Novel immunomodulatory properties of low dose cytarabine entrapped in a mannosylated cationic liposome.

Cancer treatment remains unsatisfactory with high rates of recurrence and metastasis. Immunomodulatory agents capable of promoting cellular antitumor immunity while inhibiting the local immunosuppressive tumor microenvironment could greatly improve cancer treatment. We have developed a multi-targeted mannosylated cationic liposome delivery system containing muramyl dipeptide (DS) and low doses of the chemotherapeutic agent cytarabine (Ara-C). Immunomodulation of primary immune cells and immortalized cancer cell lines by Ara-C/DS was assessed by measuring cytokine levels and surface marker expression. As a proof of concept, the generation of targeted cellular immunity was investigated in the context of responses to viral antigens. This report is the first demonstrating that Ara-C combined with DS can modulate immune responses and revert immunosuppression as evidenced by increased IFN-γ and IL-12p40 without changes in IL-10 in peripheral blood mononuclear cells, and increased CD80 and decreased CD163 on immunosuppressive macrophages. Furthermore, Ara-C/DS increased MHC class I expression on cancer cells while increasing the production of antigen-specific IFN-γ+ CD8+ T cells in viral peptide-challenged lymphocytes from both humans and vaccinated mice. Taken together, these results are the first to document immunomodulatory properties of Ara-C linked with recognition of antigens and potentially the generation of antitumor immune memory.

Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer.

Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option.

Ileal pouch-anal anastomosis for ulcerative colitis: a Canadian institution's experience.

BACKGROUND: We aimed to summarize the outcomes of ulcerative colitis (UC) patients receiving an ileal pouch-anal anastamosis (IPAA) over an 11-year period at a high-volume Canadian inflammatory bowel disease (IBD) center. METHODS: A retrospective chart review was performed for subjects with UC who underwent IPAA between 2002 and 2013. Patient charts were reviewed for demographic data, clinical characteristics, preoperative medical treatment, and surgical outcomes. Univariate and multivariate logistic regression modeling were used to determine significant factors in postoperative outcomes. RESULTS: Seven hundred fifty-eight were included from the IBD database. The median age at the time of surgery was 37.1 (±12.1). Mean preoperative disease duration was 8.1 years (±8.7). Three hundred sixty-nine patients (48.7 %) had systemic corticosteroids (>15 mg/day) within 30 days prior to surgery. Of these, 286 patients had high dose (>30 mg/day) corticosteroids within 7 days of their first surgery. One hundred nine (14.0 %) IPAA procedures were performed laparoscopically. Pelvic pouches were created in traditional 2 (n = 460) and 3 (n = 285) stages; the remainder (n = 13) was performed in non-traditional staged operations. Early complications, defined as occurring within the same stay in hospital, consisted of pelvic abscess (n = 135, 17.8 %), small bowel obstruction (n = 134, 17.7 %), wound infection (n = 108, 14.3 %), and deep vein thrombosis (n = 33, 4.4 %). The overall pouch leak rate was 92 (12.1 %). There was one death in our study. The median length of stay was 10.3 days (SD6.0). Late complications, defined as occurring after discharge from hospital, consisted of anal stricture (n = 55, 7.3 %), pouch fistula (n = 26, 3.4 %), and functional pouch failure (n = 7, 0.9 %). CONCLUSIONS: IPAA has been found to be a safe and effective method of surgical management of UC patients in a high-volume IBD center.

Preoperative Anti-tumor Necrosis Factor Therapy in Patients with Ulcerative Colitis Is Not Associated with an Increased Risk of Infectious and Noninfectious Complications After Ileal Pouch-anal Anastomosis.

BACKGROUND: There are conflicting data regarding the effect of previous exposure to anti-tumor necrosis factor (anti-TNF) therapy on complication rates after pelvic pouch surgery for patients with ulcerative colitis (UC). In particular, there is concern surrounding the rates of pouch leaks and infectious complications, including pelvic abscesses, in anti-TNF-treated subjects who require ileal pouch-anal anastomosis (IPAA) surgery. METHODS: A retrospective study was performed in UC subjects who underwent IPAA between 2002 and 2013. Demographic data, clinical data, use of anti-TNF therapy, steroids, immunosuppressants, and surgical outcomes were assessed. RESULTS: Seven hundred seventy-three patients with UC/IPAA were reviewed. Fifteen patients were excluded from the analysis because of missing data. There were 196 patients who were exposed to anti-TNF therapy and 562 patients who were not exposed to anti-TNF therapy preoperatively. There were no significant differences in the postoperative IPAA leak rate between those exposed to anti-TNF therapy and the control group (n = 26 [13.2%] versus 66 [11.7%], respectively, P = 0.44). In addition, there were no significant differences in the postoperative 2-stage IPAA leak rate in those who had been operated on within 15 days from the last anti-TNF dose (n = 10), within 15 to 30 days (n = 17), or 31 to 180 days (n = 54) (10%, 5.9%, and 14.8% respectively, P = 0.43) nor were there differences based on the presence of detectable infliximab serum levels. CONCLUSIONS: Preoperative anti-TNF therapy in patients with UC is not associated with an increased risk of infectious and noninfectious complications after IPAA including pelvic abscesses, leaks, and wound infections.

Modified Two-stage Ileal Pouch-Anal Anastomosis Results in Lower Rate of Anastomotic Leak Compared with Traditional Two-stage Surgery for Ulcerative Colitis.

BACKGROUND AND AIMS: There is a paucity of evidence in ulcerative colitis [UC] comparing the traditional two-stage [total proctocolectomy with ileal pouch-anal anastomosis [IPAA] and diverting ileostomy, followed by ileostomy closure] vs the modified two-stage restorative proctocolectomy [subtotal colectomy with end ileostomy, followed by completion proctectomy and IPAA, without diverting ileostomy]. This study examines the risk of anastomotic leak following IPAA in traditional vs modified two-stage IPAA for UC patients. METHODS: This was a single-institution, retrospective study of all UC patients who underwent a traditional or modified two-stage IPAA between 2002 and 2013. The primary outcome was anastomotic leak following IPAA. RESULTS: In all, 460 patients had a two-stage IPAA procedure; 223 [48.5%] patients underwent traditional two-stage IPAA and 237 [51.5%] patients received the modified two-stage procedure. There was more preoperative enteral corticosteroid use [44.7% vs 33.2%, p = 0.04] before the first surgery in the modified two-stage group compared with the traditional two-stage group. The modified two-stage group had higher UC disease severity at presentation [86.9% patients with moderate/severe UC vs 73.1%, p < 0.01]. However, the modified two-stage group had a lower rate of anastomotic leak following IPAA [4.6% vs 15.7%, p < 0.01] and was associated with a lower risk of anastomotic leak on univariate (odds ratio [OR] 0.26, 95% confidence interval [CI] 0.13, 0.52] and multivariate analysis [OR 0.27, 95% CI 0.12, 0.57]. CONCLUSIONS: Patients with ulcerative colitis who received the modified two-stage IPAA had a significantly lower rate of anastomotic leak following pouch creation, compared with the traditional two-stage procedure.

An unconventional therapeutic approach to a migratory IUD causing perforation of the rectum.

Intrauterine devices (IUDs) are a commonly used form of contraception. The risk of perforation and migration of these devices have been reported to be 1 in 1000. Migration into the rectum is even more uncommon. The following case illustrates a previously healthy 37-year-old woman who experienced a perforation and migration of an IUD into the rectum necessitating endoscopic removal. To our knowledge, this complication of IUD and subsequent endoscopic removal has not been previously described and presents a viable first-line therapeutic option in a stable patient.

Quality of inguinal hernia operative reports: room for improvement.

BACKGROUND: Operative reports (ORs) serve as the official documentation of surgical procedures. They are essential for optimal patient care, physician accountability and billing, and direction for clinical research and auditing. Nonstandardized narrative reports are often of poor quality and lacking in detail. We sought to audit the completeness of narrative inguinal hernia ORs. METHODS: A standardized checklist for inguinal hernia repair (IHR) comprising 33 variables was developed by consensus of 4 surgeons. Five high-volume IHR surgeons categorized items as essential, preferable or nonessential. We audited ORs for open IHR at 6 academic hospitals. RESULTS: We audited 213 ORs, and we excluded 7 femoral hernia ORs. Tension-free repairs were the most common (82.5%), and the plug-and-patch technique was the most frequent (52.9%). Residents dictated 59% of ORs. Of 33 variables, 15 were considered essential and, on average, 10.8 ± 1.3 were included. Poorly reported elements included first occurrence versus recurrent repair (8.3%), small bowel viability in incarcerated hernias (10.7%) and occurrence of intraoperative complications (32.5%). Of 18 nonessential elements, deep vein thrombosis prophylaxis, preoperative antibiotics and urgency were reported in 1.9%, 11.7% and 24.3% of ORs, respectively. Repair-specific details were reported in 0 to 97.1% of ORs, including patch sutured to tubercle (55.1%) and location of plug (67.0%). CONCLUSION: Completeness of IHR ORs varied with regards to essential and nonessential items but were generally incomplete, suggesting there is opportunity for improvement, including implementation of a standardized synoptic OR.

CONTEXTE: Les notes opératoires (NO) servent à documenter officiellement les interventions chirurgicales. Elles sont indispensables à des soins optimaux aux patients, à l'imputabilité des médecins, à la facturation de leurs actes, à l'orientation de la recherche clinique et aux vérifications. Les notes narratives non standardisées sont souvent de piètre qualité et incomplètes. Nous avons voulu vérifier l'exhaustivité des notes opératoires narratives concernant les réparations d'hernies inguinales (RHI). MÉTHODES: Une équipe de 4 chirurgiens a créé une liste de vérification standardisée consensuelle comprenant 33 variables applicables à la RHI. Cinq chirurgiens experts des RHI ont classé ces éléments selon qu'ils leurs semblaient essentiels, préférables ou non essentiels. Nous avons passé en revue les NO des RHI ouvertes effectuées dans 6 hôpitaux universitaires. RÉSULTATS: Nous avons passé en revue 213 NO et nous avons exclus les NO concernant 7 hernies fémorales. Les réparations sans tension se sont révélées les plus communes (82,5 %) et la technique plug-and-patch a été la plus fréquente (52,9 %). Les résidents ont dicté 59 % des NO. Sur les 33 variables, 15 étaient considérées essentielles et en moyenne, 10,8 ± 1,3 ont été incluses dans les NO. Parmi les éléments qui laissaient à désirer, mentionnons : première réparation c. réparation récurrente (8,3 %), viabilité du grêle dans les hernies incarcérées (10,7 %) et complications peropératoires (32,5 %). Parmi les 18 éléments jugés non essentiels, la prophylaxie contre la thrombose veineuse profonde, l'antibioprophylaxie et le degré d'urgence ont été mentionnés dans 1,9 %, 11,7 % et 24,3 % des NO, respectivement. Les détails spécifiques à la réparation ont été notés dans 0 à 97,1 % des NO, y compris la fixation de la prothèse au tubercule par des sutures (55,1 %) et la localisation du bouchon (67,0 %). CONCLUSION: L'exhaustivité des NO consignées dans les cas de RHI a varié en ce qui a trait aux éléments jugés essentiels et non essentiels et les NO se sont généralement révélées incomplètes. On en conclut qu'il y a place à amélioration, entre autre par l'adoption d'un modèle synoptique standardisé de NO.