Publications by authors named "Thomas Herzog"

263 Publications

Utilizing an interim futility analysis of the OVAL study (VB-111-701/GOG 3018) for potential reduction of risk: A phase III, double blind, randomized controlled trial of ofranergene obadenovec (VB-111) and weekly paclitaxel in patients with platinum resistant ovarian cancer.

Gynecol Oncol 2021 Feb 23. Epub 2021 Feb 23.

Massachusetts General Hospital, Boston, MA, USA.

Objective: Report the results from a preplanned interim analysis of a phase III, double blind, randomized controlled study of ofranergene obadenovec (VB-111), a targeted anti-cancer gene therapy, in combination with paclitaxel in patients with platinum resistant ovarian cancer (PROC).

Methods: The OVAL (NCT03398655) study is an on-going study where patients are randomly assigned in a 1:1 ratio to weekly paclitaxel 80 mg/m with VB-111 or placebo. The protocol specifies a pre-planned unblinded futility interim analysis of CA-125 response per GCIG criteria in the first 60 evaluable patients. The futility rule determined for this analysis was that the response rate of VB-111 must be greater than the response rate of placebo by at least 10% in order to continue the study. Coincident with the interim analysis, the blinded CA-125 response rate was estimated as a proportion of the first 60 evaluable patients with CA-125 response per GCIG criteria. Post-treatment fever is provided as a possible surrogate marker of VB-111 therapy activity.

Results: The median age of the evaluable patients was 62 years (range 41-82); 97% had high-grade serous cancer; 58% had been treated with 3 or more previous lines of therapy, 70% received prior anti-angiogenic treatment, 43% received prior PARP inhibitors. CA-125 response in the VB-111 and weekly paclitaxel treated arm met the pre-specified interim criterion of an absolute advantage of 10% or higher compared to the control. Blinded results show a 53% CA-125 response rate (32/60) with 15% complete response (n=9). Assuming balanced randomization and an absolute advantage of 10% or higher to the VB-111 arm, it may be deducted that the response in the VB-111 treatment arm is 58% or higher. Among patients with post-treatment fever, the CA-125 response rate was 69%.

Conclusions: At the time of the interim analysis, response rate findings are comparable to the responses seen in a similar patient population in the phase I/II study. The independent data and safety monitoring committee (iDSMC) recommended continuing the OVAL trial as planned. No new safety signals were identified.
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http://dx.doi.org/10.1016/j.ygyno.2021.02.014DOI Listing
February 2021

Clinical trials, adaptability and the COVID-19 pandemic.

Gynecol Oncol Rep 2021 Feb 8;35:100680. Epub 2020 Dec 8.

Despite the impact of the COVD-19 pandemic and public health crisis on health care delivery, the GOG-Foundation has continued to prioritize the delivery of novel and state-of-the-science treatment options to patients via clinical trials.
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http://dx.doi.org/10.1016/j.gore.2020.100680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723439PMC
February 2021

Gemogenovatucel-T (Vigil) immunotherapy as maintenance in frontline stage III/IV ovarian cancer (VITAL): a randomised, double-blind, placebo-controlled, phase 2b trial.

Lancet Oncol 2020 12;21(12):1661-1672

US Oncology Research, The Woodlands, TX, USA.

Background: Gemogenovatucel-T is an autologous tumour cell vaccine manufactured from harvested tumour tissue, which specifically reduces expression of furin and downstream TGF-β1 and TGF-β2. The aim of this study was to determine the safety and efficacy of gemogenovatucel-T in front-line ovarian cancer maintenance.

Methods: This randomised, double-blind, placebo-controlled, phase 2b trial involved 25 hospitals in the USA. Women aged 18 years and older with stage III/IV high-grade serous, endometrioid, or clear cell ovarian cancer in clinical complete response after a combination of surgery and five to eight cycles of chemotherapy involving carboplatin and paclitaxel, and an Eastern Cooperative Oncology Group status of 0 or 1 were eligible for inclusion in the study. Patients were randomly assigned (1:1) to gemogenovatucel-T or placebo by an independent third party interactive response system after successful screening using randomly permuted block sizes of two and four and stratified by extent of surgical cytoreduction and neoadjuvant versus adjuvant chemotherapy. Gemogenovatucel-T (1 × 10 cells per injection) or placebo was administered intradermally (one per month) for a minimum of four and up to 12 doses. Patients, investigators, and clinical staff were masked to patient allocation until after statistical analysis. The primary endpoint was recurrence-free survival, analysed in the per-protocol population. All patients who received at least one dose of gemogenovatucel-T were included in the safety analysis. The study is registered with ClinicalTrials.gov, NCT02346747.

Findings: Between Feb 11, 2015, and March 2, 2017, 310 patients consented to the study at 22 sites. 217 were excluded. 91 patients received gemogenovatucel-T (n=47) or placebo (n=44) and were analysed for safety and efficacy. The median follow-up from first dose of gemogenovatucel-T was 40·0 months (IQR 35·0-44·8) and from first dose of placebo was 39·8 months (35·5-44·6). Recurrence-free survival was 11·5 months (95% CI 7·5-not reached) for patients assigned to gemogenovatucel-T versus 8·4 months (7·9-15·5) for patients assigned to placebo (HR 0·69, 90% CI 0·44-1·07; one-sided p=0·078). Gemogenovatucel-T resulted in no grade 3 or 4 toxic effects. Two patients in the placebo group had five grade 3 toxic events, including arthralgia, bone pain, generalised muscle weakness, syncope, and dyspnea. Seven patients (four in the placebo group and three in the gemogenovatucel-T group) had 11 serious adverse events. No treatment-related deaths were reported in either of the groups.

Interpretation: Front-line use of gemogenovatucel-T immunotherapy as maintenance was well tolerated but the primary endpoint was not met. Further investigation of gemogenovatucel-T in patients stratified by BRCA mutation status is warranted.

Funding: Gradalis.
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http://dx.doi.org/10.1016/S1470-2045(20)30533-7DOI Listing
December 2020

Highlights in ovarian cancer from the American Society of Clinical Oncology annual meeting.

Authors:
Thomas J Herzog

Clin Adv Hematol Oncol 2020 10;18(10):620-623

University of Cincinnati Medical Center, Cincinnati, Ohio.

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October 2020

Selecting new upfront regimens for advanced ovarian cancer with biomarker guidance.

Gynecol Oncol 2020 Dec 28;159(3):604-606. Epub 2020 Sep 28.

Stanford University School of Medicine, Stanford, CA, United States; University of California, Los Angeles, CA, United States.

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http://dx.doi.org/10.1016/j.ygyno.2020.09.017DOI Listing
December 2020

Oxygen vacancy injection-induced resistive switching in combined mobile and static gradient doped tin oxide nanorods.

Nanoscale 2020 Sep;12(35):18322-18332

Leibniz-University Hannover, Institute of Inorganic Chemistry, Callinstrasse 9, 30167 Hannover, Germany. and University of Konstanz, Department of Chemistry, Universitätsstrasse 10, 78457 Konstanz, Germany.

Resistive switching devices offer a great potential for advanced computing and data storage, including neuromorphic networks and random-access memory. State-of-the-art memristors are mostly realized by a three-layer structure, which is comprised of an active metal oxide layer sandwiched between two metal electrodes. Thus, there is always an interface involving two materials differing strongly in crystallographic and electronic properties. In this study, we present a resistive switching nanorod device based on a metal oxide sandwiched between two transparent conductive oxide electrodes. Thus, the system is characterized by a different, smooth interface offering new possibilities for increased energy efficiency and transparent electronics. Antimony-doped tin oxide (ATO) is used as an electrode material. The heavily doped ATO nanorods, exhibiting a good conductivity, are produced by a templated electrochemical deposition approach of alloy particles with subsequent thermal oxidation. The process enables precise control of the doping level within the nanorods and the formation of a doping level gradient. Electrical characterization reveals that a stronger gradient between heavily doped and undoped tin oxide within the nanorods results in a more rectifying character of the junction. Three-domain nanorods consisting of an undoped tin oxide segment in between two ATO segments are utilized to introduce memristive properties into the nanorod device. The resistive switching of these nanorods can be attributed to an oxygen vacancy doping gradient introduced during thermal oxidation. These vacancies are mobile within the tin oxide host structure and their injection from the ATO segment into the undoped tin oxide segment results in altered conductivity of the device, when an external bias is applied.
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http://dx.doi.org/10.1039/d0nr03734fDOI Listing
September 2020

The current status of secondary cytoreduction in ovarian cancer: a systematic review.

Clin Adv Hematol Oncol 2020 Jun;18(6):332-343

University of Cincinnati Medical Center, Cincinnati, Ohio.

Purpose: Ovarian cancer causes more deaths than any other cancer of the female genital tract. Despite improvements in management and treatment, survival remains low in patients with extensive disease at presentation, which usually leads to eventual recurrence. Treatment of recurrence remains challenging. Although the use of secondary cytoreduction to treat recurrent disease has become widespread, its utility remains unproven.

Methods: This systematic review examines all the relevant electronic literature. An electronic literature search was conducted in the PubMed, MEDLINE, and EMBASE databases from January 1980 through December 2019.

Results: Several relevant retrospective studies have been published, and these unanimously suggest that secondary cytoreduction is associated with an increase in progression-free and overall survival after relapse. Despite sound statistical methods, these studies are unfortunately limited by significant confounding inherent to the retrospective approach and by selection bias, given that healthier patients with less disease have historically been selected for surgery. Data from clinical trials are currently evolving. Early data from DESKTOP III demonstrate improved progression-free survival with secondary cytoreduction, whereas GOG-0213 found no difference in progression-free or overall survival.

Conclusions: Secondary cytoreduction remains a viable treatment option for select patients for now, but this is entirely dependent on the highly anticipated overall survival results of DESKTOP III and SOC 1.
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June 2020

COVID-19 pandemic and impact on cancer clinical trials: An academic medical center perspective.

Cancer Med 2020 09 10;9(17):6141-6146. Epub 2020 Jul 10.

UC Cancer Center, University of Cincinnati Medical Center, Cincinnati, OH, USA.

The COVID-19 pandemic changed health-care operations around the world and has interrupted standard clinical practices as well as created clinical research challenges for cancer patients. Cancer patients are uniquely susceptible to COVID-19 infection and have some of the worst outcomes. Importantly, cancer therapeutics could potentially render cancer patients more susceptible to demise from COVID-19 yet the poor survival outcome of many cancer diagnoses outweighs this risk. In addition, the pandemic has resulted in risks to health-care workers and research staff driving important change in clinical research operations and procedures. Remote telephone and video visits, remote monitoring, electronic capture of signatures and data, and limiting sample collections have allowed the leadership in our institution to ensure the safety of our staff and patients while continuing critical clinical research operations. Here we discuss some of these unique challenges and our response to change that was necessary to continue cancer clinical research; and, the impacts the pandemic has caused including increases in efficiency for our cancer research office.
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http://dx.doi.org/10.1002/cam4.3292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404529PMC
September 2020

A case of a unique presentation of a primary vaginal endometrioid adenocarcinoma arising in the setting of a recurrent peritoneal inclusion cyst fistulized to the vagina.

Gynecol Oncol Rep 2020 Aug 16;33:100585. Epub 2020 May 16.

University of Cincinnati Department of Obstetrics & Gynecology: Division of Gynecologic Oncology, 234 Goodman Street, Cincinnati, OH 45219, USA.

Primary vaginal endometrioid adenocarcinoma is a rare cancer that is often associated with chronic endometriosis. We present the case of a 72-year-old female who underwent right salpingo-oophorectomy followed by hysterectomy with benign pathology 25 years prior to her cancer diagnosis. She had an extensive surgical history in the intervening years and several complicating factors including a history of endometriosis as well as a recurrent peritoneal inclusion cyst treated with ethanol sclerotherapy, followed by formation of a peritoneal-vaginal fistula. Endometriosis is associated with malignant transformation to endometrioid adenocarcinoma through genomic alteration, oxidative stress, inflammation, and hyperestrogenism. Frequency of surveillance examinations and imaging prior to diagnosis were based on patient symptoms, and ultimately a vaginal cuff mass was detected with invasion of the rectosigmoid colon, bladder and levators at time of diagnosis, necessitating infralevator total pelvic exenteration for removal.
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http://dx.doi.org/10.1016/j.gore.2020.100585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243260PMC
August 2020

Data on prior pegylated liposomal doxorubicin (PLD) treatment in recurrent ovarian cancer: Post-hoc data analysis from the phase 3 randomized, open-label study comparing trabectedin and PLD versus PLD alone in patients with recurrent ovarian cancer.

Data Brief 2020 Jun 20;30:105465. Epub 2020 Mar 20.

The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

The data presented herein are supplementary to our published primary article "A phase 3 randomized, open-label, multicenter trial for safety and efficacy of combined trabectedin and pegylated liposomal doxorubicin therapy for recurrent ovarian cancer"[1]. The exploratory analysis evaluated the impact of prior pegylated liposomal doxorubicin (PLD) therapy in patients who participated in a randomized, open-label study comparing combination therapy of trabectedin and PLD vs PLD alone in third-line recurrent ovarian cancer (ROC). These exploratory analyses showed that prior treatment with PLD in ROC does not impact the response and survival rates nor does it increase toxicities or negatively influence survival and response rates in both treatment groups.
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http://dx.doi.org/10.1016/j.dib.2020.105465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178483PMC
June 2020

Early diagnosis and treatment challenges of endodermal sinus tumors: A case report.

Case Rep Womens Health 2020 Jul 3;27:e00198. Epub 2020 Apr 3.

Division of Gynecologic Oncology, University of Cincinnati, Cincinnati, OH, United States.

Background: Ovarian endodermal sinus tumors (ESTs) are rapidly growing and highly malignant tumors that respond well to chemotherapy. They can be difficult to diagnose and delayed diagnosis can worsen prognosis.

Case: We present the case of a 20-year-old woman with an EST initially misdiagnosed as a tubo-ovarian abscess who then experienced rapid progression within weeks of initial presentation and was subsequently found to have unresectable advanced stage disease.

Conclusion: ESTs are extremely aggressive and require prompt referral and early treatment with chemotherapy. Presenting symptoms of pain and a mass can lead to a broad range of differential diagnoses. In such patients, early consideration of tumor markers is warranted. This case report reviews the key aspects for prompt diagnosis and rapid treatment of these tumors, which significantly impacts the prognosis.
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http://dx.doi.org/10.1016/j.crwh.2020.e00198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152713PMC
July 2020

Molecular variations in uterine carcinosarcomas identify therapeutic opportunities.

Int J Gynecol Cancer 2020 04 28;30(4):480-484. Epub 2020 Feb 28.

Levine Cancer Institution, Charlotte, North Carolina, USA.

Objective: To perform comprehensive genomic profiling on a large cohort of patients with uterine carcinosarcomas to identify potential therapeutic targets.

Methods: Molecular profiling was conducted on 168 retrospectively de-identified patients with uterine carcinosarcomas using the Caris Life Sciences platform. Specimens were evaluated for aberrations in protein expression by immunohistochemistry, DNA sequence mutation using a 592-gene next generation sequencing panel, copy number amplification using next generation sequencing or in situ hybridization, and fusion events using NextGen RNA sequencing. Tumor mutational load and microsatellite instability were also evaluated.

Results: We identified 168 patients with uterine carcinosarcoma; median age of the cohort was 67 years. The most common mutations were observed in the following genes: (86%), (34%), (23%), (18%), (16%), (10%). Tumor mutational load was low to moderate in most cases (50% and 45%, respectively). ) was amplified in 9% of tumors. Immunohistochemistry protein expression was elevated in (95%) (80%) (76%), and (66%). Mismatch repair deficiency was rare (4%).

Conclusions: Multiple somatic mutations and copy number alterations in genes that are therapeutic targets were identified in half of cases. Uterine carcinosarcomas represent an aggressive histology with limited treatment options and poor outcomes, and clinical trials are needed to validate new therapeutic targets.
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http://dx.doi.org/10.1136/ijgc-2019-000920DOI Listing
April 2020

A virtual molecular tumor board to improve efficiency and scalability of delivering precision oncology to physicians and their patients.

JAMIA Open 2019 Dec 7;2(4):505-515. Epub 2019 Oct 7.

Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC, USA.

Objectives: Scalable informatics solutions that provide molecularly tailored treatment recommendations to clinicians are needed to streamline precision oncology in care settings.

Materials And Methods: We developed a cloud-based virtual molecular tumor board (VMTB) platform that included a knowledgebase, scoring model, rules engine, an asynchronous virtual chat room and a reporting tool that generated a treatment plan for each of the 1725 patients based on their molecular profile, previous treatment history, structured trial eligibility criteria, clinically relevant cancer gene-variant assertions, biomarker-treatment associations, and current treatment guidelines. The VMTB systematically allows clinician users to combine expert-curated data and structured data from clinical charts along with molecular testing data to develop consensus on treatments, especially those that require off-label and clinical trial considerations.

Results: The VMTB was used as part of the cancer care process for a focused subset of 1725 patients referred by advocacy organizations wherein resultant personalized reports were successfully delivered to treating oncologists. Median turnaround time from data receipt to report delivery decreased from 14 days to 4 days over 4 years while the volume of cases increased nearly 2-fold each year. Using a novel scoring model for ranking therapy options, oncologists chose to implement the VMTB-derived therapies over others, except when pursuing immunotherapy options without molecular support.

Discussion: VMTBs will play an increasingly critical role in precision oncology as the compendium of biomarkers and associated therapy options available to a patient continues to expand.

Conclusion: Further development of such clinical augmentation tools that systematically combine patient-derived molecular data, real-world evidence from electronic health records and expert curated knowledgebases on biomarkers with computational tools for ranking best treatments can support care pathways at point of care.
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http://dx.doi.org/10.1093/jamiaopen/ooz045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994017PMC
December 2019

A phase 3 randomized, open-label, multicenter trial for safety and efficacy of combined trabectedin and pegylated liposomal doxorubicin therapy for recurrent ovarian cancer.

Gynecol Oncol 2020 03 8;156(3):535-544. Epub 2020 Jan 8.

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Objective: This phase 3 study aimed to compare overall survival (OS) of women with platinum-sensitive, recurrent ovarian cancer (ROC) treated with third-line trabectedin (T) + pegylated liposomal doxorubicin (PLD) vs. PLD monotherapy.

Methods: Women with advanced-relapsed epithelial ovarian cancer were randomly assigned 1: 1 to intravenous infusions of either T + PLD (trabectedin 1.1 mg/m for 3 h; PLD 30 mg/m for 1.5 h, every 3 weeks) or PLD (50 mg/m for 1.5 h, every 4 weeks). Primary endpoint was OS. Secondary endpoints included investigator-assessed progression free survival (PFS) and objective response rates (ORR). At randomization, patients were stratified by time from last dose of first-line platinum therapy to disease progression, ECOG grade 0 or 1, BRCA1/2 germline mutational status, and prior PLD therapy. Exploratory endpoints included OS, PFS, and ORR in the stratified subgroups (PFI, ECOG, BRCA1/2 status, and prior PLD therapy). This trial is registered with ClinicalTrials.gov, number NCT01846611.

Results: 576 patients were randomized (T + PLD, n = 289; PLD, n = 287). Median OS was 23.8 months with T + PLD vs. 22.2 months with PLD (HR:0.92, 95%CI:0.73-1.18; p = 0.52). Median PFS was 7.52 vs. 7.26 months (HR:0.93, 95%CI:0.76-1.15; p = 0.52); ORR was 46% vs. 35.9% (OR:1.52, 95%CI:1.07-2.16; p = 0.01). Patients with BRCA1/2 mutations had median OS of 34.2 months with T + PLD vs. 20.9 months with PLD (HR:0.54, 95%CI:0.33-0.90; p = 0.016). Patients with BRCA1/2 mutations had median PFS of 10.1 months with T + PLD vs. 7.6 months with PLD (HR:0.72, 95%CI:0.48-1.08; p = 0.039). Patients with BRCA1/2 mutations and a 6-12 months platinum-free interval (PFI), median OS was 31.5 vs. 14.9 months, respectively (HR:0.37, 95%CI:0.17-0.82; p = 0.011). Grade 3-4 AEs were higher in T + PLD (79%) vs. PLD (54%).

Conclusion: Combination of T and PLD did not show favorable OS benefit nor safety; however, patients with germline BRCA1/2 mutations and/or a PFI of 6-12 months appear to have clinically relevant survival benefit with T + PLD. No new safety signals were identified.
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http://dx.doi.org/10.1016/j.ygyno.2019.12.043DOI Listing
March 2020

European society of medical oncology (ESMO) 2019 meeting report features practice changing data in gynecologic malignancies.

Gynecol Oncol 2020 02 3;156(2):265-270. Epub 2020 Jan 3.

Levine Cancer Institute, Atrium Health, Charlotte, NC, USA.

Multiple practice changing studies were presented at the 2019 ESMO Congress in Barcelona, Spain. The ovarian cancer studies presented at the Presidential session will likely refine and redefine the initial treatment of ovarian cancer. Other compelling trial data in ovarian, uterine and cervical cancer were also unveiled. The key oral abstracts from this meeting are summarized in this meeting report.
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http://dx.doi.org/10.1016/j.ygyno.2019.11.010DOI Listing
February 2020

Immune checkpoint expression, microsatellite instability, and mutational burden: Identifying immune biomarker phenotypes in uterine cancer.

Gynecol Oncol 2020 02 24;156(2):393-399. Epub 2019 Dec 24.

Wayne State University, Detroit, MI, USA.

Objectives: Increasing grade of endometrioid endometrial cancer (EEC) is associated with aggressive behavior and poor prognosis. The traditional classification system is limited in its ability to guide treatment planning and prognostication. We identify distinct immune biomarker phenotypes using known markers of immunogenicity to identify patients who may benefit from immune therapy (IT).

Methods: 621 tumors were analyzed by multiplatform profiling. NextGen sequencing was performed on 592 genes. Tumor mutational burden (TMB) was defined as high (H) ≥10mutations/megabase. Microsatellite Instability (MSI) by NGS was ≥46 loci. PD-L1 positivity was ≥2+, >5% by IHC. Chi-square tests were used.

Results: Overall, MSI-H was found in 33% of EECs, most frequent in grade 3 (G3), followed by grade 2 (G2) and grade 1 (G1) tumors (G3: 37%, G2: 32%, G1: 22%, p = 0.007). TMB-H was identified in 25% of EECs. TMB-H was most common in G3, followed by G2 and G1 tumors (G3: 34%, G2: 23%, G1: 13%, p = 0.006). Overall, PD-L1 expression was found in 5.5% of EECs. G3 EECs had the most frequent PD-L1 expression, followed by G2 and G1 tumors (G3: 12%, G2: 3.0%, G1: 0.9%, p < 0.0001). We identified POLE mutations in 4.5% (28/618). All POLE mutated tumors harbored TMB-H phenotypes but MSI-H and PD-L1 were only present in 10.7% and 14.8% of tumors respectively, suggesting upregulation of T-cell immune response in only a fraction of POLE mutated EECs. Triple negative (TN) biomarker phenotype (ER-/PR-/Her2-) was evaluated as a potential surrogate marker of tumor immunogenicity. We identified TN phenotype in 4% of G1 EEC compared with 9% in G2 and 33% in G3, suggesting loss of hormone expression and possible greater immunogenicity with increasing tumor grade.

Conclusions: High grade tumors appear to be more immunogenic than low grade tumors and may preferentially benefit from IT.
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http://dx.doi.org/10.1016/j.ygyno.2019.11.035DOI Listing
February 2020

Secondary Surgical Cytoreduction for Recurrent Ovarian Cancer.

N Engl J Med 2019 11;381(20):1929-1939

From the University of Texas M.D. Anderson Cancer Center, Houston (R.L.C., K.B.-E.); Women's Cancer Center of Nevada, Las Vegas (N.M.S.); NRG Oncology Statistical and Data Management Center, Roswell Park Cancer Institute, Buffalo (D.E., H.Q.H., M.F.B.), and Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (P.S.) - both in New York; the University of Cincinnati, University of Cincinnati Cancer Institute, Cincinnati (T.J.H.); the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore (D.K.A.); Seoul National University College of Medicine (J.-W.K.), Samsung Medical Center, Sungkyunkwan University School of Medicine (B.-G.K.), and Asan Medical Center, University of Ulsan College of Medicine (J.-H.N.), Seoul, and the Research Institute and Hospital, National Cancer Center, Goyang (S.-Y.P.) - all in South Korea; Saitama Medical University International Medical Center, Hidaka, Japan (K.F.); the University of Oklahoma Health Sciences Center, Oklahoma City (J.L.W., R.S.M.); National Surgical Adjuvant Breast and Bowel Project/NRG Oncology, U.S. Oncology Research, and Metro-Minnesota Community Oncology Research Consortium, Minneapolis (A.C.C.); Duke Cancer Institute, Duke University Medical Center, Durham, NC (A.A.S.); Abramson Cancer Center, University of Pennsylvania, Philadelphia (S.R.); Gynecologic Cancer Program, California Pacific-Palo Alto Medical Foundation, Sutter Research Institute, San Francisco (J.K.C.); Women and Infants Hospital, Providence, RI (P.D.); the University of Colorado School of Medicine, Aurora, and Denver Health Medical Center, Denver (S.A.D.); Ohio State University, Columbus (D.E.C.); and the University of California, Irvine, Orange (K.S.T.).

Background: Secondary surgical cytoreduction in women with platinum-sensitive, recurrent epithelial ovarian, primary peritoneal, or fallopian-tube ("ovarian") cancer is widely practiced but has not been evaluated in phase 3 investigation.

Methods: We randomly assigned patients with recurrent ovarian cancer who had received one previous therapy, had an interval during which no platinum-based chemotherapy was used (platinum-free interval) of 6 months or more, and had investigator-determined resectable disease (to no macroscopic residual disease) to undergo secondary surgical cytoreduction and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Adjuvant chemotherapy (paclitaxel-carboplatin or gemcitabine-carboplatin) and use of bevacizumab were at the discretion of the investigator. The primary end point was overall survival.

Results: A total of 485 patients underwent randomization, 240 to secondary cytoreduction before chemotherapy and 245 to chemotherapy alone. The median follow-up was 48.1 months. Complete gross resection was achieved in 67% of the patients assigned to surgery who underwent the procedure. Platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance was administered to 84% of the patients overall and was equally distributed between the two groups. The hazard ratio for death (surgery vs. no surgery) was 1.29 (95% confidence interval [CI], 0.97 to 1.72; P = 0.08), which corresponded to a median overall survival of 50.6 months and 64.7 months, respectively. Adjustment for platinum-free interval and chemotherapy choice did not alter the effect. The hazard ratio for disease progression or death (surgery vs. no surgery) was 0.82 (95% CI, 0.66 to 1.01; median progression-free survival, 18.9 months and 16.2 months, respectively). Surgical morbidity at 30 days was 9%; 1 patient (0.4%) died from postoperative complications. Patient-reported quality of life decreased significantly after surgery but did not differ significantly between the two groups after recovery.

Conclusions: In this trial involving patients with platinum-sensitive, recurrent ovarian cancer, secondary surgical cytoreduction followed by chemotherapy did not result in longer overall survival than chemotherapy alone. (Funded by the National Cancer Institute and others; GOG-0213 ClinicalTrials.gov number, NCT00565851.).
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http://dx.doi.org/10.1056/NEJMoa1902626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941470PMC
November 2019

OVQUEST - Life after the diagnosis and treatment of ovarian cancer - An international survey of symptoms and concerns in ovarian cancer survivors.

Gynecol Oncol 2019 10 13;155(1):126-134. Epub 2019 Aug 13.

Prince of Wales Clinical School UNSW, and Department of Medical Oncology, Prince of Wales Hospital, Sydney, Australia.

Objectives: Our aim was to investigate the prevalence and potential risk factors for persistent and troublesome physical and psychological symptoms following treatment for ovarian cancer (OC).

Methods: OvQuest is an international, internet-based, cross-sectional questionnaire which explored symptom burden and quality of life (QOL) after treatment for OC. Eligible women were aged 18 and over, diagnosed with OC at least 6 months previously and had received chemotherapy. Self-report data were collected including demographics, diagnosis and treatment, and standardised instruments for treatment-related toxicities, QOL, physical activity (PA) and supportive care needs.

Results: The survey included 1360 patients, of whom 421 (31%) had been treated for recurrent OC. 78% reported symptoms of peripheral neuropathy, 60% significant fatigue, 48% mood disturbance and 59% moderate-severe insomnia. Rates of fatigue, mood disorders, neuropathy and insomnia did not differ between women with or without recurrence. The majority of respondents were overweight or obese (high BMI, 59%) and 35% reported low PA. Low PA and high BMI were associated with poorer QOL scores and higher symptom burden across a range of domains.

Conclusion: Women living after a diagnosis of OC report a substantial and ongoing symptom burden which impacts significantly on their quality of life across multiple domains. The reported associations between obesity, physical inactivity and poor QOL warrant prospective evaluation of lifestyle interventions to improve QOL.
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http://dx.doi.org/10.1016/j.ygyno.2019.08.009DOI Listing
October 2019

An unusual case of uterine PEComa presenting with disseminated intravascular coagulation.

Gynecol Oncol Rep 2019 Aug 25;29:76-78. Epub 2019 Jun 25.

Department of Obstetrics and Gynecology, Division of Gynecology Oncology, University of Cincinnati, 231 Albert Sabin Way, Academic Health Center, PO Box 670526, Cincinnati, OH 45267-0526, United States of America.

Perivascular epithelioid cell neoplasms (PEComas) are mesenchymal neoplasms originating from the perivascular epithelioid cell (PEC) line. The World Health Organization (WHO) further defines PEComa as "a mesenchymal tumor composed of histologically and immunohistochemically distinctive perivascular epithelioid cells". Gynecologic PEComas account for approximately ¼ of the PEComa cases reported in the literature and are histologically characterized by stromal hyalinization with complete or partial circumscription with hyaline background and diffuse, small vessel vascularity (Musella et al., 2015). Uterine PEComas typically present with vaginal bleeding and/or a uterine mass, are managed surgically with resection, and can be followed by adjuvant treatment if indicated based on pathologic risk factors for aggression. Adjuvant therapy is not standardized given the rarity of these tumors, and can include chemotherapy, radiation, targeted therapy (mTOR inhibitors due to common gene mutations and a hypothesized pathophysiology of this neoplasm) and/or hormones. In this case report, we describe an unusual presentation for a uterine PEComa in a woman initially complaining of worsening cutaneous bruising and petechiae, found to be in florid disseminated intravascular coagulation (DIC) without a clear etiology. Ultimately her extensive hematology evaluation only found a large uterine mass that appeared to be a 9 cm fibroid. She underwent hysterectomy following recovery from her DIC, and was diagnosed with a large uterine PEComa.
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http://dx.doi.org/10.1016/j.gore.2019.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664096PMC
August 2019

Joint ENGOT and GOG Foundation requirements for trials with industry partners.

Gynecol Oncol 2019 08;154(2):255-258

GOG-F and Gynecologic Oncology, Ohio State University Wexner Medical Center and JamesCare Gynecologic Oncology at Mill Run, Columbus, Ohio, USA.

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http://dx.doi.org/10.1016/j.ygyno.2019.04.677DOI Listing
August 2019

Joint ENGOT and GOG Foundation requirements for trials with industry partners.

Int J Gynecol Cancer 2019 09 18;29(7):1094-1097. Epub 2019 Jul 18.

GOG-F and Gynecologic Oncology, Ohio State University Wexner Medical Center and JamesCare Gynecologic Oncology at Mill Run, Columbus, Ohio, USA.

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http://dx.doi.org/10.1136/ijgc-2019-000441DOI Listing
September 2019

Final Overall Survival of a Randomized Trial of Bevacizumab for Primary Treatment of Ovarian Cancer.

J Clin Oncol 2019 09 19;37(26):2317-2328. Epub 2019 Jun 19.

University of Arizona and Creighton University, Phoenix, AZ.

Purpose: We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma.

Methods: A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration time curve 6) and paclitaxel (175 mg/m) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry.

Results: Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non- HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). , HRR, and CD31 were not predictive of bevacizumab activity.

Conclusion: No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for mutations and homologous recombination deficiency is essential.
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http://dx.doi.org/10.1200/JCO.19.01009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879307PMC
September 2019

Advancing Drug Development in Gynecologic Malignancies.

Clin Cancer Res 2019 08 24;25(16):4874-4880. Epub 2019 May 24.

University of Cincinnati Cancer Institute, Cincinnati, Ohio.

Gynecologic malignancies continue to be a major cause of morbidity and mortality in the United States despite recent advances in oncologic therapies. To realize the promise of immunotherapy and biomarker-driven approaches to improve clinical outcomes for patients, better communication among stakeholders in the drug development and approval pathways is needed. To this end, the FDA-AACR-SGO Drug Development in Gynecologic Malignancies Workshop brought together clinicians, patient advocates, researchers, industry representatives, and regulators in June 2018, to review the state of the science in gynecologic cancers and explore how scientific advances impact approval processes. Topics of discussion and key takeaways are summarized in this article. Single-agent immunotherapies have demonstrated variable and often modest response rates among gynecologic cancers. Combination therapies and other novel approaches, such as cell-based therapies, may show improved efficacy compared with single-agent immunotherapies; however, utilizing innovative clinical trial designs will be necessary to progress further. Companion and complementary diagnostics inform physicians of potential benefits of specific therapeutics for patients; however, they serve different functions that have important regulatory implications, thus trialists should understand the distinctions between diagnostic types. PARP inhibitors hold great promise for treating ovarian cancers, both as monotherapies and in combination with chemotherapeutics, other targeted agents, and immunotherapies. Rare gynecologic cancers often exhibit unique molecular characteristics that can serve as effective targets to which novel therapeutics can be developed. This workshop highlighted the importance of future open discussions on scientific and regulatory challenges in drug development for gynecologic malignancies.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697564PMC
August 2019

Loss of BRUCE reduces cellular energy level and induces autophagy by driving activation of the AMPK-ULK1 autophagic initiating axis.

PLoS One 2019 15;14(5):e0216553. Epub 2019 May 15.

Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.

Autophagy is an intracellular catabolic system. It delivers cellular components to lysosomes for degradation and supplies nutrients that promote cell survival under stress conditions. Although much is known regarding starvation-induced autophagy, the regulation of autophagy by cellular energy level is less clear. BRUCE is an ubiquitin conjugase and ligase with multi-functionality. It has been reported that depletion of BRUCE inhibits starvation-induced autophagy by blockage of the fusion step. Herein we report a new function for BRUCE in the dual regulation of autophagy and cellular energy. Depletion of BRUCE alone (without starvation) in human osteosarcoma U2OS cells elevated autophagic activity as indicted by the increased LC3B-II protein and its autophagic puncta as well as further increase of both by chloroquine treatment. Such elevation results from enhanced induction of autophagy since the numbers of both autophagosomes and autolysosomes were increased, and recruitment of ATG16L onto the initiating membrane structure phagophores was increased. This concept is further supported by elevated lysosomal enzyme activities. In contrast to starvation-induced autophagy, BRUCE depletion did not block fusion of autophagosomes with lysosomes as indicated by increased lysosomal cleavage of the GFP-LC3 fusion protein. Mechanistically, BRUCE depletion lowered the cellular energy level as indicated by both a higher ratio of AMP/ATP and the subsequent activation of the cellular energy sensor AMPK (pThr-172). The lower energy status co-occurred with AMPK-specific phosphorylation and activation of the autophagy initiating kinase ULK1 (pSer-555). Interestingly, the higher autophagic activity by BRUCE depletion is coupled with enhanced cisplatin resistance in human ovarian cancer PEO4 cells. Taken together, BRUCE depletion promotes induction of autophagy by lowering cellular energy and activating the AMPK-ULK1-autophagy axis, which could contribute to ovarian cancer chemo-resistance. This study establishes a BRUCE-AMPK-ULK1 axis in the regulation of energy metabolism and autophagy, as well as provides insights into cancer chemo-resistance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216553PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519829PMC
January 2020

Ovarian Cancer Maintenance: Practice-Changing Data Calls for Changing Practice.

Oncologist 2019 05 20;24(5):576-579. Epub 2019 Mar 20.

University of Cincinnati Cancer Institute, University of Cincinnati Medical Center, Cincinnati, Ohio, USA

Staying current on the rapidly evolving therapeutic landscape in oncology is challenging for clinicians. This commentary discusses exciting practice‐changing data specific to ovarian cancer.
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http://dx.doi.org/10.1634/theoncologist.2019-0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516122PMC
May 2019

Limits of Life and the Habitability of Mars: The ESA Space Experiment BIOMEX on the ISS.

Astrobiology 2019 02;19(2):145-157

23 Department of Ecological and Biological Sciences, University of Tuscia, Viterbo, Italy.

BIOMEX (BIOlogy and Mars EXperiment) is an ESA/Roscosmos space exposure experiment housed within the exposure facility EXPOSE-R2 outside the Zvezda module on the International Space Station (ISS). The design of the multiuser facility supports-among others-the BIOMEX investigations into the stability and level of degradation of space-exposed biosignatures such as pigments, secondary metabolites, and cell surfaces in contact with a terrestrial and Mars analog mineral environment. In parallel, analysis on the viability of the investigated organisms has provided relevant data for evaluation of the habitability of Mars, for the limits of life, and for the likelihood of an interplanetary transfer of life (theory of lithopanspermia). In this project, lichens, archaea, bacteria, cyanobacteria, snow/permafrost algae, meristematic black fungi, and bryophytes from alpine and polar habitats were embedded, grown, and cultured on a mixture of martian and lunar regolith analogs or other terrestrial minerals. The organisms and regolith analogs and terrestrial mineral mixtures were then exposed to space and to simulated Mars-like conditions by way of the EXPOSE-R2 facility. In this special issue, we present the first set of data obtained in reference to our investigation into the habitability of Mars and limits of life. This project was initiated and implemented by the BIOMEX group, an international and interdisciplinary consortium of 30 institutes in 12 countries on 3 continents. Preflight tests for sample selection, results from ground-based simulation experiments, and the space experiments themselves are presented and include a complete overview of the scientific processes required for this space experiment and postflight analysis. The presented BIOMEX concept could be scaled up to future exposure experiments on the Moon and will serve as a pretest in low Earth orbit.
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http://dx.doi.org/10.1089/ast.2018.1897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383581PMC
February 2019

Systemic Treatment of Metastatic/Recurrent Uterine Leiomyosarcoma: A Changing Paradigm.

Oncologist 2018 12 23;23(12):1533-1545. Epub 2018 Aug 23.

Department of Obstetrics and Gynecology, University of Cincinnati Cancer Institute and College of Medicine, Cincinnati, Ohio, USA

The treatment of metastatic and recurrent uterine leoimyosarcoma (uLMS) has evolved rapidly in the past several years. Leoimyosarcoma is extremely aggressive and responds poorly to traditional chemotherapeutics. Recent regulatory approval of novel treatment options has significantly expanded the therapeutic armamentarium, and the addition of these therapies has challenged clinicians to select and optimally sequence these new compounds. Additionally, the potential role of immunotherapy is being assessed in current uLMS clinical trials. Given the increasing number of agents available both in the U.S. and globally, a treatment template that addresses optimal sequencing based upon expert consensus would be useful. Current guidelines, although listing various options, lack granularity by line of therapy. Most patients with leiomyosarcoma, even in early stage, are treated with surgery followed by adjuvant chemotherapy despite uLMS being relatively chemoresistant. Adjuvant chemotherapy often includes the combination of gemcitabine and docetaxel with or without doxorubicin in first-line systemic therapy, but these cytotoxic agents only provide patients with advanced disease a 5-year survival <30%. This review will focus on examination of current guidelines and consensus building for optimal sequencing of systemic therapies for advanced or recurrent uLMS. Critical ongoing studies investigating novel approaches including immunotherapeutics and genetic alterations also will be discussed. IMPLICATIONS FOR PRACTICE: Recent regulatory approval of novel treatment options has significantly expanded the therapeutic armamentarium, and the addition of these therapies has challenged clinicians to select and optimally sequence these compounds. This review will focus on examination of current guidelines and consensus building for optimal sequencing of systemic therapies for advanced or recurrent uterine leoimyosarcoma.
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http://dx.doi.org/10.1634/theoncologist.2018-0095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292548PMC
December 2018

Does adjuvant chemotherapy dose modification have an impact on the outcome of patients diagnosed with advanced stage ovarian cancer? An NRG Oncology/Gynecologic Oncology Group study.

Gynecol Oncol 2018 10 19;151(1):18-23. Epub 2018 Aug 19.

The Permanente Medical Group, Inc. 2350 Geary Blvd, Room 115 San Francisco, CA 94115, United States of America. Electronic address:

Purpose: To determine the relationship between chemotherapy dose modification (dose adjustment or treatment delay), overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma (PPC) who receive carboplatin and paclitaxel.

Methods: Women with stages III and IV EOC and PPC treated on the Gynecologic Oncology Group phase III trial, protocol 182, who completed eight cycles of carboplatin with paclitaxel were evaluated in this study. The patients were grouped per dose modification and use of granulocyte colony stimulating factor (G-CSF). The primary end point was OS; Hazard ratios (HR) for PFS and OS were calculated for patients who completed eight cycles of chemotherapy. Patients without dose modification were the referent group. All statistical analyses were performed using the R programming language and environment.

Results: A total of 738 patients were included in this study; 229 (31%) required dose modification, 509 did not. The two groups were well-balanced for demographic and prognostic factors. The adjusted hazard ratios (HR) for disease progression and death among dose-modified patients were: 1.43 (95% CI, 1.19-1.72, P < 0.001) and 1.26 (95% CI, 1.04-1.54, P = 0.021), respectively. Use of G-CSF was more frequent in dose-modified patients with an odds ratio (OR) of 3.63 (95% CI: 2.51-5.26, P < 0.001) compared to dose-unmodified patients.

Conclusion: Dose-modified patients were at a higher risk of disease progression and death. The need for chemotherapy dose modification may identify patients at greater risk for adverse outcomes in advanced stage EOC and PPC.
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http://dx.doi.org/10.1016/j.ygyno.2018.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151871PMC
October 2018