[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.

Building an Efficient Peritoneal Surface Malignancies Program Despite the Lower-Middle-Income Barriers: Ukraine Experience.

PURPOSE: Cytoreductive surgery/hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) programs are often limited to centers in developed countries because of extensive requirements. We aimed to analyze efficacy and challenges of CRS/HIPEC centers in lower-middle-income settings in the Ukraine example. METHODS: A multicenter descriptive study was conducted using data sets (2008-2022) from Kyiv, Lviv, and Odesa centers. Patients with appendiceal neoplasm (AN); colorectal cancer (CRC); malignant peritoneal mesothelioma (MPM); and epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC) treated with CRS ± HIPEC were included. Overall survival (OS) was analyzed for N ≥ 20 cohorts using the Kaplan-Meier method. RESULTS: We included 596 patients. At Kyiv and Lviv centers, 37 and 28 patients with AN had completeness of cytoreduction (CC-0/1) rates of 84% and 71%, respectively. Thirty-day major morbidity stood at 24% and 18%, respectively. Median OS was not reached (NR) at both centers. Nineteen patients with CRC from Kyiv, 11 from Lviv, and 156 from Odesa had CC-0/1 rates of 84%, 91%, and 86%, respectively. Thirty-day major complications occurred in 16%, 18%, and 8%, respectively. Median OS in the Odesa cohort was 35 (95% CI, 32 to 38) months. Among 15 Kyiv, five Lviv, and six Odesa patients with MPM, CC-0/1 rates were 67%, 80%, and 100%, respectively, while major complications occurred in 13%, 0%, and 17%, respectively. OS was not analyzed because of small MPM cohorts. At Kyiv, Lviv, and Odesa centers, 91, 40, and 89 patients, respectively, had primary EOC. CC-0/1 rates were 79%, 100%, and 80%, and 30-day major morbidity rates were 23%, 5%, and 6%, respectively. Median OS was NR, 71 (95% CI, 32 to 110), and 67 (95% CI, 61 to 73) months, respectively. CONCLUSION: CRS/HIPEC programs in lower-middle-income environment can achieve safety and survival that meet global standards. Our discussion highlights common obstacles in such settings and proposes effective overcoming strategies.

Macrophages reprogramming improves immunotherapy of IL-33 in peritoneal metastasis of gastric cancer.

Peritoneal metastasis (PM) has a suppressive tumor immune microenvironment (TIME) that limits the effects of immunotherapy. This study aimed to investigate the immunomodulatory effects of intraperitoneal administration of IL-33, a cytokine that is reported to potentiate antitumor immunity and inhibit metastasis. We found survival was significantly prolonged in patients with high IL-33 mRNA expression. In immunocompetent mice, intraperitoneal administration of IL-33 could induce a celiac inflammatory environment, activate immunologic effector cells, and reverse the immunosuppressive tumor microenvironment, which effectively delayed tumor progression and PM of gastric cancer. Mechanistically, IL-33 could induce M2 polarization by activating p38-GATA-binding protein 3 signaling. IL-33 combined with anti-CSF1R or p38 inhibitor to regulate tumor-associated macrophages (TAMs) had a synergistic antitumor effect. Inducing a local inflammatory milieu by IL-33 administration provided a novel approach for treating peritoneal metastasis, which, when combined with TAM reprogramming to reshape TIME, can achieve better treatment efficacy.

Intra- and Interpatient Drug Response Heterogeneity Exist in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Nongynecologic Cancers.

BACKGROUND: Select patients with peritoneal metastases are treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). We assayed for intra- and interpatient drug response heterogeneity through testing of patient-derived tumor organoids (PDTOs). METHODS: PDTOs were generated from CRS/HIPEC patients from December 2021 to September 2022 and subjected to an in vitro HIPEC drug screen. Drug response was assessed with a cell viability assay and cleaved caspase-3 staining. RESULTS: A total of 31 patients were consented for tissue collection. Viable tissue was harvested from 23, and PDTO generation was successful in 13 (56%). PDTOs were analyzed from six appendiceal, three colorectal, two small bowel, one gastric, and one adrenal tumor. Drug screen results were generated in as few as 7 days (62%), with an average time of 12 days. Most patients received mitomycin-C (MMC) intraoperatively (n = 9); however, in only three cases was this agent considered the optimal choice in vitro. Three sets of PDTOs were resistant (defined as > 50% PDTO viability) to all agents tested and two were pan-sensitive (defined as 3 or more agents with < 50% PDTO viability). In three patients, organoids were generated from multiple metastatic sites and intrapatient drug response heterogeneity was observed. CONCLUSIONS: Both intra- and interpatient drug response heterogeneity exist in patients undergoing CRS/HIPEC for nongynecologic abdominal cancers. Caution must be used when interpreting patient response to chemotherapeutic agents based on a single site of testing in those with metastatic disease.

Risk factors and prognosis of malignant peritoneal mesothelioma with paraneoplastic syndrome.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare and highly aggressive tumor. Its clinical manifestations are diverse, and the symptoms are not specific. Some patients will develop paraneoplastic syndrome (PS) during the disease course. This study aims to analyze the risk factors of PS in patients with MPM and their impacts on prognosis. METHODS: The clinical data of MPM patients who underwent cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) at our center from June 2015 to May 2023 were retrospectively analyzed. MPM patients were divided into PS group and non-PS group according to the diagnostic criteria. Univariate and multivariate analyses were performed to explore the risk factors of PS in MPM patients, and to analyze the impact of PS on prognosis. RESULTS: There were 146 MPM patients in this study, including 60 patients (41.1%) with PS and 86 patients (58.9%) without PS. The highest incidence of PS was thrombocytosis (33.6%), followed by neoplastic fever (9.6%). Univariate analysis revealed 8 factors (P < 0.05) with statistically significant differences between the two groups: prior surgical scores, targeted therapy history, Karnofsky performance status score, preoperative carbohydrate antigen (CA) 125 level, vascular tumor embolus, peritoneal cancer index, completeness of cytoreduction (CC) score and intraoperative ascites. Multivariate analysis identified 3 independent factors associated with PS: preoperative CA 125 level, vascular tumor embolus, and CC score. Survival analysis demonstrated that MPM patients with PS had worse prognosis, although PS was not an independent prognostic factor. CONCLUSIONS: PS is not rare in patients with MPM, and is independently associated with preoperative CA 125 level, vascular tumor embolus and CC score. PS often indicates advanced disease and poor prognosis.

Transarterial Chemoembolization Plus Tyrosinkinase Inhibitors and PD-1 Inhibitors for Spontaneously Ruptured Hepatocellular Carcinoma.

PURPOSE: To compare the efficacy and safety of transcatheter arterial chemoembolization (TACE) in combination with tyrosinkinase inhibitors (TKI) and PD-1 inhibitors, versus TACE monotherapy for the treatment of ruptured hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This study included 104 patients with ruptured HCC receiving either combination therapy or TACE monotherapy at two centers between June 2015 and June 2022. Propensity score matching (PSM) analysis was used at a 1:2 ratio to reduce bias between the two groups. The primary outcome measures were overall survival (OS) and progression-free survival (PFS), and the secondary outcome measures were the occurrence of adverse events (AEs, Common Terminology Criteria for AEs, version 5.0.) and the peritoneal metastasis rate. RESULTS: A total of 69 patients were enrolled after PSM, including 23 patients in the combination group and 46 patients in the monotherapy group. The combination group exhibited a significantly longer median OS (553 days, 95% confidence interval [CI] 222.6-883.9) compared to the monotherapy group (105 days, 95% CI 81.2-128.7; P < 0.001). Similarly, the combination group showed a better median PFS (356 days, 95% CI 299.5-412.4) compared to the monotherapy group (97 days, 95% CI 75.9-118.1; P < 0.001). Moreover, there was no significant difference in the peritoneal metastasis rate (combination group: 8.6% vs. monotherapy group: 26.1%, P = 0.119). Grade 3 AEs occurred at a rate of 21.7% and 13% in combination and monotherapy groups, respectively. No Grade 4/5 AEs were observed in either group. CONCLUSIONS: Our study demonstrated that the combination of TACE with TKI and PD-1 inhibitors significantly enhances OS and PFS compared to TACE monotherapy in ruptured HCC patients. Furthermore, this combined approach exhibited an acceptable safety profile.

Gastric Extent of Tumor Predicts Peritoneal Metastasis in Siewert II Adenocarcinoma.

BACKGROUND: Whereas current guidelines recommend staging laparoscopy for most patients with potentially resectable gastric cancer, such a recommendation for patients with adenocarcinoma of the gastroesophageal junction (AEG) is lacking. This study sought to identify baseline clinicopathologic characteristics associated with peritoneal metastasis (PM) among patients with Siewert II AEG. METHODS: Trimodality therapy-eligible patients with Siewert II AEG (2000-2015, single institution) were retrospectively identified. A composite PM outcome was defined as follows: (1) PM at staging laparoscopy; (2) PM diagnosed during neoadjuvant chemoradiation; or (3) PM ≤6 months postoperatively. Logistic regression was used to identify features associated with PM; bootstrapped analysis (Youden J) identified the distal tumor extension that best discriminated the composite outcome. RESULTS: Of 188 patients, a composite PM outcome was observed in 26 of 188 (13.8%); 12 of 26 had positive staging laparoscopy, 10 of 26 experienced PM during chemoradiation, and 4 of 26 had PM ≤6 months postoperatively. Tumor extension below the GEJ was greater in patients with PM (median, 4.0 cm [interquartile range, 3.0-5.0] vs 3.0 cm [interquartile range, 2.0-3.0]; P < .001). All patients with PM had cT3 to cT4 tumors. Among patients with cT3 to cT4 tumors (n = 168 of 188; 89.4%), distal tumor extent (odds ratio, 1.67/cm; 95% CI, 1.23-2.28; P = .001) was independently associated with increased odds of PM. Gastric tumor extension ≥4 cm remained independently associated with PM (OR, 5.14; 95% CI, 2.11-12.53; P < .001) after adjustment for signet ring cell status. CONCLUSIONS: Distal tumor extent beyond the GEJ is independently associated with increased odds of PM in patients with Siewert II AEG. Patients with extensive gastric involvement should therefore be considered for staging laparoscopy before trimodality therapy.

Peritoneal metastases from gastric cancer in a nationwide cohort: Incidence, treatment and survival.

The aims of this study were to investigate incidence, risk factors and treatment of synchronous or metachronous peritoneal metastases (PM) from gastric cancer and to estimate survival of these patients using population-based data. Patients diagnosed with gastric cancer in 2015 to 2016 were selected from the Netherlands Cancer Registry. The incidence of synchronous and metachronous PM were calculated. Multivariable regression analyses were performed to identify factors associated with the occurrence of PM. Treatment and survival were compared between patients with synchronous and metachronous PM. Of 2206 patients with gastric cancer, 741 (34%) were diagnosed with PM. Of these, 498 (23%) had synchronous PM. The cumulative incidence of metachronous PM in patients who underwent potentially curative treatment (n = 675) was 22.8% at 3 years. A factor associated with synchronous and metachronous PM was diffuse type histology. Patients diagnosed with synchronous PM more often received systemic treatment than patients with metachronous PM (35% vs 18%, respectively, P < .001). Median overall survival was comparable between synchronous and metachronous PM (3.2 vs 2.3 months, respectively, P = .731). Approximately one third of all patients with gastric cancer are diagnosed with PM, either at primary diagnosis or during 3-year follow-up after potentially curative treatment. Patients with metachronous PM less often received systemic treatment than those with synchronous PM but survival was comparable between both groups. Future trials are warranted to detect gastric cancer at an earlier stage and to examine strategies that lower the risk of peritoneal dissemination. Also, specific treatment options for patients with gastric PM should be further investigated.

A case of pseudomyxoma peritonei arising from a perforated intraductal papillary mucinous neoplasm that underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Pseudomyxoma peritonei (PMP) of pancreatic origin arising from an intraductal papillary mucinous neoplasm (IPMN) is rare. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has been established as the optimal treatment for PMP. However, the benefits and safety of CRS with HIPEC for treating PMP of pancreatic origin remain unclear. Herein, we describe a case of PMP of pancreatic origin that was treated with CRS and HIPEC without postoperative complications. A 75-year-old woman was referred to our department. Computed tomography (CT) revealed a multilocular cystic tumor in the pancreatic tail, notable mucinous ascites in the abdominal cavity, and scalloping of the liver and spleen. CT did not reveal the appendix, and the ovaries were normal in size. The patient was diagnosed with PMP of pancreatic origin, and CRS and HIPEC were performed. Intraoperatively, the pancreatic tumor was perforated, and there was a large amount of mucinous ascites. We performed distal pancreatectomy in addition to CRS and HIPEC, with no intraoperative complications. The postoperative course was uneventful, and the patient survived after 6 months without recurrence. CRS with HIPEC may be a feasible treatment option for PMP of pancreatic origin.

Actual 5-Year Survival After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Patients with Peritoneal Carcinomatosis of Colorectal Origin.

BACKGROUND: Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) improves survival compared with chemotherapy alone in patients with peritoneal carcinomatosis (PC) of colorectal (CRC) origin, however, long-term survival data are lacking. We report the actual survival of patients who underwent CRS/HIPEC for PC of CRC origin with a minimum potential 5-year follow-up period to identify factors that preclude long-term survival. METHODS: We performed a retrospective analysis of a prospective database, analyzing patients undergoing CRS/HIPEC for PC of CRC origin from 2007 to 2017. Patients with aborted CRS/HIPEC, postoperative follow-up <90 days, or non-CRC histology were excluded. Overall survival (OS) and disease-free survival (DFS) were measured from date of surgery. Surviving patients with <60 months of follow-up were censored at date of last follow-up. RESULTS: A total of 103 patients met inclusion criteria and were analyzed. CC score 0-1 was achieved in 89.3% of patients, and median peritoneal cancer index (PCI) was 9 (interquartile range [IQR] 5-17). Ninety-day mortality was 2.9%. The median follow-up of survivors was 88 months. Five-year OS was 36%, and median OS was 42.5 months. Factors independently associated with poor survival included high PCI (PCI = 14-20, hazard ratio [HR] 3.1, p = 0.007, and PCI > 20, HR 5.3, p ≤ 0.001) and incomplete CRS (CC score-2, HR 2.96, p = 0.02). Patients with low PCI (0-6) had 5-year OS 60.7%. CONCLUSIONS: Actual 5-year OS was 36% and median OS was 42.5 months. Our study demonstrates that patients with PC from CRC origin with low PCI who undergo complete surgical resection can achieve favorable long-term survival.

Comparison of outcomes between surgical treatment of colorectal cancer metastatic to the liver and the peritoneum: Review of the literature.

BACKGROUND: Liver and peritoneum are two of the most common sites of colorectal metastases. METHODS: We searched for articles comparing outcomes of surgical management for metastatic colorectal cancer to the liver and peritoneum. CONCLUSION: Cytoreductive surgery/heated intraperitoneal chemotherapy has a similar safety profile and survival outcomes as hepatectomy for colorectal metastases after stratifying by resection status and should be incorporated earlier in the management algorithm for colorectal cancer patients with peritoneal metastases METHODS: We performed a wide search on PubMed, EMBASE, and Google Scholar for articles comparing outcomes of surgical management for metastatic colorectal cancer to the liver and peritoneum. We focused on studies comparing their perioperative clinical outcomes as well as their oncological outcomes. The following words were included in the search: comparison, outcomes, metastasectomy, colorectal cancer, liver, peritoneal surface disease, hepatectomy, and cytoreduction. RESULTS: One hundred and twenty studies were evaluated. Six of these studies met the criteria for this review.