Background: As one of the 12 clinical pathways of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Masters Program, the Colorectal Pathway intends to deliver didactic content organized along 3 levels of performance (competency, proficiency and mastery) each represented by an anchoring procedure (laparoscopic right colectomy, laparoscopic left/sigmoid colectomy, and intracorporeal anastomosis during minimally invasive (MIS) ileocecal or right colon resection). In this article, the SAGES Colorectal Task Force presents focused summaries of the top 10 seminal articles selected for laparoscopic right colectomy which surgeons should be familiar with. Methods: Using a systematic literature search of Web of Science, the most cited articles on laparoscopic right colectomy were identified, reviewed, and ranked by the SAGES Colorectal Task Force and invited subject experts. Additional articles not identified in the literature search were included if deemed impactful by expert consensus. The top 10 ranked articles were then summarized, with emphasis on relevance and impact in the field, findings, strengths and limitations, and conclusions. Results: The top 10 seminal articles selected for the laparoscopic right colectomy anchoring procedure include articles on surgical techniques for benign and malignant disease, with anatomical and video illustrations, comparative outcomes of laparoscopic vs open colectomy, variations in technique with impact on clinical outcomes, and assessment of the learning curve. Conclusions: The top 10 seminal articles selected for laparoscopic right colectomy illustrate the diversity both in content and format of the educational curriculum of the SAGES Masters Program to support practicing surgeon progression to mastery within the Colorectal Pathway.

OBJECTIVES: To review published clinical evidence on management of Clostridioides difficile infection in critically ill patients. DATA SOURCES: We obtained relevant studies from a PubMed literature review and bibliographies of reviewed articles. STUDY SELECTION: We selected English-language studies addressing aspects of C. difficile infection relevant to critical care clinicians including epidemiology, risk factors, diagnosis, treatment, and prevention, with a focus on high-quality clinical evidence. DATA EXTRACTION: We reviewed potentially relevant studies and abstracted information on study design, methods, patient selection, and results of relevant studies. This is a synthetic (i.e., not systematic) review. DATA SYNTHESIS: C. difficile infection is the most common healthcare-associated infection in the United States. Antibiotics are the most significant C. difficile infection risk factor, and among antibiotics, cephalosporins, clindamycin, carbapenems, fluoroquinolones, and piperacillin-tazobactam confer the highest risk. Age, diabetes mellitus, inflammatory bowel disease, and end-stage renal disease are risk factors for C. difficile infection development and mortality. C. difficile infection diagnosis is based on testing appropriately selected patients with diarrhea or on clinical suspicion for patients with ileus. Patients with fulminant disease (C. difficile infection with hypotension, shock, ileus, or megacolon) should be treated with oral vancomycin and IV metronidazole, as well as rectal vancomycin in case of ileus. Patients who do not respond to initial therapy should be considered for fecal microbiota transplant or surgery. Proper infection prevention practices decrease C. difficile infection risk. CONCLUSIONS: Strong clinical evidence supports limiting antibiotics when possible to decrease C. difficile infection risk. For patients with fulminant C. difficile infection, oral vancomycin reduces mortality, and adjunctive therapies (including IV metronidazole) and interventions (including fecal microbiota transplant) may benefit select patients. Several important questions remain regarding fulminant C. difficile infection management, including which patients benefit from fecal microbiota transplant or surgery.

Introduction: There is little consensus of quality measurements for restorative proctocolectomy with ileal pouch-anal anastomosis(RPC-IPAA) performed for ulcerative colitis(UC). The National Surgical Quality Improvement Program(NSQIP) cannot accurately classify RPC-IPAA staged approaches. We formed an IBD-surgery registry that added IBD-specific variables to NSQIP to study these staged approaches in greater detail. Methods: We queried our validated database of IBD surgeries across 11 sites in the US from March 2017 to March 2019, containing general NSQIP and IBD-specific perioperative variables. We classified cases into delayed versus immediate pouch construction and looked for independent predictors of pouch delay and postoperative Clavien-Dindo complication severity. Results: 430 patients received index surgery or completed pouches. Among completed pouches, 46(28%) and 118(72%) were immediate and delayed pouches, respectively. Significant predictors for delayed pouch surgery included higher UC surgery volume(p = 0.01) and absence of colonic dysplasia(p = 0.04). Delayed pouch formation did not significantly predict complication severity. Conclusions: Our data allows improved classification of complex operations. Curating disease-specific variables allows for better analysis of predictors of delayed versus immediate pouch construction and postoperative complication severity. Short summary: We applied our previously validated novel NSIP-IBD database for classifying complex, multi-stage surgical approaches for UC to a degree that was not possible prior to our collaborative effort. From this, we describe predictive factors for delayed pouch formation in UC RPC-IPAA with the largest multicenter effort to date.

Islet transplantation to treat type 1 diabetes has been limited in part by toxicities of current immunosuppression and recipient humoral sensitization. Blockade of the CD28/CD80/86 and CD40/CD154 pathways has shown promise to remedy both these limitations, but translation has been hampered by difficulties in translating CD154-directed therapies. Prior CD40-directed regimens have led to prolonged islet survival, but fail to prevent humoral allosensitization. We therefore evaluated the addition of CTLA4Ig to a CD40-blockade based regimen in nonhuman primate (NHP) alloislet transplantation. Diabetic rhesus macaques were transplanted allogeneic islets using the CD40-specific antibody 3A8, basiliximab induction, and sirolimus with or without CTLA4Ig maintenance therapy. Allograft survival was determined by fasting blood glucose levels and flow cytometric techniques were used to test for donor-specific antibody (DSA) formation. CTLA4Ig plus 3A8, basiliximab and sirolimus was well tolerated and induced long-term islet allograft survival. The addition of CTLA4Ig prevented DSA formation, but did not facilitate withdrawal of the 3A8-based regimen. Thus, CTLA4Ig combines with a CD40-specific regimen to prevent DSA formation in NHPs, and offers a potentially translatable calcineurin inhibitor-free protocol inclusive of a single investigational agent for use in clinical islet transplantation without relying upon CD154 blockade.

Sirolimus is a potent anti-proliferative agent used clinically to prevent renal allograft rejection. However, little is known about the effects of maintenance immunosuppressive agents on the immune response to potentially protective vaccines. Here we show that sirolimus paradoxically increases the magnitude and quality of the CD8+ T cell response to vaccinia vaccination in non-human primates, fostering more robust recall responses compared to untreated and tacrolimus-treated controls. Enhancement of both the central and effector memory compartments of the vaccinia-specific CD8+ T cell response was observed. These data elucidate new mechanistic characteristics of sirolimus and suggest immune applications extending beyond its role as an immunosuppressant.

As COVID-19 infections soar worldwide, surgical teams must quickly adapt to care for the COVID-19-positive patient in the operating room (OR). This challenge comes in the face of constant change in data and conditions, reliable evidence yet to emerge, shortages of personal protective equipment (PPE), uncertainty due to lack of testing equipment and capacity, and unprecedented strain on caregivers, hospital systems, and resources.

Memory CD8 T cells are a critical component of protective immunity, and inducing effective memory T-cell responses is a major goal of vaccines against chronic infections and tumours. Considerable effort has gone into designing vaccine regimens that will increase the magnitude of the memory response, but there has been minimal emphasis on developing strategies to improve the functional qualities of memory T cells. Here we show that mTOR (mammalian target of rapamycin, also known as FRAP1) is a major regulator of memory CD8 T-cell differentiation, and in contrast to what we expected, the immunosuppressive drug rapamycin has immunostimulatory effects on the generation of memory CD8 T cells. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus infection enhanced not only the quantity but also the quality of virus-specific CD8 T cells. Similar effects were seen after immunization of mice with a vaccine based on non-replicating virus-like particles. In addition, rapamycin treatment also enhanced memory T-cell responses in non-human primates following vaccination with modified vaccinia virus Ankara. Rapamycin was effective during both the expansion and contraction phases of the T-cell response; during the expansion phase it increased the number of memory precursors, and during the contraction phase (effector to memory transition) it accelerated the memory T-cell differentiation program. Experiments using RNA interference to inhibit expression of mTOR, raptor (also known as 4932417H02Rik) or FKBP12 (also known as FKBP1A) in antigen-specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 (mTOR complex 1) pathway to regulate memory T-cell differentiation. Thus these studies identify a molecular pathway regulating memory formation and provide an effective strategy for improving the functional qualities of vaccine- or infection-induced memory T cells.

The widespread clinical implementation of alloislet transplantation as therapy for type 1 diabetes has been hindered by the lack of suitable islet donors. Pig-to-human islet xenotransplantation is one strategy with potential to alleviate this shortage. Long-term survival of porcine islets has been achieved using CD154-specific antibodies to interrupt the CD40/CD154 costimulation pathway; however, CD154-specific antibodies seem unlikely candidates for clinical translation. An alternative strategy for CD40/CD154 pathway interruption is use of CD40-specific antibodies. Herein, we evaluate the ability of a chimeric CD40-specific monoclonal antibody (Chi220) to protect islet xenografts. Neonatal porcine islets (∼50 000 IEQ/kg) were transplanted intraportally into pancreatectomized diabetic macaques. Immunosuppression consisted of induction therapy with Chi220 and the IL-2 receptor-specific antibody basiliximab, and maintenance therapy with sirolimus and the B7-specific fusion protein belatacept. Chi220 effectively promoted xenoislet engraftment and survival, with five of six treated recipients achieving insulin-independent normoglycemia (median rejection-free survival 59 days; mean 90.8 days, maximum 203 days). No thromboembolic phenomena were observed. CD40 represents a promising alternative to CD154 as a therapeutic target, and the efficacy of CD40-specific antibodies in islet xenotransplantation warrants further investigation.