Primary Peritoneal Research Articles

Peritoneal surface malignancy spread reoperations after cytoreductive surgery + HIPEC.

Peritoneal malignancies (PM) are observed in about 1030% of patients suffering from gastrointestinal malignant diseases, both in connection with the primary surgical management or as metachronous metastases due to cancer recurrence. In the 1980s a new method of cytoreductive surgery (CRS) + HIPEC (hyperthermic intraperitoneal chemotherapy) was introduced. Today, we consider this method to be the gold standard for treatment of pseudomyxoma peritonei and peritoneal mesothelioma. The method increases overall survival (OS) of patients diagnosed with colorectal cancer, primary peritoneal and ovarian cancers. However, the disease recurs after this demanding treatment in the certain group of patients, approximately in 2544% of patients treated for pseudomyxoma peritonei, and in 40% and up to 82% of those treated for mesothelioma and colorectal cancer, respectively. Based on literary data (PubMed-Medline, last 5 years) and our own experience we present the basic factors associated with tumor recurrence, possibility of treatment using repeated CRS + HIPEC, data regarding second-look operations, and as applicable, prophylactic HIPEC. The method CRS + HIPEC provides an effective treatment of peritoneal carcinomatosis even in cases of recurrence. The second-look operations and prophylactic HIPEC may favorably affect the prognosis after primary R0 resections.

Comparison of 18F-FDG PET/CT and 68Ga-FAPI-04 PET/CT in the staging and restaging of gastric adenocarcinoma.

In this study, we aimed to evaluate the diagnostic sensitivities of 68Ga-FAPI-04 PET/CT and 18F-FDG PET/CT in the primary tumor, and nodal, peritoneal and distant organ metastases of primary and recurrent gastric adenocarcinoma (GAc) with patient and lesion-based comparison. Twenty-one patients with histopathologically proven newly diagnosed or recurrent GAc who underwent 18F-FDG and 68Ga-FAPI-04 imaging were included in the study. Both imaging techniques were evaluated visually according to the intensity of organ-based uptake. SUVmax and tumor-to-background ratio (TBR) values obtained from primary tumor/relapse and metastatic organs were compared statistically. 68Ga-FAPI-04 uptake was positive in all 15 newly diagnosed patients, while two patients among them who had mucinous and signet ring cell carcinoma did not exhibit 18F-FDG uptake. The sensitivity and specificity of 68Ga-FAPI-04 PET/CT in detecting primary gastric were 100%, while the sensitivity and specificity of 18F-FDG were 86.6 and 100%, respectively. 68Ga-FAPI-04 imaging revealed diffuse stomach uptake in seven patients, while 18F-FDG could only show two of them. The sensitivity and specificity of in-patient-based detection of lymph node metastases were 100 and 95.2%, respectively, while these values were 71.4 and 93.7%, respectively, for 18F-FDG. For peritoneal involvement 68Ga-FAPI-04 had a sensitivity and specificity of 100%, whereas 18F-FDG had a sensitivity of 40% and a specificity of 100%. 68Ga-FAPI-04 PET/CT is an imaging modality with the potential of yielding more sensitive and specific findings 18F-FDG PET/CT. This modality may help avoid invasive diagnostic procedures that may be frequently required in GAc.

ATHENA (GOG-3020/ENGOT-ov45): a randomized, phase III trial to evaluate rucaparib as monotherapy (ATHENA–MONO) and rucaparib in combination with nivolumab (ATHENA–COMBO) as maintenance treatment following frontline platinum-based chemotherapy in ovarian cancer

BackgroundThe optimal treatment strategy for women with newly diagnosed ovarian cancer has yet to be determined. Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated substantial improvement in progression-free survival as monotherapy maintenance...

The incidence and survival of cervical, ovarian, and endometrial cancer in Korea, 1999-2017: Korea Central Cancer Registry.

ObjectiveThe three major gynecologic cancers are cervical, endometrial, and ovarian cancer. This study aimed to describe the 19-year trends and survival rates in cervical, endometrial, and ovarian cancer in a Korean female population.MethodsWe searched the Korea Central Cancer Registry to identify patients with gynecologic cancer between 1999 and 2017. Age-standardized rates and annual percent changes were calculated. The relative survival rate (RSR) was reported by histology, age, and stage for each gynecological cancer.ResultsThe total number of cervical, endometrial, primary peritoneal, ovarian epithelial, fallopian tube (POFT) cancer was 134,863, with the number of cases increasing every year: 6,077 in 1999 to 8,011 in 2017. The incidence of cervical cancer has decreased; however, that of POFT and endometrial cancer has increased. The 5-year RSR of cervical, POFT, and endometrial cancer was reported to be 80.8%, 61.4%, and 88.1%, respectively. In the case of cervical cancer, squamous cell carcinoma showed better survival than other histology (82.8% vs. 73.5%). Furthermore, in the case of endometrial cancer, endometrioid histology had substantially better 5-year RSR than the others (93.2% vs. 76.5%). Contrastingly, in the case of ovarian cancer, serous carcinoma had worse 5-year RSR than other types of histology.ConclusionThe incidence rates for gynecologic cancers increased from 2005 to 2017, with an annual increase of 2.76 per year until 2017. Endometrial cancer had the highest RSR, while ovarian cancer had the lowest. Active cancer screening and the introduction of effective treatments might have contributed to the improved RSRs of gynecologic cancers.

Therapeutic Potential of PARP Inhibitors in the Treatment of Gastrointestinal Cancers

Gastrointestinal (GI) malignancies are a major global health burden, with high mortality rates. The identification of novel therapeutic strategies is crucial to improve treatment and survival of patients. The poly (ADP-ribose) polymerase (PARP) enzymes involved in the DNA damage response (DDR) play major roles in the development, progression and treatment response of cancer, with PARP inhibitors (PARPi) currently used in the clinic for breast, ovarian, fallopian, primary peritoneal, pancreatic and prostate cancers with deficiencies in homologous recombination (HR) DNA repair. This article examines the current evidence for the role of the DDR PARP enzymes (PARP1, 2, 3 and 4) in the development, progression and treatment response of GI cancers. Furthermore, we discuss the role of HR status as a predictive biomarker of PARPi efficacy in GI cancer patients and examine the pre-clinical and clinical evidence for PARPi and cytotoxic therapy combination strategies in GI cancer. We also include an analysis of the genomic and transcriptomic landscape of the DDR PARP genes and key HR genes (BRCA1, BRCA2, ATM, RAD51, MRE11, PALB2) in GI patient tumours (n = 1744) using publicly available datasets to identify patients that may benefit from PARPi therapeutic approaches.

Hyperthermic intraperitoneal chemotherapy in primary peritoneal cancer: Our experience in a young male

Primary peritoneal carcinomatosis (PPC) is a rare tumor, described in the literature almost exclusively in women. Patients with peritoneal carcinomatosis were considered incurable with low survival rates. This underwent a paradigm shift with hyperthermic intraperitoneal chemotherapy (HIPEC) after optimal cytoreductive surgery which changed the entire scenario. This case report describes the management of a 28-year-old male patient who was diagnosed to have PPC when he presented with massive ascites, who underwent cytoreductive surgery combined with HIPEC in our hospital. This procedure was complex for both the surgical team due to an extensive surgery, but also the anesthetist during the hyperthermic phase where the chemotherapy was administered. The post-operative recovery in such a case is also many times stormy and requires extreme vigilance. We had major challenges such as prolonged surgery, massive blood loss, temperature management, maintaining adequate urine output, and post-operative critical care. Extensive pre-operative preparation and proper coordination with the multidisciplinary team led us to handle the condition satisfactorily. The PPC in a young patient itself is a rare which enthuses us to report the case.

Identification and utilization of solid tumor genomic sequencing in the treatment of ovarian and endometrial cancer

Identification and utilization of solid tumor genomic sequencing in the treatment of ovarian and endometrial cancer

Phase I dose escalation safety and feasibility study of autologous WT1-sensitized T cells for the treatment of patients with recurrent ovarian cancer

BackgroundThis phase I dose escalation trial evaluated the feasibility of production, safety, maximum tolerated dose, and preliminary efficacy of autologous T cells sensitized with peptides encoding Wilms’ tumor protein 1...

Disparities in the enrollment of racial and ethnic minorities in clinical trials of poly ADP ribose polymerase inhibitors for women's cancers

<h3>Objectives:</h3> Disparities persist in the enrollment of diverse racial and ethnic groups in clinical trials for ovarian and breast cancers. We sought to analyze the enrollment of participants by race/ethnicity in phase II and III clinical trials involving poly ADP ribose polymerase (PARP) inhibitors for ovarian and breast cancers and compare these to the racial/ethnic prevalence of ovarian and breast cancer in the United States. <h3>Methods:</h3> This study was designed as a retrospective review of clinical trials registered with Clinicaltrials.gov. Studies included evaluated PARP inhibitors for the treatment of ovarian, fallopian tube, primary peritoneal, and breast cancers. Enrollment rates for clinical trials were stratified by race/ethnicity and type of cancer. Enrollment fractions (EF) were calculated using prevalence data from the Surveillance, Epidemiology, and End Results (SEER) Database. Odds ratios (OR) and 95% Confidence Intervals (CI) were calculated to compare minority enrollment rates to Non-Hispanic (NH) White enrollment rates. <h3>Results:</h3> A 48 trials were identified, 17 of which met inclusion criteria (12 ovarian, 2 breast and 3 breast and ovarian). For ovarian cancer trials, enrollment fractions were NH-White 1.5%, NH-Black 0.3%, Hispanic 0.5%, and Asian/Pacific Islander the largest at 2.4%. For breast cancer trials, the EF for NH-White participants was 0.005%, for NH-Black patients was 0.008%, for Hispanic patients was 0.003%, and for Asian/Pacific Islander patients, still the highest at 0.009%. Patients identified as NH-Black and Hispanic were significantly underrepresented compared to those identified as NH-White in clinical trials for ovarian cancer (OR 0.23, 95% CI [0.18-0.29] and OR 0.3, 95% CI [0.25-0.38] respectively, <i>p</i>-value of < 0.0001). In breast cancer trials, both NH-Black and Asian/Pacific Islander groups were significantly overrepresented compared to the NH-White (OR 1.54, 95% CI [1.02, 2.33] p=0.042, and OR 1.81, 95% CI [1.01, 3.26] p=0.047 respectively). EF comparisons for ovarian and breast cancer are noted in Table 1. <h3>Conclusions:</h3> NH-Black and Hispanic participants are significantly underrepresented in clinical trials evaluating PARP inhibitors for ovarian cancer compared to NH-White cohorts. Phase II and III trials assessing PARP inhibitors for ovarian and breast cancer do not accurately represent the populations diagnosed with these malignancies. Enrollment strategies are needed to increase diversity in PARP inhibitor clinical trials for women's cancers.

Factors influencing rates of genetic testing in African American Women with heritable gynecologic cancers in a racially diverse academic institution

<h3>Objectives:</h3> The purpose of this retrospective study is to determine racial and social determinants associated with use of genetic testing for heritable cancer mutations in a high risk, low community resource academic institution population. <h3>Methods:</h3> Women with a personal or family history of heritable cancer (ovarian, fallopian tube, primary peritoneal, breast, colorectal, and endometrial) were identified through the electronic medical record database from August 2015 through August 2019. Demographics (age, sex, race, ethnicity), insurance, and clinical parameters including medical, surgical, social determinants, prior cancer, and family cancer history were evaluated. Patients without a heritable cancer history were excluded.Summary statistics and exact binomial testing were used for comparisons of the rate of genetic testing at the study hospital versus that of reported normative data. To examine whether the internal rates of testing are associated with either demographic or clinical factors, both bivariate and multivariate analyses were performed. For bivariate analyses, chi-square or fisher exact tests for categorical measures and either t-tests or Wilcoxon rank sum tests for continuous measures were used. The effect of the integration of panel testing, which was instituted in August 2017, was determined using a bivariate analysis comparing the groups of patients that were seen before or after August 2017. <h3>Results:</h3> Of the 344 patients analyzed, only 54 (16%) underwent genetic testing, which is significantly lower than the national average (p<0.0003). Race played a significant factor in rates of genetic testing, with African Americans testing at a lower rate than the overall population (p<0.03). Interestingly, insurance type and Hispanic ethnicity did not have an impact on the likelihood of genetic testing. Genetic testing rates were higher in patients with a personal or family history of breast cancer (p<0.015). Notably, although the overall rates of genetic testing increased from 10.3% (95% CI, 6.23 to 16.5) to 18.5% (95% CI, 13.8 to 24.3) after the inclusion of the panel testing, race still played a significant factor in determining the probability of whether testing was performed. <h3>Conclusions:</h3> The findings of this study highlight a lower rate of genetic testing among African American women diagnosed with heritable cancers relative to national recommendations. Our results indicate that despite inclusion of panel testing, racial disparities in rates of testing persist in our vulnerable, high risk population. Interventions to overcome implicit bias and patient education should be further developed.

Efficacy of niraparib by timing of surgery and residual disease: a post-hoc analysis of patients in the PRIMA/ENGOT-OV26/GOG-3012 study

<h3>Objectives:</h3> Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved as maintenance treatment for patients (pts) with newly diagnosed advanced or recurrent ovarian cancer following a response to platinum-based chemotherapy (CT) doublet. The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) study showed that niraparib following first-line treatment improved progression-free survival (PFS) in the overall intention-to-treat (ITT) population (hazard ratio [HR] 0.62; 95% CI 0.50-0.76). <h3>Methods:</h3> This double-blind, placebo (PBO)-controlled, phase 3 trial evaluated niraparib in pts with newly diagnosed, advanced, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer with a complete or partial response to first-line CT. Pts were considered to be at a high risk for disease progression based on their clinical characteristics. This post-hoc analysis presents the efficacy of niraparib, measured by PFS, based on time of surgery and residual disease status, and was not powered to determine differences among the subgroups. <h3>Results:</h3> Data cutoff was May 2019. In total, 733 pts were randomized in the PRIMA study. Efficacy outcomes by surgical timing, either primary debulking surgery (PDS) or interval debulking surgery (IDS), and postoperative residual disease status, either no visible residual disease (NVRD) or visible residual disease (VRD), are shown in Table. Pts who underwent PDS or IDS had similar efficacy with niraparib maintenance treatment versus PBO in the ITT population (PFS HRs were 0.67 and 0.57, respectively). Niraparib treatment reduced risk of progression by 42% in pts who received PDS and had VRD, 35% in those with IDS and NVRD, and 59% in those with IDS and VRD. Efficacy was not evaluable for pts with PDS and NVRD due to low sample size. <h3>Conclusions:</h3> In this post-hoc analysis, the impact of residual disease after PDS or IDS on the efficacy of niraparib was comparable across subgroups. Pts with IDS and VRD had the highest reduction in the risk of progression

Fuzuloparib maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer: a multicenter, randomized, double-blind, placebo-controlled, phase III trial

<h3>Objectives:</h3> Fuzuloparib (formerly fluzoparib), a poly (ADP-ribose) polymerase inhibitor, has shown promising antitumor activity and acceptable safety for the treatment of relapsed ovarian cancer patients harboring the <i>BRCA1/2</i> mutation after 2-4 lines of platinum-based chemotherapy in previous phase 2 trial. This study aimed to assess the efficacy and safety of fuzuloparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. <h3>Methods:</h3> This is a multicenter, double-blind, randomized, placebo-controlled, phase 3 trial conducted at 36 sites in China. Eligible patients had platinum-sensitive, relapsed, high-grade serious ovarian, fallopian tube, primary peritoneal or endometrioid ovarian carcinoma (≥grade 2), had received at least two prior platinum-based regimens and had achieved complete or partial response to their last platinum-based regimen. Patients were randomly assigned in a 2:1 ratio to fuzuloparib (150 mg, twice daily) or matching placebo using an interactive web response system. Randomization was stratified by <i>BRCA1/2</i> mutation (presence or absence), progression-free interval after penultimate platinum-based regimen (6-12 months or >12 months) and best response to most recent regimen (complete or partial response). The co-primary endpoints were progression-free survival (PFS) assessed by blinded independent central review (BICR) in the overall population and in the <i>BRCA1/2</i> mutation population. Here, we reported the results of the prespecified interim analysis from this ongoing study, which was planned for formal statistical testing on PFS per BICR in the overall population. <h3>Results:</h3> Between Apr. 30, 2019 and Jan. 10, 2020, 252 patients were randomly assigned to the fuzuloparib (n=167) or placebo (n=85). <i>BRCA1/2</i> mutations were confirmed in 100 (39.7%) patients. Sixty-one (24.2%) patients had received more than two lines of previous platinum-based regimen, and 127 (50.4%) patients had the complete response to the most recent regimen. As of Jul 1, 2020, the median PFS per BICR assessment in the overall population was significantly improved with fuzuloparib (hazard ratio [HR], 0.25; 95% CI, 0.17-0.36; one-sided P<0.0001; Figure 1). The HR derived from prespecified subgroup analyses showed a consistent trend of benefit in patients with <i>BRCA1/2</i> mutation (HR, 0.14, 95% CI, 0.07-0.28) or without it (HR, 0.46; 95% CI, 0.29-0.74). The most common Grade ≥3 adverse events reported in the fuzuloparib group were anemia (25.1%), decreased platelet count (16.8%), decreased neutrophil count (12.6%) and decreased white blood cell count (10.8%), which were manageable with treatment interruption or dose modifications, with only one (0.6%) patient discontinuing treatment due to neutropenia. <h3>Conclusions:</h3> Fuzuloparib as maintenance therapy achieved a statistically significant and clinically meaningful improvement in PFS for patients with platinum-sensitive, relapsed ovarian cancer compared with placebo, regardless of <i>BRCA1/2</i> mutation, and had a manageable safety profile.

Clinicopathologic Features of Gynecologic Malignancies Presenting Clinically as Colonic Malignancies.

To systematically evaluate gynecologic malignancies (adnexal or uterine) causing gastrointestinal (GI) signs (eg, mass on colonoscopy) or symptoms (eg, bloody stools) clinically mimicking a GI primary malignancy. The archives of 2 institutions were retrospectively reviewed for gynecologic malignancies clinically manifesting as colonic lesions. For each case, available radiologic, endoscopic, and histologic findings were recorded. We identified 16 cases: 13 biopsies and 3 resections. The masses were localized in the rectosigmoid (14 cases [88%]), right (1 case [6%]), and transverse (1 case [6%]) colon. Gastrointestinal-type complaints included abdominal pain, weight loss, hematochezia, and obstruction; 1 case was asymptomatic and found during screening colonoscopy. Nine patients (56%) had no known prior gynecologic malignancy, and in only 2 of these patients was there some clinical suspicion of a noncolonic primary malignancy. Most cases (13 [81%]) were serous carcinoma, usually high-grade adnexal or primary peritoneal. Six cases (38%) directly extended into the colon, and 7 (44%) metastasized; route of spread was unclear in the others. Only 1 case (6%) showed mucosal involvement, and none showed desmoplasia or dirty necrosis. Four of the 13 serous carcinomas (31%) showed psammoma bodies. Advanced gynecologic malignancies, most commonly serous carcinoma, can rarely manifest as GI lesions. Clues to noncolonic origin on biopsy include lack of colonic mucosal involvement/dysplasia, desmoplasia, or dirty necrosis.

Head-to-head comparison of [68Ga]Ga-FAPI-04 and [18F]-FDG PET/CT in evaluating the extent of disease in gastric adenocarcinoma

Background[18F]-Fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET/CT) may sometimes be suboptimal for imaging gastric adenocarcinoma. The recently introduced [68Ga]Ga-FAPI-04 (FAPI) PET/CT targets tumor stroma and has shown considerable potential in evaluating the extent of disease in a variety of tumors.MethodsWe performed a head-to-head prospective comparison of FAPI and FDG PET/CT in the same group of 13 patients with gastric adenocarcinoma who presented for either initial staging (n = 10) or restaging (n = 3) of disease. Lesion detection and maximum standardized uptake value (SUVmax) were compared between the two types of radiotracers.ResultsAll ten primary gastric tumors were FAPI-positive (100% detection rate), whereas only five were also FDG-positive (50%). SUVmax was not significantly different, but the tumor-to-background ratio was higher for FAPI (mean, median, and range of 4.5, 3.2, and 0.8–9.7 for FDG and 12.9, 11.9, and 2.2–23.9 for FAPI, P = 0.007). The level of detection of regional lymph node involvement was comparable. FAPI showed a superior detection rate for peritoneal carcinomatosis (100% vs. none). Two patients with widespread peritoneal carcinomatosis underwent a follow-up FAPI scan after chemotherapy: one showed partial remission and the other showed progressive disease.ConclusionsThe findings of this pilot study suggest that FAPI PET/CT outperforms FDG PET/CT in detecting both primary gastric adenocarcinoma and peritoneal carcinomatosis from gastric cancer. FAPI PET/CT also shows promise for monitoring response to treatment in patients with peritoneal carcinomatosis from gastric cancer; however, larger trials are needed to validate these preliminary findings.

Abstract 3186: Differential expression of PD-L1 between primary and metastatic Middle-Eastern epithelial ovarian carcinoma and its clinico-pathological correlation

Abstract Ovarian cancer (OC) is one of the most common gynecologic cancer, which has the worst prognosis and highest mortality rate. The lack of curative treatment and the high relapse rate, especially in advanced OC, continues to present a clinical challenge, highlighting the need for new therapeutic strategies. This study was conducted to compare the expression of PD-L1 in Middle-Eastern primary epithelial ovarian carcinoma to that in peritoneal metastases and its correlation with clinico-pathological parameters. In total, 194 treatment naïve paired EOC and peritoneal metastases were analyzed by immunohistochemistry for PD-L1 expression. Clinico-pathological information was available for all patients. Significant differences in PD-L1 expression were found between primary EOC and peritoneal metastasis (p &amp;lt; 0.0001). We found discordant tumor cell PD-L1 expression between primary tumors and corresponding peritoneal metastasis in 34% (66/194) of cases. Furthermore, PD-L1 expression in peritoneal metastasis samples was significantly associated with adverse prognostic factors, such as high proliferative index (Ki67) (p = 0.0039) and high histologic grade (p = 0.0330). In conclusion, the heterogeneity of PD-L1 expression in EOC suggests its assessment as a potential biomarker for PD-L1 blockade may require analysis of metastatic lesions. Citation Format: Sandeep K. Parvathareddy, Abdul K. Siraj, Padmanaban Annaiyappanaidu, Felisa De Vera, Yan Kong, Zeeshan Qadri, Saeeda O. Ahmed, Hassan AlDossari, Khawla S. Al-Kuraya. Differential expression of PD-L1 between primary and metastatic Middle-Eastern epithelial ovarian carcinoma and its clinico-pathological correlation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3186.

Assessment of Adult Women With Ovarian Masses and Treatment of Epithelial Ovarian Cancer: ASCO Resource-Stratified Guideline.

PURPOSETo provide expert guidance to clinicians and policymakers in three resource-constrained settings on diagnosis and staging of adult women with ovarian masses and treatment of patients with epithelial ovarian (including fallopian tube and primary peritoneal) cancer.METHODSA multidisciplinary, multinational ASCO Expert Panel reviewed existing guidelines, conducted a modified ADAPTE process, and conducted a formal consensus process with additional experts.RESULTSExisting sets of guidelines from eight guideline developers were found and reviewed for resource-constrained settings; adapted recommendations from nine guidelines form the evidence base, informing two rounds of formal consensus; and all recommendations received ≥ 75% agreement.RECOMMENDATIONSEvaluation of adult symptomatic women in all settings includes symptom assessment, family history, and ultrasound and cancer antigen 125 serum tumor marker levels where feasible. In limited and enhanced settings, additional imaging may be requested. Diagnosis, staging, and/or treatment involves surgery. Presurgical workup of every suspected ovarian cancer requires a metastatic workup. Only trained clinicians with logistical support should perform surgical staging; treatment requires histologic confirmation; surgical goal is staging disease and performing complete cytoreduction to no gross residual disease. In first-line therapy, platinum-based chemotherapy is recommended; in advanced stages, patients may receive neoadjuvant chemotherapy. After neoadjuvant chemotherapy, all patients should be evaluated for interval debulking surgery. Targeted therapy is not recommended in basic or limited settings. Specialized interventions are resource-dependent, for example, laparoscopy, fertility-sparing surgery, genetic testing, and targeted therapy. Multidisciplinary cancer care and palliative care should be offered.Additional information can be found at www.asco.org/resource-stratified-guidelines. It is ASCO's view that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines.

Incidence and patient characteristics of venous thromboembolism during neoadjuvant chemotherapy for ovarian cancer.

There is paucity of data on venous thromboembolism (VTE) in patients receiving neoadjuvant chemotherapy (NACT) for advanced stage ovarian cancer. We explored the incidence and predictors of VTE in this patient population. We performed a retrospective review of women with primary ovarian, fallopian tube or peritoneal cancer who received NACT between January 2012 and October 2018 at Cooper University Hospital. Patients with history of VTE, heparin therapy or direct oral anticoagulant use prior to cancer diagnosis were excluded. The primary outcome was incidence of deep vein thrombosis (DVT) or pulmonary embolism (PE) after cancer diagnosis. We explored demographic and clinical variables associated with VTE. Of 90 patients included, 25 (28%) were diagnosed with VTE and 16 (64%) had PE. Eight patients were diagnosed after cancer diagnosis prior to the start of chemotherapy and 17 patients during NACT. Most patients had stage III disease and serous adenocarcinoma. There was a trend towards increased risk of VTE for Black patients (OR 3.22; CI 0.997-10.42; P = 0.051). Significantly fewer patients with VTE had debulking surgery (60% vs. 88%, P = 0.005). The risk of DVT increased by 8.7% per year of age (OR 1.087; 95% CI 1.01-1.17). Obesity, smoking status, medical comorbidities, disease stage, histology, invasive diagnostic surgery, and length of NACT were not associated with VTE. The incidence of VTE during neoadjuvant chemotherapy is high. Older age and Black race may increase the risk of VTE, and this morbid complication may adversely impact cancer treatment.

Maximum Tolerated Dose and Anti-Tumor Activity of Intraperitoneal Cantrixil (TRX-E-002-1) in Patients with Persistent or Recurrent Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer: Phase I Study Results.

Simple SummarySurvival outcomes with standard cytotoxic chemotherapy are poor, and most patients with ovarian cancer will die with platinum-resistant disease. This may reflect the existence of drug-resistant ovarian cancer stem cells. Cantrixil is a novel third-generation benzopyran molecule, with potent cytotoxicity against chemoresistant ovarian cancer stem cells and chemosensitive ovarian cancer cell lines. The aims of this Phase I study were to define the maximum tolerated dose, tolerability, and antitumor activity of Cantrixil when administered via an intraperitoneal (IP) port. Cantrixil was tolerable even in patients with heavily pretreated disease. This first in-human study has demonstrated the potential for prolonged survival in advanced ovarian cancer by inducing ovarian cancer stem cells’ death and sensitizing cells to standard chemotherapy with IP-administered Cantrixil. Future studies should focus on confirming its mechanism of action alongside further assessment of cancer stem cell biomarkers, and determining optimal clinical settings to maximize survival outcomes in ovarian cancer.Survival outcomes in ovarian cancer are poor. The aims of this Phase I progressive design study (NCT02903771) were to evaluate the maximum tolerated dose (MTD), tolerability, and antitumor activity of Cantrixil—a novel third-generation benzopyran molecule—in patients (n = 25) with advanced, recurrent/persistent epithelial ovarian, primary peritoneal, or fallopian tube cancer. All had completed ≥ 2 prior regimens; 3 (12%) had platinum-refractory disease, and 17 (68%) had platinum-resistant disease. Following intraperitoneal (IP) port placement, patients received weekly IP Cantrixil in 3-week cycles as monotherapy (Cycles 1–2), and then in combination with intravenous (IV) chemotherapy (Cycles 3–8). Part A (dose escalation) enrolled 11 patients in 6 dose-level cohorts. An MTD of 5 mg/kg was established with dose-limiting toxicity of ileus. Most treatment-related adverse events were gastrointestinal. Across Parts A and B (dose expansion), 16 (64%) patients received ≥ 1 3-week Cantrixil cycle, and had ≥ 1 post-baseline efficacy measurement available. The results show promising anti-tumor activity in monotherapy (stable disease rate of 56%) and in combination with IV chemotherapy (objective response rate of 19%, disease control rate of 56%, and median progression-free survival of 13.1 weeks). The molecular target and mechanism of action of Cantrixil are yet to be confirmed. Preliminary analysis of stem cell markers suggests that IP Cantrixil might induce ovarian cancer stem cell death and sensitize cells to standard chemotherapy, warranting further evaluation.

Prevalence of BRCA1 and BRCA2 Mutations Among Patients With Ovarian, Primary Peritoneal, and Fallopian Tube Cancer in India: A Multicenter Cross-Sectional Study.

PURPOSEThere are deficient data on prevalence of germline mutations in breast cancer susceptibility genes 1 and 2 (BRCA1/BRCA2) in Indian patients with ovarian cancer who are not selected by clinical features.METHODSThis prospective, cross-sectional, noninterventional study in nine Indian centers included patients with newly diagnosed or relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer. The primary objective was to assess the prevalence of BRCA1/BRCA2 mutations, and the secondary objective was to correlate BRCA1/BRCA2 status with clinicopathologic characteristics. Mutation testing was performed by a standard next-generation sequencing assay.RESULTSBetween March 2018 and December 2018, 239 patients with a median age of 53.0 (range, 23.0-86.0 years) years were included, of whom 203 (84.9%) had newly diagnosed disease, 36 (15.1%) had family history of ovarian or breast cancer, and 159 (66.5%) had serous subtype of epithelial ovarian cancer. Germline pathogenic or likely pathogenic mutations in BRCA1 and BRCA2 were detected in 37 (15.5%; 95% CI, 11.1 to 20.7) and 14 (5.9%; 95% CI, 3.2 to 9.6) patients, respectively, whereas variants of uncertain significance in these genes were seen in four (1.7%; 95% CI, 0.5 to 4.2) and six (2.5%; 95% CI, 0.9 to 5.4) patients, respectively. The prevalence of pathogenic or likely pathogenic BRCA mutations in patients with serous versus nonserous tumors, with versus without relevant family history, and ≤ 50 years versus > 50 years, were 40 of 159 (25.2%; 95% CI, 18.6 to 32.6) versus 11 of 80 (13.8%; 95% CI, 7.1 to 23.3; P = .0636), 20 of 36 (55.6%; 95% CI, 38.1 to 72.1) versus 41 of 203 (20.2%; 95% CI, 14.9 to 26.4; P < .0001), and 20 of 90 (22.2%; 95% CI, 14.1 to 32.2) versus 31 of 149 (20.8%; 95% CI, 14.6 to 28.2; P = .7956), respectively.CONCLUSIONThere is a high prevalence of pathogenic or likely pathogenic germline BRCA mutations in Indian patients with ovarian cancer.

FC 105LITHIUM PRESERVES PERITONEAL MEMBRANE INTEGRITY BY REDUCING MESOTHELIAL CELL ΑB-CRYSTALLIN

Abstract Background and Aims Renal replacement therapy by peritoneal dialysis (PD) is limited in use and duration by progressive impairment of peritoneal membrane integrity and homeostasis. Preservation of peritoneal membrane integrity during chronic PD remains an urgent but long-unmet medical need. PD therapy failure results from peritoneal fibrosis and angiogenesis caused by hypertonic PD fluid (PDF)-induced mesothelial cytotoxicity. The incompletely defined pathophysiological mechanisms involved confound informed selection of therapeutic targets. Addition of cytoprotective agents to PDF have been shown to counteract pathophysiological mechanisms induced by current PDF. Lithium is a well described inhibitor of glycogen synthase kinase 3β and has recently been shown to also have nephroprotective effects in low doses. Here, we aim to characterize icodextrin-based, PDF-induced cellular injury with a combined omics approach and to investigate the effects of LiCl on the PD-induced observed molecular perturbations. Method To investigate mechanisms of acute cellular damage by PDF we chose an in vitro model of primary omental-derived peritoneal mesothelial cells with direct exposure to icodextrin-based PDF, followed by short-term or extended recovery for detection of short-term and long-term changes in transcriptome, proteome, and cell injury. 0, 2.5 or 10 mM LiCl were added to the PDF. In-vitro findings were validated in peritoneal biopsies (n=41) from pediatric PD and CDK5 patients or healthy controls and peritoneal effluents from adult and pediatric PD patients (n=27) or ascites samples (n=4) as control. For in-vivo experiments, healthy and uremic mice (C57/Bl6, female) were chronically exposed to PD-fluid without or with the addition of 5 mM LiCl via an implanted catheter. In-vivo overexpression of CRYAB was induced by i.p. injection of an adenoviral vector. All animal experiments and use of patient samples were approved by the local ethics committees and performed according to animal protection laws or the Declaration of Helsinki, respectively. Results LiCl significantly improved mesothelial cell survival in a dose-dependent manner. Combined transcriptomic and proteomic characterization of icodextrin-based PDF-induced mesothelial cell injury identified αB-crystallin as the mesothelial cell protein most significantly and consistently counter-regulated by LiCl. In-vitro and in-vivo overexpression of αB-crystallin triggered a fibrotic phenotype and PDF-like upregulation of vascular endothelial growth factor (VEGF), CD31-positive cells, and TGFβ-independent activation of TGFβ-regulated targets. In contrast, αB-crystallin knock-down decreased VEGF expression and early mesothelial-to-mesenchymal transition (MMT). LiCl reduced VEGF release and counteracted fibrosis- and angiogenesis-associated processes. αB-crystallin in patient-derived mesothelial cells was specifically upregulated in response to PDF and increased in peritoneal mesothelial cells from pediatric PD patient biopsies, correlating with markers of angiogenesis and fibrosis. Conclusion The cytoprotective effects of LiCl-supplemented PDF may be explained by counter-regulation of PD-induced angiogenesis via the novel target αB-crystallin. Reduction of mesothelial cell damage, peritoneal fibrosis and VEGF suggests therapeutic potential of this intervention. Repurposing LiCl as a cytoprotective PDF additive may offer a translatable therapeutic strategy to combat peritoneal membrane deterioration during PD therapy. Further study of LiCl-supplemented PDF is merited as a realistic approach to improving treatment longevity and patient outcomes during PD treatment.