Sialyltransferase ST6GAL-1 mediates resistance to chemoradiation in rectal cancer.

Locally advanced rectal cancer is typically treated with chemoradiotherapy followed by surgery. Most patients do not display a complete response to chemoradiotherapy, but resistance mechanisms are poorly understood. ST6GAL-1 is a sialyltransferase that adds the negatively charged sugar, sialic acid (Sia), to cell surface proteins in the Golgi, altering their function. We therefore hypothesized that ST6GAL-1 could mediate resistance to chemoradiation in rectal cancer by inhibiting apoptosis. Patient-derived xenograft and organoid models of rectal cancer and rectal cancer cell lines were assessed for ST6GAL-1 protein with and without chemoradiation treatment. ST6GAL-1 mRNA was assessed in untreated human rectal adenocarcinoma by PCR assays. Samples were further assessed by Western blotting, Caspase-Glo apoptosis assays, and colony formation assays. The presence of functional ST6GAL-1 was assessed via flow cytometry using the Sambucus nigra lectin, which specifically binds cell surface α2,6-linked Sia, and via lectin precipitation. In patient-derived xenograft models of rectal cancer, we found that ST6GAL-1 protein was increased after chemoradiation in a subset of samples. Rectal cancer cell lines demonstrated increased ST6GAL-1 protein and cell surface Sia after chemoradiation. ST6GAL-1 was also increased in rectal cancer organoids after treatment. ST6GAL-1 knockdown in rectal cancer cell lines resulted in increased apoptosis and decreased survival after treatment. We concluded that ST6GAL-1 promotes resistance to chemoradiotherapy by inhibiting apoptosis in rectal cancer cell lines. More research will be needed to further elucidate the importance and mechanism of ST6GAL-1-mediated resistance.

Racial Differences in Aging-Related Deficits Among Older Adults With Colorectal Cancer.

BACKGROUND: Despite the known influences of both race- and aging-related factors in colorectal cancer outcomes and mortality, limited literature is available on the intersection between race and aging-related impairments. OBJECTIVE: To explore racial differences in frailty and geriatric deficit subdomains among patients with colorectal cancer. DESIGN: Retrospective study using data from the Cancer and Aging Resilience Evaluation registry. SETTINGS: A comprehensive cancer center in the Deep South. PATIENTS: Older adults (aged ≥60 years) with colorectal cancer. MAIN OUTCOME MEASURES: Measure of frailty and geriatric assessment subdomains of physical function, functional status, cognitive complaints, psychological function, and health-related quality of life. RESULTS: Black patients lived in areas with a higher social vulnerability index compared to White patients (0.69 vs 0.49; p < 0.01) and had limited social support more often (54.5% vs 34.9%; p = 0.01). After adjustment for age, cancer stage, comorbidities, and social vulnerability index, Black patients were found to have a higher rate of frailty than White patients (adjusted OR 3.77; 95% CI, 1.76-8.18; p = 0.01). In addition, Black patients had more physical limitations (walking 1 block: adjusted OR 1.93; 95% CI, 1.02-3.69; p = 0.04), functional limitations (activities of daily living: adjusted OR 3.21; 95% CI, 1.42-7.24; p = 0.01), and deficits in health-related quality of life (poor global self-reported health: adjusted OR 2.45; 95% CI, 1.23-5.13; p = 0.01). Similar findings were shown after stratification by stage I to III vs IV. LIMITATIONS: Retrospective study at a single institution. CONCLUSIONS: Among older patients with colorectal cancer, Black patients were more likely to be frail than White patients, with deficits observed specifically in physical function, functional status, and health-related quality of life. Geriatric assessment may provide an important tool in addressing racial inequities in colorectal cancer. DIFERENCIAS RACIALES EN LOS DFICITS RELACIONADOS CON EL ENVEJECIMIENTO ENTRE ADULTOS MAYORES CON CNCER COLORRECTAL: ANTECEDENTES: A pesar de las influencias conocidas de los factores relacionados con la raza y el envejecimiento en los resultados y la mortalidad del cáncer colorectal, hay muy poca literatura sobre la intersección entre los impedimentos relacionados con la raza y el envejecimiento.OBJETIVO: El objetivo era explorar las diferencias raciales en los subdominios de fragilidad y déficit geriátrico entre los pacientes con cáncer colorectal.DISEÑO: Estudio retrospectivo utilizando datos del registro Cancer and Aging Resilience Evaluation.AJUSTES: Un centro oncológico integral en el Sur Profundo.PACIENTES: Adultos mayores (≥60 años) con cáncer colorrectal de raza Negra o Blanca.PRINCIPALES MEDIDAS DE RESULTADO: Medida compuesta de fragilidad y subdominios de evaluación geriátrica de función física, estado funcional, quejas cognitivas, función psicológica y calidad de vida relacionada con la salud.RESULTADOS: De los 304 pacientes incluidos, el 21,7% (n = 66) eran negros y la edad media era de 69 años. Los pacientes negros vivían en áreas con un índice de vulnerabilidad social (SVI) más alto en comparación con los pacientes blancos (SVI 0,69 vs 0,49; p < 0,01) y con mayor frecuencia tenían apoyo social limitado (54,5% vs 34,9%; p = 0,01). Después de ajustar por edad, estadio del cáncer, comorbilidades y SVI, los pacientes de raza negra tenían una mayor tasa de fragilidad en comparación con los pacientes de raza blanca (ORa 3,77, IC del 95%: 1,76-8,18; p = 0,01). Además, los pacientes negros tenían más limitaciones físicas (caminar 1 cuadra: ORa 1,93, IC 95% 1,02-3,69; p = 0,04), limitaciones funcionales (actividades de la vida diaria: ORa 3,21, IC 95% 1,42-7,24; p = 0,01 ) y déficits en la calidad de vida relacionada con la salud (mala salud global autoinformada: ORa 2,45, IC 95% 1,23-5,13; p = 0,01). Las quejas cognitivas y las funciones psicológicas no difirieron según la raza (p > 0,05). Se mostraron hallazgos similares después de la estratificación por estadio I-III frente a IV.LIMITACIONES: Estudio retrospectivo en una sola institución.CONCLUSIONES: Entre los pacientes mayores con cáncer colorrectal, los pacientes negros tenían más probabilidades que los pacientes blancos de ser frágiles, observándose déficits específicamente en la función física, el estado funcional y la calidad de vida relacionada con la salud. La evaluación geriátrica puede proporcionar una herramienta importante para abordar las desigualdades raciales en el cáncer colorrectal.

Preserving the Pipeline of Surgeon Scientists: The Role of a Structured Research Curriculum.

INTRODUCTION: With shrinking National Institute of Health support, increased clinical demands, and less time for research training during residency, the future of surgeon scientists is in jeopardy. We evaluate the role of a structured research curriculum and its association with resident academic productivity. METHODS: Categorical general surgery residents who matched between 2005 and 2019 at our institution were analyzed (n = 104). An optional structured research curriculum, including a mentor program, grant application support, didactic seminars, and travel funding was implemented in 2016. Academic productivity, including the number of publications and citations, was compared between residents who started in or after 2016 (postimplementation, n = 33) and those before 2016 (preimplementation, n = 71). Descriptive statistics, Mann-Whitney U test, multivariable logistic regression, and inverse probability treatment weighting were performed. RESULTS: The postimplementation group had more female (57.6% versus 31.0%, P = 0.010), and nonwhite (36.4% versus 5.6%, P < 0.001) residents and had more publications and citations at the start of residency (P < 0.001). Postimplementation residents were more likely to choose academic development time (ADT) (66.7% versus 23.9%, P < 0.001) and had higher median (IQR) number of publications (2.0 (1.0-12.5) versus 1.0 (0-5.0), P = 0.028) during residency. After adjusting the number of publications at the start of residency, multivariable logistic regression analysis showed that the postimplementation group was five times more likely to choose ADT (95% CI 1.7-14.7, P = 0.04). Further, inverse probability treatment weighting revealed an increase of 0.34 publications per year after implementing the structured research curriculum among residents who chose ADT (95% CI 0.1-0.9, P = 0.023). CONCLUSIONS: A structured research curriculum was associated with increased academic productivity and surgical resident participation in dedicated ADT. A structured research curriculum is effective and should be integrated into residency training to support the next generation of academic surgeons.

NIH Funding of Researchers in Surgery: Decreased Career Development Awards Over Time.

BACKGROUND: Over time, NIH funding has become increasingly competitive. In addition, academic surgeons' research competes with time required for patient care, operating, and administrative work. Due to these competing interests for surgeons, we hypothesize that the percentage of NIH grants awarded to researchers from departments of surgery is decreasing. METHODS: The NIH Research Portfolio Online Reporting Tool was queried for the number and value of new and renewal R01 grants, and career development awards noting which surgery departments received awards from 1998 to -2018. Statistical analysis was performed using univariate and multivariable logistic regression. RESULTS: The number of career development awards granted to researchers from departments of surgery decreased significantly over time (P = 0.007) while new R01's and R01 renewal awards were stable. The number of grants awarded to researchers from all procedural departments were compared to non-procedural departments and again, career development awards decreased significantly (P = 0.005) over time but new R01's and R01 renewals stayed stable. Looking at the difference in average dollar amount received for new R01, renewal R01, or career development awards between department of surgery awardees and non-surgery over time, there was no significant difference. CONCLUSIONS: NIH funding is becoming increasingly competitive and surgeons have many competing interests. Our study found that there has been a significant decrease in career development awards to department of surgery awardees and procedural specialists. The decrease in receipt of these awards is particularly concerning given that they are meant to provide protected time for developing researchers and thus have potential consequences for future research.

Characteristics of Patients Seeking Second Opinions at a Multidisciplinary Colorectal Cancer Clinic.

BACKGROUND: Patients seeking second opinions are a challenge for the colorectal cancer provider because of complexity, failed therapeutic relationship with another provider, need for reassurance, and desire for exploration of treatment options. OBJECTIVE: The purpose of this study was to describe the patient and treatment characteristics of patients seeking initial and second opinions in colorectal cancer care at a multidisciplinary colorectal cancer clinic. DESIGN: This was a retrospective cohort study. SETTINGS: A prospectively collected clinical registry of a multidisciplinary colorectal cancer clinic was included. PATIENTS: The study included patients with colon or rectal cancer seen from 2012 to 2017. MAIN OUTCOME MEASURES: Data were analyzed for initial versus second opinion and demographic and clinical characteristics. RESULTS: Of 1711 patients with colorectal cancer, 1008 (58.9%) sought an initial opinion and 700 (40.9%) sought a second opinion. As compared with initial-opinion patients, second-opinion patients were more likely to have stage IV disease (OR = 1.94 (95% CI, 1.47-2.58)), recurrent disease (OR = 1.67 (95% CI, 1.13-2.46)), and be ages 40 to 49 years (OR = 1.47 (95% CI, 1.02-2.12)). Initial- and second-opinion cohorts were similar in terms of sex, race, and proportion of colon versus rectal cancer. Among second-opinion patients, 246 (35%) transitioned their care to the multidisciplinary colorectal cancer clinic. LIMITATIONS: We were unable to capture the final treatment plan for those patients who did not transfer care to the multidisciplinary colorectal cancer clinic. CONCLUSIONS: Patients seeking a second opinion represent a unique subset of patients with colorectal cancer. In general, they are younger and more likely to have stage IV or recurrent disease than patients seeking an initial opinion. Although transfer of care to a multidisciplinary colorectal cancer clinic after second opinion is lower than for initial consultations, multidisciplinary colorectal cancer clinics provide an important role for patients with complex disease characteristics and treatment needs. See Video Abstract at http://links.lww.com/DCR/B192. CARACTERíSTICAS DE LOS PACIENTES QUE BUSCAN UNA SEGUNDA OPINIóN EN CLíNICAS MULTIDISCIPLINARIAS ESPECIALIZADAS EN CáNCER COLORECTAL: Los pacientes que buscan una segunda opinión son un desafío para el médico que trata el cáncer colorrectal debido a la complejidad de la situación, a la relación terapéutica fallida con otro especialista, a la necesidad de tranquilidad y el deseo de explorar otras opciones del tratamiento.El describir las características y el tratamiento de los pacientes que buscan opiniones iniciales y secundarias en la atención del cáncer colorrectal en una clínica especializada de manera multidisciplinaria en cáncer colorrectal.Este es un estudio de cohortes retrospectivo.Registro clínico de casos obtenidos prospectivamente en una clínica especializada de manera multidisciplinaria en cáncer colorrectal.Todos aquellos pacientes con cáncer de colon o recto examinados entre 2012-2017.Se analizaron los datos obtenidos en la opinión inicial y se compararon con la segunda opinión, se revisaron tanto sus características demográficas como clínicas.De 1711 pacientes con cáncer colorrectal, 1008 (58.9%) buscaron una opinión inicial, 700 (40.9%) buscaron una segunda opinión. En comparación con los pacientes de opinión inicial, los pacientes de segunda opinión presentaron más probabilidades de tener enfermedad en estadio IV (OR 1.94, IC 95% 1.47-2.58), enfermedad recurrente (OR 1.67, IC 95% 1.13-2.46) y tener edades entre 40 y 49 (O 1.47, IC 95% 1.02-2.12). Las cohortes iniciales y de segunda opinión fueron similares en términos de género, raza y proporción del cáncer de colon versus cáncer de recto. Entre los pacientes de segunda opinión, 246 (35%) transfirieron su tratamiento hacia una clínica multidisplinaria especializada en cáncer colorrectal.No se obtuvieron los planes del tratamiento final de aquellos pacientes que no transfirieron sus cuidados hacia una la clínica especializada en cáncer colorrectal.Los pacientes que buscan una segunda opinión representan un subconjunto único de personas con cáncer colorrectal. En general, son más jóvenes y tienen más probabilidades de tener enfermedad en estadio IV o recurrente, con relación a aquellos pacientes que buscan una opinión inicial. Aunque la transferencia de los cuidados hacia una clínica multidisciplinaria especializada en cáncer colorrectal después de una segunda opinión es menor que para las consultas iniciales. Las clínicas multidisciplinarias especializadas en cáncer colorrectal juegan un papel importante con los pacientes que tienen características complejas de enfermedad y necesidades particulares en el tratamiento. Consulte Video Resumen en http://links.lww.com/DCR/B192. (Traducción-Dr Xavier Delgadillo).

Use of Accelerated Induction Strategy of Infliximab for Ulcerative Colitis in Hospitalized Patients at a Tertiary Care Center.

BACKGROUND: Infliximab can prevent colectomy in patients hospitalized with acute severe ulcerative colitis (ASUC). In cases of ASUC, fecal losses of infliximab may lead to low drug levels and reduced efficacy. AIM: To determine 90-day colectomy risk and postoperative complications in patients receiving single-dose and accelerated induction of infliximab for ASUC. METHODS: We conducted a retrospective review of patients hospitalized with ASUC requiring infliximab therapy between 2013 and 2017 at the University of Michigan. Patients were excluded if they had an enteric infection, received an anti-TNF previously, or received cyclosporine during the same admission. The primary outcome was colectomy within 90 days of admission. Patients receiving single-dose induction infliximab were compared to those receiving accelerated rescue induction with two doses of infliximab prior to day 14. Administration of accelerated induction was guided by a protocol, suggesting administering a second dose of infliximab to those with only a partial response in CRP 3 days after the initial dose. Postoperative outcomes including 30-day readmission rates and complications were compared using descriptive statistics. RESULTS: From 2013 to 2017, 66 patients with ASUC met our criteria. Thirty-three received accelerated induction (50.0%). The colectomy rate in the accelerated induction group was 30.3% versus 24.2% in the single-dose induction group (p = 0.58). There was no detected difference in postoperative outcomes between the accelerated and single-dose rescue induction. CONCLUSIONS: In this retrospective review, 69.7% of those failing to respond to single-dose infliximab were able to avoid colectomy with an accelerated rescue induction strategy without worsening postoperative outcomes. Larger studies of accelerated dosing infliximab are needed.

Patient-Reported Unmet Needs in Colorectal Cancer Survivors After Treatment for Curative Intent.

BACKGROUND: With improving survival from colorectal cancer, there is a growing population of patients undergoing surveillance. National accreditation organizations have increasingly endorsed formal survivorship care planning. To effectively design patient-centered survivorship programs, an understanding of the prevalence of unmet psychosocial and symptomatic needs is required. OBJECTIVE: The aim of this study is to understand the breadth of unmet needs among survivors of colorectal cancer. DESIGN: This is a cross-sectional survey of patients undergoing surveillance after curative-intent therapy for colorectal cancer. SETTING: This study was conducted June 2017 to January 2018 at an academic cancer center. PATIENTS: There were 99 patients (58 with colon cancer, 41 with rectal cancer). MAIN OUTCOME MEASURES: We measured patient-reported unmet needs by using a modification of the Cancer Survivor Unmet Needs instrument, within domains of emotional (stress, concerns about recurrence), relationship (fertility, interpersonal), logistical (need for accessible parking, case management), financial, treatment-related (neuropathy, bowel function), and surveillance-related needs. RESULTS: The mean (±SD) age was 58 (±12), and the time from diagnosis was 34 (±18) months. Overall, 74% of patients reported at least one unmet need, 49% reported emotional needs, 24% relationship needs, 24% financial needs, 25% logistical needs, and 33% surveillance needs. Thirty-six (62%) patients with colon cancer and 37 (90%) patients with rectal cancer reported at least one ongoing problem (p = 0.002). Thirty-five (82%) patients with rectal cancer reported an unmet treatment-related need in comparison with 23 (40%) patients with colon cancer (p < 0.001). The median (interquartile range) number of ongoing needs were 1 (0-5) in patients with colon cancer and 4 (2-8) in patients with rectal cancer (p = 0.007). LIMITATIONS: This study was limited by its small sample size and lack of generalizability, given the tertiary care setting. CONCLUSIONS: The majority of colorectal cancer survivors reported unmet needs years after completion of curative-intent therapy. Patients with rectal cancer were significantly more likely to have unmet needs and may benefit from additional care during survivorship. Colorectal cancer survivorship programs should incorporate psychosocial and symptomatic care in addition to cancer surveillance. See Video Abstract at http://links.lww.com/DCR/A885.

Clinical and pathological outcomes of induction chemotherapy before neoadjuvant radiotherapy in locally-advanced rectal cancer.

BACKGROUND AND OBJECTIVES: In North America, preoperative combination chemoradiation is the most commonly recommended and utilized approach to locally advanced rectal cancer. There is increasing interest in the use of induction chemotherapy (IC) before radiation and surgery in locally advanced rectal cancer. How widely IC is being used and whether it improves pathologic and oncologic outcomes is unknown. METHODS: We evaluated clinical stage 2 or 3 rectal cancer patients in the National Cancer Database between 2006 and 2015. We identified predictors of use of IC with multivariable logistic regression and compared survival between groups using Cox proportional hazards regression. RESULTS: Among 36 268 patients, IC use increased significantly over time from 5.5% in 2006 to 15.9% in 2015 (P < 0.001). Treatment at a hospital with a high IC rate was an independent predictor of receipt of IC. IC and traditional therapy yielded similar pathologic complete response rates (32.2% vs 30.5%, P = 0.2) and similar 5-year survival (82.4% vs 81.4%, 0.71). CONCLUSIONS: Use of IC for locally advanced rectal cancer has increased significantly. The choice of IC seems to be driven more by institutional and regional practice patterns than clinical characteristics and is not associated with improved pathologic or oncologic outcomes.

Surgical management of primary colonic lymphoma: Big data for a rare problem.

BACKGROUND AND OBJECTIVES: Primary colonic lymphoma (PCL) is rare, heterogeneous, and presents a therapeutic challenge for surgeons. Optimal treatment strategies are difficult to standardize, leading to variation in therapy. Our objective was to describe the patient characteristics, short-term outcomes, and five-year survival of patients undergoing nonpalliative surgery for PCL. METHODS: We performed a retrospective cohort analysis in the National Cancer Database. Included patients underwent surgery for PCL between 2004 to 2014. Patients with metastases and palliative operations were excluded. Univariate predictors of overall survival were analyzed using multivariable Cox proportional hazard analysis. RESULTS: We identified 2153 patients. Median patient age was 68. Diffuse large B-cell lymphoma accounted for 57% of tumors. 30- and 90-Day mortality were high (5.6% and 11.1%, respectively). Thirty-nine percent of patients received adjuvant chemotherapy. For patients surviving 90 days, 5-year survival was 71.8%. Chemotherapy improved survival (surgery+chemo, 75.4% vs surgery, 68.6%; P = .01). Adjuvant chemotherapy was associated with overall survival after controlling for age, comorbidity, and lymphoma subtype (HR 1.27; 95% CI, 1.07-1.51; P = .01). CONCLUSIONS: Patients undergoing surgery for PCL have high rates of margin positivity and high short-term mortality. Chemotherapy improves survival, but <50% receive it. These data suggest the opportunity for improvement of care in patients with PCL.

Biology of Nodal Spread in Colon Cancer: Insights from Molecular and Genetic Studies.

Colorectal cancer (CRC) lymph node metastases are common but their genetics and the mechanism whereby these metastases occur are not well understood. Here we present recent data regarding genetic heterogeneity in primary CRCs and their metastasis. In addition, we explain the different potential models describing the mechanisms of metastasis and the data supporting them. Multiple studies have also revealed a variety of prognostic molecular markers that are associated with lymph node metastasis in CRC. A better understanding of genetic heterogeneity and the mechanisms of metastasis is critical to predicting clinical response and resistance to targeted therapy.

Update on Sporadic Colorectal Cancer Genetics.

Our understanding of the genetics of colorectal cancer has changed dramatically over recent years. Colorectal cancer can be classified in multiple different ways. Along with the advent of whole-exome sequencing, we have gained an understanding of the scale of the genetic changes found in sporadic colorectal cancer. We now know that there are multiple pathways that are commonly involved in the evolution of colorectal cancer including Wnt/ß-catenin, RAS, EGFR, and PIK3 kinase. Another recent leap in our understanding of colorectal cancer genetics is the recognition that many, if not all tumors, are actually genetically heterogeneous within individual tumors and also between tumors. Recent research has revealed the prognostic and possibly therapeutic implications of various specific mutations, including specific mutations in BRAF and KRAS . There is increasing interest in the use of mutation testing for screening and surveillance through stool and circulating DNA testing. Recent advances in translational research in colorectal cancer genetics are dramatically changing our understanding of colorectal cancer and will likely change therapy and surveillance in the near future.

Intra-tumor genetic heterogeneity in rectal cancer.

Colorectal cancer arises in part from the cumulative effects of multiple gene lesions. Recent studies in selected cancer types have revealed significant intra-tumor genetic heterogeneity and highlighted its potential role in disease progression and resistance to therapy. We hypothesized the existence of significant intra-tumor genetic heterogeneity in rectal cancers involving variations in localized somatic mutations and copy number abnormalities. Two or three spatially disparate regions from each of six rectal tumors were dissected and subjected to the next-generation whole-exome DNA sequencing, Oncoscan SNP arrays, and targeted confirmatory sequencing and analysis. The resulting data were integrated to define subclones using SciClone. Mutant-allele tumor heterogeneity (MATH) scores, mutant allele frequency correlation, and mutation percent concordance were calculated, and copy number analysis including measurement of correlation between samples was performed. Somatic mutations profiles in individual cancers were similar to prior studies, with some variants found in previously reported significantly mutated genes and many patient-specific mutations in each tumor. Significant intra-tumor heterogeneity was identified in the spatially disparate regions of individual cancers. All tumors had some heterogeneity but the degree of heterogeneity was quite variable in the samples studied. We found that 67-97% of exonic somatic mutations were shared among all regions of an individual's tumor. The SciClone computational method identified 2-8 shared and unshared subclones in the spatially disparate areas in each tumor. MATH scores ranged from 7 to 41. Allele frequency correlation scores ranged from R(2)=0.69-0.96. Measurements of correlation between samples for copy number changes varied from R(2)=0.74-0.93. All tumors had some heterogeneity, but the degree was highly variable in the samples studied. The occurrence of significant intra-tumor heterogeneity may allow selected tumors to have a genetic reservoir to draw from in their evolutionary response to therapy and other challenges.

Colorectal cancer outcomes and treatment patterns in patients too young for average-risk screening.

BACKGROUND: Although colorectal cancer (CRC) screening guidelines recommend initiating screening at age 50 years, the percentage of cancer cases in younger patients is increasing. To the authors' knowledge, the national treatment patterns and outcomes of these patients are largely unknown. METHODS: The current study was a population-based, retrospective cohort study of the nationally representative Surveillance, Epidemiology, and End Results registry for patients diagnosed with CRC from 1998 through 2011. Patients were categorized as being younger or older than the recommended screening age. Differences with regard to stage of disease at diagnosis, patterns of therapy, and disease-specific survival were compared between age groups using multinomial regression, multiple regression, Cox proportional hazards regression, and Weibull survival analysis. RESULTS: Of 258,024 patients with CRC, 37,847 (15%) were aged <50 years. Young patients were more likely to present with regional (relative risk ratio, 1.3; P<.001) or distant (relative risk ratio, 1.5; P<.001) disease. Patients with CRC with distant metastasis in the younger age group were more likely to receive surgical therapy for their primary tumor (adjusted probability: 72% vs 63%; P<.001), and radiotherapy also was more likely in younger patients with CRC (adjusted probability: 53% vs 48%; P<.001). Patients younger than the recommended screening age had better overall disease-specific survival (hazards ratio, 0.77; P<.001), despite a larger percentage of these individuals presenting with advanced disease. CONCLUSIONS: Patients with CRC diagnosed at age <50 years are more likely to present with advanced-stage disease. However, they receive more aggressive therapy and achieve longer disease-specific survival, despite the greater percentage of patients with advanced-stage disease. These findings suggest the need for improved risk assessment and screening decisions for younger adults.

Sigmoid diverticulitis: a systematic review.

IMPORTANCE: Diverticulitis is a common disease. Recent changes in understanding its natural history have substantially modified treatment paradigms. OBJECTIVE: To review the etiology and natural history of diverticulitis and recent changes in treatment guidelines. EVIDENCE REVIEW: We searched the MEDLINE and Cochrane databases for English-language articles pertaining to diagnosis and management of diverticulitis published between January 1, 2000, and March 31, 2013. Search terms applied to 4 thematic topics: pathophysiology, natural history, medical management, and indications for surgery. We excluded small case series and articles based on data accrued prior to 2000. We hand searched the bibliographies of included studies, yielding a total of 186 articles for full review. We graded the level of evidence and classified recommendations by size of treatment effect, according to the guidelines from the American Heart Association Task Force on Practice Guidelines. FINDINGS: Eighty articles met criteria for analysis. The pathophysiology of diverticulitis is associated with altered gut motility, increased luminal pressure, and a disordered colonic microenvironment. Several studies examined histologic commonalities with inflammatory bowel disease and irritable bowel syndrome but were focused on associative rather than causal pathways. The natural history of uncomplicated diverticulitis is often benign. For example, in a cohort study of 2366 of 3165 patients hospitalized for acute diverticulitis and followed up for 8.9 years, only 13.3% of patients had a recurrence and 3.9%, a second recurrence. In contrast to what was previously thought, the risk of septic peritonitis is reduced and not increased with each recurrence. Patient-reported outcomes studies show 20% to 35% of patients managed nonoperatively progress to chronic abdominal pain compared with 5% to 25% of patients treated operatively. Randomized trials and cohort studies have shown that antibiotics and fiber were not as beneficial as previously thought and that mesalamine might be useful. Surgical therapy for chronic disease is not always warranted. CONCLUSIONS AND RELEVANCE: Recent studies demonstrate a lesser role for aggressive antibiotic or surgical intervention for chronic or recurrent diverticulitis than was previously thought necessary.

ST6GAL1 is associated with poor response to chemoradiation in rectal cancer.

INTRODUCTION: Colorectal cancer is the third most common cause of cancer death. Rectal cancer makes up a third of all colorectal cases. Treatment for locally advanced rectal cancer includes chemoradiation followed by surgery. We have previously identified ST6GAL1 as a cause of resistance to chemoradiation in vitro and hypothesized that it would be correlated with poor response in human derived models and human tissues. METHODS: Five organoid models were created from primary human rectal cancers and ST6GAL1 was knocked down via lentivirus transduction in one model. ST6GAL1 and Cleaved Caspase-3 (CC3) were assessed after chemoradiation via immunostaining. A tissue microarray (TMA) was created from twenty-six patients who underwent chemoradiation and had pre- and post-treatment specimens of rectal adenocarcinoma available at our institution. Immunohistochemistry was performed for ST6GAL1 and percent positive cancer cell staining was assessed and correlation with pathological grade of response was measured. RESULTS: Organoid models were treated with chemoradiation and both ST6GAL1 mRNA and protein significantly increased after treatment. The organoid model targeted with ST6GAL1 knockdown was found to have increased CC3 after treatment. In the tissue microarray, 42 percent of patient samples had an increase in percent tumor cell staining for ST6GAL1 after treatment. Post-treatment percent staining was associated with a worse grade of treatment response (p = 0.01) and increased staining post-treatment compared to pre-treatment was also associated with a worse response (p = 0.01). CONCLUSION: ST6GAL1 is associated with resistance to treatment in human rectal cancer and knockdown in an organoid model abrogated resistance to apoptosis caused by chemoradiation.