Spread Of Ovarian Cancer Research Articles

Nationwide analysis of patients with ovarian cancer: Racial status and risk of metastasis.

124 Background: Literature review has found profound disparities in clinical outcomes, for patient with ovarian cancer. Metastasis is the primary cause of cancer morbidity and mortality. However, data on the metastasis risks on hospitalized individuals with ovarian cancer is still limited. Therefore, we aim to assess the association between metastatic ovarian cancer and racial differences using large database analysis. Methods: We analyzed the 2020 U.S. National Inpatient Sample (NIS) to explore patients who have ovarian cancer as the primary diagnosis. Additionally, we identified evidence of metastasis, as recorded by ICD-10-CM. Adjusted odds ratios (aORs) for specified outcomes were calculated through multivariable logistic and linear regression analyses. The primary outcome was racial differences in organ metastasis and secondary outcomes included mortality and length of stay. Statistical significance was established at p-value of 0.05. Results: We identified 19,789 patients with primary diagnosis of ovarian cancer at discharge. The mean age was 61.6 years. Caucasians accounted for 68.3%, with Hispanics at 11.1 % and African Americans at 9.7%. We found that 7% of the patients had liver metastasis. In a multivariate analysis adjusting for patient, COVID-19, chemotherapy usage and hospital factors, African Americans and Hispanics had higher risk of liver metastasis (aOR 1.95; 95%CI (1.32, 2.88), p = 0.001) (aOR 1.78; 95%CI (1.19, 2.66), p = 0.004). We also observed reduced length of stay for Asian Americans (b = -0.74; 95%CI (-1.31, -0.17), p = 0.011). We observed an increase in risk of metastasis and mortality but non-statistically significant in some parameters and races, as shown in table provided. Conclusions: In conclusion, our study revealed that racial difference is associated with higher risk of metastasis, as well as other outcomes. More studies following patients over time are needed to determine if race directly affects how ovarian cancer spreads and other clinical outcomes. [Table: see text]

The role of Piezo1 mechanotransduction in high-grade serous ovarian cancer: Insights from an in vitro model of collective detachment.

Slowing peritoneal spread in high-grade serous ovarian cancer (HGSOC) would improve patient prognosis and quality of life. HGSOC spreads when single cells and spheroids detach, float through the peritoneal fluid and take over new sites, with spheroids thought to be more aggressive than single cells. Using our in vitro model of spheroid collective detachment, we determine that increased substrate stiffness led to the detachment of more spheroids. We identified a mechanism where Piezo1 activity increased MMP-1/MMP-10, decreased collagen I and fibronectin, and increased spheroid detachment. Piezo1 expression was confirmed in omental masses from patients with stage III/IV HGSOC. Using OV90 and CRISPR-modified PIEZO1-/- OV90 in a mouse xenograft model, we determined that while both genotypes efficiently took over the omentum, loss of Piezo1 significantly decreased ascitic volume, tumor spheroids in the ascites, and the number of macroscopic tumors in the mesentery. These results support that slowing collective detachment may benefit patients and identify Piezo1 as a potential therapeutic target.

Metastasis of serous ovarian carcinoma to the breast: a case report and review of the literature

BackgroundBreast metastasis from primary ovarian cancer is rare, with an estimated frequency of 0.07%. More than 110 cases are reported in the literature of metastatic spread of ovarian cancer to the breast and axilla. This entity usually represents aggressive late disease characterized by multi-drug chemoresistance and a poor prognosis with a median survival time of 16 months. Currently no standardized treatment protocol exists for this condition.Case presentationWe present a case of a 59-year-old Caucasian female with recurrent high-grade serous ovarian cancer who was diagnosed with symptomatic unilateral breast metastasis while on fourth line chemotherapy with weekly paclitaxel. She was treated with local radiation with 2300 cGy to the right breast with a complete response. She then had a subsequent recurrence in the ipsilateral breast 8 months after completion of post treatment imaging. She remains alive to date approximately 2 years after her initial diagnosis of breast metastasis on seventh line treatment.ConclusionsBreast metastasis from primary ovarian cancer is rare and represents advanced disease characterized by multi-drug chemoresistance and a poor prognosis. This case describes radiation therapy as a safe, effective treatment option to improve local control and quality of life in these patients, but with limited durability of response.

Abstract 2744: Exploring the role of the MSLN/MUC16 interaction in cancer progression via the in situ proximity ligation technique

Abstract Introduction: Mesothelin (MSLN) is a glycoprotein present on the surface of mesothelial cells, sometimes used as a tumor marker. Its overexpression in various cancers, including mesothelioma, ovarian, pancreatic, and lung, is linked to increased tumor aggressiveness, evasion of apoptosis, metastasis, and resistance to treatments. Mucin16 (MUC16) belongs to a family of proteins that play a crucial role in cell adhesion, signaling, and immune responses. In cancer, alterations in mucin expression and structure may contribute to tumor progression and metastasis by enhancing cell survival and immune evasion. Mesothelin is known to interact with mucins, influencing tumor cell behavior and metastatic potential. More specifically, the MSLN/MUC16 interaction facilitates tumor cell invasion and peritoneal spread in ovarian cancer. However, reliable molecular tools to study protein interactions have been scarce. Here, we relied on the Naveni® in situ proximity ligation technology to identify MSLN/MUC16 in various cancer samples. The method detects proteins located within interaction range (<40 nm) by means of antibodies conjugated to oligonucleotides that create amplified fluorescent signal. Since the technique does not compromise the structural integrity of tissues, communication between proteins can be studied in their native environment. Materials & Methods: Human FFPE tissue microarrays (TMA) with ovarian primary carcinoma and matched metastatic cancer (80 cores) and ovarian cancer tissue with normal tissue (100 cores) were deparaffinized and subjected to standard heat-induced antigen retrieval and blocking. Staining against the MSLN/MUC16 interaction was performed with the NaveniFlex Tissue MR Atto647N kit (Navinci Diagnostics). Co-staining antibodies against pan-Cytokeratin and Ki67 were included in the detection mix. Immunofluorescence (IF), using the same MSLN and MUC1 primary antibodies, was completed on an additional slide of each TMA, and then secondary antibodies conjugated to Alexa Fluor™ 488 and 594 were used for detection. Imaging was performed on an Olympus scanner VS200. Results & Discussion: In this study, we showed that the interaction is abundant in ovarian cancer, with a distinguishable difference in the signal presence between cancerous and normal adjacent tissue. Furthermore, the additional tumor marker co-stainings give insights into the tumor invasion and growth. When comparing the Naveni® signal of MSLN/MUC16 against IF staining of each, the Naveni® signal shows true interactions, as opposed to expression patterns. Understanding the roles of mesothelin and mucin in cancer, both individually and in interaction, is crucial for developing targeted therapies and diagnostic tools. Further research on their interaction and specific molecular pathways triggered by it is essential for devising effective strategies to combat cancer progression. Citation Format: Sara Bodbin, Doroteya Raykova, Agata Zieba-Wicher. Exploring the role of the MSLN/MUC16 interaction in cancer progression via the in situ proximity ligation technique [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2744.

Environmental physical factors produce mitotic aberration and multicellularity in the ovarian cancer cell line SKOV3

The spread of ovarian cancer (OC) to the coelomic cavity triggers the secretion and accumulation of ascitic fluid (AF). Although its biochemical composition has been well studied, less is known about the implications of physical factors such as the pH and the mechanical properties of the AF for the malignancy of tumor cells. In this work, we investigated the effect of pH and the mechanical properties of AF on cell proliferation and mitotic morphology. We employed biopsies from patients with OC and the SKOV3 cell line as an in vitro model of OC with HeLa cells as controls. Sections of each tumor were stained with HE, analyzed, and related to clinical data. AF from patients with OC exhibited an alkaline pH (ranging from 7.3 to 7.8). Compared to control conditions, the 3 AFs significantly enhanced the proliferation of SKOV3 and HeLa cells. These effects were more pronounced at a more alkaline pH. In addition, we found that AFs have different densities that correlated with a significant increase in multinucleated tumor cells and severe morphological defects in cells undergoing mitosis. In agreement with these data, we found that higher concentrations of soft agar provoked significantly higher numbers of multinucleated and morphologically abnormal SKOV3 cells with no effect on HeLa cells.We conclude that an alkaline pH and greater rigidity could enhance the metastatic potential of OC cells. We propose that these two physical factors could be parameters of clinical importance as predictors of malignancy.

Imaging of Peritoneal Carcinomatosis in Advanced Ovarian Cancer: CT, MRI, Radiomic Features and Resectability Criteria.

PC represents the most striking picture of the loco-regional spread of ovarian cancer, configuring stage III. In the last few years, many papers have evaluated the role of imaging and therapeutic management in patients with ovarian cancer and PC. This paper summed up the literature on traditional approaches to the imaging of peritoneal carcinomatosis in advanced ovarian cancer, presenting classification systems, most frequent patterns, routes of spread and sites that are difficult to identify. The role of imaging in diagnosis was investigated, with particular attention to the reported sensitivity and specificity data-computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography-CT (PET-CT)-and to the peritoneal cancer index (PCI). In addition, we explored the therapeutic possibilities and radiomics applications that can impact management of patients with ovarian cancer. Careful staging is mandatory, and patient selection is one of the most important factors influencing complete cytoreduction (CCR) outcome: an accurate pre-operative imaging may allow selection of patients that may benefit most from primary cytoreductive surgery.

Defining the Role of Metastasis-Initiating Cells in Promoting Carcinogenesis in Ovarian Cancer.

Ovarian cancer is the deadliest gynecological malignancy with a high prevalence of transcoelomic metastasis. Metastasis is a multi-step process and only a small percentage of cancer cells, metastasis-initiating cells (MICs), have the capacity to finally establish metastatic lesions. These MICs maintain a certain level of stemness that allows them to differentiate into other cell types with distinct transcriptomic profiles and swiftly adapt to external stresses. Furthermore, they can coordinate with the microenvironment, through reciprocal interactions, to invade and establish metastases. Therefore, identifying, characterizing, and targeting MICs is a promising strategy to counter the spread of ovarian cancer. In this review, we provided an overview of OC MICs in the context of characterization, identification through cell surface markers, and their interactions with the metastatic niche to promote metastatic colonization.

Prognostic Impact of Mesenteric Lymph Node Status on Digestive Resection Specimens During Cytoreductive Surgery for Ovarian Peritoneal Metastases

BackgroundThe most common mode of ovarian cancer (OC) spread is intraperitoneal dissemination, with the peritoneum as the primary site of metastasis. Cytoreductive surgery (CRS) with chemotherapy is the primary treatment. When necessary, a digestive resection can be performed, but the role of mesenteric lymph nodes (MLNs) in advanced OC remains unclear, and its significance in treatment and follow-up evaluation remains to be determined. This study aimed to evaluate the prevalence of MLN involvement in patients who underwent digestive resection for OC peritoneal metastases (PM) and to investigate its potential prognostic value.MethodsThis retrospective, descriptive study included patients who underwent CRS with curative intent for OC with PM between 1 January 2007 and 31 December 2020. The study assessed MLN status and other clinicopathologic features to determine their prognostic value in relation to overall survival (OS) and progression-free survival (PFS).ResultsThe study enrolled 159 women with advanced OC, 77 (48.4%) of whom had a digestive resection. For 61.1% of the patients who underwent digestive resection, MLNs were examined and found to be positive in 56.8%. No statistically significant associations were found between MLN status and OS (p = 0.497) or PFS ((p = 0.659).ConclusionsIn anatomopathologic studies, MLNs are not systematically investigated but are frequently involved. In the current study, no statistically significant associations were found between MLN status and OS or PFS. Further prospective studies with a systematic and standardized approach should be performed to confirm these findings.

Surgical Anatomy of the Liver-Significance in Ovarian Cancer Surgery.

Ovarian cancer is the leading cause of death among all gynecological malignancies. Most patients present with an advanced stage of the disease. The routes of spread in ovarian cancer include peritoneal dissemination, direct invasion, and lymphatic or hematogenous spread, with peritoneal and lymphatic spread being the most common among them. The flow direction of the peritoneal fluid makes the right subphrenic space a target site for peritoneal metastases, and the most frequently affected anatomical area in advanced cases is the right upper quadrant. Complete cytoreduction with no macroscopically visible disease is the most important prognostic factor. We reviewed published clinical anatomy reports associated with surgery of the liver in cases of advanced ovarian cancer. The disease could disseminate anatomical areas, where complex surgery is required-Morrison's pouch, the liver surface, or porta hepatis. The aim of the present article is to emphasize and delineate the gross anatomy of the liver and its surgical application for oncogynecologists. Moreover, the association between the gross and microscopic anatomy of the liver is discussed. Additionally, the vascular supply and variations of the liver are clearly described. Oncogynecologists performing liver mobilization, diaphragmatic stripping, and porta hepatis dissection must have a thorough knowledge of liver anatomy, including morphology, variations, functional status, potential diagnostic imaging mistakes, and anatomical limits of dissection.

Proteomic profiling of peritoneal fluid-derived exosomes as a tool for the identification of prognostic markers in advanced ovarian carcinomas.

e17561 Background: Exosomes have been involved in tumor progression and development of therapeutic resistances in several malignancies. This subtype of extracellular vesicles (EVs) promote angiogenesis, premetastatic niches formation and communication between the tumor and its microenvironment. Ovarian cancer (OC) is a highly lethal tumor that typically spreads within the abdominal cavity rather than through blood vessels. Based on this behavior, we aimed to study the presence of EVs in ascitic fluid of OC patients and explore their potential as predictors of tumor volume and chemoresistance. Methods: Observational prospective study in advanced OC patients who underwent a diagnostic laparoscopy or cytoreductive surgery. Abdominal washings of a cohort of non-cancer patients were collected as controls. All cases provided written consent. Clinical data and tumor genomic alterations (NGS, FoundationOne CDx) were recorded. EVs pellets were collected by ultracentrifugation and profiled by NTA and western blot (EVs markers: CD9, TSG101 and ALIX; non EVs related markers: ALB and APOB). EVs proteins were quantified by BCA assay and profiled by mass spectrometry. Results: We obtained 75 peritoneal fluids from 66 OC patients (median age at diagnosis [range] 62 [26-83] years) and 29 peritoneal washings from controls. Our cohort comprises various histological subtypes (high grade serous, n 55; low grade serous, n 2; endometrioid, n 6; clear cell, n 2 and mucinous, n 1) and tumor stages (I-II, n 7; III; n 39; IV, n 20). Samples were collected either from primary (n 36); interval, (n 25); or relapse surgery (n 14). Pathogenic BRCA events: 15 patients. Mean concentration of exosomes (MCE) was 3.0x106 vs. 1.6x106 particles/ml (p/ml) in cases vs. controls (p < 0.0017). No difference in MCE was observed regarding stages I-II vs. III-IV (3.9x106 vs. 3.3x106 p/ml; p = 0.38). A higher MCE was observed in those samples collected after relapse surgeries compared to those collected from primary (7.2x106 vs. 2.8x106 p/ml; p < 0.0001) and interval surgeries (7.2x106 vs. 3.4x106 p/ml; p < 0.0007). Median exosomal protein concentration (MEPC) in EVs of cancer patients vs. controls was 0.99µg/µl and 0.57µg/µl respectively (p = 0.02). Proteomic characterization by mass spectrometry of EVs cargo has identified 1827 proteins, of which 405 proteins were differentially expressed between cases and controls. We also found 38 differentially expressed proteins comparing platinum-sensitive vs. resistant patient samples. Conclusions: Our data show higher concentration of exosomes and exosomal proteins in OC cases vs controls. Differentially expressed proteins have also been found between samples from platinum-sensitive and platinum-resistant patients. These results suggest that exosomes may be involved in the progression and spread of OC and may provide insights into current treatment response.

The Effect of Upper Abdominal Surgery on Complication Profile in Ovarian Cancer.

Introduction: Due to the superficial peritoneal spread of ovarian cancer, upper abdominal surgical procedures are often required to achieve optimal surgical cytoreduction. This study compares the mortality and morbidity rates of patients undergoing upper and lower abdominal cytoreductive surgery in our institution. Material and Methods: Patients who underwent cytoreductive surgery for ovarian malignancies from 2014 to 2020 were retrospectively identified from an institutional database. Upper abdominal cytoreduction was defined anatomically as debulking of disease proximal to the ligament of Treitz. Perioperative and postoperative outcomes were analyzed. Results: A total of 148 operations were performed. A single gynecologic oncologist performed all procedures. When all cytoreductive procedures were evaluated, diaphragm injury, blood transfusion, hospital stay, atelectasis, pneumonia, effusion, wound infection and need for intensive care were found to be statistically significantly higher in patients who underwent upper abdominal surgery compared to patients in the lower abdominal surgery group (p=0.001, p=0.017, p=0.002, p=0.045, p=0.006, p=0.005, respectively). Conclusion: In patients scheduled for cytoreductive surgery with the diagnosis of ovarian cancer, upper abdominal surgery is a viable procedure, although it carries a higher risk of complications compared to lower abdominal surgery alone. Upper abdominal surgery in advanced ovarian cancer can be applied to patients with an acceptable complication profile when the possible survival advantage is considered.

P-055 COMPLEX ABDOMINAL WALL RECONSTRUCTION AFTER THE RESECTION OF ADVANCED OVARIAN CANCER SPREAD TO ABDOMINAL WALL AND ILIAC VESSELS

Abstract Aim We present the case of an advanced ovarian cancer spread to the abdominal wall and iliac vessels where a complete resection was performed with immediatly reconstruction of the abdominal wall to achieve a complete R0 resection. Material and Methods A 66-year-old woman with history of hysterectomy, double adnexectomy and adjuvant chemotherapy for ovarian cancer 36 years ago. The CT scan showed an 8×7 cm lesion involving the anterior rectus muscle with compression of the ipsilateral iliac vessels. A biopsy was positive for adenocarcinoma with gynecological origin. She received neoadjuvant treatment with chemotherapy. In the control CT scan persisted a mass the abdominal wall mass with slight reduction in size and compressing the iliac vessels. Results Following a karakousys incision, an anterior abdominal wall tumor intimately attached to the pubic symphysis was observed. The tumor measured 6 cm, it infiltrated the femoral vein but there was not invasion of the artery. A completed resection of the anterior abdominal wall musculature up to the pubic symphysis was performed, disconnecting the inguinal ligament and leaving a 10×10 cm wall defect. This defect was repaired with the placement of a preperitoneal biological mesh to provide a reinforcement plane and a polypropylene mesh above the previous one. Conclusions Wide abdominal wall resections may be necessary to obtain R0 resections. Numerous studies have shown that morbidity rates associated with these procedures are not high. In fact, in our case, an immediate abdominal wall reconstruction achieved good functional and aesthetic results in a single surgical procedure.

Norepinephrine promotes anoikis resistance in fallopian tube secretory cells through beta adrenergic receptor signaling (247)

<b>Objectives:</b> High-grade serous ovarian cancer (HGSOC) remains the most lethal gynecologic malignancy with a 5-year survival rate approaching 40%. Unfortunately, most women present at an advanced stage due to subtle symptomatology at disease onset and inadequate screening protocols. Thus, understanding the cellular events that lead to the development and malignant transformation of fallopian tube (FT) precursor cells into metastatic disease may lead to actionable targets to improve outcomes. Fallopian tube secretory epithelium is considered the cell of origin of HGSOC, where <i>TP53</i> and other genetic defects accrue to permit exfoliation and seeding of the ovary and peritoneum, leading to widespread metastasis. Follicular fluid bathes the fallopian tube monthly during the reproductive years and contains several factors contributing to carcinogenesis. Recently, neurotransmitters such as norepinephrine (NE) have been implicated in ovarian cancer growth and metastasis through multiple mechanisms and are also present within the follicular fluid. Thus, the objective of the current study was to evaluate the effects of NE on FT epithelial cell function under 3D conditions. <b>Methods:</b> FT cell lines (FT189, FT190, FT194, FT237, FT240, FT246, FT282), previously immortalized through several mechanisms, were plated into round bottom ultralow adhesion plates with 10µM NE or vehicle control (VHC), in the presence or absence of adrenergic antagonist propranolol (10µM). Spheroids were serially imaged over 24h. For FT237 and FT246, live/dead cell staining was performed using ReadyProbe cell viability assay, and apoptotic activity was assessed via annexin staining analyzed by flow cytometry. qPCR and western blotting were used to assess receptor expression. <b>Results:</b> All FT lines examined expressed <i>ADRB1</i> and <i>ADRB2</i> by both western blot and qPCR. Treatment with NE resulted in significant compaction of spheroid formation by 33% (+/- 5%, p <0.001) at 24h compared to VHC. This response was completely abrogated by preexposure to propranolol (p <0.05). NE nor propranolol had a significant impact on cell viability under immunofluorescence. However, annexin staining revealed a significant 5% increase in cell survival with a concomitant decrease in early and late apoptotic cell populations exposed to NE in 3D culture (p<0.05), compared to VHC. FT exposure to NE resulted in significantly increased expression of EMT genes, <i>SNAI1</i> and <i>SNAI2</i>, which was completely reversed by pretreatment with propranolol (p<0.05). <b>Conclusions:</b> Taken together, these findings demonstrate that NE exposure promotes FT cell spheroid formation and EMT gene transcription through activation of ADRB-mediated signaling. Thus, NE may potentiate metastasis of early ovarian cancer precursor lesions through stimulation of EMT genes and enhancing anoikis resistance, two factors that are critical to the coelomic spread of ovarian cancer. Future studies examining NE-induced carcinogenesis in FT cells are warranted.

ROR2 can function independent of tyrosine kinase activity to promote ovarian cancer metastasis (264)

ROR2 can function independent of tyrosine kinase activity to promote ovarian cancer metastasis (264)

The Role of Urologist in Ovarian Cancer Debulking Surgery

Although spread of advanced ovarian cancer (OC) into the urinary tract was considered a contraindication for surgery until the last decade, advancement of oncological centers tries to perform these radical surgeries. Urologist plays a significant role during these surgeries in order to obtain an optimal cytoreductive surgery (CRS). The aim of debulking surgeries is to achieve radical resection of involved organs by eliminating macroscopic disease. If urinary organs are involved, patients’ survival depends on tumor resection with free postoperative margins and without residual disease and the incidence of postoperative obstruction. Preoperative evaluation of the extent of tumor into the urinary tract or dilation of the renal tract caused by ovarian spread is considered challenging. First, urologists should aim to the decompression of the lower urinary tract by placing either ureteral stents or nephrostomy tubes. After initial decompression of ureteral obstruction, urinary surgeries should follow aiming to initial identification of ureters and reconstruction of ureteral lesions. Optimal CRS in cases of OC invading the urinary bladder can be achieved either by radical or by bladder-sparing surgical procedures. Furthermore, urologists should aim to the surgical management, pre- and postoperative evaluation of patients with advanced OC involving the kidney. Due to restricted knowledge on this topic, there are no current guidelines concerning the surgical approach of urinary organs during debulking surgeries for OC, while surgical treatment of these patients should follow guidelines for the management of advanced OC invading other types of organs.

Current Status of Metastatic Cardiophrenic Lymph Nodes (CPLNs) in Patients With Ovarian Cancer: A Review.

One of the most common sites of extra-abdominal disease spread of advanced stage ovarian cancer is the cardiophrenic lymph node (CPLN) region. The role and impact of extra-abdominal cytoreduction is not obvious in patients with cardiophrenic lymph node metastases. We examined the relevant and currently available literature to determine the prognostic value and management of enlarged CPLNs in ovarian cancer patients. Transdiaphragmatic excision of CPLNs or via video-assisted thoracoscopic surgery (VATS) is achievable without major complications. The most common postoperative complications were pleural effusion, pneumothorax and pneumonia. On preoperative CT scan, the cut-off size of suspicious CPLNs is not uniform and is indicated as 5 to 10 mm short-axis dimension. CPLNs were detected in up to 60% of patients and malignancy was pathologically confirmed in 45-95% of the cases. The presence of enlarged CPLNs was found to be a negative prognostic factor, although its impact on progression-free and overall survival is not yet clarified and needs further investigation.

Ovarian Cancer-Driven Mesothelial-to-Mesenchymal Transition is Triggered by the Endothelin-1/β-arr1 Axis

Transcoelomic spread of serous ovarian cancer (SOC) results from the cooperative interactions between cancer and host components. Tumor-derived factors might allow the conversion of mesothelial cells (MCs) into tumor-associated MCs, providing a favorable environment for SOC cell dissemination. However, factors and molecular mechanisms involved in this process are largely unexplored. Here we investigated the tumor-related endothelin-1 (ET-1) as an inducer of changes in MCs supporting SOC progression. Here, we report a significant production of ET-1 from MCs associated with the expression of its cognate receptors, ETA and ETB, along with the protein β-arrestin1. ET-1 triggers MC proliferation via β-arrestin1-dependent MAPK and NF-kB pathways and increases the release of cancer-related factors. The ETA/ETB receptor activation supports the genetic reprogramming of mesothelial-to-mesenchymal transition (MMT), with upregulation of mesenchymal markers, as fibronectin, α-SMA, N-cadherin and vimentin, NF-kB-dependent Snail transcriptional activity and downregulation of E-cadherin and ZO-1, allowing to enhanced MC migration and invasion, and SOC transmesothelial migration. These effects are impaired by either blockade of ETAR and ETBR or by β-arrestin1 silencing. Notably, in peritoneal metastases both ETAR and ETBR are co-expressed with MMT markers compared to normal control peritoneum. Collectively, our report shows that the ET-1 axis may contribute to the early stage of SOC progression by modulating MC pro-metastatic behaviour via MMT.

Role of integrins in the metastatic spread of high-grade serous ovarian cancer

PurposeIntegrins may be involved in the metastatic spread of high-grade serous ovarian cancer (HGSOC) which determines the therapeutical approach and prognosis. We investigated the integrin expression in primary tumor and metastases of advanced HGSOC.MethodsThe expression of integrin α2, α4, α5, α6, and β1 was assessed by immunostaining in tumor samples of the ovary, omentum, and peritoneum of each patient. Differences in integrin expression among tumor localizations and their association with clinicopathological parameters were examined by Fisher’s exact test. The impact of integrin expression on progression-free survival (PFS) and overall survival (OS) was examined by Cox regression and Kaplan–Meier analyses.ResultsHundred and thirteen tumor samples of 40 HGSOC patients were examined. The expression of the integrins did not differ between the three tumor localizations (all p values > 0.05) with the exception of high expression of integrin α4 in primary tumor and omentum (52.5% versus 47.5%, p = 0.008) and primary tumor and peritoneum (52.5% versus 47.5%, p = 0.050). High expression of integrin α4 in peritoneum was associated with poorer PFS (HR 2.02 95% CI 1.01–4.05, p = 0.047), younger age (p = 0.047), and death (p = 0.046). Median PFS in patients with high expression of integrin α4 was 13.00 months, whereas median PFS in patients without high expression of integrin α4 was 21.00 months (p = 0.040). Expression of other integrins did not correlate with PFS or OS.ConclusionExpression of integrin α4 may be altered during the metastatic spread of HGSOC and affect prognosis, whereas expression of integrin α2, α5, α6, and β1 did not reveal any prognostic value.

Supplementary Files: Accuracy of Pretreatment Ultrasonography Assessment of Intra-Abdominal Spread in Epithelial Ovarian Cancer: A Prospective Study

Supplementary Files: Accuracy of Pretreatment Ultrasonography Assessment of Intra-Abdominal Spread in Epithelial Ovarian Cancer: A Prospective Study

Accuracy of Pretreatment Ultrasonography Assessment of Intra-Abdominal Spread in Epithelial Ovarian Cancer: A Prospective Study.

The aim of this study was to test the accuracy of ultrasonography performed by gynecological oncologists for the preoperative assessment of epithelial ovarian cancer (EOC) spread in the pelvis and abdominal cavity. A prospective, observational cohort study was performed at a single tertiary cancer care unit. Patients with suspected EOC were recruited and underwent comprehensive transvaginal and abdominal ultrasonography performed by a gynecological oncologist. Sixteen intra-abdominal localizations and parameters were assessed using ultrasonography and compared with surgical-pathological status (reference standard). Sensitivity, specificity, positive and negative predictive values, and overall accuracy were calculated. Differences were analyzed using Fisher’s exact and chi-square tests. Ultimately, we included 132 patients (median age 62 years), of whom 67% were in stage IIIC–IVB and 72% had serous cancer. Overall prediction accuracies for the involvement of the omentum, small bowel mesentery root, and frozen pelvis, and detecting ascites were >90%. Detecting the involvement of the pelvis peritoneum, liver and spleen hilum, and rectosigmoid colon, and predictions of disease stage and residual disease had overall accuracies of 80–90%. The lowest accuracy was for involvement of the abdominal peritoneum (69%) and diaphragm peritoneum (right 71%; left 75%) and surgical complexity prediction (77%). Stratification of results by presence or absence of ascites revealed significantly higher specificity of ultrasonography (clinically meaningful) for assessments of the abdominal/pelvic peritoneum, spleen hilum, and rectum wall, if there were ascites. A gynecological oncologist, experienced in surgery and sonology, performing comprehensive ultrasonography on patients with EOC can accurately detect intraperitoneal lesions and recognize critical disease manifestations and predict stage, surgical complexity, and residual disease, which allow accurate qualification of patients for primary debulking surgery or neoadjuvant chemotherapy.