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Delays in time to treatment initiation (TTI) for new cancer diagnoses cause patient distress and may adversely affect outcomes. We investigated trends in TTI for common solid tumors treated with curative intent, determinants of increased TTI and association with overall survival. We utilized prospective data from the National Cancer Database for newly diagnosed United States patients with early-stage breast, prostate, lung, colorectal, renal and pancreas cancers from 2004-13. TTI was defined as days from diagnosis to first treatment (surgery, systemic or radiation therapy). Negative binomial regression and Cox proportional hazard models were used for analysis. The study population of 3,672,561 patients included breast (N = 1,368,024), prostate (N = 944,246), colorectal (N = 662,094), non-small cell lung (N = 363,863), renal (N = 262,915) and pancreas (N = 71,419) cancers. Median TTI increased from 21 to 29 days (P<0.001). Aside from year of diagnosis, determinants of increased TTI included care at academic center, race, education, prior history of cancer, transfer of facility, comorbidities and age. Increased TTI was associated with worsened survival for stages I and II breast, lung, renal and pancreas cancers, and stage I colorectal cancers, with hazard ratios ranging from 1.005 (95% confidence intervals [CI] 1.002-1.008) to 1.030 (95% CI 1.025-1.035) per week of increased TTI. TTI has lengthened significantly and is associated with absolute increased risk of mortality ranging from 1.2-3.2% per week in curative settings such as early-stage breast, lung, renal and pancreas cancers. Studies of interventions to ease navigation and reduce barriers are warranted to diminish potential harm to patients.

Colorectal cancer (CRC) survivors often experience long-term symptoms after cancer treatments. But gastrointestinal (GI) symptom experiences are under-investigated in CRC survivors. We described persistent GI symptoms after cancer treatments in female CRC survivors and assessed GI symptoms' risk and life-impact factors. A cross-sectional study utilized data from the Women's Health Initiative (WHI) Life and Longevity After Cancer (LILAC) study that recruited postmenopausal women. Correlation analyses and multivariable linear regression models were used. CRC survivors after cancer treatments were included (N = 413, mean age 71.2 years old, mean time since diagnosis = 8.1 years). 81% of CRC survivors experienced persistent GI symptoms. Bloating/gas was the most prevalent (54.2%± 0.88) and severe GI symptom, followed by constipation (44.1%±1.06), diarrhea (33.4%±0.76), and abdominal/pelvic pain (28.6%±0.62). Significant risk factors for GI symptoms include time since cancer diagnosis (<5 years), advanced cancer stage, high psychological distress, poor dietary habits, and low physical activity. Fatigue and sleep disturbance were the most significant risk factors for long-term GI symptoms (β = 0.21, t = 3.557; β = 0.20, t = 3.336, respectively, Ps < .001). High severity of GI symptoms was positively associated with poor quality of life (QOL), increased daily life interferences (social and physical functions), and low body image satisfaction (Ps < .001). Women CRC survivors experience a high GI symptom burden, highlighting the need to inform policy and improve the QOL of cancer survivors. Our findings will aid in identifying those more vulnerable to symptoms, and inform future survivorship care interventions (i.e., community-based cancer symptom management) by considering multiple risk factors (e.g., psychological distress).

Copper levels are known to be elevated in inflamed and malignant tissues. But the mechanism underlying this selective enrichment has been elusive. In this study, we report a axis by which inflammatory cytokines, such as IL-17, drive cellular copper uptake via the induction of a metalloreductase, STEAP4. IL-17-induced elevated intracellular copper level leads to the activation of an E3-ligase, XIAP, which potentiates IL-17-induced NFκB activation and suppresses the caspase 3 activity. Importantly, this IL-17-induced STEAP4-dependent cellular copper uptake is critical for colon tumor formation in a murine model of colitis-associated tumorigenesis and STEAP4 expression correlates with IL-17 level and XIAP activation in human colon cancer. In summary, this study reveals a IL-17-STEAP4-XIAP axis through which the inflammatory response induces copper uptake, promoting colon tumorigenesis. STEAP4 promotes the uptake of copper, and copper is known to be enhanced in cancer tissues. Here, the authors show that STEAP4 is induced by IL17, which is increased in inflamed tissues, consequently the increased copper levels activate NFκB signalling and suppression of apoptosis.

Accumulating evidence suggests that ketogenic diets (KDs) mediate the rise of circulating ketone bodies and exert a potential anti-inflammatory effect; however, the consequences of this unique diet on colitis remain unknown. We performed a series of systematic studies using a dextran sulfate sodium (DSS) animal model of inflammatory colitis. Animals were fed with a KD, low-carbohydrate diet (LCD), or normal diet (ND). Germ-free mice were utilized in validation experiments. Colon tissues were analyzed by transcriptome sequencing, RT2 profiler PCR array, histopathology, and immunofluorescence. Serum samples were analyzed by metabolic assay kit. Fecal samples were analyzed by 16S rRNA gene sequencing, liquid chromatography–mass spectrometry and gas chromatography–mass spectrometry. We observed that KD alleviated colitis by altering the gut microbiota and metabolites in a manner distinct from LCD. Quantitative diet experiments confirmed the unique impact of KD relative to LCD with a reproducible increase in Akkermansia , whereas the opposite was observed for Escherichia/Shigella . After colitis induction, the KD protected intestinal barrier function, and reduced the production of RORγt + CD3 − group 3 innate lymphoid cells (ILC3s) and related inflammatory cytokines (IL-17α, IL-18, IL-22, Ccl4). Finally, fecal microbiota transplantation into germ-free mice revealed that the KD- mediated colitis inhibition and ILC3 regulation were dependent on the modification of gut microbiota. Taken together, our study presents a global view of microbiome-metabolomics changes that occur during KD colitis treatment, and identifies the regulation of gut microbiome and ILC3s as novel targets involving in IBD dietary therapy.

Serrated lesions of the colorectum are the precursors of perhaps one-third of colorectal cancers (CRCs). Cancers arising in serrated lesions are usually in the proximal colon, and account for a disproportionate fraction of cancer identified after colonoscopy. We sought to provide guidance for the clinical management of serrated colorectal lesions based on current evidence and expert opinion regarding definitions, classification, and significance of serrated lesions. A consensus conference was held over 2 days reviewing the topic of serrated lesions from the perspectives of histology, molecular biology, epidemiology, clinical aspects, and serrated polyposis. Serrated lesions should be classified pathologically according to the World Health Organization criteria as hyperplastic polyp, sessile serrated adenoma/polyp (SSA/P) with or without cytological dysplasia, or traditional serrated adenoma (TSA). SSA/P and TSA are premalignant lesions, but SSA/P is the principal serrated precursor of CRCs. Serrated lesions have a distinct endoscopic appearance, and several lines of evidence suggest that on average they are more difficult to detect than conventional adenomatous polyps. Effective colonoscopy requires an endoscopist trained in the endoscopic appearance of serrated lesions. We recommend that all serrated lesions proximal to the sigmoid colon and all serrated lesions in the rectosigmoid > 5 mm in size, be completely removed. Recommendations are made for post-polypectomy surveillance of serrated lesions and for surveillance of serrated polyposis patients and their relatives.

Cancer is characterized by gene expression aberrations. Studies have largely focused on coding sequences and promoters, even though distal regulatory elements play a central role in controlling transcription patterns. We used the histone mark H3K4me1 to analyze gain and loss of enhancer activity genome-wide in primary colon cancer lines relative to normal colon crypts. We identified thousands of variant enhancer loci (VELs) that comprise a signature that is robustly predictive of the in vivo colon cancer transcriptome. Furthermore, VELs are enriched in haplotype blocks containing colon cancer genetic risk variants, implicating these genomic regions in colon cancer pathogenesis. We propose that reproducible changes in the epigenome at enhancer elements drive a specific transcriptional program to promote colon carcinogenesis.

Background Locoregional recurrence (LR) in colon cancer is uncommon but often incurable, while the factors associated with it are unclear. The purpose of this study was to identify patterns and predictors of LR after curative resection for colon cancer. Methods All patients who underwent colon cancer resection with curative intent between 1994 and 2008 at a tertiary referral center were identified from a prospectively maintained institutional database. The association of LR with clinicopathologic and treatment characteristics was determined using univariable and multivariable analyses. Results A total of 1397 patients were included with a median follow-up of 7.8 years; 635 (45%) were female, and the median age was 69 years. LR was detected in 61 (4.4%) patients. Median time to LR was 21 months. On multivariable analysis, the independent predictors of LR were disease stage [hazard ratio (HR) for Stage II 4.6, 95% confidence interval (CI) 1.05–19.9, HR for Stage III 10.8, 95% CI 2.6–45.8], bowel obstruction (HR 3.8, 95% CI 1.9–7.4), margin involvement (HR 4.1, 95% CI 1.9–8.6), lymphovascular invasion (HR 1.9, 95% CI 1.06–3.5), and local tumor invasion (fixation to another structure, perforation, or presence of associated fistula, HR 2.2, 95% CI 1.1–4.5). Adjuvant chemotherapy was not associated with reduced LR in patients with either Stage II or Stage III tumors. Conclusions Adherence to oncologic surgical principles in colon cancer resection results in low rates of LR, which is associated with tumor-dependent factors. Recognition of these factors can help to determine appropriate postoperative surveillance.

In addition to mutations in genes, aberrant enhancer element activity at non-coding regions of the genome is a key driver of tumorigenesis. Here, we perform epigenomic enhancer profiling of a cohort of more than forty genetically diverse human colorectal cancer (CRC) specimens. Using normal colonic crypt epithelium as a comparator, we identify enhancers with recurrently gained or lost activity across CRC specimens. Of the enhancers highly recurrently activated in CRC, most are constituents of super enhancers, are occupied by AP-1 and cohesin complex members, and originate from primed chromatin. Many activate known oncogenes, and CRC growth can be mitigated through pharmacologic inhibition or genome editing of these loci. Nearly half of all GWAS CRC risk loci co-localize to recurrently activated enhancers. These findings indicate that the CRC epigenome is defined by highly recurrent epigenetic alterations at enhancers which activate a common, aberrant transcriptional programme critical for CRC growth and survival. Active enhancers are defined by the presence of post-translational modifications of histones. Here, the authors use these marks to identify enhancers recurrently activated in colorectal cancer and find that these enhancers turn on oncogenes and are associated with known risk loci for developing the disease.

We evaluated the relationship between residing in persistent poverty (PP) and low socioeconomic census tracts on all-cause and colorectal cancer (CRC)-specific mortality, providing a current assessment of economic disadvantage and health outcomes. Using Surveillance, Epidemiology, and End Results Program Data (2006–2020), CRC cases were identified using ICD-10 codes and stage I-III were included in the analysis. Overlap propensity score weighting with marginal structural models estimated the risk of all-cause and CRC-specific mortality. Individuals living in PP had higher risk of all-cause mortality at 15-year follow-up, with an adjusted risk difference (ARD) and adjusted risk ratio (aRR) of 7.2 (95% CI 5.9–8.7) and 1.1 (95% CI 1.1–1.1), respectively, with similar results for CRC-specific mortality. Individuals living in low socioeconomic census tracts had higher risk of all-cause (ARD: 5.3, 95% CI 4.0–6.6; aRR: 1.1, 95% CI 1.6–1.1) and CRC-specific mortality (ARD: 2.7, 95% CI 1.7–3.7; aRR: 1.1, 95% CI 1.1–1.1) at 15-year follow-up. Thus, residing in PP or low socioeconomic census tract may impact health outcomes.

BackgroundLimited data on the relationship between postoperative complications (POCs) after colorectal cancer resection and oncologic outcomes are available. We hypothesized that the increased severity of POCs is associated with progressively worse oncologic outcomes.MethodsPatients with pathological stages I–III colorectal adenocarcinoma undergoing elective curative resection in a single institution between 2000 and 2012 were identified from a prospectively collected database. The severity of POCs was determined using the Clavien–Dindo classification, and oncologic outcomes were assessed.ResultsOf 2266 patients, 669 (30%) had at least one POC. POCs were not associated with pathologic stage (p = 0.58) or use of adjuvant therapy (p = 0.19). With a mean follow-up of 5.3 years, POCs were associated with decreased 5-year overall survival (OS) (60% vs. 77%, p < 0.001), disease-free survival (DFS) (53% vs. 70%, p < 0.001), cancer-specific survival (CSS) (81% vs. 87%, p < 0.001), and increased overall recurrence rates (19% vs. 15%, p = 0.008). Increasing Clavien–Dindo scores from I to IV was significantly associated with progressively decreasing OS (71, 64, 60, 22%, p < 0.001), DFS (65, 58, 51, 19%, p < 0.001), CSS (88, 77, 79, 74%, p < 0.001), and increasing recurrence rates (12, 20, 26, 18%, p = 0.002). Multivariate analysis confirmed POCs as an independent factor associated with decreased OS [hazard ratio (HR) 0.63, 95% CI 0.52–0.76], DFS (HR 0.64, 95% CI 0.54–0.76), CSS (HR 0.73, 95% CI 0.56–0.97), and increased recurrence rates (HR 1.36, 95% CI 1.02–1.80).ConclusionsPOCs are associated with adverse oncologic outcomes, with increasing effect with higher Clavien–Dindo score. Efforts to reduce both the incidence and severity of complications should result in improved oncologic outcomes.