Targeting carcinoma-associated mesothelial cells with antibody-drug conjugates in ovarian carcinomatosis.

Ovarian carcinomatosis is characterized by the accumulation of carcinoma-associated mesothelial cells (CAMs) in the peritoneal stroma and mainly originates through a mesothelial-to-mesenchymal transition (MMT) process. MMT has been proposed as a therapeutic target for peritoneal metastasis. Most ovarian cancer (OC) patients present at diagnosis with peritoneal seeding, which makes tumor progression control difficult by MMT modulation. An alternative approach is to use antibody-drug conjugates (ADCs) targeted directly to attack CAMs. This strategy could represent the cornerstone of precision-based medicine for peritoneal carcinomatosis. Here, we performed complete transcriptome analyses of ascitic fluid-isolated CAMs in advanced OC patients with primary-, high-, and low-grade, serous subtypes and following neoadjuvant chemotherapy. Our findings suggest that both cancer biological aggressiveness and chemotherapy-induced tumor mass reduction reflect the MMT-associated changes that take place in the tumor surrounding microenvironment. Accordingly, MMT-related genes, including fibroblast activation protein (FAP), mannose receptor C type 2 (MRC2), interleukin-11 receptor alpha (IL11RA), myristoylated alanine-rich C-kinase substrate (MARCKS), and sulfatase-1 (SULF1), were identified as specific actionable targets in CAMs of OC patients, which is a crucial step in the de novo design of ADCs. These cell surface target receptors were also validated in peritoneal CAMs of colorectal cancer peritoneal implants, indicating that ADC-based treatment could extend to other abdominal tumors that show peritoneal colonization. As proof of concept, a FAP-targeted ADC reduced tumor growth in an OC xenograft mouse model with peritoneal metastasis-associated fibroblasts. In summary, we propose MMT as a potential source of ADC-based therapeutic targets for peritoneal carcinomatosis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Ovarian Cancer-Driven Mesothelial-to-Mesenchymal Transition is Triggered by the Endothelin-1/ß-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 ß-arrestin1. ET-1 triggers MC proliferation via ß-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 ß-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.

Mesothelial-to-Mesenchymal Transition and Exosomes in Peritoneal Metastasis of Ovarian Cancer.

Most patients with ovarian cancer (OvCA) present peritoneal disseminated disease at the time of diagnosis. During peritoneal metastasis, cancer cells detach from the primary tumor and disseminate through the intraperitoneal fluid. The peritoneal mesothelial cell (PMC) monolayer that lines the abdominal cavity is the first barrier encountered by OvCA cells. Subsequent progression of tumors through the peritoneum leads to the accumulation into the peritoneal stroma of a sizeable population of carcinoma-associated fibroblasts (CAFs), which is mainly originated from a mesothelial-to-mesenchymal transition (MMT) process. A common characteristic of OvCA patients is the intraperitoneal accumulation of ascitic fluid, which is composed of cytokines, chemokines, growth factors, miRNAs, and proteins contained in exosomes, as well as tumor and mesothelial suspended cells, among other components that vary in proportion between patients. Exosomes are small extracellular vesicles that have been shown to mediate peritoneal metastasis by educating a pre-metastatic niche, promoting the accumulation of CAFs via MMT, and inducing tumor growth and chemoresistance. This review summarizes and discusses the pivotal role of exosomes and MMT as mediators of OvCA peritoneal colonization and as emerging diagnostic and therapeutic targets.

Cellular Integrin α5ß1 and Exosomal ADAM17 Mediate the Binding and Uptake of Exosomes Produced by Colorectal Carcinoma Cells.

Approximately 25% of colorectal cancer (CRC) patients develop peritoneal metastasis, a condition associated with a bleak prognosis. The CRC peritoneal dissemination cascade involves the shedding of cancer cells from the primary tumor, their transport through the peritoneal cavity, their adhesion to the peritoneal mesothelial cells (PMCs) that line all peritoneal organs, and invasion of cancer cells through this mesothelial cell barrier and underlying stroma to establish new metastatic foci. Exosomes produced by cancer cells have been shown to influence many processes related to cancer progression and metastasis. In epithelial ovarian cancer these extracellular vesicles (EVs) have been shown to favor different steps of the peritoneal dissemination cascade by changing the functional phenotype of cancer cells and PMCs. Little is currently known, however, about the roles played by exosomes in the pathogenesis and peritoneal metastasis cascade of CRC and especially about the molecules that mediate their interaction and uptake by target PMCs and tumor cells. We isolated exosomes by size-exclusion chromatography from CRC cells and performed cell-adhesion assays to immobilized exosomes in the presence of blocking antibodies against surface proteins and measured the uptake of fluorescently-labelled exosomes. We report here that the interaction between integrin α5ß1 on CRC cells (and PMCs) and its ligand ADAM17 on exosomes mediated the binding and uptake of CRC-derived exosomes. Furthermore, this process was negatively regulated by the expression of tetraspanin CD9 on exosomes.

Intraoperative subcutaneous culture as a predictor of surgical site infection in open gynecological surgery.

PURPOSE: To analyze the relationship between intraoperative cultures and the development of surgical site infection (SSI) in women undergoing laparotomy for gynecological surgery. METHODS: Prospective observational cohort study. Over a six-year period, women who underwent elective laparotomy at our hospital were included. Patients' demographics, underlying co-morbidities, surgical variables, type and etiology of postoperative surgical site infections were collected. Skin and subcutaneous samples were taken just prior to skin closure and processed for microbiological analysis. Univariate and multivariate analyses (logistic regression model) were conducted to explore the association of the studied variables with SSIs. RESULTS: 284 patients were included in our study, of which 20 (7%) developed surgical site infection, including 11 (55%) superficial and nine (45%) organ-space. At univariate analysis, length of surgery, colon resection, transfusion and positive intraoperative culture were associated with surgical site infection occurrence. Skin and subcutaneous cultures were positive in 25 (8.8%) and 20 (7%) patients, respectively. SSI occurred in 35% of women with positive subcutaneous culture and in 20% of those with positive skin cultures. Using multivariate analysis, the only independent factor associated with surgical site infection was a positive subcutaneous culture (OR 10.4; 95% CI 3.5-30.4; P<0.001). CONCLUSION: Intraoperative subcutaneous cultures before skin closure may help early prediction of surgical site infection in open gynecological procedures.

Prognosis and treatment-selection criteria for patients with high-grade stage IIIc-IV serous ovarian, fallopian tube or peritoneal cancer / Pronóstico y selección de tratamiento en pacientes con cáncer seroso de ovario, de trompas de Falopio o peritoneal de alto grado, estadio IIIc-IV

Objective: To determine the impact of implementing strict treatment-selection criteria on the overall outcome of women with high-grade serous advanced stage ovarian, fallopian tube, or primary peritoneal carcinoma. Material and methods: We included patients treated for high-grade serous advanced stage ovarian, fallopian tube, or primary peritoneal carcinoma at our Institution from January 2007 to March 2015. All other non-serous, low-grade histology tumors and secondary cytoreductions were excluded. strict treatment-selection criteria was used to decide on primary cytoreductive surgery versus neoad-juvant chemotherapy and type of adjuvant therapy. Collected data included patient and tumor characteristics, preoperative diagnostic procedures, surgical treatment, perioperative complications, and neoadjuvant and adjuvant chemotherapies. Appropriate statistical tests were used and survival analysis performed. Results: We identified 71 eligible patients. Mean age was 58.5 ± 11.8 years, 28.2% received neoadjuvant chemotherapy, and 77.5% had optimal cytoreductive surgery to < 1 cm residual disease. Major complications were observed in 16.9% of women, with no significant difference between neoadjuvant chemotherapy and primary cytoreductive surgery groups. With a median follow-up of 35.7 months, median overall survival was not achieved and 57.2% of patients were alive 54 months after surgery. A total of 24 out of 71 (33.8%) died of disease, 11 (45.8%) within two years after surgery. Median progression-free survival was 19.5 months (95% CI 14.8-24.3). Conclusions: Applying strict treatment-selection criteria for patients with high-grade serous advanced stage ovarian, fallopian tube, or primary peritoneal carcinoma ensures few surgical complications and excellent survival rates for the majority of these women

Objetivo: determinar el impacto de la implementación de criterios estrictos de selección de tratamiento sobre el pronóstico de las mujeres con carcinoma seroso de ovario, trompa de Falopio o peritoneal primario en estadio avanzado y de alto grado. Material y métodos: entre enero de 2007 y marzo de 2015 se incluyeron pacientes tratadas por carcinoma ovárico seroso avanzado de alto grado, trompa de Falopio o carcinoma peritoneal primario en nuestro hospital. Se utilizaron criterios estrictos de selección de tratamiento para decidir sobre la cirugía citorreductora primaria versus quimioterapia neoadyuvante y el tipo de tratamiento adyuvante. Los datos recogidos incluyeron características del paciente y del tumor, procedimientos diagnósticos preoperatorios, tratamiento quirúrgico, complicaciones perioperatorias y quimioterapias neoadyuvantes y adyuvantes. Se utilizaron pruebas estadísticas adecuadas y se realizó un análisis de supervivencia. Resultados: se incluyeron 71 pacientes. La edad media fue de 58,5 ± 11,8 años, el 28,2% recibió quimioterapia neoadyuvante y el 77,5% tuvo una cirugía citorreductora óptima (< 1 cm de enfermedad residual). Se observaron complicaciones mayores en el 16,9% de las mujeres, sin diferencias significativas entre los grupos de quimioterapia neoadyuvante y de cirugía citorreductora primaria. Con una mediana de seguimiento de 35,7 meses, no se alcanzó la mediana de supervivencia global y el 57,2% de los pacientes estaban vivas 54 meses después de la cirugía. Un total de 24 de 71 (33.8%) murieron de enfermedad, 11 (45.8%) en los dos años después de la cirugía. La mediana de supervivencia libre de progresión fue de 19,5 meses (IC del 95%: 14,8-24,3). Conclusiones: la aplicación de criterios estrictos de selección de tratamiento para pacientes con carcinoma seroso ovárico, de trompa de Falopio o carcinoma peritoneal primario en estadio avanzado de alto grado asegura pocas complicaciones quirúrgicas y buenas tasas de supervivencia para la mayoría de estas pacientes

Sonographic Evaluation of Fetal Adrenal Gland in Gestational Diabetes: Relation to Fetal Growth and Maternal Biochemical Markers.

OBJECTIVES: To relate measurements and volume of the fetal adrenal gland in third trimester ultrasound in diabetic pregnancies (1) to birth weight; (2) to other sonographic markers of diabetic fetopathy (expected fetal weight, sectional area, and fractional volume in fetal limbs); and (3) to maternal biochemical markers of diabetes (HbA1c, leptin). METHODS: Fetal adrenal gland measurements were obtained between 32 and 34 weeks. The gland length, width, depth, and volume (by Virtual Organ Computer-Aided Analysis [VOCAL]) were measured for total gland and fetal zone. Fetal total and fat sectional area and fractional volume were obtained in arm and thigh. A maternal blood sample was obtained. Univariate and multivariate models were used to assess the associations. RESULTS: Thirty-nine diabetic pregnancies were included. Birth weight related significantly to total and fetal zone adrenal depth, and total adrenal volume in third trimester. Total adrenal length and corrected adrenal gland volume also showed a significant correlation to birth weight percentile in univariate and multivariate models. Total adrenal volume associated significantly to total and fat areas and volumes in fetal limbs. Both maternal leptin and HbA1c levels found a significant positive relation to fetal total adrenal volume and corrected adrenal gland volume. Total adrenal gland volume showed a significant association to maternal HbA1c level in multivariate model. CONCLUSIONS: An enlargement of the fetal adrenal gland may be observed in gestational diabetes, not only related to birth weight, but also to distinctive features of diabetic pregnancies, such as fat tissue fetal deposits or maternal biochemical markers.

Primary breast angiosarcoma in a young woman.

INTRODUCTION: Angiosarcomas of the breast are a rare subtype of sarcomas that frequently are diagnosed after radiation therapy for primary breast cancer. Primary angiosarcomas are rare entities accounting 0.05% of all malignant breast neoplasm. PRESENTATION OF CASE: We report a case of primary angiosarcoma of the breast in a 25 years woman, with no previous radiotherapy, treated with a total mastectomy followed by radio-chemotherapy. DISCUSSION: Total mastectomy appears to be the only treatment known that has proven to benefit these patients. Adjuvant treatment has not proven value up until today. The 5-year disease free survival for grade 1 tumors can be as high as 76%, and up to 15% for grade 3. CONCLUSION: Due to the rarity of these tumors there is no standard therapies approach.

Weight-related and analytical maternal factors in gestational diabetes to predict birth weight and cord markers of diabetic fetopathy.

OBJECTIVE: The objective was to determine the value of clinical and analytical maternal factors to predict birth weight and umbilical cord biochemical markers of diabetic fetopathy. METHODS: Prospective evaluation of gestational diabetes pregnancies (n = 50). Maternal weight-related clinical and analytical factors were collected during pregnancy. After birth, an umbilical cord sample was taken. RESULTS: Univariate linear regression analysis showed relationship between maternal weight, glycated hemoglobin (HbA1c) and insulin-like growth factor 1 (IGF1) with birth weight percentile. A significant association was found between maternal weight and cord insulin and C-peptide. Maternal HbA1c, leptin and insulin during pregnancy showed a positive linear association to cord leptin, insulin and C-peptide. In multivariate analysis models, final maternal BMI showed an independent positive association with cord C-peptide. CONCLUSIONS: Maternal weight-related and analytical parameters show diagnostic value to birth weight and cord markers.

Fetal limb soft tissue assessment for prediction of birth weight and umbilical cord blood analytes in gestational diabetes.

OBJECTIVE: To evaluate the value of third trimester ultrasound (estimated fetal weight, cheek-to-cheek diameter, sectional Wharton's jelly area, sectional areas and fractional volumes in extremities) to predict birth weight and cord biochemical markers at birth (leptin, insulin, c-peptide, IGF1, erythropoietin and ferritin) in diabetic pregnancies. METHOD: Prospective study in 49 patients with gestational diabetes. An ultrasound was performed between 32 and 34 weeks. Clinical data were collected, and a blood sample was obtained from cord after birth. ROC curve models were evaluated for 75(th) and 90(th) birth weight percentile. Univariate and multivariate models were used to assess the association between ultrasound and neonatal outcomes. RESULTS: Sectional areas and fractional volumes showed significant differences and highest AUC values for predicting birth weight. A significant association was found for extremities measurements with total birth weight and its percentile. The only marker which showed a significant association to estimated fetal weight was erythropoietin. Sectional areas and fractional volumes related to cord leptin, erythropoietin, insulin and c-peptide. CONCLUSION: Sectional areas and fractional volumes improve the predictive value of estimated fetal weight in diabetic pregnancies. They also show a predictive association to biochemical changes in cord (leptin, insulin and erythropoietin) related to increased adiposity and risk of fetal hypoxia. © 2015 John Wiley & Sons, Ltd.

Diffusion-weighted magnetic resonance imaging evaluation of intra-abdominal sites of implants to predict likelihood of suboptimal cytoreductive surgery in patients with ovarian carcinoma.

OBJECTIVES: To analyse the diagnostic accuracy and to establish a predictive score based on diffusion-weighted magnetic resonance imaging (DWMRI) compared to exploratory laparotomy (EL) for predicting suboptimal cytoreductive surgery for different intra-abdominal sites of implants in patients with ovarian cancer. METHODS: Thirty-four patients with advanced ovarian carcinoma were studied. Preoperative DWMRI of the abdomen and pelvis was performed. DWMRI findings were compared with EL. Ten anatomical sites were selected for inclusion in the score. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy for suboptimal cytoreduction were calculated for both DWMRI and EL. Receiver operating characteristic (ROC) curve analysis was used to assess the ability to predict suboptimal cytoreduction. RESULTS: Using predictive score, ROC curves were generated with an area under the curve of 0.938 for DWMRI and 0.947 for EL (P < 0.0001). For DWMRI, a score ≥6 had the highest overall accuracy at 91.1 % and identified patients with unnecessary EL with a sensitivity of 75 %. For EL, a score ≥4 had the highest overall accuracy at 88.2 % and was able to identify patients with unnecessary EL with a sensitivity of 87.5 %. CONCLUSIONS: DWMRI is an emerging technique that may be useful to predict suboptimal cytoreduction in ovarian cancer. KEY POINTS: • DWMRI is increasingly used in ovarian cancer. • DWMRI is an accurate technique for depicting intra-abdominal sites of implants • DWMRI is useful for predicting optimal cytoreductive surgical outcome. • We report a high predictive value similar to exploratory laparotomy.

Fetal magnetic resonance imaging and neurosonography in congenital neurological anomalies: supplementary diagnostic and postnatal prognostic value.

OBJECTIVE: To compare the diagnostic conclusions between fetal neurosonography and MRI in the cases of congenital neurological abnormalities, and with postnatal clinical and imaging evaluation, when available. METHODS: A retrospective study of 28 patients who underwent a fetal MRI study for suspected congenital neurological anomalies. The diagnoses obtained by neurosonography and MRI were collected and compared. Both of them were compared with the final diagnosis when available by necropsy or postnatal evaluation. Postnatal imaging tests were performed only when clinically indicated. RESULTS: The indications for the fetal MRI examination were: fetal ventriculomegaly, posterior fossa anomalies, suspected midline defects, small-for-gestational-age cephalic biometry and confirmed congenital CMV infection. There was a good degree of agreement beyond chance between both techniques (kappa test = 0.76). CONCLUSIONS: Both imaging modalities give a high-diagnostic performance with a good degree of agreement between them, when made by specialized staff. Fetal MRI is a valuable complementary tool to detailed neurosonography which allows an evaluation of the normal brain maturation from the second trimester. It also offers a higher diagnostic performance for some congenital abnormalities such as cortical development or acquired lesions.

Does fluid hysteroscopy increase the stage or worsen the prognosis in patients with endometrial cancer? A randomized controlled trial.

OBJECTIVE: To determine whether fluid hysteroscopic directed biopsies, in patients with endometrial cancer upstages the tumor and worsens the prognosis. STUDY DESIGN: Between January 1996 and September 2001, a total of 62 consecutive patients with endometrial cancer, treated at our institution, were randomized 3:2 to have or not to have a fluid hysteroscopic biopsy just prior to surgery. A total of 38 patients underwent a hysteroscopy after the induction of anesthesia. All patients had pelvic washings performed, followed by a hysterectomy, bilateral salpingooforectomy and pelvic +/- para-aortic lymph node dissections. Only stages I and II endometrioid type tumors or stage IIIa, secondary to positive pelvic washings, were included in the study. Eight patients in the hysteroscopy group and four patients in the control group were excluded for various reasons. Patients received post-operative radiation therapy depending on the surgical-pathological risk factors. The median follow up was 34 months. Fisher's Exact Test was performed to compare differences between the hysteroscopic (n = 30) and the control (n = 20) groups. RESULTS: We found three patients (10%) with positive washings in the hysteroscopic group compared to one (5%) among the controls (P = 0.64), with a statistical power of <20%. If the differences would persist, we would need 588 patients in each arm to obtain a power of 80%, and reach definitive conclusions. The Odds Ratio (OR) of performing a hysteroscopy and upstaging the tumor in this study was: 2.1 95% CI (0.20-21.09). Prognostic variables were compared between both groups and no differences were observed. All patients but one (dead due to intercurrent disease), were alive and with no evidence of disease at the completion of the study. CONCLUSIONS: Fluid hysteroscopy and directed biopsies may have a small risk of upstaging early endometrial cancers, but does not seem to influence prognosis.

Increased prevalence of p53 overexpression from typical endometriosis to atypical endometriosis and ovarian cancer associated with endometriosis.

OBJECTIVE: To evaluate the expression of p53, c-erb-B-2, MIB1 and Bcl-2 in normal endometrium, endometriosis, atypical endometriosis and ovarian cancer associated with endometriosis, looking for immunohistochemical markers that may help determine endometriosis with premalignant potential. STUDY DESIGN: Between 1948 and 1999, 410 epithelial ovarian cancers and 521 cases of endometriosis were surgically treated at Fundación Jiménez Díaz. Pathology reports and slides were reviewed. Four groups were defined: (1) endometriosis/cancer (n=17); (2) atypical endometriosis (n=6); (3) endometriosis (n=17); (4) endometrium (n=7). Tumors and controls were immunostained and evaluated for expression of p53, c-erb-B-2, MIB1 and Bcl-2. Statistical analysis was performed using Chi-square for linear trends, Fisher exact and Kruskal-Wallis tests. RESULTS: Of the 410 cancers, 17 (4.1%) had associated endometriosis and of the 521 endometriosis, 6 (1.2 %) had atypical changes. Fourteen of 17 (82.4%) cancers associated with endometriosis and all atypical endometriosis had p53 overexpression. Only 2 of 17 (11.8%) endometriosis and none of the endometriums had mutant p53 (P<0.01). We found a trend towards increased expression of MIB1 (0.073) in the cancer and atypical endometriosis groups, and no differences in expression of Bcl-2 or c-erb-B-2. The sensitivity and specificity of p53 as a marker for the diagnosis of atypical endometriosis and cancer associated with endometriosis were 87%; CI 95% (73.2-100%) and 92% (80.6-100%), respectively. When comparing all groups, the mean positive p53 and MIB1 cell count was statistically significant (P=0.01). CONCLUSIONS: Overexpression of p53 in atypical endometriosis and cancer associated with endometriosis is a common finding and may be used to identify endometriosis with premalignant potential.