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BackgroundIncisional hernia (IH) is a known complication after colorectal surgery. Despite advances in minimally invasive surgery, colorectal surgery still requires extraction sites for specimen retrieval, increasing the likelihood of postoperative IH development. The objective of this study is to determine the effect of specimen extraction site on the rate of IH after minimally invasive right-sided colectomy for patients with available imaging.Study designThis is a retrospective multi-institutional cohort study at 2 large academic medical centers in the US. Adults who underwent right-sided minimally invasive colectomy from 2012 to 2020 with abdominal imaging available at least 1 year postoperatively were included in the analysis. The primary exposure was specimen extraction via a midline specimen extraction vs Pfannenstiel specimen extraction. The main outcome was the development of IH at least 1 year postoperatively as visualized on a CT scan.ResultsOf the 341 patients sampled, 194 (57%) had midline specimen extraction and 147 (43%) had a Pfannenstiel specimen extraction. Midline extraction patients were older (66 ± 15 vs 58 ± 16; p < 0.001) and had a higher rate of previous abdominal operation (99, 51% vs 55, 37%, p = 0.01). The rate of IH was higher in midline extraction at 25% (48) compared with Pfannenstiel extraction (0, 0%; p < 0.001). The average length of stay was higher in the midline extraction group at 5.1 ± 2.5 compared with 3.4 ± 3.1 days in the Pfannenstiel extraction group (p < 0.001). Midline extraction was associated with IH development (odds ratio 24.6; 95% CI 1.89 to 319.44; p = 0.004). Extracorporeal anastomosis was associated with a higher IH rate (odds ratio 25.8; 95% CI 2.10 to 325.71; p = 0.002).ConclusionsPatients who undergo Pfannenstiel specimen extraction have a lower risk of IH development compared with those who undergo midline specimen extraction.

BackgroundThe Affordable Care Act expanded Medicaid coverage for people with low income in the United States. Expanded insurance coverage could promote more timely access to cancer treatment, which could improve overall survival (OS), yet the long-term effects of Medicaid expansion (ME) remain unknown. We evaluated whether ME was associated with improved timely treatment initiation (TTI) and 3-year OS among patients with breast, cervical, colon, and lung cancers who were affected by the policy.MethodsMedicaid-insured or uninsured patients aged 40-64 with stage I-III breast, cervical, colon, or non-small cell lung cancer within the National Cancer Database (NCDB). A difference-in-differences (DID) approach was used to compare changes in TTI (within 60 days) and 3-year OS between patients in ME states versus nonexpansion (NE) states before (2010-2013) and after (2015-2018) ME. Adjusted DID estimates for TTI and 3-year OS were calculated using multivariable linear regression and Cox proportional hazards regression models, respectively.ResultsME was associated with a relative increase in TTI within 60 days for breast (DID = 4.6; p

BackgroundSurvivors of rectal cancer experience persistent bowel dysfunction after treatments. Dietary interventions may be an effective approach for symptom management and posttreatment diet quality. SWOG S1820 was a pilot randomized trial of the Altering Intake, Managing Symptoms in Rectal Cancer (AIMS-RC) intervention for bowel dysfunction in survivors of rectal cancer.MethodsNinety-three posttreatment survivors were randomized to the AIMS-RC group (N = 47) or the Healthy Living Education attention control group (N = 46) after informed consent and completion of a prerandomization run-in. Outcome measures were completed at baseline and at 18 and 26 weeks postrandomization. The primary end point was total bowel function score, and exploratory end points included low anterior resection syndrome (LARS) score, quality of life, dietary quality, motivation, self-efficacy, and positive/negative affect.ResultsMost participants were White and college educated, with a mean age of 55.2 years and median time since surgery of 13.1 months. There were no statistically significant differences in total bowel function score by group, with the AIMS-RC group demonstrating statistically significant improvements in the exploratory end points of LARS (p = .01) and the frequency subscale of the bowel function index (p = .03). The AIMS-RC group reported significantly higher acceptability of the study.ConclusionsSWOG S1820 did not provide evidence of benefit from the AIMS-RC intervention relative to the attention control. Select secondary end points did demonstrate improvements. The study was highly feasible and acceptable for participants in the National Cancer Institute Community Oncology Research Program. Findings provide strong support for further refinement and effectiveness testing of the AIMS-RC intervention.

The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+ T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.

The insights into interactions between host genetics and gut microbiome (GM) in colorectal tumor susceptibility (CTS) remains lacking. We used Collaborative Cross mouse population model to identify genetic and microbial determinants of Azoxymethane-induced CTS. We identified 4417 CTS-associated single nucleotide polymorphisms (SNPs) containing 334 genes that were transcriptionally altered in human colorectal cancers (CRCs) and consistently clustered independent human CRC cohorts into two subgroups with different prognosis. We discovered a set of genera in early-life associated with CTS and defined a 16-genus signature that accurately predicted CTS, the majority of which were correlated with human CRCs. We identified 547 SNPs associated with abundances of these genera. Mediation analysis revealed GM as mediators partially exerting the effect of SNP UNC3869242 within Duox2 on CTS. Intestine cell-specific depletion of Duox2 altered GM composition and contribution of Duox2 depletion to CTS was significantly influenced by GM. Our findings provide potential novel targets for personalized CRC prevention and treatment.

PurposeMany survivors of rectal cancer experience persistent bowel dysfunction. There are few evidence-based symptom management interventions to improve bowel control. The purpose of this study is to describe recruitment and pre-randomization baseline sociodemographic, health status, and clinical characteristics for SWOG S1820, a trial of the Altering Intake, Managing Symptoms in Rectal Cancer (AIMS-RC) intervention.MethodsSWOG S1820 aimed to determine the preliminary efficacy, feasibility, and acceptability of AIMS-RC, a symptom management intervention for bowel health, comparing intervention to attention control. Survivors with a history of cancers of the rectosigmoid colon or rectum, within 6-24 months of primary treatment completion, with a post-surgical permanent ostomy or anastomosis, and over 18 years of age were enrolled. Outcomes included total bowel function, low anterior resection syndrome, quality of life, motivation for managing bowel health, self-efficacy for managing symptoms, positive and negative affect, and study feasibility and acceptability.ResultsThe trial completed accrual over a 29-month period and enrolled 117 participants from 34 institutions across 17 states and one US Pacific territory. At baseline, most enrolled participants reported self-imposed diet adjustments after surgery, persistent dietary intolerances, and bowel discomfort post-treatment, with high levels of constipation and diarrhea (grades 1-4).ConclusionsSWOG S1820 was able to recruit, in a timely manner, a study cohort that is demographically representative of US survivors of rectal cancer. Baseline characteristics illustrate the connection between diet/eating and bowel symptoms post-treatment, with many participants reporting diet adjustments and persistent inability to be comfortable with dietary intake.ClinicaltrialsGov registration date12/19/2019.ClinicaltrialsGov identifierNCT#04205955.

Recent research has shown that membrane trafficking plays an important role in canonical Wnt signaling through sequestration of the β-catenin destruction complex inside multivesicular bodies (MVBs) and lysosomes. In this study, we introduce Ouabain, an inhibitor of the Na,K-ATPase pump that establishes electric potentials across membranes, as a potent inhibitor of Wnt signaling. We find that Na,K-ATPase levels are elevated in advanced colon carcinoma, that this enzyme is elevated in cancer cells with constitutively activated Wnt pathway and is activated by GSK3 inhibitors that increase macropinocytosis. Ouabain blocks macropinocytosis, which is an essential step in Wnt signaling, probably explaining the strong effects of Ouabain on this pathway. In Xenopus embryos, brief Ouabain treatment at the 32-cell stage, critical for the earliest Wnt signal in development-inhibited brains, could be reversed by treatment with Lithium chloride, a Wnt mimic. Inhibiting membrane trafficking may provide a way of targeting Wnt-driven cancers.

Live microorganisms can be manipulated and engineered for colorectal cancer detection and treatment through methods such as faecal microbiota transplantation, native bacteria engineering and synthetic circuit engineering. Although promising, substantial effort is required to translate these approaches for clinical use.

IntroductionThis study determined the safety and recommended phase 2 dose (RP2D) of the multikinase inhibitor cabozantinib in combination with trifluridine/tipiracil (FTD/TPI) in refractory metastatic colorectal carcinoma (mCRC).Patients and methodsSingle institution investigator-initiated phase 1 study using 3+3 design. Eligible mCRC patients had received prior standard regimens. Cabozantinib was given orally (p.o.) at 20 mg (dose level [DL] 0) or 40 mg (DL 1) daily on days 1-28, and FTD/TPI p.o. at 35 mg/m2 on days 1-5 and 8-12 every 28 days. Prophylactic growth-factor support was allowed.ResultsFifteen patients were enrolled. Median age 56 years (31-80), male (12/15), ECOG 0/1 = 9/6. Three patients were treated at DL 0 and another nine were treated at DL 1, none exhibiting a DLT. Most common any grade (G) treatment related adverse events (TRAE) were diarrhea (50%), nausea (42%), neutropenia (42%), fatigue (33%), and rash (25%). G3-4 TRAE were neutropenia (25%) and thrombocytopenia, hypokalemia, and weight loss (each 8%). No serious TRAE or G5 were reported. The RP2D was determined to be DL 1. Median PFS was 3.8 months (95% CI 1.9-6.8) and disease control rate was 86.7%.ConclusionThe combination of cabozantinib and FTD/TPI is feasible and tolerable at standard doses with the use of growth factors and showed encouraging clinical activity in refractory mCRC.ClinicaltrialsGOV: NCT04868773.

The maintenance of DNA sequence integrity is critical to avoid accumulation of cancer-causing mutations. Inactivation of DNA Mismatch Repair (MMR) genes (e.g., MLH1 and MSH2) is common among many cancers, including colorectal cancer (CRC) and is the driver of classic microsatellite instability (MSI) in tumors. Somatic MSH3 alterations have been linked to a specific form of MSI called elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) that is associated with patient poor prognosis and elevated among African American (AA) rectal cancer patients. Genetic variants of MSH3 and their pathogenicity vary among different populations, such as among AA, which are not well-represented in publicly available databases. Targeted exome sequencing of MSH3 among AA CRC samples followed by computational bioinformatic pipeline and molecular dynamic simulation analysis approach confirmed six identified MSH3 variants (c.G1237A, c.C2759T, c.G1397A, c.G2926A, c.C3028T, c.G3241A) that corresponded to MSH3 amino-acid changes (p.E413K; p.S466N; p.S920F; p.E976K; p.H1010Y; p.E1081K). All identified MSH3 variants were non-synonymous, novel, pathogenic, and show loss or gain of hydrogen bonding, ionic bonding, hydrophobic bonding, and disulfide bonding and have a deleterious effect on the structure of MSH3 protein. Some variants were located within the ATPase site of MSH3, affecting ATP hydrolysis that is critical for MSH3's function. Other variants were in the MSH3-MSH2 interacting domain, important for MSH3's binding to MSH2. Overall, our data suggest that these variants among AA CRC patients affect the function of MSH3 making them pathogenic and likely contributing to the development or advancement of CRC among AA. Further clarifying functional studies will be necessary to fully understand the impact of these variants on MSH3 function and CRC development in AA patients.

The base excision repair glycosylase MUTYH prevents mutations associated with the oxidatively damaged base, 8-oxo-7,8-dihydroguanine (OG), by removing undamaged misincorporated adenines from OG:A mispairs. Defects in OG:A repair in individuals with inherited MUTYH variants are correlated with the colorectal cancer predisposition syndrome known as MUTYH-associated polyposis (MAP). Herein, we reveal key structural features of OG required for efficient repair by human MUTYH using structure-activity relationships (SAR). We developed a GFP-based plasmid reporter assay to define SAR with synthetically generated OG analogs in human cell lines. Cellular repair results were compared with kinetic parameters measured by adenine glycosylase assays in vitro. Our results show substrates lacking the 2-amino group of OG, such as 8OI:A (8OI = 8-oxoinosine), are not repaired in cells, despite being excellent substrates in in vitro adenine glycosylase assays, new evidence that the search and detection steps are critical factors in cellular MUTYH repair functionality. Surprisingly, modification of the O8/N7H of OG, which is the distinguishing feature of OG relative to G, was tolerated in both MUTYH-mediated cellular repair and in vitro adenine glycosylase activity. The lack of sensitivity to alterations at the O8/N7H in the SAR of MUTYH substrates is distinct from previous work with bacterial MutY, indicating that the human enzyme is much less stringent in its lesion verification. Our results imply that the human protein relies almost exclusively on detection of the unique major groove position of the 2-amino group of OG within OGsyn:Aanti mispairs to select contextually incorrect adenines for excision and thereby thwart mutagenesis. These results predict that MUTYH variants that exhibit deficiencies in OG:A detection will be severely compromised in a cellular setting. Moreover, the reliance of MUTYH on the interaction with the OG 2-amino group suggests that disrupting this interaction with small molecules may provide a strategy to develop potent and selective MUTYH inhibitors.

BackgroundCancer is the leading cause of death among Asian Americans, who often face barriers to cancer care. Cancer supportive care needs among Asian Americans remain understudied.AimsWe examined cancer supportive care needs and participant factors correlated with these needs, identified profiles of supportive care needs, and examined whether needs profiles are associated with quality of life among Asian American adults.Methods and resultsWe recruited 47 Asian American adults with colorectal, liver, or lung cancer who spoke Chinese, English, or Vietnamese, and were starting or undergoing cancer treatment. We assessed cancer supportive care needs in four domains: cancer information, daily living, behavioral health, and language assistance. Hierarchical cluster analysis was used to identify clusters of participants based on their supportive need profiles to further examine the association between need profiles and quality of life (QoL) assessed by the Functional Assessment of Cancer Therapy. Participants (mean age = 57.6) included 72% males and 62% spoke English less than very well. Older participants (age ≥ 65) and those with annual income

Bile acids (BAs) affect the intestinal environment by ensuring barrier integrity, maintaining microbiota balance, regulating epithelium turnover, and modulating the immune system. As a master regulator of BA homeostasis, farnesoid X receptor (FXR) is severely compromised in patients with inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). At the front line, gut macrophages react to the microbiota and metabolites that breach the epithelium. We aim to study the role of the BA/FXR axis in macrophages. This study demonstrates that inflammation-induced epithelial abnormalities compromised FXR signaling and altered BAs' profile in a mouse CAC model. Further, gut macrophage-intrinsic FXR sensed aberrant BAs, leading to pro-inflammatory cytokines' secretion, which promoted intestinal stem cell proliferation. Mechanistically, activation of FXR ameliorated intestinal inflammation and inhibited colitis-associated tumor growth, by regulating gut macrophages' recruitment, polarization, and crosstalk with Th17 cells. However, deletion of FXR in bone marrow or gut macrophages escalated the intestinal inflammation. In summary, our study reveals a distinctive regulatory role of FXR in gut macrophages, suggesting its potential as a therapeutic target for addressing IBD and CAC.

PurposePersistent gastrointestinal (GI) symptoms are frequently experienced by colon cancer survivors and may help identify patients with higher utilization of healthcare services. To assess the relationship between GI symptoms and specialty care utilization among colon cancer survivors.MethodsA prospective longitudinal cohort study at an academic medical center of 126 adults surgically treated for stage I-IV colon cancer between February 2017 and June 2022. Participants reported GI symptoms through the EORTC QLQ-C30 and QLQ-CR29 at enrollment and as frequently as every 6 months for 5 years. Main outcome measures were visits, telephone encounters, and secure messages with a medical provider within specialty oncology clinics within 6 months after each survey completion. Generalized linear mixed regression model for repeated measurements with random trajectory for each participant was performed to estimate the associations between symptoms and healthcare use. Models were adjusted for demographics, clinical and surgical factors, and timing in relation to onset of the COVID-19 pandemic.ResultsIn the 6 months after each survey time point, patients averaged 1.2 visits, 0.5 telephone encounters, and 3.2 patient-initiated messages. In adjusted models, those with any abdominal pain (RR 1.45; p = 0.002), buttock pain (RR 1.30; p = 0.050), or increased stool frequency (RR 1.26; p = 0.046) had more clinic visits in the following 6 months than those without these symptoms. Including these three symptoms in one model revealed that only abdominal pain was statistically significantly associated with increased clinic visits (RR 1.36; p = 0.016). Patients with any blood or mucus in stool (RR 2.46; p = 0.009) had significantly more telephone encounters, and those with any abdominal pain (RR 1.65; p = 0.002) had significantly more patient-initiated messages than those without these symptoms.ConclusionsOur findings identify GI symptoms associated with increased use of oncologic specialty care among colon cancer survivors, with abdominal pain as an important predictor of utilization.Implications for cancer survivorsEarly identification and anticipatory management of colon cancer survivors experiencing abdominal pain may decrease healthcare utilization.

Introduction/objectivesColonoscopy completion rates after an abnormal fecal immunochemical test (FIT) are suboptimal, resulting in missed opportunities for early detection and prevention of colorectal cancer. Patient navigation and structured follow-up may improve colonoscopy completion, but implementation of these strategies is not widespread.MethodsWe conducted a quality improvement study using a Plan-Do-Study-Act (PDSA) Model to increase colonoscopy completion after abnormal FIT in a large federally qualified health center serving a diverse and low-income population. Intervention components included patient navigation, and a checklist to promote completion of key steps required for abnormal FIT follow-up. Primary outcome was proportion of patients achieving colonoscopy completion within 6 months of abnormal FIT, assessed at baseline for 156 patients pre-intervention, and compared to 208 patients during the intervention period from April 2017 to December 2019. Drop offs at each step in the follow-up process were assessed.ResultsColonoscopy completion improved from 21% among 156 patients with abnormal FIT pre-intervention, to 38% among 208 patients with abnormal FIT during the intervention (P

Background & aimsChronic inflammatory illnesses are debilitating and recurrent conditions associated with significant comorbidities, including an increased risk of developing cancer. Extensive tissue remodeling is a hallmark of such illnesses, and is both a consequence and a mediator of disease progression. Despite previous characterization of epithelial and stromal remodeling during inflammatory bowel disease, a complete understanding of its impact on disease progression is lacking.MethodsA comprehensive proteomic pipeline using data-independent acquisition was applied to decellularized colon samples from the Muc2 knockout (Muc2KO) mouse model of colitis for an in-depth characterization of extracellular matrix remodeling. Unique proteomic profiles of the matrisomal landscape were extracted from prepathologic and overt colitis. Integration of proteomics and transcriptomics data sets extracted from the same murine model produced network maps describing the orchestrating role of matrisomal proteins in tissue remodeling during the progression of colitis.ResultsThe in-depth proteomic workflow used here allowed the addition of 34 proteins to the known colon matrisomal signature. Protein signatures of prepathologic and pathologic colitic states were extracted, differentiating the 2 states by expression of small leucine-rich proteoglycans. We outlined the role of this class and other matrisomal proteins in tissue remodeling during colitis, as well as the potential for coordinated regulation of cell types by matrisomal ligands.ConclusionsOur work highlights a central role for matrisomal proteins in tissue remodeling during colitis and defines orchestrating nodes that can be exploited in the selection of therapeutic targets.

IntroductionOlder adults living with Alzheimer's disease and related dementias (ADRD) who are then diagnosed with cancer are an understudied population. While the role of cognitive impairment during and after cancer treatment have been well-studied, less is understood about patients who are living with ADRD and then develop cancer. The purpose of this study is to contribute evidence about our understanding of this vulnerable population.Materials and methodsThis was a retrospective cohort study of a linked, representative family of databases of cancer registries and Medicare administrative claims that make up the SEER-Medicare database. Older adults ages 68 and older with a first primary cancer type: breast, cervical, colorectal, lung, oral, or prostate were eligible for inclusion (N = 337,932). Prevalence estimates of ADRD across cancer types and a 5% non-cancer comparison sample were compared by patient factors.ResultsThe overall prevalence of patients who had an ADRD diagnosis anytime in the three years prior to their cancer diagnosis was 5.6%. Patients with ADRD were more likely to be female, older (over age 75), a racial/ethnic minority, single, with multiple chronic conditions, and a tumor diagnosed early (stage I) or were unstaged. Black patients with colorectal and oral cancer had the highest and second highest prevalence of ADRD compared to White patients (13.46% vs 7.95% and 12.64% vs 7.82% respectively, p  .0001).DiscussionThe higher prevalence of ADRD among Black and Latine older adults with cancer not only aligns with the trend observed in our non-cancer comparison sample, but also, these findings demonstrate the compounded risk experienced by minoritized older adults over the life course. The greater than expected prevalence of patients with ADRD who go on to develop cancer demonstrates better assessment of cognition is urgently needed. Accurate identification of these vulnerable populations is critical to improve assessment, care coordination, and address inequities in screening and treatment planning.

BackgroundUlcerative colitis (UC) and Crohn's disease are 2 types of inflammatory bowel disease (IBD), a group of chronic digestive disorders caused by aberrant immune responses to intestinal microbes. Although changes in the composition of immune cell subsets in the context of IBD have been previously described, the interactions and communication among cells are less well understood. Moreover, the precise mechanisms of action underlying many biologic therapies, including the anti-α4β7 integrin antagonist vedolizumab, remain incompletely understood. Our study aimed to explore possible additional mechanisms through which vedolizumab acts.MethodsWe performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) on peripheral blood and colon immune cells derived from patients with ulcerative colitis treated with the anti-α4β7 integrin antagonist vedolizumab. We applied a previously published computational approach, NicheNet, to predict immune cell-cell interactions, revealing putative ligand-receptor pairs and key transcriptional changes downstream of these cell-cell communications (CCC).ResultsWe observed decreased proportions of T helper 17 (TH17) cells in UC patients who responded to vedolizumab and therefore focused the study on identifying cell-cell communications and signals of TH17 cells with other immune cells. For example, we observed that colon TH17 cells from vedolizumab nonresponders were predicted to have a greater degree of interactions with classical monocytes compared with responders, whereas colon TH17 cells from vedolizumab responders exhibited more interactions with myeloid dendritic cells compared with nonresponders.ConclusionsOverall, our results indicate that efforts to elucidate cell-cell communications among immune and nonimmune cell types may increase the mechanistic understanding of current and investigational therapies for IBD.

IntroductionRigid proctosigmoidoscopy (RP) and flexible sigmoidoscopy (FS) are two modalities commonly used for intraoperative evaluation of colorectal anastomoses. This study seeks to determine whether there is an association between the endoscopic modality used to evaluate colorectal anastomoses and the rate of anastomotic leak (AL), organ space infection, and overall infectious complication.MethodsThe 2012-2018 American College of Surgeons National Surgical Quality Improvement Program database was queried for patients undergoing colorectal anastomoses. Anastomotic evaluation method (RP versus FS) was identified by Current Procedural Terminologycoding and used for group classification. Outcomes measured included AL, organ space infections, and overall infection. Multivariable logistic regression analysis for predicting AL was performed.ResultsWe identified 7100 patients who underwent a colorectal anastomosis with intraoperative endoscopic evaluation. RP was utilized in 3397 (47.8%) and FS in 3703 (52.2%) patients. RP was used more commonly in diverticulitis (44.5% versus 36.2%, P

BackgroundGiven high rates of cancer mortality in Native communities, we examined how urban American Indian and Alaska Native elders talk about colorectal cancer (CRC) and CRC screening.MethodsWe conducted seven focus groups with a total of 46 participants in two urban clinics in the Pacific Northwest to assess participant awareness, perceptions, and concerns about CRC and CRC screening. Using speech codes theory, we identified norms that govern when and how to talk about CRC in this population.ResultsOur analyses revealed that male participants often avoided screening because they perceived it as emasculating, whereas women often avoided screening because of embarrassment and past trauma resulting from sexual abuse. Both men and women used humor to mitigate the threatening nature of discussions about CRC and CRC screening.ConclusionsWe offer our analytic results to assist others in developing culturally appropriate interventions to promote CRC screening among American Indians and Alaska Natives.

Platinum-based chemotherapy is known to cause taste and smell changes (TSCs) via a host of mechanisms, including altered receptor activity, saliva/mucus production, and induction of receptor destruction via mitotic inhibition. In the literature to date, these changes have primarily resulted in worsening of taste and smell. In this case report, we document the first instance of an individual regaining their sense of olfactory detection following treatment with oxaliplatin for colorectal adenocarcinoma. We theorize that the improvement in his sense of smell may have resulted from oxaliplatin-induced destruction of his nasal polyps through the caspase-9/procaspase-9 apoptotic pathway, a pathway shared with other mechanisms of nasal polyp destruction. These findings were supported by nasal endoscopy and sphenoid sinusoscopy, which demonstrated no clinical persistence of nasal polyps, in contrast to nasal endoscopy prior to chemotherapy which demonstrated persistent nasal polyposis. Objective smell testing post-treatment revealed a diminished ability to discriminate odors. Chemotherapy-induced TSCs play a key role in poor weight gain, food aversion, emotional distress, and an overall decrease in quality of life, and patients should be informed of these potential consequences prior to starting treatment. However, in patients with anosmia secondary to nasal polyposis, treatment with platinum-based chemotherapy may provide an additional therapeutic benefit. Further studies may help elucidate the potential therapeutic benefits of these agents in managing steroid-resistant polyposis for patients suffering from olfactory dysfunction.

BackgroundAdherence to the American Cancer Society (ACS) guidelines of avoiding obesity, maintaining physical activity, and consuming a diet rich in fruits, vegetables, and whole grains is associated with longer survival in colorectal cancer (CRC) survivors. Dietary components of the ACS guidelines may act in part by changing the microbiome, which is implicated in CRC outcomes.ObjectivesWe conducted a pilot cross-sectional study to explore associations between ACS guidelines and the gut microbiome.MethodsStool samples and questionnaires were collected from 28 CRC survivors at the University of California, San Francisco from 2019 to 2020. ACS scores were calculated based on validated questionnaires. Gut microbial community structure from 16S amplicons and gene/pathway abundances from metagenomics were tested for associations with the ACS score and its components using ANOVA and general linear models.ResultsThe overall ACS score was not significantly associated with variations in the fecal microbiota. However, fruit and vegetable intake and alcohol intake accounted for 19% (P = 0.005) and 13% (P = 0.01) of variation in the microbiota, respectively. Fruit/vegetable consumption was associated with increased microbial diversity, increased Firmicutes, decreased Bacteroidota, and changes to multiple genes and metabolic pathways, including enriched pathways for amino acid and short-chain fatty acid biosynthesis and plant-associated sugar degradation. In contrast, alcohol consumption was positively associated with overall microbial diversity, negatively associated with Bacteroidota abundance, and associated with changes to multiple genes and metabolic pathways. The other components of the ACS score were not statistically significantly associated with the fecal microbiota in our sample.ConclusionsThese results guide future studies examining the impact of changes in the intake of fruits, vegetables, and alcoholic drinks on the gut microbiome of CRC survivors.

Colorectal cancer (CRC) is driven by genomic alterations in concert with dietary influences, with the gut microbiome implicated as an effector in disease development and progression. While meta-analyses have provided mechanistic insight into patients with CRC, study heterogeneity has limited causal associations. Using multi-omics studies on genetically controlled cohorts of mice, we identify diet as the major driver of microbial and metabolomic differences, with reductions in α diversity and widespread changes in cecal metabolites seen in high-fat diet (HFD)-fed mice. In addition, non-classic amino acid conjugation of the bile acid cholic acid (AA-CA) increased with HFD. We show that AA-CAs impact intestinal stem cell growth and demonstrate that Ileibacterium valens and Ruminococcus gnavus are able to synthesize these AA-CAs. This multi-omics dataset implicates diet-induced shifts in the microbiome and the metabolome in disease progression and has potential utility in future diagnostic and therapeutic developments.

PurposeThis was a review of circulating tumor DNA (ctDNA) in patients with peritoneal metastases from colorectal cancer.MethodsWe searched the PubMed database for studies reporting detection of ctDNA in patients with colorectal cancer (CRC) and with peritoneal metastases (PM) from colorectal cancer (CRPM). We extracted data on the population included, number of subjects, study design, type of ctDNA assay used and schedule, and the major findings from these publications.ResultsWe identified 13 studies for review investigating ctDNA, using a variety of ctDNA assays, among 1787 patients with CRC without PM, as well as four eligible published and one unpublished (in press) studies, which included 255 patients with PM from any primary site and 61 patients with CRPM. Among the 13 studies investigating ctDNA among CRC without PM, posttreatment surveillance ctDNA was associated with recurrence and was generally more sensitive than imaging or tumor markers. Among the five studies including patients with PM, ctDNA was not universally able to detect the presence of PM, but when present, ctDNA predicted worse outcomes.ConclusionCirculating-tumor DNA is a potentially useful surveillance tool for patients with CRC. However, the sensitivity of ctDNA to detect CRPM is variable and warrants further inquiry.