Medical Management of Inflammatory Bowel Disease.

The past few decades have seen significant advancements in the medical management of both ulcerative colitis (UC) and Crohn's disease (CD). The previous dependence on steroids is no longer an acceptable strategy following the Food and Drug Administration approval for several new classes of medication. These medications include aminosalicylates, immunomodulators, biologics, and oral targeted small-molecule inhibitors. This article highlights several key trials and discusses modern treatment paradigms for both UC and CD based on disease severity.

Colorectal Neoplasia in the Setting of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (colorectal adenocarcinoma [CRC]) compared with the general population. IBD-related CRC is related to poorer outcomes than non-IBD-related CRC, and it accounts for 10% to 15% of death in patients with IBD. As such, screening guidelines have been made specific to this population recommending shorter intervals of endoscopic screening to detect dysplasia and CRC relative to the general population. Advances in endoscopic technology allow for improved visualization of dysplasia, which has led to widespread adoption of dye-spray chromoendoscopy with targeted biopsy.

Colorectal Disease and the Gut Microbiome: What a Surgeon Needs to Know.

The gut microbiome is defined as the microorganisms that reside within the gastrointestinal tract and produce a variety of metabolites that impact human health. These microbes play an intricate role in human health, and an imbalance in the gut microbiome, termed gut dysbiosis, has been implicated in the development of varying diseases. The purpose of this review is to highlight what is known about the microbiome and its impact on colorectal cancer, inflammatory bowel disease, constipation, Clostridioides difficile infection, the impact of bowel prep, and anastomotic leaks.

Evaluation and Management of Malignant Colorectal Polyps.

The detection rate of dysplastic colorectal polyps has significantly increased with improved screening programs. Treatment of dysplastic polyps attempt to limit morbidity of a procedure while also considering the risk of occult lymph node metastasis. Therefore, a variety of methods have been developed to predict the rate of lymph node metastasis to help identify the optimal treatment of patients. These include both the endoscopic and pathologic assessment of the lesion. In order to reduce the morbidity of surgery for patients with low-risk lesions, multiple endoscopic therapies have been developed, including endoscopic mucosal resection, endoscopic submucosal dissection, endoscopic intermuscular dissection, and transanal endoscopic surgery.

Combinatorial Inhibition of Complement Factor D and BCL2 for Early-Onset Colorectal Cancer.

BACKGROUND: The tumor immune microenvironment is distinct between early-onset and late-onset colorectal cancer, which facilitates tumor progression. We previously identified several genes, including complement factor D, as having increased expression in patients with early-onset colorectal cancer. OBJECTIVE: This study aimed to assess and validate the differential expression of immune genes in early-onset and late-onset colorectal cancer. We also aimed to test known drugs targeting genes increased in early-onset colorectal cancer in preclinical mouse models. DESIGN: A retrospective cohort study with analysis was performed using tumor RNA from formalin-fixed paraffin-embedded cell culture and immunohistochemistry to validate gene expression and function and in vivo preclinical tumor study to assess drug efficacy. SETTINGS: The Oregon Colorectal Cancer Registry was queried to identify patients with colorectal cancer. PATIENTS: The study included 67 patients with early-onset colorectal cancer and 54 patients with late-onset colorectal cancer. INTERVENTIONS: Preclinical animal models using the HCT-116 colon cancer cell line were treated with the complement factor D inhibitor danicopan and the BCL2 inhibitor venetoclax, or with vehicle controls. MAIN OUTCOME MEASURES: Elevated RNA signatures using NanoString data were evaluated by the retrospective cohort. When inhibiting these markers in the mouse preclinical model, tumor volume and weight were the main outcome measures. RESULTS: After updating our sample size from our previously published data, we found that complement factor D and BCL2, genes with known function and small molecule inhibitors, are elevated in patients with early-onset colorectal cancer. When inhibiting these markers with the drugs danicopan and venetoclax in a mouse model, we found that the combination of these drugs decreased tumor burden but also resulted in toxicity. LIMITATIONS: This study is limited by a small sample size and a subcutaneous tumor model. CONCLUSIONS: Combinatorial inhibition of early-onset associated genes complement factor D and BCL2 slows the growth of early-onset colorectal cancer in a mouse preclinical model. See Video Abstract . INHIBICIN COMBINADA DEL FACTOR DCOMPLEMENTARIO Y DEL BCL EN CASOS DE CNCER COLORRECTAL DE APARICIN TEMPRANA: ANTECEDENTES:El microambiente inmunológico del tumor es distinto entre el cáncer colorrectal de aparición temprana y el de aparición tardía, lo que facilita la progresión de dicho tumor. Anteriormente identificamos varios genes, incluidos el factor D-Complementario, con una mayor expresión en pacientes con cáncer colorrectal de aparición temprana.OBJETIVO:El presente estudio tuvo como objetivo el evaluar y validar la expresión diferenciada de genes inmunes en casos de cáncer colorrectal de aparición temprana y tardía. También nos propusimos evaluar los fármacos conocidos dirigidos sobre los genes aumentados en el cáncer colorrectal de aparición temprana en modelos pre-clínicos en ratones.DISEÑO:Estudio de cohortes con análisis retrospectivo utilizando el ARN tumoral procedente de cultivos celulares fijados con formalina e incluidos en parafina, y el analisis por inmunohistoquímica para validar la expresión y la función genética. Se realizó el estudio pre-clínico de los tumores in vivo para evaluar la eficacia de los fármacos.AJUSTES:Se consultó el Registro de Oregon de casos de Cáncer Colorrectal para encontrar los pacientes afectados.SUJETOS:67 pacientes con cáncer colorrectal de aparición temprana y 54 pacientes con cáncer colorrectal de aparición tardía.INTERVENCIONES (SI LAS HUBIESE):Los modelos animales pre-clínicos que utilizaron la línea celular de cáncer de colon HCT-116 se trataron con el inhibidor del factor D-Complementario o Danicopan y con el inhibidor de BCL-2 o Venetoclax, ambos con control del transportador.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluaron las firmas de ARN elevadas utilizando los datos del NanoString a partir de la cohorte retrospectiva. Al inhibir estos marcadores del modelo pre-clínico en los ratones, el volumen y el peso del tumor fueron las principales medidas de resultado.RESULTADOS:Después de actualizar el tamaño de nuestra muestra a partir de datos publicados con anterioridad, encontramos que el factor D-Complementario y BCL-2, genes con función conocida e inhibidores de moléculas pequeñas, se encuentran elevados en aquellos pacientes con cáncer colorrectal de aparición temprana. Al inhibir estos marcadores con los medicamentos Danicopan y Venetoclax en el modelo de ratones vivos, encontramos que la combinación de estos dos farmacos disminuyó la carga tumoral pero también produjo toxicidad.LIMITACIONES:Estudio limitado por un tamaño de muestra pequeño y el modelo de tumor subcutáneo.CONCLUSIONES:La inhibición combinada de genes asociados de aparición temprana, el factor D-Complementario y el BCL-2, enlentecen el crecimiento del cáncer colorrectal de aparición temprana del modelo preclínico en ratones. (Traducción-Dr. Xavier Delgadillo ).

Gut microbial metabolites and its impact on human health.

One of the primary methods by which the gut microbiome interacts with its host is through the interactions that occur through the production of the metabolites produced, either directly, or indirectly, through microbial metabolism. Decades of research has demonstrated that these metabolic products play a vital role in human health, either for its benefit or detriment. This review article highlights the main metabolites produced by the interactions between diet and the gut microbiome, bile acids and the gut microbiome, and products produced by the gut microbiome alone. Additionally, this article reviews the literature on the effects that these metabolites play on human health.

Dietary and lifestyle associations with microbiome diversity.

BACKGROUND: Microbial dysbiosis has been closely linked with colorectal cancer development. However, data is limited regarding the relationship of the mucosal microbiome, adenomatous polyps and dietary habits. Understanding these associations may elucidate pathways for risk stratification according to diet. RESULTS: Patients undergoing screening colonoscopy were included in our prospective, single center study and divided into adenoma or no adenoma cohorts. Oral, fecal, and mucosal samples were obtained. Microbial DNA was extracted, and amplicon libraries generated using primers for the 16S rRNA gene V4 region. Patient and dietary information was collected. Of 104 participants, 44% presented with polyps, which were predominantly tubular adenomas (87%). Adenoma formation and multiple patient dietary and lifestyle characteristics were associated with mucosal microbiome diversity. Lifestyle factors included age, body mass index, adenoma number, and dietary consumption of red meats, processed meats, vegetables, fruit, grain, fermented foods and alcohol. CONCLUSION: In this study we showed associations between dietary habits, adenoma formation and the mucosal microbiome. These early findings suggest that ongoing research into diet modification may help reduce adenoma formation and subsequently the development of CRC.

The evolution of rectal cancer treatment: the journey to total neoadjuvant therapy and organ preservation.

There has been a staggering increase in the incidence of rectal cancer, drawing our attention to early detection and optimization of its medical and surgical treatment. With this review we highlight all the major trials that revolutionized rectal cancer management and improved oncologic outcomes. We present the origins of the trimodal therapy and the studies that supported the sequence of treatment. We describe the evolution in surgical management with total mesorectal excision as the standard of care, and we review the most impactful short- vs. long-course long-course radiation therapy trials. Today, the current standard of care for non-metastatic locally advanced rectal cancer includes preoperative chemoradiation with either induction or consolidation chemotherapy, total mesorectal excision and adjuvant therapy. We discuss the advent of the "watch and wait" strategy for patients who have a complete clinical response after total neoadjuvant treatment, as well as possible future directions in the treatment of locoregional disease.

Conservative management of malignant colorectal polyps in select cases is safe in long-term follow-up: An institutional review.

BACKGROUND: Non-operative management of early-stage polypectomy-identified colorectal cancer (CRC) may be a safe alternative, but limited data exist. METHODS: We compared outcomes between adults with post-polypectomy CRC who did and did not ultimately undergo resection from 2003 to 2018. Overall (OS) and recurrence-free (RFS) survival were calculated via log rank analysis using the Mantel-Cox method and plotted on Kaplan-Meier curves with significance evaluated at P < 0.05. RESULTS: N = 78 patients were included, most commonly with rectal/rectosigmoid CRC (45%). Almost half (47%) had resections, and the remaining 41 patients (53%) underwent organ-sparing techniques. Chemoradiation was administered to 5 of these 41 patients (12%), all with rectal cancer. At median follow-up of 52 months, 5-year OS and RFS were 78% and 100% with no significant differences when compared to resection (all P > 0.1). DISCUSSION: Using evidence-based patient selection and adjuvant therapy, organ-sparing management provides equal survival when compared to resection for post-polypectomy CRC.

Emerging evidence and recent controversies in diverticulitis: a 5-year review.

Diverticulitis is a common gastrointestinal disease that still garners significant attention and study because of its heterogeneity in presentation and outcome. We provide a review of the newest and most controversial topics in diverticulitis. Recent discoveries on the influence of diet and other environmental risk factors are discussed, showing how the epidemiology of the disease process is shifting away from what was previously felt to be a disorder primarily limited to older western populations. Interestingly, as has long been suspected, genetic mutations and variations associated with the development of diverticulitis are being discovered and are summarized here. The data for non-operative and outpatient management of diverticulitis are reviewed, as are pharmacologic agents studied for use in the secondary prevention of diverticulitis. Lastly, we present controversies in the surgical treatment of diverticulitis. This review will provide a synopsis of the last 5 years of literature relating to diverticulitis.

First experience in clinical application of hyperspectral endoscopy for evaluation of colonic polyps.

Early detection and resection of adenomatous polyps prevents their progression to colorectal cancer (CRC), significantly improving patient outcomes. Polyps are typically identified and removed during white-light colonoscopy. Unfortunately, the rate of interval cancers that arise between CRC screening events remains high, linked to poor visualization of polyps during screening and incomplete polyp removal. Here, we sought to evaluate the potential of a hyperspectral endoscope (HySE) to enhance polyp discrimination for detection and resection. We designed, built and tested a new compact HySE in a proof-of-concept clinical study. We successfully collected spectra from three tissue types in seven patients undergoing routine colonoscopy screening. The acquired spectral data from normal tissue and polyps, both pre- and post- resection, were subjected to quantitative analysis using spectral angle mapping and machine learning, which discriminated the data by tissue type, meriting further investigation of HySE as a clinical tool.

Differential Expression of PEG10 Contributes to Aggressive Disease in Early Versus Late-Onset Colorectal Cancer.

BACKGROUND: Colorectal cancer is a leading cause of cancer-related death. Early onset colorectal cancer (age ≤45 y) is increasing and associated with advanced disease. Although distinct molecular subtypes of colorectal cancer have been characterized, it is unclear whether age-related molecular differences exist. OBJECTIVE: We sought to identify differences in gene expression between early and late-onset (age ≥65 y) colorectal cancer. DESIGN: We performed a review of our institution's colorectal cancer registry and identified patients with colorectal cancer with tissue specimens available for analysis. We used the Cancer Genome Atlas to initially identify differences in gene expression between early and late-onset colorectal cancer. In vitro experiments were performed on 2 colorectal cancer cell lines. SETTINGS: The study was conducted at a tertiary medical center. PATIENTS: Patients with early onset (n = 28) or late onset (age ≥65 y; n = 38) at time of diagnosis were included. MAIN OUTCOME MEASURES: The primary outcome was differential gene expression in patients with early versus late-onset colorectal cancer. The secondary outcome was patient mortality. RESULTS: Seven genes had increased expression in younger patients using The Cancer Genome Atlas. Only PEG10 was sufficiently expressed with quantitative polymerase chain reaction and had increased expression in our early onset group. Multivariable linear regression analysis identified age as a significant independent predictor of increased PEG10 expression. Outcomes data from The Cancer Genome Atlas suggests that PEG10 is associated with poor overall survival. In vitro studies in HCT-116 and HT-29 cell lines showed that PEG10 contributes to cellular proliferation and invasion in colorectal cancer. LIMITATIONS: Tissue samples were from formalin-fixed, paraffin-embedded sections. Many patients did not have mutational status for review. CONCLUSIONS: PEG10 is differentially expressed in early onset colorectal cancer and may functionally contribute to tumor cell proliferation and invasion. An increase in PEG10 expression correlates with decreased overall survival. See Video Abstract at http://links.lww.com/DCR/B343. LA EXPRESIÓN DIFERENCIAL DE PEG10 CONTRIBUYE A LA ENFERMEDAD AGRESIVA EN EL CÁNCER COLORRECTAL DE INICIO TEMPRANO VERSUS INICIO TARDÍO: El cáncer colorrectal es una de las principales causas de muerte relacionada con el cáncer. El cáncer colorrectal de inicio temprano (edad ≤45 años) está en aumento y asociado con enfermedad avanzada. Aunque se han caracterizado distintos subtipos moleculares del cáncer colorrectal, no está claro si existen diferencias moleculares relacionadas con la edad.Se buscó identificar diferencias en la expresión génica entre el cáncer colorrectal de inicio temprano y tardío (edad ≥ 65 años).Realizamos una revisión del registro de cáncer colorrectal de nuestra institución e identificamos pacientes con cáncer colorrectal con muestras de tejido disponibles para su análisis. Utilizamos el Atlas del Genoma del Cáncer para identificar inicialmente las diferencias en la expresión génica entre el cáncer colorrectal de inicio temprano y de inicio tardío. Se realizaron experimentos in vitro en dos líneas celulares de cáncer colorrectal.El estudio se realizó en un centro médico de tercer nivel.Se incluyeron pacientes con inicio temprano (n = 28) e inicio tardío (edad ≥65 años, n = 38) al momento del diagnóstico.El resultado primario fue la expresión diferencial de genes en pacientes con cáncer colorrectal de inicio temprano versus tardío. El resultado secundario fue la mortalidad de los pacientes.Siete genes aumentaron su expresión en pacientes más jóvenes usando el Atlas del Genoma del Cáncer. Solo PEG10 se expresó suficientemente con la reacción en cadena de la polimerasa cuantitativa y tuvo una mayor expresión en nuestro grupo de inicio temprano. El análisis de regresión lineal multivariable identificó la edad como un predictor independiente significativo del aumento de la expresión de PEG10. Los datos de resultados de el Atlas del Genoma del Cáncer sugieren que PEG10 está asociado con una pobre supervivencia general. Los estudios in vitro en líneas celulares HCT-116 y HT-29 mostraron que PEG10 contribuye a la proliferación e invasión celular en el cáncer colorrectal.Las muestras de tejido fueron de portaobjetos embebidos en parafina fijados con formalina. Muchos pacientes no tenían el estado de mutación para su revisión.El PEG10 se expresa diferencialmente en el cáncer colorrectal de inicio temprano y puede contribuir funcionalmente a la proliferación e invasión de células tumorales. El aumento en la expresión de PEG10 se correlaciona con la disminución de la supervivencia general. Consulte Video Resumen en http://links.lww.com/DCR/B343.

Understanding the microbiome: a primer on the role of the microbiome in colorectal neoplasia.

Colorectal cancer is a leading cause of cancer-related death internationally, with mounting evidence pointing to the role of the microbiome in adenoma and cancer development. This article aims to provide clinicians with a foundation for understanding the field of research into the microbiome. We also illustrate the various ways in which the microbiota have been linked to colorectal cancer, with a specific focus on microbiota with identified virulence factors, and also on the ways that byproducts of microbiota metabolism may result in oncogenesis. We also review strategies for manipulating the microbiome for therapeutic effects.

Benign anorectal disease: hemorrhoids, fissures, and fistulas.

Hemorrhoids, anal fissures, and fistulas are common benign anorectal diseases that have a significant impact on patients' lives. They are primarily encountered by primary care providers, including internists, gastroenterologists, pediatricians, gynecologists, and emergency care providers. Most complex anorectal disease cases are referred to colorectal surgeons. Knowledge of these disease processes is essential for proper treatment and follow up. Hemorrhoids and fissures frequently benefit from non-operative treatment; they may, however, require surgical procedures. The treatment of anorectal abscess and fistulas is mainly surgical. The aim of this review is to examine the etiology, diagnosis, medical, and surgical treatment for these benign anorectal diseases.

Feasibility and benefits of an enhanced recovery after surgery protocol for patients undergoing cytoreductive surgery and heated intraperitoneal chemotharpy: A single institution experience.

BACKGROUND: Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is reported to have a prolonged length of stay (LOS). We incorporated an enhanced recovery after surgery (ERAS) protocol to examine whether we could reduce our LOS. METHODS: Patients were identified who underwent CRS/HIPEC from 2015 to 2018 before and after initiation of ERAS protocol. The protocol included pre-operative, peri-operative and post-operative interventions. Primary end point was LOS. Secondary endpoints were morbidity and mortality. RESULTS: Forty patients were identified, thirty-one of which underwent CRS/HIPEC: 16 before and 15 after ERAS. The median LOS prior to ERAS was 11 days (5-20) and 7 days (5-27) after ERAS (P < 0.05). There was no significant difference in 30-day morbidity (Clavien-Dindo ≥3) or mortality between the groups. CONCLUSIONS: An ERAS protocol can safely be implemented in patients undergoing CRS/HIPEC with earlier return of bowel function and decrease in LOS without increasing morbidity or mortality.

Anal intraepithelial neoplasia: diagnosis, screening, and treatment.

Anal intraepithelial neoplasia (AIN) is a premalignant lesion for anal cancer. It is more commonly found in high-risk patients (e.g., human papilloma virus (HPV)/human immunodeficiency virus infections, post-organ transplantation patients, and men who have sex with men) and development is driven by HPV infection. The incidence of AIN is difficult to estimate, but is heavily skewed by preexisting conditions, particularly in high-risk populations. The diagnosis is made from cytology or biopsy during routine examinations, and can be performed at a primary care provider's office. A pathologist can then review and classify cells, based on nucleus-to-cytoplasm ratios. The classification of low or high grade can better predict progression from AIN to anal cancer. There is little debate that AIN can develop into anal cancer, and the main rationale for treatment is to delay the progression. Significant controversy remains regarding screening, surveillance, and treatment for AIN. Management options are separated into surveillance (watchful waiting) and interventional strategies. Emerging data suggest that close patient follow up with a combination of ablative and topical treatments may offer the greatest benefit. HPV vaccination offers a unique treatment prior to HPV infection and the subsequent development of AIN, but its use after the development of AIN is limited. Ablative treatment includes excision, fulguration, and laser therapy.

Does a fine line exist between regional and metastatic pelvic lymph nodes in rectal cancer-striking discordance between national guidelines and treatment recommendations by US radiation oncologists.

BACKGROUND: Management of rectal cancer with involved lateral pelvic lymph nodes (LPLNs) at the time of diagnosis-the stage we refer institutionally to as Stage 3.5-is controversial. The American Joint Committee on Cancer's 7th edition classifies internal iliac lymph nodes (LNs) as regional (Stage III), but both external and common iliac LNs as metastatic (Stage IV). However, in many Asian countries all LPLNs are considered regional and patients are treated with curative intent, with literature supporting improved outcomes with LPLN dissection. Management patterns of these patients by US radiation oncologists (ROs) are unknown. METHODS: American ROs completed an anonymous institutional review board-approved online questionnaire regarding rectal cancer management. RESULTS: Among the 220 completed responses, 45% treat more than 10 patients annually and 39% work in academia. We found 10.5% and 34.2% recommend biopsy of clinically involved internal and common iliac LNs, respectively. The vast majority of responders-98.6% and 94.5%-treat involved internal and common iliac LNs with curative intent, respectively. Respondents recommend treatment intensification to involved internal iliac LNs by dissection of the nodal basin (88.2%) and radiation therapy (RT) boost (59.1%), and treatment intensification to involved common iliac LNs by LN dissection (76.4%) and RT boost (63.6%). CONCLUSIONS: Our analysis reveals that the vast majority of US ROs approach patients with involved LPLNs, both regional (internal iliac) and metastatic (common iliac), with curative intent. They recommend treatment intensification with surgical resection and/or RT boost to involved nodes. Prospective clinical trials need to determine the appropriate management of patients with Stage 3.5 rectal cancer.

Colorectal polyposis and inherited colorectal cancer syndromes.

The majority of colorectal cancer (CRC) cases are sporadic, with hereditary factors contributing to approximately 35% of CRC cases. Less than 5% of CRC is associated with a known genetic syndrome. Although adenomatous polyposis syndromes, hamartomatous polyposis syndromes, and those previously classified as non-polyposis CRC syndromes are quite rare, it is important for clinicians to know the characteristics of each syndrome and to understand the differences in cancer risks between the different conditions. This information is very important when treatment and surveillance plans are formulated for each individual patient.

Survey results of US radiation oncology providers' contextual engagement of watch-and-wait beliefs after a complete clinical response to chemoradiation in patients with local rectal cancer.

BACKGROUND: Watchful waiting in rectal cancer patients with a complete clinical response (cCR) to chemoradiation therapy (CRT) forgo upfront resection has been proposed. Growing evidence suggests that a watch-and-wait approach using resection for salvage of local recurrence may improve quality of life without jeopardizing outcomes. The current acceptance of watch-and-wait by US radiation oncologists (ROs) is unknown. METHODS: US ROs completed our IRB-approved anonymous e-survey regarding non-surgical management of patients who achieved a cCR to neoadjuvant CRT. Self-ranked knowledge of the OnCoRe Project-UK prospective observational study of watch-and-wait-was tested for its association with ROs' attitudes using the Chi-squared or Fisher's test, as indicated. Supporters of observation are self-identified. RESULTS: Of the 220 respondents, 48% (n=106) of respondents support watchful waiting and 48% claimed familiarity with the OnCoRe Project. Respondents supporting observation were more likely to be familiar with the publication (P=0.029). Among watch-and-wait supporters, 59% (n=62) felt comfortable discussing this approach and 41% preferred the conversation be initiated by other specialists. There was no association between comfort level in discussing watch-and-wait and familiarity with the OnCoRe Project. ROs treating more than 10 locally advanced rectal cancer (LARC) patients annually felt more comfortable discussing watch-and-wait (P=0.015) compared to ROs seeing fewer patients. CONCLUSIONS: Almost half of surveyed US ROs support watch-and-wait, though many do not feel comfortable discussing this paradigm with patients. Knowledge of the OnCoRe Project is associated with support of watch-and-wait, yet not comfort level in leading the discussion. These results inform provider attitudes toward future clinical study participation.