The Impact of the Gut Microbiome, Environment, and Diet in Early-Onset Colorectal Cancer Development.

Traditionally considered a disease common in the older population, colorectal cancer is increasing in incidence among younger demographics. Evidence suggests that populational- and generational-level shifts in the composition of the human gut microbiome may be tied to the recent trends in gastrointestinal carcinogenesis. This review provides an overview of current research and putative mechanisms behind the rising incidence of colorectal cancer in the younger population, with insight into future interventions that may prevent or reverse the rate of early-onset colorectal carcinoma.

Trends and Determinants of Location of Death Due to Colorectal Cancer in the United States : A Nationwide Study.

BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States (US); however, there are limited data on location of death in patients who die from CRC. We examined the trends in location of death and determinants in patients dying from CRC in the US. METHODS: We utilized the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database to extract nationwide data on underlying cause of death as CRC. A multinomial logistic regression was performed to assess associations between clinico-sociodemographic characteristics and location of death. RESULTS: There were 850,750 deaths due to CRC from 2003 to 2019. There was a gradual decrease in deaths in hospital, nursing home, or outpatient facility/emergency department over time and an increase in deaths at home and in hospice. Relative to White decedents, Black, Asian, and American Indian/Alaska Native decedents were less likely to die at home and in hospice compared with hospitals. Individuals with lower educational status also had a lower risk of dying at home or in hospice compared with in hospitals. CONCLUSIONS: The gradual shift in location of death of patients who die of CRC from institutionalized settings to home and hospice is a promising trend and reflects the prioritization of patient goals for end-of-life care by healthcare providers. However, there are existing sociodemographic disparities in access to deaths at home and in hospice, which emphasizes the need for policy interventions to reduce health inequity in end-of-life care for CRC.

Immune Microenvironment in Sporadic Early-Onset versus Average-Onset Colorectal Cancer.

The incidence of left-sided colon and rectal cancer in young people are increasing worldwide, but its causes are poorly understood. It is not clear if the tumor microenvironment is dependent on age of onset, and little is known about the composition of tumor-infiltrating T cells in early-onset colorectal cancer (EOCRC). To address this, we investigated T-cell subsets and performed gene expression immune profiling in sporadic EOCRC tumors and matched average-onset colorectal cancer (AOCRC) tumors. Left-sided colon and rectal tumors from 40 cases were analyzed; 20 EOCRC (<45 years) patients were matched 1:1 to AOCRC (70-75 years) patients by gender, tumor location, and stage. Cases with germline pathogenic variants, inflammatory bowel disease or neoadjuvant-treated tumors were excluded. For T cells in tumors and stroma, a multiplex immunofluorescence assay combined with digital image analysis and machine learning algorithms was used. Immunological mediators in the tumor microenvironment were assessed by NanoString gene expression profiling of mRNA. Immunofluorescence revealed no significant difference between EOCRC and AOCRC with regard to infiltration of total T cells, conventional CD4+ and CD8+ T cells, regulatory T cells, or γδ T cells. Most T cells were located in the stroma in both EOCRC and AOCRC. Immune profiling by gene expression revealed higher expression in AOCRC of the immunoregulatory cytokine IL-10, the inhibitory NK cell receptors KIR3DL3 and KLRB1 (CD161), and IFN-a7 (IFNA7). In contrast, the interferon-induced gene IFIT2 was more highly expressed in EOCRC. However, in a global analysis of 770 tumor immunity genes, no significant differences could be detected. T-cell infiltration and expression of inflammatory mediators are similar in EOCRC and AOCRC. This may indicate that the immune response to cancer in left colon and rectum is not related to age of onset and that EOCRC is likely not driven by immune response deficiency.

Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) Versus the Standard of Care Imaging in the Diagnosis of Peritoneal Carcinomatosis.

OBJECTIVE: To compare positron emission tomography (PET)/magnetic resonance imaging (MRI) to the standard of care imaging (SCI) for the diagnosis of peritoneal carcinomatosis (PC) in primary abdominopelvic malignancies. SUMMARY BACKGROUND DATA: Identifying PC impacts prognosis and management of multiple cancer types. METHODS: Adult subjects were prospectively and consecutively enrolled from April 2019 to January 2021. Inclusion criteria were: 1) acquisition of whole-body contrast-enhanced (CE) 18F-fluorodeoxyglucose PET/MRI, 2) pathologically confirmed primary abdominopelvic malignancies. Exclusion criteria were: 1) greater than 4 weeks interval between SCI and PET/MRI, 2) unavailable follow-up. SCI consisted of whole-body CE PET/computed tomography (CT) with diagnostic quality CT, and/or CE-CT of the abdomen and pelvis, and/or CE-MRI of the abdomen±pelvis. If available, pathology or surgical findings served as the reference standard, otherwise, imaging followup was used. When SCI and PET/MRI results disagreed, medical records were checked for management changes. Follow-up data were collected until August 2021. RESULTS: One hundred sixty-four subjects were included, 85 (52%) were female, and the median age was 60 years (interquartile range 50-69). At a subject level, PET/MRI had higher sensitivity (0.97, 95% CI 0.86-1.00) than SCI (0.54, 95% CI 0.37-0.71), P < 0.001, without a difference in specificity, of 0.95 (95% CI 0.90-0.98) for PET/MRI and 0.98 (95% CI 0.93-1.00) for SCI, P » 0.250. PET/MRI and SCI results disagreed in 19 cases. In 5/19 (26%) of the discordant cases, PET/MRI findings consistent with PC missed on SCI led to management changes. CONCLUSION: PET/MRI improves detection of PC compared with SCI which frequently changes management.

Molecular Basis of Extramural Vascular Invasion (EMVI) in Colorectal Carcinoma.

BACKGROUND: Extramural vascular invasion (EMVI) is a known poor prognostic factor in colorectal carcinoma; however, its molecular basis has not been defined. This study aimed to assess the expression of molecular markers in EMVI positive colorectal carcinoma to understand their tumor microenvironment. METHODS: Immunohistochemistry was performed on tissue microarrays of surgically resected colorectal cancer specimens for immunological markers, and BRAFV600E mutation (and on the tissue blocks for mismatch repair proteins). Automated quantification was used for CD8, LAG3, FOXP3, PU1, and CD163, and manual quantification was used for PDL1, HLA I markers (beta-2 microglobulin, HC10), and HLA II. The Wilcoxon rank-sum test was used to compare EMVI positive and negative tumors. A logistic regression model was fitted to assess the predictive effect of biomarkers on EMVI. RESULTS: There were 340 EMVI positive and 678 EMVI negative chemo naïve tumors. PDL1 was barely expressed on tumor cells (median 0) in the entire cohort. We found a significantly lower expression of CD8, LAG3, FOXP3, PU1 cells, PDL1 positive macrophages, and beta-2 microglobulin on tumor cells in the EMVI positive subset (p ≤ 0.001). There was no association of BRAFV600E or deficient mismatch repair proteins (dMMR) with EMVI. PU1 (OR 0.8, 0.7-0.9) and low PDL1 (OR 1.6, 1.1-2.3) independently predicted EMVI on multivariate logistic regression among all biomarkers examined. CONCLUSION: There is a generalized blunting of immune response in EMVI positive colorectal carcinoma, which may contribute to a worse prognosis. Tumor-associated macrophages seem to play the most significant role in determining EMVI.

Patient Survival With ypT0N+ Following Neoadjuvant Therapy in Rectal Cancer.

BACKGROUND: After neoadjuvant therapy, pathologic analysis of rectal cancer resected specimens may show a complete response in the primary tissue cancer with residual tumor in the lymph nodes (ypT0N+). OBJECTIVES: The aim of this study was to describe the 5-year overall survival and factors associated with survival of ypT0N+ patients with rectal cancer who had neoadjuvant therapy followed by surgery and to compare these patients' survival with patients in other pathologic categories. DESIGN: We conducted a retrospective analysis. SETTINGS: We used the National Cancer Database. PATIENTS: We identified patients with rectal adenocarcinoma who underwent total neoadjuvant therapy or neoadjuvant chemoradiation followed by surgery between 2006 and 2016. Besides ypT0N+, 5 pathologic categories were identified: ypT0N0, ypT1-2N0, ypT3-4N0, ypT1-2N+, and ypT3-4N+. MAIN OUTCOME MEASURE: The primary outcome measure was 5-year overall survival. RESULTS: We included 30,751 patients with rectal adenocarcinoma. A total of 342 patients developed ypT0N+, of whom 181 (52.9%) received total neoadjuvant therapy. Among patients who received total neoadjuvant therapy, developing ypT0N+ was associated with a lower 5-year overall survival than ypT0N0 and ypT1-2N0. However, ypT0N+ disease was associated with a higher 5-year overall survival than ypT3-4N+. There were no differences in 5-year overall survival between ypT0N+ and ypT3-4N0 or ypT1-2N+. Similar findings were noticed among patients who received neoadjuvant chemoradiation and adjuvant chemotherapy. For patients with ypT0N+, older age, male gender, and higher number of positive lymph nodes were all associated with a decrease in the overall survival. LIMITATIONS: Limitations include the retrospective nature of this study, lack of variables describing the chemotherapy and radiation regimens used, and paucity of data on disease-specific survival or recurrence. CONCLUSIONS: Developing ypT0N+ was associated with a lower 5-year overall survival than ypT0N0 and ypT1-2N0. However, it was associated with a higher 5-year overall survival than ypT3-4N+. See Video Abstract at http://links.lww.com/DCR/B863 . SOBREVIDA DE LOS PACIENTES CON YPTN DESPUS DE LA TERAPIA NEOADYUVANTE EN EL CNCER DE RECTO: ANTECEDENTES:Después del tratamiento neoadyuvante en el cáncer de recto bajo, el análisis patológico de la pieza operatoria resecada, puede mostrar una respuesta patológica completa del tumor primario pero con tumor residual en los ganglios linfáticos (ypT0N+).OBJETIVOS:Describir la sobrevida general a 5 años y los factores asociados con la sobrevida de los pacientes ypT0N+ con cáncer de recto, que recibieron terapia neoadyuvante seguida de cirugía y comparar la sobrevida de estos pacientes con la de pacientes con otros estadios patológicos.DISEÑO:Realizamos un análisis retrospectivo.AJUSTES:Utilizamos la base de datos nacional del cáncer.PACIENTES:Identificamos pacientes con adenocarcinoma de recto que se sometieron a terapia neoadyuvante total, seguida de cirugía entre 2006 y 2016. Además de ypT0N +, se identificaron 5 categorías patológicas: ypT0N0, ypT1-2N0, ypT3-4N0, ypT1-2N+, e ypT3-4N+.PRINCIPAL MEDIDA DE RESULTADO:La medida de resultado principal fue la supervivencia general a 5 años.RESULTADOS:Se incluyeron 30.751 pacientes con adenocarcinoma de recto. Un total de 342 pacientes desarrollaron ypT0N+, de los cuales 181 (52,9%) recibieron terapia neoadyuvante total. Entre los pacientes que recibieron terapia neoadyuvante total, el desarrollo de ypT0N+ se asoció con una supervivencia general a 5 años más baja que ypT0N0 e ypT1-2N0. Sin embargo, la enfermedad ypT0N+ se asoció con una supervivencia general a 5 años más alta que ypT3-4N+. No hubo diferencias en la supervivencia global a 5 años entre ypT0N+ y ypT3-4N0 o ypT1-2N+. Se observaron hallazgos similares entre los pacientes que recibieron terapia neoadyuvante y quimioterapia adyuvante. Para los pacientes con ypT0N+, la edad avanzada, el sexo masculino y un mayor número de ganglios linfáticos positivos se asociaron con una disminución en la supervivencia general.LIMITACIONES:Las limitaciones incluyen la naturaleza retrospectiva del estudio, la falta de variables que describan los regímenes de quimioterapia y radiación utilizados y la escasez de datos sobre la supervivencia o la recurrencia específicas de la enfermedad.CONCLUSIONES:El desarrollo de ypT0N+ se asoció con una supervivencia general a 5 años más baja que ypT0N0 e ypT1-2N0. Sin embargo, se asoció con una supervivencia global a 5 años más alta que ypT3-4N+. Consulte Video Resumen en http://links.lww.com/DCR/B863 . (Traducción-Dr. Rodrigo Azolas ).