Significance: Clostridioides difficile is the most common cause of hospital-acquired diarrhea. It is responsible for more than half of all hospital enteric infections and >90% of mortalities resulting from these infections. Gut damage sustained during C. difficile infection is devastating, inducing epithelial damage deep into the gut tissue, to regions where stem cells responsible for tissue repair reside. Our work has shown that toxin-mediated damage during severe murine C. difficile infection alters the colonic epithelial protective barrier, which promotes colonic stem cell dysfunction, exacerbating disease and perturbing the repair capacity of the host. Furthermore, we have shown that this damage induces a chronically dysfunctional stem cell state, which prevents homeostatic cellular repair, possibly increasing susceptibility to subsequent infections or disease recurrence.

Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide and is heterogeneous both morphologically and molecularly. In an era of personalized medicine, the greatest challenge is to predict individual response to therapy and distinguish patients likely to be cured with surgical resection of tumors and systemic therapy from those resistant or non-responsive to treatment. Patients would avoid futile treatments, including clinical trial regimes and ultimately this would prevent under- and over-treatment and reduce unnecessary adverse side effects. In this review, the potential of specific biomarkers will be explored to address two key questions—1) Can the prognosis of patients that will fare well or poorly be determined beyond currently recognized prognostic indicators? and 2) Can an individual patient’s response to therapy be predicted and those who will most likely benefit from treatment/s be identified? Identifying and validating key prognostic and predictive biomarkers and an understanding of the underlying mechanisms of drug resistance and toxicity in CRC are important steps in order to personalize treatment. This review addresses recent data on biological prognostic and predictive biomarkers in CRC. In addition, patient cohorts most likely to benefit from currently available systemic treatments and/or targeted therapies are discussed in this review.

Colorectal cancer stem cells have been proposed to drive disease progression, tumour recurrence and chemoresistance. However, studies ablating leucine rich repeat containing G protein-coupled receptor 5 (LGR5)-positive stem cells have shown that they are rapidly replenished in primary tumours. Following injury in normal tissue, LGR5+ stem cells are replaced by a newly defined, transient population of revival stem cells. We investigated whether markers of the revival stem cell population are present in colorectal tumours and how this signature relates to chemoresistance. We examined the expression of different stem cell markers in a cohort of patient-derived colorectal cancer organoids and correlated expression with sensitivity to 5-fluorouracil (5-FU) treatment. Our findings revealed that there was inter-tumour variability in the expression of stem cell markers. Clusterin (CLU), a marker of the revival stem cell population, was significantly enriched following 5-FU treatment and expression correlated with the level of drug resistance. Patient outcome data revealed that CLU expression is associated with both lower patient survival and an increase in disease recurrence. This suggests that CLU is a marker of drug resistance and may identify cells that drive colorectal cancer progression.

Background and Aim: Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. To improve outcomes for these patients, we need to develop new treatment strategies. Personalized cancer medicine, where patients are treated based on the characteristics of their own tumor, has gained significant interest for its promise to improve outcomes and reduce unnecessary side effects. The purpose of this study was to examine the potential utility of patient‐derived colorectal cancer organoids (PDCOs) in a personalized cancer medicine setting.Methods: Patient‐derived colorectal cancer organoids were derived from tissue obtained from treatment‐naïve patients undergoing surgical resection for the treatment of CRC. We examined the recapitulation of key histopathological, molecular, and phenotypic characteristics of the primary tumor.Results: We created a bio‐resource of PDCOs from primary and metastatic CRCs. Key histopathological features were retained in PDCOs when compared with the primary tumor. Additionally, a cohort of 12 PDCOs, and their corresponding primary tumors and normal sample, were characterized through whole exome sequencing and somatic variant calling. These PDCOs exhibited a high level of concordance in key driver mutations when compared with the primary tumor.Conclusions: Patient‐derived colorectal cancer organoids recapitulate characteristics of the tissue from which they are derived and are a powerful tool for cancer research. Further research will determine their utility for predicting patient outcomes in a personalized cancer medicine setting.

BACKGROUND: Anastomotic leak after restorative surgery for rectal cancer is a major complication and may lead to worse long-term oncological and survival outcomes. OBJECTIVE: The purpose of this study was to identify risk factors associated with anastomotic leak and to assess the perioperative and long-term oncological impact of anastomotic leak in our cohort of patients with rectal cancer. DESIGN: A retrospective analysis was performed on data from the prospectively maintained Cabrini Monash colorectal neoplasia database. Patients who had undergone rectal cancer resection and subsequently received anastomosis between November 2009 and May 2020 were included in this study. Patient and tumor characteristics, technical risk factors, and short-term and perioperative as well as long-term oncological and survival outcomes were assessed. SETTINGS: The study was conducted in 3 tertiary hospitals. PATIENTS: A total of 693 patients met the inclusion criteria for this study. MAIN OUTCOME MEASURES: Univariate analyses were performed to assess the relationship between anastomotic leak and patient and technical risk factors, as well as perioperative and long-term outcomes. Univariate and multivariate proportional HR models of overall and disease-free survival were calculated. Kaplan-Meier survival analyses assessed disease-free and overall survival. RESULTS: Anastomotic leak rate was 3.75%. Males had an increased risk of anastomotic leak, as did patients with hypertension and ischemic heart disease. Patients who experience an anastomotic leak were more likely to require reoperation and hospital readmission and were more likely to experience an inpatient death. Disease-free and overall survival were also negatively impacted by anastomotic leaks. LIMITATIONS: This is a retrospective analysis of data from only 3 centers with the usual limitations. However, these effects have been minimized because of the high quality and completeness of the prospective data collection. CONCLUSIONS: Anastomotic leaks after restorative surgery negatively affect long-term oncological and survival outcomes for patients with rectal cancer. See Video Abstract at http://links.lww.com/DCR/C81. IMPACTO DE LA FUGA ANASTOMÓTICA EN LOS RESULTADOS ONCOLÓGICOS A LARGO PLAZO TRAS CIRUGÍA RESTAURADORA PARA EL CÁNCER DE RECTO: UN ESTUDIO DE COHORTE RETROSPECTIVO: ANTECEDENTES: La fuga anastomótica tras una cirugía restauradora para el cáncer de recto es una complicación mayor y puede conducir a peores resultados oncológicos y de supervivencia a largo plazo. OBJETIVO: El propósito de este estudio fue identificar los factores de riesgo asociados con la fuga anastomótica y evaluar el impacto oncológico perioperatorio y a largo plazo de la fuga anastomótica en nuestra cohorte de pacientes con cáncer de recto. DISEÑO: Se realizó un análisis retrospectivo de datos obtenidos de la base de datos Cabrini Monash sobre neoplasia colorrectal la cual es mantenida prospectivamente. Se incluyeron en este estudio pacientes que fueron sometidos a una resección del cáncer de recto y que posteriormente recibieron una anastomosis entre noviembre de 2009 y mayo de 2020. Se evaluaron las características del paciente y del tumor, los factores de riesgo relacionados a la técnica, los resultados oncológicos y de supervivencia perioperatorio, así como los resultados a corto y largo plazo. AJUSTES: El estudio se realizó en tres hospitales terciarios. PACIENTES: Un total de 693 pacientes cumplieron con los criterios de inclusión para este estudio. PRINCIPALES MEDIDAS DE RESULTADO: Se realizaron análisis univariados para evaluar la relación entre la fuga anastomótica y aquellos factores relacionados al paciente, a la técnica, así como los resultados perioperatorios y a largo plazo. Se calcularon modelos de razón de riesgo proporcional univariante y multivariante de supervivencia global y libre de enfermedad. Los análisis de supervivencia de Kaplan-Meier evaluaron la supervivencia libre de enfermedad y la supervivencia global. RESULTADOS: La tasa de fuga anastomótica fue del 3,75%. Los hombres tenían un mayor riesgo de fuga anastomótica al igual que aquellos pacientes con hipertensión y cardiopatía isquémica. Los pacientes que sufrieron una fuga anastomótica tuvieron mayores probabilidades de requerir una reintervención y reingreso hospitalario, así como también tuvieron mayores probabilidades de sufrir una muerte hospitalaria. La supervivencia libre de enfermedad y general también se vio afectada negativamente por las fugas anastomóticas. LIMITACIONES: Este es un análisis retrospectivo de datos de solo tres centros con las limitaciones habituales. Sin embargo, estos efectos han sido minimizados debido a la alta calidad y la exhaustividad de la recopilación prospectiva de datos. CONCLUSIONES: Las fugas anastomóticas después de una cirugía restauradora afectan negativamente los resultados oncológicos y de supervivencia a largo plazo para los pacientes con cáncer de recto. Consulte Video Resumen en http://links.lww.com/DCR/C81. (Traducción—Dr. Osvaldo Gauto)