Outcome In Colorectal Cancer Patients Research Articles

Abstract B013: Activin’s influence on the tumor microenvironment in colon cancer

Abstract Background and aims: Activin A (activin) is a key molecule that regulates cell specific and context dependent signaling in tumor growth and metastasis as well as local and systemic inflammatory responses. Understanding the link between tumor-promotive and inflammatory effects may provide a novel opportunity for targeted therapy in colorectal cancer (CRC). We have previously shown that activin signaling promotes epithelial to mesenchymal transition, tumor migration, and that serum activin correlates with advanced stage in CRC patients. Recently, activin has been implicated in enhancing CD4+ to CD8+ communications to promote cytotoxic elimination of tumor cells. We now hypothesize that activin exerts cell-specific effects in the tumor microenvironment (TME) to both promote anti-tumoral activity of immune cells and pro-metastatic behavior of tumor cells in a context-dependent manner. Methods: Western blot and transwell migration assays with and without activin were performed in human epithelial colon cancer cells with varying expression levels of ACVR2 and in human colonic fibroblasts. The influence of the canonical Smad4 pathway was elucidated in a Ts4-Cre;Apcflox;Smad4flox mouse model for CRC. We analyzed a TMA of 1055 stage II and III CRC patients from the QUASAR2 cohort to correlate activin and CD4+ expression with outcome. The TMAs were also analyzed via Digital Spatial Profiling (DSP, NanoString) to determine the immune cell heterogeneity and cell signaling patterns within the tumor microenvironment relative to activin. Results: The non-canonical pAkt pathway is activated in ACVR2-restored but not ACVR2-mutated HCT116+chr2 colon cancer cells, which leads to tumor cell migration in a PI3K-dependent manner. In vivo, ablation of downstream canonical SMAD signaling is associated with elevated activin, alpha-SMA and pAkt and increases in tissue dysplasia, intestinal stromal disorganization, and animal mortality. While there are direct pro-metastatic effects of activin on tumor cells, activin expression in the TME of stage II or III CRC patients is associated with elevated CD4 and survival benefit (High activin/high CD4: 1.665 hazard ratio, 95% Cl of ratio 1.379 to 2.010). DSP analysis confirmed co-localization of activin with immune cells in the TME which influences cell signaling patterns found in these regions. Conclusion: In colon cancer cells, activin leads to preferential prometastatic PI3K/Akt pathway activation. Within the TME, high levels of activin in the presence of CD4+ T-cells is associated with better outcomes in CRC patients. This work lays the foundation to further study context-dependent activin signaling as an adjunct or target in CRC. Citation Format: Mark B. Wiley, Jessica Bauer, Kunaal Mehrotra, David N. Church, Rachel S. Kerr, David J. Kerr, Paul Grippo, Barbara Jung. Activin’s influence on the tumor microenvironment in colon cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B013.

Contact X-Ray Brachytherapy for Early Rectal Cancer: A Review of Outcomes From a Single UK Centre

AimsColorectal cancer is the fourth most prevalent cancer in the UK. Fortunately, with modern surveillance programmes, more patients are being diagnosed at an earlier stage. Although surgical excision remains the gold standard, many patients have co-morbidities that preclude them from having radical surgery. Additionally, a number of patients do not wish to live with a permanent colostomy. Radiotherapy has an established role in the non-surgical treatment of patients with rectal cancer. Increasing the radiation dose to the tumour increases the chance of local control. Using contact X-ray brachytherapy (CXB) it is possible to escalate the dose to the tumour and minimise the dose received by surrounding normal tissues. The aim of this study was to evaluate the outcomes of patients from our centre who have undergone CXB with or without external beam radiotherapy. Materials and methodsA prospectively maintained and locally managed colorectal database was used to collect clinical details and outcomes for colorectal cancer patients. All patients who were treated with CXB at our institution from the commencement of the service in April 2014 to the end of December 2019 were analysed. There was a minimum of 18 months of follow-up. ResultsOne hundred and ninety-three patients received at least one fraction of CXB. The median age at first treatment was 72 years (range 33–103 years). Seventy-three per cent of patients were male. Of the operable or high surgical risk patients, 105 were treated radically with radiotherapy, 28 were treated radically with radiotherapy after local resection and 22 patients were medically unfit for surgery. Most patients received external beam radiotherapy 45 Gy/25 fractions (87/146) or 25 Gy in five fractions (35/146). Forty-seven patients received CXB as sole treatment (51% had previous radiotherapy). Of those with a response assessment, with a median follow-up of 35 months, 78% of all patients achieved a clinical complete response (cCR) or a near cCR, 6% had a partial response and 16% had persistent disease. Of 154 radically treated patients with a response assessment, 84% achieved cCR or near cCR, 19% (24/129) of these subsequently relapsed. ConclusionThis series shows that CXB is a well-tolerated and effective treatment in a diverse cohort of patients with rectal cancer. Comparable favourable oncological outcomes were seen, in keeping with previously published work.

Survival outcomes among colorectal cancer patients at Kenyatta National Hospital: A retrospective cohort study.

Colorectal cancer is a growing burden in Africa. However, survival for patients with colorectal cancer remains low in sub-Saharan African countries, with the poorest survival, particularly at a late stage at diagnosis. Despite this, there is a paucity of sufficient data about the survival outcomes of colorectal cancer patients in Kenya. This study aimed to determine the survival outcomes among colorectal cancer patients at Kenyatta National Hospital. A retrospective cohort study was employed among 232 eligible medical records of colorectal cancer patients. Simple random sampling was used to select the medical records of the patients. The included medical records of the study participants were followed up retrospectively from the date of primary cancer diagnosis until the last visit to the hospital. All relevant data, such as sociodemographics, clinical characteristics, and outcome-measuring parameters, were recorded in the predesigned data abstraction tool by reviewing the documented clinical records of the patients. The data were entered and analyzed using International Business Machines (IBM) Statistical Package for the Social Sciences (SPSS) version 26 software. Mean, median, standard deviation, frequency tables, and figures were used to present the data. Kaplan Meier analyses were employed to determine survival outcomes. The mean age of the study participants was 54.1 ± 13.3 years, and the majority were males (126, 54.3%). Almost a third (34.1%) of patients had evidence of disease progression despite treatment in the follow-up period, with 7.8% showing no response to therapy and 23.6% experiencing new distant metastasis. The survival rate dwindled from the first year (87.9%) to the fifth year (45.4%), and the mortality rate was 22.8% CONCLUSION: There was a high mortality rate, disease progression, and distant metastasis in the last follow-up period suggesting the need to strengthen the healthcare system by ensuring access to prevention, early diagnosis, and optimal treatment of colorectal cancer.

Effect of perioperative COX-2 and beta-adrenergic inhibition on 5-year disease-free-survival in colorectal cancer: A pilot randomized controlled Colorectal Metastasis PreventIon Trial (COMPIT)

IntroductionBased on translational and epidemiological evidence, perioperative inhibition of beta-adrenergic and COX2 signaling can reduce the risk for post-surgical metastatic disease. Here we aimed to assess in a pilot study the impact of a perioperative combined COX-2 and beta-adrenergic blockade on long-term cancer outcomes in colorectal cancer patients undergoing curative surgery. Materials and methodsThirty-four newly diagnosed colorectal cancer patients without evidence of metastases enrolled in this double-blinded placebo-controlled randomized clinical trial (treatment, n = 16; placebo, n = 18). A 20-day oral treatment of propranolol and etodolac regimen was initiated 5 days before surgery. Beneficial effects on short-term molecular biomarkers of cancer progression were reported earlier. Here we present outcomes of five postoperative years of disease-free-survival and overall survival. ResultsAdverse event rates were equivalent between the two groups. Intent-to-treat analyses of 5-year follow-up showed that 2/16 (12.5%) vs 9/18 (50%) patients exhibited recurrence in treatment vs placebo groups, respectively (p = 0.033), and 2/16 (12.5%) vs 4/18 (22%) died (p = 0.467). In protocol compliant patients 0/11 (0%) vs. 8/17 (47%) exhibited recurrence in treatment vs. placebo groups, respectively (p = 0.007), and 0/11 (0%) and 3/17 (17.6%) died (p = 0.151). ConclusionsIn this pilot clinical trial, a combined perioperative treatment with propranolol and etodolac significantly improved 5-year disease-free-survival. The small sample size and a single center study design merits caution in interpreting these results, specifically in estimating the effect-size. Larger studies in colorectal cancer are warranted and needed.

Improved Postoperative Outcomes after Prehabilitation for Colorectal Cancer Surgery in Older Patients: An Emulated Target Trial

BackgroundThe aim of this study was to assess the effect of a multimodal prehabilitation program on perioperative outcomes in colorectal cancer patients with a higher postoperative complication risk, using an emulated target trial (ETT) design.Patients and MethodsAn ETT design including overlap weighting based on propensity score was performed. The study consisted of all patients with newly diagnosed colorectal cancer (2016–2021), in a large nonacademic training hospital, who were candidate to elective colorectal cancer surgery and had a higher risk for postoperative complications defined by: age ≥ 65 years and or American Society of Anesthesiologists score III/IV. Intention-to-treat (ITT) and per-protocol analyses were performed to evaluate the effect of prehabilitation compared with usual care on perioperative complications and length of stay (LOS).ResultsTwo hundred fifty-one patients were included: 128 in the usual care group and 123 patients in the prehabilitation group. In the ITT analysis, the number needed to treat to reduce one or more complications in one person was 4.2 (95% CI 2.6–10). Compared with patients in the usual care group, patients undergoing prehabilitation had a 55% lower comprehensive complication score (95% CI −71 to −32%). There was a 33% reduction (95% CI −44 to −18%) in LOS from 7 to 5 days.ConclusionsThis study showed a clinically relevant reduction of complications and LOS after multimodal prehabilitation in patients undergoing colorectal cancer surgery with a higher postoperative complication risk. The study methodology used may serve as an example for further larger multicenter comparative effectiveness research on prehabilitation.

Colorectal cancer in patients with SARS-CoV-2: a systematic review and meta-analysis

BackgroundPatients with colorectal cancer (CRC) are more likely to develop severe course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and experience increased risk of mortality compared to SARS-CoV-2 patients without CRC.ObjectivesTo estimate the prevalence of SARS-CoV-2 infection in CRC patients and analyse the demographic parameters, clinical characteristics and treatment outcomes in CRC patients with COVID-19 illness.MethodsFor this systematic review and meta-analysis, we searched Proquest, Medline, Embase, Pubmed, CINAHL, Wiley online library, Scopus and Nature for studies on the incidence of SARS-CoV-2 infection in CRC patients, published from December 1, 2019 to December 31, 2021, with English language restriction. Effect sizes of prevalence were pooled with 95% confidence intervals (CIs). Sub-group analyses were performed to minimize heterogeneity. Binary logistic regression model was used to explore the effect of various demographic and clinical characteristics on patient’s final treatment outcome (survival or death).ResultsOf the 472 papers that were identified, 69 articles were included in the systematic review and meta-analysis (41 cohort, 16 case-report, 9 case-series, 2 cross-sectional, and 1 case-control studies). Studies involving 3362 CRC patients with confirmed SARS-CoV-2 (all patients were adults) were analyzed. The overall pooled proportions of CRC patients who had laboratory-confirmed community-acquired and hospital-acquired SARS-CoV-2 infections were 8.1% (95% CI 6.1 to 10.1, n = 1308, 24 studies, I2 98%, p = 0.66), and 1.5% (95% CI 1.1 to 1.9, n = 472, 27 studies, I2 94%, p < 0.01). The median patient age ranged from 51.6 years to 80 years across studies. The majority of the patients were male (n = 2243, 66.7%) and belonged to White (Caucasian) (n = 262, 7.8%), Hispanic (n = 156, 4.6%) and Asian (n = 153, 4.4%) ethnicity. The main source of SARS-CoV-2 infection in CRC patients was community-acquired (n = 2882, 85.7%; p = 0.014). Most of those SARS-CoV-2 patients had stage III CRC (n = 725, 21.6%; p = 0.036) and were treated mainly with surgical resections (n = 304, 9%) and chemotherapies (n = 187, 5.6%), p = 0.008. The odd ratios of death were significantly high in patients with old age (≥ 60 years) (OR 1.96, 95% CI 0.94–0.96; p < 0.001), male gender (OR 1.44, 95% CI 0.41–0.47; p < 0.001) CRC stage III (OR 1.54, 95% CI 0.02–1.05; p = 0.041), CRC stage IV (OR 1.69, 95% CI 0.17–1.2; p = 0.009), recent active treatment with chemotherapies (OR 1.35, 95% CI 0.5–0.66; p = 0.023) or surgical resections (OR 1.4, 95% CI 0.8–0.73; p = 0.016) and admission to ICU (OR 1.88, 95% CI 0.85–1.12; p < 0.001) compared to those who survived.ConclusionSARS-CoV-2 infection in CRC patient is not uncommon and results in a mortality rate of 26.2%. Key determinants that lead to increased mortality in CRC patients infected with COVID-19 include older age (≥ 60 years old); male gender; Asian and Hispanic ethnicity; if SARS-CoV-2 was acquired from hospital source; advanced CRC (stage III and IV); if patient received chemotherapies or surgical treatment; and if patient was admitted to ICU, ventilated or experienced ARDS.

Identification and Validation of the lncRNA MYOSLID as a Regulating Factor of Necroptosis and Immune Cell Infiltration in Colorectal Cancer following Necroptosis-Related LncRNA Model Establishment

Simple SummaryColorectal cancer is one of the most common cancers and the second leading cause of deaths due to cancer. In this study, we developed a neural model based on only four lncRNAs to predict the overall survival rate of colorectal cancer patients. Moreover, we validated the value of analysing the lncRNA MYOSLID, one of the hub lncRNAs in our model, which promotes colorectal cancer by regulating necroptosis. Our study offered some essential insights into predicting the prognosis of colorectal cancer patients and may help to assist diagnosis and treatment in the future.Necroptosis is a newly defined form of programmed cell death that plays an important role in cancers. However, necroptosis-related lncRNAs (NRLs) involved in colorectal cancer (CRC) have not yet been thoroughly studied. Methods: In this study, a 4-NRL model was developed based on the least absolute shrinkage and selection operator (LASSO) algorithm. A series of informatic, in vitro and in vivo analyses were applied to validate the prognostic value of the model and the potential function of the hub lncRNA MYOSLID. Results: The model exhibited an excellent capacity for the prediction of overall survival and other clinicopathological features of CRC patients using Kaplan–Meier (K–M) survival curves and receiver operating characteristic (ROC) curves. Furthermore, a significant difference in the levels of immune cells, such as CD4 memory T cells and activated mast cells, between two risk groups was observed. The low-risk patients had a higher expression of immune checkpoints, such as PDCD1 (PD-1) and CD274 (PD-L1). The levels of MYOSLID, a hub lncRNA in our model, were higher in CRC tissues than in normal tissues. Knockdown of MYOSLID induced necroptosis and inhibited the proliferation of CRC cells in vitro and in vivo. Interestingly, knockdown of MYOSLID also increased the percentage of CD4+ and CD8+ T cells in subcutaneously transplanted tumours. Conclusion: Our model is a promising biomarker that can be used to predict clinical outcomes in CRC patients, and MYOSLID plays an important role in regulating necroptosis and immune cell infiltration in CRC.

Effect of hospital-based case management on psychosocial wellbeing and treatment outcomes in colorectal cancer patients: A quasi-experimental study.

Case management has been regarded as the front line of necessary change for fragmented healthcare system. This study proposed a case management intervention that is suitable for Chinese colorectal cancer patients and explored its effectiveness over a 12-month follow-up. A quasi-experimental study was conducted in an oncology hospital in China. A total of 188 patients were recruited from May 2015 to February 2017; 85 patients in the control group and 80 patients in the intervention group were included in data analysis. The intervention group was managed for 1 year by a case manager who organized the multidisciplinary team, provided regular assessment, a consulting service and referrals. Quality of life, anxiety and depression, symptom distress, treatment adherence and unplanned readmission rates were measured. Repeated measurement ANOVA showed significant intervention and time effects in global quality of life, anxiety and depression, symptom distress and oral chemotherapy adherence. The intervention group showed statistically significantly better overall treatment adherence and lower unplanned readmission rate. Nurse-led case management was effective in improving psychosocial outcomes, treatment adherence and unplanned readmission rate of colorectal cancer patients. A case management model is feasible and effective in colorectal cancer patients and in hospital-dominated healthcare systems where primary care is underutilized.

Long-term resistance to 5-fluorouracil promotes epithelial–mesenchymal transition, apoptosis evasion, autophagy, and reduced proliferation rate in colon cancer cells

The drug, 5-fluorouracil (5FU) is a standard first-line treatment for colorectal cancer (CRC) patients. However, drug resistance acquisition remains an important challenge for effective clinical outcomes. Here, we established a long-term drug-resistant CRC model and explored the cellular events underlying 5FU resistance. We showed that 5FU-treated cells (HCT-116 5FUR) using a prolonged treatment protocol were significantly more resistant than parental cells. Likewise, cell viability and IC50 values were also observed to increase in HCT-116 5FUR cells when treated with increasing doses of oxaliplatin, indicating a cross-resistance mechanism to other cytotoxic agents. Moreover, HCT-116 5FUR cells exhibited metabolic and molecular changes, as evidenced by increased thymidylate synthase levels and upregulated mRNA levels of ABCB1. HCT-116 5FUR cells were able to overcome S phase arrest and evade apoptosis, as well as activate autophagy, as indicated by increased LC3B levels. Cells treated with low and high doses displayed epithelial–mesenchymal transition (EMT) features, as observed by decreased E-cadherin and claudin-3 levels, increased vimentin protein levels, and increased SLUG, ZEB2 and TWIST1 mRNA levels. Furthermore, HCT-116 5FUR cells displayed enhanced migration and invasion capabilities. Interestingly, we found that the 5FU drug-resistance gene signature is positively associated with the mesenchymal signature in CRC samples, and that ABCB1 and ZEB2 co-expressed at high levels could predict poor outcomes in CRC patients. Overall, the 5FU long-term drug-resistance model established here induced various cellular events, and highlighted the importance of further efforts to identify promising targets involved in more than one cellular event to successfully overcome drug-resistance.

The Impact of Virtual Cancer Care on Chemotherapy Delivery and Clinical Outcomes in Colorectal Cancer Patients Receiving Systemic Therapy: A Pre- and Intra-Pandemic Analysis.

(1) Background: The coronavirus 2019 pandemic has resulted in an abrupt transition to virtual oncology care worldwide. This study’s objective is to evaluate chemotherapy delivery and clinical outcomes in patients on systemic treatment for colorectal cancer before and during the pandemic. (2) Methods: Clinical data was collected on patients with colorectal cancer receiving intravenous chemotherapy at The Ottawa Hospital from June 2019 to March 2021. Patients were stratified by whether they were started on chemotherapy pre-pandemic (June 2019–January 2020) or intra-pandemic (February 2020–March 2021). Multiple regression analysis was used to compare outcomes between pandemic periods; (3) Results: There were 220 patients included in this study. The proportion of virtual consultations (1.2% to 64.4%) and follow-up visits (5.2% to 83.3%) increased during the pandemic. There was no difference in the incidence of treatment delays (OR = 1.01, p = 0.78), chemotherapy dose reductions (OR = 0.99, p = 0.69), emergency department visits (OR = 1.23, p = 0.37) or hospitalizations (OR = 0.73, p = 0.43) between pandemic periods. A subgroup analysis revealed no difference in outcomes independent of the presence of metastases; (4) Conclusion: These findings serve as an important quality-care indicator and demonstrate that virtual oncology care appears safe in a cohort of high-risk colorectal cancer patients.

Asparagine, colorectal cancer, and the role of sex, genes, microbes, and diet: A narrative review.

Asparagine (Asn) and enzymes that catalyze the metabolism of Asn have been linked to the regulation and propagation of colorectal cancer (CRC). Increased Asn and asparagine synthetase (ASNS) expression, both contribute to CRC progression and metastasis. In contradistinction, L-asparaginase (ASNase) which breaks down Asn, exhibits an anti-tumor effect. Metabolic pathways such as KRAS/PI3K/AKT/mTORC1 signaling and high SOX12 expression can positively regulate endogenous Asn production. Conversely, the tumor suppressor, TP53, negatively impacts ASNS, thus limiting Asn synthesis and reducing tumor burden. Asn abundance can be altered by factors extrinsic to the cancer cell such as diet, the microbiome, and therapeutic use of ASNase. Recent studies have shown that sex-related factors can also influence the regulation of Asn, and high Asn production results in poorer prognosis for female CRC patients but not males. In this narrative review, we critically review studies that have examined endogenous and exogenous modulators of Asn bioavailability and summarize the key metabolic networks that regulate Asn metabolism. We also provide new hypotheses regarding sex-related influences on Asn, including the involvement of the sex-steroid hormone estrogen and estrogen receptors. Further, we hypothesize that sex-specific factors that influence Asn metabolism can influence clinical outcomes in CRC patients.

The role of microbiota in immunotherapy outcomes in colorectal cancer patients: A protocol for a systematic review.

In the human gut, there are many microbes, including bacteria, viruses and parasites. The imbalance in the numbers of each type of these microbes can translate into gastrointestinal disorders. Lately, different microbiota patterns have been associated with the levels of efficacy of immunotherapy in multiple cancer conditions. Studies have shown that patients with a more diverse gut microbiome respond better to immunotherapy than those with a homogeneous microbiome. This systematic review aims to identify and assess the available evidence on the efficacy of immunotherapy in treating colorectal cancer (CRC) patients and the effect of their microbiota on their treatment outcomes. The researchers will study the literature regarding CRC and immunotherapy outcomes to survey the different approaches employed to assess the treatment outcomes. A systematic search will be performed in five biomedical databases (PubMed, Scopus, Web of Science, Embase, and the Cochrane Library) in June-July, 2022. Also, open-access registers of clinical trials will be trawled. The search will be conducted without geographical or publication date restrictions; however, only papers published in the English language will be sought. Details regarding patients’ diets, lifestyles, and characteristics will be assessed. We will define the primary outcome to compare CRC patients’ immunotherapy responses with their gut microbiota composition. The systematic review methodology does not require ethics approval due to the nature of the study design. The systematic review results will be published in an open-access peer-reviewed journal.PROSPERO ID: CRD42021277691.

DDX39B drives colorectal cancer progression by promoting the stability and nuclear translocation of PKM2

Metastasis is a major cause of colorectal cancer (CRC) mortality, but its molecular mechanisms are still not fully understood. Here, we show that upregulated DDX39B correlates with liver metastases and aggressive phenotypes in CRC. DDX39B is an independent prognostic factor associated with poor clinical outcome in CRC patients. We demonstrate that Sp1 potently activates DDX39B transcription by directly binding to the GC box of the DDX39B promoter in CRC cells. DDX39B overexpression augments the proliferation, migration, and invasion of CRC cells, while the opposite results are obtained in DDX39B-deficient CRC cells. Mechanistically, DDX39B interacts directly with and stabilizes PKM2 by competitively suppressing STUB1-mediated PKM2 ubiquitination and degradation. Importantly, DDX39B recruits importin α5 to accelerate the nuclear translocation of PKM2 independent of ERK1/2-mediated phosphorylation of PKM2, leading to the transactivation of oncogenes and glycolysis-related genes. Consequently, DDX39B enhances glucose uptake and lactate production to activate Warburg effect in CRC. We identify that Arg319 of DDX39B is required for PKM2 binding as well as PKM2 nuclear accumulation and for DDX39B to promote CRC growth and metastasis. In addition, blocking PKM2 nuclear translocation or treatment with glycolytic inhibitor 2-deoxy-D-glucose efficiently abolishes DDX39B-triggered malignant development in CRC. Taken together, our findings uncover a key role for DDX39B in modulating glycolytic reprogramming and aggressive progression, and implicate DDX39B as a potential therapeutic target in CRC.

Higher vitamin B6 status is associated with improved survival among patients with stage I–III colorectal cancer

Folate-mediated 1-carbon metabolism requires several nutrients, including vitamin B6. Circulating biomarker concentrations indicating high vitamin B6 status are associated with a reduced risk of colorectal cancer (CRC). However, little is known about the effect of B6 status in relation to clinical outcomes in CRC patients. We investigated survival outcomes in relation to vitamin B6 status in prospectively followed CRC patients. A total of 2031 patients with stage I-III CRC participated in 6 prospective patient cohorts in the international FOCUS (folate-dependent 1-carbon metabolism in colorectal cancer recurrence and survival) Consortium. Preoperative blood samples were used to measure vitamin B6 status by the direct marker pyridoxal 5'-phosphate (PLP), as well as the functional marker HK-ratio (HKr)[3'-hydroxykynurenine: (kynurenic acid+xanthurenic acid+3'-hydroxy anthranilic acid+anthranilic acid)]. Using Cox proportional hazards regression, we examined associations of vitamin B6 status with overall survival (OS), disease-free survival (DFS), and risk of recurrence, adjusted for patient age, sex, circulating creatinine concentrations, tumor site, stage, and cohort. After a median follow-up of 3.2 y for OS, higher preoperative vitamin B6 status as assessed by PLP and the functional marker HKr was associated with 16-32% higher all-cause and disease-free survival, although there was no significant association with disease recurrence (doubling in PLP concentration: HROS, 0.68; 95% CI: 0.59, 0.79; HRDFS, 0.84; 95% CI: 0.75, 0.94; HRRecurrence, 0.96; 95% CI: 0.84, 1.09; HKr: HROS, 2.04; 95% CI: 1.67, 2.49; HRDFS, 1.56; 95% CI: 1.31, 1.85; HRRecurrence, 1.21; 95% CI: 0.96,1. 52). The association of PLP with improved OS was consistent across colorectal tumor site (right-sided colon: HROS, 0.75; 95% CI: 0.59, 0.96; left-sided colon: HROS, 0.71; 95% CI: 0.55, 0.92; rectosigmoid junction and rectum: HROS, 0.61; 95% CI: 0.47, 0.78). Higher preoperative vitamin B6 status is associated with improved OS among stage I-III CRC patients.

LINC00839 promotes colorectal cancer progression by recruiting RUVBL1/Tip60 complexes to activate NRF1.

The long noncoding RNA LINC00839 has been shown to be involved in the progression of some cancer types, such as bladder cancer, prostate cancer, breast cancer, and neuroblastoma. However, if LINC00839 has roles in colorectal cancer (CRC), it has not been elucidated so far. Here, we focus on the biological role and involved mechanisms of LINC00839 in CRC. We show that LINC00839 is selectively upregulated in CRC and locates to the nucleus. High expression of LINC00839 is associated with poor outcomes in CRC patients. Functional experiments show that LINC00839 promotes CRC proliferation, invasion, and metastasis in vitro and in vivo. Mechanistically, LINC00839 recruits Ruvb1 to the Tip60 complex and increases its acetylase activity. LINC00839 guides the complex to the NRF1 promoter and promotes acetylation of lysines 5 and 8 of histones H4, thereby upregulating the expression of NRF1. Subsequently, NRF1 activates mitochondrial metabolism and biogenesis, thereby promoting CRC progression. In summary, our study reports on a mechanism by which LINC00839 positively regulates NRF1, thus promoting mitochondrial metabolism and biogenesis, as well as CRC progression.

Perioperative Management and Surgical Outcomes of Colorectal Cancer Patients Undergoing Peritoneal Dialysis for End-Stage Kidney Disease.

Introduction: Despite the fact that the number of peritoneal dialysis (PD) patients is increasing, there is little evidence on the surgical outcomes of PD patients who have colorectal cancer surgery, and there is no consensus on the safety and practicality of continuing PD.Methods: We retrospectively evaluated the short- and long-term results, as well as the feasibility of continuing PD, in eight patients with PD who had colorectal cancer surgery at our institution between January 2010 and January 2021.Results: The scheduled open-fashioned resection was performed in one patient, whereas the other seven surgeries were all conducted laparoscopically, with no intraoperative conversion to laparotomy necessary. Except for one patient with a history of recurring PD-related peritonitis, the PD catheter was kept in seven of the eight cases. Five of the seven patients continuing PD underwent temporary postoperative hemodialysis. At a median of 24.5 months of postoperative monitoring, no infectious complications were observed, six cases continued PD, and no recurrence of colorectal cancer was observed in all cases.Conclusions: Routine curative-intent colorectal cancer surgery with the preservation of the PD catheter is possible and safe in individuals receiving PD. This patient population's short- and long-term oncological results are comparable to general surgical outcomes of those without chronic kidney disease. PD can be maintained for a long period of time following major colorectal cancer surgery.

Microbiome modulation in the prevention and management of colorectal cancer: a systematic review of clinical interventions.

The role of probiotics/prebiotics in modulating the procarcinogenic effects of microbiota have been studied with inconclusive results. This systematic review aimed to identify the role of several studied interventions on the gut microbiota modulation in humans for the prevention and management of colorectal cancer (CRC). We conducted a systematic search using PubMed and Cochrane Central electronic databases, identifying clinical studies published within the last 20 years. We performed a qualitative analysis of eligible studies included in our review on each of the 4 investigated topics: CRC potential biomarkers, dietary interventions, probiotic administration in non-surgical and surgical patients, respectively. A total of 54 studies involving healthy volunteers, in addition to colorectal adenoma and CRC patients were included in our qualitative synthesis. We were able to identify bacterial signatures of CRC including Fusobacterium nucleatum and Clostridium butyricum. Moreover, dietary supplementation with oligosaccharides or fibers increased short chain fatty acid-producing bacteria levels, thus inhibiting tumorigenesis. Furthermore, we have confirmed that Lactobacilli and Bifidobacterium intake modulates gut microbiota towards tumor suppression. We have also showed that probiotic intake around colectomy significantly reduces complications. Bacterial metabolism is strongly linked with colonic carcinogenesis and influenced by diet. Probiotics and prebiotics can act as microbiota modulators, suppressing epithelial proliferation and reversing DNA toxicity. As adjuvants to surgery or chemotherapy, Lactobacilli and Bifidobacteria decrease complications. Improved outcomes in CRC patients can possibly be achieved through future research directed towards the benefits of bacterial agents as tumor suppressors or as treatment of oncological therapy resistance.

Zebrafish Patient-Derived Xenograft Model to Predict Treatment Outcomes of Colorectal Cancer Patients.

The use of zebrafish embryos for personalized medicine has become increasingly popular. We present a co-clinical trial aiming to evaluate the use of zPDX (zebrafish Patient-Derived Xenografts) in predicting the response to chemotherapy regimens used for colorectal cancer patients. zPDXs are generated by xenografting tumor tissues in two days post-fertilization zebrafish embryos. zPDXs were exposed to chemotherapy regimens (5-FU, FOLFIRI, FOLFOX, FOLFOXIRI) for 48 h. We used a linear mixed effect model to evaluate the zPDX-specific response to treatments showing for 4/36 zPDXs (11%), a statistically significant reduction of tumor size compared to controls. We used the RECIST criteria to compare the outcome of each patient after chemotherapy with the objective response of its own zPDX model. Of the 36 patients enrolled, 8 metastatic colorectal cancer (mCRC), response rate after first-line therapy, and the zPDX chemosensitivity profile were available. Of eight mCRC patients, five achieved a partial response and three had a stable disease. In 6/8 (75%) we registered a concordance between the response of the patient and the outcomes reported in the corresponding zPDX. Our results provide evidence that the zPDX model can reflect the outcome in mCRC patients, opening a new frontier to personalized medicine.

The Effect of Complications on Oncological Outcomes of Colorectal Cancer Patients After Primary Surgery: A Propensity Score Matching Analysis.

PurposeThe purpose of this study is to explore the oncologic outcomes of complications on colorectal cancer (CRC) patients who underwent primary surgery using a propensity score matching (PSM) analysis.MethodsA retrospective study was conducted from Jan 2011 to Jan 2020 in a clinical center. The overall survival (OS) and disease-free survival (DFS) were compared among the no complications group, the major complications group and the minor complications group.ResultsA total of 4250 CRC patients who underwent radical primary surgery were included in the current study. Among them, 927 (21.8%) patients suffered complications. After 1:1 ratio PSM, there were 98 patients in the major complications group and in the minor complications group, and 911 patients in the overall complications group and in the no complications group. There was no significant difference in terms of baseline information after PSM (p>0.05). Complications were independent predictors of OS (p=0.000, HR=1.693, 95% CI=1.476-1.941) and DFS (p=0.000, HR=1.555, 95% CI=1.367-1.768). In terms of specific tumor stage, the no complications group had better OS on all stages (p=0.006) and stage III (p=0.003) CRC than the complications group after PSM. Furthermore, the no complications group had better DFS on all stages (p=0.005) and stage III (p=0.021) CRC than the complications group after PSM. However, there was no significant difference between the minor complications group and the major complications group in different tumor stages (p>0.05).ConclusionComplications were associated with poor prognosis of CRC and surgeons should be cautious of the adverse events.

Integrative Analysis Revealed Stemness Features and a Novel Stemness-Related Classification in Colorectal Cancer Patients.

Cancer stem cells play crucial roles in colorectal cancer (CRC) tumorigenesis and treatment response. This study aimed to determine the value of the mRNA stemness index (mRNAsi) in CRC and introduce a stemness-related classification to predict the outcome of patients. mRNAsi scores and RNA sequence data of CRC patients were analyzed. We found that high mRNAsi scores were related to early-stage CRC and a better patient prognosis. Two stemness-based subtypes (subtype I and II) were identified. Patients in subtype I presented a significantly better prognosis than those in subtype II. Patients in these two subtype groups presented significantly different tumor immunity scores and immune cell infiltration patterns. Genomic variations revealed that patients in subtype I had a lower tumor mutation burden than those in subtype II. A three-gene stemness subtype predictor was established, showing good diagnostic value in discriminating patients in different subtypes. A prognostic signature based on five stemness-related genes was established and validated in two independent cohorts and clinical samples, showing a better predictive performance than other clinical parameters. We concluded that mRNAsi scores were associated with the clinical outcome in CRC patients. The stemness-related classification was a promising prognostic predictor for CRC patients.