Primary omental smooth muscle tumor in an adult male: a diagnostic dilemma for leiomyoma: a case report.

BACKGROUND: The greater omentum comprises peritoneal, adipose, vascular, and lymphoid tissues. Most omental malignancies are metastatic tumors, and the incidence of primary tumors is rare. We report on a prior omental smooth muscle tumor case in an adult male patient. CASE PRESENTATION: A 54-year-old Japanese male patient with no relevant medical history was diagnosed with an abdominal mass during a routine medical checkup. Subsequent contrast-enhanced computed tomography revealed a mass of approximately 3 cm in size in the greater omentum, and a laparotomy was performed. A 27 × 25 × 20 mm raised lesion was found in the omentum. Microscopically, spindle cells were observed and arranged in whorls and fascicles. Individual tumor cells had short spindle-shaped nuclei with slightly increased chromatin and were characterized by a slightly eosinophilic, spindle-shaped cytoplasm. The mitotic count was less than 1 per 50 high-power fields. The tumor cells showed positive immunoreactivity for α smooth muscle actin, HHF35, and desmin on immunohistochemical examination. The Ki-67 labeling index using the average method was 1.76% (261/14806). No immunoreactivity was observed for any of the other tested markers. We considered leiomyoma owing to a lack of malignant findings. However, primary omental leiomyoma has rarely been reported, and it can be difficult to completely rule out the malignant potential of smooth muscle tumors in soft tissues. Our patient was decisively diagnosed with a primary omental smooth muscle tumor considering leiomyoma. Consequently, the patient did not undergo additional adjuvant therapy and was followed up. The patient was satisfied with treatment and showed neither recurrence nor metastasis at the 13-month postoperative follow-up. DISCUSSION AND CONCLUSION: We encountered a primary smooth muscle tumor of the greater omentum with no histological findings suggestive of malignancy in an adult male patient. However, omental smooth muscle tumors are extremely difficult to define as benign, requiring careful diagnosis. Further case reports with long-term follow-up and case series are required to determine whether a true omental benign smooth muscle tumor (leiomyoma) exists. In addition, proper interpretation of the Ki-67 labeling index should be established. This case study is a foundation for future research.

Intraperitoneal chemotherapy for peritoneal metastases of gastric origin: a systematic review and meta-analysis.

BACKGROUND: Gastric cancer with peritoneal metastases is associated with a dismal prognosis. Normothermic catheter-based intraperitoneal chemotherapy and normothermic pressurized intraperitoneal aerosol chemotherapy (PIPAC) are methods to deliver chemotherapy intraperitoneally leading to higher intraperitoneal concentrations of cytotoxic drugs compared to intravenous administration. We reviewed the effectiveness and safety of different methods of palliative intraperitoneal chemotherapy. METHODS: Embase, MEDLINE, Web of Science and Cochrane were searched for articles studying the use of repeated administration of palliative intraperitoneal chemotherapy in patients with gastric cancer and peritoneal metastases, published up to January 2024. The primary outcome was overall survival. RESULTS: Twenty-three studies were included, representing a total of 999 patients. The pooled median overall survival was 14.5 months. The pooled hazard ratio of the two RCTs using intraperitoneal paclitaxel and docetaxel favoured the intraperitoneal chemotherapy arm. The median overall survival of intraperitoneal paclitaxel, intraperitoneal docetaxel and PIPAC with cisplatin and doxorubicin were respectively 18.4 months, 13.2 months and 9.0 months. All treatment methods had a relatively safe toxicity profile. Conversion surgery after completion of intraperitoneal therapy was performed in 16% of the patients. CONCLUSIONS: Repeated intraperitoneal chemotherapy, regardless of method of administration, is safe for patients with gastric cancer and peritoneal metastases. Conversion surgery after completion of the intraperitoneal chemotherapy is possible in a subset of patients.

Superiority of 18F-FAPI-42 PET/CT in the detection of primary tumor and management of appendiceal neoplasm to 18F-FDG PET/CT and CE-CT.

BACKGROUND: In the present study, we investigated the value of 18F-fibroblast-activation protein inhibitor (FAPI) positron emission tomography/computed tomography (18F-FAPI-42 PET/CT) to preoperative evaluations of appendiceal neoplasms and management for patients. METHODS: This single-center retrospective clinical study, including 16 untreated and 6 treated patients, was performed from January 2022 to May 2023 at Southern Medical University Nanfang Hospital. Histopathologic examination and imaging follow-up served as the reference standard. 18F-FAPI-42 PET/CT was compared to 18F-fluorodeoxyglucose (18F-FDG) PET/CT and contrast-enhanced CT (CE-CT) in terms of maximal standardized uptake value (SUVmax), diagnostic efficacy and impact on treatment decisions. RESULTS: The accurate detection of primary tumors and peritoneal metastases were improved from 28.6% (4/14) and 50% (8/16) for CE-CT, and 43.8% (7/16) and 85.0% (17/20) for 18F-FDG PET/CT, to 87.5% (14/16) and 100% (20/20) for 18F-FAPI-42 PET/CT. Compared to 18F-FDG PET/CT, 18F-FAPI-42 PET/CT detected more regions infiltrated by peritoneal metastases (108 vs. 43), thus produced a higher peritoneal cancer index (PCI) score (median PCI: 12 vs. 5, P < 0.01). 18F-FAPI-42 PET/CT changed the intended treatment plans in 35.7% (5/14) of patients compared to CE-CT and 25% (4/16) of patients compared to 18F-FDG PET/CT but did not improve the management of patients with recurrent tumors. CONCLUSIONS: The present study revealed that 18F-FAPI-42 PET/CT can supplement CE-CT and 18F-FDG PET/CT to provide a more accurate detection of appendiceal neoplasms and improved treatment decision making for patients.

Hyperthermic intraperitoneal chemotherapy in colorectal cancer.

BACKGROUND: This study evaluated the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer with peritoneal metastases (pmCRC) in a large international data set of patients. PATIENTS AND METHODS: Patients with pmCRC from 39 centres who underwent cytoreductive surgery with HIPEC between 1991 and 2018 were selected and compared for the HIPEC protocols received-oxaliplatin-HIPEC versus mitomycin-HIPEC. Following analysis of crude data, propensity-score matching (PSM) and Cox-proportional hazard modelling were performed. Outcomes of interest were overall survival (OS), recurrence-free survival (RFS) and the HIPEC dose-response effects (high versus low dose, dose intensification and double drug protocols) on OS, RFS and 90-day morbidity. Furthermore, the impact of the treatment time period was assessed. RESULTS: Of 2760 patients, 2093 patients were included. Median OS was 43 months (95% c.i. 41 to 46 months) with a median RFS of 12 months (95% c.i. 12 to 13 months). The oxaliplatin-HIPEC group had an OS of 47 months (95% c.i. 42 to 53 months) versus 39 months (95% c.i. 36 to 43 months) in the mitomycin-HIPEC group (P = 0.002), aHR 0.77, 95% c.i. 0.67 to 0.90, P < 0.001. The OS benefit persisted after PSM of the oxaliplatin-HIPEC group and mitomycin-HIPEC group (48 months (95% c.i. 42 to 59 months) versus 40 months (95% c.i. 37 to 44 months)), P < 0.001, aHR 0.78 (95% c.i. 0.65 to 0.94), P = 0.009. Similarly, matched RFS was significantly higher for oxaliplatin-HIPEC versus others (13 months (95% c.i. 12 to 15 months) versus 11 months (95% c.i. 10 to 12 months, P = 0.02)). High-dose mitomycin-HIPEC protocols had similar OS compared to oxaliplatin-HIPEC. HIPEC dose intensification within each protocol resulted in improved survival. Oxaliplatin + irinotecan-HIPEC resulted in the most improved OS (61 months (95% c.i. 51 to 101 months)). Ninety-day mortality in both crude and PSM analysis was worse for mitomycin-HIPEC. There was no change in treatment effect depending on the analysed time period. CONCLUSIONS: Oxaliplatin-based HIPEC provided better outcomes compared to mitomycin-based HIPEC. High-dose mitomycin-HIPEC was similar to oxaliplatin-HIPEC. The 90-day mortality difference favours the oxaliplatin-HIPEC group. A trend for dose-response between low- and high-dose HIPEC was reported.

Colorectal carcinoma peritoneal metastases-derived organoids: results and perspective of a model for tailoring hyperthermic intraperitoneal chemotherapy from bench-to-bedside.

BACKGROUND: Peritoneal metastases from colorectal cancer (CRCPM) are related to poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been reported to improve survival, but peritoneal recurrence rates are still high and there is no consensus on the drug of choice for HIPEC. The aim of this study was to use patient derived organoids (PDO) to build a relevant CRCPM model to improve HIPEC efficacy in a comprehensive bench-to-bedside strategy. METHODS: Oxaliplatin (L-OHP), cisplatin (CDDP), mitomycin-c (MMC) and doxorubicin (DOX) were used to mimic HIPEC on twelve PDO lines derived from twelve CRCPM patients, using clinically relevant concentrations. After chemotherapeutic interventions, cell viability was assessed with a luminescent assay, and the obtained dose-response curves were used to determine the half-maximal inhibitory concentrations. Also, induction of apoptosis by different HIPEC interventions on PDOs was studied by evaluating CASPASE3 cleavage. RESULTS: Response to drug treatments varied considerably among PDOs. The two schemes with better response at clinically relevant concentrations included MMC alone or combined with CDDP. L-OHP showed relative efficacy only when administered at low concentrations over a long perfusion period. PDOs showed that the short course/high dose L-OHP scheme did not appear to be an effective choice for HIPEC in CRCPM. HIPEC administered under hyperthermia conditions enhanced the effect of chemotherapy drugs against cancer cells, affecting PDO viability and apoptosis. Finally, PDO co-cultured with cancer-associated fibroblast impacted HIPEC treatments by increasing PDO viability and reducing CASPASES activity. CONCLUSIONS: Our study suggests that PDOs could be a reliable in vitro model to evaluate HIPEC schemes at individual-patient level and to develop more effective treatment strategies for CRCPM.

Malignant Extrarenal Rhabdoid tumor derived from the greater omentum: A case report and literature review.

BACKGROUND: Malignant extrarenal rhabdoid tumor (MERT) is a rare and highly metastatic tumor, which is more than 75% of patients dying within 6 months of initial diagnosis, and it often leads to misdiagnosis and delayed treatment. CASE: This paper reports a 16-year-old girl who presented with the chief complaint of acute abdominal pain. She underwent laparoscopic exploration and excisional biopsy, then pathological examination and immunohistochemistry revealed "extrarenal malignant rhabdomyoma." One month after operation, she died of intra-abdominal hemorrhage and multiple organ dysfunction. CONCLUSION: MERT were often misdiagnosed and had a poor prognosis. The surgery and chemotherapy are usually beneficial to prolong the survival time of patients with MERT.

The Role of Palliative Surgery in the Management of Acute Intestinal Obstruction Secondary to Peritoneal Carcinomatosis.

Introduction: Acute intestinal obstruction secondary to extensive peritoneal carcinomatosis is an end stage event. The role of palliative surgery in these patients is debatable in view of the anticipated severe complications and its doubtful role in achieving adequate palliation. The primary objective of our study was to evaluate the feasibility and ability of patients to resume oral nutrition after palliative surgery for acute intestinal obstruction due to peritoneal carcinomatosis. Patients and Methods: It is an observational study in which we retrospectively reviewed the data from a prospectively maintained clinical database of 40 patients. The predefined pre- and intraoperative variables were obtained. The immediate outcome variables like postoperative complications, length of hospital stay, and mortality were analyzed. The short-term outcomes at 3 months in the form of survival, ability to resume enteral nutrition were analyzed. Results: Among the 40 patients 18 were males and 22 females. Ovarian cancer was the most common primary (27.5%) in the study. Twelve patients had acute intestinal obstruction as their first presentation without any past events and 25 (62.5%) patients had been operated on previously or received adjuvant systemic treatment. The palliative surgical option was technically feasible in 37 (93.5%) patients. The median length of hospitalization for the patients who were discharged was 10 days with a range of 6-18 days. Six (15%) patients died in the postoperative period. Severe post-operative complications were seen in 9 (26.4%) patients. Among the patients (n=34) discharged 26 (76.4%) were alive at 3 months. In those who were alive, 21 (80.7%) of them were on some form of oral nutrition at 3 months. Conclusion: Palliative surgery in patients with acute intestinal obstruction secondary to peritoneal carcinomatosis is feasible with acceptable morbidity and mortality. The enteral nutrition can be restored in the majority of these patients.

The management of goal-directed fluid therapy during cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Cytoreductive surgery is a surgical treatment approach that has been applied over the last 3 decades in patients with peritoneal metastases originating from intraabdominal organs. Goal-directed fluid therapy (GDFT) is an approach in which a patient fluid therapy during a medical procedure or surgery is carefully managed based on a specific goal. In this study, we aimed to present the results of GDFT in patients who underwent cytoreductive surgery for peritoneal carcinomatosis (PC) during the perioperative period. This retrospective study included 398 patients patient who underwent cytoreductive surgery + hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) due to PC originating from intraabdominal malignancies. Of the cases, 233 (58.6%) were female, and 165 (41.4%) were male patients. The mean age was 58.9. Perioperative findings revealed an average PC score of 12 (3-24), average lactate levels of 3 (2-7) mmol/L, Pao2/fio2 of 3.3 (2.4-4.1) mm Hg, mean arterial pressure (MAP) of 60 (55-70), average surgery duration of 6.5 hours (3-14), and average blood loss of 400 (200-4000) cc. The mean intraoperative fluid rate was 6.4 mL/kg/h (IQR 5.8-7.1). Sixteen (16.3%) patients experienced Clavien-Dindo Grade 3-4 adverse events. Within 30 days, 25 patients (6.3%) died. CRS + HIPEC procedures utilizing perioperative GDFT along with advanced anesthesia monitoring devices have shown successful application, offering an alternative to traditional and restrictive fluid management approaches.

Enhanced anti-tumor efficacy with multi-transgene armed mesenchymal stem cells for treating peritoneal carcinomatosis.

BACKGROUND: Mesenchymal stem cells (MSCs) have garnered significant interest for their tumor-tropic property, making them potential therapeutic delivery vehicles for cancer treatment. We have previously shown the significant anti-tumour activity in mice preclinical models and companion animals with naturally occurring cancers using non-virally engineered MSCs with a therapeutic transgene encoding cytosine deaminase and uracil phosphoribosyl transferase (CDUPRT) and green fluorescent protein (GFP). Clinical studies have shown improved response rate with combinatorial treatment of 5-fluorouracil and Interferon-beta (IFNb) in peritoneal carcinomatosis (PC). However, high systemic toxicities have limited the clinical use of such a regime. METHODS: In this study, we evaluated the feasibility of intraperitoneal administration of non-virally engineered MSCs to co-deliver CDUPRT/5-Flucytosine prodrug system and IFNb to potentially enhance the cGAS-STING signalling axis. Here, MSCs were engineered to express CDUPRT or CDUPRT-IFNb. Expression of CDUPRT and IFNb was confirmed by flow cytometry and ELISA, respectively. The anti-cancer efficacy of the engineered MSCs was evaluated in both in vitro and in vivo model. ES2, HT-29 and Colo-205 were cocultured with engineered MSCs at various ratio. The cell viability with or without 5-flucytosine was measured with MTS assay. To further compare the anti-cancer efficacy of the engineered MSCs, peritoneal carcinomatosis mouse model was established by intraperitoneal injection of luciferase expressing ES2 stable cells. The tumour burden was measured through bioluminescence tracking. RESULTS: Firstly, there was no changes in phenotypes of MSCs despite high expression of the transgene encoding CDUPRT and IFNb (CDUPRT-IFNb). Transwell migration assays and in-vivo tracking suggested the co-expression of multiple transgenes did not impact migratory capability of the MSCs. The superiority of CDUPRT-IFNb over CDUPRT expressing MSCs was demonstrated in ES2, HT-29 and Colo-205 in-vitro. Similar observations were observed in an intraperitoneal ES2 ovarian cancer xenograft model. The growth of tumor mass was inhibited by ~ 90% and 46% in the mice treated with MSCs expressing CDUPRT-IFNb or CDUPRT, respectively. CONCLUSIONS: Taken together, these results established the effectiveness of MSCs co-expressing CDUPRT and IFNb in controlling and targeting PC growth. This study lay the foundation for the development of clinical trial using multigene-armed MSCs for PC.

Exosomal miR-493 suppresses MAD2L1 and induces chemoresistance to intraperitoneal paclitaxel therapy in gastric cancer patients with peritoneal metastasis.

Intraperitoneal (IP) chemotherapy with paclitaxel (PTX) for gastric cancer (GC) with peritoneal metastasis (PM) is considered a promising treatment approach, however, there are no useful biomarkers to predict the efficacy of IP therapy. We examined the association between intra-peritoneal exosomes, particularly exosomal micro-RNAs (exo-miRNAs), and IP-chemo sensitivity. MKN45 cells that were cultured with intra-peritoneal exosomes from patients who did not respond to IP therapy with PTX (IPnon-respond group) exhibited resistance to PTX compared with exosomes from responding patients (IPrespond group) (p = 0.002). A comprehensive search for exo-miRNAs indicated that miR-493 was significantly up-regulated in exosomes from the IPnon-respond group compared with those collected from the IPrespond group. The expression of miR-493 in PTX-resistant MKN45 cells (MKN45PTX-res) was higher compared with that in MKN45. In addition, MKN45PTX-res cells exhibited lower MAD2L1 gene and protein expression compared with MKN45. Finally, miR-493 enhancement by transfection of miR-493 mimics significantly down-regulated MAD2L1 expression in MKN45 cells and reduced PTX sensitivity. Our results suggest that intra-peritoneal exo-miR-493 is involved in chemoresistance to PTX by downregulating MAD2L1 in GC with PM. Exo-miR-493 may be a biomarker for chemoresistance and prognosis of GC patients with PM and may also be a promising therapeutic target.

Vagus nerve signal has an inhibitory influence on the development of peritoneal metastasis in murine gastric cancer.

The vagus nerve is the only pathway for transmitting parasympathetic signals between the brain and thoracoabdominal organs, thereby exhibiting anti-inflammatory functions through the cholinergic anti-inflammatory pathway. Despite often being resected during lymph node dissection in upper gastrointestinal cancer surgery, the impact of vagotomy on postoperative outcomes in gastric cancer patients remains unclear. Sub-diaphragmatic vagotomy was performed on C57BL/6 mice. Three weeks later, syngeneic murine gastric cancer cell line YTN16P was injected into the peritoneal cavity, and the number of peritoneal metastases (PM) on the mesentery and omentum compared with control mice. The phenotypes of immune cells in peritoneal lavage and omental milky spots one day after tumor inoculation were analyzed using flow cytometry and immunohistochemistry. Intraperitoneal transfer of 3 × 105 YTN16P significantly increased the number of metastatic nodules on the mesentery in the vagotomy group compared to the control group. The omental metastasis grade was also significantly higher in the vagotomy group. Phenotypic analysis of immune cells in peritoneal lavage did not reveal significant differences after vagotomy. However, vagotomized mice exhibited a notable increase in milky spot area, with a higher presence of cytokeratin(+) tumor cells, F4/80(+) macrophages, and CD3(+) T cells. Vagus nerve signaling appears to regulate the immune response dynamics within milky spots against disseminated tumor cells and inhibits the development of PM. Preserving the vagus nerve may offer advantages in advanced gastric cancer surgery to reduce peritoneal recurrence.

Repeat cytoreductive surgery with HIPEC for colorectal peritoneal metastases: a systematic review.

BACKGROUND: Colorectal peritoneal metastases (CRPM) are present in 10-20% of patients at the time of their initial cancer diagnosis, and affects over 20% of those who develop colorectal cancer recurrence. Cytoreductive surgery (CRS) with HIPEC is firmly established as the optimal surgical treatment, but there is very little known about the benefit of repeat or iterative CRS. The aim of this review is to provide a systematic evaluation of the perioperative complications, survival outcomes and quality of life in patients undergoing repeat CRS with HIPEC for CRPM. METHODS: A systematic review of PubMed, Ovid MEDLINE, EMBASE, Scopus and Cochrane databases was performed to identify all studies that reported outcomes for repeat CRS with or without HIPEC for CRPM. RESULTS: Four hundred and ninety-three manuscripts were screened, and 15 retrospective studies were suitable for inclusion. Sample sizes ranged from 2 to 30 participants and comprised a total of 229 patients. HIPEC was used in all studies, but exact rates were not consistently stated. Perioperative morbidity was reported in four studies, between 16.7% and 37.5%. Nine studies reported mortality rate which was consistently 0%. The median overall survival after repeat CRS ranged from 20 to 62.6 months. No studies provided quality of life metrics. CONCLUSION: Repeat CRS for CRPM has perioperative morbidity and mortality rates comparable to initial CRS, and offers a potential survival benefit in selected patients. There is however limited high-quality data in the literature.

Ovarian tumor cell-derived JAGGED2 promotes omental metastasis through stimulating the Notch signaling pathway in the mesothelial cells.

The primary site of metastasis for epithelial ovarian cancer (EOC) is the peritoneum, and it occurs through a multistep process that begins with adhesive contacts between cancer cells and mesothelial cells. Despite evidence that Notch signaling has a role in ovarian cancer, it is unclear how exactly it contributes to ovarian cancer omental metastasis, as well as the cellular dynamics and intrinsic pathways that drive this tropism. Here we show that tumor cells produced the Notch ligand Jagged2 is a clinically and functionally critical mediator of ovarian cancer omental metastasis by activating the Notch signaling in single-layered omental mesothelial cells. In turn, Jagged2 promotes tumor growth and therapeutic resistance by stimulating IL-6 release from mesothelial cells. Additionally, Jagged2 is a potent downstream mediator of the omental metastasis cytokine TGF-ß that is released during omental destruction. Importantly, therapeutic inhibition of Jagged2-mediated omental metastasis was significantly improved by directly disrupting the Notch pathway in omental mesothelial cells. These findings highlight the key role of Jagged2 to the functional interplay between the TGF-ß and the Notch signaling pathways during the metastatic process of ovarian cancer cells to the omentum and identify the Notch signaling molecule as a precision therapeutic target for ovarian cancer metastasis.

Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases.

Peritoneal metastases (PMs) from colorectal cancer (CRC) respond poorly to treatment and are associated with unfavorable prognosis. For example, the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery in resectable patients shows limited benefit, and novel treatments are urgently needed. The majority of CRC-PMs represent the CMS4 molecular subtype of CRC, and here we queried the vulnerabilities of this subtype in pharmacogenomic databases to identify novel therapies. This reveals the copper ionophore elesclomol (ES) as highly effective against CRC-PMs. ES exhibits rapid cytotoxicity against CMS4 cells by targeting mitochondria. We find that a markedly reduced mitochondrial content in CMS4 cells explains their vulnerability to ES. ES demonstrates efficacy in preclinical models of PMs, including CRC-PMs and ovarian cancer organoids, mouse models, and a HIPEC rat model of PMs. The above proposes ES as a promising candidate for the local treatment of CRC-PMs, with broader implications for other PM-prone cancers.

Prognostic value of specific KRAS mutations in patients with colorectal peritoneal metastases.

BACKGROUND: There is little evidence on KRAS mutational profiles in colorectal cancer (CRC) peritoneal metastases (PM). This study aims to determine the prevalence of specific KRAS mutations and their prognostic value in a homogeneous cohort of patients with isolated CRC PM treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. MATERIALS AND METHODS: Data were collected from 13 Italian centers, gathered in a collaborative group of the Italian Society of Surgical Oncology. KRAS mutation subtypes have been correlated with clinical and pathological characteristics and survival [overall survival (OS), local (peritoneal) disease-free survival (LDFS) and disease-free survival (DFS)]. RESULTS: KRAS mutations occurred in 172 patients (47.5%) out of the 362 analyzed. Two different prognostic groups of KRAS mutation subtypes were identified: KRASMUT1 (G12R, G13A, G13C, G13V, Q61H, K117N, A146V), median OS > 120 months and KRASMUT2 (G12A, G12C, G12D, G12S, G12V, G13D, A59E, A59V, A146T), OS: 31.2 months. KRASMUT2 mutations mainly occurred in the P-loop region (P < 0.001) with decreased guanosine triphosphate (GTP) hydrolysis activity (P < 0.001) and were more frequently related to size (P < 0.001) and polarity change (P < 0.001) of the substituted amino acid (AA). When KRASMUT1 and KRASMUT2 were combined with other known prognostic factors (peritoneal cancer index, completeness of cytoreduction score, grading, signet ring cell, N status) in multivariate analysis, KRASMUT1 showed a similar survival rate to KRASWT patients, whereas KRASMUT2 was independently associated with poorer prognosis (hazard ratios: OS 2.1, P < 0.001; DFS 1.9, P < 0.001; LDFS 2.5, P < 0.0001). CONCLUSIONS: In patients with CRC PM, different KRAS mutation subgroups can be determined according to specific codon substitution, with some mutations (KRASMUT1) that could have a similar prognosis to wild-type patients. These findings should be further investigated in larger series.

RAC1-mediated integrin alpha-6 expression in E-cadherin-deficient gastric cancer cells promotes interactions with the stroma and peritoneal dissemination.

Diffuse-type gastric cancer (DGC) is a subtype of gastric cancer that is prone to peritoneal dissemination, with poor patient prognosis. Although intercellular adhesion loss between cancer cells is a major characteristic of DGCs, the mechanism underlying the alteration in cell-to-extracellular matrix (ECM) adhesion is unclear. We investigated how DGCs progress and cause peritoneal dissemination through interactions between DGC cells and the tumour microenvironment (TME). P53 knockout and KRASG12V-expressing (GAN-KP) cells and Cdh1-deleted GAN-KP (GAN-KPC) cells were orthotopically transplanted into the gastric wall to mimic peritoneal dissemination. The GAN-KPC tumour morphology was similar to that of human DGCs containing abundant stroma. RNA sequencing revealed that pathways related to Rho GTPases and integrin-ECM interactions were specifically increased in GAN-KPC cells compared with GAN-KP cells. Notably, we found that Rac Family Small GTPase 1 (RAC1) induces Integrin Subunit Alpha 6 (ITGA6) trafficking, leading to its enrichment on the GC cell membrane. Fibroblasts activate the FAK/AKT pathway in GC cells by mediating extracellular matrix (ECM)-Itga6 interactions, exacerbating the malignant phenotype. In turn, GC cells induce abnormal expression of fibroblast collagen and its transformation into cancer-associated fibroblasts (CAFs), resulting in DGC-like subtypes. These findings indicate that Cdh1 gene loss leads to abnormal expression and changes in the subcellular localization of ITGA6 through RAC1 signalling. The latter, through interactions with CAFs, allows for peritoneal dissemination.

[Call for attention to the value and challenge of liquid biopsy in diagnosis and treatment for peritoneal metastasis of gastric cancer].

Peritoneal metastasis is the common route of metastasis in gastric cancer and is a major cause of death in advanced gastric cancer. Early intervention with comprehensive treatment can effectively improve the prognosis of some patients with peritoneal metastasis. However, early peritoneal metastasis in gastric cancer is predominantly micro-metastasis, which cannot be effectively evaluated by imaging studies. Moreover, the detection of disseminated cancer cells in peritoneal lavage suffers from a low detection rate and significant heterogeneity. In recent years, the development and application of new liquid biopsy technologies such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have provided new means to assess potential peritoneal metastasis at the cellular and molecular levels, gradually becoming research hotspots in this field. This review will summarize the relevant progress of liquid biopsy in peritoneal metastasis, which holds significant importance for improving the prognosis of gastric cancer patients in China.

Investigating locations of recurrences with MRI after CRS-HIPEC for colorectal peritoneal metastases.

PURPOSE: Patients with colorectal peritoneal metastases (PM) treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are at high risk of recurrent disease. Understanding where and why recurrences occur is the first step in finding solutions to reduce recurrence rates. Although diffusion-weighted (DW) MRI is not routinely used in the follow-up of CRC patients, it has a clear advantage over CT in detecting the location and spread of (recurrent) PM. This study aimed to identify common locations of recurrence in CRC patients after CRS-HIPEC with MRI. METHOD: This was a single-centre retrospective study of patients with recurrent PM after CRS-HIPEC performed between January 2016 and August 2020. Patients were eligible for inclusion if they had both an MRI preoperatively (MRI1) and at the time of recurrent disease (MRI2). Two abdominal radiologists reviewed in consensus and categorized recurrences according to their location on MRI2 and in correlation with previous disease location on prior imaging (MRI1) and the surgical report of the CRS-HIPEC. RESULTS: Thirty patients were included, with a median surgical PCI of 7 (range 3-21) at the time of primary CRS-HIPEC. In total, 68 recurrent metastases were detected on MRI2, of which 14 were extra-peritoneal. Of the remaining 54 PM, 42 (78%) occurred where the peritoneum was damaged due to earlier resections or other surgical procedures (e.g. inserted surgical abdominal drains). Most recurrent metastases were found in the mesentery, lower abdomen/pelvis and abdominal wall (87%). CONCLUSIONS: Most recurrent PMs appeared in the mesentery, lower abdomen/pelvis and abdominal wall, especially where the peritoneum was previously damaged.

Extremely high peritoneal cancer index in colorectal peritoneal metastases demonstrates safety and overall survival benefit in selected patients undergoing cytoreductive surgery and heated intraperitoneal chemotherapy.

BACKGROUND: Colorectal peritoneal metastases are a devastating consequence of colorectal cancer (CRC) with extremely poor prognosis. Patients that can undergo complete cytoreduction by cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) have a markedly improved overall survival. Traditionally, patients with extremely high peritoneal cancer index (PCI), PCI >20, are not offered CRS/HIPEC. METHODS: We performed a retrospective analysis of our prospectively maintained CRS/HIPEC database and evaluated all patients with CRC peritoneal metastases between 2012 and 2022. We divided the cohorts between those with low operative PCI (PCI<20) and high operative PCI (PCI =>20). We examined demographic, clinicopathologic data, perioperative, and oncological outcomes between the cohorts. RESULTS: Of the 691 patients who underwent CRS/HIPEC, 289 were evaluable with CRC metastases, 234 with PCI <20 and 43 with PCI => 20. Median radiologic preoperative and operative PCI was 4 and 10 versus 7 and 24.5 in the low and high PCI cohorts, respectively. Operative time was longer (6 vs. 4 h) and blood loss higher (500 vs. 400 mL) in the high PCI cohort. All other demographic, clinicopathological, and operative characteristics were similar. Median disease free survival (DFS) was longer in the low PCI cohort (11.5 vs. 7 months) but overall survival (OS) showed benefit (41.3 vs. 31.8 months), (p = 0.001 and p = 0.189, respectively), comparatively with an only chemotherapy strategy. CONCLUSIONS: Appropriately selected patients with CRC metastases and extremely high PCI demonstrate similar perioperative safety outcomes in experienced tertiary referral centers. Despite a shorter median DFS, these carefully selected patients demonstrated similar median OS.