Search

Objective: Cervical cancer results from persistent infection with high-risk human papillomavirus (HR-HPV) and the expression of E6 and E7 oncoproteins. E6 and E7 compromise the activity of p53 and Rb, the G1-S cell cycle checkpoint, and ATM-mediated DNA damage repair (DDR), which in turn increases reliance on ATR- and PARP-mediated DDR at the G2 cell cycle checkpoint. This study aimed to determine the effects of an ATR inhibitor (ATRi, AZD6738) and a PARP-inhibitor (PARPi, AZD2281) on HR-HPV+ cervical cancer cell lines., Methods: The effects of ATRi and PARPi, alone and in combination, on metabolic viability, cell cycle arrest, apoptosis, and DDR pathways in cervical cancer cell lines were evaluated in vitro, and the in vivo tumor response was evaluated using a xenograft model., Results: Cervical cancer cells were sensitive to ATRi and PARPi monotherapy. The combination therapy was only synergistic in reducing metabolic viability when exposed to ATRi first, followed by PARPi, owing to ATRi-mediated upregulation of PARP expression. Combination of ATRi and PARPi induced G2 cell cycle arrest and apoptosis. PARPi induced DNA damage and γH2AX phosphorylation, which was further increased by ATRi treatment. However, PARPi-induced Rad51 foci formation was reduced by ATRi treatment, suggesting the inhibition of homologous recombination repair. ATRi significantly reduced cervical cancer xenograft tumor growth and was not affected by simultaneous PARPi treatment at the doses studied., Conclusions: Our findings show that ATRi increased reliance on PARP for metabolic viability, the combination of ATRi and PARPi induced synthetic lethality in cervical cancer in vitro, and reduced tumor burden in vivo., Competing Interests: Declaration of competing interest Author K.M.M serves on the American Board of Obstetrics and Gynecology, and is a member of the NRG Oncology Cervix and Diversity Equity and Inclusion committees. The remaining authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Advanced-stage endometrial cancer patients typically receive a combination of platinum and paclitaxel chemotherapy. However, limited treatment options are available for those with recurrent disease, and there is a need to identify alternative treatment options for the advanced setting. Our goal was to evaluate the pre-clinical efficacy and mechanism of action of Oklahoma Nitrone 007 (OKN-007) alone and in combination with carboplatin and paclitaxel in endometrial cancer. The effect of OKN-007 on the metabolic viability of endometrial cancer cells in both two- and three-dimensional (2D and 3D) cultures, as well as on clonogenic growth, in vitro was assessed. We also evaluated OKN-007 in vivo using an intraperitoneal xenograft model and targeted gene expression profiling to determine the molecular mechanism and gene expression programs altered by OKN-007. Our results showed that endometrial cancer cells were generally sensitive to OKN-007 in both 2D and 3D cultures. OKN-007 displayed a reduction in 3D spheroid and clonogenic growth. Subsequent targeted gene expression profiling revealed that OKN-007 significantly downregulated the immunosuppressive and immunometabolic enzyme indolamine 2,3-dioxygenase 1 (IDO1) (-11.27-fold change) and modulated upstream inflammatory pathways that regulate IDO1 expression (interferon- (IFN-), Jak-STAT, TGF-β, and NF-kB), downstream IDO1 effector pathways (mTOR and aryl hydrocarbon receptor (AhR)) and altered T-cell co-signaling pathways. OKN-007 treatment reduced IDO1, SULF2, and TGF-β protein expression in vivo, and inhibited TGF-β, NF-kB, and AhR- receptor-mediated nuclear signaling in vitro. These findings indicate that OKN-007 surmounts pro-inflammatory, immunosuppressive, and pro-tumorigenic pathways and is a promising approach for the effective treat endometrial cancer. Significance Statement Women with advanced and recurrent endometrial cancer have limited therapeutic options. OKN-007, which has minimal toxicity and is currently being evaluated in early-phase clinical trials for the treatment of cancer, is a potential new strategy for the treatment of endometrial cancer., (© 2024 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.)

Objective: The aim of this study was to examine the tolerability and efficacy of combination bevacizumab rucaparib therapy in patients with recurrent cervical or endometrial cancer., Patients & Methods: Thirty-three patients with recurrent cervical or endometrial cancer were enrolled. Patients were required to have tumor progression after first line treatment for metastatic, or recurrent disease. Rucaparib was given at 600 mg BID twice daily for each 21-day cycle. Bevacizumab was given at 15 mg/kg on day 1 of each 21-day cycle. The primary endpoint was efficacy as determined by objective response rate or 6-month progression free survival., Results: Of the 33 patients enrolled, 28 were evaluable. Patients with endometrial cancer had a response rate of 17% while patients with cervical cancer had a response rate of 14%. Median progression free survival was 3.8 months (95% C·I 2.5 to 5.7 months), and median overall survival was 10.1 months (95% C·I 7.0 to 15.1 months). Patients with ARID1A mutations displayed a better response rate (33%) and 6-month progression free survival (PFS6) rate (67%) than the entire study population. Observed toxicity was similar to that of previous studies with bevacizumab and rucaparib., Conclusions: The combination of bevacizumab with rucaparib did not show significantly increased anti-tumor activity in all patients with recurrent cervical or endometrial cancer. However, patients with ARID1A mutations had a higher response rate and PFS6 suggesting this subgroup may benefit from the combination of bevacizumab and rucaparib. Further study is needed to confirm this observation. No new safety signals were seen., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Platinum-based chemotherapy is the standard of care for platinum-sensitive ovarian cancer, but complications from repeated platinum therapy occur. We assessed the activity of two all-oral nonplatinum alternatives, olaparib or olaparib/cediranib, versus platinum-based chemotherapy., Patients and Methods: NRG-GY004 is an open-label, randomized, phase III trial conducted in the United States and Canada. Eligible patients had high-grade serous or endometrioid platinum-sensitive ovarian cancer. Patients were randomly assigned 1:1:1 to platinum-based chemotherapy, olaparib, or olaparib/cediranib. The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included activity within germline BRCA -mutated or wild-type subgroups and patient-reported outcomes (PROs)., Results: Between February 04, 2016, and November 13, 2017, 565 eligible patients were randomly assigned. Median PFS was 10.3 (95% CI, 8.7 to 11.2), 8.2 (95% CI, 6.6 to 8.7), and 10.4 (95% CI, 8.5 to 12.5) months with chemotherapy, olaparib, and olaparib/cediranib, respectively. Olaparib/cediranib did not improve PFS versus chemotherapy (hazard ratio [HR] 0.86; 95% CI, 0.66 to 1.10; P = .077). In women with germline BRCA mutation, the PFS HR versus chemotherapy was 0.55 (95% CI, 0.32 to 0.94) for olaparib/cediranib and 0.63 (95% CI, 0.37 to 1.07) for olaparib. In women without a germline BRCA mutation, the PFS HR versus chemotherapy was 0.97 (95% CI, 0.73 to 1.30) for olaparib/cediranib and 1.41 (95% CI, 1.07 to 1.86) for olaparib. Hematologic adverse events occurred more commonly with chemotherapy; however, nonhematologic adverse events were higher with olaparib/cediranib. In 489 patients evaluable for PROs, patients receiving olaparib/cediranib scored on average 1.1 points worse on the NFOSI-DRS-P subscale (97.5% CI, -2.0 to -0.2, P = .0063) versus chemotherapy; no difference between olaparib and chemotherapy was observed., Conclusion: Combination olaparib/cediranib did not improve PFS compared with chemotherapy and resulted in reduced PROs. Notably, in patients with a germline BRCA mutation, both olaparib and olaparib/cediranib had significant clinical activity., Competing Interests: Joyce F. LiuConsulting or Advisory Role: Tesaro, Mersana, Clovis Oncology, Genentech/Roche, GlaxoSmithKline, Regeneron, AstraZenecaResearch Funding: Genentech/Roche (Inst), AstraZeneca (Inst), Boston Biomedical (Inst), Acetylon Pharmaceuticals (Inst), Bristol Myers Squibb (Inst), Agenus (Inst), CytomX Therapeutics (Inst), Regeneron (Inst), Tesaro (Inst), Clovis Oncology (Inst), Surface Oncology (Inst), 2X Oncology (Inst), Vigeo Therapeutics (Inst), Aravive (Inst), Arch Oncology (Inst)Travel, Accommodations, Expenses: AstraZeneca, MerckUncompensated Relationships: Merck Mark F. BradyConsulting or Advisory Role: Cel-Sci Ursula A. MatulonisHonoraria: Advaxis, Alkermes, SymphogenConsulting or Advisory Role: Merck, Novartis, NextCure, AstraZeneca, Blueprint Medicines, Trillium Therapeutics, GlaxoSmithKline, AgenusResearch Funding: Merck, Novartis, Tesaro, Syndax, Immunogen, Mersana, Leap Therapeutics, Fujifilm, SQZ BiotechTravel, Accommodations, Expenses: AstraZeneca Austin MillerConsulting or Advisory Role: AstraZeneca/Merck, Regeneron (Inst)Uncompensated Relationships: Genetect Elizabeth M. SwisherLeadership: IDEAYA Biosciences David CellaStock and Other Ownership Interests: FACIT.orgConsulting or Advisory Role: AbbVie, GlaxoSmithKline, Pfizer, Astellas Pharma, Novartis, Bristol Myers Squibb, Asahi Kasei, Ipsen, Mei PharmaResearch Funding: Novartis (Inst), Ipsen (Inst), Pfizer (Inst), PledPharma (Inst), Bristol Myers Squibb (Inst), AbbVie (Inst), Regeneron (Inst), Clovis Oncology (Inst) Noelle G. ClovenConsulting or Advisory Role: Toray Industries Carolyn Y. MullerResearch Funding: AstraZeneca (Inst), Genmab (Inst), VBL Therapeutics (Inst), Roche/Genentech (Inst), TapImmune Inc (Inst), Linnaeus Therapeutics (Inst), agenus (Inst), Incyte (Inst), Merck (Inst)Patents, Royalties, Other Intellectual Property: Have a pending patent on the cancer use for R-ketorolac - not yet its own new drug (Inst)Other Relationship: NCI, NCI, Department of Defense Richard G. MooreHonoraria: Fujirebio DiagnosticsConsulting or Advisory Role: Abcodia, Fujirebio DiagnosticsResearch Funding: Angle Steven E. WaggonerConsulting or Advisory Role: Regeneron Melissa A. GellerResearch Funding: Tesaro, Genentech, FATE Therapeutics, Morphotek, Bayer Keiichi FujiwaraHonoraria: Kyowa Hakko Kirin, Zeria Pharmaceutical, Nippon Kayaku, Chugai Pharma, Eisai, Taiho Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, TakedaConsulting or Advisory Role: MSD, Taiho Pharmaceutical, Eisai, Takeda, Genmab, NanoCarrierResearch Funding: Eisai (Inst), Kaken Pharmaceutical (Inst), Chugai Pharma (Inst), Immunogen (Inst), Oncotherapeutics (Inst), AstraZeneca (Inst), Zeria Pharmaceutical (Inst), Ono Pharmaceutical (Inst), MSD (Inst), Regeneron (Inst), Merck KGaA (Inst), Ono Pharmaceutical (Inst), Genmab (Inst), Seattle Genetics (Inst)Travel, Accommodations, Expenses: MSD Angeles Alvarez SecordHonoraria: Myriad GeneticsResearch Funding: Tesaro (Inst), AstraZeneca (Inst), Genentech (Inst), Boehringer Ingelheim (Inst), AbbVie (Inst), Merck (Inst), PharmaMar (Inst), Clovis Oncology (Inst), Eisai (Inst), Seattle Genetics (Inst), Immutep (Inst), GlaxoSmithKline (Inst), VBL Therapeutics (Inst), OncoQuest Pharmaceuticals (Inst)Travel, Accommodations, Expenses: GlaxoSmithKlineUncompensated Relationships: Roche/Genentech, VBL Therapeutics, GOG Foundation, OncoQuest Pharmaceuticals, Regeneron, Aravive Katherine M. MoxleyConsulting or Advisory Role: Tessa Therapeutics (Inst), Clovis Oncology (Inst), GlaxoSmithKline Michael A. BookmanEmployment: The Permanente Medical GroupConsulting or Advisory Role: AstraZeneca, AbbVie, Immunogen, Merck Sharp & Dohme, Genentech/Roche, Seattle Genetics, AraviveNo other potential conflicts of interest were reported.

The presence of lymph node metastases in endometrial cancer patients is a critical factor guiding treatment decisions; however, surgical and imaging methods for their detection are limited by morbidity and inaccuracy. To determine if sera can predict the presence of positive lymph nodes, sera collected from endometrial cancer patients with or without lymph node metastases, and benign gynecology surgical patients (N = 20 per group) were subjected to electron spray ionization mass spectrometry (ES-MS). Peaks that were significantly different among the groups were evaluated by leave one out cross validation (LOOCV) for their ability to differentiation between the groups. Proteins in the peaks were identified by MS/MS of five specimens in each group. Ingenuity Pathway Analysis was used to predict pathways regulated by the protein profiles. LOOCV of sera protein discriminated between each of the group comparisons and predicted positive lymph nodes. Pathways implicated in metastases included loss of PTEN activation and PI3K, AKT and PKA activation, leading to calcium signaling, oxidative phosphorylation and estrogen receptor-induced transcription, leading to platelet activation, epithelial-to-mesenchymal transition and senescence. Upstream activators implicated in these events included neurostimulation and inflammation, activation of G-Protein-Coupled Receptor Gβγ, loss of HER-2 activation and upregulation of the insulin receptor.

Introduction: Chemotherapy plus radiation (Cis-RT + CP) did not demonstrate superiority in prolonging relapse-free survival compared to chemotherapy alone in patients with stage III or IVA endometrial carcinoma. The impact of treatment on quality of life (QOL), neurotoxicity (NTX) and psychometric properties of the gastrointestinal (GI) symptoms subscale during treatment and up to 1 year are described herein., Methods: QOL assessments were scheduled at baseline, 6 weeks (post completion of RT (Cis-RT + CP) or prior to cycle 3 (CP)), then 18 weeks (end of treatment) and 70 weeks (1 year after the end of treatment) after starting treatment. QOL instruments included the FACT-En TOI, FACT/GOG-neurotoxicity (Ntx) subscale (short), and the gastrointestinal (GI) symptoms subscale., Results: At the end of treatment, patients receiving Cis-RT + CP reported a statistically significant decreased QOL when compared to CP. The decline in QOL was reflected in physical well-being, functional well-being, and endometrial cancer specific concerns, but the minimally important differences (MID) were not considered clinically meaningful. Patients in both groups reported increased chemotherapy-induced Ntx symptoms with the CP group having worse scores and reaching peak symptoms at the time of chemotherapy completion. Patients on Cis-RT + CP reported statistically significantly worse GI symptoms after radiation therapy compared to patients on CP, this occurred across assessment intervals, though the MID was not meaningful. Psychometric evaluations indicated that the GI symptom scale is reliable, valid, and responsive to change., Conclusions: PROs indicate that the chemoradiotherapy group experienced worse HRQoL and GI toxicity compared to patients randomized to chemotherapy alone for locally advanced endometrial cancer though based on the MID, these were not clinically meaningful differences. The GI symptom subscale was a reliable and valid scale that has value for future trials., Trial Registration: NCT00942357., Competing Interests: Declaration of Competing Interest Dr. Matulonis reports receiving consulting fees received from Merck, Novartis, Blueprint Medicine and Next Cure as well as participating on a Data Safety Monitoring Board or Advisory Board for Symphogen and Advaxis. Ms. Helen Huang, Dr. Marcus Randall, Dr. Paul DiSilvestro, Dr. Fowler, Dr. Powell, Dr. Dr. Spirtos, Dr. Tewari, Dr. Nakayama, Dr. Mutch have no conflicts of interest to disclose. Dr. Virginia L. Filiaci reports receiving support for the present manuscript from NCTN and NCORP SDMC grant funding from the NIH/NCI. She also reports grants from GOG Foundation, Inc. for contracts with institution for clinical trial work and NCI/NIH for IOTN, BIQSFP, MP2PRT and miscellaneous other subcontracts. Dr. Filiaci also reports receiving support for attending IDMC meeting from VBL Therapeutics as well as participating on Advisory Board for Tesaro. Monitoring Board. Dr. Katherine Moxley reports P20 grant to University of Oklahoma for Drug Resistance Core from the NIH as well as support for travel to attend NRG Oncology 2019 Winter and Summer meetings. Additionally, Dr. Moxley reports serving in a Leadership role for the SGO Program Committee. Dr. David Miller reports grants received from EMD Serono Research and Development Institute to him as well as grants to his Institution from the following entities: US Biotest, Advenchen Laboratories, Tesaro, Xenetic Biosciences, Advaxis, Janssen, Aeterna Zentaris, TRACON Pharma, Pfizer, Immunogen, Mateon Therapeutics, Merck Sharp & Dohme, AstraZeneca, Millenium Pharmaceuticals, Aprea AB, Regeneron, NVision, Leap Therapeutics, Novartis, Syros Pharmaceuticals, Karyopharm Therapeutics, Agenus and Akesobio. Dr. Miller also personally received consulting fees from the following: Genentech, Tesaro, Eisai, AstraZeneca, Guardant Health, Janssen Oncology, Alexion Pharmaceuticals, Karyopharm Therapeutics, Incyte, Guardant Health, Janssen, Alexion Pharmaceuticals, Clovis Oncology, Asymmetric Therapeutics, LLC, Boston Biomedical Research Institute, Tarveda Therapeutics, Myriad Genetic Laboratories Inc., GlaxoSmithKline LLC, AbbVie Inc., Incyte, EMD Serono Inc. and Seager Inc. as well as consulting fees paid to his Institution from Merck Sharp & Dohme. Dr. Miller also received honoraria from Clovis Oncology and Genentech. He also reports participating on an Advisory Board for Incyte. Dr. Lari Wenzel reports serving as Co-Chair of the NRG Oncology PCOR Committee. Dr. Daniela Matei reports NCI NRG Support grant received. Due to his unfortunate passing before publication, no statement is available for Dr. William Richards., (Copyright © 2021 Elsevier Inc. All rights reserved.)

(1) Background. PDX models have become the preferred tool in research laboratories seeking to improve development and pre-clinical testing of new drugs. PDXs have been shown to capture the cellular and molecular characteristics of human tumors better than simpler cell line-based models. More recently, however, hints that PDXs may change their characteristics over time have begun to emerge, emphasizing the need for comprehensive analysis of PDX evolution. (2) Methods. We established a panel of high-grade serous ovarian carcinoma (HGSOC) PDXs and developed and validated a 300-SNP signature that can be successfully utilized to assess genetic drift across PDX passages and detect PDX contamination with lymphoproliferative tissues. In addition, we performed a detailed histological characterization and functional assessment of multiple PDX passages. (3) Results. Our data show that the PDXs remain largely stable throughout propagation, with marginal genetic drift at the time of PDX initiation and adaptation to mouse host. Importantly, our PDX lines retained the major histological characteristics of the original patients' tumors even after multiple passages in mice, demonstrating a strong concordance with the clinical responses of their corresponding patients. (4) Conclusions. Our data underline the value of defined HGSOC PDXs as a pre-clinical tumor model.

Purpose: Sparing active bone marrow (ABM) can reduce acute hematologic toxicity in patients undergoing chemoradiotherapy for cervical cancer, but ABM segmentation based on positron emission tomography/computed tomography (PET/CT) is costly. We sought to develop an atlas-based ABM segmentation method for implementation in a prospective clinical trial., Methods and Materials: A multiatlas was built on a training set of 144 patients and validated in 32 patients from the NRG-GY006 clinical trial. ABM for individual patients was defined as the subvolume of pelvic bone greater than the individual mean standardized uptake value on registered 18 F-fluorodeoxyglucose PET/CT images. Atlas-based and custom ABM segmentations were compared using the Dice similarity coefficient and mean distance to agreement and used to generate ABM-sparing intensity modulated radiation therapy plans. Dose-volume metrics and normal tissue complication probabilities of the two approaches were compared using linear regression., Results: Atlas-based ABM volumes (mean [standard deviation], 548.4 [88.3] cm 3 ) were slightly larger than custom ABM volumes (535.1 [93.2] cm 3 ), with a Dice similarity coefficient of 0.73. Total pelvic bone marrow V 20 and D mean were systematically higher and custom ABM V 10 was systematically lower with custom-based plans (slope: 1.021 [95% confidence interval (CI), 1.005-1.037], 1.014 [95% CI, 1.006-1.022], and 0.98 [95% CI, 0.97-0.99], respectively). We found no significant differences between atlas-based and custom-based plans in bowel, rectum, bladder, femoral heads, or target dose-volume metrics., Conclusions: Atlas-based ABM segmentation can reduce pelvic bone marrow dose while achieving comparable target and other normal tissue dosimetry. This approach may allow ABM sparing in settings where PET/CT is unavailable., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors are being considered for locally advanced cervical cancer (LACC) together with standard-of-care pelvic chemoradiation (CRT). However, the safety of the combination and its optimal schedule are unknown. Defining the safety of the combination is a primary objective of a study examining concurrent and sequential schedules. This article presents a safety analysis that was fully accrued and met reporting requirements., Methods: Pembrolizumab was given after CRT (arm 1) or during CRT (arm 2) according to a randomized phase 2 design. Patients who were 18 years old or older and had LACC (stages IB-IVA according to the 2009 International Federation of Gynecology and Obstetrics system) were randomized 1:1 to the treatment regimens. The CRT was identical in the 2 arms. Pembrolizumab was administered every 3 weeks for 3 doses; no maintenance was allowed. All patients receiving any treatment were evaluated for safety. Safety assessments included the incidence and severity of adverse events (AEs) and the occurrence of protocol-defined dose-limiting toxicity (DLT) through 30 days after the last pembrolizumab infusion., Results: As of August 2019, 52 of the 88 planned patients had completed treatment and were evaluable for toxicity. Treatment-related grade 2 or higher toxicity was experienced by 88%; 11 had at least 1 grade 4 AE, and another 23 had at least 1 grade 3 AE. Grade 1 or higher diarrhea was reported in 34 patients (65%; 50% of these were grade 1), and there was no difference between arms (63% in arm 1 vs 68% in arm 2). Two patients experienced 3 DLTs. Most patients completed cisplatin (100% in arm 1 vs 82% in arm 2); 83% in both arms completed all pembrolizumab., Conclusions: Preliminary results support the safety and feasibility of adding pembrolizumab to pelvic CRT concurrently or sequentially., Lay Summary: Pembrolizumab is a humanized antibody against programmed cell death protein 1 that is used in cancer immunotherapy. Preliminary data suggest that pembrolizumab can be safely combined with chemotherapy and pelvic radiation in the treatment of locally advanced cervical cancer. Future studies of the addition of immunotherapy to traditional chemoradiation are planned to determine the best way to deliver the treatment and whether any improvement is seen with the addition of immunotherapy to traditional therapy., (© 2020 American Cancer Society.)

Purpose: A phase I clinical trial (GOG-9929) examined the safety and efficacy of adjuvant immune-modulation therapy with the checkpoint inhibitor ipilimumab [anti-CTL antigen-4 (anti-CTLA-4)] following chemoradiation therapy (CRT) for newly diagnosed node-positive human papillomavirus (HPV)-related cervical cancer. To better understand the mechanism of action and to identify predictive biomarkers, immunologic and viral correlates were assessed before, during, and after treatment., Patients and Methods: Twenty-one patients who received CRT and ≥2 doses of ipilimumab and 5 patients who received CRT only were evaluable for translational endpoints. Circulating T-cell subsets were evaluated by multiparameter flow cytometry. Cytokines were evaluated by multiplex ELISA. HPV-specific T cells were evaluated in a subset of patients by IFNγ ELISpot., Results: Expression of the activation markers ICOS and PD-1 significantly increased on T-cell subsets following CRT and were sustained or increased following ipilimumab treatment. Combined CRT/ipilimumab treatment resulted in a significant expansion of both central and effector memory T-cell populations. Genotype-specific E6/E7-specific T-cell responses increased post-CRT in 1 of 8 HPV16 + patients and in 2 of 3 HPV18 + patients. Elevation in levels of tumor-promoting circulating cytokines (TNFα, IL6, IL8) post-CRT was significantly associated with worse progression-free survival., Conclusions: Our data indicate that CRT alone and combined with ipilimumab immunotherapy show immune-modulating activity in women with locally advanced cervical cancer and may be a promising therapeutic option for the enhancement of antitumor immune cell function after primary CRT for this population at high risk for recurrence and metastasis. Several key immune biomarkers were identified that were associated with clinical response., (©2020 American Association for Cancer Research.)

The sfRon kinase is an important therapeutic target in ovarian cancer that contributes to prominent tumor growth and disease progression. We reasoned that a multi-kinase inhibition of sfRon pathway might be an effective strategy to achieve a sustained anti-tumor response, while simultaneously preventing treatment resistance. We performed a detailed dissection of sfRon signaling in vitro and demonstrated that S6K1 is a key component of a multi-kinase targeting strategy in sfRon expressing ovarian tumors. We selected AD80 compound that targets several kinases within sfRon pathway including AKT and S6K1, and compared its efficacy with inhibitors that selectively target either sfRon or PI3 kinase. Using human ovarian xenografts and clinically relevant patient-derived xenografts (PDXs), we demonstrated that in vivo treatment with single agent AD80 shows superior efficacy to a standard-care chemotherapy (cisplatin/paclitaxel), or to the direct inhibition of sfRon kinase by BMS777607. Our findings indicate that ovarian tumors expressing sfRon are most effectively treated with multi-kinase inhibitors simultaneously targeting AKT and S6K1, such as AD80, which results in long-term anti-tumor response and prevents metastasis development., Competing Interests: CONFLICT OF INTEREST All authors declare that they have no conflicts of interest., (Copyright: © 2020 Wang et al.)

Background: Stage III or IVA endometrial cancer carries a significant risk of systemic and locoregional recurrence., Methods: In this randomized phase 3 trial, we tested whether 6 months of platinum-based chemotherapy plus radiation therapy (chemoradiotherapy) is associated with longer relapse-free survival (primary end point) than six cycles of combination chemotherapy alone in patients with stage III or IVA endometrial carcinoma. Secondary end points included overall survival, acute and chronic toxic effects, and quality of life., Results: Of the 813 patients enrolled, 736 were eligible and were included in the analysis of relapse-free survival; of those patients, 707 received the randomly assigned intervention (346 received chemoradiotherapy and 361 received chemotherapy only). The median follow-up period was 47 months. At 60 months, the Kaplan-Meier estimate of the percentage of patients alive and relapse-free was 59% (95% confidence interval [CI], 53 to 65) in the chemoradiotherapy group and 58% (95% CI, 53 to 64) in the chemotherapy-only group (hazard ratio, 0.90; 90% CI, 0.74 to 1.10). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%; hazard ratio, 0.36; 95% CI, 0.16 to 0.82) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%; hazard ratio, 0.43; 95% CI, 0.28 to 0.66) than chemotherapy alone, but distant recurrence was more common in association with chemoradiotherapy (27% vs. 21%; hazard ratio, 1.36; 95% CI, 1.00 to 1.86). Grade 3, 4, or 5 adverse events were reported in 202 patients (58%) in the chemoradiotherapy group and 227 patients (63%) in the chemotherapy-only group., Conclusions: Chemotherapy plus radiation was not associated with longer relapse-free survival than chemotherapy alone in patients with stage III or IVA endometrial carcinoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00942357.)., (Copyright © 2019 Massachusetts Medical Society.)

Cancer-associated fibroblasts (CAFs) play a critical role in cancer progression, metastasis, and therapy resistance. Molecular events that confer CAF-phenotype to predecessor-cells are not fully understood. We demonstrate here that the ovarian cancer cell-conditioned medium (OCC-CM) induces CAF-phenotype in MRC5 lung-fibroblasts and it can be mimicked by LPA. While OCC-CM and LPA stimulated the expression of cellular CAF-markers by 3-days, they induced aerobic glycolysis, a metabolic marker for CAF, by 6 hrs. OCC-CM/LPA-induced glycolysis in lung (MRC5) as well as ovarian fibroblasts (NOF151) was inhibited by the LPA-receptor antagonist, Ki16425. Ovarian cancer patient-derived ascitic fluid-induced aerobic glycolysis in both NFs and Ovarian CAFs and it was inhibited by Ki16425. Further analysis indicated that LPA upregulated HIF1α-levels and the silencing of HIF1α attenuated LPA-induced glycolysis in both NOFs and CAFs. These results establish LPA-induced glycolytic-shift as the earliest, potentially priming event, in NF to CAF-transition. These findings also identify a role for LPA-LPAR-HIF1α signaling-hub in the maintenance of the glycolytic-phenotype in CAFs. Our results provide evidence that targeted inhibition of LPA-mediated metabolic reprogramming in CAFs may represent an adjuvant therapy in ovarian cancer., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The tumor-stroma ratio (TSR) reflected on hematoxylin and eosin (H&E)-stained histological images is a potential prognostic factor for survival. Automatic image processing techniques that allow for high-throughput and precise discrimination of tumor epithelium and stroma are required to elevate the prognostic significance of the TSR. As a variant of deep learning techniques, transfer learning leverages nature-images features learned by deep convolutional neural networks (CNNs) to relieve the requirement of deep CNNs for immense sample size when handling biomedical classification problems. Herein we studied different transfer learning strategies for accurately distinguishing epithelial and stromal regions of H&E-stained histological images acquired from either breast or ovarian cancer tissue. We compared the performance of important deep CNNs as either a feature extractor or as an architecture for fine-tuning with target images. Moreover, we addressed the current contradictory issue about whether the higher-level features would generalize worse than lower-level ones because they are more specific to the source-image domain. Under our experimental setting, the transfer learning approach achieved an accuracy of 90.2 (vs. 91.1 for fine tuning) with GoogLeNet, suggesting the feasibility of using it in assisting pathology-based binary classification problems. Our results also show that the superiority of the lower-level or the higher-level features over the other ones was determined by the architecture of deep CNNs.

Objective: Preclinical data suggest elesclomol increases oxidative stress and enhances sensitivity to cytotoxic agents. The objective of this prospective multicenter phase 2 trial was to estimate the activity of IV elesclomol plus weekly paclitaxel in patients with platinum-resistant recurrent ovarian, tubal or peritoneal cancer through the frequency of objective tumor responses (ORR)., Methods: Patients with measurable disease, acceptable organ function, performance status ≤ 2, and one prior platinum containing regimen were eligible. A two-stage design was utilized with a target sample size of 22 and 30 subjects, respectively. Prior Gynecologic Oncology Group studies within the same population involving single agent taxanes showed an ORR of approximately (20%) and served as a historical control for direct comparison. The present study was designed to determine if the regimen had an ORR of ≥40% with 90% power., Results: Fifty-eight patients were enrolled, of whom 2 received no study treatment and were inevaluable. The median number of cycles was 3 (268 total cycles, range 1-18). The number of patients responding was 11 (19.6%; 90% CI 11.4% to 30.4%) with one complete response. The median progression-free survival and overall survival was 3.6 months and 13.3 months, respectively. The median ORR duration was 9.2 months. Percentages of subjects with grade 3 toxicity included: Neutropenia 9%; anemia 5%; metabolic 5%; nausea 4%; infection 4%; neurologic (mostly neuropathy) 4%; and vascular (mostly thromboembolism) 4%. There were no grade 4 toxicities reported., Conclusions: This combination was well tolerated but is unworthy of further investigation based on the proportion responding [ClinicalTrials.gov Identifier: NCT00888615]., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: We conducted a randomized phase III trial to determine whether adjuvant chemotherapy improves survival in women with uterine leiomyosarcoma., Methods: Women with uterus-confined, high-grade leiomyosarcoma who were confirmed disease free by imaging were randomly assigned to four cycles of gemcitabine plus docetaxel, followed by four cycles of doxorubicin, or to observation. All were followed for evidence of recurrence. The primary end point was overall survival (OS)., Results: With international collaboration, 38 of the targeted accrual of 216 patients were enrolled, after which the study was closed by the National Cancer Institute for accrual futility. Twenty patients were assigned to chemotherapy, 18 to observation. Among the 17 patients treated with at least one cycle of chemotherapy, grade 3 or 4 toxicities were observed in 47%; among the 18 patients assigned to observation, one had grade 3 hypertension. There were six deaths (chemotherapy, n = 5; observation, n = 1), all due to disease. The restricted mean survival time for OS was estimated as 34.3 months (95% CI, 25.3 to 43.3 months) in the chemotherapy arm and as 46.4 months (95% CI, 43.6 to 49.1 months) in the observation arm. There were eight recurrences in each arm. The restricted mean survival time for recurrence-free survival was estimated as 18.1 (95% CI, 14.2 to 22.0) months in the chemotherapy arm and as 14.6 months (95% CI, 10.3 to 19.0 months) in the observation arm. Neither survival outcome comparison was considered statistically robust, due to the small sample size., Conclusion: Despite international collaboration to test the role of adjuvant chemotherapy in uterine-confined leiomyosarcoma, this study was closed for accrual futility. Although the sample size precludes robust statistical comparison, observed OS and recurrence-free survival data do not show superior outcomes with adjuvant chemotherapy.

Rationale and Objectives: The study aimed to investigate the role of applying quantitative image features computed from computed tomography (CT) images for early prediction of tumor response to chemotherapy in the clinical trials for treating ovarian cancer patients., Materials and Methods: A dataset involving 91 patients was retrospectively assembled. Each patient had two sets of pre- and post-therapy CT images. A computer-aided detection scheme was applied to segment metastatic tumors previously tracked by radiologists on CT images and computed image features. Two initial feature pools were built using image features computed from pre-therapy CT images only and image feature difference computed from both pre- and post-therapy images. A feature selection method was applied to select optimal features, and an equal-weighted fusion method was used to generate a new quantitative imaging marker from each pool to predict 6-month progression-free survival. The prediction accuracy between quantitative imaging markers and the Response Evaluation Criteria in Solid Tumors (RECIST) criteria was also compared., Results: The highest areas under the receiver operating characteristic curve are 0.684 ± 0.056 and 0.771 ± 0.050 when using a single image feature computed from pre-therapy CT images and feature difference computed from pre- and post-therapy CT images, respectively. Using two corresponding fusion-based image markers, the areas under the receiver operating characteristic curve significantly increased to 0.810 ± 0.045 and 0.829 ± 0.043 (P < 0.05), respectively. Overall prediction accuracy levels are 71.4%, 80.2%, and 74.7% when using two imaging markers and RECIST, respectively., Conclusions: This study demonstrated the feasibility of predicting patients' response to chemotherapy using quantitative imaging markers computed from pre-therapy CT images. However, using image feature difference computed between pre- and post-therapy CT images yielded higher prediction accuracy., (Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Objective: To assess whether the addition of oncolytic reovirus (Reolysin®) to weekly paclitaxel prolonged progression-free survival (PFS) in the treatment of women with recurrent or persistent ovarian, tubal or primary peritoneal cancer., Patients and Methods: Patients with recurrent or persistent epithelial ovarian, tubal, or peritoneal carcinoma, measurable or detectable disease, and three or fewer prior regimens were randomly assigned to paclitaxel (80mg/m 2 intravenously days 1, 8, and 15 every 4weeks) or the combination of paclitaxel (80mg/m 2 intravenously days 1, 8, and 15) plus reovirus 3×10 10 TCID 50 /day intravenously on days 1-5, both every 4weeks until disease progression or toxicity. The primary end point was PFS. The study was designed with 80% power for a one-sided alternative at a 10% level of significance to detect a reduction in the hazard by 37.5%., Results: The study accrued 108 patients, 100 of whom were evaluable for toxicity. Median PFS was 4.3months for paclitaxel and 4.4months for paclitaxel plus reovirus (hazard ratio, 1.11; 90% two-sided CI, 0.78 to 1.59; one-sided P=0.687). The proportion responding (overall response rate) to paclitaxel was 20% among 45 patients with measurable disease receiving paclitaxel alone, and 17.4% among the 46 patients treated with the combination. The asymptotic relative probability of responding was 0.87 (90% CI, 0.42 to 1.79). Severe adverse events were more common in the combination regimen than in paclitaxel arm for severe neutropenia (grade≥4, 12% versus 0%), and severe respiratory adverse events (grade≥3, 25% versus 2%). No deaths were considered treatment related., Conclusion: The addition of reovirus to weekly paclitaxel in the treatment of women with recurrent or persistent ovarian, tubal or peritoneal cancer did not sufficiently reduce the hazard of progression or death to warrant further investigation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

With the goal of identifying diagnostic and prognostic biomarkers in endometrial cancer, miRNA-profiling was carried out with formalin-fixed paraffin embedded (FFPE) tissue samples from 49 endometrial cancer patients. Results using an 84-cancer specific miRNA panel identified the upregulation of miR-141-3p and miR-96-5p along with a downregulation of miR-26, miR-126-3p, miR-23b, miR-195-5p, miR-374a and let-7 family of miRNAs in endometrial cancer. We validated the dysregulated expression of the identified miRNAs in a panel of endometrial cancer cell-lines. Immunohistochemical analysis of the tissue micro array derived from these patients established the functional correlation between the decreased expression of tumor suppressive miRNAs and their target oncogenes: ERBB2, EGFR, EPHA2, BAX, GNA12, GNA13, and JUN. Comparative analysis of the samples from the patients with extended progression-free survival (PFS) ( > 21 months) versus the patients with the PFS of < 21 months indicated increased expression of tumor suppressive miR-142-3p, miR-142-5p, and miR-15a-5p in samples from extended PFS patients. In addition to defining a specific set of miRNAs and their target genes as potential diagnostic biomarkers, our studies have identified tumor suppressive miR-142 cluster and miR-15a as predictors of favorable prognosis for therapy response in endometrial cancer., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflict of interest.

Purpose To assess the diagnostic accuracy of fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with diagnostic contrast material-enhanced computed tomography (CT) in detecting lymph node (LN) metastasis in high-risk endometrial cancer. Materials and Methods This prospective multicenter HIPAA-compliant study had institutional review board approval, and all participants gave written informed consent. Data were accrued between January 2010 and June 2013. Patients underwent PET/CT and pelvic and abdominal lymphadenectomy. Two hundred seven of 215 enrolled patients had PET/CT and pathologic examination results for the abdomen and pelvis. Mean patient age was 62.7 years ± 9.6 (standard deviation). Data in all 23 patients with a positive abdominal examination and in 26 randomly selected patients with a negative abdominal examination were used for this central reader study. Seven independent blinded readers reviewed diagnostic CT and PET/CT results in different sessions 1 month apart. Accuracy was calculated at the participant level, correlating abdominal (right and left para-aortic and common iliac) and pelvic (right and left external iliac and obturator) LN regions with pathologic results, respecting laterality. Reader-average sensitivities, specificities, and areas under the receiver operating characteristic curve (AUCs) of PET/CT and diagnostic CT were compared. Power calculation was for sensitivity and specificity in the abdomen. Results Sensitivities of PET/CT versus diagnostic CT for the detection of LN metastasis were 0.65 (95% confidence interval [CI]: 0.57, 0.72) versus 0.50 (95% CI: 0.43, 0.58) (P = .01) in the abdomen and 0.65 (95% CI: 0.57, 0.72) versus 0.48 (95% CI: 0.41, 0.56) (P = .004) in the pelvis. Corresponding specificities were 0.88 (95% CI: 0.83, 0.92) versus 0.93 (95% CI: 0.89, 0.96) (P = .11) and 0.93 (95% CI: 0.86, 0.96) versus 0.89 (95% CI: 0.82, 0.94) (P = .27), and AUCs were 0.78 (95% CI: 0.66, 0.89) versus 0.74 (95% CI: 0.63, 0.86) (P = .39) and 0.82 (95% CI: 0.71, 0.92) versus 0.73 (95% CI: 0.63, 0.84) (P = .02). Conclusion FDG PET/CT has satisfactory diagnostic accuracy in the detection of abdominal LN metastasis in high-risk endometrial cancer. Compared with diagnostic CT alone, addition of PET to diagnostic CT significantly increased sensitivity in both the abdomen and pelvis while maintaining high specificity. © RSNA, 2017 Online supplemental material is available for this article.

Background: The polycomb group protein, BMI1 plays important roles in chromatin modification, stem cell function, DNA damage repair and mitochondrial bioenergetics. Such diverse cellular functions of BMI1 could be, in part, due to post-translational modifications, especially phosphorylation. To date, AKT has been reported as a kinase that by site specific phosphorylation of BMI1 modulates its oncogenic functions., Methods: Immunoprecipitation in conjunction with kinase assay and mass spectrometry was used to determine association with and site specific phosphorylation of BMI1 by CK2α. Functional implications of the BMI1/CK2α axis was examined in cancer cells utilizing siRNA and exogenous gene expression followed by biochemical and phenotypic studies. Correlations between expression of CK2α and BMI1 were determined from cell lines and formalin fixed paraffin embedded tissues representing the normal fallopian tube epithelium and high grade serous ovarian cancer samples., Results: Here we report that CK2α, a nuclear serine threonine kinase, phosphorylates BMI1 at Serine 110 as determined by in-vitro/ex-vivo kinase assay and mass spectrometry. In ovarian cancer cell lines, expression of CK2α correlated with the phospho-species, as well as basal BMI1 levels. Preventing phosphorylation of BMI1 at Serine 110 significantly decreased half-life and stability of the protein. Additionally, re-expression of the phosphorylatable but not non-phosphorylatable BMI1 rescued clonal growth in endogenous BMI1 silenced cancer cells leading us to speculate that CK2α-mediated phosphorylation stabilizes BMI1 and promotes its oncogenic function. Clinically, compared to normal fallopian tube epithelial tissues, the expression of both BMI1 and CK2α were significantly higher in tumor tissues obtained from high-grade serous ovarian cancer patients. Among tumor samples, the expression of BMI1 and CK2α positively correlated (Spearman coefficient = 0.62, P = 0.0021) with each other., Conclusion: Taken together, our findings establish an important regulatory role of CK2α on BMI1 phosphorylation and stability and implicate the CK2α/BMI1 axis in ovarian cancer.

Objectives: Surgery is a cornerstone for patients with gynecologic malignancies. Surgical site infections (SSI) remain a source of post-operative morbidity. Consequences range from escalated costs, delay in adjuvant therapy, and increased morbidity. Our primary objective was to evaluate the effectiveness of a cyanoacrylate microbial sealant (CMS) to reduce post-operative SSI following laparotomy for suspected gynecologic malignancy., Methods: Patients were randomized using a 1:1 allocation to receive either standard skin preparation or standard preparation with CMS and stratified by BMI. Patients were followed for 6weeks for SSI. Demographic data was collected through the EMR. Associations between SSI, use of CMS, and clinicopathologic factors were explored using descriptive statistics, chi-square and multivariate analysis., Results: 300 patients underwent randomization. Median age of the cohort was 58. Arms were matched and there was no difference in rate of medical comorbidities. Mean BMI was 38.8kg/m 2 in patients randomized to BMI≥30 and 26.3kg/m 2 randomized to BMI<30. Surgical characteristics for the entire cohort: 66% malignancy, 91% clean-contaminated, 21% bowel surgery, 25% transfusion. Seventy-six (25%) patients developed a SSI: 43 patients (28%) treated with CMS, compared to 33 (21%) patients treated without CMS (p=0.18). Multivariate model demonstrated that BMI≥30 (p<0.005), surgery for malignancy (p=0.010), transfusion in the OR (p<0.001), and closure with staples (p=0.0005) were associated with post-operative SSI., Conclusions: Patients presenting to a gynecologic oncologist for surgery frequently present with multiple risk factors for SSI and laparotomy is complicated by surgical-site complications in up to 30% of cases. The addition of CMS alone does not appear to reduce risk of overall SSI. Additional risk-reducing strategies including use of antimicrobial agents and optimization of modifiable risk factors prior to surgery should be explored as pathways for reducing this significant post-operative morbidity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The bottleneck in current vector-based cancer therapy is the targeted and controlled release of therapeutics in tumors. Exosomes are submicron-sized vesicles that are secreted by all cell types and are involved in communication and transportation of materials between cells. Analogous in size and function to synthetic nanoparticles, exosomes offer many advantages, rendering them the most promising candidates for targeted drug or gene delivery vehicles. Patient-specific customized therapeutic strategies can be engineered using exosomes derived from the patient's own healthy cells. Therefore, exosome-based cancer therapy has the potential to become an important part of personalized medicine. Interest in exosomes as carrier organelles is relatively recent. Knowledge about exosomal biology and its applications remains limited. The present review is an attempt to describe the current status of the application of exosomes to cancer therapy and the potential challenges associated with their use.

Short-form Ron (sfRon) is an understudied, alternative isoform of the full-length Ron receptor tyrosine kinase. In contrast to Ron, which has been shown to be an important player in many cancers, little is known about the role of sfRon in cancer pathogenesis. Here we report the striking discovery that sfRon expression is required for development of carcinogen-induced malignant ovarian tumors in mice. We also show that sfRon is expressed in several subtypes of human ovarian cancer including high-grade serous carcinomas, which is in contrast to no detectable expression in healthy ovaries. In addition, we report that introduction of sfRon into OVCAR3 cells resulted in epithelial-to-mesenchymal transition, activation of the PI3K and PDK1 pathway, and inhibition of the MAPK pathway. We demonstrated that sfRon confers an aggressive cancer phenotype in vitro characterized by increased proliferation and migration, and decreased adhesion of ovarian cancer cells. Moreover, the in vivo studies show that OVCAR3 tumors expressing sfRon exhibit significantly more robust growth and spreading to the abdominal cavity when compared with the parental sfRon negative OVCAR3 cells. These data suggest that sfRon plays a significant role in ovarian cancer initiation and progression, and may represent a promising therapeutic target for ovarian cancer treatment.

The success in recent clinical trials using T cell receptor (TCR)-genetically engineered T cells to treat melanoma has encouraged the use of this approach toward other malignancies and viral infections. Although hepatitis C virus (HCV) infection is being treated with a new set of successful direct anti-viral agents, potential for virologic breakthrough or relapse by immune escape variants remains. Additionally, many HCV+ patients have HCV-associated disease, including hepatocellular carcinoma (HCC), which does not respond to these novel drugs. Further exploration of other approaches to address HCV infection and its associated disease are highly warranted. Here, we demonstrate the therapeutic potential of PBL-derived T cells genetically engineered with a high-affinity, HLA-A2-restricted, HCV NS3:1406-1415-reactive TCR. HCV1406 TCR-transduced T cells can recognize naturally processed antigen and elicit CD8-independent recognition of both peptide-loaded targets and HCV+ human HCC cell lines. Furthermore, these cells can mediate regression of established HCV+ HCC in vivo. Our results suggest that HCV TCR-engineered antigen-reactive T cells may be a plausible immunotherapy option to treat HCV-associated malignancies, such as HCC.

The ability to genetically modify T cells is a critical component to many immunotherapeutic strategies and research studies. However, the success of these approaches is often limited by transduction efficiency. As retroviral vectors require cell division for integration, transduction efficiency is dependent on the appropriate activation and culture conditions for T cells. Naive CD8(+) T cells, which are quiescent, must be first activated to induce cell division to allow genetic modification. To optimize this process, we activated mouse T cells with a panel of different cytokines, including interleukin-2 (IL-2), IL-4, IL-6, IL-7, IL-12, IL-15 and IL-23, known to act on T cells. After activation, cytokines were removed, and activated T cells were retrovirally transduced. We found that IL-12 preconditioning of mouse T cells greatly enhanced transduction efficiency, while preserving function and expansion potential. We also observed a similar transduction-enhancing effect of IL-12 preconditioning on human T cells. These findings provide a simple method to improve the transduction efficiencies of CD8(+) T cells.

Exosomes are 30-100 nm bodies secreted from almost all types of cells into the extracellular spaces. They enclose in their lumen active genetic information in the form of messenger RNA (mRNA), micro RNA (miRNA), DNA and active peptides that are representative of the parental cell and can be isolated from different body fluids. Exosomes can participate in inter-cellular communication by trafficking molecules to their target cells. Because they can stably carry cargo including miRNA, mRNA, and proteins and can pass through stringent biological barriers (e.g., blood brain barrier) without eliciting an immune response, they are considered as an ideal acellular vehicle for drug delivery. In this review, we describe the structure and biogenesis of exosomes and new directions related to their role in diagnosis and treatment of diseases, especially for cancer. We also discuss potential challenges associated with exosomes that should be addressed before exosome-based therapy can be applied to clinical settings.

Objective: Carcinosarcomas of the female genital tract, also called malignant mixed müllerian tumors, are aggressive biphasic tumors. Second-line treatment options in the recurrent/persistent setting have yielded marginal responses. Given the potential role of angiogenesis in the gynecological carcinomas, pazopanib, a VEGFR inhibitor, was investigated in the management of patients with recurrent carcinosarcoma of the uterus., Methods: Eligible patients had histologically confirmed carcinosarcoma of the uterus, a maximum of two prior lines of therapy, adequate renal, hepatic and hematologic function and a performance status of 0-2. Pazopanib was administered orally at 800mg. Two dose reductions were allowed. The primary objective was to ascertain the activity of pazopanib as measured by the proportion of patients who survive progression-free for at least six months and the proportion of patients that have objective tumor responses. Secondary objectives included the frequency and severity of adverse events as assessed by CTCAE v4.0., Results: Of the 22 enrolled patients, 19 were eligible and evaluable for toxicity and survival. No patients had a partial or complete response (90% confidence interval [CI]: 0%, 14.6%). Three patients (15.8%) had PFS ≥6months (90% CI: 4.4%, 35.9%). The median PFS was 2.0months (first and third quartiles were 1.6 and 4.0months, respectively). The median overall survival was 8.7months (first and third quartiles were 2.6 and 14.0months, respectively)., Conclusion: Pazopanib demonstrated minimal activity as a second or third line treatment for advanced uterine carcinosarcoma. Potential clinical trial participation should be discussed with the patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: This study aims to assess the role of polymorphisms in DNA repair genes, excision repair cross-complementation group 1 (ERCC1) and methyl-methanesulfonate sensitivity 19 (MMS19), in tumor response to platinum-based chemotherapy and survival in advanced epithelial ovarian cancer (EOC)., Methods: Single nucleotide polymorphism (SNP) analysis was performed on the paraffin-embedded tumor tissue of women with advanced EOC, treated with platinum-based chemotherapy at the University of Oklahoma Health Sciences Center. Polymorphisms from two ERCC1 (codon-118 and C8092A) and three MMS19 (rs2211243, rs2236575 and rs872106) gene loci were evaluated by real time PCR Allelic Discrimination Assay., Results: Genotyping was performed in 107 patients, 45 platinum-sensitive and 62 platinum-resistant. ERCC1, codon-118 and C8092A genotyping was evaluable in 98 and 106 patients respectively and in all 107 patients for MMS19 polymorphisms. No differences were observed in genotype between platinum-sensitive and platinum-resistant patients. Polymorphisms in the ERCC1, codon-118 and MMS19 genes did not correlate with overall survival (OS), although a trend toward improved progression free survival (PFS) was observed in patients expressing the minor (GG) alleles of the rs872106 MMS19 gene. Women homozygous for the ERCC1-C8092A minor (AA) alleles had a significant increase in PFS compared to AC and CC patients and both AA and AC genotypes conferred improved survival over the major (CC) genotype., Conclusions: Polymorphisms in ERCC1, codon-118 and MMS19 genes are not associated with clinical response to platinum or survival. The ERCC1-C8092A genotypes containing an "A" allele were associated with significant improvement in PFS and OS strengthening the value of this specific genotype in survival., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Infrequent Pap screening is an important risk factor for cervical cancer. We studied the association between contraceptive methods, screening frequency, and cancer., Methods: Women (n=2004) enrolled in the cross-sectional Study to Understand Cervical Cancer Endpoints and Determinants (SUCCEED) underwent colposcopy to evaluate an abnormal Pap test. Questionnaire data were compared between those with cervical intraepithelial neoplasia (CIN) 3/adenocarcinoma in situ (AIS) and those with invasive cancer to identify factors associated with cancer. Logistic regression was used to calculate age-stratified measures of association between contraceptive method and Pap frequency as well as tubal ligation (TL) and cancer risk., Results: In all age groups, women with TL were more likely to have had no Pap screening in the previous 5 years compared to women using other contraception: 26-35 years (OR 4.6, 95% CI 2.4-8.6; p<0.001), 36-45 years (OR 3.8, 95% CI 2.1-7.0; p<0.001), and 46-55 years (OR 2.2, 95% CI 1.0-4.9; p=0.050). Subjects with cancer (n=163) were more likely to have had a TL (41% vs. 21%, p<0.001) than those with CIN 3/AIS (n=370). Age-stratified analyses showed increased odds of tubal ligation in women with cancer versus those with CIN 3/AIS between 25 and 45 years, with a significant increase in women 26 to 35 years old (OR 3.3, 95% CI 1.4-8.1; p=0.009). Adjusting for Pap frequency changed the effect only slightly, suggesting that increased risk was not fully mediated by lack of screening., Conclusion: Contraceptive type is associated with Pap screening. Women with TLs obtain less frequent Pap testing and may be at an increased risk for cervical cancer., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: Controversy continues over the importance of lymph node (LN) status in treating and predicting recurrence in endometrial cancer. Several predictive models are available which use uterine factors to stratify risk groups. Our objective was to determine how LN status affects recurrence and survival compared to uterine factors alone., Methods: A retrospective review was performed of patients undergoing complete surgical staging for clinical stage 1 endometrioid adenocarcinoma of the uterus. Patients were assessed based on PORTEC 1 high intermediate risk (H-IR) criteria (2 factors : age>60, grade 3, >50% DOI), GOG-99 H-IR criteria (age >70+1 factor, age 50-70+2 factors, any age +3 factors: grade 2 or 3, LVSI, >50% DOI), and PORTEC 2 criteria. Rates of nodal involvement, recurrence rates, PFS, and OS were compared., Results: We identified 352 clinical stage I patients with positive LN in 24% (87). 175 patients met PORTEC 1 eligibility and 66 met H-IR criteria. Rates of LN positivity were similar among groups (18.4% vs 19.7%, p=0.83) but recurrence rates were dissimilar (7.4% vs 27.3%, p=0.0004). Only 93 met PORTEC 2 criteria for treatment with no association between LN status, recurrence, and eligibility. 188 patients met H-IR eligibility criteria for GOG-99 with LN positive and recurrence rates higher in the H-IR group compared to GOG-99 eligible (34.6% vs 16.3%, p=0.0004, 28.3% vs. 10.6%, p=0.0002)., Conclusions: Patients with H-IR disease based on uterine characteristics alone have substantial risk of nodal involvement. Knowledge of LN status may better define risk, prognosis, and postoperative treatment., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To determine the prognostic significance of the 2002 revisions of the American Joint Committee on Cancer (AJCC) Staging System for cutaneous melanoma in melanoma of the vulva and review the current surgical utilized for treatment of this neoplasm., Methods: Demographic, surgical and outcomes data were obtained from the records of vulvar melanoma patients treated from 1990 to 2006 at five academic medical centers. The 2002 modifications of the AJCC staging system for cutaneous melanoma, Breslow thickness and Clark level, were applied to all subjects. Kaplan-Meier Modeling and Linear Regression analysis were utilized for data analysis. Statistics were performed with SAS v 9.1., Results: Seventy-seven patients were identified with a median age of 62 years. 73% had Stage I/II disease. Surgical radicality did not impact recurrence rates or survival. Breslow thickness was associated with recurrence (p=0.002) but not survival. Only the 2002 modified AJCC staging criteria were predictive of overall survival (p=0.006) in patients with malignant melanoma of the vulva., Conclusions: In the largest multi-site series of vulvar melanoma, the AJCC-2002 staging system for cutaneous malignant melanoma appears to be applicable to primary vulvar melanoma. Moreover, surgical radicality was associated with significant morbidity but not with improvement in survival. Utilization of standard operative staging and resection principles in cutaneous melanoma should be used for all vulvar melanoma patients. Moreover, these patients should also be considered for enrollment in cutaneous melanoma clinical trials., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Hepatitis C Virus (HCV) is a major public health concern, with no effective vaccines currently available and 3% of the world's population being infected. Despite the existence of both B- and T-cell immunity in HCV-infected patients, chronic viral infection and HCV-related malignancies progress. Here we report the identification of a novel HCV TCR from an HLA-A2-restricted, HCV NS3:1073-1081-reactive CTL clone isolated from a patient with chronic HCV infection. We characterized this HCV TCR by expressing it in human T cells and analyzed the function of the resulting HCV TCR-transduced cells. Our results indicate that both the HCV TCR-transduced CD4(+) and CD8(+) T cells recognized the HCV NS3:1073-1081 peptide-loaded targets and HCV(+) hepatocellular carcinoma cells (HCC) in a polyfunctional manner with cytokine (IFN-gamma, IL-2, and TNF-alpha) production as well as cytotoxicity. Tumor cell recognition by HCV TCR transduced CD8(-) Jurkat cells and CD4(+) PBL-derived T cells indicated this TCR was CD8-independent, a property consistent with other high affinity TCRs. HCV TCR-transduced T cells may be promising for the treatment of patients with chronic HCV infections.

Cytosolic 10-formyltetrahydrofolate dehydrogenase (FDH, ALDH1L1) is an abundant enzyme of folate metabolism. It converts 10-formyltetrahydrofolate to tetrahydrofolate and CO(2) in an NADP(+)-dependent reaction. We have identified a gene at chromosome locus 12q24.11 of the human genome, the product of which has 74% sequence similarity with cytosolic FDH. This protein has an extra N-terminal sequence of 22 amino acid residues, predicted to be a mitochondrial translocation signal. Transfection of COS-7 or A549 cell lines with a construct in which green fluorescent protein was introduced between the leader sequence and the rest of the putative mitochondrial FDH (mtFDH) has demonstrated mitochondrial localization of the fusion protein, suggesting that the identified gene encodes a mitochondrial enzyme. Purified pig liver mtFDH displayed dehydrogenase/hydrolase activities similar to cytosolic FDH. Real-time PCR performed on an array of human tissues has shown that although cytosolic FDH mRNA is highest in liver, kidney, and pancreas, mtFDH mRNA is most highly expressed in pancreas, heart, and brain. In contrast to the cytosolic enzyme, which is not detectable in cancer cells, the presence of mtFDH was demonstrated in several human cancer cell lines by conventional and real-time PCR and by Western blot. Analysis of genomes of different species indicates that the mitochondrial enzyme is a later evolutionary product when compared with the cytosolic enzyme. We propose that this novel mitochondrial enzyme is a likely source of CO(2) production from 10-formyltetrahydrofolate in mitochondria and plays an essential role in the distribution of one-carbon groups between the cytosolic and mitochondrial compartments of the cell.

Adenocarcinoma of the endometrium represents the most common gynecologic malignancy in developed countries. Although early-stage cancers are effectively treated surgically, commonly without adjuvant therapy, the treatment of high-risk and advanced disease is more complex. Chemotherapy has evolved into an important modality in high-risk early-stage and advanced-stage disease, and in recurrent endometrial cancer. Taxane-based therapy consistently demonstrates the highest response rates in the first-line and salvage settings of endometrial cancer. Unfortunately, response to chemotherapy is modest and strategies are needed to predict chemotherapy-responsive and chemotherapy-resistant populations. Chemotherapy resistance mediated by overexpression of drug efflux pump proteins and mutations in β-tubulin isoforms in both primary and recurrent disease represent unique treatment challenges and highlight the need for new agents that are less susceptible to these known resistance pathways. Epothilone B analogs are novel cytotoxic agents with activity in solid tumors, including advanced/recurrent endometrial carcinoma, and may have unique properties that can overcome resistance in some settings. These agents alone and in combination represent a new therapeutic opportunity in endometrial carcinoma.

Objective: To assess the abilities of cisplatin, paclitaxel, and flexible heteroarotinoid (Flex-Het) compound (SHetA2) to sensitize ovarian cancer cells to induction of the extrinsic apoptosis pathway by death receptor ligands, tumor necrosis factor alpha (TNFalpha), and TNF-related apoptosis-inducing ligand (TRAIL)., Study Design: The effects of various combinations of TNFalpha, TRAIL, cisplatin, paclitaxel, and SHetA2 on viability and apoptosis in two established ovarian cancer cell lines, A2780 and SK-OV-3, and normal human primary endometrial cultures were measured with a cytotoxicity assay, flow cytometric analysis of annexin-V, and propidium iodide staining and Western blot analysis of caspase 8 and 3 activation., Results: Ovarian cancer and normal cells were resistant to TNFalpha and TRAIL. Cisplatin and paclitaxel did not increase sensitivity to these agents in either cell type. In contrast, combination of SHetA2 with TNFalpha or TRAIL induced a synergistic induction of apoptosis in cancer cells that involved activation of the extrinsic pathway caspase 8 and executioner caspase 3. The TRAIL combination was more potent than the TNFalpha combination. SHetA2 did not harm the viability of normal cells as a single agent or in combination with the death receptor ligands., Conclusions: SHetA2, but not cisplatin or paclitaxel, can overcome resistance of ovarian cancer cells to TNFalpha and TRAIL without increasing sensitivity of normal cells to these death receptor ligands.

Objective: The cornerstone of therapy for advanced ovarian cancer is cytoreductive surgery (CRS) followed by platinum based chemotherapy. Optimal management for very elderly women (>80) is unclear. This study sought to review the experience with treating ovarian cancer in this population., Materials and Methods: This is a retrospective analysis of patients treated between 1991 and 2006. Outcomes included post-operative complications, chemotherapy received and overall survival. Statistical analysis was performed with SAS v.9.1., Results: 85 patients were identified with a mean age of 84 years. 86% of patients presented with advanced disease. Primary CRS was performed on 80%. Among patients with advanced disease who underwent either primary (68) or interval debulking (2), 74% were left with <1 cm residual disease. Post-operative complications were common with 15% of patients suffering cardiac or pulmonary complications, over 10% with prolonged ileus, wound complications or mental status changes and over 30% requiring transfusion or antibiotics. Death prior to hospital discharge and within 60 days of surgery occurred in 13% and 20%. Among patients who underwent CRS, 13% were unable to receive indicated adjuvant therapy. Among those who were treated, 25% were treated with single agent platinum and 43% completed <3 cycles. Two-year overall survival for those who underwent CRS followed by adjuvant therapy is 51%., Conclusions: Our data suggests that patients >80 may not tolerate combination surgery and chemotherapy. The extremely high proportion of post-operative complications and relatively high proportion of post-operative deaths argues for a more prudent approach to this group of patients.

Objective: Primary carcinoma of the fallopian tube (PCFT) is a rare malignancy comprising 1% of genital tract cancers. We sought to compare survival trends between PCFT and ovarian carcinoma (OC) patients (pts) in a matched, case-control comparison., Materials and Methods: Patients with PCFT were identified from five academic centers. Two OC controls were identified for each PCFT pt based on age, stage, and residual disease. All pts were surgically staged and treated with platinum based chemotherapy (CT) if indicated. PFS and OS were then compared with Kaplan-Meier analysis., Results: 96 PCFT cases and 189 OC controls were identified. 50 early stage PCFT were matched with 97 OC pts. The most common CT regimen was carboplatinum and paclitaxel in 84 and 86% respectively. Median follow-up was 57 and 42 months for the PCFT and OC groups and 5-year overall survival (OS) differed at 95% and 76% (p=0.02). 46 Stage III/IV PCFT pts were matched with 92 OC controls. 88.5% were optimally debulked. Median follow-up was 33 and 35 months for PCFT and OC pts and 3-year overall survival was 59% for both groups., Conclusions: This is the first study to compare outcomes for PCFT and OC in a matched, case-control comparison. Our study demonstrates that, for advanced stage PCFT, a similar survival outcome is obtained compared to OC patients. This should reassure clinicians that treatment of PCFT should mirror that of OC and that PCFT should be included in clinical trials.