Metastatic Ovarian Carcinoma Research Articles

Increased circulating tumor DNA as a noninvasive biomarker of early treatment response in patients with metastatic ovarian carcinoma: A pilot study.

Detection of circulating tumor DNA is a new noninvasive technique with potential roles in diagnostic, follow-up, and prognostic evaluation of patients with many types of solid tumors. We aimed to evaluate the role of circulating tumor DNA in the setting of metastatic ovarian carcinoma. A prospective cohort of patients with metastatic ovarian cancer who were referred to systemic therapy was enrolled. Blood samples were collected before the start of treatment and monthly thereafter for 6 months. Circulating tumor DNA was quantified by real-time quantitative reverse transcription polymerase chain reaction of different lengths of Arthrobacter luteus elements as described by Umetani et al. A total of 11 patients were included, 2 for primary disease and 9 for recurrent disease. After the first cycle of chemotherapy, patients whose circulating tumor DNA levels increased from baseline were more likely to respond to chemotherapy than those whose circulating tumor DNA levels did not increase (p = 0.035). Furthermore, patients whose circulating tumor DNA levels rose after the first cycle of chemotherapy also had improved disease-free survival compared to those whose circulating tumor DNA levels did not increase (p = 0.0074). We conclude that the increase in circulating tumor DNA values collected in peripheral blood after the first cycle of systemic treatment in patients with advanced ovarian cancer is associated with an early response to systemic treatment and correlates with superior disease-free survival in this population. Circulating tumor DNA might be a specific, noninvasive, and cost-effective new biomarker of early response to systemic treatment in these patients.

Peroxiredoxin 2 Controls Proliferation in Extracellular Matrix-Detached SKOV3 Ovarian Cancer Cells

Ovarian carcinoma is one of the leading causes of cancer death for women living in the United States, where approximately 53% of individuals diagnosed succumb to this disease. This is primarily due to lack of early detection and the ability of ovarian cancer cells to spread, or metastasize, thus making the disease more difficult to treat. Non-tumorigenic epithelial cells rely on attachment to the extracellular matrix (ECM) to thrive; however, cancer cells must be able to survive detached from the ECM in order to metastasize to other areas of the body. Studies have examined how cancer cells can metastasize and survive detachment, and it is evident that these cancer cells must contend with increased reactive oxygen species (ROS). This study focuses on the antioxidant enzyme peroxiredoxin 2 (PRDX2) and its role in proliferation and cell survival in metastatic ovarian carcinoma. Here, we report that PRDX2 deficiency severely compromises growth in anchorage independence, and that PRDX2 deficiency uniquely abrogates proliferation in ECM detachment. Consequently, PRDX2 should be further explored as a therapeutic target for late-stage ovarian carcinoma.

Comparative\xa0transcriptome analysis of matched primary and distant metastatic ovarian carcinoma

BackgroundHigh grade serous ovarian carcinoma (HGSOC) is the most common subtype of epithelial ovarian cancers (EOC) with poor prognosis. In most cases EOC is widely disseminated at the time of diagnosis. Despite the optimal cytoreductive surgery and chemotherapy most patients develop chemoresistance, and the 5-year overall survival being only 25–35%.MethodsHere we analyzed the gene expression profiles of 10 primary HGSOC tumors and 10 related omental metastases using RNA sequencing and identified 100 differentially expressed genes.ResultsThe differentially expressed genes were associated with decreased embryogenesis and vasculogenesis and increased cellular proliferation and organismal death. Top upstream regulators responsible for this gene signature were NR5A1, GATA4, FOXL2, TP53 and BMP7. A subset of these genes were highly expressed in the ovarian cancer among the cancer transcriptomes of The Cancer Genome Atlas. Importantly, the metastatic gene signature was suggestive of poor survival in TCGA data based on gene enrichment analysis.ConclusionBy comparing the gene expression profiles of primary HGSOC tumors and their matched metastasis, we provide evidence that a signature of 100 genes is able to separate these two sample types and potentially predict patient survival. Our study identifies functional categories of genes and transcription factors that could play important roles in promoting metastases and serve as markers for cancer prognosis.

Abstract GMM-023: PATIENT DERIVED XENOGRAFTS (PDXS) AND PDX DERIVED TUMOR CELLS (PDTC) ALLOW THE IDENTIFICATION OF ACTIONABLE CANCER GENES AND TREATMENT OPTIONS FOR PLATINUM REFRACTORY/RESISTANT OVARIAN CARCINOMAS

Abstract Patients with advanced ovarian cancers have experienced little improvement in overall survival with standard treatments even after the incorporation of anti-angiogenic therapies. Besides anti-PARP inhibitors, matching individual critical genomic alterations with the best available drugs has not advanced as in other cancers, likely because a handful of cancer-related genes are mutated at high frequency, while many more are found mutated at much lower frequencies. This so called “mutation tail” is not only long but also mostly unexplored. We used Patient Derived Xenografts (PDXs) to identify actionable cancer genes and PDX Derived Tumor Cells (PDTCs) to accelerate the discovery of treatment options. We envisioned that the alleged weakness of PDX models, i.e. lack of human stromal and immune cells, might be instrumental to identify mutations in cancer and to test approved or experimental targeted drugs as monotherapy or in different combinations to link biomarkers to treatments. Forty-nine PDX lines from metastatic epithelial ovarian carcinomas have been propagated and fully characterized as far as histology, immunohistochemistry of epithelial and high-grade serous-specific markers and presence of TP53 and BRCA1/2 mutations. Copy number variations (CNV) analysis and Whole Exome Sequencing (WES) were carried out PDX lines derived from naïve metastatic high-grade epithelial ovarian carcinomas, which came out to be refractory/resistant to platinum drugs. We studied non-synonymous mutations with allele frequencies ≥0.1. Only mutations in cancer genes listed in databases were further analyzed. SNPdb allowed ruling out polymorphisms. SIFT and PROVEAN softwares predicted deleterious or damaging effects onto the protein sequences. DGIdb helped selecting actionable genes. We identified in one PDX line, a possibly loss-of-function mutation of the PIK3R1 gene (encoding the p85alpha regulatory subunit of PI3K) had an allele frequency=0.9 in early and late passages. Moreover, in two micro-dissected FFPE samples of the source tumor this mutation had an allele frequency nearly identical to that of the mutated TP53. Hence, PIK3R1W624R could be a trunk mutation in the PDX line and possibly in the human counterpart. Treatment options were assayed ex-vivo, on short-term cultures of PDTCs of the PIK3R1W624R PDX line. Buparlisib, a pan-class I PI3K inhibitor, showed the ability to block proliferation of PDTCs and the growth in vivo of PDXs in regression preclinical trial. These data proofed-the-concept that a PDX-based pipeline is able to unveil actionable pathways for the treatment of advanced/metastatic ovarian cancer. Citation Format: Martina Olivero, Jessica Erriquez, Maddalena Arigoni, Sonia Capellero, Concetta D'Ambrosio, Gloria Mittica, Fulvio Borella, Dionyssios Katsaros, Silvana Privitera, Enrico Berrino, Tiziana Venesio, Giorgio Valabrega, Raffaele Calogero and Maria Flavia Di Renzo. PATIENT DERIVED XENOGRAFTS (PDXS) AND PDX DERIVED TUMOR CELLS (PDTC) ALLOW THE IDENTIFICATION OF ACTIONABLE CANCER GENES AND TREATMENT OPTIONS FOR PLATINUM REFRACTORY/RESISTANT OVARIAN CARCINOMAS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-023.

CircPLEKHM3 acts as a tumor suppressor through regulation of the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis in ovarian cancer

BackgroundEmerging evidence has shown that circular RNAs (circRNAs) play essential roles in cancer biology and are potential biomarkers and targets for cancer therapy. However, the expression and function of circRNAs in ovarian carcinogenesis and its progression remain elusive.MethodsRNA sequencing was performed to reveal circRNA expression profiles in ovarian cancerous and normal tissues. Single-molecule RNA in-situ hybridization was used to quantify circPLEKHM3 expression in tumor tissues. Cell-based in-vitro and in-vivo assays were subsequently conducted to support the clinical findings.ResultsCircPLEKHM3 was identified as one of the most significantly down-regulated circRNAs in ovarian cancer tissues compared with normal tissues. Its expression was further decreased in peritoneal metastatic ovarian carcinomas compared to primary ovarian carcinomas. Patients with lower circPLEKHM3 tend to have a worse prognosis. Functionally, circPLEKHM3 overexpression inhibited cell growth, migration and epithelial–mesenchymal transition, whereas its knockdown exerted an opposite role. Further analyses showed that circPLEKHM3 sponged miR-9 to regulate the endogenous expression of BRCA1, DNAJB6 and KLF4, and consequently inactivate AKT1 signaling. In addition, AKT inhibitor MK-2206 could block the tumor-promoting effect of circPLEKHM3 depletion, and potentiate Taxol-induced growth inhibition of ovarian cancer cells.ConclusionsOur findings demonstrated that circPLEKHM3 functions as a tumor suppressor in ovarian cancer cells by targeting the miR-9/BRCA1/DNAJB6/KLF4/AKT1 axis and may be used as a prognostic indicator and therapeutic target in ovarian cancer patients. The new strategy for treating ovarian cancer by a combination therapy of Taxol with MK-2206 is worth further investigation, especially in ovarian cancer patients with loss of circPLEKHM3 expression.

1033P - Phase Ib/IIa study assessing the safety and efficacy of adding AL3818 (anlotinib) to standard platinum-based chemotherapy in subjects with recurrent or metastatic endometrial, ovarian or cervical carcinoma

BackgroundAL 3818 (Anlotinib, Catequentinib) is a novel small molecule tyrosine kinase inhibitor that is administered orally. The primary objective of this study is to evaluate the safety, tolerability, and efficacy of adding AL3818, to standard platinum-based plus/or paclitaxel chemotherapy in patients with recurrent or metastatic endometrial, ovarian or cervical carcinoma in Phase 1b/2a studies. MethodsPatients with a diagnosis of recurrent or metastatic endometrial, ovarian, or cervical carcinomas requiring ≥ 2nd line treatment with standard platinum-based chemotherapy were eligible for enrollment on a 21 days cycle. In the Phase 1b study, after chemotherapy at Day 1, patients were started on Day 8 with daily AL 3818 at an initial dose of 12mg for 14 days on a 21day cycle. A 3+3 dose de-escalation design to 10mg, 8mg, and 6mg to determine the recommended Phase II dose (RP2D) was utilized. In the Phase 2a study, patients were treated with the RP2D in combination with either combination platinum based therapy or single agent paclitaxel based on origin of disease. 1st line endometrial patients are allowed. Maintenance monotherapy with AL3818 was given after chemotherapy stopped. ResultsIn the Phase 1b study: (1) 9 subjects with recurrent or metastatic endometrial, ovarian or cervical carcinomas participated with RP2D determined; (2) common treatment emergent adverse event (TEAE) include abdominal pain), alopecia, anemia, arthralgia, asthenia, back pain, and constipation. Overall, most TEAEs were well tolerated by subjects. In Phase 1b and 2a studies: (1) the objective response rate (ORR) and disease control rate (DCR) were 58% and 79% for 19 evaluable endometrial subjects; (2) ORR and DCR were 50% and 93% for all 14 evaluable ovarian subjects; (3) 48 subjects with recurrent or metastatic endometrial, ovarian, and cervical carcinoma were enrolled in the Phase 2a study. ConclusionsAL3818 has demonstrated positive combined synergic efficacy with standard platinum-based plus/or paclitaxel chemotherapy in both endometrial and ovarian cancer patients. Clinical trial identificationNCT02584478. Legal entity responsible for the studyAdvenchen Laboratories, LLC. FundingAdvenchen Laboratories. DisclosureZ. Li: Full / Part-time employment: Advenchen laboratories. M. Chen: Full / Part-time employment: Advenchen laboratories. J. Chen: Full / Part-time employment: Advenchen laboratories. All other authors have declared no conflicts of interest.

2645 Small Bowel Bleeding Due to Solitary Metastatic Ovarian Clear Cell Carcinoma: A Case Report and Review of the Literature

INTRODUCTION: Small bowel bleeding (SBB) accounts for 5–10% of gastrointestinal bleeding cases. Common causes of SBB are inflammatory bowel disease, angioectasias, ulcers, & primary & metastatic neoplasms. The aim of this case report & literature review is to present ovarian clear cell carcinoma (CCC) as a rare cause of SBB. CASE DESCRIPTION/METHODS: A 51 year old woman with dual primary stage IIB CCC of bilateral ovaries & uterus, & stage IA, grade 1 endometrioid adenocarcinoma underwent total laparoscopic hysterectomy, bilateral salphingo-oophorectomy, bilateral pelvic lymph node dissection, & omentectomy. Pathology from the right pelvic side wall peritoneum was positive for CCC involving fibroadipose tissue. She completed 6 cycles of chemotherapy with paclitaxel & carboplatin. Following treatment, she achieved clinical remission for 14 months until computed tomography (CT) scan performed for new abdominal pain & constipation showed a 6.3 × 4.6 cm heterogeneously enhancing lobular mass lesion within the pelvis in close contact with the sigmoid colon without definite invasion. A month later, she was admitted with lower abdominal pain & bloody stools. Colonoscopy showed blood in the entire colon & terminal ileum (TI), without active source of bleeding identified. CT Angiography showed no evidence of active bleeding, but revealed increasing pelvic mass size (6.5 × 6.4 cm). No lymphadenopathy was noted on CT scan. Upper endoscopy was unrevealing. Video capsule endoscopy (VCE) showed an actively bleeding mass likely in the distal small bowel, without VCE passage beyond the mass or cecal intubation. Exploratory laparotomy revealed an 8cm mass arising from the distal TI adherent to the epiploica of the rectosigmoid, not involving the vaginal cuff or prior resection sites. A portion of distal TI was resected with a side-to-side ileo-ascending colon anastomosis. TI pathology was positive for CCC, with negative omental & lymph node pathology. Chemotherapy with carboplatin & doxorubicin was initiated without further bleeding. DISCUSSION: Ovarian cancer is thought to metastasize via direct invasion, lymphatic or hematogenous infiltration, or peritoneal dissemination. Solitary metastasis of ovarian CCC to the small bowel without peritoneal carcinomatosis or lymphatic involvement is a rare phenomenon. Our literature review revealed only one other published case report describing this entity. Solitary CCC metastases should be added to the list of potential neoplastic causes of SBB.

Unusual Early Cerebral Metastasis of Ovarian Carcinoma as Initial Presentation

Background: Although systemic malignancies are frequently metastasizing to the central nervous system (CNS), ovarian carcinoma, which is a common malignancy in females, is rarely affecting brain. In general, the outcome for ovarian carcinoma with brain metastases is dismal as most of these patients usually present late with metastases elsewhere.Materials and methods: A retrospective review of four cases with cerebral metastases as the initial presentation of ovarian carcinoma in patients ages 25 to 45 years. Three patients received hormonal therapy for infertility. All cases presented initially with symptoms and signs suggestive of increased intracranial pressure with unknown primary pathology. CT and MRI scans showed intracranial enhancing lesions in different locations. Full malignancy work up showed a primary lesion arising from the pelvis with no other lesions detected.Results: Three patients underwent laparotomy for ovarian carcinoma resection once their neurological condition optimized, one case died early before she had laparotomy. All cases underwent Craniotomy for excision of the solitary metastatic lesion. In all cases, the histopathology demonstrated metastatic ovarian carcinoma. Subsequently, patients received chemo-radiotherpy. Although treatment all cases died within two years.Conclusion: It is unusual for ovarian carcinoma to present initially with CNS involvement. Unlike other primary tumours, ovarian carcinoma does not have a predilection for the central nervous system. However, CNS involvement occurs at late stage of the disease. Although multimodal treatment the outcome still poor. Hormonal therapy for infertility may be a risk factor for ovarian carcinoma and its aggressive behavior with cerebral metastasis.

Abstract 2850: Characterization of cadherin 6 as a novel therapeutic target in metastatic ovarian carcinoma

Abstract Cadherin 6 (CDH6) is a type II cadherin containing a RGD motif in a similar way to LI-cadherin (CDH17) and VE-cadherin (CDH5), which are able to activate α2β1 integrin signalling to promote lung and liver metastasis. CDH6 gene is frequently overexpressed in late stages of some types of ovarian carcinoma, clear cell renal carcinoma, renal papillary carcinoma and thyroid cancers. Therefore, as reported for CDH17 and CDH5, we hypothesized that CDH6 might be a potential therapeutic target for metastatic ovarian cancer. Indeed, an “in silico” analysis revealed a significant association between CDH6 expression, tumour stage and poor survival in renal and ovarian cancer patients. We confirmed a high CDH6 expression in ovarian cancer cell lines, although with significant differences in cell surface availability, as determined by flow cytometry. In addition, we noticed a variable α2β1 integrin expression in the same cell lines. Indeed, CDH6 RGD peptide caused β1 integrin activation in OVCAR3 cells but not in SKOV-3, suggesting the existence of alternative mechanisms. In this regard, as CDH6 has been reported to be a αIIbβ3 integrin ligand in platelets, we investigated and confirmed the expression of αIIbβ3 integrin in SKOV3 but not in OVCAR3 cells. Remarkably, CDH6 was able to activate αIIbβ3 integrin in SKOV3 cells. Moreover, silencing of CDH6 or β3 integrin triggered a significant loss of prometastatic traits in ovarian cells, such as cell adhesion, migration, invasion and proliferation. Signalling pathway analysis demonstrated that β3 integrin activation was triggering the phosphorylation of AKT and SRC, but not FAK, promoting cell invasion. Finally, treatment with monoclonal antibodies against the cadherin RGD motif inhibited the metastatic behaviour in ovarian cancer cell lines “in vitro”. Experiments with metastatic mouse models to confirm the inhibitory capacity of cadherin RGD-specific monoclonal antibodies are in progress. In summary, these findings suggest that CDH6 RGD motif could activate α2β1 or αIIbβ3 integrins, according to the cell context, and be targeted to avoid metastatic dissemination and cancer progression in those ovarian tumours overexpressing CDH6. Citation Format: Miranda Burdiel, Ruben Bartolomé, Marta Jaén, Ignacio Casal. Characterization of cadherin 6 as a novel therapeutic target in metastatic ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2850.

Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma

Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited. To evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma. The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to ≥23.0 months). Data were collected from April 15, 2016, through September 4, 2018, with September 4, 2018, as a data cutoff, and analyzed from September 4, 2018, through January 30, 2019. The recommended phase 2 dose (RP2D) was 200 mg of oral niraparib once daily and 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. The primary objectives of phase 1 were to evaluate dose-limiting toxic effects and establish the RP2D and dosing schedule. The primary objective of phase 2 was to assess objective response rate (ORR; complete plus partial responses). Results from the phase 1 ovarian carcinoma and TNBC cohorts and phase 2 ovarian carcinoma cohort are reported. Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis. Fourteen patients (9 with ovarian carcinoma and 5 with TNBC) in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, 46-83 years]). In the integrated efficacy phases 1 and 2 ovarian carcinoma population (60 of 62 evaluable patients), ORR was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, 28 (47%) with stable disease, and 20 (33%) with progressive disease. The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status. Median duration of response was not reached (range, 4.2 to ≥14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment. Niraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab. Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy. ClinicalTrials.gov identifier: NCT02657889.

Epidemiological overview of metastatic ovarian carcinoma: long-term experience of TOTSG database.

ABSTRACTMalignant ovarian neoplasm is one of the most lethal malignancies among cancers of the female reproductive system. Occasionally, these tumors originate from non-ovarian organs as metastatic lesions since the ovary is a frequent metastatic target of many cancers. However, there limited clinical information on metastatic ovarian carcinoma (MOC) and its hallmarks are unknown. During the period of 1986–2015, 4,284 patients with malignant ovarian neoplasm were identified using the Tokai Ovarian Tumor Study Group (TOTSG) database. Of these, excluding borderline malignant tumor, 3,478 patients with malignant ovarian cancer were extracted. The pathological slides were evaluated under central pathological review. Among them, a total of 143 (4.1%) patients with MOC were identified. The median age of patients with MOC was 54 (29–82) years. The most and second most frequent original tumors were colorectal (43%, N=62) and gastric (29%, N=42) carcinoma, respectively. The rates of carcinoma of the appendix, breast, and pancreas were 8, 6, and 4%, respectively. This is the one of the largest studies clarifying the rates of MOC among malignant ovarian neoplasms. Although the rate is low, we should keep in mind that MOC, particularly from colorectal and gastric cancer should be considered when encountering clinical practice of ovarian cancer.

LINK-A Long Non-Coding RNA (lncRNA) Participates in Metastasis of Ovarian Carcinoma and Upregulates Hypoxia-Inducible Factor 1 (HIF1α).

BackgroundThe functionality of LINK-A lncRNA as an oncogenic lncRNA has only been characterized in triple-negative breast cancer. The present study investigated the possible involvement of LINK-A in ovarian carcinoma.Material/MethodsWe enrolled 76 patients with ovarian carcinoma. Quantitative real-time PCR (qRT-PCR) was performed to analyze LINK-A expression in ovarian biopsies. Effects of LINK-A overexpression on HIF1α and cancer cell migration and invasion were assessed.ResultsWe found that LINK-A was significantly higher in ovarian carcinoma patients than in healthy controls in ovarian biopsies and in serum. LINK-A expression effectively distinguished patients with metastatic ovarian carcinoma from healthy controls. LINK-A overexpression promoted cancer cell migration and invasion, and also upregulated the expression of HIF1α.ConclusionsLINK-A lncRNA may be involved in the metastasis of ovarian carcinoma by upregulating HIF1α.

PRSS21/testisin inhibits ovarian tumor metastasis and antagonizes proangiogenic angiopoietins ANG2 and ANGPTL4.

Ovarian cancer is the leading cause of death among all the gynecological cancers in the USA. Ovarian cancer employs a unique mode of metastasis, as exfoliated tumor cells disseminate within the peritoneal cavity, colonizing in several sites as well as accumulating ascites. Tumor recurrence and widespread metastasis are significant factors contributing to poor prognosis. PRSS21 is a metastasis-associated ovarian cancer gene that encodes the glycosyl-phosphatidylinositol-linked serine protease, testisin. Testisin expression is increased in multiple ovarian tumor types, with relatively little expression in normal tissues, but is differentially decreased in metastatic ovarian serous carcinomas compared to primary tumors. Here we explored the function of testisin in late-stage ovarian cancer progression using a murine xenograft model of ovarian intraperitoneal tumor metastasis. Increased tumor testisin expression inhibited intra-peritoneal tumor seeding and colonization, ascites accumulation, and metastatic tumor burden that was dependent on catalytically active testisin. The known testisin substrate, protease-activated receptor-2 (PAR-2), is a target of testisin activity. Gene profiling and mechanistic studies demonstrate that testisin activity suppresses the synthesis and secretion of pro-angiogenic angiopoietins, ANG2 and ANGPTL4, which normally promote vascular leak and edema. These observations support a model wherein testisin activates PAR-2 to antagonize proangiogenic angiopoietins that modulate vascular permeability and ascites accumulation associated with ovarian tumor metastasis. KEY MESSAGES: Testisin inhibits metastatic ovarian tumor burden and ascites production. Testisin activity antagonizes ANG2 and ANGPTL4 synthesis and secretion. PAR-2 is a proteolytic target of testisin on the surface of ovarian cancer cells.

Tunneling Nanotubular Expressways for Ultrafast and Accurate M1 Macrophage Delivery of Anticancer Drugs to Metastatic Ovarian Carcinoma.

It is extremely difficult for cancer chemotherapy to control the peritoneal metastasis of advanced ovarian carcinoma given its inability to target disseminated tumors and the severe toxic side effects on healthy organs. Here, we report antitumorM1 macrophages developed as live-cell carriers that deliver anticancer drugs for the treatment of the metastatic ovarian carcinoma. Engineered doxorubicin-loaded M1 macrophages (M1-Dox) significantly enhanced tumor tropism by upregulation of CCR2 and CCR4 compared with their parent cells. Meanwhile, M1-Dox inhibited doxorubicin-induced tumor invasion, whereas commercial Lipo-Dox did not limit these side effects. Importantly, our data uncovered a drug delivery mechanism by which M1-Dox transferred drug cargoes into tumor cells via a tunneling nanotube pathway. The tunneling nanotube network acted as a transportation expressway for ultrafast drug delivery of M1-Dox, leading to efficient ovarian carcinoma cell death. Furthermore, genetic, pharmacological, and physical perturbations of these tunneling nanotubes obviously decreased drug transfer of M1-Dox, which further validated the evident correlation between drug delivery of M1-Dox and tunneling nanotubes. Finally, in peritoneal metastatic ovarian carcinoma-burdened mice, M1-Dox specifically penetrated into and accumulated deep within disseminated neoplastic lesions compared with commercial Lipo-Dox, resulting in reducing metastatic tumors to a nearly undetectable level and significantly increasing overall survival. Overall, the strategy of engineered macrophages for ultrafast and accurate drug delivery via the tunneling nanotubular expressway potentially revolutionizes the treatment of metastatic ovarian carcinoma.

Widespread subacute cutaneous lupus erythematosus in a patient receiving checkpoint inhibitor immunotherapy with ipilimumab and nivolumab

Checkpoint inhibitor immunotherapy, including ipilimumab and nivolumab, is associated with numerous immune-related adverse events including dermatitis, pruritus, hepatitis, diarrhea, and hypophysitis. As the number of patients undergoing immunotherapy treatment increases, however, rare and unusual immune-related adverse events are observed. Many of these resemble known autoimmune phenomenon, such as subacute lupus erythematosus and myositis. Herein, we report a patient with metastatic serous ovarian carcinoma undergoing treatment with combination ipilimumab and nivolumab who developed subacute cutaneous lupus erythematosus (SCLE). Recent case reports have documented SCLE as a novel immune-related adverse event. In our case, she was able to successfully restart immunotherapy after a course of oral corticosteroids and maintenance oral hydroxychloroquine and topical corticosteroid therapy.

Cytological diagnosis of metastatic ovarian carcinoma in a young female presenting as Sister Mary Joseph's Nodule

Cytological diagnosis of metastatic ovarian carcinoma in a young female presenting as Sister Mary Joseph's Nodule

Krukenberg tumours from gastrointestinal cancers-analysis from a tertiary care centre in India.

Krukenberg tumour (KT) is clinically defined as any ovarian metastatic carcinoma derived from a primary malignancy (usually from the gastrointestinal tract). Our aim was to analyse the incidence, demographic profile, clinical features, management and survival of patients with KTs from gastrointestinal tract malignancies at our centre. This was a retrospective analysis data at our centre between Jan 2015 and Dec 2017. A total of 8 patients of KTs (2 from gastric and 6 from colorectal cancers) were observed with an incidence of 0.66% in gastric and 2.90% in colorectal cancers. The mean age of all the patients was 40 years (44 in gastric and 39 in colorectal group) and most of them (5 out of 8) occurred in premenopausal women. They were also most commonly bilateral (6 out of 8) and synchronous (6 out of 8). Surgical debulking was possible in 7 patients and all patients underwent systemic chemotherapy. Interestingly, 4 patients in the colorectal KT group with metastasis limited to ovary alone managed by surgical debulking and chemotherapy had a significantly higher 1-year survival compared to the others with peritoneal disease are alive at an average of 14.5 months. The incidence of KTs from colorectal cancers is on the rise. KTs from colorectal cancers and KTs without peritoneal metastases have a better prognosis showing significantly higher 1-year survival rates following complete surgical resection and systemic chemotherapy.

Molecular Mechanisms Regulating Organ-Specific Metastases in Epithelial Ovarian Carcinoma

Epithelial ovarian carcinoma is the most predominant type of ovarian carcinoma, the deadliest gynecologic malignancy. It is typically diagnosed late when the cancer has already metastasized. Transcoelomic metastasis is the most predominant mechanism of dissemination from epithelial ovarian carcinoma, although both hematogenously and lymphogenously spread metastases also occur. In this review, we describe molecular mechanisms known to regulate organ-specific metastasis from epithelial ovarian carcinoma. We begin by discussing the sites colonized by metastatic ovarian carcinoma and rank them in the order of prevalence. Next, we review the mechanisms regulating the transcoelomic metastasis. Within this chapter, we specifically focus on the mechanisms that were demonstrated to regulate peritoneal adhesion—one of the first steps in the transcoelomic metastatic cascade. Furthermore, we describe mechanisms of the transcoelomic metastasis known to regulate colonization of specific sites within the peritoneal cavity, including the omentum. Mechanisms underlying hematogenous and lymphogenous metastatic spread are less comprehensively studied in ovarian cancer, and we summarize mechanisms that were identified to date. Lastly, we discuss the outcomes of the clinical trials that attempted to target some of the mechanisms described in this review.

Role of CD70 in pathogenesis of ovarian cancer cell metastasis

American Cancer Society identifying ovarian carcinoma as the gynecologic malignancy with the highest case-to-fatality. Ovarian carcinoma metastasizes either by direct extension from the ovarian/fallopian tumor to neighboring organs (bladder/colon) or when cancer cells detach from the primary tumor. Exfoliated tumor cells are transported throughout the peritoneum by physiological peritoneal fluid and disseminate within the abdominal cavity. Extensive seeding of the peritoneal cavity by tumor cells is often associated with ascites, particularly in advanced, high-grade serous carcinomas. CD70 (encoded by the TNFSF7 gene) is a co-stimulatory factor present on B-cells, activated T-cells, and dendritic cells. CD70 is over expressed in tumor cells of various solid cancers including ovarian carcinoma, recently reported the role of CD70 expression as a predictive marker of resistance to chemotherapy in ovarian cancers. We evaluated the expression of CD70 level in the pathogenesis of metastasis ovarian cancer cell. Seventy five tissue samples from metastatic ovarian carcinoma were evaluated by quantitative real-time PCR for CD70 and statistical analyses were performed using the Mann-Whitney test. Further, humanized anti-CD70 antibodies were investigated in xenograft mice models of ovarian cancer. Increasing expression of CD70 level was associated with increased risks for disease progression (HR = 1.04; 95% CI, 1.03 to 1.14) and death (HR = 1.13; 95% CI, 1.09 to 1.2). expression of CD70 was associated with a worse PFS and OS compared with non- expression of CD70 carcinomas. Furthermore, humanized anti-CD70 antibodies have shown significant antitumor activity in preclinical xenograft models of ovarian cancer cell.

Isolation of Nocardia cyriacigeorgica from Patient Suspected to Tuberculosis

Isolation of Nocardia cyriacigeorgica from Patient Suspected to Tuberculosis