Molecular Oncology in Management of Colorectal Cancer.

Colorectal cancers are the third most common cancers in the world. Management of both primary and metastatic colorectal cancers has evolved over the last couple of decades. Extensive research in molecular oncology has helped us understand and identify these complex intricacies in colorectal cancer biology and disease progression. These advances coupled with improved knowledge on various mutations have helped develop targeted chemotherapeutics and has allowed planning an effective treatment regimen in this era of immunotherapy with precision. The diverse chemotherapeutic and biological agents at our disposal can make decision making a very complex process. Molecular profile, including CIN, RAS, BRAF mutations, microsatellite instability, ctDNA, and consensus molecular subtypes, are some of the important factors which are to be considered while planning an individualized treatment regimen. This article summarizes the current status of molecular oncology in the management of colorectal cancer and should serve as a practical guide for the clinical team.

Treatment of Patients With Late-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline.

PURPOSE: To provide expert guidance to clinicians and policymakers in resource-constrained settings on the management of patients with late-stage colorectal cancer. METHODS: ASCO convened a multidisciplinary, multinational Expert Panel that reviewed existing guidelines, conducted a modified ADAPTE process, and used a formal consensus process with additional experts for two rounds of formal ratings. RESULTS: Existing sets of guidelines from four guideline developers were identified and reviewed; adapted recommendations from five guidelines form the evidence base and provided evidence to inform the formal consensus process, which resulted in agreement of ≥ 75% on all recommendations. RECOMMENDATIONS: Common elements of symptom management include addressing clinically acute situations. Diagnosis should involve the primary tumor and, in some cases, endoscopy, and staging should involve digital rectal exam and/or imaging, depending on resources available. Most patients receive treatment with chemotherapy, where chemotherapy is available. If, after a period of chemotherapy, patients become candidates for surgical resection with curative intent of both primary tumor and liver or lung metastatic lesions on the basis of evaluation in multidisciplinary tumor boards, the guidelines recommend patients undergo surgery in centers of expertise if possible. On-treatment surveillance includes a combination of taking medical history, performing physical examinations, blood work, and imaging; specifics, including frequency, depend on resource-based setting.Additional information is available at www.asco.org/resource-stratified-guidelines.

Treatment of Patients With Early-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline.

PURPOSE: To provide resource-stratified, evidence-based recommendations on the treatment and follow-up of patients with early-stage colorectal cancer. METHODS: ASCO convened a multidisciplinary, multinational Expert Panel that reviewed existing guidelines and conducted a modified ADAPTE process and a formal consensus process with additional experts for one round of formal ratings. RESULTS: Existing sets of guidelines from 12 guideline developers were identified and reviewed; adapted recommendations from six guidelines form the evidence base and provide evidence to inform the formal consensus process, which resulted in agreement of 75% or more on all recommendations. RECOMMENDATIONS: For nonmaximal settings, the recommended treatments for colon cancer stages nonobstructing, I-IIA: in basic and limited, open resection; in enhanced, adequately trained surgeons and laparoscopic or minimally invasive surgery, unless contraindicated. Treatments for IIB-IIC: in basic and limited, open en bloc resection following standard oncologic principles, if not possible, transfer to higher-level facility; in emergency, limit to life-saving procedures; in enhanced, laparoscopic en bloc resection, if not possible, then open. Treatments for obstructing, IIB-IIC: in basic, resection and/or diversion; in limited or enhanced, emergency surgical resection. Treatment for IIB-IIC with left-sided: in enhanced, may place colonic stent. Treatment for T4N0/T3N0 high-risk features or stage II high-risk obstructing: in enhanced, may offer adjuvant chemotherapy. Treatment for rectal cancer cT1N0 and cT2n0: in basic, limited, or enhanced, total mesorectal excision principles. Treatment for cT3n0: in basic and limited, total mesorectal excision, if not, diversion. Treatment for high-risk patients who did not receive neoadjuvant chemotherapy: in basic, limited, or enhanced, may offer adjuvant therapy. Treatment for resectable cT3N0 rectal cancer: in enhanced, base neoadjuvant chemotherapy on preoperative factors. For post-treatment surveillance, a combination of medical history, physical examination, carcinoembryonic antigen testing, imaging, and endoscopy is performed. Frequency depends on setting. Maximal setting recommendations are in the guideline. Additional information can be found at www.asco.org/resource-stratified-guidelines . NOTICE: It is the view of the American Society of Clinical Oncology that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guidelines are intended to complement but not replace local guidelines.

Early Detection for Colorectal Cancer: ASCO Resource-Stratified Guideline.

PURPOSE: To provide resource-stratified, evidence-based recommendations on the early detection of colorectal cancer in four tiers to clinicians, patients, and caregivers. METHODS: American Society of Clinical Oncology convened a multidisciplinary, multinational panel of medical oncology, surgical oncology, surgery, gastroenterology, health technology assessment, cancer epidemiology, pathology, radiology, radiation oncology, and patient advocacy experts. The Expert Panel reviewed existing guidelines and conducted a modified ADAPTE process and a formal consensus-based process with additional experts (Consensus Ratings Group) for two round(s) of formal ratings. RESULTS: Existing sets of guidelines from eight guideline developers were identified and reviewed; adapted recommendations form the evidence base. These guidelines, along with cost-effectiveness analyses, provided evidence to inform the formal consensus process, which resulted in agreement of 75% or more. CONCLUSION: In nonmaximal settings, for people who are asymptomatic, are ages 50 to 75 years, have no family history of colorectal cancer, are at average risk, and are in settings with high incidences of colorectal cancer, the following screening options are recommended: guaiac fecal occult blood test and fecal immunochemical testing (basic), flexible sigmoidoscopy (add option in limited), and colonoscopy (add option in enhanced). Optimal reflex testing strategy for persons with positive screens is as follows: endoscopy; if not available, barium enema (basic or limited). Management of polyps in enhanced is as follows: colonoscopy, polypectomy; if not suitable, then surgical resection. For workup and diagnosis of people with symptoms, physical exam with digital rectal examination, double contrast barium enema (only in basic and limited); colonoscopy; flexible sigmoidoscopy with biopsy (if contraindication to latter) or computed tomography colonography if contraindications to two endoscopies (enhanced only).

Hindgut Neuroendocrine Neoplasia.

Neuroendocrine neoplasias (NENs) consist of a spectrum of tumors which can originate throughout the body, behave in a variety of different ways but are characterized by a similar histological appearance. This article reviews the classification, staging, diagnosis and treatment of Hindgut Neuroendocrine Neoplasias.

Features Associated With Metastases Among Well-Differentiated Neuroendocrine (Carcinoid) Tumors of the Appendix: The Significance of Small Vessel Invasion in Addition to Size.

BACKGROUND: The risk of metastatic disease among carcinoid tumors of the appendix increases with tumor size. However, it is unclear if any features other than size are also associated with an increased risk of metastatic disease. OBJECTIVE: The aim of this study was to review the characteristics of appendiceal carcinoid tumors and determine if other histologic features besides size should guide surgical decision making. DESIGN: This study involved a retrospective case series. SETTINGS: This study was conducted at a single tertiary acute care hospital. PATIENTS: Patients diagnosed with an appendiceal carcinoid tumor between 2000 and 2014 were identified. Goblet cell carcinoids, adenocarcinomas with neuroendocrine features, and tumors from other primary locations were excluded. INTERVENTIONS: Simple appendectomy or segmental/total colectomy with lymphadenectomy was performed. MAIN OUTCOME MEASURES: The primary outcomes measured were metastases, recurrence, and overall survival. RESULTS: Seventy-nine patients were included. The overall incidence of metastatic disease was 10%. Patients with metastatic disease were more likely to be male (75% vs 28%, p = 0.008), have small-vessel invasion (43% vs 5%, p = 0.001), and have larger tumors (median 2.0 cm vs 0.5 cm, p < 0.001). Among tumors <2 cm, the incidence of metastases among tumors with small-vessel invasion was 60% compared with 0% among those without small-vessel invasion (p < 0.001). Among tumors ≥2 cm, the incidence of metastases was 50% irrespective of small-vessel invasion. If small-vessel invasion was used as a second indication for performing a right hemicolectomy along with size ≥2 cm, both the sensitivity and negative predictive value would have been 100% compared with 63% and 96% if size was used alone. Patients with metastatic disease had a higher incidence of recurrence (13% vs 0%, p = 0.003), but overall survival was 100% in both groups. LIMITATIONS: Small sample size, retrospective design, and limited long-term follow-up were the limitations of this study. CONCLUSIONS: Carcinoid tumors of the appendix <2 cm with small-vessel invasion have similar metastatic potential as tumors ≥2 cm. Therefore, a recommendation for a right hemicolectomy should be considered for tumors <2 cm with small-vessel invasion. Additional prospective multicenter studies are warranted.

Endoscopic Gallbladder Drainage for Acute Cholecystitis.

BACKGROUND/AIMS: Surgery is the mainstay of treatment for cholecystitis. However, gallbladder stenting (GBS) has shown promise in debilitated or high-risk patients. Endoscopic transpapillary GBS and endoscopic ultrasound-guided GBS (EUS-GBS) have been proposed as safe and effective modalities for gallbladder drainage. METHODS: Data from patients with cholecystitis were prospectively collected from August 2004 to May 2013 from two United States academic university hospitals and analyzed retrospectively. The following treatment algorithm was adopted. Endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy and cystic duct stenting was initially attempted. If deemed feasible by the endoscopist, EUS-GBS was then pursued. RESULTS: During the study period, 139 patients underwent endoscopic gallbladder drainage. Among these, drainage was performed in 94 and 45 cases for benign and malignant indications, respectively. Successful endoscopic gallbladder drainage was defined as decompression of the gallbladder without incidence of cholecystitis, and was achieved with ERCP and cystic duct stenting in 117 of 128 cases (91%). Successful endoscopic gallbladder drainage was also achieved with EUS-guided gallbladder drainage using transmural stent placement in 11 of 11 cases (100%). Complications occurred in 11 cases (8%). CONCLUSIONS: Endoscopic gallbladder drainage techniques are safe and efficacious methods for gallbladder decompression in non-surgical patients with comorbidities.

Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting.

Current orthotopic xenograft models of human colorectal cancer (CRC) require surgery and do not robustly form metastases in the liver, the most common site clinically. CCR9 traffics lymphocytes to intestine and colorectum. We engineered use of the chemokine receptor CCR9 in CRC cell lines and patient-derived cells to create primary gastrointestinal (GI) tumors in immunodeficient mice by tail-vein injection rather than surgery. The tumors metastasize inducibly and robustly to the liver. Metastases have higher DKK4 and NOTCH signaling levels and are more chemoresistant than paired subcutaneous xenografts. Using this approach, we generated 17 chemokine-targeted mouse models (CTMMs) that recapitulate the majority of common human somatic CRC mutations. We also show that primary tumors can be modeled in immunocompetent mice by microinjecting CCR9-expressing cancer cell lines into early-stage mouse blastocysts, which induces central immune tolerance. We expect that CTMMs will facilitate investigation of the biology of CRC metastasis and drug screening.

Colonic salvage with antiperistaltic cecorectal anastomosis.

BACKGROUND: Following colon resection, the construction of a well-perfused, tension-free isoperistaltic anastomosis can be made difficult by multiple factors including prior abdominal surgery or compromised vascular supply. Here, we describe the technique of antiperistaltic cecorectal anastomosis as a method for preserving viable colon without compromising functional outcome. TECHNIQUE: Following extensive colorectal resection, different techniques for isoperistaltic reconstruction using the cecum and ascending colon have been described, including the Deloyers procedure and limited isoperistaltic cecorectal anastomosis. However, these isoperistaltic reconstructions often require ligation of the middle colic and right colic arteries and/or sacrifice of viable distal colon to aid reconstruction. In complex situations that require preservation of normal vascular anatomy, an antiperistaltic cecorectal anastomosis can be constructed that maintains the orientation of the vascular pedicle. In addition to the preservation of the colonic arterial supply, a distinguishing feature of this technique is the substantial portion of antiperistaltic colon that is preserved and interposed to reestablish continuity. RESULTS: In a case where it was used, construction of an antiperistaltic cecorectal anastomosis was technically successful and led to a good functional outcome. CONCLUSION: Antiperistaltic cecorectal anastomosis should be considered as an option in colonic reconstruction for patients with extensive prior abdominal surgery or when complex anatomic issues require preservation of native vascular anatomy. In these situations, this technique offers several advantages over isoperistaltic reconstruction and may be the only option for reconstruction that uses the remaining cecum and colon.

Accuracy of CT enterography and magnetic resonance enterography imaging to detect lesions preoperatively in patients undergoing surgery for Crohn's disease.

BACKGROUND: CT enterography and magnetic resonance enterography have emerged as first-line imaging technologies for the evaluation of the gastrointestinal tract in Crohn's disease. OBJECTIVE: The purpose of this work was to evaluate the accuracy of these imaging modalities to identify Crohn's disease lesions preoperatively. DESIGN: This was a retrospective chart review. SETTINGS: The study was conducted at a single institution. PATIENTS: Seventy-six patients with Crohn's disease with preoperative CT enterography and/or magnetic resonance enterography were included in the study. MAIN OUTCOME MEASURES: The number of stenoses, fistulas, and abscesses on CT enterography and/or magnetic resonance enterography before surgery were compared with operative findings. RESULTS: Forty patients (53%) were women, 46 (60%) underwent surgery for recurrent Crohn's disease, and 46 (57%) had previous abdominal surgery. Thirty-six (47%) had a preoperative CT enterography and 43 (57%) had a preoperative magnetic resonance enterography. CT enterography sensitivity was 75% for stenosis and 50% for fistula. MRE sensitivity was 68% for stenosis and 60% for fistula. The negative predictive values of CT enterography and magnetic resonance enterography for stenosis were very low (54% and 65%) and were 85% and 81% for fistula. CT enterography had 76% accuracy for stenosis and 79% for fistula; magnetic resonance enterography had 78% accuracy for stenosis and 85% for fistula. Both were accurate for abscess. False-negative rates for CT enterography were 50% for fistula and 25% for stenosis. False-negative rates for magnetic resonance enterography were 40% for fistula and 32% for stenosis. Unexpected intraoperative findings led to modification of the planned surgical procedure in 20 patients (26%). LIMITATIONS: This study was limited by its small sample size, its retrospective nature, and that some studies were performed at outside institutions. CONCLUSIONS: CT enterography and magnetic resonance enterography in patients with Crohn's disease were accurate for the identification of abscesses but not for fistulas or stenoses. Surgeons should search for additional lesions intraoperatively. Patients should be appropriately counseled regarding the need for unexpected interventions (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A162).

Surveillance, epidemiology, and end results-based analysis of the impact of preoperative or postoperative radiotherapy on survival outcomes for T3N0 rectal cancer.

PURPOSE: Preoperative chemoradiation has been established as standard of care for T3/T4 node-positive rectal cancer. Recent work, however, has called into question the overall benefit of radiation for tumors with lower risk characteristics, particularly T3N0 rectal cancers. We retrospectively analyzed T3N0 rectal cancer patients and examined how outcomes differed according to the sequence of treatment received. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to analyze T3N0 rectal cancer cases diagnosed between 1998 and 2008. Treatment consisted of surgery alone (No RT), preoperative radiation followed by surgery (Neo-Adjuvant RT), or surgery followed by postoperative radiation (Adjuvant RT). Demographic and tumor characteristics of the three groups were compared using t-tests for the comparison of means. Survival information from the SEER database was utilized to estimate cause-specific survival (CSS) and to generate Kaplan-Meier survival curves. Multivariate analysis (MVA) of features associated with outcomes was conducted using Cox proportional hazards regression models with Adjuvant RT, Neo-Adjuvant RT, No RT, histological grade, tumor size, year of diagnosis, and demographic characteristics as covariates. RESULTS: 10-Year CSS estimates were 66.1% (95% CI 62.3-69.6%; P=0.02), 73.5% (95% CI 68.9-77.5%; P=0.02), and 76.1% (95% CI 72.4-79.4%; P=0.02), for No RT, Neo-Adjuvant RT, and Adjuvant RT, respectively. On MVA, Adjuvant RT (HR=0.688; 95% CI, 0.578-0.819; P<0.001) was associated with significantly decreased risk for cancer death. By contrast, Neo-Adjuvant RT was not significantly associated with improved cancer survival (HR=0.863; 95% CI, 0.715-1.043; P=0.127). CONCLUSION: Adjuvant RT was associated with significantly higher CSS when compared with surgery alone, while the benefit of Neo-Adjuvant RT was not significant. This indicates that surgery followed by Adjuvant RT may still be an important treatment plan for T3N0 rectal cancer with potentially significant survival advantages over other treatment sequences.

The management of gastrointestinal tract malignancies.

Surgery is the mainstay of treatment for many patients with malignancies of the gastrointestinal (GI) tract. The coordination of patient care and timing of surgical intervention require a multidisciplinary approach. It is not unusual for GI malignancies to be discovered in a hospital setting; patients with these malignancies are frequently admitted and discharged from nonsurgical services. Therefore, it is imperative that all physicians involved in the care of patients with GI malignancies have knowledge regarding the workup and surgical treatment of GI tract lesions. This article is a brief overview of the workup and surgical management of malignancies of the GI tract.

Laparoscopic surgery for benign and malignant colorectal diseases.

Laparoscopic approaches to many benign and malignant colorectal diseases continue to expand and become more ubiquitous. Numerous studies have shown that diverticulitis, inflammatory bowel disease, and rectal prolapse can safely be managed laparoscopically. Laparoscopy for colon cancer is well studied and offers significant short-term benefits while preserving oncologic outcome. There are several large prospective studies underway to document long-term oncologic outcomes for the use of laparoscopy in the treatment of rectal cancer. With appropriate patient and surgeon selection, many significant clinical benefits can be achieved with this less invasive approach without compromising surgical quality.

Laparoscopy for rectal cancer.

Several large case series and single-institution trials have shown that laparoscopy is feasible for rectal cancer. Pending the results of the UK CLASICC, COLOR II, Japanese JCOG 0404, and ACOSOG Z6051 trials, the oncologic and long-term safety of laparoscopic rectal cancer surgery is unclear and the technique is best used at centers that can effectively collect and analyze outcomes data. Robotic and endoluminal techniques may change our approach to the treatment of rectal cancer in the future. Training, credentialing, and quality control are important considerations as new and innovative surgical treatments for rectal cancer are developed.

Surgical adhesive increases burst pressure and seals leaks in stapled gastrojejunostomy.

BACKGROUND: Leakage from a gastrointestinal anastomosis in bariatric surgery is a catastrophic complication and is the second-most preventable cause of death after Roux-en-Y gastric bypass. Several adjuncts for staple line reinforcement have been investigated to reduce the incidence of this complication. The purpose of our study was to determine whether a commercially available tissue sealant (BioGlue) could reinforce a stapled gastrojejunal anastomosis and whether it could seal an artificially created anastomotic leak. METHODS: Circular-stapled gastrojejunostomies were performed on freshly explanted porcine stomach and intestine. Experiment 1 consisted of 10 control nonreinforced gastrojejunostomies and 10 gastrojejunostomies reinforced with BioGlue. The staple lines were submerged in saline and exposed to increased pressure using constant-rate infusion of air. The burst pressures were recorded at the point of visible leakage from the anastomosis. In experiment 2, a small defect was created in 10 gastrojejunostomies. The burst pressures were recorded before and after application of BioGlue to the anastomosis. The data were analyzed using the 2-tailed paired t test. RESULTS: In experiment 1, the burst pressure was significantly increased in the reinforced gastrojejunostomies, from 27.4 ± 8.4 mm Hg to 59.1 ± 19.2 mm Hg (P <.001). In experiment 2, the defective gastrojejunostomies had an average burst pressure of 1.2 ± 0.8 mm Hg. After application of BioGlue, the burst pressure increased to 42.8 ± 15.9 mm Hg (P <.001). CONCLUSION: These ex vivo findings suggest that the surgical adhesive BioGlue can reinforce both intact and defective stapled gastrojejunal anastomoses. Additional in vivo study is warranted to determine whether BioGlue can prevent or help seal gastrojejunal leaks.

Laparoscopy for colon and rectal cancer.

Laparoscopy has emerged as a useful tool in the surgical treatment of diseases of the colon and rectum. Specifically, in the application of colon cancer, a laparoscopic-assisted approach offers short-term benefits to patients while maintaining a long-term oncologic outcome. Hand-assisted laparoscopic surgery may help decrease operative times while preserving the benefits of laparoscopy. The literature on the use of laparoscopy for rectal cancer is still in its early stages. Limited data suggest short-term benefits without compromising oncologic outcome; however, data from large multicenter trials will clarify the role of laparoscopy in the treatment of rectal cancer. Robotic proctectomy is a novel technique that may offer considerable advantage and overcome some limitations laparoscopy creates while working in the confines of the pelvis. The improved magnification and visualization offered with the robot may also assist in preserving bladder and sexual function. Transanal endoscopic microsurgery (TEM) for the treatment of T1 rectal cancers with low-risk features appears to be safe. However, TEM has a significantly higher recurrence rate when used to treat invasive cancer. Endoluminal techniques and equipment are under development and could offer more minimally invasive approaches to the treatment of colon and rectal cancer. Credentialing and training of surgeons and teams involved in the use of laparoscopy is important prior to making these techniques ubiquitous.

Anastomoses of the lower gastrointestinal tract.

Patients with gastrointestinal anastomoses are treated by physicians of multiple specialties, including gastroenterologists, radiologists and surgeons. This Review provides an overview of the surgical principles and techniques involved in the creation of lower intestinal anastomoses, including some of the mechanisms of healing. Anatomical configurations of small and large bowel anastomoses are illustrated. Stapled, hand-sewn, and sutureless anstomotic techniques are also discussed. Laparoscopy has revolutionized our approach to surgery of the gastrointestinal tract and we describe some of the current and future minimally invasive techniques for creating anastomoses. The article also highlights principles important in minimizing potential short-term and long-term complications such as anastomotic leaks and strictures. Common risk factors for dehiscence include poor nutrition, immunosuppression, microvascular disease, obesity and technical errors. An evidence-based review of perioperative and postoperative management of intestinal anastomoses is provided to help optimize patient care. The routine use of nasogastric tubes and mechanical bowel preparation has no documented benefits and could contribute to postoperative complications. Upcoming strategies that might prove useful to reinforce anastomoses are also reviewed.

Familial polyposis coli: clinical manifestations, evaluation, management and treatment.

Familial adenomatous polyposis (FAP) is an autosomal dominant, hereditary colon cancer syndrome that is characterized by the presence of innumerable adenomatous polyps in the colon and rectum. Gardner's syndrome is a variant of FAP, which in addition to the colonic polyps, also presents extracolonic manifestations, including desmoid tumors, osteomas, epidermoid cysts, various soft tissue tumors, and a predisposition to thyroid and periampullary cancers. Mutations of the APC gene are thought to be responsible for the development of FAP, and the location of the mutation on the gene is thought to influence the nature of the extracolonic manifestations that a given patient might develop. Though patients are often asymptomatic, bleeding, diarrhea, abdominal pain and mucous discharge frequently occur. Diagnostic tools include genetic testing, endoscopy, and monitoring for extra-intestinal manifestations. Currently, surgery is the only effective means of preventing progression to colorectal carcinoma. Restorative proctocolectomy with ileal pouch anal anastomosis (RPC/IPAA) with mucosectomy is the preferred surgical procedure, since it attempts to eliminate all colorectal mucosa without the need for an ostomy. Periampullary carcinoma and intra-abdominal desmoid tumors are a significant cause of morbidity and mortality in these patients after colectomy. Frequent endoscopy is needed to prevent the former, while there is no definitive treatment available yet for the latter. The following article presents a case and reviews the evaluation, management and treatment of Gardner's syndrome.