Comparison of the effect of Everolimus, Prednisolone, and a combination of both on experimentally induced peritoneal adhesions in rats.

Postoperative intra-abdominal adhesions represent a significant post-surgical problem. Its complications can cause a considerable clinical and cost burden. Herein, our study aimed to investigate the effect of Everolimus on peritoneal adhesion formation after inducing adhesions in rats. In this experimental study, adhesion bands were induced by intraperitoneal injection of 3 ml of 10% sterile talc solution in 64 male albino rats. The first group served as the control group. The second one received oral Prednisolone (1 mg/kg/day), the third received Everolimus (0.1 mg/kg/day), and group four received both drugs with similar dosages for four consecutive weeks. The formation of adhesion bands was qualitatively graded according to the Nair classification. The rats in the control group had extensive adhesions between the abdominal wall and the organs. Regarding substantial adhesion formation, 50% (8/16) of animals in the control group had substantial adhesions, while this rate in the groups receiving Prednisolone, Everolimus, and combination treatment was 31%, 31%, and 31%, respectively. Also, 68.75% (5/11) of the Prednisolone recipients had insubstantial adhesions, the same as Everolimus recipients, while in the combination group, 66.66% (10/15) rats had insubstantial adhesions. Everolimus demonstrated satisfactory results in reducing the rates of induced peritoneal adhesion in an experimental model, similar to Prednisolone and superior to a combination regime.

Neoadjuvant chemotherapy does not improve survival for patients with high volume colorectal peritoneal metastases undergoing cytoreductive surgery.

BACKGROUND: Colorectal peritoneal metastases (CRPM) affects 15% of patients at initial colorectal cancer diagnosis. Neoadjuvant chemotherapy (NAC) prior to cytoreductive surgery (CRS) has been demonstrated to be a safe and feasible option, however there is limited data describing its efficacy in advanced peritoneal disease. This study evaluated the effect of NAC on survival in patients with high volume CRPM undergoing CRS with or without HIPEC. METHODS: A retrospective review of all patients who underwent CRS with or without HIPEC for CRPM from 2004 to 2019 at our institution was performed. The cohort was divided based on peritoneal carcinomatosis index (PCI) at surgery: Low Volume (PCI ≤ 16) and High Volume (PCI > 16). RESULTS: A total of 326 patients underwent CRS with HIPEC for CRPM. There were 39 patients (12%) with High Volume disease, and 15 of these (38%) received NAC. Patients with High Volume disease had significantly longer operating time, lower likelihood of complete macroscopic cytoreduction (CC-0 score), longer intensive care unit length of stay and longer hospital stay compared to Low Volume disease. In High Volume disease, the NAC group had a significantly shorter median survival of 14.4 months compared to 23.8 months in the non-NAC group (p = 0.046). CONCLUSION: Patients with High Volume CRPM achieved good median survival following CRS with HIPEC, which challenges the current PCI threshold for offering CRS. The use of NAC in this cohort did not increase perioperative morbidity but was associated with significantly shorter median survival compared to upfront surgery.

The Naples Prognostic Score Is an Independent Prognostic Factor for Gastric Cancer Patients Who Receive Curative Treatment.

BACKGROUND/AIM: This study aimed to evaluate the clinical impact of the Naples Prognostic Score (NPS) in patients with gastric cancer and to clarify the potential of the NPS as a nutritional and inflammation evaluation system. PATIENTS AND METHODS: This study included 158 patients who underwent curative treatment for gastric cancer between 2005 and 2020. The prognosis and clinical pathological parameters of the high-NPS (NPS >2) and low-NPS (NPS=0, 1) groups were analyzed. RESULTS: The overall survival (OS) rates at 3 and 5 years were 86.7% and 77.7%, respectively, in the low-NPS group and 55.4% and 47.4%, respectively, in the high-NPS group. There were significant differences in OS between the two groups. Uni- and multivariate analyses demonstrated that the NPS was an independent prognostic factor for OS (HR=2.495, 95%CI=1.240-5.451). In addition, the 3- and 5-year recurrence-free survival (RFS) rates were 82.1% and 76.0%, respectively, in the NPS-low group, and 43.8% and 36.6% in the NPS-high group. Univariate and multivariate analyses demonstrated that the NPS was an independent prognostic factor for RFS (HR=2.739, 95%CI=1.509-4.972). When the first site of recurrence was compared between the low-NPS group and high-NPS group, there were significant differences in peritoneal recurrence (8.7% vs. 34.3%, p=0.001) and hematologic recurrence (5.6% vs. 21.9%, p=0.004). CONCLUSION: The NPS was a significant prognostic factor in patients with gastric cancer who received curative treatment. The NPS may be a promising biomarker for the treatment and management of gastric cancer.

Nanomechanical Analysis of Living Small Extracellular Vesicles to Identify Gastric Cancer Cell Malignancy Based on a Biomimetic Peritoneum.

Gastric cancer is one of the most prevalent digestive malignancies. The lack of effective in vitro peritoneal models has hindered the exploration of the potential mechanisms behind gastric cancer's peritoneal metastasis. An accumulating body of research indicates that small extracellular vesicles (sEVs) play an indispensable role in peritoneal metastasis of gastric cancer cells. In this study, a biomimetic peritoneum was constructed. The biomimetic model is similar to real peritoneum in internal microstructure, composition, and primary function, and it enables the recurrence of peritoneal metastasis process in vitro. Based on this model, the association between the mechanical properties of sEVs and the invasiveness of gastric cancer was identified. By performing nanomechanical analysis on sEVs, we found that the Young's modulus of sEVs can be utilized to differentiate between malignant clinical samples (ascites) and nonmalignant clinical samples (peritoneal lavage). Furthermore, patients' ascites-derived sEVs were verified to stimulate the mesothelial-to-mesenchymal transition, thereby promoting peritoneal metastasis. In summary, nanomechanical analysis of living sEVs could be utilized for the noninvasive diagnosis of malignant degree and peritoneal metastasis of gastric cancer. This finding is expected to contribute future treatments.

Blocking EGR1/TGF-ß1 and CD44s/STAT3 Crosstalk Inhibits Peritoneal Metastasis of Gastric Cancer.

Peritoneal metastasis (PM) continues to limit the clinical efficacy of gastric cancer (GC). Early growth response 1 (EGR1) plays an important role in tumor cell proliferation, angiogenesis and invasion. However, the role of EGR1 derived from the tumor microenvironment in reshaping the phenotypes of GC cells and its specific molecular mechanisms in increasing the potential for PM are still unclear. In this study, we reported that EGR1 was significantly up-regulated in mesothelial cells from GC peritoneal metastases, leading to enhanced epithelial-mesenchymal transformation (EMT) and stemness phenotypes of GC cells under co-culture conditions. These phenotypes were achieved through the transcription and secretion of TGF-ß1 by EGR1 in mesothelial cells, which could regulate the expression and internalization of CD44s. After being internalized into the cytoplasm, CD44s interacted with STAT3 to promote STAT3 phosphorylation and activation, and induced EMT and stemness gene transcription, thus positively regulating the metastasis of GC cells. Moreover, TGF-ß1 secretion in the PM microenvironment was significantly increased compared with the matched primary tumor. The blocking effect of SHR-1701 on TGF-ß1 was verified by inhibiting peritoneal metastases in xenografts. Collectively, the interplay of EGR1/TGF-ß1/CD44s/STAT3 signaling between mesothelial cells and GC cells induces EMT and stemness phenotypes, offering potential as a therapeutic target for PM of GC.

Giant peritoneal loose body and its protein composition: a case report.

Peritoneal loose body (PLB) is a kind of lesions located in the abdominal cavity or pelvic cavity, which is rare and difficult to diagnose. The diameter of PLB is mostly 0.5-2.5 cm. Most PLBS are asymptomatic. Here we reported a case of giant PLB in the pelvis and analyzed its structure and protein composition. Surgical exploration revealed a white oval mass (4.5*4*3 cm) in the pelvic cavity. After the mass was removed, the symptoms of hematuria disappeared and the patient was discharged on the second postoperative day. Histochemical staining showed that PLB was mainly composed of collagen and scattered calcification. The protein components of PLB were detected by proteome analysis, and a variety of proteins related to collagen deposition and calcification were identified in PLB.

Inhibition of chemokine receptor CXCR2 attenuates postoperative peritoneal adhesion formation.

BACKGROUND: Postoperative peritoneal adhesions remain a problem after general and gynecological surgery. METHODS: Hematoxylin and eosin and Masson's trichrome staining of ischemic buttons were performed 6, 12, 24 hours, and 7 days after button induction. Scanning electron microscopy, ribonucleic acid sequencing, quantitative real-time polymerase chain reaction, immunohistochemical staining, and flow cytometry were used to elucidate the pathophysiology of postoperative peritoneal adhesions. RESULTS: The results showed that thickening of the peritoneum and abscission of mesothelial cells and collagen fibers increased significantly on the surface of the "button" in the control groups at 24 hours postoperatively. Scanning electron microscopy revealed a large number of granulocytes on the button surface in the control group at 24 hours. Ribonucleic acid sequencing and quantitative real-time polymerase chain reaction also revealed that CXCR2 expression was significantly upregulated. In addition, danirixin, a CXCR2 inhibitor, reduced abdominal adhesion in the injured area by inhibiting the infiltration of inflammatory cells and collagen production. Immunohistochemical staining showed decreased expression of CXCR2 in the adhesion area 7 days after surgery in the treatment group. Flow cytometry showed a significantly decreased neutrophil ratio in the treatment group compared with that in the control group 24 hours after the operation. CONCLUSIONS: Inflammation plays an important role in the early stages of postoperative peritoneal adhesion formation, whereas collagen fibers and angiogenesis play important roles in the late stages. The CXCL2-CXCL3-CXCR2 signaling axis is an important link in the mechanism of postoperative peritoneal adhesion formation, and the application of CXCR2 inhibitors can alleviate the formation of postoperative peritoneal adhesions.

Reviving peritoneal cytology: Exploring its role in endometrial cancer molecular classification.

OBJECTIVE: The prognostic significance of positive peritoneal cytology in endometrial cancer has long been debated. In 2009, the Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) removed cytology as a staging criterion from the endometrial cancer staging system. However, there is still evidence that positive peritoneal cytology may decrease survival among patients with endometrial cancer. The aim of this study was to determine the prognostic significance of positive peritoneal cytology among the different molecular subgroups. METHODS: This study included patients with endometrial cancer who underwent primary surgical treatment between 2004 and 2015 at the Bern University Hospital, Switzerland, with molecular classification of the primary tumor and peritoneal cytology performed. RESULTS: A total, 250 patients with endometrial cancer were enrolled. Peritoneal cytology was assessed in 206 patients, of whom 24% were positive: 25% of the POLEmut, 16% of the MMRd, 41% of the p53abn, and 24% of the NSMP cases. The mean follow-up was 128.7 months. Presence of positive peritoneal cytology was associated with significantly decreased mean recurrence-free and overall survival in patients with p53abn (p = .003 and p = .001) and NSMP (p = .020 and p = .049) endometrial cancer. In multivariable Cox regression analysis, positive peritoneal cytology remained an independent predictor of recurrence (p = .033) and death (p = .008) in p53abn endometrial cancer patients. CONCLUSION: Positive peritoneal cytology is associated with worse oncologic outcomes in NSMP and p53abn endometrial cancer and remains an independent predictor of recurrence and death in patients with p53abn endometrial cancer.

Mesothelial cells with mesenchymal features enhance peritoneal dissemination by forming a protumorigenic microenvironment.

Malignant ascites accompanied by peritoneal dissemination contain various factors and cell populations as well as cancer cells; however, how the tumor microenvironment is shaped in ascites remains unclear. Single-cell proteomic profiling and a comprehensive proteomic analysis are conducted to comprehensively characterize malignant ascites. Here, we find defects in immune effectors along with immunosuppressive cell accumulation in ascites of patients with gastric cancer (GC) and identify five distinct subpopulations of CD45(-)/EpCAM(-) cells. Mesothelial cells with mesenchymal features in CD45(-)/EpCAM(-) cells are the predominant source of chemokines involved in immunosuppressive myeloid cell (IMC) recruitment. Moreover, mesothelial-mesenchymal transition (MMT)-induced mesothelial cells strongly express extracellular matrix (ECM)-related genes, including tenascin-C (TNC), enhancing metastatic colonization. These findings highlight the definite roles of the mesenchymal cell population in the development of a protumorigenic microenvironment to promote peritoneal dissemination.

High-grade B-cell lymphoma, not otherwise specified, presenting as primary peritoneal lymphomatosis and successfully treated with dose-adjusted EPOCH-R.

Peritoneal lymphomatosis (PL) is a rare lymphoma-associated condition defined as the dissemination of lymphoma cells in the peritoneum. An 82-year-old man presented with abdominal pain, heartburn, and high fever. Radiological findings, including positron emission tomography-computed tomography (PET-CT), and gastrointestinal fiberscopy, showed diffuse thickening of the peritoneum, omentum, and mesentery; however, no lymphadenopathy, hepatosplenomegaly, or gastrointestinal lesions were observed. Under suspicion of peritonitis carcinomatosa of unknown origin, exploratory laparoscopy was performed that revealed multiple white nodules and masses on the surfaces of the peritoneum, mesentery, and intestinal serosa. The histopathological and cytogenetic findings of the peritoneum revealed high-grade B-cell lymphoma, not otherwise specified, and a gain of MYC by fluorescence in-situ hybridization. The patient was treated with two cycles of R-CHOP therapy, followed by six cycles of dose-adjusted EPOCH-R therapy, and a complete metabolic response was confirmed by PET-CT. Since there are no specific radiological findings to confirm the diagnosis of PL, a histopathological diagnosis is usually required. Most PL exhibit an aggressive lymphoma phenotype and can be cured by appropriate chemotherapy. Therefore, early diagnosis and treatment are desirable.

Collaborative expertise of gynecological and surgical oncologists in managing advanced epithelial ovarian cancer.

BACKGROUND: Most patients with epithelial ovarian cancer (EOC) present with significant peritoneal spread. We assessed collaborative efforts of surgical and gynecological oncologists with expertise in cytoreductive surgery (CRS) in the management of advanced EOC. METHODS: Using a prospective single-center database (2014-2022), we described the operative and oncologic outcomes of stage IIIC-IVA primary and recurrent EOC perioperatively managed jointly by gynecological and surgical oncologists both specializing in CRS and presented components of this collaboration. RESULTS: Of 199 identified patients, 132 (66 %) had primary and 53 (27 %) had recurrent EOC. Due to inoperable disease, 14 (7 %) cases were aborted and excluded from analysis. Median peritoneal cancer index (PCI) in primary and recurrent patients was 21 (IQR: 11-28) and 21 (IQR: 6-31). Upper abdominal surgery was required in 95 % (n = 125) of primary and 89 % (n = 47) of recurrent patients. Bowel resections were performed in 83 % (n = 110) and 72 % (n = 38), respectively. Complete cytoreduction (CC-0/1) with no disease or residual lesions <2.5 mm was achieved in 95 % (n = 125) of primary and 91 % (n = 48) of recurrent patients. Ninety-day Clavien-Dindo grade III-IV morbidity was 12 % (n = 16) and 21 % (n = 11), respectively. Median follow-up was 44 (95%CI: 33-55) months. Median overall survival in primary and recurrent EOC was 68 (95%CI: 45-91) and 50 (95%CI: 16-84) months. Median progression-free survival was 26 (95%CI: 22-30) and 14 (95%CI: 7-21) months, respectively. CONCLUSIONS: Perioperative collaboration between surgical and gynecological oncologists specializing in CRS allows safe performance of complete cytoreduction in the majority of patients with primary and recurrent EOC, despite high tumor burden.

Mesothelioma in situ of the peritoneum: report of three cases and review of the literature.

AIM: Diagnosis of mesothelioma in situ (MIS) is historically controversial and, until recently, specific features defining the entity have not been well characterized. Most reported cases of MIS occurred in the pleura; peritoneal MIS is very rare. This study investigates the morphologic features and results of ancillary testing in peritoneal MIS. METHODS: We present three patients with peritoneal MIS, as defined by a single layer of mesothelial cells with loss of nuclear BRCA-1-associated protein-1 (BAP1) immunostaining and without evidence of invasive tumour by microscopic evaluation, imaging, or direct examination of the peritoneum. Histology and immunostains were reviewed by three expert thoracic pathologists with multidisciplinary input. Next-generation sequencing (NGS) was performed in all three cases. A literature review was conducted to characterize this rare precursor lesion. RESULTS: BAP1 was lost in all three lesions, while methylthioadenosine phosphorylase (MTAP) was retained in two (not performed in the third). NGS revealed BAP1 pathogenic alterations in all three cases as well as mutations of SMO, ERCC3, TET2, and U2AF1. Progression to invasive mesothelioma occurred in one patient at 13 months postdiagnosis (case 1). One patient was diagnosed at age 24 and was later found to harbour a BAP1 germline mutation (case 3). CONCLUSION: This work describes the histologic features and clinicopathologic characteristics of peritoneal MIS in three cases, highlights BAP1 somatic and germline mutations in peritoneal MIS, and strengthens the importance of ancillary studies (including immunohistochemical and molecular studies) in the diagnosis of MIS.

A preoperative predictive tool to assess the need for staging laparoscopy in oesophagogastric cancer patients.

INTRODUCTION: Staging laparoscopy (SL) has become commonplace in the preoperative staging pathway for oesophagogastric (OG) cancer. SL is often performed before curative treatment to examine for macroscopic peritoneal metastases (PM) or positive peritoneal cytology (PPC). The aim of this study was to develop an objective risk scoring system to predict both PM and PPC at SL. METHODS: A prospectively collected and maintained database of all OG cancer patients treated between 2006 and 2020 was reviewed. Univariate and multivariate analyses were performed to identify risk factors for both PM and PPC at SL. A risk score was produced for both PM and PPC, and then validated internally. RESULTS: Among 968 patients who underwent SL, 96 (9.9%) had PM and 81 (8.4%) had PPC at SL. Tumour site (p < 0.001), computed tomography (CT) T stage (p < 0.001) and N stage (p = 0.029) were significantly associated with PM at SL (p < 0.001). Tumour site (p < 0.001), biopsy histology (p = 0.041), CT T stage (p < 0.001) and N stage (p < 0.001) were significantly associated with PPC. The risk scoring model for PM included cancer site and CT T stage. This was successfully tested on the validation set (area under the receiver operating characteristic [AUROC] = 0.730). The risk scoring model for PPC included cancer site, CT T and N stage. This was successfully tested on the validation set (AUROC = 0.773). CONCLUSIONS: The current risk scores are valid tools with which to predict the risk PM and PPC in patients undergoing SL for OG cancer and may help to avoid subjecting patients to unnecessary SL.

Exosomes secreted by ST3GAL5high cancer cells promote peritoneal dissemination by establishing a premetastatic microenvironment.

Peritoneal dissemination of cancer affects patient survival. The behavior of peritoneal mesothelial cells (PMCs) and immune cells influences the establishment of a microenvironment that promotes cancer cell metastasis in the peritoneum. Here, we investigated the roles of lactosylceramide alpha-2,3-sialyltransferase (ST3G5; also known as ST3GAL5 and GM3 synthase) in the exosome-mediated premetastatic niche in peritoneal milky spots (MSs). Exosomes secreted from ST3G5high cancer cells (ST3G5high -cExos) were found to contain high levels of hypoxia-inducible factor 1-alpha (HIF1α) and accumulated in MSs via uptake in macrophages (MΦs) owing to increased expression of sialic acid-binding Ig-like lectin 1 (CD169; also known as SIGLEC1). ST3G5high -cExos induced pro-inflammatory cytokines and glucose metabolic changes in MΦs, and the interaction of these MΦs with PMCs promoted mesothelial-mesenchymal transition (MMT) in PMCs, thereby generating αSMA+ myofibroblasts. ST3G5high -cExos also increased the expression of immune checkpoint molecules and T-cell exhaustion in MSs, which accelerated metastasis to the omentum. These events were prevented following ST3G5 depletion in cancer cells. Mechanistically, ST3G5high -cExos upregulated chemokines, including CC-chemokine ligand 5 (CCL5), in recipient MΦs and dendritic cells (DCs), which induced MMT and immunosuppression via activation of signal transducer and activator of transcription 3 (STAT3). Maraviroc, a C-C chemokine receptor type 5 (CCR5) antagonist, prevented ST3G5high -cExo-mediated MMT, T-cell suppression, and metastasis in MSs. Our results suggest ST3G5 as a suitable therapeutic target for preventing cExo-mediated peritoneal dissemination.

Does total omentectomy prevent peritoneal seeding for advanced gastric cancer with serosal invasion?

BACKGROUND: Radical gastrectomy is composed of gastrectomy, lymph node dissection, and omentectomy. Total omentectomy (TO) is expected to reduce the incidence of peritoneal recurrence. We aimed to investigate the necessity of TO for advanced gastric cancer (AGC) with serosal invasion. METHODS: We retrospectively reviewed 310 patients who underwent radical gastrectomy with TO and 93 patients who underwent partial omentectomy (PO) for gastric cancer with serosal invasion between August, 2005 and December, 2017. Finally, 91 patients in the PO group and 91 in the TO group were enrolled based on a 1:1 propensity-score matching analysis. We evaluated surgical and oncological outcomes, including 5-year overall and recurrence-free survival rates. RESULTS: There was no statistically significant difference between the two groups in postoperative complications. Recurrence sites showed similar patterns in both groups, including peritoneal recurrence (PO vs. TO, 18.7% vs. 28.6%; p = 0.188). Five-year overall survival was better in the PO group (p = 0.018), while 5-year recurrence-free survival was similar in both groups (p = 0.066). CONCLUSION: TO might not be an essential part of preventing peritoneal recurrence for AGC with serosal invasion. PO could be considered a radical gastrectomy for T4a gastric cancer.

Feasibility of laparoscopic Visceral-Peritoneal Debulking (L-VPD) in patients with stage III-IV ovarian cancer: the ULTRA-LAP trial pilot study.

OBJECTIVE: A non-randomized prospective clinical trial (ULTRA-LAP) was registered to test safety, side effects and efficacy of laparoscopic Visceral-Peritoneal Debulking (L-VPD) in patients with stage III-IV ovarian cancer (OC). A pilot study was designed to identify which OC patients are suitable to undergo L-VPD. METHODS: Between March 2016 and October 2021, all consecutive patients with OC underwent exploratory laparoscopy (EXL). All patients whose disease was deemed amenable for a complete resection (CR) at imaging review and EXL, underwent VPD. In all patients a consistent attempt was made at completing L-VPD. RESULTS: Two hundred and eight OC had EXL in the study period: 121 underwent interval VPD and 87 up-front VPD. Overall, 158 patients had VPD by laparotomy (75.9%) and 50 (24.1%) had L-VPD, of which 34 patients as interval (iL-VPD) and 16 as up-front (uL-VPD). Intra- and post-operative morbidity was very low in the L-VPD group. CR rate was 98% in L-VPD group and 94% in VPD. Most common reason for conversion was diaphragmatic disease extending dorsally. CONCLUSION: In the pilot study of ULTRA-LAP, L-VPD was completed in 24,1% of OC. Initial analysis supports the feasibility of L-VPD in 2 groups of OC: those with no gross disease at interval surgery and those with gross visible disease at upfront or interval surgery, but limited to: pelvis (including recto-sigmoid), gastro colic omentum, peritoneum and diaphragm, the latter not requiring dorsal liver mobilization. Both groups had 100% feasibility and have been thus forth recruited to ULTRA-LAP. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05862740.