Peritoneal Metastases Of Colorectal Cancer Research Articles

Results of complete cytoreductive strategy in patients with peritoneal metastases of colorectal origin with or without extraperitoneal metastases: A bicentric analysis

BackgroundIncreased survival can be achieved in patients with colorectal cancer peritoneal metastases (CRPM) treated with cytoreductive surgery. The benefit of this strategy remains uncertain when CRPM are associated with extraperitoneal metastases (EPM). The aim of this study was to compare short- and long-term outcomes of patients treated with CRS for CRPM, with or without EPM. MethodsThis study included 413 consecutive patients who underwent CRS for CRPM: 120 with EPM (EPM+) and 293 without (EPM-). Patients with isolated ovarian metastases were included in EPM-group (n = 83). ResultsEPM were mainly located to the liver (66 %,n = 79), retroperitoneal lymph nodes (33 %,n = 40); less frequently to the spleen (9 %,n = 12), lung (9 %,n = 10) or pleura (1 %,n = 1). Ovarian metastases were present in 126 patients (83 in EMP-, 43 in EPM+). Peritoneal carcinomatosis index (PCI) was similar in EPM- (8 [4–14]) and EPM+ (8 [3–13],p = 0.335) groups, as postoperative mortality (3 % vs 3 %,p = 1) and major morbidity rates (28 % vs 35 %,p = 0.223). Median overall survival (mOS) and disease-free survival were significantly higher in the EPM-group (58m vs 39m, and 16m vs 10m,p = 0.003). We highlighted 3 prognostic groups 1) EPM-with PCI<10 (mOS 93m), 2) EPM+ with PCI<10 (mOS 57m), 3) EPM-with 10<PCI<15 (mOS 35m) or EPM+ with 10<PCI<15 (mOS 31m) or PCI>15 regardless EPM (mOS 26m, p < 0.001). ConclusionComplete cytoreductive surgery seems to be feasible in patients with EPM, without increase in postoperative morbidity and mortality compared to patients without EPM. This strategy provides prolonged survival in selected patients with limited peritoneal metastases from colorectal cancer.

Impact of preoperative inflammatory and nutritional markers on the prognosis of patients with peritoneal metastasis of colorectal cancer.

Identifying patients with peritoneal metastasis (PMs) of colorectal cancer (CRC) who will benefit from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is crucial before surgery. Inflammatory and nutritional indicators play essential roles in cancer development and metastasis. To investigate the association of preoperative inflammatory and nutritional markers with prognosis in patients with CRC-PM. We included 133 patients diagnosed with CRC-PM between July 2012 and July 2018. Patients' demographics, overall survival (OS), and preoperative inflammatory and nutritional markers were evaluated. The Kaplan-Meier method and log-rank test were used to estimate differences. Of the 133 patients, 94 (70.6%) had normal hemoglobin (Hb) and 54 (40.6%) had a high neutrophil-to-lymphocyte ratio (NLR). The median OS (mOS) was significantly lower for patients with high NLR (7.9 months) than for those with low NLR (25.4 months; P = 0.002). Similarly, patients with normal Hb had a longer mOS (18.5 months) than those with low Hb (6.3 months; P < 0.001). Multivariate analysis identified age, carbohydrate antigen 199 levels, NLR, Hb, and peritoneal cancer index as independent predictors of OS. Based on these findings, a nomogram was constructed, which demonstrated a good capacity for prediction, with a C-index of 0.715 (95% confidence interval: 0.684-0.740). Furthermore, the 1- and 2-year survival calibration plots showed good agreement between predicted and actual OS rates. The areas under the curve for the 1- and 2-year survival predictions of the nomogram were 0.6238 and 0.6234, respectively. High NLR and low Hb were identified as independent predictive risk factors for poor prognosis in patients with CRC-PM. The established nomogram demonstrated high accuracy in predicting OS for patients with CRC-PM, indicating its potential as a valuable prognostic tool for this patient population.

Stemness and hybrid epithelial-mesenchymal profiles guide peritoneal dissemination of malignant mesothelioma and pseudomyxoma peritonei.

Intrabdominal dissemination of malignant mesothelioma (MM) and pseudomyxoma peritonei (PMP) is poorly characterized with respect to the stemness window which malignant cells activate during their reshaping on the epithelial-mesenchymal (E/M) axis. To gain insights into stemness properties and their prognostic significance in these rarer forms of peritoneal metastases (PM), primary tumor cultures from 55 patients selected for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy were analyzed for cancer stem cells (CSC) by aldehyde dehydrogenase 1 (ALDH1) and spheroid formation assays, and for expression of a set of plasticity-related genes to measure E/M transition (EMT) score. Intratumor heterogeneity was also analyzed. Samples from PM of colorectal cancer were included for comparison. Molecular data were confirmed using principal component and cluster analyses. Associations with survival were evaluated using Kaplan-Meier and Cox regression models. The activity of acetylsalicylic acid (ASA), a stemness modifier, was tested in five cultures. Significantly increased amounts of ALDH1bright-cells identified high-grade PMP, and discriminated solid masses from ascitic/mucin-embedded tumor cells in both forms of PM. Epithelial/early hybrid EMT scores and an early hybrid expression pattern correlated with pluripotency factors were significantly associated with early peritoneal progression (p = .0343 and p = .0339, respectively, log-rank test) in multivariable models. ASA impaired spheroid formation and increased cisplatin sensitivity in all five cultures. These data suggest that CSC subpopulations and hybrid E/M states may guide peritoneal spread of MM and PMP. Stemness could be exploited as targetable vulnerability to increase chemosensitivity and improve patient outcomes. Additional research is needed to confirm these preliminary data.

Preoperative chemotherapy response and survival in patients with colorectal cancer peritoneal metastases.

Treatment guidelines provided by PRODIGE-7 recommend perioperative systemic chemotherapy before cytoreductive surgery (CRS) for colorectal cancer peritoneal metastases (CRPM). Toxicity with multimodal treatment needs to be better defined. Chemotherapy response and impact on survival have not been reported. We assessed CRPM patients who received systemic oxaliplatin/irinotecan before CRS (preoperative) with Mitomycin C (35 mg/m2, 90 min) or Oxaliplatin (368 mg/m2, 30 min) heated intraperitoneal chemotherapy(HIPEC). Secondary analysis was performed from a prospective database. Overall survival (OS) in chemotherapy responders (R) and nonresponders (NR) was compared. Toxicity was assessed by rate of adverse events (AEs). From April 2005 to April 2021, 436 patients underwent CRS + HIPEC; 125 (29%) received preoperative chemotherapy. The 112 (90%) received oxaliplatin (64, 57%) or irinotecan (48, 43%). R, defined as complete (CR) or partial responseon preoperative imaging and/or postoperative histology, was seen in 71, 63% (53.8-72.3); 16, 14% (8.4-22.2) had CR. Median OS in R versusNR was 43.7 months (37.9-49.4) versus 23.9 (16.3-31.4) p = 0.007, HR 0.51 (0.31-0.84). OS multivariable analysis showed HR 0.48 (0.25-0.95), p = 0.03 for chemotherapy response corrected byperitoneal cancer index, completeness of cytoreduction score. CRS led to 21% grade 3-4 AEs versus 4% for preoperative chemotherapy. HIPEC grade 3-4 AEs were 0.5%. Preoperative chemotherapy response is an independent predictor for OS in CRPM.

Intraperitoneal chemotherapy for colorectal cancer peritoneal metastasis

Peritoneal metastasis is one of the common site of colorectal cancer metastasis and associated with a poor prognosis. The core strategy for colorectal cancer peritoneal metastasis primarily revolves around a comprehensive treatment approach with cytoreductive surgery and systemic chemotherapy as the mainstay, supplemented by intraperitoneal chemotherapy. As an important supplement to treatment, intraperitoneal chemotherapy has broad application prospects. The main modalities are hyperthermic intraperitoneal chemotherapy (HIPEC), neoadjuvant intraperitoneal and systemic chemotherapy (NIPS), early postoperative intraperitoneal chemotherapy (EPIC), sequential postoperative intraperitoneal chemotherapy (SPIC), normothermic intraperitoneal chemotherapy (NIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). To promote the standardized application of intraperitoneal chemotherapy, further research on the mechanisms underlying peritoneal metastasis of colorectal cancer, selection of effective intraperitoneal chemotherapy agents, determination of optimal timing and administration protocols, exploration of the feasibility of sequential intraperitoneal chemotherapy and conduction of valuable basic and clinical research are currently needed. This paper will review the development and origins of intraperitoneal chemotherapy, treatment modalities, as well as the current application status and prospects of various treatment approaches in the context of peritoneal metastasis of colorectal cancer.

A radiomics-boosted deep-learning for risk assessment of synchronous peritoneal metastasis in colorectal cancer

ObjectivesSynchronous colorectal cancer peritoneal metastasis (CRPM) has a poor prognosis. This study aimed to create a radiomics-boosted deep learning model by PET/CT image for risk assessment of synchronous CRPM.MethodsA total of 220 colorectal cancer (CRC) cases were enrolled in this study. We mapped the feature maps (Radiomic feature maps (RFMs)) of radiomic features across CT and PET image patches by a 2D sliding kernel. Based on ResNet50, a radiomics-boosted deep learning model was trained using PET/CT image patches and RFMs. Besides that, we explored whether the peritumoral region contributes to the assessment of CRPM. In this study, the performance of each model was evaluated by the area under the curves (AUC).ResultsThe AUCs of the radiomics-boosted deep learning model in the training, internal, external, and all validation datasets were 0.926 (95% confidence interval (CI): 0.874–0.978), 0.897 (95% CI: 0.801–0.994), 0.885 (95% CI: 0.795–0.975), and 0.889 (95% CI: 0.823–0.954), respectively. This model exhibited consistency in the calibration curve, the Delong test and IDI identified it as the most predictive model.ConclusionsThe radiomics-boosted deep learning model showed superior estimated performance in preoperative prediction of synchronous CRPM from pre-treatment PET/CT, offering potential assistance in the development of more personalized treatment methods and follow-up plans.Critical relevance statementThe onset of synchronous colorectal CRPM is insidious, and using a radiomics-boosted deep learning model to assess the risk of CRPM before treatment can help make personalized clinical treatment decisions or choose more sensitive follow-up plans.Key PointsPrognosis for patients with CRPM is bleak, and early detection poses challenges.The synergy between radiomics and deep learning proves advantageous in evaluating CRPM.The radiomics-boosted deep-learning model proves valuable in tailoring treatment approaches for CRC patients.Graphical

Development of a deep learning survival model to predict the individual risks of peritoneal metastasis of colorectal cancer

Background : Peritoneal metastasis (PM) has been considered to be the terminal stage of colorectal cancer (CRC) due to poor prognosis. We purposed to construct an AI model of clinicopathological parameters to predict the survival prognosis of PM in CRC. Methods : Our model was constructed through modifying a classic neural network with COX proportional hazards as loss function in the training cohort. It is able to predict the overall survival (OS) of each individual patient with clinicopathological parameters. Multivariate analysis was conducted to identify independent risk factors for the prognosis of PM patients. Results and Conclusion : In the testing cohort, the deep learning model show good performance with the c-index of 0.76 and brier score of 0.20. Conclusions : We have developed a deep learning model to predict the survival of individual patients precisely. It can provide evidence to apply personalized treatments and assisted surgeon to select optical treatments for CRC patients with PM.

Microsatellite instability should not determine candidacy for cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion in patients with peritoneal metastases from colorectal cancer

BackgroundCytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is a multimodal therapeutic option for the management of peritoneal metastases (PM). Treatment outcomes for patients with colorectal cancer (CRC) PM undergoing CRS+HIPEC with microsatellite instability (MSI) remain unknown. We examined the patient characteristics and outcomes in patients with MSI CRC after CRS+HIPEC. MethodsThis was a retrospective cohort study of a prospectively maintained database of all patients with CRC PM undergoing CRS+HIPEC (2010–2020). Categorical and continuous variables were analyzed using the chi-square test and independent samples t test, respectively. Survival was evaluated with the Kaplan-Meier analysis. ResultsThere were 324 patients diagnosed as having CRC PM undergoing CRS+HIPEC (MSI, n = 23; microsatellite stable [MSS], n = 301). There was no statistically significant difference in patient demographics, tumor characteristics, or perioperative factors between the 2 groups. There was a trend toward improved survival in the MSI group with a median overall survival (OS) of 96.7 month compared with patients with MSS disease (median OS, 51.4 months; P = .10). Patients with MSI demonstrated median progression-free survival (PFS) 8.5 months compared with 11.4 months in the MSS cohort (P = .28). ConclusionPatients with CRC PM, regardless of MSI or MSS status, demonstrate similar OS and PFS after CRS+HIPEC. MSI status should not change a patient’s candidacy for CRS+HIPEC.

Adipose-derived stem cells promote glycolysis and peritoneal metastasis via TGF-β1/SMAD3/ANGPTL4 axis in colorectal cancer

Peritoneal metastasis, the third most common metastasis in colorectal cancer (CRC), has a poor prognosis for the rapid progression and limited therapeutic strategy. However, the molecular characteristics and pathogenesis of CRC peritoneal metastasis are poorly understood. Here, we aimed to elucidate the action and mechanism of adipose-derived stem cells (ADSCs), a prominent component of the peritoneal microenvironment, in CRC peritoneal metastasis formation. Database analysis indicated that ADSCs infiltration was increased in CRC peritoneal metastases, and high expression levels of ADSCs marker genes predicted a poor prognosis. Then we investigated the effect of ADSCs on CRC cells in vitro and in vivo. The results revealed that CRC cells co-cultured with ADSCs exhibited stronger metastatic property and anoikis resistance, and ADSCs boosted the intraperitoneal seeding of CRC cells. Furthermore, RNA sequencing was carried out to identify the key target gene, angiopoietin like 4 (ANGPTL4), which was upregulated in CRC specimens, especially in peritoneal metastases. Mechanistically, TGF-β1 secreted by ADSCs activated SMAD3 in CRC cells, and chromatin immunoprecipitation assay showed that SMAD3 facilitated ANGPTL4 transcription by directly binding to ANGPTL4 promoter. The ANGPTL4 upregulation was essential for ADSCs to promote glycolysis and anoikis resistance in CRC. Importantly, simultaneously targeting TGF-β signaling and ANGPTL4 efficiently reduced intraperitoneal seeding in vivo. In conclusion, this study indicates that tumor-infiltrating ADSCs promote glycolysis and anoikis resistance in CRC cells and ultimately facilitate peritoneal metastasis via the TGF-β1/SMAD3/ANGPTL4 axis. The dual-targeting of TGF-β signaling and ANGPTL4 may be a feasible therapeutic strategy for CRC peritoneal metastasis.

Abstract 2759: Transcriptional intra-tumoral heterogeneity of putative therapeutic targets in colorectal cancer peritoneal metastases

Abstract Background: The poor prognosis of peritoneal metastasis (PM) in colorectal cancer (CRC) is typically attributed to, and characterized by, resistance to systemic chemotherapy and immunotherapy. The evolutionarily conserved plasma-peritoneal barrier as well as reduced tumor tissue vascularity contributes to poorer responses to systemically administered antineoplastic therapy. Beyond these, we sought to understand transcriptomic variations of important therapeutic targets implicated in peritoneal organotropism and by extension, resistance to systemic regimens in CRC PM. Methodology: FFPE tissue samples from CRC patients were collected during oncological surgical resection of the synchronous PM (cytoreductive surgery [CRS] with or without hyperthermic intra-peritoneal chemotherapy [HIPEC]), or exploratory laparotomy for palliative surgery, with the majority of patients receiving systemic therapy prior to surgery. Samples were sequenced with whole transcriptomic sequencing. Paired and unpaired T-tests between PT and PM samples were undertaken with log2(fragments per kilobase of exon per million mapped [FPKM]) gene expression values. Results: Fifty-six (22 primary tumor [PT], 34 peritoneal metastases [PM]) samples from 35 patients, comprising 21 paired PT-PM samples, were included in this analysis. TEAD1 (unpaired T-test, p=0.087; paired T-test, p=0.041), FGFR1 (unpaired T-test, p=0.003; paired T-test, p&amp;lt;0.001), PIK3CA (unpaired T-test, p=0.034; paired T-test, p=0.003), SMAD4 (unpaired T-test, p=0.095; paired T-test, p=0.010), and HAVCR2 (unpaired T-test, p=0.009; paired T-test, p=0.007) were found to be upregulated in the PM. Conversely, MET was found to be downregulated in PM samples (unpaired T-test, p=0.004; paired T-test, p=0.002). There were no significant differences in gene expression profiles of BRAF, RHOA, CD274, CTLA4, PDCD1 and TIGIT between PT-PM (all p&amp;gt;0.05). Conclusion: Through CRC PT-PM comparisons, we identify potential therapeutic targets implicated in transcoelomic metastasis and provide rationale for development of immunotherapeutic biology and drug discovery for CRC PM. These findings underscore an exigent need to develop intra-peritoneal therapeutic strategies to overcome resistance to systemic regimens. Citation Format: Joseph J. Zhao, Johnny CA Ong, Daryl Kai Ann Chia, Melissa Ching Ching Teo, Qiu Xuan Tan, Gillian Ng, Joey Wee-Shan Tan, Haoran Ma, Xuewen Ong, Su Ting Tay, Patrick Tan, Raghav Sundar. Transcriptional intra-tumoral heterogeneity of putative therapeutic targets in colorectal cancer peritoneal metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2759.

The mechanistic study of cancer-associated adipocytes promoting colorectal cancer peritoneal metastasis via FKBP5/UCP1-mediated lipid metabolism reprogramming.

178 Background: Colorectal cancer (CRC) is a prevalent malignant tumor globally, with peritoneal metastasis as a significant late-stage dissemination pathway, severely impacting patient prognosis. Recent research increasingly suggests the critical role of lipid metabolism within the tumor microenvironment in tumor progression. Cancer associated adipocytes (CAAs), a vital component, contribute to tumor progression, yet the exact molecular mechanisms remain unclear. We aim to explore the role of CAAs in CRC peritoneal metastasis and their specific regulatory mechanisms. Methods: In this study, we analyzed clinical samples from 312 CRC patients to assess the expression levels of FKBP5 and UCP1 proteins in tumor-adjacent tissues. Purified exosomes from co-cultured adipocytes and tumor cells, along with exosomes from ordinary tumor cells, underwent miRNA profiling via sequencing to evaluate exosomal miR-200a-3p expression. We established FKBP5 stable knockdown (FKBP5-/-) transgenic mouse models, organotypic co-culture models, and patient-derived xenograft (PDX) models. Through experiments involving metabolomics, mass spectrometry, immunoprecipitation, western blotting, and qPCR, we investigated the role of the miR-200a-3p/FKBP5/PPARγ/UCP1 signaling pathway in CAAs in CRC peritoneal metastasis. Results: After co-culturing adipocytes and tumor cells, we observed brown adipocyte differentiation, resulting in significant downregulation of FKBP5 protein expression. FKBP5 exhibited a strong association with UCP1 expression. Tumor cells highly expressed miR-200a-3p, released via exosomes into the tumor microenvironment and internalized by adipocytes. Within adipocytes, miR-200a-3p orchestrated metabolic reprogramming via the FKBP5/PPARγ/UCP1 pathway, inducing brown adipocyte differentiation, generating CAAs. CAAs released FFAs, promoting tumor peritoneal metastasis by activating tumor cell surface G-protein coupled receptors (GPCRs). Conversely, miR-200a-3p inhibition in tumor cells yielded opposing effects. In a spontaneous mouse model of colorectal cancer using azoxymethane (AOM)/dextran sulfate sodium salt (DSS), FKBP5-/- mice exhibited increased brown adipocyte content in the tumor microenvironment, along with notably higher spontaneous colorectal tumor numbers and sizes compared to wild-type mice. Conclusions: This study elucidates the pivotal role of CAAs in the peritoneal metastasis of CRC, confirming the regulatory role of the FKBP5/UCP1 pathway-mediated lipid metabolism reprogramming in this process. These findings offer a fresh perspective for further exploration of the molecular mechanisms underlying CRC peritoneal metastasis, and provide a theoretical foundation for the identification of novel therapeutic targets.

Prophylactic hyperthermic intraperitoneal chemotherapy in T4 colorectal cancer: Can it improve the oncologic prognosis? – A propensity score matching study

BackgroundSome studies show that cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) may improve overall survival and is a possible curative treatment for selected colorectal cancer (CRC) patients with restricted peritoneal metastasis (PM). The value of HIPEC in preventing PM of CRC is still controversial. Materials and methodsIn this retrospective propensity score matching (PSM) cohort study, all patients with cT4N0-2M0 undergoing treatment at a single institution in China (2014–2018) were reviewed. The 3-year disease-free survival (DFS) was set as the primary outcome, and the 3-year PM rate was also analyzed. Results220 patients were included in this study for analysis. After 1:3 PSM: HIPEC (n = 45) and No HIPEC (n = 135). Through analysis, it was found that prophylactic HIPEC correlated to better DFS [hazard ratio (HR) 0.43, 95 % confidence interval (CI) 0.19–0.95; p = 0.037], and N2 stage correlated to worse DFS [HR 1.97, 95 % CI 1.09–3.56; p = 0.025]. For laparoscopic surgery subgroup analyses, 3-year PM rate of patients with laparoscopic surgery was 13.8 % in No HIPEC group, and 2.6 % in HIPEC group (p = 0.070). Besides, no post-operative death occurred, the anastomotic leakage rate was 2.2 % in HIPEC group and 0.7 % in the control group (p = 0.439). ConclusionsProphylactic HIPEC may improve the prognosis in patients with cT4N0-1M0 CRC, but not in cT4N2M0 CRC, and it does not significantly increase surgery-related complications. Laparoscopic surgery followed by HIPEC for T4 stage CRC may not increase risk of PM.

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.

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. 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. 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. 4h) and blood loss higher (500 vs. 400mL) 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. 7months) but overall survival (OS) showed benefit (41.3 vs. 31.8months), (p=0.001 and p=0.189, respectively), comparatively with an only chemotherapy strategy. 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.

Identification and validation of Rab GTPases RAB13 as biomarkers for peritoneal metastasis and immune cell infiltration in colorectal cancer patients.

As one of the most common cancer, colorectal cancer (CRC) is with high morbidity and mortality. Peritoneal metastasis (PM) is a fatal state of CRC, and few patients may benefit from traditional therapies. There is a complex interaction between PM and immune cell infiltration. Therefore, we aimed to determine biomarkers associated with colorectal cancer peritoneal metastasis (CRCPM) and their relationship with immune cell infiltration. By informatic analysis, differently expressed genes (DEGs) were selected and hub genes were screened out. RAB13, one of the hub genes, was identificated from public databases and validated in CRC tissues. The ESTIMATE, CEBERSORT and TIMER algorithms were applied to analyze the correlation between RAB13 and immune infiltration in CRC. RAB13's expression in different cells were analyzed at the single-cell level in scRNA-Seq. The Gene Set Enrichment Analysis (GSEA) was performed for RAB13 enrichment and further confirmed. Using oncoPredict algorithm, RAB13's impact on drug sensitivity was evaluated. High RAB13 expression was identified in public databases and led to a poor prognosis. RAB13 was found to be positively correlated with the macrophages and other immune cells infiltration and from scRNA-Seq, RAB13 was found to be located in CRC cells and macrophages. GSEA revealed that high RAB13 expression enriched in a various of biological signaling, and oncoPredict algorithm showed that RAB13 expression was correlated with paclitaxel sensitivity. Our study indicated clinical role of RAB13 in CRC-PM, suggesting its potential as a therapeutic target in the future.

2022 Peritoneal Surface Oncology Group International Consensus on HIPEC Regimens for Peritoneal Malignancies: Colorectal Cancer

BackgroundSelected patients with peritoneal metastases of colorectal cancer (PM-CRC) can benefit from potentially curative cytoreductive surgery (CRS) ± hyperthermic intraperitoneal chemotherapy (HIPEC), with a median overall survival (OS) of more than 40 months.ObjectiveThe aims of this evidence-based consensus were to define the indications for HIPEC, to select the preferred HIPEC regimens, and to define research priorities regarding the use of HIPEC for PM-CRC.MethodsThe consensus steering committee elaborated and formulated pertinent clinical questions according to the PICO (patient, intervention, comparator, outcome) method and assessed the evidence according to the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) framework. Standardized evidence tables were presented to an international expert panel to reach a consensus (4-point, weak and strong positive/negative) on HIPEC regimens and research priorities through a two-round Delphi process. The consensus was defined as ≥ 50% agreement for the 4-point consensus grading or ≥ 70% for either of the two combinations.ResultsEvidence was weak or very weak for 9/10 clinical questions. In total, 70/90 eligible panelists replied to both Delphi rounds (78%), with a consensus for 10/10 questions on HIPEC regimens. There was strong negative consensus concerning the short duration, high-dose oxaliplatin (OX) protocol (55.7%), and a weak positive vote (53.8–64.3%) in favor of mitomycin-C (MMC)-based HIPEC (preferred choice: Dutch protocol: 35 mg/m2, 90 min, three fractions), both for primary cytoreduction and recurrence. Determining the role of HIPEC after CRS was considered the most important research question, regarded as essential by 85.7% of the panelists. Furthermore, over 90% of experts suggest performing HIPEC after primary and secondary CRS for recurrence > 1 year after the index surgery.ConclusionsBased on the available evidence, despite the negative results of PRODIGE 7, HIPEC could be conditionally recommended to patients with PM-CRC after CRS. While more preclinical and clinical data are eagerly awaited to harmonize the procedure further, the MMC-based Dutch protocol remains the preferred regimen after primary and secondary CRS.

Enhanced Chemo-Immunotherapy Strategy Utilizing Injectable Thermosensitive Hydrogel for The Treatment of Diffuse Peritoneal Metastasis in Advanced Colorectal Cancer.

Patients with colorectal cancer (CRC) and diffuse peritoneal metastasis (PM) are not eligible for surgical intervention. Thus, palliative treatment remains the standard of care in clinical practice. Systemic chemotherapy fails to cause drug accumulation at the lesion sites, while intraperitoneal chemotherapy (IPC) is limited by high clearance rates and associated complications. Given the poor prognosis, a customized OxP/R848@PLEL hydrogel delivery system has been devised to improve the clinical benefit of advanced CRC with diffuse PM. This system is distinguished by its simplicity, security, and efficiency. Specifically, the PLEL hydrogel exhibits excellent injectability and thermosensitivity, enabling the formation of drug depots within the abdominal cavity, rendering it an optimal carrier for IPC. Oxaliplatin (OxP), a first-line drug for advanced CRC, is cytotoxic and enhances the immunogenicity of tumors by inducing immunogenic cell death. Furthermore, OxP and resiquimod (R848) synergistically enhance the maturation of dendritic cells, promote the expansion of cytotoxic T lymphocytes, and induce the formation of central memory T cells. Moreover, R848 domesticates macrophages to an anti-tumor phenotype. OxP/R848@PLEL effectively eradicates peritoneal metastases, completely inhibits ascites production, and significantly prolongs mice lifespan. As such, it provides a promising approach to managing diffuse PM in patients with CRC without surgical indications.

Microvascularized tumor assembloids model for drug delivery evaluation in colorectal cancer-derived peritoneal metastasis.

Peritoneal metastasis (PM) is a fatal state of colorectal cancer, and only a few patients may benefit from systemic chemotherapy. Although hyperthermic intraperitoneal chemotherapy (HIPEC) brings hope for affected patients, the drug development and preclinical evaluation of HIPEC are seriously lagging behind, mainly due to the lack of an ideal in vitro PM model that makes drug development over-reliant on expensive and inefficient animal experiments. This study developed an in vitro colorectal cancer PM model [microvascularized tumor assembloids (vTA)] based on an assembly strategy of endothelialized microvessels and tumor spheroids. Our data showed that the in vitro perfusion cultured vTA could maintain a similar gene expression pattern to their parental xenografts. Also, the drug penetration pattern of the in vitro HIPEC in vTA could mimic the drug delivery behavior in tumor nodules during in vivo HIPEC. More importantly, we further confirmed the feasibility of constructing a tumor burden-controlled PM animal model using vTA. In conclusion, we propose a simple and effective strategy to construct physiologically simulated PM models in vitro, thus providing a basis for PM-related drug development and preclinical evaluation of locoregional therapies. STATEMENT OF SIGNIFICANCE: This study developed an in vitro colorectal cancer peritoneal metastasis (PM) model based on microvascularized tumor assembloids (vTA) for drug evaluation. With perfusion culture, vTA could maintain a similar gene expression pattern and tumor heterogeneity to their parental xenografts. And the drug penetration pattern in vTA was similar to the drug delivery behavior in tumor nodules under in vivo treatment. Moreover, vTA was more conducive to construct PM animal models with controllable tumor burden. In conclusion, the construction of vTA could provide a new strategy for the PM-related drug development and preclinical evaluation of locoregional therapies.

External validation of prognostic scores and comparison of predictive accuracy for patients with colorectal cancer with peritoneal metastases considered for cytoreductive surgery and intraperitoneal chemotherapy.

Prognostic scores are developed to facilitate the selection of patients with colorectal cancer peritoneal metastases (CRPM) for treatment with cytoreductive surgery (CRS) ± intraperitoneal chemotherapy (IPC). Three prominent prognostic scores are the Peritoneal Surface Disease Severity Score (PSDSS), the Colorectal Peritoneal Metastases Prognostic Surgical Score (COMPASS), and the modified COloREctal-Pc (mCOREP). We externally validate these scores and compare their predictive accuracy. Data from consecutive CRPM patients who underwent CRS/IPC from 1996 to 2018 was used to externally validate COMPASS, PSDSS, and mCOREP. Analysis evaluated the efficacy of each score in predicting (1) open-close laparotomy-those found at laparotomy to not be eligible for curative intent CRS/IPC, (2) surgical futility-those who underwent open-close laparotomy, palliative debulking surgery, or had an overall survival of less than 12 months, and (3) overall and recurrence-free survival (OS, RFS). Prognostic scores were calculated for the 174-patient external validation cohort. COMPASS was most accurate in predicting open-close laparotomy, futile surgery, and survival (OS and RFS). Area under the curve (AUC) for open-close prediction was 0.78 (95% confidence interval,CI: 0.68-0.87), representing useful discrimination. However, AUC for futility prediction was 0.62 (95%CI: 0.52-0.71), and C-statistic for OS was 0.65 indicating only possibly helpful discrimination. C-statistic for RFS was 0.59 indicating poor discrimination. While COMPASS showed the best statistical behavior, accuracy for several clinically relevant outcomes remains low, and thus applicability to clinical practice limited.

A chemiluminescent reporter assisted by in-situ neutrophils for imaging O2- at inflammatory sites.

Precisely reporting the inflammatory microenvironment, which can provide important basis for disease diagnosis and progression determination, is always challenging. In this work, we develop a targeting peptide-conjugated chemiluminescent reporter (OFF), which can be recognized by in-situ circulated neutrophils once injected, and then transported to the inflamed tissues characterized with overexpressed superoxide anion (O2-), assisted by the chemotaxis natural of neutrophils. Subsequently, the chemiluminescent probe can particularly respond to O2- to release the caged photons (ON) for visualizing inflammatory diseases such as subcutaneous tumor, colorectal cancer peritoneal metastasis (CCPM), ear swelling and kidney failure. The chemiluminescent probe provides a reliable tool to early detect inflammation and precisely excise micrometastatic lesions under optical guidance. This study provides a potential approach for improving the performance of luminophore in advanced bioimaging applications.

PD-27 The use of pre-operative systemic oxaliplatin or irinotecan doublet chemotherapy in colorectal cancer peritoneal metastases (CRPM): Results from a single UK peritoneal tumour centre

PD-27 The use of pre-operative systemic oxaliplatin or irinotecan doublet chemotherapy in colorectal cancer peritoneal metastases (CRPM): Results from a single UK peritoneal tumour centre