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Gynecologic Oncology Sep 2023Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is...
A phase 2 study of dasatinib in recurrent clear cell carcinoma of the ovary, fallopian tube, peritoneum or endometrium: NRG oncology/gynecologic oncology group study 0283.
OBJECTIVE
Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas. High-throughput cell-based drug screening predicted activity of dasatinib, a tyrosine kinase inhibitor, in ARID1A-mutant clear cell carcinoma.
METHODS
We conducted a phase 2 clinical trial of dasatinib 140 mg once daily by mouth in patients with recurrent or persistent ovarian and endometrial clear cell carcinoma. Patients with measurable disease were enrolled and then assigned to biomarker-defined populations based on BAF250a immunohistochemistry. The translational endpoints included broad next-generation sequencing to assess concordance of protein expression and treatment outcomes.
RESULTS
Twenty-eight patients, 15 of whom had tumors with retained BAF250a and 13 with loss of BAF250a were evaluable for treatment response and safety. The most common grade 3 adverse events were anemia, fatigue, dyspnea, hyponatremia, pleural effusion, and vomiting. One patient had a partial response, eight (28%) had stable disease, and 15 (53.6%) had disease progression. Twenty-three patients had next-generation sequencing results; 13 had a pathogenic ARID1A alteration. PIK3CA mutations were more prevalent in ARID1A-mutant tumors, while TP53 mutations were more prevalent in ARID1A wild-type tumors.
CONCLUSIONS
Dasatinib was not an effective single-agent treatment for recurrent or persistent ovarian and endometrial clear cell carcinoma. Studies are urgently needed for this rare gynecologic subtype.
Topics: Humans; Female; Peritoneum; Dasatinib; Fallopian Tubes; Carcinoma, Endometrioid; Endometrium; Adenocarcinoma, Clear Cell; Ovarian Neoplasms
PubMed: 37418832
DOI: 10.1016/j.ygyno.2023.06.021 -
Biomedicine & Pharmacotherapy =... Sep 2023Peritoneal dialysis is an efficient renal replacement therapy for patients with end-stage kidney disease. However, continuous exposure of the peritoneal membrane to... (Review)
Review
Peritoneal dialysis is an efficient renal replacement therapy for patients with end-stage kidney disease. However, continuous exposure of the peritoneal membrane to dialysate frequently leads to peritoneal fibrosis, which alters the function of the peritoneal membrane and results in withdrawal from peritoneal dialysis in patients. Among others, high glucose dialysate is considered as a predisposing factor for peritoneal fibrosis in patients on peritoneal dialysis. Glucose-induced inflammation, metabolism disturbance, activation of the renin-angiotensin-aldosterone system, angiogenesis and noninflammation-induced reactive oxygen species are implicated in the pathogenesis of high glucose dialysate-induced peritoneal fibrosis. Specifically, high glucose causes chronic inflammation and recurrent peritonitis, which could cause migration and polarization of inflammatory cells, as well as release of cytokines and fibrosis. High glucose also interferes with lipid metabolism and glycolysis by activating the sterol-regulatory element-binding protein-2/cleavage-activating protein pathway and increasing hypoxia inducible factor-1α expression, leading to angiogenesis and peritoneal fibrosis. Activation of the renin-angiotensin-aldosterone system and Ras-mitogen activated protein kinase signaling pathway is another contributing factor in high glucose dialysate-induced fibrosis. Ultimately, activation of the transforming growth factor-β1/Smad pathway is involved in mesothelial-mesenchymal transition or epithelial-mesenchymal transition, which leads to the development of fibrosis. Although possible intervention strategies for peritoneal dialysate-induced fibrosis by targeting the transforming growth factor-β1/Smad pathway have occasionally been proposed, lack of laboratory evidence renders clinical decision-making difficult. We therefore aim to revisit the upstream pathways of transforming growth factor-beta1/Smad and propose potential therapeutic targets for high glucose-induced peritoneal fibrosis.
Topics: Humans; Peritoneal Fibrosis; Dialysis Solutions; Transforming Growth Factor beta1; Peritoneum; Fibrosis; Inflammation; Glucose
PubMed: 37523983
DOI: 10.1016/j.biopha.2023.115246 -
Cancer Reports (Hoboken, N.J.) Oct 2023Ovarian cancer seriously threatens women's health because of its poor prognosis and high mortality. Due to the lack of efficient early detection and screening methods,... (Review)
Review
BACKGROUND
Ovarian cancer seriously threatens women's health because of its poor prognosis and high mortality. Due to the lack of efficient early detection and screening methods, when patients seek doctors' help with complaints of abdominal distension, back pain and other nonspecific signs, the clinical results always hint at the widespread metastasis of disease. When referring to the metastasis of this disease, the omentum always takes precedence.
RECENT FINDINGS
The distinguishing feature of the omentum is adipose tissue, which satisfies the energy demand of cancer cells and supplies a more aggressive environment for ovarian cancer cells. In this review, we mainly focus on three important cell types: adipocytes, macrophages, and mesenchymal stem cells. Besides, several mechanisms underlying cancer-associated adipocytes (CAA)-facilitated ovarian cancer cell development have been revealed, including their capacities for storing lipids and endocrine function, and the release of hormones, growth factors, and adipokines. Blocking the reciprocity among cancer cells and various cells located on the omentum might contribute to ovarian cancer therapy. The inhibition of hormones, growth factors and adipokines produced by adipocytes will be a novel therapeutic strategy. However, a sufficient number of trials has not been performed. In spite of this, the therapeutic potential of metformin and the roles of exercise in ovarian cancer will be worth mentioning.
CONCLUSION
It is almost impossible to overcome completely ovarian cancer at the moment. What we can do is trying our best to improve these patients' prognoses. In this process, adipocytes may bring promising future for the therapy of ovarian cancer.
Topics: Female; Humans; Omentum; Ovarian Neoplasms; Cellular Microenvironment; Adipokines; Hormones; Tumor Microenvironment
PubMed: 37605299
DOI: 10.1002/cnr2.1858 -
Colorectal Disease : the Official... May 2024While neoadjuvant chemotherapy has become the standard of care for rectal cancers in most centres, there is much interest in neoadjuvant chemotherapy in colon cancer... (Review)
Review
While neoadjuvant chemotherapy has become the standard of care for rectal cancers in most centres, there is much interest in neoadjuvant chemotherapy in colon cancer after the recent publication of the FOxTROT trial. The management of colon cancers seems to be heading down the same path as rectal cancer, where the radicality of surgery is replaced by chemotherapy intensification. The role of demanding procedures such as complete mesocolic excision with central venous ligation in this new paradigm of upfront chemotherapy remains uncertain and uninvestigated.
Topics: Humans; Colonic Neoplasms; Neoadjuvant Therapy; Chemotherapy, Adjuvant; Colectomy; Mesocolon
PubMed: 38480511
DOI: 10.1111/codi.16945 -
Scientific Reports Oct 2023Next to the skin, the peritoneum is the largest human organ, essentially involved in abdominal health and disease states, but information on peritoneal paracellular...
Next to the skin, the peritoneum is the largest human organ, essentially involved in abdominal health and disease states, but information on peritoneal paracellular tight junctions and transcellular channels and transporters relative to peritoneal transmembrane transport is scant. We studied their peritoneal localization and quantity by immunohistochemistry and confocal microscopy in health, in chronic kidney disease (CKD) and on peritoneal dialysis (PD), with the latter allowing for functional characterizations, in a total of 93 individuals (0-75 years). Claudin-1 to -5, and -15, zonula occludens-1, occludin and tricellulin, SGLT1, PiT1/SLC20A1 and ENaC were consistently detected in mesothelial and arteriolar endothelial cells, with age dependent differences for mesothelial claudin-1 and arteriolar claudin-2/3. In CKD mesothelial claudin-1 and arteriolar claudin-2 and -3 were more abundant. Peritonea from PD patients exhibited increased mesothelial and arteriolar claudin-1 and mesothelial claudin-2 abundance and reduced mesothelial and arteriolar claudin-3 and arteriolar ENaC. Transperitoneal creatinine and glucose transport correlated with pore forming arteriolar claudin-2 and mesothelial claudin-4/-15, and creatinine transport with mesothelial sodium/phosphate cotransporter PiT1/SLC20A1. In multivariable analysis, claudin-2 independently predicted the peritoneal transport rates. In conclusion, tight junction, transcellular transporter and channel proteins are consistently expressed in peritoneal mesothelial and endothelial cells with minor variations across age groups, specific modifications by CKD and PD and distinct associations with transperitoneal creatinine and glucose transport rates. The latter deserve experimental studies to demonstrate mechanistic links.Clinical Trial registration: The study was performed according to the Declaration of Helsinki and is registered at www.clinicaltrials.gov (NCT01893710).
Topics: Humans; Peritoneum; Tight Junctions; Claudin-1; Endothelial Cells; Claudin-2; Creatinine; Membrane Transport Proteins; Renal Insufficiency, Chronic; Renal Insufficiency; Glucose; Sodium-Phosphate Cotransporter Proteins, Type III
PubMed: 37833387
DOI: 10.1038/s41598-023-44466-z -
The Journal of Pathology Oct 2023Ovarian carcinomatosis is characterized by the accumulation of carcinoma-associated mesothelial cells (CAMs) in the peritoneal stroma and mainly originates through a...
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.
Topics: Female; Humans; Mice; Animals; Peritoneal Neoplasms; Immunoconjugates; Carcinoma; Peritoneum; Fibroblasts; Disease Models, Animal; Ovarian Neoplasms; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37555348
DOI: 10.1002/path.6170 -
Gynecologic Oncology Sep 2023This study aimed to determine the prognostic significance of positive peritoneal cytology (PC) on endometrial carcinoma (EC) patients under the ESGO/ESTRO/ESP risk...
OBJECTIVE
This study aimed to determine the prognostic significance of positive peritoneal cytology (PC) on endometrial carcinoma (EC) patients under the ESGO/ESTRO/ESP risk classification.
METHODS
This study retrospectively analyzed EC patients from 27 medical centers in China from 2000 to 2019. Patients were divided into three ESGO risk groups: low-risk, intermediate-risk and high-intermediate risk, and high-risk groups. The covariates were balanced by using the propensity score-based inverse probability of treatment weighting (PS-IPTW). The prognostic significance of PC was assessed by Kaplan-Meier curves and multivariate Cox regression analysis.
RESULTS
A total of 6313 EC patients with PC results were included and positive PC was reported in 384 women (6.1%). The multivariate Cox analysis in all patients showed the positive PC was significantly associated with decreased PFS (hazard ratio [HR] 2.20, 95% confidence interval [CI] 1.55-3.13, P < 0.001) and OS (HR 2.25, 95% CI 1.49-3.40, P < 0.001),and the Kaplan-Meier curves also showed a poor survival in the intermediate and high-intermediate risk group (5-year PFS: 75.5% vs. 93.0%, P < 0.001; 5-year OS: 78.3% vs. 96.4%, P < 0.001); While in the low-risk group, there were no significant differences in PFS and OS between different PC status (5-year PFS: 93.1% vs. 97.3%, P = 0.124; 5-year OS: 98.6% vs. 98.2%, P = 0.823); in the high-risk group, significant difference was only found in PFS (5-year PFS: 62.5% vs. 77.9%, P = 0.033).
CONCLUSION
Positive PC was an adverse prognostic factor for EC, especially in the intermediate and high-intermediate risk patients. Gynecologic oncologists should reconsider the effect of positive PC on different ESGO risk groups.
Topics: Female; Humans; Prognosis; Retrospective Studies; Cytology; Endometrial Neoplasms; Peritoneum
PubMed: 37442025
DOI: 10.1016/j.ygyno.2023.06.578 -
Journal of Visualized Experiments : JoVE Jul 2023Early diagnosis of mesenteric ischemia remains challenging because mesenteric ischemia presents with no key symptoms or physical findings, and no laboratory data...
Early diagnosis of mesenteric ischemia remains challenging because mesenteric ischemia presents with no key symptoms or physical findings, and no laboratory data specifically indicates intestinal tissue ischemic status before necrosis develops. While computed tomography is the standard for diagnostic imaging, there are several limitations: (1) repeated assessments are associated with increased radiation exposure and risk of renal damage; (2) the computed tomography findings can be misleading because necrosis occasionally occurs despite opacified mesenteric arteries; and (3) computed tomography is not necessarily available within the golden time of salvaging the intestines for those patients in the operating room or at a place far from the hospital. This article describes a challenge to overcome such limitations using ultrasonography and near-infrared light, including clinical studies. The former is capable of providing not only morphologic and kinetic information of the intestines but also perfusion of the mesenteric vessels in real-time without transferring the patient or exposing them to radiation. Transesophageal echocardiography enables precise assessment of mesenteric perfusion in the OR, ER, or ICU. Representative findings of mesenteric ischemia in seven aortic dissection cases are presented. Near-infrared imaging with indocyanine green helps visualize the perfusion of vessels and intestinal tissues although this application requires laparotomy. Findings in two cases (aortic aneurysm) are shown. Near-infrared spectroscopy demonstrates oxygen debt in the intestinal tissue as digital data and can be a candidate for early detection of mesenteric ischemia without laparotomy. The accuracy of these assessments has been confirmed by intraoperative inspections and postoperative course (prognosis).
Topics: Humans; Mesenteric Ischemia; Multimodal Imaging; Mesenteric Arteries; Mesentery; Perfusion
PubMed: 37590532
DOI: 10.3791/65095 -
The Journal of Maternal-fetal &... Dec 2023Describe the clinical-surgical results of patients with PAS in the low-posterior cervical-trigonal space associated with fibrosis (PAS type 4) compared with PAS types in...
OBJECTIVE
Describe the clinical-surgical results of patients with PAS in the low-posterior cervical-trigonal space associated with fibrosis (PAS type 4) compared with PAS types in other locations (Types 1, upper bladder, 2 in upper parametrium) and in particular with PAS type 3, corresponding to dissectible cervical-trigonal invasion. The clinical-surgical results of using a standard hysterectomy were analyzed with a modified subtotal hysterectomy (MSTH) in patients with PAS type 4.
MATERIAL AND METHODS
A descriptive, retrospective, multicenter study included 337 patients of PAS; thirty-two corresponding to PAS type 4, from three PAS reference hospitals, CEMIC, Buenos Aires, Argentina, Fundación Valle de Lili, Cali, Colombia, and Dr. Soetomo General Hospital, Surabaya, Indonesia, between January 2015 and December 2020. PAS was diagnosed by abdominal and transvaginal ultrasound and topographically characterized by ultrafast T2 weighted MRI. In persistent macroscopic hematuria after MSTH, the surgeon performs an intentional cystotomy and uses a square compression suture to achieve the hemostasis inside the bladder wall.According to a PAS topographical classification, the patients with low-vesical cervical involvement compared with PAS located in relation with the upper blader (type1), upper parametrium (type 2 upper), and also with PAS situated in the lower vesical-trigon space (type 3). PAS 3 and 4 are located in identical area, but in type 3, group A, the vesicouterine space was dissectible, and in type 4, group B, significant fibrosis made surgical dissection extremely challenging. Furthermore, group B was divided into patients treated with total hysterectomy (HT) and those treated with a modified subtotal hysterectomy (MSTH). The surgical requirements to perform an MSHT included the availability of proximal vascular control at the aortic level (internal manual aortic compression, aortic endovascular balloon, aortic loop, or aortic cross-clamping). Then surgeon performed an upper segmental hysterotomy, avoiding the abnormal placenta invasion area; after that, the fetus was delivered, and the umbilical cord was ligated.After uterine exteriorization, the surgeon applies a continuous circular suture with number 2 polyglactin 910, taking some portions of the myometrium -to avoid unintentional slipping- around the lower uterine segment and a 3-4 cm proximal to the abnormal adhesion of the placenta. After tightening hard the circular suture, the uterine segment was circumferentially cut, three centimeters proximal to the circular hemostatic sutures. Next, the surgery follows the upper steps of conventional hysterectomy without changes. Additionally, the histological presence of fibrosis was examined in all samples.
RESULTS
Modified subtotal hysterectomy in patients with PAS type 4 (cervical-trigonal fibrosis) resulted in a significant clínico-surgical improvement over total hysterectomy. The median operative time and intraoperative bleeding were 140 min (IQR 90--240) and 1895 mL (IQR 1300-2500) in patients undergoing modified subtotal hysterectomy, and 260 min (IQR 210-287) and 2900 mL (IQR 2150-5500) in patients treated with total hysterectomy, respectively. The complication rate was 20% for MSHT and 82.3% for patients with a total hysterectomy.
CONCLUSIONS
PAS in the cervical trigonal area associated with fibrosis implies a greater risk of complications due to uncontrollable bleeding and organ damage. MSTH is associated with lower morbidity and difficulties in PAS type 4. Prenatal or intrasurgical diagnosis is essential to plan surgical alternatives to improve the results.
Topics: Pregnancy; Female; Humans; Placenta Accreta; Retrospective Studies; Uterus; Hysterectomy; Morbidity; Fibrosis; Placenta
PubMed: 37193605
DOI: 10.1080/14767058.2023.2183741