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Competing Interests: The authors have no potential conflicts of interest to disclose.

Colorectal cancer (CRC) with peritoneal metastases is a complex disease and its management presents significant clinical challenges. In well-selected patients at experienced centers, CRS/hyperthermic intraperitoneal chemotherapy (HIPEC) can be performed with acceptable morbidity and is associated with prolonged survival. Based on the results of recent randomized controlled trials, HIPEC using oxaliplatin after CRS with shortened perfusion periods (30 minutes) is no longer recommended. There is a movement toward utilizing mitomycin C as a first-line intraperitoneal agent with extended perfusion times (90-120 minutes); however, there is currently little prospective evidence to support its widespread use., Competing Interests: Disclosure None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can be activated by microbial antigens and cytokines and are abundant in mucosal tissues including the colon. MAIT cells have cytotoxic and pro-inflammatory functions and have potentials for use as adoptive cell therapy. However, studies into their anti-cancer activity, including their role in colon cancer, are limited. Using an animal model of colon cancer, we showed that peritumoral injection of in vivo-expanded MAIT cells into RAG1 -/- mice with MC38-derived tumours inhibits tumour growth compared to control. Multiplex cytokine analyses showed that tumours from the MAIT cell-treated group have higher expression of markers for eosinophil-activating cytokines, suggesting a potential association between eosinophil recruitment and tumour inhibition. In a human peripheral leukocyte co-culture model, we showed that leukocytes stimulated with MAIT ligand showed an increase in eotaxin-1 production and activation of eosinophils, associated with increased cancer cell killing. In conclusion, we showed that MAIT cells have a protective role in a murine colon cancer model, associated with modulation of the immune response to cancer, potentially involving eosinophil-associated mechanisms. Our results highlight the potential of MAIT cells for non-donor restricted colon cancer immunotherapy., (© 2024 The Author(s). Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)

Intratumoral delivery of mRNA encoding immunostimulatory molecules can initiate a robust, global antitumor response with little side effects by enhancing local antigen presentation in the tumor and the tumor draining lymph node. Neoantigen-based mRNA nanovaccine can inhibit melanoma growth in mice by intratumoral injection. Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune responses by secreting immunosuppressive agents, such as reactive oxygen species (ROS). Suppression of STAT3 activity by stattic may reduce MDSC-mediated immunosuppression in the TME and promote the antitumor immune responses. In this study, in vitro transcribed mRNA encoding tumor antigen survivin was prepared and injected intratumorally in BALB/c mice bearing subcutaneous colon cancer tumors. In vivo studies demonstrated that intratumoral survivin mRNA therapy could induce antitumor T cell response and inhibit tumor growth of colon cancer. Depletion of CD8 + T cells could significantly inhibit survivin mRNA-induced antitumor effects. RT-qPCR and ELISA analysis indicated that survivin mRNA treatment led to increased expression of receptor activator nuclear factor-κB ligand (RANKL). In vitro experiment showed that MDSCs could be induced from mouse bone marrow cells by RANKL and RANKL-induced MDSCs could produce high level of ROS. STAT3 inhibitor stattic suppressed activation of STAT3 and NF-κB signals, thereby inhibiting expansion of RANKL-induced MDSCs. Combination therapy of survivin mRNA and stattic could significantly enhance antitumor T cell response, improve long-term survival and reduce immunosuppressive tumor microenvironment compared to each monotherapy. In addition, combined therapy resulted in a significantly reduced level of tumor cell proliferation and an obviously increased level of tumor cell apoptosis in CT26 colon cancer-bearing mice, which could be conducive to inhibit the tumor growth and lead to immune responses to released tumor-associated antigens. These studies explored intratumoral mRNA therapy and mRNA-based combined therapy to treat colon cancer and provide a new idea for cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Toll-like receptor (TLR) agonists are being developed as anti-cancer therapeutics due to their potent immunostimulatory properties. However, clinical trials testing TLR agonists as monotherapy have often failed to demonstrate significant improvement over standard of care. We hypothesized that the anti-cancer efficacy of TLR agonist immunotherapy could be improved by combinatorial approaches. To prevent increased toxicity, often seen with systemic combination therapies, we developed a hydrogel to deliver TLR agonist combinations at low doses, locally, during cancer debulking surgery. Using tumor models of WEHI 164 and bilateral M3-9-M sarcoma and CT26 colon carcinoma, we assessed the efficacy of pairwise combinations of poly(I:C), R848, and CpG in controlling local and distant tumor growth. We show that combination of the TLR3 agonist poly(I:C) and TLR7/8 agonist R848 drives anti-tumor immunity against local and distant tumors. In addition, combination of local poly(I:C) and R848 sensitized tumors to systemic immune checkpoint blockade, improving tumor control. Mechanistically, we demonstrate that local therapy with poly(I:C) and R848 recruits inflammatory monocytes to the tumor draining lymph nodes early in the anti-tumor response. Finally, we provide proof of concept for intraoperative delivery of poly(I:C) and R848 together via a surgically applicable biodegradable hydrogel., Competing Interests: The authors declare a patent application related to the hydrogel biomaterial used in this work., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: The objective of this study was to quantify disparities in cancer treatment delivery between minority-serving hospitals (MSHs) and non-MSHs for breast, prostate, nonsmall cell lung, and colon cancers from 2010 to 2019 and to estimate the impact of improving care at MSHs on national disparities., Methods: Data from the National Cancer Database (2010-2019) identified patients who were eligible for definitive treatments for the specified cancers. Hospitals in the top decile by minority patient proportion were classified as MSHs. Multivariable logistic regression adjusted for patient and hospital characteristics compared the odds of receiving definitive treatment at MSHs versus non-MSHs. A simulation was used to estimate the increase in patients receiving definitive treatment if MSH care matched the levels of non-MSH care., Results: Of 2,927,191 patients from 1330 hospitals, 9.3% were treated at MSHs. MSHs had significant lower odds of delivering definitive therapy across all cancer types (adjusted odds ratio: breast cancer, 0.83; prostate cancer, 0.69; nonsmall cell lung cancer, 0.73; colon cancer, 0.81). No site of care-race interaction was significant for any of the cancers (p > .05). Equalizing treatment rates at MSHs could result in 5719 additional patients receiving definitive treatment over 10 years., Conclusions: The current findings underscore systemic disparities in definitive cancer treatment delivery between MSHs and non-MSHs for breast, prostate, nonsmall cell lung, and colon cancers. Although targeted improvements at MSHs represent a critical step toward equity, this study highlights the need for integrated, system-wide efforts to address the multifaceted nature of racial and ethnic health disparities. Enhancing care at MSHs could serve as a pivotal strategy in a broader initiative to achieve health care equity for all., (© 2024 American Cancer Society.)

Importance: Hospital-level factors, such as hospital type or volume, have been demonstrated to play a role in treatment disparities for Black patients with cancer. However, data evaluating the association of hospital accreditation status with differences in treatment among Black patients with cancer are lacking., Objective: To evaluate the association of Commission on Cancer (CoC) hospital accreditation status with receipt of guideline-concordant care and mortality among non-Hispanic Black patients with colon cancer., Design, Setting, and Participants: This population-based cohort study used the National Program of Cancer Registries, which is a multicenter database with data from all 50 states and the District of Columbia, and covers 97% of the cancer population in the US. The participants included non-Hispanic Black patients aged 18 years or older diagnosed with colon cancer between January 1, 2018, and December 31, 2020. Race and ethnicity were abstracted from medical records as recorded by health care facilities and practitioners. The data were analyzed from December 7, 2023, to January 17, 2024., Exposure: CoC hospital accreditation., Main Outcome and Measures: Guideline-concordant care was defined as adequate lymphadenectomy during surgery for patients with stages I to III disease or chemotherapy administration for patients with stage III disease. Multivariable logistic regression models investigated associations with receipt of guideline-concordant care and Cox proportional hazards regression models assessed associations with 3-year cancer-specific mortality., Results: Of 17 249 non-Hispanic Black patients with colon cancer (mean [SD] age, 64.8 [12.8] years; 8724 females [50.6%]), 12 756 (74.0%; mean [SD] age, 64.7 [12.8] years) were treated at a CoC-accredited hospital and 4493 (26.0%; mean [SD] age, 65.1 [12.5] years) at a non-CoC-accredited hospital. Patients treated at CoC-accredited hospitals compared with those treated at non-CoC-accredited hospitals had higher odds of receiving guideline-concordant lymphadenectomy (adjusted odds ratio [AOR], 1.89; 95% CI, 1.69-2.11) and chemotherapy (AOR, 2.31; 95% CI, 1.97-2.72). Treatment at CoC-accredited hospitals was associated with lower cancer-specific mortality for patients with stages I to III disease who received surgery (adjusted hazard ratio [AHR], 0.87; 95% CI, 0.76-0.98) and for patients with stage III disease eligible for chemotherapy (AHR, 0.75; 95% CI, 0.59-0.96)., Conclusions and Relevance: In this cohort study of non-Hispanic Black patients with colon cancer, patients treated at CoC-accredited hospitals compared with those treated at non-CoC-accredited hospitals were more likely to receive guideline-concordant care and have lower mortality risk. These findings suggest that increasing access to high-quality guideline-concordant care at CoC-accredited hospitals may reduce variations in cancer treatment and outcomes for underserved populations.

Background: Studies demonstrate higher mortality rates from colon cancer in American Indian/Alaskan Native (AI/AN) patients compared to non-Hispanic White (nHW). We aim to identify factors that contribute to survival disparities., Methods: We used the National Cancer Database to identify AI/AN (n = 2127) and nHW (n = 527,045) patients with stage I-IV colon cancer from 2004 to 2016. Overall survival among stage I-IV colon cancer patients was estimated by Kaplan-Meier analysis; Cox proportional hazard ratios were used to identify independent predictors of survival., Results: AI/AN patients with stage I-III disease had significantly shorter median survival than nHW (73 vs 77 months, respectively; p < 0.001); there were no differences in survival for stage IV. Adjusted analyses demonstrated that AI/AN race was an independent predictor of higher overall mortality compared to nHW (HR 1.19, 95% CI 1.01-1.33, p = 0.002). Importantly, compared to nHW, AI/AN were younger, had more comorbidities, had greater rurality, had more left-sided colon cancers, had higher stage but lower grade tumors, were less frequently treated at an academic facility, were more likely to experience a delay in initiation of chemotherapy, and were less likely to receive adjuvant chemotherapy for stage III disease. We found no differences in sex, receipt of surgery, or adequacy of lymph node dissection., Conclusion: We found patient, tumor, and treatment factors that potentially contribute to worse survival rates observed in AI/AN colon cancer patients. Limitations include the heterogeneity of AI/AN patients and the use of overall survival as an endpoint. Additional studies are needed to implement strategies to eliminate disparities., (© 2023. W. Montague Cobb-NMA Health Institute.)

Currently, sonodynamic therapy (SDT) has limited therapeutic outcomes and immune responses, highlighting the urgent need for enhanced strategies that can stimulate robust and long-lasting antitumor effects. Microcystis, a notorious microalga, reveals the possibility of mediating SDT owing to the presence of gas vesicles (GVs) and phycocyanin (PC). Herein, a nontoxic strain of Microcystis elabens (labeled Me) is developed as a novel agent for SDT because it generates O 2 under red light (RL) illumination, while GVs and PC act as cavitation nuclei and sonosensitizers, respectively. Moreover, algal debris is released after ultrasound (US) irradiation, which primes the Toll-like receptor pathway to initiate a cascade of immune responses. This sono-immune strategy inhibits CT26 colon tumor growth largely by promoting dendritic cell (DC) maturation and cytotoxic T-cell activation. After combination with the immune checkpoint blockade (ICB), the therapeutic outcome is further amplified, accompanied by satisfactory abscopal and immune memory effects; the similar potency is proven in the "cold" 4T1 triple-negative breast tumor. In addition, Me exhibits good biosafety without significant acute or chronic toxicity. Briefly, this study turns waste into wealth by introducing sono-immunotherapy based on Microcystis that achieved encouraging therapeutic effects on cancer, which is expected to be translated into the clinic., (© 2024 Wiley‐VCH GmbH.)

Purpose: The aim of this study is to assess cost-effectiveness of general practitioner (GP) versus surgeon-led colon cancer survivorship care from a societal perspective., Methods: We performed an economic evaluation alongside the I CARE study, which included 303 cancer patients (stages I-III) who were randomised to survivorship care by a GP or surgeon. Questionnaires were administered at baseline, 3-, 6-, 12-, 24- and 36-months. Costs included healthcare costs (measured by iMTA MCQ) and lost productivity costs (SF-HLQ). Disease-specific quality of life (QoL) was measured using EORTC QLQ-C30 summary score and general QoL using EQ-5D-3L quality-adjusted life years (QALYs). Missing data were imputed. Incremental cost-effectiveness ratios (ICERs) were calculated to relate costs to effects on QoL. Statistical uncertainty was estimated using bootstrapping., Results: Total societal costs of GP-led care were significantly lower compared to surgeon-led care (mean difference of - €3895; 95% CI - €6113; - €1712). Lost productivity was the main contributor to the difference in societal costs (- €3305; 95% CI - €5028; - €1739). The difference in QLQ-C30 summary score over time between groups was 1.33 (95% CI - 0.049; 3.15). The ICER for QLQ-C30 was - 2073, indicating that GP-led care is dominant over surgeon-led care. The difference in QALYs was - 0.021 (95% CI - 0.083; 0.040) resulting in an ICER of 129,164., Conclusions: GP-led care is likely to be cost-effective for disease-specific QoL, but not for general QoL., Implications for Cancer Survivors: With a growing number of cancer survivors, GP-led survivorship care could help to alleviate some of the burden on more expensive secondary healthcare services., (© 2023. The Author(s).)

At present, tumor immunotherapy has been widely applied to treat various cancers. However, the accuracy of predicting treatment efficacy has not yet achieved a significant breakthrough. This study aimed to construct a prediction model based on the modified WGCNA algorithm to precisely judge the anti-tumor immune response. First, we used a murine colon cancer model to screen corresponding DEGs according to different groups. GSEA was used to analyze the potential mechanisms of the immune-related DEGs (irDEGs) in each group. Subsequently, the intersection of the irDEGs in every group was acquired, and 7 gene-modules were mapped. Finally, 4 gene-modules including cogenes, antiPD-1 immu-genes, chemo immu-genes and comb immu-genes, were selected for subsequent study. Furthermore, a clinical dataset of gastric cancer patients receiving immunotherapy was enrolled, and the irDEGs were identified. A total of 34 vital irDEGs were obtained from the intersections of the vital irDEGs and the four gene-modules. Next, the vital irDEGs were analyzed by the modified WGCNA algorithm, and the correlation coefficients between the 4 gene-modules and the response status to immunotherapy were calculated. Thus, a prediction model based on correlation coefficients was built, and the corresponding model scores were acquired. The AUC calculated according to the model score was 0.727, which was non-inferior to that of the ESTIMATE score and the TIDE score. Meanwhile, the AUC calculated according to the classification of the model scores was 0.705, which was non-inferior to that of the ESTIMATE classification and the TIDE classification. The prediction accuracy of the model was validated in clinical datasets of other cancers., (© 2024. The Author(s).)

Background: The majority of experimental approaches for cancer immunotherapy are tested against relatively small tumors in tumor-bearing mice, because in most cases advanced cancers are resistant to the treatments. In this study, we asked if even late-stage mouse tumors can be eradicated by a rationally designed combined radio-immunotherapy (CRI) regimen., Methods: CRI consisted of local radiotherapy, intratumoral IL-12, slow-release systemic IL-2 and anti- CTLA-4 antibody. Therapeutic effects of CRI against several weakly immunogenic and immunogenic mouse tumors including B78 melanoma, MC38 and CT26 colon carcinomas and 9464D neuroblastoma were evaluated. Immune cell depletion and flow cytometric analysis were performed to determine the mechanisms of the antitumor effects., Results: Tumors with volumes of 2,000 mm 3 or larger were eradicated by CRI. Flow analyses of the tumors revealed reduction of T regulatory (Treg) cells and increase of CD8/Treg ratios following CRI. Rapid shrinkage of the treated tumors did not require T cells, whereas T cells were involved in the systemic effect against the distant tumors. Cured mice developed immunological memory., Conclusions: These findings underscore that rationally designed combination immunotherapy regimens can be effective even against large, late-stage tumors., Competing Interests: Author WO was formerly employed by the company Nektar Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rakhmilevich, Tsarovsky, Felder, Zaborek, Moram, Erbe, Pieper, Spiegelman, Cheng, Witt, Overwijk, Morris and Sondel.)

Management of colon cancer has changed over the last few decades. We assessed the trends in management and outcomes using the US National Cancer Database (NCDB). A retrospective analysis of all patients with colonic adenocarcinoma between 2005 and 2019 was conducted. The cohort was divided into three equal time periods: Period 1 (2005-2009), Period 2 (2010-2014), and Period 3 (2015-2019) to examine treatment and outcomes trends. The primary outcome was 5-year overall survival (OS). The study included 923,275 patients. A significant increase in patients with stage IV disease was noted in Period 3 compared to Period 1 (47.9% vs. 27.9%, respectively), whereas a reciprocal reduction was seen in patients with locally advanced disease (stage II: 20.8%-12%; stage III: 14.5%-7.7%). Use of immunotherapy significantly increased from 0.3% to 7.6%. Mean 5-year OS increased (43.6 vs. 42.1 months) despite the increase in metastatic disease and longer time from diagnosis to definitive surgery (7 vs. 14 days). A reduction in 30-day readmission (5.1%-4.2%), 30- (3.9%-2.8%), and 90-day mortality (7.1%-5%) was seen. Laparoscopic and robotic surgery increased from 45.8% to 53.1% and 2.9% to 12.7%, respectively. Median postoperative length of hospital stay decreased by 2 days. Rate of positive resection margins (7.2%-6%) and median number of examined lymph nodes (14-16) also improved. Minimally invasive surgery and immunotherapy for colon cancer significantly increased in recent years. Patient outcomes including OS improved over time., (© 2024 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Squamous cell carcinoma of the colon (CSCC) is a rare subtype of colon cancer. This study aimed to evaluate treatment strategies and overall survival (OS)., Methods: Using the Surveillance, Epidemiology, and End Results program database from 2008 to 2019, patients aged 18 years with CSCC were identified. Treatment strategies and OS were summarized using the Kaplan-Meier analysis and the log-rank test. Adjusted Cox proportional hazards regression model ratios were calculated to evaluate the effect of confounding variables., Results: After exclusions, 153 patients met the inclusion criteria. The most common treatment modalities included surgery alone (52.1%), surgery and adjuvant chemotherapy (12.9%), and no treatment (26.4%). Kaplan-Meier analysis revealed that patients who underwent surgery and adjuvant chemotherapy had significant improvements in OS (log-rank P = .002). Cox regression analysis revealed tumor grade (hazard ratio [HR], 2.12; 95% CI, 1.17-3.86) and receipt of chemotherapy (HR, 2.66; 95% CI, 1.23-5.76) as the only factors associated with improvements in OS., Conclusion: Patients who underwent surgery in combination with chemotherapy had better OS than those who underwent surgery alone. Tumor grade and receipt of chemotherapy were independently associated with OS., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Aggressive nature of colon cancer and current imprecise therapeutic scenarios simulate the development of precise and effective treatment strategies. To achieve this, a tumor environment-activated photosensitized biomimetic nanoplatform (PEG 2000 -SiNcTI-Ph/CpG-ZIF-8@CM) is fabricated by encapsulating metal-organic framework loaded with developed photosensitizer PEG 2000 -SiNcTI-Ph and immunoadjuvant CpG oligodeoxynucleotide within fusion cell membrane expressing programmed death protein 1 (PD-1) and cluster of differentiation 47 (CD47). By stumbling across, systematic evaluation, and deciphering with quantum chemical calculations, a unique attribute of tumor environment (low pH plus high concentrations of adenosine 5'-triphosphate (ATP))-activated photodynamic effect sensitized by long-wavelength photons is validated for PEG 2000 -SiNcTI-Ph/CpG-ZIF-8@CM, advancing the precision of cancer therapy. Moreover, PEG 2000 -SiNcTI-Ph/CpG-ZIF-8@CM evades immune surveillance to target CT26 colon tumors in mice mediated by CD47/signal regulatory proteins α (SIRPα) interaction and PD-1/programmed death ligand 1 (PD-L1) interaction, respectively. Tumor environment-activated photodynamic therapy realized by PEG 2000 -SiNcTI-Ph/CpG-ZIF-8@CM induces immunogenic cell death (ICD) to elicit anti-tumor immune response, which is empowered by enhanced dendritic cells (DC) uptake of CpG and PD-L1 blockade contributed by the nanoplatform. The photodynamic immunotherapy efficiently combats primary and distant CT26 tumors, and additionally generates immune memory to inhibit tumor recurrence and metastasis. The nanoplatform developed here provides insights for the development of precise cancer therapeutic strategies., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Background: Despite contributions provided by the recent clinical trials, several issues and challenges still remain unsolved in adjuvant colon cancer (CC). Hence, further studies should be planned to better refine risk assessment as well as to establish the optimal treatment strategy in the adjuvant setting. However, it is necessary to request adequate, contemporary and relevant variables and report them homogeneously in order to bring maximal information when analyzing their prognostic value., Material and Methods: The project was devised to gain a consensus from experts engaged in the planning, accrual and analyses of stage II and III CC clinical trials, to identify mandatory and recommended baseline variables in order to i) harmonize future data collection worldwide in clinical trials dedicated to adjuvant treatment of CC; ii) propose guidance for Case Report Forms to be used for clinical trials in this setting. A total of 72 questions related to variables that should be reported and how to report them in adjuvant clinical trials were approved and then voted to reach a final consensus from panelists., Results: Data items on patient-related factors, histopathological features, molecular profile, circulating biomarkers and blood analyses were analyzed and discussed by the whole expert panel. For each item, we report data supporting the acquired consensus and the relevant issues that were discussed. Nineteen items were deemed to be mandatory for resected stage III patients and 24 for resected stage II disease. In addition, 9 and 4 items were judged as recommended for stage III and II, respectively., Conclusion: In our opinion, these 28 variables should be used and uniformly reported in more comprehensive CRFs as research groups design future clinical trials in the field of adjuvant colon cancer., Competing Interests: Declaration of Competing Interest All authors declare no competing interest regarding this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The limitations of conventional cancer therapies necessitate target-oriented, highly invasive, and safe treatment approaches. Hence, the intrinsic anti-tumor activity of Salmonella can offer better options to combat cancers., Objectives: This study aims to utilize attenuated Salmonella and deliver cytolytic protein cytolysin A (ClyA) under quorum sensing (QS) signaling for precise localized expression in tumors but not in healthy organs., Methods: The therapeutic delivery strain was imposed with tryptophan auxotroph for selective colonization in tumors by trpA and trpE deletion, and lipid-A and O-antigen were altered by pagL and rfaL deletions using lambda red recombination method. The strain was transformed with the designed QS-controlled ClyA expression vector which was validated by western blot. The in vivo passaged therapeutic strain was used for treatment four times at a weekly interval, with a dose of 5 × 10 6 CFU/mouse for cancer therapy., Results: The attenuated strain induced minimal endotoxicity-related cytokines TNF-α, IL-1β, and IFN-γ and exhibited adequate colonization despite earlier exposure in mice. The QS-controlled ClyA expression was confirmed by western blot from bacterial cultures grown at different cell densities. The results demonstrated that the in vivo passaged strain preferentially colonized the tumor after vacating the spleen, liver, and lung, leaving no outward histological scars. The anti-cancer effect of the designed construct was evaluated in the murine CT26 colon cancer model. The expression of ClyA increased tumoricidal activity by 67 % compared to vector control., Conclusion: Hence, the anti-tumor effect of the engineered Salmonella strain was improved by ClyA expression via QS activation after achieving the threshold bacterial cell density. Further, immunohistochemical staining of the tumor and other organs corroborated the QS-controlled tumor-specific expression of ClyA. Overall, the results imply that the developed anti-cancer Salmonella has low endotoxicity and QS-controlled expression of ClyA as beneficial safety elements and supports recurrent Salmonella inoculation by O-antigen deficiency., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Colon cancer (CC) stands as one of the most common malignancies related to the gastrointestinal system, whose increasing incidence and death rates have been reported all over the world. Standard treatments for fighting cancers like CC comprise surgical approaches, chemotherapy, and radiotherapy, which are suggested by clinicians according to patients' conditions and disease stages. However, patients who utilize these modalities may suffer from serious side effects and adverse outcomes, for example, toxicity and tumor recurrence, as well as a low 5-year survival rate. The present shreds of evidence showed that mesenchymal stem cells (MSCs) can have a suitable capacity for treating different health problems, especially neoplasms. These multipotent stem cells can be isolated from several sources, such as the umbilical cord, bone marrow, adipose tissue, and placenta. Among these mesenchymal sources, umbilical cord-MSCs have gathered much attention in scientific societies due to their advantages (e.g., low immunogenicity, lack of ethical problems, and easy collection). These days, the efficacy of umbilical cord-MSCs and umbilical cord-MSCs-based strategies, such as conditioned medium, extracellular vesicles, and exosomes, on CC have been explored, and promising findings have been stated. Therefore, in this review, we aimed to summarize and debate evidence regarding the effects of UC-MSCs and their related products on CC with a focus on molecular and cellular mechanisms involved in its treatment and pathogenesis of this malignant tumor., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Summary: Immunotherapy for the systemic treatment of cancer offers new treatment possibilities for advanced malignancies. Despite promising initial results, evidence on efficacy of immunotherapy for colon cancer is lacking. Thus, we aimed to assess short-term and long-term outcomes of immunotherapy in patients with advanced colon cancer. A US National Cancer Database was searched for patients with stage III-IV colonic adenocarcinoma between 2010 and 2019. Propensity score matching was used to classify the cohort into 2 groups: patients who received immunotherapy and controls. Main outcome measures were primary outcome was overall survival (OS). A total of 23,778 patients with stage III-IV colonic adenocarcinoma were treated with immunotherapy during the study period compared to 114,753 controls. Immunotherapy treated patients were younger (median age 61 vs. 67 y; P <0.001), more often male (57.3% vs. 50.7%, P <0.001), had more private insurance (44.1% vs. 33.7%; P <0.001), had more left-sided tumors (49.5% vs. 39.1%; P <0.001) and liver metastasis (80.2% vs. 61.7%; P <0.001) than controls. Immunotherapy patients received more standard chemotherapy (49.8% vs. 41.6%; P <0.001). After propensity-score matching, mean OS was significantly shorter in the immunotherapy group compared with controls (34.7 vs. 36.2 mo; P =0.008). Cox regression analysis demonstrated that immunotherapy was associated with increased risk for mortality (HR: 1.1; 95% CI: 1.02-1.18; P =0.005). Patients who received immunotherapy had lower 90-day mortality rates compared with controls (2.3% vs. 3.6%; P =0.004), but the groups had equivalent 30-day mortality rates (0.7% vs. 0.8%; P =0.76). Immunotherapy showed no improvement in OS in patients with stage III-IV colon cancer., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The treatment landscape for patients with colon cancer is continuously evolving. Risk-adapted treatment strategies, including neoadjuvant chemotherapy and immunotherapy, are slowly finding their way into clinical practice and guidelines. Radiologists are pivotal in guiding clinicians toward the most optimal treatment for each colon cancer patient. This review provides an overview of recent and upcoming advances in the diagnostic management of colon cancer and the radiologist's role in the multidisciplinary approach to treating colon cancer., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Blockade of PD-1/PD-L1 immune checkpoint is wildly used for multiple types of cancer treatment, while the low response rate for patients is still completely unknown. As nuclear hormone receptor, PPARδ (peroxisome-proliferator-activated receptor) regulates cell proliferation, inflammation, and tumor progression, while the effect of PPARδ on tumor immune escape is still unclear. Here we found that PPARδ antagonist GSK0660 significantly reduced colon cancer cell PD-L1 protein and gene expression. Luciferase analysis showed that GSK0660 decreased PD-L1 gene transcription activity. Moreover, reduced PD-L1 expression in colon cancer cells led to increased T cell activity. Further analysis showed that GSK0660 decreased PD-L1 expression in a PPARδ dependent manner. Implanted tumor model analysis showed that GSK0660 inhibited tumor immune escape and the combined PD-1 antibody with GSK0660 effectively enhanced colorectal cancer immunotherapy. These findings suggest that GSK0660 treatment could be an effective strategy for cancer immunotherapy., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the authors., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Over the past decade, our understanding of the diversity of colorectal cancer has expanded significantly, raising hopes of tailoring treatments more precisely for individual patients. A key achievement in this direction was the establishment of the consensus molecular classification, particularly identifying the challenging consensus molecular subtype (CMS) CMS4 associated with poor prognosis. Because of its aggressive nature, extensive research is dedicated to the CMS4 subgroup. Recent years have unveiled molecular and microenvironmental features at the tissue level specific to CMS4 colorectal cancer. This has paved the way for mechanistic studies and the development of preclinical models. Simultaneously, efforts have been made to easily identify patients with CMS4 colorectal cancer. Reassessing clinical trial results through the CMS classification lens has improved our understanding of the therapeutic challenges linked to this subtype. Exploration of the biology of CMS4 colorectal cancer is yielding potential biomarkers and novel treatment approaches. This overview aims to provide insights into the clinico-biological characteristics of the CMS4 subgroup, the molecular pathways driving this subtype, and available diagnostic options. We also emphasize the therapeutic challenges associated with this subtype, offering potential explanations. Finally, we summarize the current tailored treatments for CMS4 colorectal cancer emerging from fundamental and preclinical studies., (©2024 The Authors; Published by the American Association for Cancer Research.)

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.

Background: In April 2023, the National Comprehensive Cancer Network endorsed neoadjuvant immunotherapy for select patients with nonmetastatic mismatch repair deficient colon cancer. Approximately 15% of incident colon cancers are mismatch repair deficient, resulting in a distinct molecular subtype with high microsatellite instability that is responsive to immune checkpoint inhibition., Objective: To describe the existing evidence supporting neoadjuvant immunotherapy for mismatch repair deficient, microsatellite unstable nonmetastatic colon cancer., Data Sources: A medical librarian performed PubMed, Embase, and Web of Science searches most recently on April 24, 2023. The PubMed search was re-run on September 26, 2023, to identify any additional studies published between April 24 and September 26, 2023., Study Selection: Two authors screened titles and abstracts in the published studies. The inclusion criteria were 1) English language, 2) adults with primary cancer of the colon, 3) nonmetastatic disease, 4) neoadjuvant immunotherapy, and 5) reporting on 10 or more cases., Intervention: Neoadjuvant immunotherapy., Main Outcome Measures: Safety (grade 3+ treatment-related adverse events) and efficacy (complete pathologic responses)., Results: From 7691 studies identified, 6370 were screened and 8 were included. Various agents, dosing regimens, and treatment durations were used, with durations of immunotherapy ranging from 1 to 16 cycles. Complete R0 resections were consistently achieved in 98% to 100% of resections. Of patients who received neoadjuvant immunotherapy and underwent resection, 50% to 91% had ypT0N0 pathology. The safety profiles were generally favorable, with grade 1 to 2 treatment-related adverse events (mostly immune-related) during immunotherapy reported in 22.2% to 70% of patients. Postoperative complications after neoadjuvant immunotherapy were reassuring, with no severe complications reported., Limitations: Small number of heterogeneous and uncontrolled studies precluding a meta-analysis., Conclusions: Neoadjuvant immune checkpoint inhibition is associated with high rates of pathologic complete responses in locally advanced colon cancer. The literature is limited, particularly for postoperative outcomes, and more studies are needed to understand the safety and positioning of these regimens in the neoadjuvant context., (Copyright © The ASCRS 2024.)

Aim: Real-life estimations of survival by stage in colorectal cancer are scanty. We estimated population-based net survival by pathological stage and location, and for rectal cancer by patterns of evolution according to clinical and pathological stage with regard to neoadjuvant therapy., Method: Age-standardized net survival was estimated on 19,630 colorectal cancers diagnosed between 2009 and 2015., Results: Five-year net survival was 64 % for colon and 62 % for rectal cancer. The highest absolute difference between colon and rectum was 12 % for stage II women aged 75 (91% vs. 79 %). Among patients with clinical stage III rectal cancer, 67 % no longer had pathological node involvement after neoadjuvant treatment. Survival was similar in clinical stage I, II or III and pathological stage III after neoadjuvant treatment and in pathological stage III without neoadjuvant treatment (between 67 % and 72 %). It ranged between 80 and 82 % in pathological stage II, without neoadjuvant treatment or with clinical stage I, II or III before neoadjuvant treatment. Survival ranged between 93 % and 95 % in pathological stage I, treated with surgery only or with clinical stage II or III before neoadjuvant treatment., Conclusion: Prognosis is associated with stage determined on surgical specimens rather than stage at the initial workup., Competing Interests: Conflict of interest None., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: For relief of bowel obstruction in left-sided obstructive colon cancer (LSOCC), a self-expandable metal stent (SEMS) or decompressing stoma (DS) can be placed. In a curative setting, these two strategies have been extensively studied as a bridge to elective resection. Guidelines recommend SEMS as the preferred option in the palliative setting, but adherence in daily practice is unknown. Therefore, this study aimed to gain more insight into patients with LSOCC who received palliative treatment with SEMS or DS at a national level., Methods: A retrospective population-based cohort study was conducted in the Netherlands. Data from the Netherlands Cancer Registry (NCR) on all patients with LSOCC treated with DS or SEMS not followed by resection of the primary tumour between January 1, 2015, and December 31, 2019, were analysed. Type of treatment (DS or SEMS) for different clinical scenarios, was the main outcome of this study, and was also evaluated over the years (2015-2019)., Results: Palliative treatment with SEMS or DS for LSOCC was performed in 1077 patients, of whom 79.2% had metastatic disease (M1). Patients without metastatic disease (M0) were older (≥ 80 years M0 67.4%, M1 25.3%, P < 0.001), had a worse clinical condition (ASA III 51.4% versus 36.37%, ASA IV-V 13.3% versus 4.0% P < 0.001) and presented with higher tumour stage (cT4 55.4% versus 33.5%, % P < 0.001). DS was performed in 91.5% of the patients and SEMS in 8.5%. The proportion of DS did not significantly differ between patients with M1 and M0 (91.8% vs. 90.2% respectively, P = 0.525). No increase in SEMS application was observed over the years, with a stable overall proportion of DS of 91-92% per year. In the multivariable analyses, ninety-day mortality and overall survival were not significantly different between SEMS and DS., Conclusions: This study revealed that DS was the primary treatment modality for palliative management of LSOCC in the Netherlands between 2015 and 2019, while the guidelines recommended SEMS as preferred treatment. For patients with LSOCC eligible for stenting in the palliative setting, SEMS placement should become more available and accessible as the preferred treatment option, to avoid a stoma in the terminal phase of life., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Messenger RNA (mRNA)-based immunogene therapy holds significant promise as an emerging tumor therapy approach. However, the delivery efficiency of existing mRNA methods and their effectiveness in stimulating anti-tumor immune responses require further enhancement. Tumor cell lysates containing tumor-specific antigens and biomarkers can trigger a stronger immune response to tumors. In addition, strategies involving multiple gene therapies offer potential optimization paths for tumor gene treatments., Methods: Based on the previously developed ideal mRNA delivery system called DOTAP-mPEG-PCL (DMP), which was formed through the self-assembly of 1.2-dioleoyl-3-trimethylammonium-propane (DOTAP) and methoxypoly (ethylene glycol)-b-poly (ε-caprolactone) (mPEG-PCL), we introduced a fused cell-penetrating peptide (fCPP) into the framework and encapsulated tumor cell lysates to form a novel nanovector, termed CLSV system (CLS: CT26 tumor cell lysate, V: nanovector). This system served a dual purpose of facilitating the delivery of two mRNAs and enhancing tumor immunogene therapy through tumor cell lysates., Results: The synthesized CLSV system had an average size of 241.17 nm and a potential of 39.53 mV. The CLSV system could not only encapsulate tumor cell lysates, but also deliver two mRNAs to tumor cells simultaneously, with a transfection efficiency of up to 60%. The CLSV system effectively activated the immune system such as dendritic cells to mature and activate, leading to an anti-tumor immune response. By loading Bim-encoded mRNA and IL-23A-encoded mRNA, CLSV/Bim and CLSV/IL-23A complexes were formed, respectively, to further induce apoptosis and anti-tumor immunity. The prepared CLSV/dual-mRNA complex showed significant anti-cancer effects in multiple CT26 mouse models., Conclusion: Our results suggest that the prepared CLSV system is an ideal delivery system for dual-mRNA immunogene therapy., Competing Interests: The authors declare that they have no conflicts of interest in this work., (© 2024 Wang et al.)

Medullary Carcinoma of the Colon (MCC) is a rare histological subtype of colon cancer, and there is currently no recognized optimal treatment plan for it, with its prognosis remaining unclear. The aim of this study is to analyze the independent prognostic factors for MCC patients and develop and validate nomograms to predict overall survival (OS). A total of 760 patients newly diagnosed with MCC from 2004 to 2020 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. All patients were randomly allocated to a training group and a validation group in a 7:3 ratio. Univariate and multivariable Cox regression analyses were conducted to identify prognostic factors and construct nomograms. The nomogram prediction model was evaluated and validated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). The study found that elderly women are more susceptible to MCC, and the ascending colon and cecum are the most common sites of involvement. MCC is poorly differentiated, with stages II and III being the most common. Surgery is the primary treatment for MCC. The prognosis for patients with stage IV MCC is poor, with a median survival time of only 10 months. Independent prognostic factors for MCC include age, N stage, M stage, surgery, chemotherapy, and tumor size. Among them, age < 75 years and completion of chemotherapy were protective factors for colon medullary carcinoma, while N2 (HR = 2.18, 95%CI 1.40-3.38), M1 (HR = 3.31, 95%CI 2.01-5.46), no surgery (HR = 27.94, 95%CI 3.69-211.75), and tumor diameter > 7 cm (HR = 1.66, 95%CI 1.20-2.30) were risk factors for colon medullary carcinoma. The results of ROC, AUC, calibration curves, and DCA demonstrate that the nomogram prediction model exhibits good predictive performance. We have updated the demographic characteristics of colon medullary carcinoma and identified age, N staging, M staging, surgery, chemotherapy and tumor size as independent prognostic factors for colon medullary carcinoma. Additionally, we have established nomograms for prognostic prediction. These nomograms can provide personalized predictions and serve as valuable references for clinical decision-making., (© 2024. The Author(s).)

The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKβ independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses., (© 2024. The Author(s).)

The molecular categorization of colon cancer patients remains elusive. Gene set enrichment analysis (GSEA), which investigates the dysregulated genes among tumor and normal samples, has revealed the pivotal role of epithelial-to-mesenchymal transition (EMT) in colon cancer pathogenesis. In this study, we employed multi-clustering method for grouping data, resulting in the identification of two clusters characterized by varying prognostic outcomes. These two subgroups not only displayed disparities in overall survival (OS) but also manifested variations in clinical variables, genetic mutation, and gene expression profiles. Using the nearest template prediction (NTP) method, we were able to replicate the molecular classification effectively within the original dataset and validated it across multiple independent datasets, underscoring its robust repeatability. Furthermore, we constructed two prognostic signatures tailored to each of these subgroups. Our molecular classification, centered on EMT, hold promise in offering fresh insights into the therapy strategies and prognosis assessment for colon cancer., (© 2024. The Author(s).)

Colon adenocarcinoma (COAD), a frequently encountered and highly lethal malignancy of the digestive system, has been the focus of intensive research regarding its prognosis. The intricate immune microenvironment plays a pivotal role in the pathological progression of COAD; nevertheless, the underlying molecular mechanisms remain incompletely understood. This study aims to explore the immune gene expression patterns in COAD, construct a robust prognostic model, and delve into the molecular mechanisms and potential therapeutic targets for COAD liver metastasis, thereby providing critical support for individualized treatment strategies and prognostic evaluation. Initially, we curated a comprehensive dataset by screening 2600 immune-related genes (IRGs) from the ImmPort and InnateDB databases, successfully obtaining a rich data resource. Subsequently, the COAD patient cohort was classified using the non-negative matrix factorization (NMF) algorithm, enabling accurate categorization. Continuing on, utilizing the weighted gene co-expression network analysis (WGCNA) method, we analyzed the top 5000 genes with the smallest p-values among the differentially expressed genes (DEGs) between immune subtypes. Through this rigorous screening process, we identified the gene modules with the strongest correlation to the COAD subpopulation, and the intersection of genes in these modules with DEGs (COAD vs COAD vs Normal colon tissue) is referred to as Differentially Expressed Immune Genes Associated with COAD (DEIGRC). Employing diverse bioinformatics methodologies, we successfully developed a prognostic model (DPM) consisting of six genes derived from the DEIGRC, which was further validated across multiple independent datasets. Not only does this predictive model accurately forecast the prognosis of COAD patients, but it also provides valuable insights for formulating personalized treatment regimens. Within the constructed DPM, we observed a downregulation of CALB2 expression levels in COAD tissues, whereas NOXA1, KDF1, LARS2, GSR, and TIMP1 exhibited upregulated expression levels. These genes likely play indispensable roles in the initiation and progression of COAD and thus represent potential therapeutic targets for patient management. Furthermore, our investigation into the molecular mechanisms and therapeutic targets for COAD liver metastasis revealed associations with relevant processes such as fat digestion and absorption, cancer gene protein polysaccharides, and nitrogen metabolism. Consequently, genes including CAV1, ANXA1, CPS1, EDNRA, and GC emerge as promising candidates as therapeutic targets for COAD liver metastasis, thereby providing crucial insights for future clinical practices and drug development. In summary, this study uncovers the immune gene expression patterns in COAD, establishes a robust prognostic model, and elucidates the molecular mechanisms and potential therapeutic targets for COAD liver metastasis, thereby possessing significant theoretical and clinical implications. These findings are anticipated to offer substantial support for both the treatment and prognosis management of COAD patients.

Colon lymphoma is a rare type of gastrointestinal lymphoma and represents 0.2% to -1.2% of all primary colon cancers. This study aimed to retrospectively examine the general characteristics, treatment methods, and survival characteristics of patients with colon lymphoma who were followed-up at our center. This retrospective study included patients diagnosed with colon lymphoma who were followed up at Ankara Numune Training and Research Hospital and Ankara Bilkent City Hospital between December 2005 and June 2023. Clinicopathological features, radiological findings, treatments, and modalities of patients were obtained from their medical records. Fourteen patients with primary colon lymphoma were included in the study. Thirteen patients (92.9%) were diagnosed with diffuse large B-cell lymphoma. The median age of the patients was 55 (28-84) years. The tumor location was the terminal ileum/cecum in 50% of the patients. At the time of diagnosis, 10 patients (7 with stage 1E-2E disease, 2 with stage 3E disease, and 1 with stage 4E disease due to tumor obstruction) underwent surgery. Twelve patients received chemotherapy (6 patients as adjuvant and 6 patients as first-line treatment). The median overall survival (OS) was 10 years (0.1-21.5) years, the 5-year median OS was 71%, and the 10-year median OS was 53%. Primary colon lymphoma is a rare disease and its optimal treatment is not clearly defined. The primary treatment for primary colon lymphoma is a combination of surgery and chemotherapy. A clear consensus on the treatment can be established through prospective studies., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: A survival paradox between T4N0 (Stage IIB/IIC) and Stage IIIA colon cancer exists, even after adjusting for adequate lymph node (LN) retrieval and receipt of adjuvant chemotherapy (C). We conducted a large hospital-based study to re-evaluate this survival paradox based on the newest 8th edition staging system., Methods: The National Cancer Data Base was queried to evaluate 35,606 patients diagnosed with Stage IIB, IIC, and IIIA colon cancer between 2010 and 2017. The Kaplan-Meier method and log-rank test were used to compare unadjusted overall survival (OS). Multivariable Cox proportional hazards model was used to determine the association of stage with hazard ratios adjusted for relevant demographic and clinical variables including ≥ 12 LNs retrieved and receipt of adjuvant chemotherapy. P value < 0.05 was considered statistically significant., Results: The 5-year OS for optimally treated stage IIIA colon cancer (receipt of C) was 84.3%, which was significantly higher than stage IIB/C (≥ 12 LNs retrieved + C) (72.8%; P < 0.0001). Stage was an independent predictor of OS. Among optimally treated Stage IIIA patients, T1N1 had the best survival (90.6%) while stage T4bN0 (stage IIC) had the worst (70.9%) (P < 0.0001). Compared to stage IIB, stage IIC had a 17% increased risk of overall death while stage IIIA had a 21% reduction in death (P < 0.0001)., Conclusion: Stage IIB/C and Stage IIIA survival paradox persists even after accounting for receipt of adjuvant chemotherapy and adequate lymph node retrieval. Future iteration of the TNM system should take this paradox into consideration., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Novel strategies in intratumoral injection and emerging immunotherapies have heralded a new era of precise cancer treatments. The affinity of SARS-CoV-2 to ACE2 receptors, a feature which facilitates virulent human infection, is leveraged in this research. Colon cancer cells, with their high ACE2 expression, provide a potentially strategic target for using this SARS-CoV-2 feature. While the highly expression of ACE2 is observed in several cancer types, the idea of using the viral spike protein for targeting colon cancer cells offers a novel approach in cancer treatment. Intratumoral delivery of nucleic acid-based drugs is a promising alternative to overcoming the limitations of existing therapies. The increasing importance of nucleic acids in this realm, and the use of Lipid Nanoparticles (LNPs) for local delivery of nucleic acid therapeutics, are important breakthroughs. LNPs protect nucleic acid drugs from degradation and enhance cellular uptake, making them a rapidly evolving nano delivery system with high precision and adaptability. Our study leveraged a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) combined with a receptor-binding domain from the SARS-CoV-2 spike protein, encapsulated in LNPs, to target colon cancer cells. Our results indicated that the TRAIL fusion-mRNA induced apoptosis in vitro and in vivo. Collectively, our findings highlight LNP-encapsulated TRAIL fusion-mRNA as a potential colon cancer therapy., Competing Interests: Declaration of Competing Interest, (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: In the 1930s, the federally sponsored Home Owners' Loan Corporation (HOLC) used racial composition in its assessment of areas worthy of receiving loans. Neighborhoods with large proportions of Black residents were mapped in red (ie, redlining) and flagged as hazardous for mortgage financing. Redlining created a platform for systemic disinvestment in these neighborhoods, leading to barriers in access to resources that persist today. We investigated the association between residing in areas with different HOLC ratings and receipt of quality cancer care and outcomes among individuals diagnosed with colon cancer-a leading cause of cancer deaths amenable to early detection and treatment., Methods: Individuals who resided in zip code tabulation areas in 196 cities with HOLC rating and were diagnosed with colon cancer from 2007 to 2017 were identified from the National Cancer Database and assigned a HOLC grade (A, best; B, still desirable; C, definitely declining; and D, hazardous and mapped in red). Multivariable logistic regression models investigated association of area-level HOLC grade and late stage at diagnosis and receipt of guideline-concordant care. The product-limit method evaluated differences in time to adjuvant chemotherapy. Multivariable Cox proportional hazard models investigated differences in overall survival (OS)., Results: There were 149,917 patients newly diagnosed with colon cancer with a median age of 68 years. Compared with people living in HOLC A areas, people living in HOLC D areas were more likely to be diagnosed with late-stage disease (adjusted odds ratio, 1.06 [95% CI, 1.00 to 1.12]). In addition, people living in HOLC B, C, and D areas had 8%, 16%, and 24% higher odds of not receiving guideline-concordant care, including lower receipt of surgery, evaluation of ≥12 lymph nodes, and chemotherapy. People residing in HOLC B, C, or D areas also experienced delays in initiation of adjuvant chemotherapy after surgery. People residing in HOLC C (adjusted hazard ratio [aHR], 1.09 [95% CI, 1.05 to 1.13]) and D (aHR, 1.13 [95% CI, 1.09 to 1.18]) areas had worse OS, including 13% and 20% excess risk of death for individuals diagnosed with early- and 6% and 8% for late-stage disease for HOLC C and D, respectively., Conclusion: Historical housing discrimination is associated with worse contemporary access to colon cancer care and outcomes.

Purpose: Real-world evidence (RWE)-derived from analysis of real-world data (RWD)-has the potential to guide personalized treatment decisions. However, because of potential confounding, generating valid RWE is challenging. This study demonstrates how to responsibly generate RWE for treatment decisions. We validate our approach by demonstrating that we can uncover an existing adjuvant chemotherapy (ACT) guideline for stage II and III colon cancer (CC)-which came about using both data from randomized controlled trials and expert consensus-solely using RWD., Methods: Data from the population-based Netherlands Cancer Registry from a total of 27,056 patients with stage II and III CC who underwent curative surgery were analyzed to estimate the overall survival (OS) benefit of ACT. Focusing on 5-year OS, the benefit of ACT was estimated for each patient using G-computation methods by adjusting for patient and tumor characteristics and estimated propensity score. Subsequently, on the basis of these estimates, an ACT decision tree was constructed., Results: The constructed decision tree corresponds to the current Dutch guideline: patients with stage III or stage II with T stage 4 should receive surgery and ACT, whereas patients with stage II with T stage 3 should only receive surgery. Interestingly, we do not find sufficient RWE to conclude against ACT for stage II with T stage 4 and microsatellite instability-high (MSI-H), a recent addition to the current guideline., Conclusion: RWE, if used carefully, can provide a valuable addition to our construction of evidence on clinical decision making and therefore ultimately affect treatment guidelines. Next to validating the ACT decisions advised in the current Dutch guideline, this paper suggests additional attention should be paid to MSI-H in future iterations of the guideline.

Introduction: This article is a summary of the French intergroup guidelines regarding the management of non-metastatic colon cancer (CC), revised in November 2022., Methods: These guidelines represent collaborative work of all French medical and surgical societies involved in the management of CC. Recommendations were graded in three categories (A, B, and C) according to the level of evidence found in the literature published up to November 2022., Results: Initial evaluation of CC is based on clinical examination, colonoscopy, chest-abdomen-pelvis computed tomography (CT) scan, and carcinoembryonic antigen (CEA) assay. CC is usually managed by surgery and adjuvant treatment depending on the pathological findings. The use of adjuvant therapy remains a challenging question in stage II disease. For high-risk stage II CC, adjuvant chemotherapy must be discussed and fluoropyrimidine monotherapy or oxaliplatin-based chemotherapy proposed according to the type and number of poor prognostic features. Oxaliplatin-based chemotherapy (FOLFOX or CAPOX) is the current standard for adjuvant therapy of patients with stage III CC. However, these regimens are associated with significant oxaliplatin-induced neurotoxicity. The results of the recent IDEA study provide evidence that 3 months of treatment with CAPOX is as effective as 6 months of oxaliplatin-based therapy in patients with low-risk stage III CC (T1-3 and N1). A 6-month oxaliplatin-based therapy remains the standard of care for high-risk stage III CC (T4 and/or N2). For patients unfit for oxaliplatin, fluoropyrimidine monotherapy is recommended., Conclusion: French guidelines for non-metastatic CC management help to offer the best personalized therapeutic strategy in daily clinical practice. Each individual case must be discussed within a multidisciplinary tumor board and then the treatment option decided with the patient., Competing Interests: Conflict of interest T. Lecomte: Amgen, Merck Serono, Pierre Fabre, and Servier. D. Tougeron: Amgen, Merck Serono, Pierre Fabre, Servier, MSD, BMS, Astra Zeneca, Sanofi, and Roche. F. Bibeau: Astellas, Astra-Zeneca, BMS, Incyte, MSD, Pierre Fabre, and Sanofi. R. Cohen: MSD Oncology, Pierre Fabre, Bristol-Myers Squibb, Mylan Medical, Servier, Exeliom Biosciences, and Enterome Bioscience. T. Aparicio: MSD, Pierre Fabre, BMS, Servier, and Amgen. O. Bouché: Amgen, Apmomia Therapeutics Bayer, Grunenthal, Merck KGaA, MSD, Pierre Fabre, and Servier. The other authors have reported no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Immunotherapy based on the PD-1/PD-L1 axis blockade has no benefit for patients diagnosed with colon cancer liver metastasis (CCLM) for the microsatellite stable/proficient mismatch repair (MSS/pMMR)) subtype, which is known as an immune-desert cancer featuring poor immunogenicity and insufficient CD8 + T cell infiltration in the tumor microenvironment. Here, a multifunctional nanodrug carrying a cyclin-dependent kinase (CDK)1/2/5/9 inhibitor and PD-L1 antibody is prepared to boost the immune checkpoint blockade (ICB)-based immunotherapy against MSS/pMMR CCLM via reversing the immunosuppressive tumor microenvironment. To enhance the MSS/pMMR CCLM-targeting efficacy, we modify the nanodrug with PD-L1 knockout cell membrane of this colon cancer subtype. First, CDKs inhibitor delivered by nanodrug down-regulates phosphorylated retinoblastoma and phosphorylated RNA polymerase II and meanwhile arrests the G2/M cell cycle in CCLM to promote immunogenic signal release, stimulate dendritic cell maturation, and enhance CD8 + T cell infiltration. Moreover, CDKi suppresses the secretion of immunosuppressive cytokines in tumor-associated myeloid cells sensitizing ICB therapy in CCLM. Notably, the great efficacy to activate immune responses is demonstrated in the patient-derived xenograft model and the patient-derived organoid model as well, revealing a clinical application potential. Overall, our study represents a promising therapeutic approach for targeting liver metastasis, remolding the tumor immune microenvironment (TIME), and enhancing the response of MSS/pMMR CCLM to boost ICB immunotherapy., Competing Interests: Declaration of competing interest The authors declare that there are no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: In recent years, immunotherapy has been emerging as a promising alternative therapeutic method for cancer patients, offering potential benefits. The expression of PD-L1 by tumors can inhibit the T-cell response to the tumor and allow the tumor to evade immune surveillance. To address this issue, cancer immunotherapy has shown promise in disrupting the interaction between PD-L1 and its ligand PD-1., Methods: We used mirror-image phage display technology in our experiment to screen and determine PD-L1 specific affinity peptides (PPL-C). Using CT26 cells, we established a transplanted mouse tumor model to evaluate the inhibitory effects of PPL-C on tumor growth in vivo. We also demonstrated that PPL-C inhibited the differentiation of T regulatory cells (Tregs) and regulated the production of cytokines., Results: In vitro, PPL-C has a strong affinity for PD-L1, with a binding rate of 0.75 μM. An activation assay using T cells and mixed lymphocytes demonstrated that PPL-C inhibits the interaction between PD-1 and PD-L1. PPL-C or an anti-PD-L1 antibody significantly reduced the rate of tumor mass development in mice compared to those given a control peptide (78% versus 77%, respectively). The results of this study demonstrate that PPL-C prevents or retards tumor growth. Further, immunotherapy with PPL-C enhances lymphocyte cytotoxicity and promotes proliferation in CT26-bearing mice., Conclusion: PPL-C exhibited antitumor and immunoregulatory properties in the colon cancer. Therefore, PPL-C peptides of low molecular weight could serve as effective cancer immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liang, Luo, Li, Liu, Habib, Liu, Huang, Wang, Yi, Hu, Zheng, Xie and Zhu.)

The elevated level of hydrogen sulfide (H 2 S) in colon cancer hinders complete cure with a single therapy. However, excessive H 2 S also offers a treatment target. A multifunctional cascade bioreactor based on the H 2 S-responsive mesoporous Cu 2 Cl(OH) 3 -loaded hypoxic prodrug tirapazamine (TPZ), in which the outer layer was coated with hyaluronic acid (HA) to form TPZ@Cu 2 Cl(OH) 3 -HA (TCuH) nanoparticles (NPs), demonstrated a synergistic antitumor effect through combining the H 2 S-driven cuproptosis and mild photothermal therapy. The HA coating endowed the NPs with targeting delivery to enhance drug accumulation in the tumor tissue. The presence of both the high level of H 2 S and the near-infrared II (NIR II) irradiation achieved the in situ generation of photothermic agent copper sulfide (Cu 9 S 8 ) from the TCuH, followed with the release of TPZ. The depletion of H 2 S stimulated consumption of oxygen, resulting in hypoxic state and mitochondrial reprogramming. The hypoxic state activated prodrug TPZ to activated TPZ (TPZ-ed) for chemotherapy in turn. Furthermore, the exacerbated hypoxia inhibited the synthesis of adenosine triphosphate, decreasing expression of heat shock proteins and subsequently improving the photothermal therapy. The enriched Cu 2+ induced not only cuproptosis by promoting lipoacylated dihydrolipoamide S-acetyltransferase (DLAT) heteromerization but also performed chemodynamic therapy though catalyzing H 2 O 2 to produce highly toxic hydroxyl radicals ·OH. Therefore, the nanoparticles TCuH offer a versatile platform to exert copper-related synergistic antitumor therapy., (© 2024. The Author(s).)

Background: Hypofractionated radiotherapy (hRT) can induce a T cell-mediated abscopal effect on non-irradiated tumor lesions, especially in combination with immune checkpoint blockade (ICB). However, clinically, this effect is still rare, and ICB-mediated adverse events are common. Lenalidomide (lena) is an anti-angiogenic and immunomodulatory drug used in the treatment of hematologic malignancies. We here investigated in solid tumor models whether lena can enhance the abscopal effect in double combination with hRT. Methods: In two syngeneic bilateral tumor models (B16-CD133 melanoma and MC38 colon carcinoma), the primary tumor was treated with hRT. Lena was given daily for 3 weeks. Besides tumor size and survival, the dependence of the antitumor effects on CD8 + cells, type-I IFN signaling, and T cell costimulation was determined with depleting or blocking antibodies. Tumor-specific CD8 + T cells were quantified, and their differentiation and effector status were characterized by multicolor flow cytometry using MHC-I tetramers and various antibodies. In addition, dendritic cell (DC)-mediated tumor antigen cross-presentation in vitro and directly ex vivo and the composition of tumor-associated vascular endothelial cells were investigated. Results: In both tumor models, the hRT/lena double combination induced a significant abscopal effect. Control of the non-irradiated secondary tumor and survival were considerably better than with the respective monotherapies. The abscopal effect was strongly dependent on CD8 + cells and associated with an increase in tumor-specific CD8 + T cells in the non-irradiated tumor and its draining lymph nodes. Additionally, we found more tumor-specific T cells with a stem-like (TCF1 + TIM3 - PD1 + ) and a transitory (TCF1 - TIM3 + CD101 - PD1 + ) exhausted phenotype and more expressing effector molecules such as GzmB, IFNγ, and TNFα. Moreover, in the non-irradiated tumor, hRT/lena treatment also increased DCs cross-presenting a tumor model antigen. Blocking type-I IFN signaling, which is essential for cross-presentation, completely abrogated the abscopal effect. A gene expression analysis of bone marrow-derived DCs revealed that lena augmented the expression of IFN response genes and genes associated with differentiation, maturation (including CD70, CD83, and CD86), migration to lymph nodes, and T cell activation. Flow cytometry confirmed an increase in CD70 + CD83 + CD86 + DCs in both irradiated and abscopal tumors. Moreover, the hRT/lena-induced abscopal effect was diminished when these costimulatory molecules were blocked simultaneously using antibodies. In line with the enhanced infiltration by DCs and tumor-specific CD8 + T cells, including more stem-like cells, hRT/lena also increased tumor-associated high endothelial cells (TA-HECs) in the non-irradiated tumor. Conclusions: We demonstrate that lena can augment the hRT-induced abscopal effect in mouse solid tumor models in a CD8 T cell- and IFN-I-dependent manner, correlating with enhanced anti-tumor CD8 T cell immunity, DC cross-presentation, and TA-HEC numbers. Our findings may be helpful for the planning of clinical trials in (oligo)metastatic patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: Spouses are often the front-line caregivers for colon cancer patients. Providing this support requires a particular set of coping skills. Our objective was to identify key skills that healthcare and medico-social sector professionals could assess in routine practice that would allow them to propose appropriate support to spouses who are accompanying colon cancer patients in their care pathway., Methods: An online two-round Delphi study was conducted among French colon cancer patients, spouses and professionals. The content of the Delphi study was developed from a previously published qualitative study., Results: In the first round of the study, 63% of the participants were professionals (n = 40), 19% spouses (n = 12) and 17% patients (n = 11). In the second round, they were respectively 55% (n = 22), 22% (n = 9) and 22% (n = 9). Twenty-seven of the 75 proposed skills were consensually identified as key skills. Nine were related to emotional and psychological well-being, six to social relations, four to organisation, five to health and three to domestic domains. The three most consensual skills (≥ 90% agreement) for spouses were (1) helping the tired patient in everyday life, (2) stimulating the patient to prevent him/her from giving up and (3) limiting one's amount of personal time to care for the patient., Conclusion: The study identified the key skills needed by spouses of patients being treated for colon cancer. Better awareness of these skills among professionals would enable them to offer tailored support to help patients and spouses maintain their physical and emotional well-being., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Colon cancer (CC) is a public health concern with increasing incidence in younger populations. Treatment for locally advanced CC (LACC) involves oncological surgery and adjuvant chemotherapy (AC) to reduce recurrence and improve overall survival (OS). Neoadjuvant chemotherapy (NAC) is a novel approach for the treatment of LACC, and research is underway to explore its potential benefit in terms of survival. This trial will assess the efficacy of NAC in LACC., Methods: This is a multicentre randomised, parallel-group, open label controlled clinical trial. Participants will be selected based on homogenous inclusion criteria and randomly assigned to two treatment groups: NAC, surgery, and AC or surgery followed by AC. The primary aim of this study is to evaluate the 2-year progression-free survival (PFS), with secondary outcomes including 5-year PFS, 2- and 5-year OS, toxicity, radiological and pathological response, morbidity, and mortality., Discussion: The results of this study will determine whether NAC induces a clinical and histological tumour response in patients with CCLA and if this treatment sequence improves survival without increasing morbidity and mortality., Registration Number: NCT04188158., (© 2024 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

The integrated landscape of ferroptosis regulatory patterns and their association with colon microenvironment have been demonstrated in recent studies. However, the ferroptosis-related immunotherapeutic signature for colon cancer (CC) remains unclear. We comprehensively evaluated 1623 CC samples, identified patterns of ferroptosis modification based on ferroptosis-associated genes, and systematically correlated these patterns with tumor microenvironment (TME) cell infiltration characteristics. In addition, the ferroptosis-regulated gene score (FRG-score) was constructed to quantify the pattern of ferroptosis alterations in individual tumors. Three distinct patterns of ferroptosis modification were identified, including antioxidant defense, iron toxicity, and lipid peroxidation. The characteristics of TME cell infiltration under these three patterns were highly consistent with the three immune phenotypes of tumors, including immune-inflamed, immune-excluded and immune-desert phenotypes. We also demonstrated that evaluation of ferroptosis regulatory patterns within individual tumors can predict tumor inflammatory status, tumor subtype, TME stromal activity, genetic variation, and clinical outcome. Immunotherapy cohorts confirmed that patients with low FRG-scores showed remarkable therapeutic and clinical benefits. Furthermore, the hub gene apolipoprotein L6 (APOL6), a drug-sensitive target associated with cancer cell ferroptosis, was identified through our proposed novel key gene screening process and validated in CC cell lines and scRNA-seq., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Colon cancer is one of the most common digestive tract malignancies. Although immunotherapy has brought new hope to colon cancer patients, there is still a large proportion of patients who do not benefit from immunotherapy. Studies have shown that neutrophils can interact with immune cells and immune factors to affect the prognosis of patients., Methods: We first determined the infiltration level of neutrophils in tumors using the CIBERSORT algorithm and identified key genes in the final risk model by Spearman correlation analysis and subsequent Cox analysis. The risk score of each patient was obtained by multiplying the Cox regression coefficient and the gene expression level, and patients were divided into two groups based on the median of risk score. Differences in overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier survival analysis, and model accuracy was validated in independent dataset. Differences in immune infiltration and immunotherapy were evaluated by immunoassay. Finally, immunohistochemistry and western blotting were performed to verify the expression of the three genes in the colon normal and tumor tissues., Results: We established and validated a risk scoring model based on neutrophil-related genes in two independent datasets, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, with SLC11A1 and SLC2A3 as risk factors and MMP3 as a protective factor. A new nomogram was constructed and validated by combining clinical characteristics and the risk score model to better predict patients OS and PFS. Immune analysis showed that patients in the high-risk group had immune cell infiltration level, immune checkpoint level and tumor mutational burden, and were more likely to benefit from immunotherapy., Conclusions: The low-risk group showed better OS and PFS than the high-risk group in the neutrophil-related gene-based risk model. Patients in the high-risk group presented higher immune infiltration levels and tumor mutational burden and thus may be more responsive to immunotherapy., (© 2024 John Wiley & Sons, Ltd.)

Background: The TNM (tumor-node-metastasis) Evaluation Committee of Union for International Cancer Control (UICC) and College of American Pathologists (CAP) recommended to prospectively validate the cost-effective and robust tumor-stroma ratio (TSR) as an independent prognostic parameter, since high intratumor stromal percentages have previously predicted poor patient-related outcomes., Patients and Methods: The 'Uniform Noting for International application of Tumor-stroma ratio as Easy Diagnostic tool' (UNITED) study enrolled patients in 27 participating centers in 12 countries worldwide. The TSR, categorized as stroma-high (>50%) or stroma-low (≤50%), was scored through standardized microscopic assessment by certified pathologists, and effect on disease-free survival (DFS) was evaluated with 3-year median follow-up. Secondary endpoints were benefit assessment of adjuvant chemotherapy (ACT) and overall survival (OS)., Results: A total of 1537 patients were included, with 1388 eligible stage II/III patients curatively operated between 2015 and 2021. DFS was significantly shorter in stroma-high (n = 428) than in stroma-low patients (n = 960) (3-year rates 70% versus 83%; P < 0.001). In multivariate analysis, TSR remained an independent prognosticator for DFS (P < 0.001, hazard ratio 1.49, 95% confidence interval 1.17-1.90). As secondary outcome, DFS was also worse in stage II and III stroma-high patients despite adjuvant treatment (3-year rates stage II 73% versus 92% and stage III 66% versus 80%; P = 0.008 and P = 0.011, respectively). In stage II patients not receiving ACT (n = 322), the TSR outperformed the American Society of Clinical Oncology (ASCO) criteria in identifying patients at risk of events (event rate 21% versus 9%), with a higher discriminatory 3-year DFS rate (stroma-high 80% versus ASCO high risk 91%). A trend toward worse 5-year OS in stroma-high was noticeable (74% versus 83% stroma-low; P = 0.102)., Conclusion: The multicenter UNITED study unequivocally validates the TSR as an independent prognosticator, confirming worse outcomes in stroma-high patients. The TSR improved current selection criteria for patients at risk of events, and stroma-high patients potentially experienced chemotherapy resistance. TSR implementation in pathology diagnostics and international guidelines is highly recommended as aid in personalized treatment., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Neoantigen nanovaccine has been recognized as a promising treatment modality for personalized cancer immunotherapy. However, most current nanovaccines are carrier-dependent and the manufacturing process is complicated, resulting in potential safety concerns and suboptimal codelivery of neoantigens and adjuvants to antigen-presenting cells (APCs). Methods: Here we report a facile and general methodology for nanoassembly of peptide and oligonucleotide by programming neoantigen peptide with a short cationic module at N-terminus to prepare nanovaccine. The programmed peptide can co-assemble with CpG oligonucleotide (TLR9 agonist) into monodispersed nanostructures without the introduction of artificial carrier. Results: We demonstrate that the engineered nanovaccine promoted the codelivery of neoantigen peptides and adjuvants to lymph node-residing APCs and instigated potent neoantigen-specific T-cell responses, eliciting neoantigen-specific antitumor immune responses with negligible systemic toxicity. Furthermore, the antitumor T-cell immunity is profoundly potentiated when combined with anti-PD-1 therapy, leading to significant inhibition or even complete regression of established melanoma and MC-38 colon tumors. Conclusions: Collectively, this work demonstrates the feasibility and effectiveness of personalized cancer nanovaccine preparation with high immunogenicity and good biosafety by programming neoantigen peptide for nanoassembly with oligonucleotides without the aid of artificial carrier., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)