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PD-1 blockade has been recommended as first-line therapy for nonresectable or metastatic mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC). However, the safety and efficacy of neoadjuvant PD-1 blockade immunotherapy for locally advanced dMMR/MSI-H CRC remain unclear.From June 2020 to June 2022, 11 locally advanced dMMR/MSI-H CRC patients treated at the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) were enrolled. All patients received 6 sintilimab (Innovent, LTD) injections (200 mg/injection, every 3 weeks) before radical laparoscopic resection. The patient clinical and pathological data were analyzed retrospectively.dMMR was confirmed by immunohistochemistry for all patients. However, polymerase chain reaction (PCR) or next-generation sequencing confirmed MSI-H for only 90.9% (10/11) of the patients, while 1 patient had microsatellite stable (MSS) disease. After 6 injections of neoadjuvant anti-PD-1 therapy, 90.9% (10/11) of the patients (those confirmed to have dMMR and MSI-H disease) achieved pathological complete response (pCR). The other patient, who achieved major pathological response with residual tumor1%, had dMMR but MSS disease. No grade 3 or above immunotherapy-related adverse events occurred [Common Terminology Criteria for Adverse Events ; version 5.0]. Overall, 72.7% (8/11) of the patients had grade 1-2 immunotherapy-related adverse events . No operational mortality or complications occurred within 30 days after surgery.Single-agent neoadjuvant PD-1 antibody immunotherapy was safe and effective in locally advanced dMMR/MSI-H CRC. Dual confirmation of MMR and MSI status by immunohistochemistry and next-generation sequencing or PCR is necessary for dMMR/MSI-H CRC patients before immunotherapy. The immunotherapy regimen used in this study deserves further validation in phase II and III clinical studies.

Background Neoadjuvant therapy followed by radical surgery is recommended for locally advanced rectal cancer (LARC). But radiotherapy can cause potential adverse effects. The therapeutic outcomes, postoperative survival and relapse rates between neoadjuvant chemotherapy (N-CT) and neoadjuvant chemoradiotherapy (N-CRT) patients have rarely been studied. Methods From February 2012 to April 2015, patients with LARC who underwent N-CT or N-CRT followed by radical surgery at our center were included. Pathologic response, surgical outcomes, postoperative complications and survival outcomes (including overall survival [OS], disease-free survival [DFS], cancer-specific survival [CSS] and locoregional recurrence-free survival [LRFS]) were analyzed and compared. Concurrently, the Surveillance, Epidemiology, and End Results Program (SEER) database was used to compare OS in an external source. Results A total of 256 patients were input into the propensity score-matching (PSM) analysis, and 104 pairs remained after PSM. After PSM, the baseline data were well matched and there was a significantly lower tumor regression grade (TRG) (P P = 0.009) (especially anastomotic fistula, P = 0.003) and a longer median hospital stay (P = 0.049) in the N-CRT group than in the N-CT group. No significant difference was observed in OS (P = 0.737), DFS (P = 0.580), CSS (P = 0.920) or LRFS (P = 0.086) between the N-CRT group and the N-CT group. In the SEER database, patients who received N-CT had similar OS in both TNM II (P = 0.315) and TNM III stages (P = 0.090) as those who received N-CRT. Conclusion N-CT conferred similar survival benefits but caused fewer complications than N-CRT. Thus, it could be an alternative treatment of LARC.

Supplemental Figures 1-10 and Reagent table

DNA methylation contributes to malignant transformation, but little is known about how the methylation drives colorectal cancer evolution at the early stages. Here we identify aberrant INA (α-internexin) gene methylation in colon adenoma and adenocarcinoma by filtering data obtained from a genome-wide screen of methylated genes. The gene encoding INA, a type IV intermediate filament, was frequently hypermethylated in CpG islands located in the promoter region. This hypermethylation preferentially occurred in large tumors and was a prognostic marker for poor overall survival in patients with colorectal cancer. This type of epigenetic alteration silenced INA expression in both adenoma and adenocarcinoma tissues. Gene silencing of INA in colorectal cancer cells increased cell proliferation, migration, and invasion. Restored INA expression blocked migration and invasion in vitro and reduced lung metastasis in vivo. Mechanistically, INA directly inhibited microtubule polymerization in vitro and decreased intracellular microtubule plus-end assembly rates. A peptide array screen surveying the tubulin-binding sites in INA identified a tubulin-binding motif located in the N-terminal head domain that plays a tumor-suppressive role by binding to unpolymerized tubulins and impeding microtubule polymerization. Thus, epigenetic inactivation of INA is an intermediate filament reorganization event that is essential to accelerate microtubule polymerization in the early stages of colorectal cancer.Significance:This work provides insight into the epigenetic inactivation of INA, a novel identified tumor suppressor, which increases microtubule polymerization during colorectal cancer progression.

Table S1. The distribution and calculated pI of peptides in the peptide arrays

Patients with peritoneal metastasis (PM) of colorectal cancer (CRC) have poorer overall survival outcomes than those without PM. Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and mediate CRC progression and PM. It is imperative to identify and develop novel therapeutic targets for PM-CRC driven by CAFs. Using lipidomics, we reveal that the abundance of phosphatidylcholine (PC) with unsaturated acyl chains was increased in clinical PM-CRC specimens. Additionally, we found that CAFs were present at a higher relative abundance in primary PM-CRC tumors and that membrane fluidity in CRC cells was increased after incubation with CAF-conditioned medium (CM) through three independent methods: lipidomics, fluorescence recovery after photobleaching (FRAP), and generalized polarization. Then, we found that increased membrane fluidity can enhance glucose uptake and metabolism, as supported by real-time bioenergetics analysis and U

Objective We conducted this multicenter cohort study to evaluate the current tumor‐node‐metastasis staging system and treatment modality by analyzing the survival outcomes of patient groups with stage III and IV colon cancer. Patients and Methods Stage III and IV colon cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database (SEER cohort) and prospectively maintained Sun Yat‐sen University (SYSU) cohort were included in this study. Kaplan‐Meier method was used to estimate the cumulative rate of overall survival (OS) between patient groups, and the inverse probability weighting method was used to calculated age and sex‐adjusted survival curves. The Cox regression model was used to identify the risk factors for OS. Results A total of 17,911 and 1135 stage III–IV cases were included in the SEER and SYSU cohorts, respectively. Among them, 1448 and 124 resectable stage IV cases underwent curative‐intent treatment in the SEER and SYSU cohorts, respectively. The T4N2b group showed a significantly worse survival outcome compared with the M1a subset receiving curative‐intent treatment (HR, 1.46; p, By analyzing the Surveillance, Epidemiology, and End Results database and in‐house cohorts, several stage III subgroups were identified in a high risk of death, especially the T4N2b group that had significantly worse overall survival than that of the M1a subset. When further categorized by risk factors, the survival of the high‐risk T4N2b patients was worse than that of the M1b subset.

ImportanceSynchronous multiple primary colorectal cancer (sMPCC) is clinically rare, but its incidence has increased over the past decade. However, little is known about the molecular and clinical features of sMPCC, which may differ from those of single primary colorectal cancer (SPCRC).ObjectiveTo evaluate the clinical characteristics and pathogenic variations in lesions and the molecular typing of sMPCC.Design, Setting, and ParticipantsFrom November 2012 to April 2021, patients with colorectal cancer (CRC) treated at the Sixth Affiliated Hospital of Sun Yat-sen University were enrolled in this cohort study. Follow-up ended on January 31, 2022.Main Outcomes and MeasuresThe primary outcome was mismatch repair (MMR) status of each lesion in all patients examined using immunohistochemistry (IHC). Microsatellite instability (MSI) and tumor mutation burden (TMB) were also calculated.ResultsA total of 13 276 patients with CRC were enrolled, and 239 patients with sMPCC (mean [SD] age, 63.3 [12.2] years; 173 men [72.4%]) with available clinical data were evaluated. Seventy-eight patients with sMPCC and 94 with SPCRC also underwent next-generation sequencing (NGS)–based molecular testing. The deficient MMR (dMMR)/MSI-H frequencies in sMPCC were significantly higher than those in SPCRC, which was confirmed by both IHC (50 of 239 patients vs 872 of 13 037 patients) and NGS (17 of 78 patients vs 5 of 94 patients). According to the MMR/MSI status of different lesions in patients with sMPCC, they were further divided into 3 subgroups: all dMMR/MSI-H, dMMR/MSI-H and proficient MMR (pMMR)/microsatellite stability (MSS), and all pMMR/MSS. The EGFR and PIK3CA variants were more common, whereas TP53 variants were less prevalent in patients with sMPCC than in those with SPCRC. Moreover, higher tumor mutation burden was associated with higher MSI in patients with sMPCC rather than in those with SPCRC.Conclusions and RelevanceIn this cohort study of sMPCC, the incidence of dMMR/MSI-H in patients with sMPCC was significantly higher than that in patients with SPCRC. These findings suggest that sMPCC can be classified into 3 subgroups according to the MMR/MSI status of each lesion, which might be applied to guide personalized therapies for better disease management.

BackgroundColony-stimulating factor 1 receptor (CSF1R), a classic tyrosine kinase receptor, has been identified as a proto-oncogene in multiple cancers. The CSF1/CSF1R axis is essential for the survival and differentiation of M2-phenotype tumor-associated macrophages (M2 TAMs). However, we found here that the CSF1R expression was abnormally down-regulated in colorectal cancer (CRC), and its biological functions and underlying mechanisms have become elusive in CRC progression.MethodsThe expression of class III receptor tyrosine kinases in CRC and normal intestinal mucosa was accessed using The Cancer Genome Atlas and Gene Expression Omnibus datasets and was further validated by our tested cohort. CSF1R was reconstructed in CRC cells to identify its biological functionsin vitroandin vivo. We compared CSF1R expression and methylation differences between CRC cells and macrophages. Furthermore, a co-culture system was used to mimic a competitive mechanism between CSF1R-overexpressed CRC cells and M2-like macrophages. We utilized a CSF1R inhibitor PLX3397 to ablate M2 TAMs and evaluated its efficacy on CRC treatment in animal models.ResultsWe found here that the CSF1R is silenced in CRC, and the reintroduced expression of the receptor in CRC cells can be cleaved by caspases and constrain tumor growthin vitroandin vivo, functioning as a tumor suppressor gene. We further identified CSF1R as a novel dependence receptor, which has the potential to act as either a tumor suppressor gene or an oncogene, depending on its activated state. In CRC tumors, CSF1R expression is enriched in TAMs, and its expression is associated with poor prognosis in patients ith CRC. In a co-culture system, CRC cells expressing CSF1R compete with M2-like macrophages for CSF1R ligands, resulting in a decrease in CSF1R activation and cell proliferation in macrophages. Blocking CSF1R by PLX3397 could deplete M2 TAMs and augments CD8+T cell infiltration, effectively inhibiting tumor growth and metastasis and improving responses to chemotherapy and immunotherapy.ConclusionOur findings revealed that CSF1R is a novel identified dependence receptor silenced in CRC. The silence abalienates its ligands to stimulate CSF1R expressed on M2 TAMs, which is an appealing therapeutic target for M2 TAM depletion and CRC treatment.

Background The local recurrence of rectal cancer has been improved by total mesorectal excision following neoadjuvant chemoradiotherapy. However, in patients with low locally advanced rectal cancer, lateral pelvic recurrence remains to be addressed. Objective This study aimed to determine the efficiency of neoadjuvant radiotherapy in addressing lateral pelvic recurrence and which subgroup of patients might be optimal to receive lateral lymph node dissection. Design The MRI/CT images were reassessed for lateral lymph node status. The lateral lymph nodes with short axis ≥5 mm and ≥4 mm were considered positive in pretreatment and restaging MRI/CT. Setting This was a post hoc analysis of a prospective randomized controlled trial (FOWARC, NCT01211210). Patients A total of 495 patients with stage II or III rectal adenocarcinoma were included in the original trial. According to the excluding criteria, the finally included population consists of 253 patients; of these, 195 patients received neoadjuvant chemoradiotherapy and 94 received chemotherapy alone. Main outcomes and measures The primary outcome was the 5-year lateral pelvic recurrence rate. Results Compared with patients receiving chemotherapy alone, patients receiving additional radiotherapy had a marginal significance of lower lateral pelvic recurrence rate (6.6% vs 13.0%; p = 0.051). In the subset with pretreatment positive lateral lymph nodes, patients had a lateral pelvic recurrence rate of 22.6% and 45.1% after neoadjuvant chemoradiotherapy and chemotherapy alone. Of note, 34.9% of the pretreatment positive lateral lymph nodes were persistent after neoadjuvant chemoradiotherapy, culminating in a lateral pelvic recurrence rate of 63.3%. Limitations This is a post hoc analysis, and only the patients from the leading center were included, which limited the sample size. In addition, the lateral lymph node dissection was not performed in this cohort. Conclusions The addition of radiotherapy in neoadjuvant regimens could not address lateral pelvic recurrence adequately. Some subgroups of patients might need additional dissection. See Video Abstract at http://links.lww.com/DCR/B613. La inclusion de la radioterapia preoperatoria es insuficiiente en el control plvico lateral en un subgrupo de pacientes con cncer de recto inferior localmente avanzado un estudio posthoc controlado y randomizado ANTECEDENTES:La recurrencia local del cancer de recto ha disminuido al efectuar una excision mesorrectal total seguida de quimioradioterapia neoadyuvante. No obstante, en pacientes con cancer de tercio inferior de recto avanzado localmente, aun esta por controlarse la recurrencia pelvicaOBJETIVOS:Determinar la eficacia de la radioterapia neoadyuvante en el control de la recurrencia pelvica lateral y en que subgrupo de pacientes seria conveniente efecutar una excision lateral de las cadenas ganglionares.DISENO:Se reevaluaron las imagenes tomograficas y de resonancia magnetica del status de las cadenas ganglionares linfaticas laterales. Los ganglios linfaticos laterales con un eje-corto > 5 mm y ≥ 4 mm se consideraron como positivos previo al tratamiento y reestadificados con RM y TAC respectivamente.ESCENARIO:Es un analisis post hoc de un studio prospectivo randomizado controlado (FOWARC, NCT01211210).PACIENTESSe incluyeron un total de 495 pacientes en estdio II o III con adenomcarcinoma rectal en el estudio original. De acuerdo a los criterios de exclusion, la poblacion final incluida consistio en 253 pacientes; de estos, 195 recibieron quimioradioterapia neoadyuvante y 94 quimioterapia sola.EVALUACION DE LOS RESULTADOS PRINCIPALES:El parametro mas importante fue la tasa de recurrencia pelvica lateral a cinco anos.RESULTADOS:En comparacion con los pacientes que recibieron quimioterapia sola, aquellos que ademas fueron sometidos a radioterapia adicional presentaron un margen significativo de menor tasa de recurrencia pelvica lateral (6.6% vs. 13.0%; p=0.051). En el grupo de pacientes con ganglios linfaticos laterales positivos, los enfermos presentaron una tasa de recurrencia pelvica lateral de 22.6% y 45.1% despues de quimioradiaterapia neoadyuvante en comparacion con quimioterapia sola respectivamente. Cabe mencionar que el 34.9% de los pacientes con ganglios linfaticos laterales positivos antes del tratamiento persistieron despues de la quimioradioterapia neoadyuvante, reportandose finalmente una recurrencia pelvica lateral de un 63.3%.LIMITACIONES:Se trata de un analisis posthoc y solo los pacientes del hospital fueron incluidos, lo que limita el tamano de la muestra. Ademas, no se efectuo la diseccion de los ganglios linfaticos laterales en este grupo.CONCLUSIONES:La radioterapia en los esquemas de neoadyuvancia no logran controlar la recurrencia pelvica lateral en forma adecuada. Algunos subgrupos de pacientes podria requerir de diseccion adicional. Consulte Video Resumen en http://links.lww.com/DCR/B613.

Background The current risk stratification system defined by clinicopathological features does not identify the risk of recurrence in early-stage (stage I-II) colorectal cancer (CRC) with sufficient accuracy. We aimed to investigate whether DNA methylation could serve as a novel biomarker for predicting prognosis in early-stage CRC patients. Methods We analyzed the genome-wide methylation status of CpG loci using Infinium MethylationEPIC array run on primary tumor tissues and normal mucosa of early-stage CRC patients to identify potential methylation markers for prognosis. The machine-learning approach was applied to construct a DNA methylation–based prognostic classifier for early-stage CRC (MePEC) using the 4 gene methylation markers FAT3, KAZN, TLE4, and DUSP3. The prognostic value of the classifier was evaluated in 2 independent cohorts (n = 438 and 359, respectively). Results The comprehensive analysis identified an epigenetic subtype with high risk of recurrence based on a group of CpG loci in the CpG-depleted region. In multivariable analysis, the MePEC classifier was independently and statistically significantly associated with time to recurrence in validation cohort 1 (hazard ratio = 2.35, 95% confidence interval = 1.47 to 3.76, P Conclusions We demonstrated the prognostic statistical significance of a DNA methylation profile in the CpG-depleted region, which may serve as a valuable source for tumor biomarkers. MePEC could identify an epigenetic subtype with high risk of recurrence and improve the prognostic accuracy of current clinical variables in early-stage CRC.

The incidence of colorectal cancer is increasing among young adults and more rectal cancers are reported. This study aimed to identify the clinical features specific for early-onset rectal cancer and provide insights on cancer management.Early-onset (50 years) and late-onset (≥50 years) rectal cancer patients from a referral tertiary care center (SYSU cohort) and Surveillance Epidemiology and End Results database (SEER cohort) were included to perform a comprehensive comparison on clinical information.A total of 552 and 80,341 patients with stages I-III rectal cancer were included in the SYSU and SEER cohorts, respectively. In the SYSU cohort, early-onset diseases had significantly higher prevalence of family history of cancer and history of HBV infection and lower incidence of comorbidities (p 0.05). In addition, early-onset patients presented more frequently with advanced node stage (N2 stage: 16.9 vs. 9.3%, p = 0.017) and high-risk features, including mucinous or signet cell carcinomas (21.8 vs. 12.9%, p = 0.014), poorly differentiated tumors (28.8 vs. 15.4%, p = 0.002), and perineural invasion (14.5 vs. 7.9%, p = 0.027) compared with late-onset patients. However, early-onset patients received more neoadjuvant (18.5 vs. 11.2%, p = 0.032) and adjuvant treatments (71.0 vs. 45.8%, p 0.001), and they had better overall survival in both SYSU (HR 0.57, 95% CI: 0.34-0.95; p = 0.029) and SEER (HR 0.38, 95% CI: 0.37-0.40; p 0.001) cohorts.Early-onset rectal cancers are distinct from late-onset cases in clinicopathological features, treatment modalities, and outcomes. The clinical trials and studies that are specific for young populations are needed to develop optimal strategies for cancer screening, treatment, and surveillance.

Neoadjuvant mFOLFOXIRI chemotherapy with selective radiotherapy didn't comprise pathological complete response and tumor downstaging in locally advanced rectal cancer.The study aimed to analyze disease-free survival and local recurrence of neoadjuvant chemotherapy with mFOLFOXIRI.This was a prospective single arm phase II study. A propensity score-adjusted method was implemented to compare outcomes against historical controls of chemoradiotherapy.The study was conducted at single institutions.One hundred six patients with stage II and III rectal cancer were included.All patients received neoadjuvant mFOLFOXIRI chemotherapy before total mesorectal excision. Patients with mesorectal fascia-positive or ycT4a/b after re-evaluation with MRI would receive radiation before surgery. Otherwise, immediate total mesorectal excision would be performed.The primary endpoint was tumor downstaging (ypStage 0-I) rate, which was reported previously. Disease-free survival and local recurrence rate are the main outcomes for the current study.After a median follow-up of 43.3 months, the 2- and 3-year disease-free survival rates were 85.6% and 78.9%, respectively. The local recurrence rate was 7.8% after surgery. After propensity score matching, 73 patients were available for comparison in each group. The pathological complete response rate was 23.3% and 13.7% (p = 0.14), the proportion of ypStage 0-I was 45.2% versus 39.7% (p = 0.5), the 3-year DFS was 87.6% versus 75.8% (HR = 0.46, 95% CI 0.22-0.95, p = 0.037) and the local recurrence rate was 5.5% and 4.1% (p = 0.70) in the mFOLFOXIRI group versus the chemoradiotherapy group, respectively. Patients receiving mFOLFOXIRI had a lower incidence of anastomotic fistula compared with the chemoradiotherapy group (5.5% vs. 17.8%, p = 0.02).This was a single-arm, non-randomized phase II study.Neoadjuvant mFOLFOXIRI with selective radiotherapy was feasible and safe, and improved 3-year DFS compared with propensity-score matched historical controls who received chemoradiotherapy. See Video Abstract at http://links.lww.com/DCR/B989.NCT02217020.

To determine the morbidity, mortality, and pathologic outcomes of transanal total mesorectal resection (taTME) versus laparoscopic total mesorectal excision (laTME) among patients with rectal cancer with clinical stage I to III rectal cancer below the peritoneal reflection.Studies with sufficient numbers of patients allowing clinical acceptance of taTME for rectal cancer are lacking. Thus, we launched a randomized clinical trial to compare the safety and efficacy of taTME versus laTME.A randomized, open-label, phase 3, noninferiority trial was performed at 16 different hospitals in 10 Chinese provinces. The primary endpoints were 3-year disease-free survival and 5-year overall survival. The morbidity and mortality within 30 days after surgery, and pathologic outcomes were compared based on a modified intention-to-treat principle; this analysis was preplanned.Between April 13, 2016, and June 1, 2021, 1115 patients were randomized 1:1 to receive taTME or laTME. After exclusion of 26 cases, modified intention-to-treat set of taTME versus laTME groups included 544 versus 545 patients. There were no significant differences between taTME and laTME groups in intraoperative complications [26 (4.8%) vs 33 (6.1%); difference, -1.3%; 95% confidence interval (CI), -4.2% to 1.7%; P=0.42], postoperative morbidity [73 (13.4%) vs 66 (12.1%); difference, 1.2%; 95% CI, -2.8% to 5.2%; P=0.53), or mortality [1 (0.2%) vs 1 (0.2%)]. Successful resection occurred in 538 (98.9%) versus 538 (98.7%) patients in taTME versus laTME groups (difference, 0.2%; 95% CI, -1.9% to 2.2%; P0.99).Experienced surgeons can safely perform taTME in selected patients with rectal cancer.

Objective: Pyroptosis is a type of programmed cell death. This study aimed to explore the roles of key pyroptosis-related genes in liver ischemia-reperfusion injury. Methods: After collection and standardization of the transcriptome data from GSE12720 database, differentially expressed pyroptosis-related genes were identified. The risk genes screened by a random forest model were used to establish the line graph model. Consensus clustering was used to classify all samples according to the differentially expressed pyroptosis-related genes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was performed to investigate the immune cell infiltration after hepatic ischemia-reperfusion. Cytoscape was used to visualize the regulatory network of transcription factor (TF)-microRNA (miRNA)-target genes. Results: We identified 18 significantly and differentially expressed pyroptosis-related genes between the disease and normal samples. Among these 18 genes, IL1β was positively correlated with CXCL8 (r = 0.791) and BIRC3 (r = 0.78), while ADORA3 was negatively correlated with GZMB (r = -0.567) and CXCL8 (r = -0.566). Furthermore, the random forest model constructed using the top 10 pyroptosis-related genes could predict the risk of hepatic ischemia-reperfusion. Importantly, the decision curve analysis showed that patients could benefit from the risk prediction model. Moreover, we found that the expression of TXNIP, IRF1, and GJA1 was the mostly regulated by miRNAs, while the expression of BIRC3, NFκB1, and TXNIP was regulated by the TF RELA. RELA had the most hub genes involved in the regulation. Conclusion: Our study provides an overview of the expression landscape and the functional significance of pyroptosis-related genes in liver ischemia-reperfusion. Our findings also shed light on the clinical application of pyroptosis-related genes in the treatment of hepatic ischemia-reperfusion injury.

Objective: The purpose of this study was to observe the factors related to T4 patients who underwent surgery for colorectal cancer (CRC) with peritoneal carcinomatosis. Methods: 154 T4 colorectal cancer patients who underwent surgery in the first Affiliated Hospital of Sun Yat-sen University were included in the study between August, 1994 and December, 2005. Some clinical variables were selected and statistically correlated with prognosis. Results: The overall survival time was 91.7 months at the end of December of 2010 or death. The complete cytoreduction had significant survival benefit than the palliative surgery group. The age, location, histological grade, complete cytoreduction and liver metastasis were associated with overall survival time (OS) according to the univariate analysis (P < 0.05). In addition, Cox multivariate analysis showed that the complete cytoreduction (CCR) and liver metastasis were independent factor influencing survival. Conclusion: Compared with palliative surgery, the incomplete cytoreduction fails to improve patient prognosis. Patients performed completed cytoreduction have a relative good prognosis.

DNA methylation contributes to malignant transformation, but little is known about how the methylation drives colorectal cancer evolution at the early stages. Here we identify aberrant INA (α-internexin) gene methylation in colon adenoma and adenocarcinoma by filtering data obtained from a genome-wide screen of methylated genes. The gene encoding INA, a type IV intermediate filament, was frequently hypermethylated in CpG islands located in the promoter region. This hypermethylation preferentially occurred in large tumors and was a prognostic marker for poor overall survival in patients with colorectal cancer. This type of epigenetic alteration silenced INA expression in both adenoma and adenocarcinoma tissues. Gene silencing of INA in colorectal cancer cells increased cell proliferation, migration, and invasion. Restored INA expression blocked migration and invasion in vitro and reduced lung metastasis in vivo. Mechanistically, INA directly inhibited microtubule polymerization in vitro and decreased intracellular microtubule plus-end assembly rates. A peptide array screen surveying the tubulin-binding sites in INA identified a tubulin-binding motif located in the N-terminal head domain that plays a tumor-suppressive role by binding to unpolymerized tubulins and impeding microtubule polymerization. Thus, epigenetic inactivation of INA is an intermediate filament reorganization event that is essential to accelerate microtubule polymerization in the early stages of colorectal cancer. Significance: This work provides insight into the epigenetic inactivation of INA, a novel identified tumor suppressor, which increases microtubule polymerization during colorectal cancer progression.

BACKGROUND Situs inversus totalis (SIT) is a rare anomaly in which structures are located opposite to their usual positions. It is not a premalignant condition and the association with colorectal cancer (CRC) is rare. We here report a patient with SIT who underwent laparoscopic radical resection of sigmoid colon cancer, and review the pertinent literature. CASE SUMMARY A 53-year-old woman presented with CRC and SIT and underwent a complete examination after admission. The patient then underwent laparoscopic radical resection of sigmoid colon cancer and hyperthermic intraperitoneal chemotherapy. The operation duration was 120 min, and no intraoperative complications occurred. The final pathological report showed stage T4aN0M0. Postoperative chemotherapy was administered and no evidence of recurrence was observed during 18 mo of follow-up. CONCLUSION Surgery in a patient with CRC and SIT can be safely performed on the basis of routine preoperative clinical examination.

Background Preoperative fluoropyrimidine with radiotherapy was regarded as the standard of care for locally advanced rectal cancer (LARC). The model for predicting pCR in LARC patients was based on standard treatment only. This study aimed to establish a nomogram with pretherapeutic parameters and different neoadjuvant regimens for predicting pathologic complete response (pCR) and tumor downstaging or good response (ypT0-2N0M0) after receiving neoadjuvant treatment in patients with LARC based on a randomized clinical trial. Methods Between January 2011 and February 2015, 309 patients with rectal cancer were enrolled from a prospective randomized study (NCT01211210). All pretreatment clinical parameters were collected to build a nomogram for predicting pCR and tumor downstaging. The model was subjected to bootstrap internal validation. The predictive performance of the model was assessed with concordance index (C-index) and calibration plots. Results Of the 309 patients, 53 (17.2%) achieved pCR and 132 (42.7%) patients were classified as tumor downstaging with ypT0-2N0M0. Based on the logistic-regression analysis and clinical consideration, tumor length (P = 0.005), tumor circumferential extent (P = 0.036), distance from the anal verge (P = 0.019), and neoadjuvant treatment regimen (P Conclusions The nomogram provided individual prediction responses to different preoperative treatment for patients with rectal cancer. This model might help physicians in selecting an optimized treatment, but warrants further external validation.

Jiaming Zhou1,2 &ast;, Xiaoyan Guo3 &ast;, Pinzhu Huang1,2 &ast;, Shuyun Tan,1,2 Rongwan Lin,4 Huanmiao Zhan,5 Xiaofeng Wu,6 Tuoyang Li,1,2 Mingzhe Huang,1,2 Meijin Huang1,2 1Department of Colon and Rectum Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 3Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 4Department of Clinical Laboratory, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 5Department of Pathology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China; 6Department of Medical Records Management, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China&ast; These authors contributed equally to this workCorrespondence: Meijin Huang, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Yuancun Erheng Road, Tianhe District, Guangzhou, Guangdong, People’s Republic of China, Tel +8613924073322, Fax +8620-38254221, Email hmjin@mail.sysu.edu.cnPurpose: Previous studies on the effect of hepatitis B virus (HBV) infection on colorectal liver metastasis (CRLM) are contradictory. This study revealed different, more specific impacts of HBV on CRLM.Patients and Methods: A total of 3132 colorectal cancer patients treated from 2013 to 2015 were analyzed retrospectively and followed up for five years. The patients were divided into three groups: group A (chronic HBV infection, CHB); group B, (occult HBV infection, OHB) and group C (no HBV infection, NHB). The risk factors for CRLM, 5-year overall survival (OS), and liver disease-free survival (LDFS) were analyzed.Results: A total of 905 patients (28.9%) had CRLM, with poor survival compared to those without CRLM (P < 0.01). The incidence of CRLM was 33.41% (138/413) in group A, 21.63% (138/638) in group B and 30.23% (629/2081) in group C (P < 0.05). Synchronous colorectal cancer liver metastasis (SYN-CRLM) was found in 425 patients (13.57%). CHB increased the risk of SYN-CRLM (P < 0.01), with a worse prognosis (P < 0.05). Metachronous colorectal cancer liver metastasis (MET-CRLM) was found in 480 patients (15.33%). OHB decreased the risk of MET-CRLM after surgery (P = 0.02), with a better 5-year LDFS (P = 0.01). Even without surgery, patients with OHB showed a lower incidence rate of MET-CRLM (P < 0.01).Conclusion: The incidence of CRLM in this study was approximately 28.9%. Surgery and different HBV infection statuses affected the occurrence of CRLM. Chronic HBV infection increased the risk of SYN-CRLM with poor prognosis. Occult HBV infection reduced the risk of MET-CRLM with better LDFS after surgery.Keywords: colorectal cancer, liver metastasis, hepatitis B virus, chronic HBV infection, occult HBV infection

BACKGROUND: There is still a lack of nomograms that can accurately predict liver metastasis and poor prognosis after neoadjuvant therapy for locally advanced rectal cancer (LARC). Effective nomograms may help clinicians better identify LARC patients with potential high-risk risks, so as to carry out more targeted monitoring, treatment and follow-up. METHODS: The nomograms were based on the FOWARC trial (NCT01211210), which included 302 LARC patients who underwent neoadjuvant treatment before surgery at the Sixth Affiliated Hospital of Sun Yat-sen University from 2011 to 2014. The predictive accuracy and discriminative ability of the nomograms were determined by the concordance index (C-index) and calibration curve. The results were validated using bootstrap resampling and a prospective study on 100 patients in 2017. RESULTS: The 3-year liver disease-free survival (LDFS) rate after neoadjuvant treatment for LARC was 91.65% (training cohort 92.22%, validation cohort 90.01%). Factors associated with LDFS were hepatitis B virus (HBV) infection, anemia, lymph node number, postoperative T stage and tumor nodule, which were all included in the nomogram for LDFS. The C-indies of the nomogram for LDFS were 0.828 and 0.845 in the training and validation cohorts. The 3-year overall survival (OS) rate was 94.14% (training cohort 94.13%, validation cohort 94.05%). Factors in the nomogram for OS were mesorectal fascia involvement (MRF), postoperative N stage, pathological differentiation, tumor nodule and neural invasion. The C-indies of the nomogram for predicting OS were 0.73 and 0.774 in the training and validation cohorts. The calibration curve for the survival probability showed good agreement between the nomogram predictions and the actual observations. CONCLUSIONS: The nomograms established in this study can effectively predict LDFS and has good clinical application potential for OS in LARC patients treated with neoadjuvant therapy.

Purpose: Immune checkpoint inhibitors (ICIs) have achieved remarkable survival improvement in multiple cancers by exerting anti-tumor effects through augmenting adaptive immunity. However, 60%-70% of patients showed primary resistance to ICIs, and the underlying mechanisms remained unclear. Pyroptosis is a programmed cell death accompanied by a robust inflammatory response with the secretion of pro-inflammatory molecules, and thus it has the potential to be a promising biomarker for immunotherapy. Methods: A dataset with the clinical and transcriptomic profiles was derived from 16 randomized controlled trials and studies on ICIs treatment in multiple solid tumors, including melanoma, urothelial cancer, non-small cell lung cancer, renal cell cancer, breast cancer, and esophageal cancer. The responder was defined as patients achieving complete or partial response, while the non-responder was defined as patients with stable or progressive disease. According to previous studies, we generated a cytotoxic pyroptosis-related gene set, including CASP1, CASP3, CASP4, CASP5, CASP8, GSDMB, GSMDC, GSDMD, GSDME, GZMA, GZMB, to explore the association of cytotoxic pyroptosis with response to ICIs. In addition, the previously defined gene set from the Gene Ontology working group that contains a pyroptosis-related gene set was also included to represent the level of total pyroptosis. Single sample Gene Set Enrichment Analysis (ssGSEA) was performed, and the fold-changes and p-values of gene sets were merged with the R package “MetaVolcanoR”. Patients in each subset were split by the median of the ssGSEA score of pyroptosis-related genes and identified as with relatively activated and inhibited pyroptosis, respectively. A P-value < 0.05 was considered significant. Results: A total of 1,407 patients were analyzed, including 475 responders and 932 non-responders. The ssGSEA revealed that both the pyroptosis and the cytotoxic pyroptosis gene sets were enriched in responders, while the cytotoxic pyroptosis-related gene set was one of the top five ones among the 545 enriched in responders. Moreover, the survival analysis showed that in urothelial and non-small cell lung cancer, patients with activated pyroptosis prior to treatment had better progression-free survival and overall survival after ICIs therapies. These results suggested that an activated status of pyroptosis, especially the pyroptotic process related to cytotoxic events, is a marker for better response to ICIs. Conclusions: The transcriptomic analysis of universal immunotherapy biomarkers identifies an pre-existing activated status of pyroptosis within the tumor microenvironment was associated with a better ICIs response across different cancer types, and thus these pyroptosis-related genes may serve as valuable immunotherapy markers and in silico fundamental tool for exploring pyroptosis in tumor immunity. Citation Format: Yumo Xie, Xiaolin Wang, Meijin Huang, Yanxin Luo, Huichuan Yu. Activated pyroptosis prior to treatment marks a potential response to immunotherapy in cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4147.