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Abstract Background Most Colorectal Cancer (CRC) patients exhibit limited responsiveness to anti-programmed cell death protein 1 (PD-1) therapy, with the underlying mechanisms remaining elusive. Circular RNAs (circRNAs) play a significant role in tumorigenesis and development, with potential applications in tumor screening and predicting treatment efficacy. However, there are few studies exploring the role of circRNAs in CRC immune evasion. Methods circRNA microarrays were used to identify circPHLPP2. RT-qPCR was used to examine the associations between the expression level of circPHLPP2 and the clinical characteristics of CRC patients. MTS assay, clone formation experiment, subcutaneous tumor implantation and multicolor flow cytometry were used to confirm the biological function of circPHLPP2. RAN-seq, RT-qPCR, and WB experiments were performed to investigate the downstream signaling pathways involved in circPHLPP2. RNA pull-down, RNA immunoprecipitation (RIP) and immunofluorescence staining were performed to identify the proteins associated with circPHLPP2. Results circPHLPP2 is up-regulated in CRC patients who exhibit resistance to anti-PD-1 based therapy. circPHLPP2 significantly promotes the proliferation and tumor growth of CRC cells. Knockdown of circPhlpp2 enhances the efficacy of anti-PD-1 in vivo. Mechanistically, the specific interaction between circPHLPP2 and ILF3 facilitates the nuclear accumulation of ILF3, which subsequently enhances the transcription of IL36γ. This process reduces NK cell infiltration and impairs NK cells’ granzyme B and IFN-γ production, thereby promoting tumor progression. Conclusions Overall, our findings reveal a novel mechanism by which circRNA regulates CRC immune evasion. circPHLPP2 may serve as a prognostic biomarker and potential therapeutic target for CRC patients.

Abstract Anaplastic lymphoma kinase (ALK) fusion-positive colorectal cancer (CRC) is a rare and chemotherapy-refractory subtype that lacks established and effective treatment strategies. Additionally, the efficacy and safety of ALK inhibitors (ALKi) in CRC remain undetermined. Herein, we examined a series of ALK-positive CRC patients who underwent various lines of ALKi treatment. Notably, we detected an ALK 1196M resistance mutation in a CRC patient who received multiple lines of chemotherapy and ALKi treatment. Importantly, we found that Brigatinib and Lorlatinib demonstrated some efficacy in managing this patient, although the observed effectiveness was not as pronounced as in non-small cell lung cancer cases. Furthermore, based on our preliminary analyses, we surmise that ALK-positive CRC patients are likely to exhibit inner resistance to Cetuximab. Taken together, our findings have important implications for the treatment of ALK-positive CRC patients.

BackgroundIt remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM.Methods and findingsThis open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection.ConclusionsThe combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity.Trial registrationClinicalTrials.gov Identifier: NCT03493048.

Abstract Solitary fibrous tumors (SFTs) are rare mesenchymal tumors with unpredictable evolution and with a recurrence or metastasis rate of 10-40%. Current medical treatments for relapsed SFTs remain ineffective. Here, we identify potential therapeutic targets and risk factors, including IDH1 p.R132S, high PD-L1 expression, and predominant macrophage infiltration, suggesting the potential benefits of combinational immune therapy and targeted therapy for SFTs. An integrated risk model incorporating mitotic count, density of Ki-67+ cells and CD163+ cells, MTOR mutation is developed, applying a discovery cohort of 101 primary non-CNS patients with negative tumor margins (NTM) and validated in three independent cohorts of 210 SFTs with the same criteria, and in 36 primary CNS SFTs with NTM. Compared with the existing models, our model shows significantly improved efficacy in identifying high-risk primary non-CNS and CNS SFTs with NTM for tumor progression.Our findings hold promise for advancing therapeutic strategies and refining risk prediction in SFTs.

Background: Patients with initially unresectable colorectal cancer liver metastases (IU-CRLM) might benefit from using an effective systemic treatment followed by resection of liver metastases but the curative success rate is quite low. Indeed, nearly one-third of patients exhibit early recurrence within the first 6 months after surgery, and these individuals often have poor overall survival. Objectives: This study aims to clarify the application value of serial circulating tumor DNA (ctDNA) analysis in predicting the clinical outcome of IU-CRLM patients following liver metastasectomy. Design: A retrospective study was conducted on a cohort of patients with IU-CRLM between February 2018 and April 2021. Methods: Plasma samples at different time points during CRLM treatment [baseline (BL), preoperation (PRE), postoperation (POST), end-of-treatment (EOT), and progressive disease (PD)] were retrospectively collected from patients with initially unresectable CRLM enrolled at the Sun Yat-sen University Cancer Center. Dynamic changes of SEPTIN 9 (SEPT9) and Neuropeptide Y (NPY) methylated circulating tumor DNA (MetctDNA) levels in serial plasma samples were detected using droplet-digital PCR (ddPCR). Results: SEPT9 and NPY genes were hypermethylated in colon cancer cell lines and tissues while no difference was observed between primary and metastatic tumors. Patients with MetctDNA positive at POST or EOT had significantly lower recurrence-free survival (RFS) compared to patients with MetctDNA negative at these time points [POST: Hazard ratio (HR) 9.44, 95% confidence interval (CI) 5.15–17.30, p < 0.001; EOT: HR 11.48, 95% CI 3.27–40.31, p < 0.001]. Multivariate analysis demonstrated that POST (OR 33.96, 95% CI 4.03–286.10, p = 0.001) and EOT (OR 18.36, 95% CI 1.14–295.71, p = 0.04) MetctDNA was an independent risk factor for early recurrence. Time-dependent receiver operating characteristic curve (T-ROC) analysis revealed that area under the curve (AUC) value was greatest at the relapse time point of 6 months post-intervention, with POST-AUC and EOT-AUC values of 0.74 (95% CI 0.66–0.81) and 0.73 (95% CI 0.53–0.94), respectively. Serial MetctDNA analysis showed that RFS was significantly lower in patients with no MetctDNA clearance compared with those with MetctDNA clearance (HR 26.05, 95% CI 4.92–137.81, p < 0.001). Conclusion: Our study confirmed that serial ctDNA analysis of NPY and SEPT9 gene methylation could effectively predict early recurrence in IU-CRLM patients, especially at POST and EOT.

Background: Transmembrane E3 ubiquitin ligase ( RNF43 ) mutations are present in approximately 6–18% of colorectal cancers (CRC) and could enhance Wnt/β-catenin signaling, which is emerging as a promising therapeutic target. This study aims to investigate the clinical and molecular characteristics and potential heterogeneity of RNF43 -mutant CRC. Methods: A total of 78 patients with RNF43 -mutant CRC were enrolled from July 2013 to November 2022. Demographic data, clinical characteristics, treatment regimens used, and survival outcomes were collected and analyzed. Results: Our study uncovered that patients with RNF43 mutations in the N-terminal domain (NTD; n = 50) exhibited shorter overall survival (OS; median months, 50.80 versus not reached; p = 0.043) compared to those in the C-terminal domain (CTD; n = 17). Most RNF43 mutations in NTD had positive primary lymph node status, low tumor mutation burden (TMB-L), and correlated with proficient mismatch repair (pMMR)/microsatellite stable (MSS) status. By contrast, RNF43 mutations in CTD were significantly enriched in deficient MMR (dMMR)/microsatellite instability (MSI-H) tumors with high TMB (TMB-H). N-terminal RNF43 -mutated tumors harbored a hotspot variant ( RNF43 R117fs ), which independently predicted a significantly worse outcome in pMMR/MSS CRC with a median OS of 18.9 months. Patients with RNF43 mutations and the BRAF V600E alterations demonstrated sensitivity to BRAF/EGFR inhibitors. Moreover, we observed that pMMR/MSS patients with RNF43 R117fs mutation had a higher incidence of stage IV, ⩾2 metastatic sites, low TMB, and none of them received PD-1/PD-L1 inhibitor therapy. Conclusion: Our findings provide the first evidence that RNF43 mutations in NTD and the R117fs variant correlate with a poorer prognosis in CRC patients, providing strategies for Wnt-targeted therapy to improve clinical efficacy.

Summary: Histopathological images of colorectal liver metastases (CRLM) contain rich morphometric information that may predict patients’ outcomes. However, to our knowledge, no study has reported any practical deep learning framework based on the histology images of CRLM, and their direct association with prognosis remains largely unknown. In this study, we developed a deep learning-based framework for fully automated tissue classification and quantification of clinically relevant spatial organization features (SOFs) in H&E-stained images of CRLM. The SOFs based risk-scoring system demonstrated a strong and robust prognostic value that is independent of the current clinical risk score (CRS) system in independent clinical cohorts. Our framework enables fully automated tissue classification of H&E images of CRLM, which could significantly reduce assessment subjectivity and the workload of pathologists. The risk-scoring system provides a time- and cost-efficient tool to assist clinical decision-making for patients with CRLM, which could potentially be implemented in clinical practice.

Abstract Background The prognostic value of lactate dehydrogenase (LDH) in colorectal cancer patients has remained inconsistent between nonmetastatic and metastatic settings. So far, very few studies have included LDH in the prognostic analysis of curative‐intent surgery for colorectal liver metastases (CRLM). Patients and Methods Five hundred and eighty consecutive metastatic colorectal cancer patients who underwent curative‐intent CRLM resection from Sun Yat‐sen University Cancer Center (434 patients) and Sun Yat‐sen University Sixth Affiliated Hospital (146 patients) in 2000–2019 were retrospectively collected. Overall survival (OS) was the primary end point. Cox regression model was performed to identify the prognostic values of preoperative serum LDH levels and other clinicopathology variables. A modification of the established Fong CRS scoring system comprising LDH was developed within this Chinese population. Results At the median follow‐up time of 60.5 months, median OS was 59.5 months in the pooled cohort. In the multivariate analysis, preoperative LDH >upper limit of normal (250 U/L) was the strongest independent prognostic factor for OS (HR 1.73, 95% confidence interval [CI], 1.22–2.44; p

Metabolic inhibition via PFKFB3 inhibition has demonstrated considerable tumor inhibitory effects in various studies; however, PFKFB3 inhibition did not show satisfactory tumor inhibition when used in clinical trials. PFKFB3 is a crucial metabolic enzyme that is highly upregulated in cancer cells and directly affects tumor glycolysis. Here, we showed that PFKFB3 inhibition suppresses tumors in vitro and in vivo in immune-deficient xenografts. However, this inhibition induces the upregulation of PD-L1 levels, which inactivated cocultured T-cells in vitro, compromises anti-tumor immunity in vivo, and reduced anti-tumor efficacy in an immune-competent mouse model. Functionally, PD-1 mAb treatment enhances the efficacy of PFKFB3 inhibition in immunocompetent and hu-PBMC NOG mouse models. Mechanistically, PFKFB3 inhibition increases phosphorylation of PFKFB3 at residue Ser461, which increases interaction with HIF-1α, and their colocalization into the nucleus, where HIF-1α transcriptionally upregulate PD-L1 expression and causes subsequent tumor immune evasion. Higher phos-PFKFB3 correlated with higher PD-L1 expression, lower CD8 and GRZMB levels, and shorter survival time in ESCC patients.

Abstract Purpose We aimed to construct a nomogram to predict personalized post‐recurrence survival (PRS) among colorectal cancer liver metastasis (CRLM) patients with post‐hepatectomy recurrence. Methods Colorectal cancer liver metastasis patients who received initial hepatectomy and had subsequent recurrence between 2001 and 2019 in Sun Yat‐sen University Cancer Center from China were included in the study. Patients were randomly assigned to a training cohort and a validation cohort on a ratio of 2:1. Univariable analysis was first employed to select potential predictive factors for PRS. Then, the multivariable Cox regression model was applied to recognize independent prognostic factors. According to the model, a nomogram to predict PRS was established. The nomogram's predictive capacity was further assessed utilizing concordance index (C‐index) values, calibration plots, and Kaplan–Meier curves. Results About 376 patients were finally enrolled, with a 3‐year PRS rate of 37.3% and a 5‐year PRS rate of 24.6%. The following five independent predictors for PRS were determined to construct the nomogram: the largest size of liver metastases at initial hepatectomy, relapse‐free survival, CEA level at recurrence, recurrent sites, and treatment for recurrence. The nomogram displayed fairly good discrimination and calibration. The C‐index value was 0.742 for the training cohort and 0.773 for the validation cohort. Patients were grouped into three risk groups very well by the nomogram, with 5‐year PRS rates of 45.2%, 23.3%, and 9.0%, respectively (p

Abstract Circular RNAs (CircRNAs) are single-stranded, covalently closed RNA molecules that are ubiquitous across species ranging from viruses to mammals. Important advances have been made in the biogenesis, regulation, localization, degradation and modification of circRNAs. CircRNAs exert biological functions by acting as transcriptional regulators, microRNA (miR) sponges and protein templates. Moreover, emerging evidence has revealed that a group of circRNAs can serve as protein decoys, scaffolds and recruiters. However, the existing research on circRNA-protein interactions is quite limited. Hence, in this review, we briefly summarize recent progress in the metabolism and functions of circRNAs and elaborately discuss the patterns of circRNA-protein interactions, including altering interactions between proteins, tethering or sequestering proteins, recruiting proteins to chromatin, forming circRNA-protein-mRNA ternary complexes and translocating or redistributing proteins. Many discoveries have revealed that circRNAs have unique expression signatures and play crucial roles in a variety of diseases, enabling them to potentially act as diagnostic biomarkers and therapeutic targets. This review systematically evaluates the roles and mechanisms of circRNAs, with the hope of advancing translational medicine involving circRNAs.

PFKFB3 enhances glycolysis to promote cancer cell proliferation. Here, the authors identify a long noncoding RNA in esophageal squamous cell carcinoma, AGPG, which interacts with PFKFB3 and promotes its stability, leading to increased glycolysis and proliferation.

Summary: This is a phase Ib/II study of regorafenib plus toripalimab for colorectal cancer. The objective response rate (ORR) is 15.2% and the disease control rate is 36.4% in evaluable patients with recommended phase II dose (80 mg regorafenib plus toripalimab). The median progression-free survival (PFS) and the median overall survival are 2.1 months and 15.5 months, respectively. Patients with liver metastases have lower ORR than those without (8.7% versus 30.0%). All patients (3/3) with lung-only metastasis respond, whereas no patients (0/4) with liver-only metastasis respond. 94.9% and 38.5% of patients have grade 1 and grade 3 treatment-related adverse events, respectively. Gut microbiome analysis of the baseline fecal samples shows significantly increased relative abundance and positive detection rate of Fusobacterium in non-responders than responders. Patients with high-abundance Fusobacterium have shorter PFS than those with low abundance (median PFS = 2.0 versus 5.2 months; p = 0.002).

Abstract Background Monosialotetrahexosylganglioside (GM1) is a neuroprotective glycosphingolipid that repairs nerves. Oxaliplatin‐based chemotherapy is neurotoxic. This study assessed the efficacy of GM1 for preventing oxaliplatin‐induced peripheral neurotoxicity (OIPN) in colorectal cancer (CRC) patients receiving oxaliplatin‐based chemotherapy. Methods In total, 196 patients with stage II/III CRC undergoing adjuvant chemotherapy with mFOLFOX6 were randomly assigned to intravenous GM1 or a placebo. The primary endpoint was the rate of grade 2 or worse cumulative neurotoxicity (NCI‐CTCAE). The secondary endpoints were chronic cumulative neurotoxicity (EORTC QLQ‐CIPN20), time to grade 2 neurotoxicity (NCI‐CTCAE or the oxaliplatin‐specific neuropathy scale), acute neurotoxicity (analog scale), rates of dose reduction or withdrawal due to OIPN, 3‐year disease‐free survival (DFS) and adverse events. Results There were no significant differences between the arms in the rate of NCI‐CTCAE grade 2 or worse neurotoxicity (GM1: 33.7% vs placebo: 31.6%; P = .76) or neuropathy measured by the EORTC QLQ‐CIPN20 or time to grade 2 neurotoxicity using NCI‐CTCAE and the oxaliplatin‐specific neuropathy scale. GM1 substantially decreased participant‐reported acute neurotoxicity (sensitivity to cold items [P

Abstract Background Long noncoding RNAs (lncRNAs) play nonnegligible roles in the epigenetic regulation of cancer cells. This study aimed to identify a specific lncRNA that promotes the colorectal cancer (CRC) progression and could be a potential therapeutic target. Methods We screened highly expressed lncRNAs in human CRC samples compared with their matched adjacent normal tissues. The proteins that interact with LINRIS (Long Intergenic Noncoding RNA for IGF2BP2 Stability) were confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assays. The proliferation and metabolic alteration of CRC cells with LINRIS inhibited were tested in vitro and in vivo. Results LINRIS was upregulated in CRC tissues from patients with poor overall survival (OS), and LINRIS inhibition led to the impaired CRC cell line growth. Moreover, knockdown of LINRIS resulted in a decreased level of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a newly found N6-methyladenosine (m6A) ‘reader’. LINRIS blocked K139 ubiquitination of IGF2BP2, maintaining its stability. This process prevented the degradation of IGF2BP2 through the autophagy-lysosome pathway (ALP). Therefore, knockdown of LINRIS attenuated the downstream effects of IGF2BP2, especially MYC-mediated glycolysis in CRC cells. In addition, the transcription of LINRIS could be inhibited by GATA3 in CRC cells. In vivo experiments showed that the inhibition of LINRIS suppressed the proliferation of tumors in orthotopic models and in patient-derived xenograft (PDX) models. Conclusion LINRIS is an independent prognostic biomarker for CRC. The LINRIS-IGF2BP2-MYC axis promotes the progression of CRC and is a promising therapeutic target.

Abstract Background Oxaliplatin, irinotecan, 5-fluorouracil, and l-leucovorin (FOLFIRINOX) has become one of the first-line treatment options for advanced pancreatic cancer (PC). However, the relatively high rate of grade 3 or 4 adverse events associated with the standard dosage of FOLFIRINOX limits its widespread use in clinical practice. In this study, we were to evaluate the efficacy and safety of a modified FOLFIRINOX regimen as a first-line chemotherapy for Chinese patients with metastatic PC. Methods Patients with histologically confirmed primary metastatic pancreatic adenocarcinoma with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2 were recruited to receive the modified FOLFIRINOX regimen (intravenous infusion of oxaliplatin, 65 mg/m2; irinotecan, 150 mg/m2; l-leucovorin, 200 mg/m2; and 5-fluorouracil, 2400 mg/m2, repeated every 2 weeks). The treatment was continued for 12 cycles unless the patient had progressive disease (PD), stable disease (SD) with symptom deterioration, unacceptable adverse events, or requested to terminate the treatment prematurely. The primary endpoint was objective response rate (ORR). Results Sixty-five patients were enrolled from July 2012 to April 2017 in three institutions, and they all received at least one cycle of chemotherapy, with a median of 8 cycles (range 1–12 cycles). No complete response was observed. Twenty-one (32.3%) patients had partial responses, and 27 (41.5%) had SD. The ORR and disease control rate of the study cohort was 32.3% and 73.8%. The estimated median overall survival and progression-free survival were 11.60 (95% confidence interval [CI] 8.76–14.44) and 5.77 (95% CI 5.00–6.54) months. Major grade 3 or 4 adverse events included neutropenia (12.3%) and diarrhea (6.2%). No treatment-related death was observed. Conclusions Modified FOLFIRINOX was well-tolerated and might be a promising option as first-line therapy for Chinese patients with metastatic PC. Trial registration ClinicalTrials.gov, NCT02028806. Registered 7 January 2014, https://clinicaltrials.gov/ct2/show/NCT02028806

Abstract Background Preclinical studies suggest synergistic effectiveness of ascorbic acid (AA, vitamin C) and cytotoxic agents in gastrointestinal malignancies. This phase 1 study aimed to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of AA combined with mFOLFOX6 or FOLFIRI regimens in patients with metastatic colorectal cancer (mCRC) or gastric cancer (mGC). Methods In the dose-escalation phase, patients received AA (0.2–1.5 g/kg, 3-h infusion, once daily, days 1–3) with mFOLFOX6 or FOLFIRI in a 14-day cycle until the MTD was reached. In the speed-expansion phase, AA was administered at the MTD or at 1.5 g/kg if the MTD was not reached at a fixed rate of 0.6, 0.8 or 1 g/min. Pharmacokinetics and preliminary efficacy were also assessed. Results Thirty-six patients were enrolled. The MTD was not reached. The RP2D was established as AA at 1.5 g/kg/day, days 1–3, with mFOLFOX6 or FOLFIRI. No dose-limiting toxicity (DLT) was detected during dose escalation. The most common treatment-emergent adverse events (TRAEs) were sensory neuropathy (50%), nausea (38.9%), vomiting (36.1%) and neutropenia (27.8%). Grade 3–4 TRAEs were neutropenia (13.9%), sensory neuropathy (2.8%), vomiting (2.8%), diarrhea (2.8%) and leukopenia (2.8%). AA exposure was dose-proportional. The objective response rate was 58.3%, and the disease control rate was 95.8%. No difference in efficacy was found between mCRC patients with wild-type RAS/BRAF and mutant RAS or BRAF. Conclusions The favorable safety profile and preliminary efficacy of AA plus mFOLFOX6/FOLFIRI support further evaluation of this combination in mCRC or mGC. Trial registration ClinicalTrial.gov Identifier: NCT02969681.

Background: We previously reported tumor mutation burden (TMB) as a potential prognostic factor for patients with advanced gastric cancer (AGC) receiving immunotherapy. We aimed to comprehensively understand the impact of tumor burden and TMB on efficacy and prognosis in immunotherapy-treated AGC patients. Methods: A total of 58 patients with refractory AGC receiving PD-1 inhibitor monotherapy from a phase Ib/II clinical trial (ClinicalTrials.gov identifier: NCT02915432) were retrospectively included. Univariate and multivariate logistical regression analyses and the Cox proportional hazards model were performed for prognostic value of baseline factors. Factors reflecting baseline tumor burden, including baseline lesion number (BLN), the maximum tumor size (MTS) and the sum of target lesion size (SLS) were analyzed. The objective response rate (ORR) and disease control rate (DCR) were compared by Chi-square test. Results: In univariate analysis, high BLN was associated with poor median progression-free survival (mPFS) [1.7 months versus 3.4 months; hazard ratio (HR), 2.696, p 0.05; 86.96% versus 54.29%, p

Abstract The hematogenous metastatic pattern of gastric cancer (GC) was not fully explored. Here we analyzed the frequency and clinicopathological features of metastasis to liver, lung, bone, and brain from GC patients. Data queried for this analysis included GC patients from the Surveillance, Epidemiology, and End Results Program database from 2010 to 2014. All of statistical analyses were performed using the Intercooled Stata 13.0 (Stata Corporation, College Station, TX). All statistical tests were two‐sided. Totally, there were 19 022 eligible patients for analysis. At the time of diagnosis, there were 7792 patients at stage IV, including 3218 (41.30%) patients with liver metastasis, 1126 (14.45%) with lung metastasis, 966 (12.40%) with bone metastasis and 151 (1.94%) with brain metastasis. GC patients with lung or liver metastasis have a higher risk of bone and brain metastasis than those without lung nor liver metastasis. Intestinal subtype had significantly higher rate of liver and lung metastasis, while diffuse type was more likely to have bone metastasis. Proximal stomach had significantly higher risk to develop metastasis than distal stomach. African‐Americans had the highest risk of liver metastasis and Caucasian had the highest prone to develop lung and brain metastasis. The median survival for patients with liver, lung, bone, and brain metastasis was 4 months, 3 months, 4 months and 3 months, respectively. It is important to evaluate the status of bone and brain metastasis in GC patients with lung or liver metastasis. Knowledge of metastatic patterns is helpful for clinicians to design personalized pretreatment imaging evaluation for GC patients.

The prognostic heterogeneity in patients with BRAF V600E metastatic colorectal cancer (mCRC) remains poorly defined. Real-world data of 93 BRAF V600E mCRC patients from Sun Yat-sen University Cancer Center were evaluated using the prognostic factors affecting overall survival (OS). Treatment of metastases served as an independent prognosticator, where curative locoregional interventions (LRIs) were associated with superior clinical outcomes (adjusted hazard ratio (HR): 0.46, 95% confidence interval (CI): 0.22–0.98; p = 0.044). The LRIs group showed an improved median OS of 49.4 months versus 18.3 months for the palliative treatments (PTs) group. The median OS of patients with colorectal liver metastasis (CRLM) was significantly prolonged after undergoing LRIs (42.4 vs. 23.7 months; HR: 0.11, 95% CI: 0.01–1.22; p = 0.030), and patients in the LRIs plus liver-limited or lung-limited metastasis (LLM) group benefited more than those in the LRIs plus non-LLM group when compared to the PTs group (LLM from LRIs vs. PTs, HR: 0.16, 95% CI: 0.04–0.68; p = 0.006. Non-LLM from LRIs vs. PTs, HR: 0.47, 95% CI: 0.21–1.05; p = 0.074). In conclusion, we confirmed the positive prognostic value of LRIs in BRAF V600E mCRC, particularly in patients with CRLM or LLM.

BACKGROUND: A phase III clinical trial has already shown the survival benefits of postoperative chemotherapy in gastric cancer. However, there are limited published data concerning the elderly. This study aims to investigate the use of adjuvant chemotherapy for gastric cancer after D2 gastrectomy among the elderly and identify its impact on survival. METHODS: We retrospectively reviewed 360 patients who had undergone D2 gastrectomy, aged 65 years or older, with non-metastatic gastric cancer in a single institution. We analyzed the predictors and survival benefits of adjuvant chemotherapy use in the elderly. Further, we analyzed the survival benefits of adjuvant chemotherapy by dividing the patients into groups according to disease stages and chemotherapeutic regimens. RESULTS: Among the 360 patients, only 34.7% of patients received adjuvant chemotherapy. Age, tumor location, lymph node involvement and tumor invasion were associated with the receipt of adjuvant chemotherapy. Adjuvant chemotherapy improved the overall survival for non-metastatic elderly patients (HR 0.60, 95%CI 0.42-0.83, P = 0.003). Significant survival benefits were found with adjuvant chemotherapy in stage III patients (HR 0.67, 95%CI 0.47-0.97, P = 0.033), but not in stage I patients or in stage II patients (HR 0.52, 95%CI 0.21-1.30 P = 0.161). Compared to adjuvant chemotherapy without platinum, no significant survival benefits were observed with platinum-containing chemotherapy (HR 0.84, 95%CI 0.49-1.45, P = 0.530). Besides adjuvant chemotherapy, other independent prognostic factors of survival included tumor location, tumor size, histologic grade, depth of tumor invasion, and lymph node status. CONCLUSIONS: This study demonstrated the survival benefits of adjuvant fluoropyrimidine-based chemotherapy among the elderly patients with non-metastatic gastric cancer after D2 gastrectomy. However, due to the limitations of this study, further well-designed prospective studies with large populations are needed to confirm these findings and identify the patients that can tolerate and benefit from adjuvant chemotherapy.

BACKGROUND: The development of pancreatic cancer is a process in which genes interact with environmental factors. We performed this study to determine the effects of the ABO blood group, obesity, diabetes mellitus, metabolic syndrome (MetS), smoking, alcohol consumption and hepatitis B viral (HBV) infection on patient survival. METHODS: A total of 488 patients with pancreatic cancer were evaluated. RESULT: Patients who presented as chronic carriers of HBV infection were younger at disease onset (p = 0.001) and more predominantly male (p = 0.020) than those never exposed to HBV. Patients with MetS had later disease staging (p = 0.000) and a lower degree of pathological differentiation (p = 0.008) than those without MetS. In a univariate analysis, the ABO blood group, smoking and alcohol consumption were not associated with overall survival. HBsAg-positivity and elevated fasting plasma glucose were significantly associated with unfavorable survival though not in the multivariate analysis. The presence of MetS (HR: 1.541, 95% CI: 1.095-2.169, p = 0.013), age ≥65, an elevated CA19-9 baseline level, TNM staging, the type of surgery, the degree of differentiation and chemotherapy were independently associated with overall survival. CONCLUSION: We report, for the first time, that patients with chronic HBV infection may represent a special subtype of pancreatic cancer, who have a younger age of disease onset and male dominancy. Patients with MetS had later disease staging and a poorer histological grade. Patients with MetS demonstrated significantly poorer survival.

BACKGROUND: In this study, we established a hypothetical tumor-lodds-metastasis (TLM) and tumor-ratio-metastasis (TRM) staging system. Moreover, we compared them with the 7(th) edition of American Joint Committee on Cancer tumor-nodes-metastasis (AJCC TNM) staging system in gastric cancer patients after D2 resection. METHODS: A total of 1000 gastric carcinoma patients receiving treatment in our center were selected for the analysis. Finally, 730 patients who received D2 resection were retrospectively studied. Patients were staged using the TLM, TRM and the 7(th) edition AJCC TNM system. Survival analysis was performed with a Cox regression model. We used two parameters to compare the TNM, TRM and TLM staging system, the -2log likelihood and the hazard ratio. RESULTS: The cut points of lymph node ratio (LNR) were set as 0, 0-0.3, 0.3-0.6, 0.6-1.0. And for the log odds of positive lymph nodes (LODDS), the cut points were established as≤-0.5, -0.5-0, 0-0.5, >0.5. There were significant differences in survival among patients in different LODDS classifications for each pN or LNR groups. When stratified by the LODDS classifications, the prognosis was highly homologous between those in the according pN or LNR classifications. Multivariate analysis showed that TLM staging system was better than the TRM or TNM system for the prognostic evaluation. CONCLUSIONS: The TLM system was superior to the TRM or TNM system for prognostic assessment of gastric adenocarcinoma patients after D2 resection.