Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis.

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

Fatores de risco para prolongamento do tempo de permanência após cirurgia colorretal

OBJETIVO: Os cirurgiões proctologistas muitas vezes enfrentam dificuldades para explicar aos administradores/contribuintes as razões para o prolongamento do tempo de internação hospitalar (TIH). O objetivo deste estudo foi identificar os fatores associados ao aumento do TIH após cirurgia colorretal. MÉTODO: A população do estudo incluiu pacientes que constam do banco de dados do American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) no ano de 2007 e que foram submetidos à ressecção ileocólica, colectomia segmentar ou ressecção anterior. A população do estudo foi dividida em normal (abaixo do percentil 75) e TIH prolongado (acima do percentil 75). A análise multivariada foi realizada usando o TIH prolongado como variável dependente e as variáveis do ACS-NSQIP como preditivas. Um valor de p < 0,01 foi considerado significativo. RESULTADOS: No total, 12.269 pacientes com um TIH mediano de 6 dias (intervalo interquartil, 4-9) foram incluídos. Havia 2.617 pacientes (21,3%) com TIH prolongado (mediana, 15 dias; intervalo interquartil, 13-22). A idade média dos pacientes era de 69 anos (intervalo interquartil, 57-79) e 1.308 (50%) eram do sexo feminino. Os fatores de risco para TIH prolongado foram sexo masculino, insuficiência cardíaca congestiva, perda de peso, doença de Crohn, albumina < 3,5 g/dL e hematócrito < 47% no pré-operatório, sepse basal, classe ASA ≥ 3, cirurgia aberta, tempo cirúrgico ≥ 190 minutos, pneumonia no pós-operatório, falha no desmame da ventilação mecânica, trombose venosa profunda, infecção do trato urinário, sepse sistêmica, infecção do sítio cirúrgico e reoperação dentro de 30 dias da cirurgia primária. CONCLUSÃO: Vários fatores estão associados ao aumento do TIH após a cirurgia colorretal. Nossos resultados são úteis para que os cirurgiões possam explicar os TIH prolongados aos administradores/contribuintes que são críticos dessa métrica.OBJECTIVE: Colorectal surgeons often struggle to explain to administrators/payers reasons for prolonged length of stay (LOS). This study aim was to identify factors associated with increased LOS after colorectal surgery. DESIGN: The study population included patients from the 2007 American-College-of-Surgeons-National-Surgical-Quality-Improvement-Program (ACS-NSQIP) database undergoing ileocolic resection, segmental colectomy, or anterior resection. The study population was divided into normal (below 75th percentile) and prolonged LOS (above the 75th percentile). A multivariate analysis was performed using prolonged LOS as dependent variable and ACS-NSQIP variables as predictive variables. P-value < 0.01 was considered significant. RESULTS: 12,269 patients with a median LOS of 6 (inter-quartile range 4-9) days were included. There were 2,617 (21.3%) patients with prolonged LOS (median 15 days, inter-quartile range 13-22). 1,308 (50%) were female, and the median age was 69 (inter-quartile range 57-79) years. Risk factors for prolonged LOS were male gender, congestive heart failure, weight loss, Crohn's disease, preoperative albumin < 3.5 g/dL and hematocrit < 47%, baseline sepsis, ASA class ≥ 3, open surgery, surgical time ≥ 190 min, postoperative pneumonia, failure to wean from mechanical ventilation, deep venous thrombosis, urinary-tract infection, systemic sepsis, surgical site infection and reoperation within 30-days from the primary surgery. CONCLUSION: Multiple factors are associated with increased LOS after colorectal surgery. Our results are useful for surgeons to explain prolonged LOS to administrators/payers who are critical of this metric

Serrated Lesions of the Colorectum: Review and Recommendations From an Expert Panel

Serrated lesions of the colorectum are the precursors of perhaps one-third of colorectal cancers. Cancers arising in serrated lesions are usually in the proximal colon, and account for a disproportionate fraction of cancer identified after colonoscopy

Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines

Background & aims: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. Methods: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. Results: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. Conclusions: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC

Characterization of the colorectal cancer–associated enhancer MYC-335 at 8q24: the role of rs67491583

Recent genome-wide association studies have identified multiple regions at 8q24 that confer susceptibility to many cancers. In our previous work, we showed that the colorectal cancer (CRC) risk variant rs6983267 at 8q24 resides within a TCF4 binding site at the MYC-335 enhancer, with the risk allele G having a stronger binding capacity and Wnt responsiveness. Here, we searched for other potential functional variants within MYC-335. Genetic variation within MYC-335 was determined in samples from individuals of European, African, and Asian descent, with emphasis on variants in putative transcription factor binding sites. A 2-bp GA deletion rs67491583 was found to affect a growth factor independent (GFI) binding site and was present only in individuals with African ancestry. Chromatin immunoprecipitation performed in heterozygous cells showed that the GA deletion had an ability to reduce binding of the transcriptional repressors GFI1 and GFI1b. Screening of 1,027 African American colorectal cancer cases and 1,773 healthy controls did not reveal evidence for association (odds ratio: 1.17, 95% confidence interval: 0.97–1.41, P = 0.095). In this study, rs67491583 was identified as another functional variant in the CRC-associated enhancer MYC-335, but further studies are needed to establish the role of rs67491583 in the colorectal cancer predisposition of African Americans

Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines

BACKGROUND & AIMS: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. METHODS: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. RESULTS: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. CONCLUSIONS: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.publishedVersionPeer reviewe