Polycytidine tract deletion from microRNA-detargeted oncolytic Mengovirus optimizes the therapeutic index in a murine multiple myeloma model.

Mengovirus is an oncolytic picornavirus whose broad host range allows for testing in immunocompetent cancer models. Two pathogenicity-ablating approaches, polycytidine (polyC) tract truncation and microRNA (miRNA) targets insertion, eliminated the risk of encephalomyocarditis. To investigate whether a polyC truncated, miRNA-detargeted oncolytic Mengovirus might be boosted, we partially or fully rebuilt the polyC tract into the 5' noncoding region (NCR) of polyC-deleted (MC0) oncolytic constructs (NC) carrying miRNA target (miRT) insertions to eliminate cardiac/muscular (miR-133b and miR-208a) and neuronal (miR-124) tropisms. PolyC-reconstituted viruses (MC24-NC and MC37-NC) replicated in vitro and showed the expected tropism restrictions, but reduced cytotoxicity and miRT deletions were frequently observed. In the MPC-11 immune competent mouse plasmacytoma model, both intratumoral and systemic administration of MC0-NC led to faster tumor responses than MC24-NC or MC37-NC, with combined durable complete response rates of 75%, 0.5%, and 30%, respectively. Secondary viremia was higher following MC0-NC versus MC24-NC or MC37-NC therapy. Sequence analysis of virus progeny from treated mice revealed a high prevalence of miRT sequences loss among MC24- and MC37- viral genomes, but not in MC0-NC. Overall, MC0-NC was capable of stably retaining miRT sites and provided a more effective treatment and is therefore our lead Mengovirus candidate for clinical translation.

Impact of COVID-19 Governmental Restrictions on Emergency General Surgery Operative Volume and Severity.

BACKGROUND: To describe the effect of the COVID-19 pandemic on emergency general surgery operative volumes during governmental shutdowns secondary to the pandemic and characterize differences in disease severity, morbidity, and mortality during this time compared to previous years. METHODS: This retrospective cohort study compares patients who underwent emergency general surgery operations at a tertiary hospital from March 1st to May 31st of 2020 to 2019. Average emergent cases per day were analyzed, comparing identical date ranges between 2020 (pandemic group) and 2019 (control group). Secondary analysis was performed analyzing disease severity, morbidity, and mortality. RESULTS: From March 1st to May 31st, 2020, 2.5 emergency general surgery operations were performed on average daily compared to 3.0 operations on average daily in 2019, a significant decrease (P = .03). No significant difference was found in presenting disease severity, morbidity, or mortality between the pandemic and control groups. DISCUSSION: This study demonstrates a decrease of 65% in emergency general surgery operations during governmental restrictions secondary to the COVID-19 pandemic. This decrease in operations was not associated with worse disease severity, morbidity, or mortality.

Impact of Chronic Immunosuppression on Short-, Mid-, and Long-Term Bariatric Surgery Outcomes.

INTRODUCTION: Bariatric surgical outcomes depend heavily on proper healing of gastrointestinal anatomy, metabolic alterations, and patient lifestyle modifications which are all negatively impacted by immunosuppression and underlying inflammatory diseases. There is a lack of literature exploring how patients with diseases requiring immunosuppression respond to bariatric surgical intervention in the long term. METHODS: A retrospective analysis of chronically immunosuppressed patients who underwent primary bariatric surgeries at Mayo Clinic was conducted (2008-2020). Data collected included patient demographics, BMI, underlying disease, and immunosuppression regimen and complications at 3, 6, 12, 24, and 60 months. RESULTS: We identified a total of 89 (RYGB = 49, SG = 34, BPD/DS = 6) patients on chronic immunosuppression who underwent bariatric surgery at our center. RYGB (N = 49), 38.2% had a SG (N = 34) and 6.7% had a BPD/DS (N = 6). Rheumatoid arthritis and renal transplantation were the most underlying condition at 20.22% each (N = 18). There were a total of 2 (2.25%) intraoperative complications. In the immediate post-operative period, there were 15 (16.5%) minor complications. In follow-up, 6.1% of RYGB patients experienced marginal ulcerations, while no gastrointestinal leaks occurred. The mean pre-surgical BMI was 48.29 kg/m2 (SD = 18.41). Percent total weight loss (%TWL) and BMI reduction were 30.89% and 14.83 kg/m2 (SD = 9.07) at 12 months and 29.48% and 14.43 kg/m2 (SD = 13.46) at 60 months, respectively. The mean follow-up time was 30.49 months. CONCLUSIONS: Bariatric surgery remains safe and effective therapy for chronically immunosuppressed patients with excellent long-term outcomes for patients with moderate to severe obesity.

Does BMI Matter? A 10-Year Single Institutional Experience on 571 Bariatric Surgery Patients With BMI >50 kg/m 2.

INTRODUCTION: Patients undergoing bariatric surgery with body mass index (BMI) >50 kg/m 2 are at a higher risk of surgical morbidity when compared with less obese patients, however, there is limited data correlating surgical risk and efficacy with increasing BMI in patients with severe obesity. We hypothesize that regardless of the degree above 50 kg/m 2 their BMI, patients with severe obesity respond similarly to bariatric surgery. MATERIALS AND METHODS: We performed a retrospective analysis of patients with BMI >50 kg/m 2 who underwent biliopancreatic diversion with duodenal switch, Roux-en-Y gastric bypass, or sleeve gastrectomy at a single institution. Outcomes were compared in patients with a BMI between 50 and 60 kg/m 2 to patients with a BMI >60 kg/m 2 and included percent total weight loss as well as early and late complications. Statistical analyses were performed using logistic regression, univariate, and multivariate models. RESULTS: There were 571 patients with BMI >50 kg/m 2 who underwent bariatric surgery at our center, 170 (29.8%) had a BMI >60 kg/m 2 . Percent total weight loss was statistically significant between the BMI 50 and 60 kg/m 2 and BMI >60 kg/m 2 groups at 24 months ( P =0.047) but not at 60 months ( P =0.54). No significant difference was found in the incidence of early complications in a univariate ( P =0.46) or a multivariate ( P =0.06) analysis. The BMI >60 subgroup was associated with a higher rate of late complications in univariate analysis (heart rate=2.37; 1.03-5.47, P =0.04), but not in multivariate analysis ( P =0.78). CONCLUSIONS: Efficacy and complication rates of bariatric surgeries are similar in patients with BMI 50 to 60 kg/m 2 and >60 kg/m 2 , providing evidence supporting similar management of patients despite specific subgroups.

Ten year comparative analysis of sleeve gastrectomy, Roux-en-Y gastric bypass, and biliopancreatic diversion with duodenal switch in patients with BMI ≥ 50 kg/m2.

INTRODUCTION: Bariatric surgery is the most effective modality to stably reduce weight and related comorbidities in patients suffering from class II and III obesity. Data comparing long-term safety and efficacy of the three most effective bariatric operations are limited in patients with BMI ≥ 50 kg/m2, which complicate shared surgeon-patient decision making regarding optimal procedure selection. METHODS: A retrospective analysis was performed on all patients with BMI ≥ 50 kg/m2 who underwent biliopancreatic diversion with duodenal switch (BPD/DS), Roux-en-Y gastric bypass (RYGB), or sleeve gastrectomy (SG) at our institution between 2009 and 2019. Data collected from patients' electronic medical records included operative details as well as BMI and presence and resolution of obesity-related comorbidities at 0, 6, 12, 24, 48, and 60 months post-operatively. RESULTS: Among 537 patients with BMI ≥ 50 kg/m2 who had a primary bariatric procedure, 93 patients underwent BPD/DS (17.3%), 341 patients underwent RYGB (63.5%), and 103 patients underwent SG (19.2%). BMI decreased by 23.7 kg/m2 in BPD/DS, 14.7 kg/m2 in RYGB, and 13.6 kg/m2 in SG cohorts at 60 months post-operatively (p < 0.0001). The greatest %TWL occurred in BPD/DS cohort (38.4%) followed by the RYGB (26.3%) and SG (23.6%) cohorts (p < 0.0001). The thirty-day complication rate was 12.9% for BPD/DS, 4.7% for RYGB, and 8.7% for SG (p = 0.015). CONCLUSIONS: Our study demonstrated that the BPD/DS is the most effective operation at long-term reduction of BMI and achieved highest %TWL while SG and RYGB had similar results at 60 months post-op. BPD/DS is associated with increased early and late surgical complications compared to RYGB and SG.

The Outcomes of Laparoscopic Biliopancreatic Diversion with Duodenal Switch on Gastro-esophageal Reflux Disease: the Mayo Clinic Experience.

PURPOSE: The outcomes of laparoscopic biliopancreatic diversion with duodenal switch (BPD-DS) on gastro-esophageal reflux disease (GERD) are not well elucidated. MATERIAL/METHODS: This retrospective review included patients undergoing laparoscopic primary BPD-DS at Mayo Clinic from 2009 to 2019. GERD parameters analyzed included subjective symptom report/anti-reflux medication intake and/or endoscopic findings. GERD-HRQL questionnaire was also utilized post-operatively. Three subgroups were employed to stratify patients depending on GERD outcomes: the "No-effect" subgroup included patients where surgery did not affect either positively (GERD resolution) or negatively (de novo GERD) GERD outcome, "De novo GERD" subgroup, and "GERD-resolved" subgroup. Multinomial logistic modeling was used to examine associations with the 3-level GERD subgroup (p<0.05). RESULTS: Seventy-six patients were included in the analysis. Thirty-four (44.7%) patients were found to be in the "GERD-resolved" subgroup, 28 (36.8%) patients in the "No-effect" subgroup, and 14 (18.4%) patients in the "De novo GERD" subgroup. Multinomial logistic modeling showed that patients with pre-surgery diabetes mellitus (DM) had lesser odds (OR= 0.248, (95% CI: 0.085-0.724, p=0.0108)) of GERD resolution than patients without pre-surgery DM. An association was also established between %TWL at 6 and 12 months following the procedure and GERD outcome (p=0.017 and 0.008, respectively). Finally, the mean (SD) post-operative GERD-HRQL score was 8.7 (8.1) points, and 69 (91%) patients were currently satisfied with their post-operative condition. CONCLUSION: Laparoscopic BPD-DS appears to have a satisfactory GERD outcome in most patients undergoing the operation. There appears to be an association between pre-operative DM, %TWL at 6 and 12 months, and GERD prognosis in this population.

Collateral Lethal Effects of Complementary Oncolytic Viruses.

Virus-infected cells release type 1 interferons, which induce an antiviral state in neighboring cells. Naturally occurring viruses are therefore equipped with stealth replication strategies to limit virus sensing and/or with combat strategies to prevent or reverse the antiviral state. Here we show that oncolytic viruses with simple RNA genomes whose spread was suppressed in tumor cells pretreated with interferon were able to replicate efficiently when the cells were coinfected with a poxvirus known to encode a diversity of innate immune combat proteins. In vivo the poxvirus was shown to reverse the intratumoral antiviral state, rescuing RNA virus replication in an otherwise restrictive syngeneic mouse tumor model leading to antitumor efficacy. Pairing of complementary oncolytic viruses is a promising strategy to enhance the antitumor activity of this novel class of anticancer drugs.

Designing and building oncolytic viruses.

Oncolytic viruses (OVs) are engineered and/or evolved to propagate selectively in cancerous tissues. They have a dual mechanism of action; direct killing of infected cancer cells cross-primes anticancer immunity to boost the killing of uninfected cancer cells. The goal of the field is to develop OVs that are easily manufactured, efficiently delivered to disseminated sites of cancer growth, undergo rapid intratumoral spread, selectively kill tumor cells, cause no collateral damage and pose no risk of transmission in the population. Here we discuss the many virus engineering strategies that are being pursued to optimize delivery, intratumoral spread and safety of OVs derived from different virus families. With continued progress, OVs have the potential to transform the paradigm of cancer care.