David Liska

Laparoscopic surgery for rectal cancer: the verdict is not final yet!

Over the last few decades, significant progress has been made in the management of rectal cancer. Advances in surgical techniques and the standardization of total mesorectal excision (TME) have radically reduced local recurrence (LR) rates and improved functional outcomes [1, 2]. Preoperative imaging with optimized magnetic resonance imaging (MRI) has allowed for more accurate staging and prediction of threatened circumferential resection (CRM) margins [3]. Multidisciplinary tumor boards help standardize care and formulate consensusbased guidelines for the selection of patients for neoadjuvant chemoradiotherapy. Collectively, these advances have led to a considerable reduction in the rate of LR, improvement in overall survival and an increase in the preservation of anal sphincter, urinary, and sexual function [4–6]. Laparoscopic surgery has become the approach of choice in most abdominal surgery owing to favorable short-term outcomes such as improved pain control, shorter hospital stay, faster recovery, decreased blood loss, and reduced postoperative complications. Laparoscopic surgery for colon cancer has rapidly evolved over the last decade. Multiple randomized controlled trials (RCTs) and metaanalyses have now proven that laparoscopic colectomy for cancer is safe and oncologically equivalent to conventional surgery, while still providing the short-term benefits associated with the minimally invasive approach [7–11]. Indeed, some studies reported better survival outcomes with laparoscopy compared to open resection of colon cancer [10, 12]. The data for the role of laparoscopy in rectal cancer are still accruing. Prerandomized controlled trials and feasibility studies have shown that radical resection of rectal cancer can safely be achieved laparoscopically in terms of adequacy of resection margins, lymph node harvest, and intactness of the specimen when compared to the open approach [13–17]. Over the last few years, several multicenter RCTs have been published. The COREAN trial compared laparoscopic and open surgery among 340 patients with stage II and III, midand low rectal cancer, who received neoadjuvant treatment [18]. The COLOR II trial included 1044 patients, with rectal cancer within 15 cm from anal verge, randomized to either laparoscopic or open surgery in a 2:1 ratio [19]. Both studies demonstrated equivalent oncologic outcomes in terms of 3-year recurrence and survival rates. These are high-quality studies with operations performed by experienced minimally invasive surgeons, comparing pure laparoscopy to open surgery. A recent meta-analysis [20], including 10,861 patients from 8 RCTs and 19 prospective or retrospective studies, compared the oncologic outcomes of laparoscopy and open surgery for rectal cancer. The positive CRM, the primary endpoint, was similar in both groups (10.3 and 11.6%). In cancers within 12 cm from the anal verge, mesorectal intactness was 85 and 86%, with a similar 5-year incidence of LR of 3.5 and 5.6% (p = 0.413). The recently published ACOSOG Z6051 [21] and ALACART [22] trials included 481 and 473 patients, respectively. These are important studies that remind us of the importance of oncologic markers for rectal cancer. Both studies used a non-inferiority design and composite pathologic indices as surrogate endpoints for oncologic & Conor P. Delaney delanec@ccf.org

Enhanced Recovery After Surgery: Recent Developments in Colorectal Surgery

Enhanced recovery after surgery (ERAS) has been established as a safe and effective tool for early recovery and discharge after colorectal resection. This article reviews the latest additions and refinements to ERAS protocols and also examines those interventions that seem to have limited clinical benefit for colorectal patients.

Cancer-predicting transcriptomic and epigenetic signatures revealed for ulcerative colitis in patient-derived epithelial organoids

Ulcerative colitis (UC) is a prevalent form of inflammatory bowel disease (IBD) whose pathogenic mechanisms remain unclear. Elucidating these mechanisms is important to reduce UC symptoms and to prevent UC progression into colitis-associated colon cancer (CAC). Our goal was to develop and validate faithful, human-derived, UC models and analyze them at histologic, transcriptomic and epigenetic levels to allow mechanistic studies of UC and CAC pathogenesis. We generated patient-derived primary-organoid cultures from UC and non-IBD colonic epithelium. We phenotyped them histologically and used next-generation-sequencing approaches to profile whole transcriptomes and epigenomes of organoids and primary tissues. Tissue organization and expression of mucin 2 (MUC2) and lysozyme (LYZ) demonstrated histologic faithfulness of organoids to healthy and diseased colonic epithelium. Transcriptomic analyses showed increased expression of inflammatory pathways in UC patient-derived organoids and tissues. Profiling for active enhancers using the H3K27ac histone modification revealed UC-derived organoid enrichment for pathways indicative of gastrointestinal cancer, including S100 calcium-binding protein P (S100P), and revealed novel markers for GI cancer, including both LYZ and neuropeptide S receptor 1 (NPSR1). Immunolocalization showed increased levels of LYZ, S100P, and NPSR1 proteins in UC and CAC. In conclusion, primary colonic organoid cultures from UC and non-IBD patients can be established that faithfully represent diseased or normal colonic states. These models reveal precancerous molecular pathways that are already activated in UC. The findings demonstrate the suitability of primary organoids for dissecting UC and CAC pathogenic mechanisms and suggest new targets for therapeutic intervention.

Stromal miR-20a controls paracrine CXCL8 secretion in colitis and colon cancer

Inflammatory bowel disease (IBD) affects one million people in the US. Ulcerative colitis (UC) is a subtype of IBD that can lead to colitis-associated cancer (CAC). In UC, the rate of CAC is 3-5-fold greater than the rate of sporadic colorectal cancer (CRC). The pathogenesis of UC and CAC are due to aberrant interactions between host immune system and microenvironment, but precise mechanisms are still unknown. In colitis and CAC, microenvironmental fibroblasts exhibit an activated, inflammatory phenotype that contributes to tumorigenesis accompanied by excessive secretion of the chemokine CXCL8. However, mechanisms regulating CXCL8 secretion are unclear. Since it is known that miRNAs regulate chemokines such as CXCL8, we queried a microRNA library for mimics affecting CXCL8 secretion. Among the identified microRNAs, miR-20a/b was further investigated as its stromal expression levels inversely correlated with the amounts of CXCL8 secreted and predicted fibroblast tumor-promoting activity. Indeed, miR-20a directly bound to the 3′UTR of CXCL8 mRNA and regulated its expression by translational repression. In vivo co-inoculation studies with CRC stem cells demonstrated that fibroblasts characterized by high miR-20a expression had reduced tumor-promoting activities. These studies reveal that in stromal fibroblasts, miR-20a modulates CXCL8 function, therefore influencing tumor latency.

SSAT State-of-the-Art Conference: Advances in the Management of Rectal Cancer

The treatment of rectal cancer has evolved significantly since the early days of total mesorectal excision (TME). Modern management now includes a variety of new surgical techniques, treatment modalities, and oncologic principles. Guidelines from key organizations such as the National Comprehensive Cancer Network (NCCN) help surgeons and providers navigate these many options, but reviews of the current state of these affairs is needed. In 2018, the Society for Surgery of the Alimentary Tract (SSAT) convened a Stateof-the-Art Conference on Advances in the Management of Rectal Cancer with international experts and emerging leaders in the field of rectal cancer treatment. Four important topics in rectal cancer management were covered: (1) Gregory Kennedy, MD, PhD from the University of Alabama at Birmingham (UAB), USA, discussed the use of surgical techniques for rectal cancer (open, laparoscopic, or robotic), (2) Rodrigo Perez, MD, PhD, from the University of Sao Paulo School of Medicine, Brazil, discussed the use of Bwatch-andwait^ when there is a complete clinical response from neoadjuvant chemotherapy, (3) John Monson, MD, from Florida Hospital, USA, discussed the use of transanal total mesorectal excision (TaTME) in rectal cancer surgery, and (4) Alessandro Fichera, MD, from the University of North Carolina Chapel Hill, USA, presented the indications for extended lymphadenectomy in rectal cancer. Each of these important topics will be summarized in this manuscript.

Reservoir Construction After Low Anterior Resection: Who and What?

The two key major outcomes after surgical treatment of rectal cancer are oncologic and functional. Improved understanding of tumor biology and advanced surgical techniques have led to improved oncologic results and also increased rates of sphincter-preserving procedures for low rectal cancers. This trend, however, has brought to light the functional consequences following low anterior resection (LAR) with total mesorectal excision (TME) and coloanal anastomosis (CAA). Many patients who have undergone sphincter-preserving low or ultra-low anterior resections with a straight CAA experience defecatory symptoms that can include frequency, urgency, clustering, incomplete evacuation, constipation, diarrhea, and incontinence [1]. This collection of symptoms, also known as low anterior resection syndrome (LARS),is partially attributable to the loss of the reservoir function of the rectum.