

• Sentinel Lymph Node Biopsies in Endometrial Cancer: Practice Patterns among Gynecologic Oncologists in the United States JOURNAL OF MINIMALLY INVASIVE GYNECOLOGY Renz, M., Diver, E., English, D., Kidd, E., Dorigo, O., Karam, A. 2020; 27 (2): 482–88

  View details for DOI 10.1016/j.jmig.2019.04.006

  View details for Web of Science ID 000510638000035

• Vulvar sarcoma outcomes by histologic subtype: a Surveillance, Epidemiology, and End Results (SEER) database review. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society Johnson, S. n., Renz, M. n., Wheeler, L. n., Diver, E. n., Dorigo, O. n., Litkouhi, B. n., Behbakht, K. n., Howitt, B. n., Karam, A. n. 2020

  Abstract

  Vulvar cancers account for 5% of all gynecologic malignancies; only 1%-3% of those vulvar cancers are primary vulvar sarcomas. Given the rarity of vulvar sarcomas, outcome data specific to histopathologic subtypes are sparse. The aim of this study was to identify clinical and pathologic factors of primary vulvar sarcomas that are associated with survival and may inform treatment decisions.The Surveillance, Epidemiology, and End Results (SEER) database was searched for women diagnosed with vulvar sarcoma between 1973 and 2018. We identified 315 patients and reviewed their demographic, clinicopathologic, surgical, and survival information. Statistical analyses included χ2 and t-tests, Kaplan-Meier survival, and Cox regression analyses.The most common histopathologies of vulvar sarcomas were dermatofibrosarcomas (85/315, 27%) and leiomyosarcomas (72/315, 22.9%). Rhabdomyosarcomas (18/315, 5.7%), liposarcomas (16/315, 5.1%), and malignant fibrous histiocytomas (16/315, 5.1%) were less frequent. The majority of patients underwent surgery (292/315, 92.7%), which included lymph node dissections in 21.6% (63/292). Survival and lymph node involvement varied significantly with histologic subtype. The 5-year disease-specific survival for dermatofibrosarcomas, liposarcomas, and fibrosarcomas was 100% and only 60.3% and 62.5% for malignant fibrous histiocytomas and rhabdomyosarcomas, respectively. None of the patients with (dermato)fibrosarcomas, liposarcomas, or leiomyosarcomas had positive lymph nodes, in contrast to rhabdomyosarcomas and malignant fibrous histiocytomas with 77.8% and 40% positive lymph nodes, respectively. The 5-year disease-specific survival for women with positive lymph nodes was 0%.Vulvar sarcomas are heterogeneous with survival highly dependent on the histopathologic subtype. While surgical excision is the mainstay of treatment for all vulvar sarcomas, staging lymphadenectomy should be deferred for (dermato)fibrosarcomas, liposarcomas, and leiomyosarcomas as there were no cases of lymph nodes metastases.

  View details for DOI 10.1136/ijgc-2020-001516

  View details for PubMedID 32641392

• Abdominal FLASH irradiation reduces radiation-induced gastrointestinal toxicity for the treatment of ovarian cancer in mice. Scientific reports Levy, K. n., Natarajan, S. n., Wang, J. n., Chow, S. n., Eggold, J. T., Loo, P. E., Manjappa, R. n., Melemenidis, S. n., Lartey, F. M., Schüler, E. n., Skinner, L. n., Rafat, M. n., Ko, R. n., Kim, A. n., H Al-Rawi, D. n., von Eyben, R. n., Dorigo, O. n., Casey, K. M., Graves, E. E., Bush, K. n., Yu, A. S., Koong, A. C., Maxim, P. G., Loo, B. W., Rankin, E. B. 2020; 10 (1): 21600

  Abstract

  Radiation therapy is the most effective cytotoxic therapy for localized tumors. However, normal tissue toxicity limits the radiation dose and the curative potential of radiation therapy when treating larger target volumes. In particular, the highly radiosensitive intestine limits the use of radiation for patients with intra-abdominal tumors. In metastatic ovarian cancer, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of abdominal metastases. However, TAI fell out of favor due to high toxicity of the intestine. Here we utilized an innovative preclinical irradiation platform to compare the safety and efficacy of TAI ultra-high dose rate FLASH irradiation to conventional dose rate (CONV) irradiation in mice. We demonstrate that single high dose TAI-FLASH produced less mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and spared cell death in crypt base columnar cells compared to TAI-CONV irradiation. Importantly, TAI-FLASH and TAI-CONV irradiation had similar efficacy in reducing tumor burden while improving intestinal function in a preclinical model of ovarian cancer metastasis. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of abdominal radiotherapy, with potential application to metastatic ovarian cancer.

  View details for DOI 10.1038/s41598-020-78017-7

  View details for PubMedID 33303827

• An enzymatic toolkit for selective proteolysis, detection, and visualization of mucin-domain glycoproteins. Proceedings of the National Academy of Sciences of the United States of America Shon, D. J., Malaker, S. A., Pedram, K. n., Yang, E. n., Krishnan, V. n., Dorigo, O. n., Bertozzi, C. R. 2020

  Abstract

  Densely O-glycosylated mucin domains are found in a broad range of cell surface and secreted proteins, where they play key physiological roles. In addition, alterations in mucin expression and glycosylation are common in a variety of human diseases, such as cancer, cystic fibrosis, and inflammatory bowel diseases. These correlations have been challenging to uncover and establish because tools that specifically probe mucin domains are lacking. Here, we present a panel of bacterial proteases that cleave mucin domains via distinct peptide- and glycan-based motifs, generating a diverse enzymatic toolkit for mucin-selective proteolysis. By mutating catalytic residues of two such enzymes, we engineered mucin-selective binding agents with retained glycoform preferences. StcEE447D is a pan-mucin stain derived from enterohemorrhagic Escherichia coli that is tolerant to a wide range of glycoforms. BT4244E575A derived from Bacteroides thetaiotaomicron is selective for truncated, asialylated core 1 structures commonly associated with malignant and premalignant tissues. We demonstrated that these catalytically inactive point mutants enable robust detection and visualization of mucin-domain glycoproteins by flow cytometry, Western blot, and immunohistochemistry. Application of our enzymatic toolkit to ascites fluid and tissue slices from patients with ovarian cancer facilitated characterization of patients based on differences in mucin cleavage and expression patterns.

  View details for DOI 10.1073/pnas.2012196117

  View details for PubMedID 32817557

• THE HYPOXIC TUMOR-MESOTHELIAL NICHE PROMOTES OVARIAN CANCER METASTASIS THROUGH COLLAGEN REMODELING Natarajan, S., Foreman, K., Soriano, M., Shehade, H., Fregoso, D., Eggold, J., Rosen, N. S., Heilshorn, S., Krieg, A. J., Krishnan, V., Dorigo, O., Sinha, S., Fuh, K. C., Rankin, E. B. AMER ASSOC CANCER RESEARCH. 2019: 168

  View details for Web of Science ID 000497337700104

• Gestational Trophoblastic Neoplasia, Version 2.2019 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Abu-Rustum, N. R., Yashar, C. M., Bean, S., Bradley, K., Campos, S. M., Chon, H., Chu, C., Cohn, D., Crispens, M., Damast, S., Dorigo, O., Eifel, P. J., Fisher, C. M., Frederick, P., Gaffney, D. K., Han, E., Huh, W. K., Lurain, J. R., Mariani, A., Mutch, D., Nagel, C., Nekhlyudov, L., Fader, A., Remmenga, S. W., Reynolds, R., Sisodia, R., Tillmanns, T., Ueda, S., Wyse, E., McMillian, N. R., Scavone, J. 2019; 17 (11): 1374–91

  Abstract

  Gestational trophoblastic neoplasia (GTN), a subset of gestational trophoblastic disease (GTD), occurs when tumors develop in the cells that would normally form the placenta during pregnancy. The NCCN Guidelines for Gestational Trophoblastic Neoplasia provides treatment recommendations for various types of GTD including hydatidiform mole, persistent post-molar GTN, low-risk GTN, high-risk GTN, and intermediate trophoblastic tumor.

  View details for DOI 10.6004/jnccn.2019.0053

  View details for Web of Science ID 000499645400011

  View details for PubMedID 31693991

• OMENTAL MACROPHAGES REGULATE OVARIAN CANCER METASTATIC COLONIZATION THROUGH THE CCL6-CCR1 SIGNALING AXIS Krishnan, V., Tallapragada, S., Schaar, B., Chanana, A., Rinker-Schaeffer, C., Dorigo, O. AMER ASSOC CANCER RESEARCH. 2019: 162

  View details for Web of Science ID 000497337700099

• ASCO 2019 meeting review. Journal of gynecologic oncology Diver, E., Dorigo, O., Berek, J. 2019; 30 (5): e107

  View details for DOI 10.3802/jgo.2019.30.e107

  View details for PubMedID 31328469

• Quantitative super-resolution microscopy of the mammalian glycocalyx Mockl, L., Pedram, K., Roy, A., Krishnan, V., Gustavsson, A., Dorigo, O., Bertozzi, C., Moerner, W. AMER CHEMICAL SOC. 2019

  View details for Web of Science ID 000525055501242

• CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature Barkal, A. A., Brewer, R. E., Markovic, M., Kowarsky, M., Barkal, S. A., Zaro, B. W., Krishnan, V., Hatakeyama, J., Dorigo, O., Barkal, L. J., Weissman, I. L. 2019

  Abstract

  Ovarian cancer and triple-negative breast cancer are among the most lethal diseases affecting women, with few targeted therapies and high rates of metastasis. Cancer cells are capable of evading clearance by macrophages through the overexpression of anti-phagocytic surface proteins called 'don't eat me' signals-including CD471, programmed cell death ligand 1 (PD-L1)2 and the beta-2 microglobulin subunit of the major histocompatibility class I complex (B2M)3. Monoclonal antibodies that antagonize the interaction of 'don't eat me' signals with their macrophage-expressed receptors have demonstrated therapeutic potential in several cancers4,5. However, variability in the magnitude and durability of the response to these agents has suggested the presence of additional, as yet unknown 'don't eat me' signals. Here we show that CD24 can be the dominant innate immune checkpoint in ovarian cancer and breast cancer, and is a promising target for cancer immunotherapy. We demonstrate a role for tumour-expressed CD24 in promoting immune evasion through its interaction with the inhibitory receptor sialic-acid-binding Ig-like lectin 10 (Siglec-10), which is expressed by tumour-associated macrophages. We find that many tumours overexpress CD24 and that tumour-associated macrophages express high levels of Siglec-10. Genetic ablation of either CD24 or Siglec-10, as well as blockade of the CD24-Siglec-10 interaction using monoclonal antibodies, robustly augment the phagocytosis of all CD24-expressing human tumours that we tested. Genetic ablation and therapeutic blockade of CD24 resulted in a macrophage-dependent reduction of tumour growth in vivo and an increase in survival time. These data reveal CD24 as a highly expressed, anti-phagocytic signal in several cancers and demonstrate the therapeutic potential for CD24 blockade in cancer immunotherapy.

  View details for DOI 10.1038/s41586-019-1456-0

  View details for PubMedID 31367043

• C-C chemokine receptor type 1 is a prognostic indicator in ovarian cancer Chanana, A. M., Krishnan, V., Tallapragada, S., Dorigo, O. AMER ASSOC CANCER RESEARCH. 2019

  View details for DOI 10.1158/1538-7445.AM2019-1964

  View details for Web of Science ID 000488129904470

• DPX-Survivac and intermittent low-dose cyclophosphamide (CPA) with or without epacadostat (E) in the treatment of subjects with advanced recurrent epithelial ovarian cancer (DeCidE(1) trial): T cell responses and tumor infiltration correlate with tumor regression. Tanyi, J., Dorigo, O., Oza, A. M., Strauss, J., Pejovic, T., Ghamande, S. A., Ghatage, P., Villella, J. A., Fiset, S., MacDonald, L., Hrytsenko, O., Stanford, M., Newton, R. C., Leopold, L., Rosu, G. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.5576

  View details for Web of Science ID 000487345805567

• Collagen Remodeling in the Hypoxic Tumor-Mesothelial Niche Promotes Ovarian Cancer Metastasis CANCER RESEARCH Natarajan, S., Foreman, K. M., Soriano, M., Rossen, N. S., Shehade, H., Fregoso, D. R., Eggold, J. T., Krishnan, V., Dorigo, O., Krieg, A. J., Heilshorn, S. C., Sinha, S., Fuh, K. C., Rankin, E. B. 2019; 79 (9): 2271–84

  View details for DOI 10.1158/0008-5472.CAN-18-2616

  View details for Web of Science ID 000466765900019

• The mucin-selective protease StcE enables molecular and functional analysis of human cancer-associated mucins PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Malaker, S. A., Pedram, K., Ferracane, M. J., Bensing, B. A., Krishnan, V., Pett, C., Yu, J., Woods, E. C., Kramer, J. R., Westerlind, U., Dorigo, O., Bertozzi, C. R. 2019; 116 (15): 7278–87

  View details for DOI 10.1073/pnas.1813020116

  View details for Web of Science ID 000463936900024

• Collagen remodeling in the hypoxic tumor-mesothelial niche promotes ovarian cancer metastasis. Cancer research Natarajan, S., Foreman, K. M., Soriano, M. I., Rossen, N. S., Shehade, H., Fregoso, D. R., Eggold, J. T., Krishnan, V., Dorigo, O., Krieg, A. J., Heilshorn, S. C., Sinha, S., Fuh, K. C., Rankin, E. B. 2019

  Abstract

  Peritoneal metastases are the leading cause of morbidity and mortality in high-grade serous ovarian cancer (HGSOC). Accumulating evidence suggests that mesothelial cells are an important component of the metastatic microenvironment in HGSOC. However, the mechanisms by which mesothelial cells promote metastasis are unclear. Here we report that the HGSOC tumor-mesothelial niche was hypoxic and hypoxic signaling enhanced collagen I deposition by mesothelial cells. Specifically, hypoxic signaling increased expression of lysyl oxidase (LOX) in mesothelial and ovarian cancer cells to promote collagen crosslinking and tumor cell invasion. The mesothelial niche was enriched with fibrillar collagen in human and murine omental metastases. Pharmacologic inhibition of LOX reduced tumor burden and collagen remodeling in murine omental metastases. These findings highlight an important role for hypoxia and mesothelial cells in the modification of the extracellular matrix and tumor invasion in HGSOC.

  View details for PubMedID 30862717

• Cervical Cancer, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Koh, W., Abu-Rustum, N. R., Bean, S., Bradley, K., Campos, S. M., Cho, K. R., Chon, H. S., Chu, C., Clark, R., Cohn, D., Crispens, M. A., Damast, S., Dorigo, O., Eifel, P. J., Fisher, C. M., Frederick, P., Gaffney, D. K., Han, E., Huh, W. K., Lurain, J. R., Mariani, A., Mutch, D., Nagel, C., Nekhlyudov, L., Fader, A. N., Remmenga, S. W., Reynolds, R. K., Tillmanns, T., Ueda, S., Wyse, E., Yashar, C. M., McMillian, N. R., Scavone, J. L. 2019; 17 (1): 64–84

  Abstract

  Cervical cancer is a malignant epithelial tumor that forms in the uterine cervix. Most cases of cervical cancer are preventable through human papilloma virus (HPV) vaccination, routine screening, and treatment of precancerous lesions. However, due to inadequate screening protocols in many regions of the world, cervical cancer remains the fourth-most common cancer in women globally. The complete NCCN Guidelines for Cervical Cancer provide recommendations for the diagnosis, evaluation, and treatment of cervical cancer. This manuscript discusses guiding principles for the workup, staging, and treatment of early stage and locally advanced cervical cancer, as well as evidence for these recommendations. For recommendations regarding treatment of recurrent or metastatic disease, please see the full guidelines on NCCN.org.

  View details for PubMedID 30659131

• Immunotherapy in Gynecologic Cancers: What We Know Now and Where We Are Headed. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting Levinson, K., Dorigo, O., Rubin, K., Moore, K. 2019: e126–e140

  Abstract

  Immunotherapy, mainly in the form of immune checkpoint inhibitors (ICIs), has been transformative in both solid tumor and hematologic malignancies. Patients with previously terminal illnesses have experienced profound responses of great durability with these agents, fueling excitement among patients and providers regarding their use. Unfortunately, the gains seen in some solid tumors have not been replicated in a large percentage of patients with gynecologic cancer. This review focuses on the clinical benefits seen to date, toxicities and management when using ICIs, ways to improve prediction of who should receive immunotherapy, and a discussion of next-generation immunotherapy with cellular therapeutics and how these might relate to gynecologic cancers.

  View details for DOI 10.1200/EDBK_237967

  View details for PubMedID 31099679

• Quantitative Super-Resolution Microscopy of the Mammalian Glycocalyx. Developmental cell Möckl, L. n., Pedram, K. n., Roy, A. R., Krishnan, V. n., Gustavsson, A. K., Dorigo, O. n., Bertozzi, C. R., Moerner, W. E. 2019

  Abstract

  The mammalian glycocalyx is a heavily glycosylated extramembrane compartment found on nearly every cell. Despite its relevance in both health and disease, studies of the glycocalyx remain hampered by a paucity of methods to spatially classify its components. We combine metabolic labeling, bioorthogonal chemistry, and super-resolution localization microscopy to image two constituents of cell-surface glycans, N-acetylgalactosamine (GalNAc) and sialic acid, with 10-20 nm precision in 2D and 3D. This approach enables two measurements: glycocalyx height and the distribution of individual sugars distal from the membrane. These measurements show that the glycocalyx exhibits nanoscale organization on both cell lines and primary human tumor cells. Additionally, we observe enhanced glycocalyx height in response to epithelial-to-mesenchymal transition and to oncogenic KRAS activation. In the latter case, we trace increased height to an effector gene, GALNT7. These data highlight the power of advanced imaging methods to provide molecular and functional insights into glycocalyx biology.

  View details for DOI 10.1016/j.devcel.2019.04.035

  View details for PubMedID 31105009

• Sentinel lymph node biopsies in endometrial cancer - practice patterns among Gynecologic Oncologists in the United States. Journal of minimally invasive gynecology Renz, M. n., Diver, E. n., English, D. n., Kidd, E. n., Dorigo, O. n., Karam, A. n. 2019

  Abstract

  To evaluate practice patterns among gynecologic oncologists with regards to sentinel lymph node injection and biopsy in endometrial cancer.Observational study with no control group.Active members of the Society of Gynecologic Oncology.After IRB approval, we performed an online survey amongst active members of the Society of Gynecologic Oncology. Members were contacted via email and their answers anonymously captured. Study data were collected using REDCap.318 of 1216 listed members completed the online survey, The majority of respondents (82.7%) perform sentinel lymph node sampling for endometrial cancer staging. Most technical aspects of sentinel lymph node sampling were consistently applied by the vast majority of respondents, including the choice of indocyanine green (ICG) as lymphatic tracer (97.3%) and its injection into the cervix (100%). Other technical aspects of sentinel lymph node sampling, such as the depth of injection, varied amongst respondents. While 50.9% of the respondents perform an intraoperative assessment of the uterus by frozen section, only 17.9% assess sentinel lymph nodes by frozen section and/or touch prep. Some of the respondents' approaches are based on limited data, including (i) the use of sentinel lymph node injection and biopsy for high-risk histologies (performed by 69 - 75% of the respondents dependent upon the histology), (ii) omitting side-specific completion lymphadenectomy in the absence of sentinel node mapping (in up to 57.8%) or (iii) when lymph node metastases are present (in 39.9%).In summary, despite the growing use of sentinel lymph node injection and biopsy in endometrial cancer, practice patterns vary considerably among providers sampled by this survey. Some of the decisions are based on limited evidence and, in some instances, deviate from current published guidelines.

  View details for PubMedID 30980995

• The mucin-selective protease StcE enables molecular and functional analysis of human cancer-associated mucins. Proceedings of the National Academy of Sciences of the United States of America Malaker, S. A., Pedram, K. n., Ferracane, M. J., Bensing, B. A., Krishnan, V. n., Pett, C. n., Yu, J. n., Woods, E. C., Kramer, J. R., Westerlind, U. n., Dorigo, O. n., Bertozzi, C. R. 2019

  Abstract

  Mucin domains are densely O-glycosylated modular protein domains that are found in a wide variety of cell surface and secreted proteins. Mucin-domain glycoproteins are known to be key players in a host of human diseases, especially cancer, wherein mucin expression and glycosylation patterns are altered. Mucin biology has been difficult to study at the molecular level, in part, because methods to manipulate and structurally characterize mucin domains are lacking. Here, we demonstrate that secreted protease of C1 esterase inhibitor (StcE), a bacterial protease from Escherichia coli, cleaves mucin domains by recognizing a discrete peptide- and glycan-based motif. We exploited StcE's unique properties to improve sequence coverage, glycosite mapping, and glycoform analysis of recombinant human mucins by mass spectrometry. We also found that StcE digests cancer-associated mucins from cultured cells and from ascites fluid derived from patients with ovarian cancer. Finally, using StcE, we discovered that sialic acid-binding Ig-type lectin-7 (Siglec-7), a glycoimmune checkpoint receptor, selectively binds sialomucins as biological ligands, whereas the related receptor Siglec-9 does not. Mucin-selective proteolysis, as exemplified by StcE, is therefore a powerful tool for the study of mucin domain structure and function.

  View details for PubMedID 30910957

• A scalable filtration method for high throughput screening based on cell deformability. Lab on a chip Gill, N. K., Ly, C., Nyberg, K. D., Lee, L., Qi, D., Tofig, B., Reis-Sobreiro, M., Dorigo, O., Rao, J., Wiedemeyer, R., Karlan, B., Lawrenson, K., Freeman, M. R., Damoiseaux, R., Rowat, A. C. 2018

  Abstract

  Cell deformability is a label-free biomarker of cell state in physiological and disease contexts ranging from stem cell differentiation to cancer progression. Harnessing deformability as a phenotype for screening applications requires a method that can simultaneously measure the deformability of hundreds of cell samples and can interface with existing high throughput facilities. Here we present a scalable cell filtration device, which relies on the pressure-driven deformation of cells through a series of pillars that are separated by micron-scale gaps on the timescale of seconds: less deformable cells occlude the gaps more readily than more deformable cells, resulting in decreased filtrate volume which is measured using a plate reader. The key innovation in this method is that we design customized arrays of individual filtration devices in a standard 96-well format using soft lithography, which enables multiwell input samples and filtrate outputs to be processed with higher throughput using automated pipette arrays and plate readers. To validate high throughput filtration to detect changes in cell deformability, we show the differential filtration of human ovarian cancer cells that have acquired cisplatin-resistance, which is corroborated with cell stiffness measurements using quantitative deformability cytometry. We also demonstrate differences in the filtration of human cancer cell lines, including ovarian cancer cells that overexpress transcription factors (Snail, Slug), which are implicated in epithelial-to-mesenchymal transition; breast cancer cells (malignant versus benign); and prostate cancer cells (highly versus weekly metastatic). We additionally show how the filtration of ovarian cancer cells is affected by treatment with drugs known to perturb the cytoskeleton and the nucleus. Our results across multiple cancer cell types with both genetic and pharmacologic manipulations demonstrate the potential of this scalable filtration device to screen cells based on their deformability.

  View details for DOI 10.1039/c8lc00922h

  View details for PubMedID 30566156

• Cell-based immunotherapy in gynecologic malignancies. Current opinion in obstetrics & gynecology Schaar, B., Krishnan, V., Tallapragada, S., Chanana, A., Dorigo, O. 2018

  Abstract

  PURPOSE OF REVIEW: To provide an update on cell-based immunotherapies in solid tumors particularly in gynecological cancers.RECENT FINDINGS: Improvements have been made in engineering T cells to overcome the immunosuppressive environment in ovarian cancer. Significant efforts are underway to create 'off the shelf' cell therapies which leverage natural killer (NK) cells and would not rely on engineering a patient's T cells.SUMMARY: Efforts to target solid tumors using cell-based therapies are expanding into cell types other than T cells (NK cells and macrophages) which may have a lower risk of significant side effects and higher efficacy in solid tumors than chimeric antigen receptor T cells.

  View details for PubMedID 30540582

• Hypoxic signaling in the tumor-mesothelial niche promotes collagen remodeling and ovarian cancer metastasis. Foreman, K., Fuh, K., SorianoJAL, M., Dorigo, O., Krishnan, V., Shehade, H., Natarajan, S., Sinha, S., Krieg, A., Rankin, E. AMER ASSOC CANCER RESEARCH. 2018: 57

  View details for Web of Science ID 000440823600067

• Omentum immune microenvironment: Metastatic niche for ovarian cancer Krishnan, V., Raju, P. A., Vierkoetter, K., Patel, S., Youngyunpipatkul, J., Tallapragada, S., Schaar, B., Folkins, A. K., Herzenberg, L. A., Dorigo, O. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-5074

  View details for Web of Science ID 000468819504076

• Uterine Neoplasms, Version 1.2018 Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Koh, W., Abu-Rustum, N. R., Bean, S., Bradley, K., Campos, S. M., Cho, K. R., Chon, H., Chu, C., Cohn, D., Crispens, M., Damast, S., Dorigo, O., Eifel, P. J., Fisher, C. M., Frederick, P., Gaffney, D. K., George, S., Han, E., Higgins, S., Huh, W. K., Lurain, J. R., Mariani, A., Mutch, D., Nagel, C., Nekhlyudov, L., Fader, A., Remmenga, S. W., Reynolds, R., Tillmanns, T., Ueda, S., Wyse, E., Yashar, C. M., McMillian, N. R., Scavone, J. L. 2018; 16 (2): 170–99

  Abstract

  Endometrial carcinoma is a malignant epithelial tumor that forms in the inner lining, or endometrium, of the uterus. Endometrial carcinoma is the most common gynecologic malignancy. Approximately two-thirds of endometrial carcinoma cases are diagnosed with disease confined to the uterus. The complete NCCN Guidelines for Uterine Neoplasms provide recommendations for the diagnosis, evaluation, and treatment of endometrial cancer and uterine sarcoma. This manuscript discusses guiding principles for the diagnosis, staging, and treatment of early-stage endometrial carcinoma as well as evidence for these recommendations.

  View details for DOI 10.6004/jnccn.2018.0006

  View details for Web of Science ID 000424512500010

  View details for PubMedID 29439178

• Tumor associated macrophages in gynecologic cancers. Gynecologic oncology Krishnan, V. n., Schaar, B. n., Tallapragada, S. n., Dorigo, O. n. 2018

  Abstract

  The complex tumor microenvironment in gynecologic cancers plays a major role in modulating anti-tumor immune responses. The interaction of cancer cells with the diverse spectrum of immune effector cells has an important impact on the efficacy of standard chemotherapy and novel immunotherapy approaches. In this review, we specifically focus on the role of macrophages in ovarian, endometrial and cervical cancers. We discuss the origins of macrophages and their polarization state dictated by the microenvironment's cues. Within the tumor niche, tumor-associated macrophages (TAMs) promote tumor growth and mediate immune-suppression thereby effecting treatment responses. We outline clinical strategies that directly target TAMs, including inhibition of macrophage differentiation, prevention of the recruitment of monocytes to the tumor, enhancement of phagocytosis and immune checkpoint blockade.

  View details for PubMedID 29395307

• Cell-based immunotherapy in gynecologic malignancies. Current opinion in obstetrics & gynecology Schaar, B. n., Krishnan, V. n., Tallapragada, S. n., Dorigo, O. n. 2018; 30 (1): 23–30

  Abstract

  To provide an overview of the principles, safety and efficacy of adoptive cell therapy (ACT) in solid tumors particularly in gynecological cancers.Efforts to target solid tumors using tumor-infiltrating lymphocytes and genetically modified T cells have shown promising efficacy in some patients. Two food and drug administration approvals for the treatment of leukemia are the first gene therapies available for cancer treatment in the United States.Genetic engineering of antitumor immunity using T cells has the potential to target specific tumor-associated antigens and overcome obstacles to successful immunotherapy like immune-suppressive factors in the tumor microenvironment.

  View details for PubMedID 29227304

• Moving forward with actionable therapeutic targets and opportunities in endometrial cancer: NCI clinical trials planning meeting report on identifying key genes and molecular pathways for targeted endometrial cancer trials ONCOTARGET MacKay, H. J., Levine, D. A., Bae-Jump, V. L., Bell, D. W., McAlpine, J. N., Santin, A., Fleming, G. F., Mutch, D. G., Nephew, K. P., Wentzensen, N., Goodfellow, P. J., Dorigo, O., Nijman, H. W., Broaddus, R., Kohn, E. C. 2017; 8 (48): 84579–94

  Abstract

  The incidence and mortality rates from endometrial cancer are increasing. There have been no new drugs approved for the treatment of endometrial cancer in decades. The National Cancer Institute, Gynecologic Cancer Steering Committee identified the integration of molecular and/or histologic stratification into endometrial cancer management as a top strategic priority. Based on this, they convened a group of experts to review the molecular data in this disease. Here we report on the actionable opportunities and therapeutic directions identified for incorporation into future clinical trials.

  View details for PubMedID 29137450

• Imaging of Tumor-Associated Macrophages in a Transgenic Mouse Model of Orthotopic Ovarian Cancer. Molecular imaging and biology He, H., Chiu, A. C., Kanada, M., Schaar, B. T., Krishnan, V., Contag, C. H., Dorigo, O. 2017

  Abstract

  Tumor-associated macrophages (TAMs) are often associated with a poor prognosis in cancer. To gain a better understanding of cellular recruitment and dynamics of TAM biology during cancer progression, we established a novel transgenic mouse model for in vivo imaging of luciferase-expressing macrophages.B6.129P2-Lyz2(tm1(cre)Ifo)/J mice, which express Cre recombinase under the control of the lysozyme M promoter (LysM) were crossed to Cre-lox Luc reporter mice (RLG), to produce LysM-LG mice whose macrophages express luciferase. Cell-type-specific luciferase expression in these mice was verified by flow cytometry, and via in vivo bioluminescence imaging under conditions where macrophages were either stimulated with lipopolysaccharide or depleted with clodronate liposomes. The distribution of activated macrophages was longitudinally imaged in two immunocompetent LysM-LG mouse models with either B16 melanoma or ID8 ovarian cancer cells.In vivo imaging of LysM-LG mice showed luciferase activity was generated by macrophages. Clodronate liposome-mediated depletion of macrophages lowered overall bioluminescence while lipopolysaccharide injection increased macrophage bioluminescence in both the B16 and ID8 models. Tracking macrophages weekly in tumor-bearing animals after intraperitoneal (i.p.) or intraovarian (i.o.) injection resulted in distinct, dynamic patterns of macrophage activity. Animals with metastatic ovarian cancer after i.p. injection exhibited significantly higher peritoneal macrophage activity compared to animals after i.o. injection.The LysM-LG model allows tracking of macrophage recruitment and activation during disease initiation and progression in a noninvasive manner. This model provides a tool to visualize and monitor the benefit of pharmacological interventions targeting macrophages in preclinical models.

  View details for DOI 10.1007/s11307-017-1061-2

  View details for PubMedID 28233218

• Improving Care With a Portfolio of Physician-Led Cancer Quality Measures at an Academic Center Improving Care With a Portfolio of Physician-Led Cancer Quality Measures at an Academic Center Porter, J. B. 2017; 13 (8): e673-e682

  Abstract

  Development and implementation of robust reporting processes to systematically provide quality data to care teams in a timely manner is challenging. National cancer quality measures are useful, but the manual data collection required is resource intensive, and reporting is delayed. We designed a largely automated measurement system with our multidisciplinary cancer care programs (CCPs) to identify, measure, and improve quality metrics that were meaningful to the care teams and their patients.Each CCP physician leader collaborated with the cancer quality team to identify metrics, abiding by established guiding principles. Financial incentive was provided to the CCPs if performance at the end of the study period met predetermined targets. Reports were developed and provided to the CCP physician leaders on a monthly or quarterly basis, for dissemination to their CCP teams.A total of 15 distinct quality measures were collected in depth for the first time at this cancer center. Metrics spanned the patient care continuum, from diagnosis through end of life or survivorship care. All metrics improved over the study period, met their targets, and earned a financial incentive for their CCP.Our quality program had three essential elements that led to its success: (1) engaging physicians in choosing the quality measures and prespecifying goals, (2) using automated extraction methods for rapid and timely feedback on improvement and progress toward achieving goals, and (3) offering a financial team-based incentive if prespecified goals were met.

  View details for DOI 10.1200/JOP.2017.021139

  View details for PubMedCentralID PMC5880618

• Women's cancer: Advancing molecular and immunotherapy CURRENT PROBLEMS IN CANCER Dorigo, O. 2017; 41 (1): 7

  View details for PubMedID 28366203

• Immunotherapy in ovarian cancer CURRENT PROBLEMS IN CANCER Krishnan, V., Berek, J. S., Dorigo, O. 2017; 41 (1): 48-63

  Abstract

  Immunotherapy aims to develop combination approaches that simultaneously augment immunity while preventing local immune suppression. Despite advances in combinatorial chemotherapy regimens and the advent of intraperitoneal chemotherapy administration, current therapeutic options for patients with ovarian cancer are inadequate. Advances in immunotherapy offer a promising frontier for treating ovarian tumors. Multiple immunotherapeutic modalities are currently developed and tested in clinical trials. Antibody-based therapies, immune checkpoint blockade, cancer vaccines, and chimeric antigen receptor-modified T cells have demonstrated preclinical success and entered clinical testing. In this review, we discuss these promising immunotherapeutic approaches and emphasize the importance of combinatorial treatment strategies and biomarker discovery.

  View details for DOI 10.1016/j.currproblcancer.2016.11.003

  View details for Web of Science ID 000398869800004

• Vulvar Cancer, Version 1.2017 Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Koh, W., Greer, B. E., Abu-Rustum, N. R., Campos, S. M., Cho, K. R., Chon, H. S., Chu, C., Cohn, D., Crispens, M. A., Dizon, D. S., Dorigo, O., Eifel, P. J., Fisher, C. M., Frederick, P., Gaffney, D. K., Han, E., Higgins, S., Huh, W. K., Lurain, J. R., Mariani, A., Mutch, D., Nagel, C., Nekhlyudov, L., Fader, A. N., Remmenga, S. W., Reynolds, R. K., Tillmanns, T., Ueda, S., Valea, F. A., Wyse, E., Yashar, C. M., McMillian, N., Scavone, J. 2017; 15 (1): 92-120

  Abstract

  Vulvar cancer is a rare gynecologic malignancy. Ninety percent of vulvar cancers are predominantly squamous cell carcinomas (SCCs), which can arise through human papilloma virus (HPV)-dependent and HPV-independent pathways. The NCCN Vulvar Cancer panel is an interdisciplinary group of representatives from NCCN Member Institutions consisting of specialists in gynecological oncology, medical oncology, radiation oncology, and pathology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Vulvar Cancer provide an evidence- and consensus-based approach for the management of patients with vulvar SCC. This manuscript discusses the recommendations outlined in the NCCN Guidelines for diagnosis, staging, treatment, and follow-up.

  View details for Web of Science ID 000392045900008

  View details for PubMedID 28040721

• Immunotherapy in ovarian cancer. Current problems in cancer Krishnan, V., Berek, J. S., Dorigo, O. 2016

  Abstract

  Immunotherapy aims to develop combination approaches that simultaneously augment immunity while preventing local immune suppression. Despite advances in combinatorial chemotherapy regimens and the advent of intraperitoneal chemotherapy administration, current therapeutic options for patients with ovarian cancer are inadequate. Advances in immunotherapy offer a promising frontier for treating ovarian tumors. Multiple immunotherapeutic modalities are currently developed and tested in clinical trials. Antibody-based therapies, immune checkpoint blockade, cancer vaccines, and chimeric antigen receptor-modified T cells have demonstrated preclinical success and entered clinical testing. In this review, we discuss these promising immunotherapeutic approaches and emphasize the importance of combinatorial treatment strategies and biomarker discovery.

  View details for DOI 10.1016/j.currproblcancer.2016.11.003

  View details for PubMedID 28169004

• Ovarian Cancer, Version 1.2016 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Morgan, R. J., Armstrong, D. K., Alvarez, R. D., Bakkum-Gamez, J. N., Behbakht, K., Chen, L., Copeland, L., Crispens, M. A., DeRosa, M., Dorigo, O., Gershenson, D. M., Gray, H. J., Hakam, A., Havrilesky, L. J., Johnston, C., Lele, S., Martin, L., Matulonis, U. A., O'Malley, D. M., Penson, R. T., Percac-Lima, S., Pineda, M., Plaxe, S. C., Powell, M. A., Ratner, E., Remmenga, S. W., Rose, P. G., Sabbatini, P., Santoso, J. T., Werner, T. L., Burns, J., Hughes, M. 2016; 14 (9): 1134-1163

  Abstract

  This selection from the NCCN Guidelines for Ovarian Cancer focuses on the less common ovarian histopathologies (LCOHs), because new algorithms were added for LCOHs and current algorithms were revised for the 2016 update. The new LCOHs algorithms include clear cell carcinomas, mucinous carcinomas, and grade 1 (low-grade) serous carcinomas/endometrioid epithelial carcinomas. The LCOHs also include carcinosarcomas (malignant mixed Müllerian tumors of the ovary), borderline epithelial tumors (also known as low malignant potential tumors), malignant sex cord-stromal tumors, and malignant germ cell tumors.

  View details for Web of Science ID 000382903900009

• Ovarian Cancer, Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network Morgan, R. J., Armstrong, D. K., Alvarez, R. D., Bakkum-Gamez, J. N., Behbakht, K., Chen, L., Copeland, L., Crispens, M. A., DeRosa, M., Dorigo, O., Gershenson, D. M., Gray, H. J., Hakam, A., Havrilesky, L. J., Johnston, C., Lele, S., Martin, L., Matulonis, U. A., O'Malley, D. M., Penson, R. T., Percac-Lima, S., Pineda, M., Plaxe, S. C., Powell, M. A., Ratner, E., Remmenga, S. W., Rose, P. G., Sabbatini, P., Santoso, J. T., Werner, T. L., Burns, J., Hughes, M. 2016; 14 (9): 1134-1163

  Abstract

  This selection from the NCCN Guidelines for Ovarian Cancer focuses on the less common ovarian histopathologies (LCOHs), because new algorithms were added for LCOHs and current algorithms were revised for the 2016 update. The new LCOHs algorithms include clear cell carcinomas, mucinous carcinomas, and grade 1 (low-grade) serous carcinomas/endometrioid epithelial carcinomas. The LCOHs also include carcinosarcomas (malignant mixed Müllerian tumors of the ovary), borderline epithelial tumors (also known as low malignant potential tumors), malignant sex cord-stromal tumors, and malignant germ cell tumors.

  View details for PubMedID 27587625

• Hemophagocytic lymphohistiocytosis as a paraneoplastic syndrome associated with ovarian dysgerminoma. Gynecologic oncology reports Nosratian-Baskovic, M., Tan, B., Folkins, A., Chisholm, K. M., Dorigo, O. 2016; 17: 38-41

  Abstract

  •Ovarian dysgerminoma associated with paraneoplastic fever, cytopenia and splenomegaly•Complete symptom resolution resulted from tumor resection and medical management•Non-hematolymphoid neoplasms are part of differential diagnosis in secondary HLH.

  View details for DOI 10.1016/j.gore.2016.05.013

  View details for PubMedID 27354999

  View details for PubMedCentralID PMC4909829

• Pilot prospective evaluation of F-18-FPPRGD(2) PET/CT in patients with cervical and ovarian cancer EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Minamimoto, R., Karam, A., Jamali, M., Barkhodari, A., Gambhir, S. S., Dorigo, O., Iagaru, A. 2016; 43 (6): 1047-1055

  Abstract

  We report the effect of antiangiogenic therapy on the biodistribution of (18)F-FPPRGD2 (a surrogate biomarker of integrin αvβ3 expression), and the potential of (18)F-FPPRGD2 to predict the prognosis in patients with cervical cancer and ovarian cancer in this clinical scenario.Data from six women, age range 30 - 59 years (mean ± SD 44.0 ± 12.5 years), who had undergone a (18)F-FPPRGD2 PET/CT scan and bevacizumab-containing therapy were prospectively collected and analyzed. We compared baseline (18)F-FPPRGD2 and (18)F-FDG uptake in the lesions and tumor-to-background (T/B) ratios. The maximum and mean (18)F-FPPRGD2 standardized uptake values (SUVmax and SUVmean) were recorded for 13 normal organs, as well as in all the identified malignant lesions on the pretreatment scan and the 1-week post-treatment scan. We also measured changes in (18)F-FPPRGD2 uptake from before to 1 week after treatment, and compared them to the changes in (18)F-FDG uptake from before to 6 weeks after treatment. Treatment outcomes were correlated with these changes.The uptake in lesions and T/B ratio of (18)F-FPPRGD2 were lower than those of (18)F-FDG (SUVmax 3.7 ± 1.3 vs. 6.0 ± 1.8, P < 0.001; SUVmean 2.6 ± 0.7 vs. 4.2 ± 1.3, P < 0.001; T/B ratio based on SUVmax 2.4 ± 1.0 vs. 2.6 ± 1.0, P < 0.04; T/B ratio based on SUVmean 1.9 ± 0.6 vs. 2.4 ± 1.0, P < 0.003). One patient did not return for the follow-up scan and in another patient no lesions were identified on the pretreatment scan. (18)F-FPPRGD2 uptake in lesions in the remaining four patients had significantly changed 1 week after treatment (SUVmean 3.3 ± 1.0 vs. 2.7 ± 1.0, P < 0.001), while uptake in all normal tissues analyzed was not affected by treatment. One patient with clinical disease progression had a decrease in lesional (18)F-FPPRGD2 SUVmean of 1.6 % and in (18)F-FDG SUVmean of 9.4 %. Two patients with a clinical complete response to treatment had decreases in lesional (18)F-FPPRGD2 SUVmean of 25.2 % and 25.0 % and in (18)F-FDG SUVmean of 6.1 % and 71.8 %. One patient with a clinical partial response had a decrease in lesional (18)F-FPPRGD2 SUVmean of 7.9 % and in (18)F-FDG SUVmean of 76.4 %.This pilot study showed that (18)F-FPPRGD2 and (18)F-FDG provide independent information about the biology of ovarian and cervical cancers. Bevacizumab-containing therapy does not affect (18)F-FPPRGD2 uptake in normal organs, but does result in statistically significant changes in lesions. In addition, (18)F-FPPRGD2 may have potential for early prediction of response to such treatments. These preliminary findings have to be confirmed in larger studies.

  View details for DOI 10.1007/s00259-015-3263-7

  View details for Web of Science ID 000374972900008

  View details for PubMedID 26611425

• Screening cell mechanotype by parallel microfiltration SCIENTIFIC REPORTS Qi, D., Gill, N. K., Santiskulvong, C., Sifuentes, J., Dorigo, O., Rao, J., Taylor-Harding, B., Wiedemeyer, W. R., Rowat, A. C. 2015; 5

  Abstract

  Cell mechanical phenotype or 'mechanotype' is emerging as a valuable label-free biomarker. For example, marked changes in the viscoelastic characteristics of cells occur during malignant transformation and cancer progression. Here we describe a simple and scalable technique to measure cell mechanotype: this parallel microfiltration assay enables multiple samples to be simultaneously measured by driving cell suspensions through porous membranes. To validate the method, we compare the filtration of untransformed and HRas(V12)-transformed murine ovary cells and find significantly increased deformability of the transformed cells. Inducing epithelial-to-mesenchymal transition (EMT) in human ovarian cancer cells by overexpression of key transcription factors (Snail, Slug, Zeb1) or by acquiring drug resistance produces a similar increase in deformability. Mechanistically, we show that EMT-mediated changes in epithelial (loss of E-Cadherin) and mesenchymal markers (vimentin induction) correlate with altered mechanotype. Our results demonstrate a method to screen cell mechanotype that has potential for broader clinical application.

  View details for DOI 10.1038/srep17595

  View details for Web of Science ID 000365638200001

  View details for PubMedCentralID PMC4667223

• Macrophage Blockade Using CSF1R Inhibitors Reverses the Vascular Leakage Underlying Malignant Ascites in Late-Stage Epithelial Ovarian Cancer CANCER RESEARCH Moughon, D. L., He, H., Schokrpur, S., Jiang, Z. K., Yaqoob, M., David, J., Lin, C., Iruela-Arispe, M. L., Dorigo, O., Wu, L. 2015; 75 (22): 4742-4752

  Abstract

  Malignant ascites is a common complication in the late stages of epithelial ovarian cancer (EOC) that greatly diminishes the quality of life of patients. Malignant ascites is a known consequence of vascular dysfunction, but current approved treatments are not effective in preventing fluid accumulation. In this study, we investigated an alternative strategy of targeting macrophage functions to reverse the vascular pathology of malignant ascites using fluid from human patients and an immunocompetent murine model (ID8) of EOC that mirrors human disease by developing progressive vascular disorganization and leakiness culminating in massive ascites. We demonstrate that the macrophage content in ascites fluid from human patients and the ID8 model directly correlates with vascular permeability. To further substantiate macrophages' role in the pathogenesis of malignant ascites, we blocked macrophage function in ID8 mice using a colony-stimulating factor 1 receptor kinase inhibitor (GW2580). Administration of GW2580 in the late stages of disease resulted in reduced infiltration of protumorigenic (M2) macrophages and dramatically decreased ascites volume. Moreover, the disorganized peritoneal vasculature became normalized and sera from GW2580-treated ascites protected against endothelial permeability. Therefore, our findings suggest that macrophage-targeted treatment may be a promising strategy toward a safe and effective means to control malignant ascites of EOC.

  View details for DOI 10.1158/0008-5472.CAN-14-3373

  View details for PubMedID 26471360

• Uterine Sarcoma, Version 1.2016 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Koh, W., Greer, B. E., Abu-Rustum, N. R., Apte, S. M., Campos, S. M., Cho, K. R., Chu, C., Cohn, D., Crispens, M. A., Dizon, D. S., Dorigo, O., Eifel, P. J., Fisher, C. M., Frederick, P., Gaffney, D. K., George, S., Han, E., Higgins, S., Huh, W. K., Lurain, J. R., Mariani, A., Mutch, D., Fader, A. N., Remmenga, S. W., Reynolds, R. K., Tillmanns, T., Valea, F. A., Yashar, C. M., McMillian, N. R., Scavone, J. L. 2015; 13 (11): 1321-1331

  Abstract

  The NCCN Guidelines for Uterine Neoplasms provide interdisciplinary recommendations for treating endometrial carcinoma and uterine sarcomas. These NCCN Guidelines Insights summarize the NCCN Uterine Neoplasms Panel's 2016 discussions and major guideline updates for treating uterine sarcomas. During this most recent update, the panel updated the mesenchymal tumor classification to correspond with recent updates to the WHO tumor classification system. Additionally, the panel revised its systemic therapy recommendations to reflect new data and collective clinical experience. These NCCN Guidelines Insights elaborate on the rationale behind these recent changes.

  View details for Web of Science ID 000364277500005

• Disseminated Intravascular Coagulation Complicating the Conservative Management of Placenta Percreta OBSTETRICS AND GYNECOLOGY Judy, A. E., Lyell, D. J., Druzin, M. L., Dorigo, O. 2015; 126 (5): 1016-1018

  Abstract

  Retention of the placenta is an option in the management of placenta percreta; however, it may be associated with significant morbidity.We present a case of conservative management of placenta percreta. Disseminated intravascular coagulation (DIC) developed 49 days after delivery. An urgent hysterectomy was performed, followed by rapid normalization of coagulation parameters.Disseminated intravascular coagulation may complicate the conservative management of placenta percreta and can manifest weeks after delivery in the absence of antecedent hemorrhage or infection. The time course and presentation of this case are similar to the development of DIC after prolonged retention of a fetal demise with a probable shared pathophysiology. Close follow-up may facilitate prompt diagnosis of DIC, thereby minimizing associated morbidity.

  View details for DOI 10.1097/AOG.0000000000000960

  View details for Web of Science ID 000363974000016

  View details for PubMedID 26132459

• Parallel microfiltration (PMF): A novel method to screen cell mechanotype Wiedemeyer, W., Qi, D., Gi, N., Santiskulvong, C., Dorigo, O., Rao, J., Taylor-Harding, B., Rowat, A. C. AMER ASSOC CANCER RESEARCH. 2015

  View details for DOI 10.1158/1538-7445.AM2015-226

  View details for Web of Science ID 000371578500215

• Single cell analysis of ascites macrophages in ovarian cancer He, H., Yu, F., Quake, S. R., Dorigo, O. AMER ASSOC CANCER RESEARCH. 2015

  View details for DOI 10.1158/1538-7445.AM2015-3202

  View details for Web of Science ID 000371597101235

• Comprehensive genomic profiling (CGP) of cervical squamous cell carcinoma (cSCC) to identifiy targeted therapy options. Elvin, J., Bailey, M., Carneiro, B. A., Ali, S., Vergilio, J., Palma, N., Chmielecki, J., Frampton, G., Lipson, D., Stephens, P., Miller, V. A., Johnson, M., Giles, F. J., Ross, J. S., Dorigo, O. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036901270

• Cervical cancer, version 2.2015. Journal of the National Comprehensive Cancer Network Koh, W., Greer, B. E., Abu-Rustum, N. R., Apte, S. M., Campos, S. M., Cho, K. R., Chu, C., Cohn, D., Crispens, M. A., Dorigo, O., Eifel, P. J., Fisher, C. M., Frederick, P., Gaffney, D. K., Han, E., Huh, W. K., Lurain, J. R., Mutch, D., Fader, A. N., Remmenga, S. W., Reynolds, R. K., Teng, N., Tillmanns, T., Valea, F. A., Yashar, C. M., McMillian, N. R., Scavone, J. L. 2015; 13 (4): 395-404

  Abstract

  The NCCN Guidelines for Cervical Cancer provide interdisciplinary recommendations for treating cervical cancer. These NCCN Guidelines Insights summarize the NCCN Cervical Cancer Panel's discussion and major guideline updates from 2014 and 2015. The recommended systemic therapy options for recurrent and metastatic cervical cancer were amended upon panel review of new survival data and the FDA's approval of bevacizumab for treating late-stage cervical cancer. This article outlines relevant data and provides insight into panel decisions regarding various combination regimens. Additionally, a new section was added to provide additional guidance on key principles of evaluation and surgical staging in cervical cancer. This article highlights 2 areas of active investigation and debate from this new section: sentinel lymph node mapping and fertility-sparing treatment approaches.

  View details for PubMedID 25870376

• Cervical Cancer, Version 2.2015 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Koh, W., Greer, B. E., Abu-Rustum, N. R., Apte, S. M., Campos, S. M., Cho, K. R., Chu, C., Cohn, D., Crispens, M. A., Dorigo, O., Eifel, P. J., Fisher, C. M., Frederick, P., Gaffney, D. K., Han, E., Huh, W. K., Lurain, J. R., Mutch, D., Fader, A. N., Remmenga, S. W., Reynolds, R. K., Teng, N., Tillmanns, T., Valea, F. A., Yashar, C. M., McMillian, N. R., Scavone, J. L. 2015; 13 (4): 395-404

  Abstract

  The NCCN Guidelines for Cervical Cancer provide interdisciplinary recommendations for treating cervical cancer. These NCCN Guidelines Insights summarize the NCCN Cervical Cancer Panel's discussion and major guideline updates from 2014 and 2015. The recommended systemic therapy options for recurrent and metastatic cervical cancer were amended upon panel review of new survival data and the FDA's approval of bevacizumab for treating late-stage cervical cancer. This article outlines relevant data and provides insight into panel decisions regarding various combination regimens. Additionally, a new section was added to provide additional guidance on key principles of evaluation and surgical staging in cervical cancer. This article highlights 2 areas of active investigation and debate from this new section: sentinel lymph node mapping and fertility-sparing treatment approaches.

  View details for Web of Science ID 000352962200005

• Immunotherapeutic approaches to ovarian cancer treatment. Journal for immunotherapy of cancer Chester, C., Dorigo, O., Berek, J. S., Kohrt, H. 2015; 3: 7-?

  Abstract

  Despite advances in combinatorial chemotherapy regimens and the advent of intraperitoneal chemotherapy administration, current therapeutic options for ovarian cancer patients are inadequate. Immunotherapy offers a novel and promising therapeutic strategy for treating ovarian tumors. Following the demonstration of the immunogenicity of ovarian tumors, multiple immunotherapeutic modalities have been developed. Antibody-based therapies, immune checkpoint blockade, cancer vaccines, and chimeric antigen receptor-modified T cells have demonstrated preclinical success and entered clinical testing. In this review, we discuss these promising immunotherapeutic approaches and emphasize the importance of combinatorial treatment strategies and biomarker discovery.

  View details for DOI 10.1186/s40425-015-0051-7

  View details for PubMedID 25806106

  View details for PubMedCentralID PMC4372273

• M2 macrophage inhibition reverses vascular leaks that cause malignant ascites in late-stage epithelial ovarian cancer Moughon, D., He, H., Schokrpur, S., Jiang, Z., Yaqoob, M., David, J., Iruela-Arispe, L., Dorigo, O., Wu, L. AMER ASSOC CANCER RESEARCH. 2015

  View details for DOI 10.1158/1538-7445.CHTME14-A48

  View details for Web of Science ID 000356630300033

• Screening cell mechanotype by parallel microfiltration. Scientific reports Qi, D., Kaur Gill, N., Santiskulvong, C., Sifuentes, J., Dorigo, O., Rao, J., Taylor-Harding, B., Ruprecht Wiedemeyer, W., Rowat, A. C. 2015; 5: 17595-?

  Abstract

  Cell mechanical phenotype or 'mechanotype' is emerging as a valuable label-free biomarker. For example, marked changes in the viscoelastic characteristics of cells occur during malignant transformation and cancer progression. Here we describe a simple and scalable technique to measure cell mechanotype: this parallel microfiltration assay enables multiple samples to be simultaneously measured by driving cell suspensions through porous membranes. To validate the method, we compare the filtration of untransformed and HRas(V12)-transformed murine ovary cells and find significantly increased deformability of the transformed cells. Inducing epithelial-to-mesenchymal transition (EMT) in human ovarian cancer cells by overexpression of key transcription factors (Snail, Slug, Zeb1) or by acquiring drug resistance produces a similar increase in deformability. Mechanistically, we show that EMT-mediated changes in epithelial (loss of E-Cadherin) and mesenchymal markers (vimentin induction) correlate with altered mechanotype. Our results demonstrate a method to screen cell mechanotype that has potential for broader clinical application.

  View details for DOI 10.1038/srep17595

  View details for PubMedID 26626154

• The role of tumor associated macrophages in ovarian cancer He, H., Moughon, D. L., Hillerup, C., ElMasri, W., Wu, L., Dorigo, O. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2014: 385

  View details for DOI 10.1016/j.ygyno.2014.07.016

  View details for Web of Science ID 000345605200042

• Mutational analysis of serous ovarian cancer using Ion Torrent sequencing Masghati, S., Dorigo, O., Santisvkulvong, C. AMER ASSOC CANCER RESEARCH. 2014

  View details for DOI 10.1158/1538-7445.AM2014-3287

  View details for Web of Science ID 000349910200287

• Increased risk and pattern of secondary malignancies in patients with invasive extramammary Paget disease. British journal of dermatology Karam, A., Dorigo, O. 2014; 170 (3): 661-671

  Abstract

  Extramammary Paget disease (EMPD) is often associated with underlying or distant synchronous malignancies. The prognosis for affected patients is generally favourable; however, the risk of secondary malignancies is unknown.The goal of the study was to analyse the incidence, prognosis and pattern of secondary malignancies for patients with invasive EMPD using data from the Surveillance, Epidemiology and End Results (SEER) Program.We searched the SEER Program database for patients diagnosed with invasive EMPD between 1973 and 2008. Demographic data, outcome and secondary malignancies more than 1 year after the initial diagnosis of invasive EMPD were included in the analysis. We calculated the standardized incidence ratio (SIR) and estimated the excess absolute risk (EAR) per 10 000 person-years (PY).There were 1439 patients who were diagnosed with invasive EMPD. Most patients (80·4%) had localized disease, while 17·1% had locoregional spread and 2·5% presented with distant disease. The SIR for secondary malignancies in patients with invasive EMPD was significantly elevated with an EAR of 97·4 additional malignancies per 10 000 PY. The excess risk was mostly due to a significantly increased incidence of colorectal and anal malignancies. The initial site of disease predicted the site of the secondary malignancies, with patients with colorectal, anal, vulvar and scrotal disease showing an increased risk of colorectal, anal, vulvar and scrotal malignancies, respectively.Our study identified a long-term increased risk of developing secondary malignancies in patients with invasive EMPD that are mainly related to the site of origin of this disease. Patients with invasive EMPD require prolonged follow-up and screening for these malignancies.

  View details for DOI 10.1111/bjd.12635

  View details for PubMedID 24617434

• Anti-N-methyl-aspartate receptor encephalitis in identical twin sisters: role for oophorectomy. Obstetrics and gynecology Masghati, S., Nosratian, M., Dorigo, O. 2014; 123 (2): 433-435

  Abstract

  Anti-N-methyl-aspartate receptor encephalitis is a potentially fatal form of encephalitis and frequently associated with ovarian teratomas. Surgical removal of ovarian teratomas improves clinical outcome, but it is unclear whether bilateral salpingo-oophorectomy for normal-appearing ovaries is of clinical benefit.Our report describes a unique clinical scenario of identical twin sisters with anti-N-methyl-aspartate receptor encephalitis. Neither patient responded to immunosuppressive therapy. Imaging studies showed normal-appearing ovaries. The first twin continued on medical therapy only and died of the disease. The second twin underwent a bilateral salpingo-oophorectomy followed by gradual recovery.Based on our experience in two genetically identical individuals, we suggest considering the removal of normal-appearing ovaries in patients with anti-N-methyl-aspartate receptor encephalitis who fail to respond to medical treatment.

  View details for DOI 10.1097/AOG.0000000000000078

  View details for PubMedID 24413237

• The role of Rho GTPase in cell stiffness and cisplatin resistance in ovarian cancer cells INTEGRATIVE BIOLOGY Sharma, S., Santiskulvong, C., Rao, J., Gimzewski, J. K., Dorigo, O. 2014; 6 (6): 611-617

  Abstract

  Changes in cell stiffness (Young's modulus, E), as measured via Atomic Force Microscopy (AFM), is a newly recognized characteristic of cancer cells and may play a role in platinum drug resistance of ovarian cancers. We previously showed that, compared to their syngeneic cisplatin-sensitive counterpart, cisplatin-resistant ovarian cancer cells are stiffer, and this cell stiffness was dependent on actin polymerization and presence of stress fibers. Here, we measured the correlation between Young's modulus (via AFM measurements on live, non-apoptotic cells in physiological buffer) and cisplatin-sensitivity (IC50 as determined via the XTT cell viability assay) in a panel of nine ovarian cancer cell lines representing a range of cisplatin sensitivities. We found that cisplatin-sensitive cells had a lower Young's modulus, compared to cisplatin-resistant cells and resistant cells had a cytoskeleton composed of long actin stress fibers. As Rho GTPase mediates stress fiber formation, we examined the role of Rho GTPase in cell stiffness and platinum resistance. Rho inhibition decreased cell stiffness in cisplatin-resistant CP70 cells and increased their cisplatin sensitivity while Rho activation increased cell stiffness in cisplatin-sensitive A2780 cells and decreased their cisplatin sensitivity. Based on changes in cell stiffness, IC50 and cellular actin stress fiber organization in CP70 and A2780 cells, our findings reveal a direct role of Rho mediated actin remodeling mechanism in cisplatin resistance of ovarian cancer cells. These findings suggest the potential applicability of cell mechanical phenotyping as a model for determining sensitivity of ovarian cancer cells that could have major implications in ovarian cancer diagnosis and personalized medicine.

  View details for DOI 10.1039/c3ib40246k

  View details for Web of Science ID 000336835100004

• MMPs in Ovarian Cancer as Therapeutic Targets ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY Karam, A., Dorigo, O. 2012; 12 (7): 764-772

  Abstract

  In the United States, about 22,000 women will be diagnosed with ovarian cancer in 2011, and an estimated 14,000 patients will succumb to the disease. Surgery and chemotherapy present the main treatment modalities, but despite the development of novel therapies, the overall 5 years survival for ovarian cancer patients with advanced disease at diagnosis remains at only about 30%. Novel therapeutic strategies are needed to prolong survival and achieve greater cure rates. Matrix metalloproteinases (MMPs) are frequently expressed in ovarian cancer, and play an important role in the metastatic process. MMPs mediate degradation of the basement membrane as a crucial step in epithelial transformation, ovarian tumorigenesis and intraperitoneal metastasis. Various preclinical and clinical studies have demonstrated that MMPs might provide a suitable therapeutic target. This review summarizes important observations regarding the expression of MMPs in ovarian cancer, their biological role, and data from clinical trials targeting MMPs in ovarian cancer patients.

  View details for Web of Science ID 000310052900009

  View details for PubMedID 22292752

• Solid pseudopapillary neoplasm, pancreas type, presenting as a primary ovarian neoplasm HUMAN PATHOLOGY Stoll, L. M., Parvataneni, R., Johnson, M. W., Gui, D., Dorigo, O., Sullivan, P. 2012; 43 (8): 1339-1343

  Abstract

  Solid pseudopapillary neoplasm has historically been associated with the pancreas, categorized as a tumor of low malignancy. Recently, solid pseudopapillary neoplasm was reported to arise as a primary ovarian tumor in 3 women. We report a fourth case identified in a 48 year-old woman with an 8-cm left ovarian mass. A left salpingo-oophorectomy was performed. Microscopic examination demonstrated a predominately cystic neoplasm comprised of solid nests of cells with an epithelioid to plasmacytoid appearance, associated with blood vessels, hemorrhage, and degenerative changes, that is, pseudopapillary structures. The tumor cells stained focally for pancytokeratin, progesterone receptor, and CD57 with diffuse nuclear expression of β-catenin. Ki-67 was 5% to 10%. Synaptophysin, inhibin, and E-cadherin stains were negative. Clinical and radiologic follow-up of our patient demonstrated no pancreatic lesions. This is a rare report of a primary ovarian solid pseudopapillary neoplasm. Prolonged follow-up is needed to determine how this case will fare clinically.

  View details for DOI 10.1016/j.humpath.2011.12.018

  View details for Web of Science ID 000306979800025

  View details for PubMedID 22534259

• Expression of thyroid transcription factor-1 in normal endometrium is associated with risk of endometrial cancer development MODERN PATHOLOGY Sullivan, P. S., Maresh, E. L., Seligson, D. B., Habeeb, O., Wadehra, M., Goodglick, L., Dorigo, O. 2012; 25 (8): 1140-1148

  Abstract

  Thyroid transcription factor-1 (TTF-1) is a DNA-binding protein that is mainly expressed in thyroid and lung tissue, but has also been found in gynecologic tissue. Recent studies have suggested that TTF-1 has tumor suppressor function in lung adenocarcinoma models. In the current study, we examined whether expression of TTF-1 in benign endometrium and endometrial hyperplasia might impact on the risk of developing endometrial cancer. Formalin-fixed paraffin-embedded endometrial tissues obtained from 535 cases were used to construct an endometrial tissue microarray. One hundred fifty of 207 patients had multiple serial endometrial specimens including 46 patients who progressed to endometrial cancer. The tissue microarray included a range of histopathologies including benign endometrium (n=231), simple hyperplasia (n=105), complex hyperplasia (n=36), simple atypical hyperplasia (n=10), complex atypical hyperplasia (n=44), and endometrial carcinoma (n=109). Expression of TTF-1 by immunohistochemistry in benign endometrium and endometrial hyperplasia was correlated with progression to cancer and clinical features known to be associated with increased risk of developing endometrial cancer. Carcinoma specimens showed a significantly greater expression of TTF-1 compared with benign endometrium and non-atypical hyperplasia (P=0.0007 and P=0.05). Presence of TTF-1 expression in benign endometrium was associated with a significantly decreased risk of cancer development (P=0.003, hazards ratio=0.104, 95% CI: 0.024-0.455). TTF-1 expression in hyperplasia did not significantly correlate with progression to cancer. The data from our study show that TTF-1 expression in normal endometrium is associated with a reduced risk of endometrial cancer development. This observation suggests that TTF-1 might function as a tumor suppressor in endometrial tissue. TTF-1 expression in normal endometrium could potentially provide clinically useful information as a biomarker for the risk of endometrial cancer.

  View details for DOI 10.1038/modpathol.2012.64

  View details for Web of Science ID 000307222200009

  View details for PubMedID 22460811

• Correlative nanomechanical profiling with super-resolution F-actin imaging reveals novel insights into mechanisms of cisplatin resistance in ovarian cancer cells NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE Sharma, S., Santiskulvong, C., Bentolila, L. A., Rao, J., Dorigo, O., Gimzewski, J. K. 2012; 8 (5): 757-766

  Abstract

  The exact molecular mechanisms of ovarian cancer platinum resistance are not well understood, and biomarkers to reliably predict ovarian cancer resistance to platinum and other chemotherapeutic agents are lacking. Biomechanics of cisplatin-treated ovarian cancer cells were measured quantitatively at nanoscale level using atomic force microscopy. We demonstrate that cisplatin modulates the cellular nanomechanics of ovarian cancer cells; sensitive cells show dose-dependent increase in cell stiffness, which is effected by disrupting the F-actin polymerization. In contrast, resistant cells show no significant changes in cell stiffness upon cisplatin treatment. Further, stimulated emission depletion, an emerging super-resolution microscopy, shows that at the molecular level, F-actin is indeed remodeled considerably in cisplatin-sensitive and cisplatin-resistant cells. These findings reveal a direct role of the actin remodeling mechanism in cisplatin resistance of ovarian cancer cells, suggesting potential future applications of nanomechanical profiling as a marker for cancer drug sensitivity.In this paper, nanomechanical profiling and an emerging super-resolution microscopy method was utilized to decipher the mechanisms of cisplatin resistance in ovarian cancer cells, paving the way to future studies of this and similar other problems with drug resistance in cancer biology.

  View details for DOI 10.1016/j.nano.2011.09.015

  View details for Web of Science ID 000305704800024

  View details for PubMedID 22024198

• Treatment outcomes in a large cohort of patients with invasive Extramammary Paget's disease GYNECOLOGIC ONCOLOGY Karam, A., Dorigo, O. 2012; 125 (2): 346-351

  Abstract

  The outcome of patients with invasive Extramammary Paget's disease (EMPD) is poorly studied. The goal of the current study was to analyze the incidence, treatment approaches and outcome of patients with invasive EMPD.We searched the SEER program database for patients diagnosed with invasive EMPD between 1973 and 2007. Demographic data, outcome and therapeutic modalities were included in the analysis. Disease specific survival (DSS) was calculated from the time of original diagnosis.1439 patients were diagnosed with invasive EMPD. Most patients (80.4%) had localized disease, while 17.1% had locoregional spread, and 2.5% had distant disease. 1230 (86.4%) patients underwent site directed surgery, and 92 (6.4%) patients radiotherapy. 139 (9.7%) patients did not undergo any surgery or radiation therapy. The 5-year DSS was 94.9% for localized disease, 84.9% for regional disease and 52.5% for distant disease. Multivariate analysis showed a significantly shorter DSS associated with older age and advanced stage treatment modality (HR for death 1.07 and 2.5). Site directed surgery was associated with a significantly improved outcome when compared to patients who underwent no intervention (HR 0.44). Patients who received radiation, alone or in combination with site directed surgery, did not fare any better than patients who underwent surgery alone.The DSS of patients with invasive EMPD is generally favorable. A poor outcome was associated with older age, advanced stage and treatment modality. The association between a shortened DSS and the use of radiotherapy, alone or in combination with surgery, is surprising and warrants further investigation.

  View details for DOI 10.1016/j.ygyno.2012.01.032

  View details for Web of Science ID 000303227500014

  View details for PubMedID 22293043

• Predictors of resolution of complex atypical hyperplasia or grade 1 endometrial adenocarcinoma in premenopausal women treated with progestin therapy GYNECOLOGIC ONCOLOGY Penner, K. R., Dorigo, O., Aoyama, C., Ostrzega, N., Balzer, B. L., Rao, J., Walsh, C. S., Cass, I., Holschneider, C. H. 2012; 124 (3): 542-548

  Abstract

  To identify clinical and pathologic predictors of response to progestin treatment in premenopausal women with complex atypical hyperplasia (CAH) and Grade 1 endometrial adenocarcinoma (Grade 1 EA).Forty premenopausal patients with Grade 1 EA or CAH who underwent progestin therapy for a minimum of 8 weeks were retrospectively identified. Patient characteristics and histopathologic features of pretreatment and first follow-up endometrial specimens were evaluated as predictors of resolution, defined as absence of hyperplasia or carcinoma.Kaplan-Meier analysis indicated 63% resolution at 18 months of follow-up. Multivariate classification analysis showed that resolution rates were higher in individuals with a low pre-treatment qualitative abnormal architecture score and a BMI <35 (Standardized Resolution Ratio (SRR)=1.48, p=0.03). The diagnosis of benign endometrium or simple hyperplasia on the first follow-up specimen was highly predictive of resolution (SRR=2.25, p=0.002). Resolution rates were lower among subjects with a high pre-treatment qualitative abnormal architecture score (SRR=0.37, p<0.03) and lowest in subjects whose first follow-up specimen showed persistent complexity, atypia, or carcinoma with adjacent stromal decidualization (SRR=0.24, p=0.002).Clinical and pathologic parameters can predict response to progestin therapy in premenopausal women with CAH and Grade 1 EA. A low likelihood of resolution is predicted by an unfavorable pre-treatment architectural score and lack of pathological response in the first specimen, despite adjacent stromal decidualization.

  View details for DOI 10.1016/j.ygyno.2011.11.004

  View details for Web of Science ID 000300751900029

  View details for PubMedID 22079678

• Effect of PI3K/Akt Pathway Inhibition-Mediated G(1) Arrest on Chemosensitization in Ovarian Cancer Cells ANTICANCER RESEARCH Fekete, M., Santiskulvong, C., Eng, C., Dorigo, O. 2012; 32 (2): 445-452

  Abstract

  Pharmacological inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway prevents G(1) cell cycle progression into S, resulting in G(1) accumulation. The hypothesis that this arrest might negatively impact on chemotherapeutic agents primarily effective in S, G(2) or M-phase was investigated.Inhibition of PI3K/Akt pathway signaling via LY294002 and Akti-1/2 was demonstrated by immunoblotting. Cell cycle progression was determined by flow cytometric analysis. Cell proliferation was assayed using the XTT cell viability assay. The Chou and Talalay median effect principal was used to evaluate drug interaction.In SKOV3 and IGROV1 human ovarian cancer cells, LY294002 and Akti-1/2 increased the percentage of cells in G(1) and reversed the cell cycle effects of cisplatin, paclitaxel, gemcitabine and topotecan. Pathway blockade synergistically enhanced the cytotoxicity of cisplatin and paclitaxel, but antagonized gemcitabine and topotecan effects.Pharmacological PI3K/Akt inhibition antagonizes the efficacy of chemotherapeutic agents primarily effective in the S or G(2)-phase of the cell cycle.

  View details for Web of Science ID 000299985800007

  View details for PubMedID 22287731

• Personalizing CA125 Levels for Ovarian Cancer Screening CANCER PREVENTION RESEARCH Dorigo, O., Berek, J. S. 2011; 4 (9): 1356-1359

  Abstract

  Screening trials for the early detection of ovarian cancer in the general population and in patients at a high risk for this disease have so far failed to show a reduction of ovarian cancer-specific mortality. Current screening modalities include pelvic examinations, transvaginal ultrasounds, and cancer antigen 125 (CA125) serum marker levels, which are associated with a high false-positive rate. The last decade has witnessed significant modifications in the interpretation of serum CA125 that extend beyond a static CA125 cutoff point. The Risk of Ovarian Cancer Algorithm (ROCA) incorporates changes of CA125 levels over time and an individual's age-specific risk. Ongoing screening trials have incorporated ROCA, but it is still unclear whether the algorithm will increase the sensitivity and specificity of early ovarian cancer diagnosis. A very recent study analyzed baseline CA125 serum marker levels from high-risk patients included in ovarian cancer screening trials conducted by the Cancer Genetics Network and the Gynecologic Oncology Group. The findings show that the distribution of CA125 serum marker levels in this population is significantly affected by various demographic and clinical factors, in particular menopausal status and oral contraceptive use in premenopausal patients. The data suggest that CA125 cutoff points might have to be stratified for subgroups of patients to reduce false-positive results. These intriguing observations will need to be validated in future screening trials for ovarian cancer.

  View details for DOI 10.1158/1940-6207.CAPR-11-0378

  View details for Web of Science ID 000294490100005

  View details for PubMedID 21893498

• Dual Targeting of Phosphoinositide 3-Kinase and Mammalian Target of Rapamycin Using NVP-BEZ235 as a Novel Therapeutic Approach in Human Ovarian Carcinoma CLINICAL CANCER RESEARCH Santiskulvong, C., Konecny, G. E., Fekete, M., Chen, K. M., Karam, A., Mulholland, D., Eng, C., Wu, H., Song, M., Dorigo, O. 2011; 17 (8): 2373-2384

  Abstract

  This study evaluates the effect of dual PI3K and mTOR inhibition using NVP-BEZ235 in preclinical models of ovarian cancer as a potential novel therapeutic strategy.Inhibition of PI3K/Akt/mTOR signaling by NVP-BEZ235 was demonstrated by immunoblotting. The effect on cell proliferation was assessed in 18 ovarian cancer cell lines, including four pairs of syngeneic cisplatin-sensitive and cisplatin-resistant cell lines. The in vivo effects of NVP-BEZ235 on established tumor growth were evaluated using an immunocompetent, transgenic murine ovarian cancer model (LSL-K-ras(G12D/+)Pten(loxP/loxP)).NVP-BEZ235 decreased cell proliferation in all ovarian cancer cell lines assayed and sensitized cisplatin-resistant cells to the cytotoxic effects of cisplatin. Cell lines with PI3K-activating mutations or Pten deletions were significantly more sensitive to the effect of NVP-BEZ235 than cell lines without these mutations (P < 0.05). A statistically significant correlation was found between relative levels of p4E-BP1 and the IC(50) for NVP-BEZ235. In LSL-K-ras(G12D/+)Pten(loxP/loxP) mice with established intraperitoneal tumor disease, oral administration of NVP-BEZ235 decreased pAkt, p4E-BP1 and Ki67 in tumor tissue, and resulted in significantly longer survival compared to control animals (P < 0.05). NVP-BEZ235 also induced cell cycle arrest, caspase 3 activity, and reduced cell migration.Targeting PI3K and mTOR simultaneously using NVP-BEZ235 effectively inhibits ovarian cancer cell growth even in the presence of platinum resistance and prolongs survival of mice with intra-abdominal ovarian tumor disease. We propose that dual PI3K and mTOR inhibition using NVP-BEZ235 may be an effective novel therapeutic approach in patients with ovarian cancer.

  View details for DOI 10.1158/1078-0432.CCR-10-2289

  View details for Web of Science ID 000289555500030

  View details for PubMedID 21372221

  View details for PubMedCentralID PMC3078990

• Cisplatin and PI3kinase Inhibition Decrease Invasion and Migration of Human Ovarian Carcinoma Cells and Regulate Matrix-Metalloproteinase Expression CYTOSKELETON Karam, A. K., Santiskulvong, C., Fekete, M., Zabih, S., Eng, C., Dorigo, O. 2010; 67 (8): 535-544

  Abstract

  Targeting of the PI3K (phosphoinositide3-kinase)/Akt/mTOR pathway in human ovarian cancer cells is a promising novel therapeutic strategy. We investigated the effects of cisplatin and the PI3K inhibitor LY294002 on invasion, migration and the expression of essential matrix metalloproteinases (MMPs) in ovarian cancer cells. SKOV3, OVCAR5 and IGROV1 human ovarian cancer cell lines were treated with cisplatin, LY294002 and a combination of both drugs. Invasion and migration of treated cells was assessed using Matrigel and uncoated PET membrane assays. Expression levels of pro-MMP2, MMP2, TIMP1, TIMP2 and MT1-MMP were determined using Western Blotting. Gel zymography was used to quantitate the functional levels of active MMP2. All three cell lines showed significantly reduced invasion and migration after treatment with cisplatin, LY294002, and the combination of both drugs compared to untreated controls. In SKOV3 cells, cisplatin alone and in combination with LY294002 resulted in a 6.3 and 7.1-fold reduction in the total amount of activated MMP2. TIMP1 expression decreased by 5.0, 6.6 and 28.4-fold with cisplatin, LY294002 and the combination respectively (P < 0.05). In contrast, only cisplatin and the combination of both drugs resulted in a significant, 3.7 and 5.1-fold reduction in the level of TIMP2. Expression levels of MT1-MMP remained unchanged. These observations were corroborated in IGROV1 cell lines that showed similar changes of activated MMP2 and TIMP2 expression, but no significant decrease in TIMP1 levels. Our data suggests that inhibition of ovarian cancer cell motility is mediated via down-regulation of activated MMP2, TIMP1 and TIMP2 expression under these treatment conditions.

  View details for DOI 10.1002/cm.20465

  View details for Web of Science ID 000280543100006

  View details for PubMedID 20607860

  View details for PubMedCentralID PMC3001291

• Robust In Vivo Transduction of a Genetically Stable Epstein-Barr Virus Episome to Hepatocytes in Mice by a Hybrid Viral Vector JOURNAL OF VIROLOGY Gallaher, S. D., Gil, J. S., Dorigo, O., Berk, A. J. 2009; 83 (7): 3249-3257

  Abstract

  To make a safe, long-lasting gene delivery vehicle, we developed a hybrid vector that leverages the relative strengths of adenovirus and Epstein-Barr virus (EBV). A fully gene-deleted helper-dependent adenovirus (HDAd) is used as the delivery vehicle for its scalability and high transduction efficiency. Upon delivery, a portion of the HDAd vector is recombined to form a circular plasmid. This episome includes two elements from EBV: an EBV nuclear antigen 1 (EBNA1) expression cassette and an EBNA1 binding region. Along with a human replication origin, these elements provide considerable genetic stability to the episome in replicating cells while avoiding insertional mutagenesis. Here, we demonstrate that this hybrid approach is highly efficient at delivering EBV episomes to target cells in vivo. We achieved nearly 100% transduction of hepatocytes after a single intravenous injection in mice. This is a substantial improvement over the transduction efficiency of previously available physical and viral methods. Bioluminescent imaging of vector-transduced mice demonstrated that luciferase transgene expression from the hybrid was robust and compared well to a traditional HDAd vector. Quantitative PCR analysis confirmed that the EBV episome was stable at approximately 30 copies per cell for up to 50 weeks and that it remained circular and extrachromosomal. Approaches for adapting the HDAd-EBV hybrid to a variety of disease targets and the potential benefits of this approach are discussed.

  View details for DOI 10.1128/JVI.01721-08

  View details for Web of Science ID 000264046000041

  View details for PubMedID 19158239

• Death from Metastatic Donor-Derived Ovarian Cancer in a Male Kidney Transplant Recipient AMERICAN JOURNAL OF TRANSPLANTATION Lipshutz, G. S., Mihara, N., Wong, R., Wallace, W. D., Allen-Auerbach, M., Dorigo, O., Rao, P. N., Pham, P. T., Pham, P. T. 2009; 9 (2): 428-432

  Abstract

  Posttransplant malignancy developing in an allograft is an uncommon complication of organ transplantation. The tumor may represent malignant transformation of donor or recipient cells that were previously normal, metastatic malignancy of recipient origin or malignancy transmitted from organ donor to recipient. Establishing the origin of the malignancy is critical to treatment algorithms. It is generally believed allograft removal and immunosuppression withdrawal will lead to resolution of transmitted malignancies in cases where the renal allograft is the origin. We report a male patient who developed metastatic ovarian malignancy secondary to donor transmission.

  View details for DOI 10.1111/j.1600-6143.2008.02507.x

  View details for Web of Science ID 000262781400027

  View details for PubMedID 19178417

• Dual targeting of mammalian target of rapamycin and phosphoinositide 3-kinase using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma Dorigo, O., Santiskulvong, C., Fekete, M., Karam, A., Mulholland, D., Eng, C., Wu, H. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2009: S9–S10

  View details for Web of Science ID 000264230200018

• HER-2/neu targeting for recurrent vulvar Paget's disease A case report and literature review GYNECOLOGIC ONCOLOGY Karam, A., Berek, J. S., Stenson, A., Rao, J., Dorigo, O. 2008; 111 (3): 568-571

  Abstract

  The treatment of Paget's disease of the vulva particularly for recurrences can be challenging. Overexpression of the HER-2/neu protein has been found in about 30% of vulvar Paget's cases therefore presenting a potential therapeutic target.We report the case of a 52-year-old patient with persistent Paget's disease of the vulva despite eight surgical excisions over a 15-year period. Immunohistochemistry demonstrated overexpression of the HER-2/neu protein in the vulva resection specimen. Treatment with Trastuzumab resulted in a significant regression of her disease and resolution of symptoms.Based on our case report, therapeutic targeting of HER-2/neu for patients with Paget's disease of the vulva using for example Trastuzumab is a potentially effective, alternative approach, and warrants further investigation.

  View details for DOI 10.1016/j.ygyno.2007.12.014

  View details for Web of Science ID 000261758000037

  View details for PubMedID 18252264

• CA125: Megadaltons of novel opportunities GYNECOLOGIC ONCOLOGY Dorigo, O., Berek, J. S. 2007; 104 (3): 505-507

  View details for DOI 10.1016/j.ygyno.2007.01.035

  View details for Web of Science ID 000244796500001

  View details for PubMedID 17306691

• Enhanced expression of hypersensitive alpha 4*nAChR in adult mice increases the loss of midbrain dopaminergic neurons FASEB JOURNAL Schwarz, J., Schwarz, S. C., Dorigo, O., Stuetzer, A., Wegner, F., Labarca, C., Deshpande, P., Gil, J. S., Berk, A. J., Lester, H. A. 2006; 20 (7): 935-946

  Abstract

  We describe an inducible genetic model for degeneration of midbrain dopaminergic neurons in adults. In previous studies, knock-in mice expressing hypersensitive M2 domain Leu9'Ser (L9'S) alpha4 nicotinic receptors (nAChR) at near-normal levels displayed dominant neonatal lethality and dopaminergic deficits in embryonic midbrain, because the hypersensitive nAChR is excitotoxic. However, heterozygous L9'S mice that retain the neomycin resistance cassette (neo) in a neighboring intron express low levels of the mutant allele (approximately 25% of normal levels), and these neo-intact mice are therefore viable and fertile. The neo cassette is flanked by loxP sites. In adult animals, we locally injected helper-dependent adenovirus (HDA) expressing cre recombinase. Local excision of the neo cassette, via cre-mediated recombination, was verified by genomic analysis. In L9'S HDA-cre injected animals, locomotion was reduced both under baseline conditions and after amphetamine application. There was no effect in L9'S HDA-control treated animals or in wild-type (WT) littermates injected with either virus. Immunocytochemical analyses revealed marked losses (> 70%) of dopaminergic neurons in L9'S HDA-cre injected mice compared to controls. At 20-33 days postinjection in control animals, the coexpressed marker gene, yellow fluorescent protein (YFP), was expressed in many neurons and few glial cells near the injection, emphasizing the neurotropic utility of the HDA. Thus, HDA-mediated gene transfer into adult midbrain induced sufficient functional expression of cre in dopaminergic neurons to allow for postnatal deletion of neo. This produced increased L9'S mutant nAChR expression, which in turn led to nicotinic cholinergic excitotoxicity in dopaminergic neurons.

  View details for DOI 10.1096/fj.05-5497com

  View details for Web of Science ID 000240157700016

  View details for PubMedID 16675851

• Enhanced Expression of L9'S Mutant nAChR in Adult Mice Increases the Loss of Midbrain Dopaminergic Neurons The Journal of the Federation of American Societies for Experimental Biology Schwarz, J., Schwarz, S. C., Dorigo, O., Labarca, C., Deshpande, P., Gil, J., Berk, A., Lester, H. A. 2006: 935-946
• Development of a novel helper-dependent adenovirus-Epstein-Barr virus hybrid system for the stable transformation of mammalian cells JOURNAL OF VIROLOGY Dorigo, O., Gil, J. S., Gallaher, S. D., Tan, B. T., Castro, M. G., Lowenstein, P. R., Calos, M. P., Berk, A. J. 2004; 78 (12): 6556-6566

  Abstract

  Epstein-Barr virus (EBV) episomes are stably maintained in permissive proliferating cell lines due to EBV nuclear antigen 1 (EBNA-1) protein-mediated replication and segregation. Previous studies showed the ability of EBV episomes to confer long-term transgene expression and correct genetic defects in deficient cells. To achieve quantitative delivery of EBV episomes in vitro and in vivo, we developed a binary helper-dependent adenovirus (HDA)-EBV hybrid system that consists of one HDA vector for the expression of Cre recombinase and a second HDA vector that contains all of the sequences for the EBV episome flanked by loxP sites. Upon coinfection of cells, Cre expressed from the first vector recombined loxP sites on the second vector. The resulting circular EBV episomes expressed a transgene and contained the EBV-derived family of repeats, an EBNA-1 expression cassette, and 19 kb of human DNA that functions as a replication origin in mammalian cells. This HDA-EBV hybrid system transformed 40% of cultured cells. Transgene expression in proliferating cells was observed for over 20 weeks under conditions that selected for the expression of the transgene. In the absence of selection, EBV episomes were lost at a rate of 8 to 10% per cell division. Successful delivery of EBV episomes in vivo was demonstrated in the liver of transgenic mice expressing Cre from the albumin promoter. This novel gene transfer system has the potential to confer long-term episomal transgene expression and therefore to correct genetic defects with reduced vector-related toxicity and without insertional mutagenesis.

  View details for DOI 10.1128/JVI.78.12.6556-6566.2004

  View details for Web of Science ID 000221772000048

  View details for PubMedID 15163748

  View details for PubMedCentralID PMC416543

• Enhanced expression of L9'S mutant alpha 4 nAChR in adult mice increases the loss of midbrain dopaminergic neurons 8th International Congress of Parkinsons Disease and Movement Disorders Schwarz, S. C., Dorigo, O., Labarca, C., Berk, A. J., Lester, H. A., Schwarz, J. WILEY-LISS. 2004: S42–S42

  View details for Web of Science ID 000221639600126

• Specific keynote: Immunological therapy for ovarian cancer 8th International Forum on Ovarian Cancer Berek, J. S., Dorigo, O., Schultes, B., Nicodemus, C. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2003: S105–S109

  View details for DOI 10.1006/gyno.2002.6695

  View details for Web of Science ID 000180777000024

  View details for PubMedID 12586097

• Antigenic and immunologic characterization of an allogeneic colon carcinoma vaccine CLINICAL AND EXPERIMENTAL IMMUNOLOGY Shawler, D. L., Bartholomew, R. M., Garrett, M. A., Trauger, R. J., Dorigo, O., Van Beveren, C., MARCHESE, A., Ferre, F., Duffy, C., Carlo, D. J., Sherman, L. A., Gold, D. P., SOBOL, R. E. 2002; 129 (1): 99-106

  Abstract

  We report the immunological characterization of three colon carcinoma cell lines, COLO 205, SW620 and SW403, which we selected to combine with cytokine-secreting fibroblasts for the development of an allogeneic tumour cell vaccine. The cell lines expressed HLA-A2 as well as shared tumour-associated antigens (TAAs) representative of colon carcinomas: CEA, Ep-CAM, MUC1, HER2/neu and MAGE antigens. They did not secrete high levels of the immunosuppressive factors TGF-beta, IL-10 or prostaglandins. The lines presented TAAs in a manner recognized by immune effector cells, which was demonstrated by the lysis of SW620 by HLA-A2-restricted anti-p53 cytotoxic T lymphocytes (CTL). COLO 205 and SW620 were genetically modified to express the co-stimulatory molecule CD80 (B7.1), which increased the ability of the cells to stimulate CTL in vitro. CTL clones derived from HLA-A2+ peripheral blood mononuclear cells stimulated with the CD80-expressing lines lysed the stimulator cell and an HLA-A2+ colon cancer cell line, but did not lyse an isogeneic fibroblast line or an HLA-A2- colon cancer cell line. CTL clones derived from colon carcinoma patients immunized with an allogeneic vaccine containing these lines demonstrated killing of autologous tumour cells, the vaccine cell lines and other HLA-A2+ colon cancer cell lines, but not fibroblasts isogeneic to certain of the target cell lines. Our studies demonstrate that these colon carcinoma cell lines express shared TAAs that can induce CTLs which recognize and lyse other colon carcinoma cells, and support the continued clinical evaluation of the CD80 gene modified allogeneic colon cell/cytokine-secreting fibroblast carcinoma vaccine.

  View details for Web of Science ID 000176518200014

  View details for PubMedID 12100028

• A radical debulking of leiomyomatosis peritonealis disseminata from a colonic obstruction: A case report and review of the literature JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Ghosh, K., Dorigo, O., Bristow, R., Berek, J. 2000; 191 (2): 212-215

  View details for Web of Science ID 000088583900019

  View details for PubMedID 10945368

• IL-2 plasmid therapy of murine ovarian carcinoma inhibits the growth of tumor ascites and alters its cytokine profile JOURNAL OF IMMUNOLOGY Horton, H. M., Dorigo, O., Hernandez, P., Anderson, D., Berek, J. S., Parker, S. E. 1999; 163 (12): 6378-6385

  Abstract

  We have evaluated whether i.p. murine ovarian tumors could be treated with an IL-2 plasmid DNA complexed with the cationic lipid, (+/-)-N-(2-hydroxyethyl)-N,N-dimethyl-2, 3-bis(tetradecyloxy)-1-propanaminium bromide/dioleoylphosphatidylethanolamine (DMRIE/DOPE). Reporter gene studies were initially conducted in which mice bearing i.p. murine ovarian teratocarcinoma (MOT) were injected i.p. with reporter gene plasmid DNA (pDNA):DMRIE/DOPE. Histochemical analyses revealed that transfection occurred primarily in the tumor cells of the ascites, with only a minority of other ascitic cells or surrounding tissues transfected. IL-2 levels in the MOT ascites were determined after i. p. injection of either IL-2 pDNA:DMRIE/DOPE or recombinant IL-2 protein. IL-2 was detected in tumor ascites for up to 10 days after a single i.p. injection of IL-2 pDNA:DMRIE/DOPE, but was undetectable 24 h after a single i.p. injection of IL-2 protein. In an antitumor efficacy study, MOT tumor-bearing mice injected i.p. with IL-2 pDNA:DMRIE/DOPE on days 5, 8, and 11 after tumor cell implant had a significant inhibition of tumor ascites (p = 0.001) as well as a significant increase in survival (p = 0.008). A cytokine profile of the MOT tumor ascites revealed that mice treated with IL-2 pDNA:DMRIE/DOPE had an IL-2-specific increase in the levels of IFN-gamma and GM-CSF. Taken together, these findings indicate that i. p. treatment of ovarian tumors with IL-2 pDNA:DMRIE/DOPE can lead to an increase in local IL-2 levels, a change in the cytokine profile of the tumor ascites, and a significant antitumor effect.

  View details for Web of Science ID 000084134200005

  View details for PubMedID 10586027

• Combination of transforming growth factor beta antisense and interleukin-2 gene therapy in the murine ovarian teratoma model GYNECOLOGIC ONCOLOGY Dorigo, O., Shawler, D. L., Royston, I., SOBOL, R. E., Berek, J. S., Fakhrai, H. 1998; 71 (2): 204-210

  Abstract

  The immunosuppressive protein transforming growth factor beta (TGF-beta) inhibits the activation of various immune effector cells including cytotoxic T lymphocytes and may therefore inhibit the efficacy of immunostimulatory interleukin-2 (IL-2) gene therapy. In this study, we investigated the effect of TGF-beta downregulation on IL-2 gene therapy in the intraperitoneal model of murine ovarian teratoma (MOT). MOT cells, like many human ovarian carcinomas, were found to produce TGF-beta. Production of TGF-beta by MOT cells was suppressed using a TGF-beta antisense plasmid vector (pCEP4/TGF-beta antisense). Subcutaneous immunization of C3H mice with a mixture of IL-2 gene-transduced fibroblasts and TGF-beta antisense-modified MOT cells induced significantly better protection against a subsequent intraperitoneal tumor challenge compared with immunization with unmodified MOT cells alone [11/16 (69%) vs 4/21 (19%) tumor-free animals, P < 0.01]. Immunization with either a mixture of IL-2 gene modified fibroblasts and unmodified MOT cells [2/12 (17%) tumor-free animals] or TGF-beta antisense-modified MOT cells alone (0/13 tumor free animals) failed to induce significant protection compared with immunization with unmodified MOT cells. These data show that combined TGF-beta antisense and IL-2 gene therapy is required to generate effective antitumor responses in the MOT model. Our findings suggest that tumor cell expression of immunosuppressive factors may inhibit cytokine immunogene therapy and may have potential implications for the development of future clinical immunogene therapy protocols.

  View details for Web of Science ID 000077351700010

  View details for PubMedID 9826461

• Sensitization of rat glioblastoma multiforme to cisplatin in vivo following restoration of wild-type p53 function JOURNAL OF NEUROSURGERY Dorigo, O., Turla, S. T., Lebedeva, S., Gjerset, R. A. 1998; 88 (3): 535-540

  Abstract

  To study the combined potential of wild-type p53 gene transfer and administration of cisplatin for the treatment of glioblastoma multiforme, the authors used the 9L rat glioblastoma cell line, which expresses a mutant p53.Stable expression of wild-type p53 in 9L cells was achieved by transfection of the cells with a wild-type p53-expressing plasmid (pCEP4p53). The resultant cell line, 9LpCEP4p53, was found to be more sensitive to cisplatin treatment in vitro than control (9LpCEP4) cells. The in vitro growth rates of control cells and wild-type p53-modified cells were similar in the absence of cisplatin. Fischer 344 rats were implanted intracerebrally with 9LpCEP4p53 cells and intraperitoneally administered 4 mg/kg cisplatin weekly for 7 weeks. These animals survived significantly longer than animals that were implanted with 9LpCEP4p53 cells but were given no cisplatin treatment. In contrast, concurrent cisplatin treatment provided no benefit for animals implanted with 9LpCEP4 cells. Tumors that developed in animals that had been implanted with 9LpCEP4p53 cells and treated with cisplatin had lost expression of wild-type p53, indicating a correlation between expression of wild-type p53 and cisplatin sensitivity in vivo.The findings of this study suggest that p53-based gene therapy in combination with cisplatin-based chemotherapy may be superior to single-modality treatment in dealing with glioblastoma multiforme.

  View details for Web of Science ID 000072133800016

  View details for PubMedID 9488309

• Gene therapy for ovarian cancer – Molecular scissors of the new millenium? Journal of Gynecologic Techniques Dorigo, O., Berek, J. S. 1998; 4: 149-162
• Synergy of transforming growth factor beta (TGF-beta) antisense and IL-2 gene therapy in the murine ovarian teratoma model Gynecologic Oncology Dorigo, O., Shawler, D. L., Royston, I., Sobol, R. E., Berek, J. S., Fakhrai, H. 1998: 204-210
• Construction and characterization of retroviral vectors for interleukin-2 gene therapy JOURNAL OF IMMUNOTHERAPY Fakhrai, H., Shawler, D. L., VANBEVEREN, C., Lin, H., Dorigo, O., Solomon, M. J., Gjerset, R. A., Smith, L., Bartholomew, R. M., Boggiano, C. A., Gold, D. P., SOBOL, R. E. 1997; 20 (6): 437-448

  Abstract

  Several investigators have employed interleukin-2 (IL-2) gene transfer to enhance the immunogenicity of tumor cell vaccines. We describe in this report the construction and characterization of retroviral vectors for IL-2 gene therapy. Human IL-2 cDNA with a chimeric rat preproinsulin/IL-2 DNA leader sequence was subcloned into the pLXSN (long terminal repeat promoter) and pLNCX (cytomegalovirus [CMV] promoter) vectors to generate the plasmids pLXSN-iIL2 and pLNCX-iIL2, respectively. Human IL-2 cDNA with a chimeric human tissue factor/IL-2 DNA leader sequence was utilized to construct the vector pLXSN-tIL2. The levels of IL-2 secreted by transduced tumor cells and fibroblasts were evaluated by enzyme-linked immunosorbent assay (ELISA) of culture supernatants and compared with those of normal peripheral blood mononuclear cells (PBMC) activated in vitro with calcium ionophore and phorbol 12-myristate 13-acetate. The highest levels of IL-2 secreted by transduced tumor cells (760 units/10(6) cells/24 h), adult fibroblasts (625 units/10(6) cells/24 h), and embryonic fibroblasts (3,975 units/10(6) cells/24 h) were 150- to 1,000-fold higher than than secreted by the activated PBMC (4 units/10(6) cells/24 h). Similar levels of IL-2 were expressed by human fibroblasts transduced with pLXSN vectors employing the preproinsulin (pLXSN-iIL2) or tissue factor (pLXSN-tIL2) leader sequences (range in IL-2 units/10(6) cells/24 h pLXSN-iIL2 = 375-625 vs. pLXSN-tIL2 = 90-440). Because IL-2-transduced cells for clinical applications are generally irradiated to prevent cellular proliferation, we evaluated the effects of radiation on IL-2 production. Radiation doses between 1,500 and 10,000 cGy resulted in gradual decreases in IL-2 secretion by transduced cells. The range of the decrease in IL-2 secretion was 7-11% by day 7, 0-29% by day 14, and 25-50% by day 35. For clinical applications, stable production of the vector in high concentrations is an important consideration. The retroviral vector pLXSN-tIL2 produced the highest viral titer and was chosen for further characterization. Southern blot analysis of SacI-digested genomic DNA from the LXSN-tIL2 producer cell line and SacI-digested pLXSN-tIL2 plasmid DNA revealed the expected 3.2-kbp fragment, suggesting the absence of transgene rearrangement and the suitability of this vector as a candidate for clinical applications.

  View details for Web of Science ID A1997YJ86800003

  View details for PubMedID 9409449

• Progress and prospects in vaccine therapy for gynecologic cancers. Oncology (Williston Park, N.Y.) Gurski, K. J., Steller, M. A. 1997; 11 (11): 1727-?

  Abstract

  Therapeutic and prophylactic vaccines that harness the potential of the immune system against a number of gynecologic cancers are now being developed. The therapeutic vaccines coerce the cellular components of the immune system to attack malignant tissue. The prophylactic vaccines induce the production of antibodies capable of neutralizing viral antigens before they infect host cells. However, malignant tumors are usually a heterogeneous mixture of different malignant cells, and it is likely that variant tumor clones within a tumor may not express the target antigen or may possess defects in their antigen-presenting mechanism. Ultimately, therapeutic vaccines may be better suited for the treatment of preinvasive disease or for use as an adjuvant following primary therapy. The prospects for developing efficacious vaccines to treat or prevent cervical, ovarian, uterine, and other gynecologic cancers are promising, however. This article describes the methodology of and rationale for these vaccines.

  View details for PubMedID 9394368

• Gene therapy for ovarian cancer: Development of novel treatment strategies INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Dorigo, O., Berek, J. S. 1997; 7 (1): 1-13

  Abstract

  In the last decade, advances in molecular biology have lead to the development of techniques that permit the manipulation of mammalian cell DNA for diagnostic and therapeutic purposes. Gene therapy has subsequently evolved as a treatment option in patients with malignancies. In this article, we have summarized current strategies in gene therapy for ovarian cancer.

  View details for Web of Science ID A1997VZ43800001

  View details for PubMedID 12795798

• Interleukin-2 (IL-2) gene therapy with allogeneic fibroblasts in the CT-26 model of murine colorectal carcinoma ONCOLOGY REPORTS Shawler, D. L., Dorigo, O., VANBEVEREN, C., Bartholomew, R. M., Fakhrai, H., SOBOL, R. E. 1997; 4 (1): 135-138

  Abstract

  We previously demonstrated the efficacy of a genetically engineered vaccine composed of syngeneic tumor cells mixed with syngeneic, IL-2 gene transduced fibroblasts in the CT-26 model of murine colorectal carcinoma. In this report, we describe a more practical approach to fibroblast mediated IL-2 gene therapy that employs syngeneic tumor cells mixed with allogeneic, IL-2 gene transduced fibroblasts. BALB/c mice were challenged with an injection of CT-26, 14 days following immunization with IL-2 modified syngeneic BALB/c 3T3 (H-2(d)) or allogeneic C3H 3T3 (H-2(k)) fibroblasts mixed with irradiated CT-26. Both syngeneic and allogeneic IL-2 modified fibroblasts provided significantly better protection compared to animals treated with control fibroblasts (syngeneic IL-2 fibroblasts 32/40-80% vs. control 15/45-33%, p<0.01; allogeneic IL-2 fibroblasts 25/37-68% vs. control 15/45-3345, p<0.01). There was no statistically significant difference between the groups immunized with syngeneic or allogeneic IL-2 modified fibroblasts. These findings support the evaluation of allogeneic IL-2 modified fibroblasts as a practical form of cytokine gene therapy for cancer.

  View details for Web of Science ID A1997WA59800027

  View details for PubMedID 21590028

• Interleukin-2 (IL-2) gene therapy with allogenic fibroblasts in the CT-26 model of murine colorectal carcinoma Oncology Reports Shawler, D. L., Dorigo, O., Van Beveren, C., Bartholomew, R. M., Fakhrai, H., Sobol, R. E. 1997; 4 (N1): 135-138
• Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Fakhrai, H., Dorigo, O., Shawler, D. L., Lin, H., MERCOLA, D., Black, K. L., Royston, I., SOBOL, R. E. 1996; 93 (7): 2909-2914

  Abstract

  Like human gliomas, the rat 9L gliosarcoma secretes the immunosuppressive transforming growth factor beta (TGF-beta). Using the 9L model, we tested our hypothesis that genetic modification of glioma cells to block TGF-beta expression may enhance their immunogenicity and make them more suitable for active tumor immunotherapy. Subcutaneous immunizations of tumor-bearing animals with 9L cells genetically modified to inhibit TGF-beta expression with an antisense plasmid vector resulted in a significantly higher number of animals surviving for 12 weeks (11/11, 100%) compared to immunizations with control vector-modified 9L cells (2/15, 13%) or 9L cells transduced with an interleukin 2 retroviral vector (3/10, 30%) (P < 0.001 for both comparisons). Histologic evaluation of implantation sites 12 weeks after treatment revealed no evidence of residual tumor. In vitro tumor cytotoxicity assays with lymph node effector cells revealed a 3- to 4-fold increase in lytic activity for the animals immunized with TGF-beta antisense-modified tumor cells compared to immunizations with control vector or interleukin 2 gene-modified tumor cells. These results indicate that inhibition of TGF-beta expression significantly enhances tumor-cell immunogenicity and supports future clinical evaluation of TGF-beta antisense gene therapy for TGF-beta-expressing tumors.

  View details for Web of Science ID A1996UD37500054

  View details for PubMedID 8610141

• Immuno-gene therapy of colon carcinoma and central nervous tumors In: Gene Therapy and Cancer Sobol, R. E., Fakhrai, H., Shawler, D. L., Dorigo, O., Gjerset, R. A., Mercola, D., Koziol, J., Royston, I., Bartholomew, R. 1996
• COMPARISON OF GENE-THERAPY WITH INTERLEUKIN-2 GENE MODIFIED FIBROBLASTS AND TUMOR-CELLS IN THE MURINE CT-26 MODEL OF COLORECTAL-CARCINOMA JOURNAL OF IMMUNOTHERAPY Shawler, D. L., Dorigo, O., Gjerset, R. A., Royston, I., SOBOL, R. E., Fakhrai, H. 1995; 17 (4): 201-208

  Abstract

  We compared the efficacy of gene therapy mediated by interleukin-2 (IL-2) gene-modified tumor cells to gene therapy mediated by IL-2 transduced fibroblasts in the CT-26 model of murine colorectal carcinoma. We transduced CT-26 tumor cells and BALB/c 3T3 fibroblasts with three different retroviral vectors using three different promoters for the human IL-2 gene: DC/TKIL-2 (thymidine kinase promoter), LXSN-iIL2 (long terminal repeat promoter), and LNCX-iIL2 (cytomegalovirus promoter). These transductions resulted in CT-26 and 3T3 subclones that secreted different amounts of IL-2. Immunization of animals with either CT-26/IL-2 cells or with fibroblast/IL-2 cells mixed with CT-26 induced similar levels of immunity that protected 62-82% of animals against a subsequent tumor challenge with parental CT-26. However, mice developed tumors at the site of inoculation in 46% of the animals immunized with CT-26/IL-2 cells. In a separate experiment, CT-26/IL-2 cells were exposed to 6,000 cGy of gamma irradiation to prevent tumor growth at the site of inoculation. Although the CT-26/IL-2 cells continued to secrete IL-2 after irradiation, they were no longer effective at inducing antitumor immunity. In contrast, both irradiated and nonirradiated fibroblast/IL-2 cells, mixed with irradiated CT-26, were equally effective at inducing antitumor immunity. These data suggest that in the CT-26 model, fibroblast-mediated IL-2 gene therapy has advantages for the induction of antitumor immunity and abrogation of tumorigenic potential at the site of inoculation compared with tumor cell-mediated IL-2 gene therapy.

  View details for Web of Science ID A1995RN34600002

  View details for PubMedID 7582256

• INTERLEUKIN-2 GENE-THERAPY IN A PATIENT WITH GLIOBLASTOMA GENE THERAPY SOBOL, R. E., Fakhrai, H., Shawler, D., GJERSET, R., Dorigo, O., Carson, C., KHALEGHI, T., KOZIOL, J., Shiftan, T. A., Royston, I. 1995; 2 (2): 164-167

  Abstract

  A patient with glioblastoma multiforme (GBM) who had failed conventional therapy was treated with IL-2 gene therapy. The patient received 10 subcutaneous immunizations with autologous tumor cells and fibroblasts genetically modified to secrete IL-2 by retroviral gene transfer. An antitumor immune response mediated in part by CD8+ cytotoxic T cells was demonstrated with the patient's peripheral blood mononuclear cells. A magnetic resonance imaging (MRI) scan performed 4 weeks after the highest treatment dose revealed marked tumor necrosis. These results support the evaluation of this form of IL-2 gene therapy in additional patients with glioblastoma.

  View details for Web of Science ID A1995QK78200012

  View details for PubMedID 7719933

• CHARACTERIZATION OF A NEW HUMAN GLIOBLASTOMA CELL-LINE THAT EXPRESSES MUTANT P53 AND LACKS ACTIVATION OF THE PDGF PATHWAY IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL Gjerset, R. A., Fakhrai, H., Shawler, D. L., Turla, S., Dorigo, O., GROVERBARDWICK, A., MERCOLA, D., Wen, S. F., Collins, H., Lin, H., Garcia, M. V., Kruse, C. A., Royston, I., SOBOL, R. E. 1995; 31 (3): 207-214

  Abstract

  We have established and characterized a new glioblastoma cell line, termed GT9, from a biopsy sample of a female adult patient with glioblastoma multiforme. The line has now undergone over 60 passages and has been successfully cultured after cryopreservation. Immunofluorescence analyses with a panel of monoclonal antibodies were positive for glial fibrillary acidic protein and vimentin, and negative for neurofilament, galactocerebroside, and fibronectin, a pattern typical of glial cells. Based on a tetraploid, the composite karyotype of GT9 cells included the loss of chromosome 10, gain of chromosome 7, and the presence of double minute chromosomes, three of the most common karyotypic abnormalities in glioblastoma. Sequence analysis of p53 cDNA revealed a homozygous double mutation at codon 249 (commonly mutated in aflatoxin-associated hepatocellular carcinoma) and codon 250. Moreover, there was a complete absence of wild-type p53. However, unlike the majority of human glioblastomas previously described, the expression of platelet-derived growth factor-B (PDGF-B), a potent mitogenic autocrine factor, was low in GT9 cells. The expression and phosphorylation of c-Jun and Jun-B, downstream mediators of the PDGF pathway, were also low. Thus, deregulation of the PDGF pathway does not appear to be involved in the pathogenesis of the GT9 glioblastoma. Conversely, Jun-D, a negative regulator of cell growth, was also low. In addition, Phosphorylated Egr-1, a recently reported suppressor of PDGF-B/v-sis-transformed cells, was also low, suggesting that the lack of activation of the PDGF pathway was not due to these suppressive mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1995QL75600010

  View details for PubMedID 7757303

• INJECTION OF COLON-CARCINOMA PATIENTS WITH AUTOLOGOUS IRRADIATED TUMOR-CELLS AND FIBROBLASTS GENETICALLY-MODIFIED TO SECRETE INTERLEUKIN-2 (IL-2) - A PHASE-I STUDY HUMAN GENE THERAPY SOBOL, R. E., Royston, I., Fakhrai, H., Shawler, D. L., Carson, C., Dorigo, O., GJERSET, R., Gold, D. P., KOZIOL, J., MERCOLA, D., VANBEVEREN, C., Wilson, D. 1995; 6 (2): 195-204

  View details for Web of Science ID A1995QG73000009

  View details for PubMedID 7734519

• Apoptosis of CD4+ and CD8+ cells from HIV-1 infected individuals: role of anti-idiotypic antibodies Vaccine Research Muller, S., Brams, P., Collins, H., Dorigo, O., Kohler, H. 1995; Vol 4 (No 4): 229-238
• VALUE OF BOWEL RESECTION AND PREOPERATIVE COLOSCOPY IN OVARIAN-CANCER 49th Meeting of the Deutschen-Gesellschaft-fur-Gynakologie-und-Geburtshilfe Dorigo, O., Meier, W., Scheidel, P., Hepp, H. SPRINGER HEIDELBERG. 1993: 966–68

  View details for Web of Science ID A1993MP00300368

• LYMPHOCYTE SUBPOPULATIONS IN WOMEN WITH MALIGNANT-TUMORS IN CORRELATION WITH KNOWN PROGNOSTIC FACTORS AND AS DISEASE PARAMETERS DURING CYTOKINE THERAPY 49th Meeting of the Deutschen-Gesellschaft-fur-Gynakologie-und-Geburtshilfe ROMISCH, M., Bauer, F., Daponte, A., Meier, W., Dorigo, O., Eiermann, W. SPRINGER HEIDELBERG. 1993: 1091–93

  View details for Web of Science ID A1993MP00300429

• ACTIVATION OF NEUTROPHILS IN THE MICROVASCULATURE OF THE ISCHEMIC AND REPERFUSED MYOCARDIUM 2nd Symposium of the German-Heart-Institute - Coronary Endothelium and Smooth Muscle : Basic Aspects and Clinical Consequences Tillmanns, H., Neumann, F. J., Tiefenbacher, C., Dorigo, O., Parekh, N., Waas, W., Zimmermann, R., Steinhausen, M., Kuebler, W. W B SAUNDERS CO LTD. 1993: 82–86

  Abstract

  In 11 rats, the microcirculation of the repeatedly ischaemic (stunned) left ventricular myocardium was studied using in vivo fluorescence microscopy. Stunning was provoked by six subsequent 10 min ligations of the left anterior descending coronary artery, each of them followed by a 20 min reperfusion period. In the stunned myocardium showing hypokinetic wall motion, myocardial blood flow dropped by 55%; in this region, leukocytes often appeared in slow-flow capillaries plugging capillary branches. Closely linking to leukocyte adherence, a rise of microvascular permeability was documented by extravascular clouds of fluorescent dextran. After nifedipine treatment, in ischaemic regions marked dilatation of larger A1 and A2 arterioles was noted, in addition to the ischaemia-induced dilatation of smaller A3 and A4 arterioles. Furthermore nifedipine and nisoldipine reduced the number of adherent leukocytes in post-capillary venules and capillaries of the repeatedly ischaemic myocardium. In 12 patients with coronary one-vessel disease and without previous transmural myocardial infarction, elective coronary angioplasty (PTCA) was performed (balloon inflation for 2 min). After elective PTCA of the LAD, a significant rise in the proportion of activated neutrophils was noted. After elective 2 min PTCA of the LAD, coronary sinus blood samples showed a marked rise of FMLC stimulated superoxide anion production, whereas passive deformability decreased considerably. Furthermore, an increase in chemotactic activity in coronary sinus blood samples was observed.

  View details for Web of Science ID A1993MK92600014

  View details for PubMedID 8293784

• A NON-LYMPHOMA IDIOTYPE IS INDICATIVE AND PREDICTIVE FOR B-CELL MALIGNANCIES IN AIDS 1ST INTERNATIONAL MEETING ON IMMUNOLOGICAL APPROACHES TO TUMOR THERAPY BY ANTIBODIES AND TUMOR CELL VACCINES Herndier, B., McGrath, M., Abbey, N., Wang, H. T., Ng, V., Dorigo, O., Kaplan, L., Muller, S., Kohler, H. MARY ANN LIEBERT INC. 1993: 529–37

  Abstract

  The 1F7 idiotype previously defined (J Immunol 147:933;1991 and Eur J Immunol 22:1749;1992) is expressed on antibodies reactive to different proteins of HIV (gp41, p24, gp120). Since serum levels of 1F7 (IgM or IgG) are significantly higher in patients with HIV lymphoma as opposed to HIV-infected individuals, normal controls and non-HIV lymphoma patients, we hypothesized the B-cell neoplasms were the source of the idiotype. However, immunohistochemistry on cryostat sections revealed no 1F7 idiotype signal on neoplastic B-cells nor tumor infiltrative T-cells (n = 8). Interestingly, reactive lymphocytosis adjacent to tumor masses and reactive follicular hyperplastic controls (n = 5) exhibited significant 1F7 reactivity. The reactivity appeared in paracortical and perifollicular lymphoid regions, predominantly regions of B, T and antigen presenting cells in lymph nodes or tonsils. A survey of electrophoretically defined paraproteins with anti-HIV specificities derived from HIV-infected patients showed no Western blot reactivity with the 1F7 anti-idiotypic antibody. Therefore, the idiotype does not appear to be a direct product of B-cell neoplasia or abnormal B-cell proliferation, but is produced by B cell clones responding to HIV infection. This high level of serum 1F7 reactivity could be an important clue in the pathogenesis of HIV lymphomas and confers a highly predictive serological test for HIV lymphoma.

  View details for Web of Science ID A1993MG99100007

  View details for PubMedID 8300126

• A MONOCLONAL-ANTIBODY (IF7) SPECIFIC FOR HUMAN ANTI-HIV IG INDUCES APOPTOSIS AND INHIBITS CTL ACTIVITY IN CD8+ LYMPHOCYTES FROM HIV-1 INFECTED INDIVIDUALS Muller, S., Collins, H., Brams, P., Wang, H., Dorigo, O., McGrath, M., Grant, M., Rosenthal, K., Kohler, H. WILEY-BLACKWELL. 1993: 68–68

  View details for Web of Science ID A1993KX96500252

• NEW TECHNIQUES FOR THE STUDY OF THE CORONARY MICROCIRCULATION - IMPORTANCE OF MEASUREMENTS OF CORONARY FLOW RESERVE IN THE CLINICAL SETTING CORONARY ARTERY DISEASE Tillmanns, H., Neumann, F. J., Waas, W., Mall, G., Parekh, N., Tiefenbacher, C., Dorigo, O., Zimmermann, R., Dart, A. M., Steinhausen, M., Kubler, W. 1992; 3 (7): 586-592

  View details for Web of Science ID A1992JJ14500007

• SHORT-TERM OUTCOME IN INFANTS WITH BIRTH WEIGHTS LESS-THAN 1750-G BORN TO MOTHERS WITH HELLP SYNDROME JOURNAL OF PERINATAL MEDICINE Gortner, L., Pohlandt, F., Bartmann, P., Terinde, R., Versmold, H., Dorigo, O. 1992; 20 (1): 25-28

  Abstract

  Premature infants born to mothers with HELLP syndrome were reported to have a less favourable outcome compared to infants with uncomplicated maternal history. We investigated the short term outcome in 21 premature infants with birth weights less than 1750 g born to mothers with HELLP syndrome. Median birth weight was 1050 g (range 420 g-1750 g), corresponding gestational age 29 weeks (range 26-35 weeks). Mechanical ventilation for RDS was necessary in 15 infants. Intracranial hemorrhage was diagnosed in 2 infants, 1 of the surviving infants developed bronchopulmonary dysplasia. Acute renal failure was observed in 3 infants immediately after birth. Mortality was attributed to progressive respiratory failure in 2 patients (b.w. 420 g and 490 g) and persisting acute renal failure in 1 patient (b.w. 520 g) Leucocytopenia (less than 9000/mm3) was observed in 13 infants and thrombocytopenia (less than 115000/mm3) was noted in 4 infants during the first day. Eighteen infants survived. We conclude, that the short term outcome in infants born to mothers with HELLP syndrome is not as poor, as previously reported.

  View details for Web of Science ID A1992HT93600004

  View details for PubMedID 1608020

• PHARMACOLOGICAL EFFECTS ON CORONARY MICROVESSELS DURING MYOCARDIAL-ISCHEMIA EUROPEAN HEART JOURNAL Tillmanns, H., Neumann, F. J., Parekh, N., Dorigo, O., Tiefenbacher, C., Zimmermann, R., Steinhausen, M., Kubler, W. 1990; 11: 10-15

  View details for Web of Science ID A1990DF56000003

  View details for PubMedID 2364953

• MICROCIRCULATION IN THE HYPERTROPHIC AND ISCHEMIC HEART EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY Tillmanns, H., Neumann, F. J., Parekh, N., Zimmermann, R., Tiefenbacher, C., Dorigo, O., Steinhausen, M., Kubler, W. 1990; 39: S9-S12

  Abstract

  1. Myocardial hypertrophy, for instance in patients with hypertensive heart disease, is characterized by a reduction of coronary vascular reserve, even in the presence of normal coronary arteries. In hypertensive animals, on the microcirculatory level functional changes can be observed before the onset of any structural rarefications. In 10 rats with renal hypertension and pressure-induced left ventricular hypertrophy (LVH), the microcirculation of the left ventricular myocardium was studied using in vivo fluorescence microscopy and morphometric analysis. Renal hypertension was provoked by clipping of the left renal artery. After 8 weeks, systolic blood pressure in LVH rats averaged 172 +/- 8 mm Hg, compared to 91 +/- 2 mm Hg in 10 normotensive (NT) rats. In LVH rats, distances of plasma-perfused capillaries were significantly increased (NT = 17.7; LVH = 20 microns; p less than 0.001). Volume density, surface density, and length density of capillaries in LVH rats were reduced by 20% compared to NT rats. Capillary red cell content as measured by the ratio of capillaries filled with red cells to those containing plasma alone (Q) in LVH animals exceeded that in NT rats (LVH: Q = 0.83 +/- 0.04; NT: Q = 0.77 +/- 0.04; p less than 0.025). During hypoxia (H, 5% O2) capillary red cell recruitment in LVH rats (Q: control c = 0.83; H = 0.95) was diminished by 33% as compared to NT rats (Q: c = 0.77; H = 0.95). Thus, in addition to the decreased capillary density, the reduction of capillary red cell recruitment may be responsible for chest pain in patients with LVH and normal coronary arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1990EF89800002

  View details for PubMedID 2148154