Primary Peritoneal Research Articles

Efficacy of niraparib by time of surgery and postoperative residual disease status: A post hoc analysis of patients in the PRIMA/ENGOT-OV26/GOG-3012 study

ObjectiveTo evaluate the association between surgical timing and postoperative residual disease status on the efficacy of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer at high risk of recurrence. MethodsPost hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) study of niraparib in patients with newly diagnosed primary advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete/partial response to first-line platinum-based chemotherapy. Progression-free survival (PFS) was assessed by surgical status (primary debulking surgery [PDS] vs neoadjuvant chemotherapy/interval debulking surgery [NACT/IDS]) and postoperative residual disease status (no visible residual disease [NVRD] vs visible residual disease [VRD]) in the intent-to-treat population. ResultsIn PRIMA (N = 733), 236 (32.2%) patients underwent PDS, and 481 (65.6%) received NACT/IDS before enrollment. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) for progression were similar in PDS (13.7 vs 8.2 months; HR, 0.67 [0.47–0.96]) and NACT/IDS (14.2 vs 8.2 months; HR, 0.57 [0.44–0.73]) subgroups. In patients who received NACT/IDS and had NVRD (n = 304), the hazard ratio (95% CI) for progression was 0.65 (0.46–0.91). In patients with VRD following PDS (n = 183) or NACT/IDS (n = 149), the hazard ratios (95% CI) for progression were 0.58 (0.39–0.86) and 0.41 (0.27–0.62), respectively. PFS was not evaluable for patients with PDS and NVRD because of sample size (n = 37). ConclusionsIn this post hoc analysis, niraparib efficacy was similar across PDS and NACT/IDS subgroups. Patients who had NACT/IDS and VRD had the highest reduction in the risk of progression with niraparib maintenance.

FC088: Molecular and Functional Characterization of the Mesothelial and Endothelial Cell Barrier in Health, Ckd and Peritoneal Dialysis

Abstract BACKGROUND AND AIMS Tight junctions (TJ) and transcellular ion channels and transporters define solute transport characteristics across cellular barriers, which is of particular interest in patients on peritoneal dialysis (PD). Little is known about their cell specific expression, and regulation in PD. We studied their expression in human endothelial and mesothelial cell lines and in paediatric peritoneal tissues. METHOD In vitro, polarized primary human peritoneal mesothelial cells (HPMC), immortalized mesothelial cells (MeT-5A), human umbilical vein endothelial cells (HUVEC) and human capillary microvascular endothelial cells (HCMEC) underwent RNA sequencing, and gene enrichment analysis (GSEA, ClueGO/Cluepedia) for functional annotation. Key findings were reconfirmed by western blotting and confocal laser scanning immunofluorescence microscopy. Transepithelial electrical resistance (TER) and permeability fluxes of fluorescent 4-, 10- and 70-kDa dextran were measured in Transwells. Ex vivo, whole transcriptome and proteome data from microdissected omental arterioles were used for targeted pathway analysis in non-CKD children, chronic kidney disease (CKD5) and on PD with low and high glucose degradation product (GDP) content (n = 6/group). Mesothelial and endothelial peritoneal solute transporting proteins were quantified in parietal peritoneum of independent paediatric non-CKD, CKD5 and PD cohorts by digital immunohistochemistry. RESULTS A total of 9853 of 12 760 transcripts were common between all four cell lines. A total of 631 transcripts were MeT-5A, 366 HPMC, 99 HUVEC and 87 HCMEC specific. Next to the tissue origin and transformation status, the transcripts reflected major differences in extracellular matrix, glycocalyx and adhesion organization between HCMEC and HUVEC, and extracellular matrix, migration, growth factor and immune response between HPMC and MeT-5A cells. While total counts of cell junction, transmembrane and endocytosis related transcripts were similar among cell lines, the specific TJ, transmembrane and endocytosis related transcript patterns, differed substantially between endothelial and mesothelial cells. Of the functionally well described sealing TJs, claudin (CLDN)1 was expressed in mesothelial cells, and CLDN5 in endothelial cells. Findings were reconfirmed by western blotting and immunofluorescence staining. Functionally, transepithelial resistance (TER) was 50% lower for HCMEC compared to HPMC, MeT-5A and HUVEC; 4-, 10- and 70-kDa dextran permeability was increased in HCMEC. Ex vivo, human arteriolar pathway analysis demonstrated upregulation of paracellular transport-related pathways in CKD5 versus non-CKD patients on protein level. Compared to CKD5, low GDP PD upregulated and high GDP PD downregulated these pathways on the transcriptome and protein levels. Transcellular transporter pathway regulation was variable. In the parietal peritoneum the endothelial surface area for transport was age dependently 1.5–2-fold higher than the mesothelial surface area and the ratio markedly increased with low GDP PD. Validation in parietal peritoneal tissues, reconfirmed arteriolar sealing TJ regulation. Arteriolar CLDN2, a paracellular pore forming cation and water transporter, correlated with D/PCreatinine (r = 0.58) and D/D0Glucose (r = –0.62), mesothelial pore forming cation transporter CLDN15 with D/PCreatinine (r = 0.57) and D/D0Glucose (–0.66). Transcellular transporters for sodium, glucose and phosphate were hardly affected by PD; phosphate transporter PIT1 abundance correlated with serum phosphate (r = –0.48). CONCLUSION We provide the first comprehensive analysis of the peritoneal paracellular and transcellular determinants of solute transporters and its regulation by CKD and PD. Mesothelial and endothelial cell barrier sealing and transporter abundance differed substantially, and associated with PD membrane function, with functional data suggesting a key role of both the mesothelial and endothelial cell barrier.

MP20-13 QUANTIFYING TIME TO ORGASM AFTER GENDER AFFIRMING VAGINOPLASTY

You have accessJournal of UrologyCME1 May 2022MP20-13 QUANTIFYING TIME TO ORGASM AFTER GENDER AFFIRMING VAGINOPLASTY Gaines Blasdel, Elijah Castle, Carmen Kloer, Augustus Parker, Rachel Bluebond-Langner, and Lee Zhao Gaines BlasdelGaines Blasdel More articles by this author , Elijah CastleElijah Castle More articles by this author , Carmen KloerCarmen Kloer More articles by this author , Augustus ParkerAugustus Parker More articles by this author , Rachel Bluebond-LangnerRachel Bluebond-Langner More articles by this author , and Lee ZhaoLee Zhao More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002553.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Many transgender and nonbinary (henceforth, “trans”) patients have goals related to sexual health when seeking gender affirming vaginoplasty, and previous investigations have only studied ability to orgasm at cross-sectional timepoints. Our aim is to quantify the time to orgasm postoperative primary robotic peritoneal gender affirming vaginoplasty and describe potential correlative factors, including pre-operative orgasm to better inform preoperative counseling. METHODS: Retrospective chart review was utilized to extract factors thought to influence pre- and post-operative orgasm in patients undergoing robotic peritoneal flap vaginoplasty. Mean days to orgasm plus one standard deviation above that mean was used to define time at which patients would be considered anorgasmic. RESULTS: A total of 199 trans patients underwent surgery from September 2017 to August 2020. Median time to orgasm was 180 days. 178 patients had completed one year of follow up or greater, and of these patients, 153 (86%) were orgasmic and 25 patients (14%) were not (Figure 1). Difficulty in pre-operative orgasm was correlated only with older age (median age 45.9 years versus 31.7, p=.03). Post-operative orgasm was not significantly correlated with pre-operative orgasm. The only factor related to post-operative orgasm was smoking history: 12 of 55 patients (21.8%) who had a positive smoking history and sufficient follow up reported anorgasmia (p-value 0.046). CONCLUSIONS: Preoperative difficulty with orgasm appears to be treated with gender affirming vaginoplasty, conferring similar post-surgical orgasm rates to those who struggled with orgasm before surgery. Smoking had a negative impact on post-operative orgasm recovery despite negative cotinine test prior to surgery, signaling that prolonged smoking cessation may improve orgasmic outcomes, or that underlying exposures correlated with smoking may be the true causal factor inhibiting recovery of orgasm. The majority of patients were orgasmic at their six month follow up appointment, however patients became newly orgasmic in appreciable numbers more than one year after surgery. Interventions for anorgasmic patients include testosterone replacement, pelvic floor physical therapy, and psychotherapy. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e322 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Gaines Blasdel More articles by this author Elijah Castle More articles by this author Carmen Kloer More articles by this author Augustus Parker More articles by this author Rachel Bluebond-Langner More articles by this author Lee Zhao More articles by this author Expand All Advertisement PDF DownloadLoading ...

Effectiveness of oral etoposide in recurrent or refractory epithelial ovarian cancer, primary peritoneal cancer and fallopian tube cancer

The aim of treatment in recurrent or refractory epithelial ovarian cancer is palliation. In a patient with platinum-resistant status, several chemotherapy regimens have been reported with similar response rates. Among these agents, the oral etoposide holds an advantage of the route of administration and management in the out-patient setting. This retrospective study was conducted to evaluate the effectiveness of oral etoposide. Data of patients with recurrent or refractory epithelial ovarian, primary peritoneal and fallopian tube cancer who received oral etoposide treatment in Ramathibodi Hospital, Mahidol University from January 1997 to December 2017 were collected. Progression-free survival (PFS) and overall survival (OS) were primary and secondary outcomes, respectively. The oral etoposide at a dose of 50 mg/m2 was prescribed. Sixty-six records were analysed. Median OS and median PFS were 8.3 months (95% confidence interval (CI): 6.8, 10.4) and 3.1 months (95%CI: 2.3, 3.9), respectively. Other factors including age, body mass index (BMI), histopathology subtype, primary treatment, result of the primary surgery, platinum status, site and size of recurrent cancer, treatment after discontinuation of oral etoposide and the line of chemotherapy regimen were not associated with the prognosis. The initial cancer stage was the only independent poor prognostic factor. The main toxicity was neutropenia. Impact Statement What is already known on this subject? After the recurrence of epithelial ovarian cancer, peritoneal cancer or fallopian tube cancer, the aim of treatment in this setting is palliation with accentuating on symptomatic control and enhancing the quality of life. According to previous clinical trials, the chemotherapy regimens which were considered as a second-line or beyond the second-line therapy have been reported with similar response rates. Among these agents, the oral etoposide could be administrated by oral route. There were several articles reported the effectiveness of oral etoposide in different dosage. What do the results of this study add? This study adds that administration of oral etoposide at a dose of 50 mg/m2 showed fairish oncologic outcomes with manageable toxicity. What are the implications of these findings for clinical practice and/ or further research? The results will provide evidence that the oral etoposide can be considerate as a choice of palliative chemotherapy because of an advantage of the route of administration and management in the out-patient setting.

Superiority of [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT to [18F]FDG PET/CT in delineating the primary tumor and peritoneal metastasis in initial gastric cancer.

This study aimed to compare [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT with [18F]FDG PET/CT in the evaluation of initial gastric cancer. We retrospectively compared [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT with [18F]FDG PET/CT in patients with initial gastric cancer from September 2020 to March 2021. Lesion detectability and the uptake of lesions quantified by the maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR) were compared between the two modalities using the Wilcoxon signed-rank test, Mann-Whitney U test, and McNemar's chi-square test. A total of 61 patients (37 males, aged 23-81 years) were included, of which 22 underwent radical gastrectomy. For primary lesions, higher uptake of [68Ga]Ga-FAPI-04/[18F]FAPI-42 was observed compared to [18F]FDG (median SUVmax, 14.60 vs 4.35, p < 0.001), resulting in higher positive detection using [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT than [18F]FDG PET/CT (95.1% vs 73.8%, p < 0.001), particularly for tumors with signet-ring cell carcinoma (SRCC) (96.4% vs 57.1%, p < 0.001). [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT detected more positive lymph nodes than [18F]FDG PET/CT (637 vs 407). However, both modalities underestimated N staging compared to pathological N staging. [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT showed a higher sensitivity (92.3% vs 53.8%, p = 0.002) and peritoneal cancer index score (18 vs 3, p < 0.001) in peritoneum metastasis and other suspect metastases compared to [18F]FDG PET/CT. Our findings indicate that [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT outperformed [18F]FDG PET/CT in the evaluation of primary tumors with SRCC and peritoneum metastasis in initial gastric cancer. However, no clinically useful improvement was seen in N staging. • The uptake of [68Ga]Ga-FAPI-04/[18F]FAPI-42 in primary tumor and metastasis was intensely higher than that of [18F]FDG (p < 0.001) in 61 patients with initial gastric cancer. • [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT had a higher sensitivity detection in primary tumors (95.1% vs 73.8%, p < 0.001) and peritoneal metastases (92.3% vs 53.8%, p = 0.002) than [18F]FDG PET/CT. • [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT depicted more positive lymph nodes than [18F]FDG PET/CT (637 vs 407); however, both underestimated N staging compared to pathological N staging.

Weekly versus tri-weekly paclitaxel with carboplatin for first-line treatment in women with epithelial ovarian cancer.

Epithelial ovarian cancer is the sixth most common cancer worldwide: 295,414 new cases were diagnosed in 2018, with 184,799 deaths. The lack of an effective screening strategy has led to the majority of women being diagnosed at an advanced stage. For these women, intravenous carboplatin combined with paclitaxel for six cycles is widely accepted as the standard first-line treatment for epithelial ovarian cancer, in combination with debulking surgery. However, there is conflicting evidence regarding the optimal dosing schedule of paclitaxel when combined with carboplatin in this setting. To compare the efficacy and tolerability of intravenous weekly paclitaxel with that of tri-weekly paclitaxel, in combination with intravenous carboplatin, as first-line treatment for epithelial ovarian cancer (defined as epithelial ovarian, primary peritoneal and fallopian tube cancer). We searched CENTRAL, MEDLINE, and Embase databases for relevant studies up to 15 November 2021, using keywords and MeSH terms. We additionally handsearched conference libraries, online clinical trial databases and screened through lists of retrieved references. We Included randomised controlled trials (RCTs) comparing weekly paclitaxel in combination with carboplatin versus tri-weekly paclitaxel in combination with carboplatin, for treatment of newly-diagnosed epithelial ovarian cancer. We used the hazard ratio (HR) to estimate the primary efficacy outcomes progression-free (PFS) and overall survival (OS). We used the risk ratio (RR) to estimate the primary toxicity outcome of severe neutropenia and secondary outcomes of quality of life (QoL) and treatment-related adverse events. Two review authors independently selected studies, extracted data, and assessed risk of bias, using standard Cochrane methodological procedures. We included individual participant data (IPD) from one of the included studies, ICON-8, provided by the study team. We analysed data using a random-effects model in Review Manager 5.4 software. Additionally, we reconstructed IPD for PFS and OS data from published Kaplan-Meier curves from all studies and subsequently pooled these to analyse the two primary efficacy outcomes. From 2469 records, we identified four eligible RCTs with data for 3699 participants. All eligible studies were included in the main meta-analysis and reported on PFS and OS. There was likely a slight improvement in PFS when paclitaxel was dosed weekly compared to tri-weekly (HR 0.89, 95% confidence interval (CI) 0.81 to 0.98; 4 studies, 3699 participants; moderate-certainty evidence). We found little to no improvement in OS when paclitaxel was dosed weekly compared to tri-weekly (HR 0.92, 95% CI 0.79 to 1.06; 4 studies, 3699 participants; high-certainty evidence). There was likely little to no difference in high-grade (grade 3 or 4) neutropenia when paclitaxel was dosed weekly compared to tri-weekly (RR 1.11, 95% CI 0.86 to 1.43; 4 studies, 3639 participants; moderate-certainty evidence). However, weekly paclitaxel increased high-grade (grade 3 or 4) anaemia when compared to tri-weekly dosing (RR 1.57, 95% CI 1.12 to 2.20; 4 studies, 3639 participants; high-certainty evidence). There may be little to no difference in high-grade neuropathy when paclitaxel was dosed weekly compared to tri-weekly (RR 1.12, 95% CI 0.64 to 1.94; 4 studies, 3639 participants; low-certainty evidence). The overall risk of detection bias and performance bias was low for OS, but was unclear for other outcomes, as treatments were not blinded. The risk of bias in other domains was low or unclear. We note that OS data were immature for three of the included studies (GOG-0262, ICON-8 and MITO-7). Weekly paclitaxel combined with carboplatin for first-line treatment of epithelial ovarian cancer likely improves PFS slightly (moderate-certainty evidence) but not OS (high-certainty evidence), compared to tri-weekly paclitaxel combined with carboplatin. However, this was associated with increased risk for high-grade anaemia, treatment discontinuation, dose delays and dose omissions (high- to low-certainty evidence). Our findings may not apply to women receiving bevacizumab in first-line therapy, those receiving treatment in the neo-adjuvant setting, or those with rare subtypes of clear cell or mucinous ovarian cancer.

C-MET/VEGFR-2 co-localisation impacts on survival following bevacizumab therapy in epithelial ovarian cancer: an exploratory biomarker study of the phase 3 ICON7 trial

IntroductionBevacizumab improves survival outcomes in women diagnosed with epithelial ovarian cancer (EOC). Pre-clinical data showed that the c-MET/VEGFR-2 heterocomplex negates VEGF inhibition through activation of c-MET signalling, leading to a more invasive and metastatic phenotype. We evaluated the clinical significance of c-MET and VEGFR-2 co-localisation and its association with VEGF pathway-related single nucleotide polymorphisms (SNPs) in women participating in the phase 3 trial, ICON7 (ClinicalTrials.gov identifier: NCT00262847).Materials and methodsPatients had FIGO stage I-IIA grade 3/poorly differentiated or clear cell carcinoma or stage IIB-IV epithelial ovarian, primary peritoneal or fallopian tube cancer. Immunofluorescence staining for co-localised c-MET and VEGFR-2 on tissue microarrays and genotyping of germline DNA from peripheral blood leukocytes for VEGFA and VEGFR-2 SNPs was performed. The significance of these biomarkers was assessed against survival.ResultsTissue microarrays from 178 women underwent immunofluorescence staining. Multivariable analysis showed that greater c-MET/VEGFR-2 co-localisation predicted worse OS in patients treated with bevacizumab after adjusting for FIGO stage and debulking surgery outcome (hazard ratio [HR] 1.034, 95% confidence interval [95%CI] 1.010–1.059). Women in the c-MET/VEGFR-2HIGH group treated with bevacizumab demonstrated significantly reduced OS (39.3 versus > 60 months; HR 2.00, 95%CI 1.08–3.72). Germline DNA from 449 women underwent genotyping. In the bevacizumab group, those women with the VEGFR-2 rs2305945 G/G variant had a trend towards shorter PFS compared with G/T or T/T variants (18.3 versus 23.0 months; HR 0.74, 95%CI 0.53–1.03).ConclusionsIn bevacizumab-treated women diagnosed with EOC, high c-MET/VEGFR-2 co-localisation on tumour tissue and the VEGFR-2 rs2305945 G/G variant, which may be biologically related, were associated with worse survival outcomes.

Primary multiple peritoneal hydatid cysts in 12 years old child

The hydatid cyst (HC) is a parasitic infection produced by cysts comprising Echinococcus granulosus larval stage. It is higher in rural areas in some underdeveloped countries, Yemen. Primary peritoneal and mesenteric HC are uncommon without a precise mechanism of manifestation. Hence, we report a 12-year-old boy was presented with recurrent abdominal pain and gradual growth of abdominal mass in the last three months. Abdominal Computed tomography confirmed three large calcified lesions (one in the left hypochondrium, one in the right and midabdominal region, and the last one in the pelvis, which caused a pressure effect on the urinary bladder). Surgical excisions were made, and the patient left the hospital with oral medication on the sixth postoperative day. Pathological specimen examinations confirmed cystic hydatidosis. In conclusion, primary peritoneal and mesentery HCs are rare. In the case of abdominal mass, HC must be considered in the differential diagnosis, particularly in endemic areas.

Rare as hen’s teeth: laparoscopic management of primary pelvic hydatid cyst

Hydatid disease is a zoonotic parasitic disease most frequently caused by echinococcus granulose Primary peritoneal hydatidosis is very rare. We report a case of primary hydatid disease of the intraperitoneal pelvic space. A 22-year-old male patient presented with a history of abdominal pain since 5 months. Abdominal examination revealed a smooth, firm, mildly tender, non-mobile lump in suprapubic region, on digital rectal examination, a smooth spherical mass was felt anteriorly and laterally outside the rectal wall, rectal mucosa was normal. All routine investigations including liver function tests were within normal limits Computed tomography scan of the whole abdomen showed giant cyst of 10×10 cm with multiple well-defined cysts in rectovesical pouch. Diagnostic laparoscopy was performed. The liver, spleen, mesentery, omentum was found to be normal. A large tense hydatid cyst was noted in the pelvic cavity. Partial peri-cystectomy with endo-cystectomy was performed. Postoperative period was uneventful and patient was discharged on 4th postoperative day. Primary intra-abdominal but extra-peritoneal localization has been reported in only 0.2-2% cases making it a very rare entity. The treatment of choice for pelvic hydatid cyst is principally a careful surgical excision. Here with minimum invasive technique this case was operated and results were excellent.

Inhibition of Orai Channel Function Regulates Mas-Related G Protein-Coupled Receptor-Mediated Responses in Mast Cells.

Mast cells (MCs) are tissue resident immune cells that play important roles in the pathogenesis of allergic disorders. These responses are mediated via the cross-linking of cell surface high affinity IgE receptor (FcϵRI) by antigen resulting in calcium (Ca2+) mobilization, followed by degranulation and release of proinflammatory mediators. In addition to FcϵRI, cutaneous MCs express Mas-related G protein-coupled receptor X2 (MRGPRX2; mouse ortholog MrgprB2). Activation of MRGPRX2/B2 by the neuropeptide substance P (SP) is implicated in neurogenic inflammation, chronic urticaria, mastocytosis and atopic dermatitis. Although Ca2+ entry is required for MRGPRX2/B2-mediated MC responses, the possibility that calcium release-activated calcium (CRAC/Orai) channels participate in these responses has not been tested. Lentiviral shRNA-mediated silencing of Orai1, Orai2 or Orai3 in a human MC line (LAD2 cells) resulted in partial inhibition of SP-induced Ca2+ mobilization, degranulation and cytokine/chemokine generation (TNF-α, IL-8, and CCL-3). Synta66, which blocks homo and hetero-dimerization of Orai channels, caused a more robust inhibition of SP-induced responses than knockdown of individual Orai channels. Synta66 also blocked SP-induced extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation and abrogated cytokine/chemokine production. It also inhibited SP-induced Ca2+ mobilization and degranulation in primary human skin MCs and mouse peritoneal MCs. Furthermore, Synta66 attenuated both SP-induced cutaneous vascular permeability and leukocyte recruitment in mouse peritoneum. These findings demonstrate that Orai channels contribute to MRGPRX2/B2-mediated MC activation and suggest that their inhibition could provide a novel approach for the modulation of SP-induced MC/MRGPRX2-mediated disorders.

Next Generation Sequencing is a Reliable Tool for Detecting BRCA1/2 Mutations, Including Large Genomic Rearrangements

Next-generation sequencing (NGS) has been implemented as a rapid and cost-effective BRCA1/2 test strategy. The Oncomine™ BRCA Research Assay is an NGS-based tool for simultaneous detection of small-scale mutations and large genomic rearrangements (LGRs). We evaluated this NGS assay using different versions of Ion Reporter™ (IR) software. A total of 258 patients with breast, ovarian, primary peritoneal, and fallopian tube cancer, or a family history thereof, were enrolled in the study. The NGS assay was implemented for all samples, and the results were compared with those of Sanger sequencing and MLPA. All small-scale variations in Sanger sequencing were successfully detected by NGS assay. For the detection of LGRs, this assay showed 100% sensitivity from IR v5.10, and the latest version of the software (v5.16) showed the highest sensitivity and specificity. NGS with an appropriately updated workflow proved reliable for comprehensive BRCA1/2 gene testing, including LGR screening, which could facilitate efficient and accurate decision-making regarding treatment.

Clinical guidelines for diagnosis, treatment and monitoring of patients with ovarian cancer, Fallopian tube cancer and primary peritoneal can

Clinical guidelines for diagnosis, treatment and monitoring of patients with ovarian cancer, Fallopian tube cancer and primary peritoneal can

Clinical outcomes of BRCA1/2 pathogenic variants in ovarian cancer cluster region in patients with primary peritoneal, epithelial ovarian, and fallopian tube cancer

ObjectiveAn “ovarian cancer cluster region” (OCCR) has been reported in both BRCA1 and BRCA2. However, the clinical significance of the OCCR of BRCA1/2 has not yet been investigated. MethodsThe medical records of 991 patients with epithelial ovarian, primary peritoneal, and fallopian tube cancer who underwent genetic testing for BRCA1 and/or BRCA2 from January 1, 2006, to August 31, 2019, were retrospectively reviewed. Sanger and next-generation sequencing analyses were used to test the BRCA1 and BRCA2 mutation status. Progression-free survival (PFS) and overall survival (OS) were compared according to the mutation location (OCCR vs. non-OCCR region). Survival outcomes were determined using Kaplan–Meier survival analysis. ResultsA total of 162 patients had BRCA1 pathogenic variants (PVs), and 76 had BRCA2 PVs. Patients with BRCA1 PV that in the OCCR region showed shorter PFS than those with BRCA1 PV outside the OCCR (22.6 months vs. 27.6 months, P = 0.038). In the platinum-sensitive subgroup of BRCA1, patients with BRCA1 PV in the OCCR region showed shorter PFS than those in the non-OCCR group (P = 0.0197). On the other hand, BRCA2 variants did not exhibit any particular trend (32.8 months vs. 27.9 months, P = 0.468). However, no significant differences were detected in OS between patients with BRCA1/2 PVs, regardless of the location of the variants. ConclusionsPatients with BRCA1 PV in the OCCR had shorter PFS than those outside the OCCR. This tendency was more pronounced in the platinum-sensitive subgroup. To our knowledge, this is the first study of BRCA1/2 mutations based on the OCCR.

Maintenance therapy of patients with recurrent epithelial ovarian carcinoma with the anti-tumor-associated-mucin-1 antibody gatipotuzumab: results from a double-blind, placebo-controlled, randomized, phase II study

BackgroundGatipotuzumab is a humanized monoclonal antibody recognizing the carbohydrate-induced epitope of the tumor-associated mucin-1 (TA-MUC1). This study aimed to evaluate the efficacy and safety of switch maintenance therapy with gatipotuzumab in patients with TA-MUC1-positive recurrent ovarian, fallopian tube, or primary high-grade serous peritoneal cancer.Patients and methodsIn this double-blind, randomized, placebo-controlled, phase II trial, patients with at least stable disease (SD) following chemotherapy were randomized 2:1 to receive intravenous gatipotuzumab (500 mg followed by 1700 mg 1 week later) or placebo every 3 weeks until tumor progression or unacceptable toxicity occurred. Stratification factors were the number of prior chemotherapy lines (2 versus 3-5), response versus SD after the most recent chemotherapy, and progression-free survival (PFS) <6 versus 6-12 months following the prior therapy. Primary endpoint was PFS according to modified immune-related RECIST 1.1 response criteria. Secondary endpoints were PFS at 6 months, safety, overall response rate, CA-125 progression, overall survival, quality of life, and pharmacokinetics.ResultsOverall, 216 patients were randomized to gatipotuzumab (n = 151) or placebo (n = 65). Median PFS with gatipotuzumab was 3.5 months as compared with 3.5 months with placebo (hazard ratio 0.96, 95% confidence interval 0.69-1.33, P = 0.80). No advantage for gatipotuzumab over placebo was seen in the secondary efficacy endpoints or in any stratified subgroups. Gatipotuzumab was well tolerated, with mild to moderate infusion-related reactions being the most common adverse events.ConclusionsGatipotuzumab switch maintenance therapy does not improve outcome in TA-MUC1-positive ovarian cancer patients.Trial registrationClinicalTrials.govNCT01899599; https://clinicaltrials.gov/ct2/show/NCT01899599

Prevalence of BRCA1 and BRCA2 pathogenic sequence variants in ovarian cancer patients in the Gulf region: the PREDICT study

BackgroundPatients with pathogenic sequence variants (PSVs) in BRCA1/BRCA2 are at high risk of developing ovarian cancer (OC). However, genetic testing for BRCA1/BRCA2 PSVs is still not a routine practice in the Middle East. With the lack of epidemiological studies in the region, we aim to describe the prevalence of BRCA1/BRCA2 PSVs in patients with OC across different countries in the Gulf region.MethodsThe PREDICT study was an observational, prospective, epidemiological study, which consecutively recruited women with ovarian, primary peritoneal, and fallopian tube cancers from the following Gulf countries over the period from July 2017 to July 2019; United Arab Emirates (UAE), Kuwait, and Oman. The study was approved by the local ethics committee of participating centers. The BRCA1/BRCA2 PSVs were assessed by tissue genetic testing using next-generation sequencing (NGS).ResultsA total of 105 women were included with a median age at diagnosis of 52 years (IQR 44.5 – 61.0). Nearly 11.4% of patients reported a family history of ovarian or breast cancer, while 4.7% of patients reported a family history of other cancers. Most of the patients (70.3%) had advanced disease (FIGO stage III/IV) at presentation. Eighty-eight patients (84%) were successfully tested for somatic BRCA1/BRCA2 PSVs. Fifteen patients (17%) were found to have PSVs in either BRCA1, BRCA2, or both genes; of them, 10 patients (11.2%) had BRCA1 somatic PSVs alone, eight patients (9.1%) had BRCA2 somatic PSVs, while three patients (2.9%) had both PSVs. Five patients with BRCA1/BRCA2 somatic PSVs had germline PSVs tests, and three of them tested positive. Concerning treatment, 87.6% of patients received perioperative chemotherapy and 6.6% as first-line palliative chemotherapy. Eighty-seven (82.9%) patients underwent debulking surgery, with no residual disease in 42.5% of patients.ConclusionOur study showed that the prevalence of BRCA1/BRCA2 somatic PSVs in patients with OC is higher than the reported global figures (2-8%). However, more studies are warranted to further elucidate the prevalence of BRCA1/BRCA2 somatic and germline PSVs, as well as other relevant genetic alterations, to better understand their impact on OC patient outcomes in Gulf countries.Trial registrationNCT03082976.

The Landmark Series: Appendiceal Primary Peritoneal Surface Malignancy.

Appendiceal primary peritoneal surface malignancies are rare and include a broad spectrum of pathologies ranging from indolent disease to aggressive disease. As such, the data that drive the management of appendiceal peritoneal surface malignancies is generally not based on prospective clinical trial data, but rather consists of level 1 data based on retrospective studies and high-volume institutional experiences. Complete surgical debulking typically offers the best chance for long-term survival. This review highlights the landmark articles on which management of primary appendiceal peritoneal surface malignancies are based.

Primary and metastatic peritoneal surface malignancies.

Primary and metastatic peritoneal surface malignancies.

Primary and metastatic peritoneal surface malignancies.

Peritoneal surface malignancies comprise a heterogeneous group of primary tumours, including peritoneal mesothelioma, and peritoneal metastases of other tumours, including ovarian, gastric, colorectal, appendicular or pancreatic cancers. The pathophysiology of peritoneal malignancy is complex and not fully understood. The two main hypotheses are the transformation of mesothelial cells (peritoneal primary tumour) and shedding of cells from a primary tumour with implantation of cells in the peritoneal cavity (peritoneal metastasis). Diagnosis is challenging and often requires modern imaging and interventional techniques, including surgical exploration. In the past decade, new treatments and multimodal strategies helped to improve patient survival and quality of life and the premise that peritoneal malignancies are fatal diseases has been dismissed as management strategies, including complete cytoreductive surgery embedded in perioperative systemic chemotherapy, can provide cure in selected patients. Furthermore, intraperitoneal chemotherapy has become an important part of combination treatments. Improving locoregional treatment delivery to enhance penetration to tumour nodules and reduce systemic uptake is one of the most active research areas. The current main challenges involve not only offering the best treatment option and developing intraperitoneal therapies that are equivalent to current systemic therapies but also defining the optimal treatment sequence according to primary tumour, disease extent and patient preferences. New imaging modalities, less invasive surgery, nanomedicines and targeted therapies are the basis for a new era of intraperitoneal therapy and are beginning to show encouraging outcomes.

Prognostic significance of ethnicity and age in advanced stage epithelial ovarian cancer: An NRG oncology/gynecologic oncology group study

BackgroundAge and ethnicity are among several factors that influence overall survival (OS) in ovarian cancer. The study objective was to determine whether ethnicity and age were of prognostic significance in women enrolled in a clinical trial evaluating the addition of bevacizumab to front-line therapy. MethodsWomen with advanced stage ovarian, primary peritoneal, or fallopian tube cancer were enrolled in a phase III clinical trial. All women had surgical staging and received adjuvant chemotherapy with one of three regimens. Cox proportional hazards models were used to evaluate the relationship between OS with age and race/ethnicity among the study participants. ResultsOne-thousand-eight-hundred-seventy-three women were enrolled in the study. There were 280 minority women and 328 women over the age of 70. Women age 70 and older had a 34% increase risk for death when compared to women under 60 (HR = 1.34; 95% CI 1.16–1.54). Non-Hispanic Black women had a 54% decreased risk of death with the addition of maintenance bevacizumab (HR = 0.46, 95% CI:0.26–0.83). Women of Asian descent had more hematologic grade 3 or greater adverse events and a 27% decrease risk of death when compared to non-Hispanic Whites (HR = 0.73; 95% CI: 0.59–0.90). ConclusionsNon-Hispanic Black women showed a decreased risk of death with the addition of bevacizumab and patients of Asian ancestry had a lower death rate than all other minority groups, but despite these clinically meaningful improvements there was no statistically significant difference in OS among the groups.

Concordance of acquired mutations between metastatic lesions and liquid biopsy in metastatic colorectal cancer.

Aim:To evaluate whether PCR-reverse sequence-specific oligonucleotide can examine the concordance between liquid biopsy and metastatic lesions with acquired resistance.Materials & methods:We examined acquired mutations in chemoresistant lesions and blood obtained from four patients with RAS wild-type metastatic colorectal cancer who underwent treatment with anti-epidermal growth factor receptor antibodies.Results:In one patient, metastatic lesions harbored diverse acquired mutations in KRAS in all seven metastases; the two acquired mutations were detectable in blood collected after the patient acquired resistance. None of the other patients exhibited liquid biopsy mutations, except one, with a BRAF mutation confirmed in primary tumor and peritoneal dissemination.Conclusion:Liquid biopsy based on PCR-reverse sequence-specific oligonucleotide is a successful procedure for capturing acquired mutations with precise information on the RAS mutational spectrum.