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Background Bariatric surgery can influence the presentation, diagnosis, and management of gastrointestinal cancers. Oesophago-Gastric (OG) malignancies in patients who have had a prior bariatric procedure have not been fully characterised. Objective To characterise OG malignancies after bariatric procedures. Setting University Hospital, United Kingdom. Methods We performed a retrospective, multi-centre observational study of patients with OG malignancies after bariatric surgery to characterise this condition. Results This study includes 170 patients from 75 centres in 25 countries who underwent bariatric procedures between 1985 and 2020. At the time of the bariatric procedure, the mean age was 50.2 ± 10 years and the mean weight 128.8 ± 28.9 kg. Females comprised 57.3% (n=98) of the population. Most (n=64) patients underwent a Roux-en-Y Gastric Bypass (RYGB) followed by Adjustable Gastric Band (AGB) (n = 46) and Sleeve Gastrectomy (SG) (n = 43). Time to cancer diagnosis after bariatric surgery was 9.5 ± 7.4 years and mean weight at diagnosis was 87.4 ± 21.9 kg. The time lag was 5.9 ± 4.1 years after SG compared to 9.4 ± 7.1 years after RYGB and 10.5 ± 5.7 years after AGB. One-third of patients presented with metastatic disease. The majority of tumours were adenocarcinoma (82.9%). Approximately 1 in 5 patients underwent palliative treatment from the outset. Time from diagnosis to mortality was under one year for most patients who died over the intervening period. Conclusions The OGMOS (Oesophago-Gastric Malignancies after Obesity/ Bariatric Surgery) study presents the largest series to date of patients developing OG malignancies after bariatric surgery and attempts to characterise this condition.

Background Studies of patients who have undergone surgery while infected with COVID-19 have shown increased risks for adverse outcomes in both pulmonary complications and mortality. It has become clear that the risk of complications from perioperative COVID-19 infection must be weighed against the risk from delayed surgical treatment. Studies have also shown that prior bariatric surgery conveys protection against mortality from COVID-19 and that obesity is the biggest risk factor for mortality from COVID-19 infection in adults under 45 years of age. Studies in patients who have fully recovered from COVID-19 and underwent elective surgery have not become widely available yet. Objectives This multi-institutional case series is presented to highlight patients who developed COVID-19, fully recovered, and subsequently underwent elective bariatric surgery with 30-day outcomes available. Setting Nine bariatric surgery centers located across the United States. Methods This multicenter case series is a retrospective chart review of patients who developed COVID-19, recovered, and subsequently underwent bariatric surgery. Fifty-three patients are included, and 30-day morbidity and mortality were analyzed. Results Thirty-day complications included esophageal spasm, dehydration, and ileus. There were no cardiovascular, venous thromboembolism (VTE) or respiratory events reported. There were no 30- day mortalities. Conclusions Bariatric surgery has been safely performed in patients who made a full recovery from COVID-19 without increased complications due to cardiovascular, pulmonary, venous thromboembolism, or increased mortality rates.

Objective The COVID-19 pandemic created a paradigm shift in medical education with a reliance upon alternative teaching methods to deliver meaningful surgery clerkship content. This study examines the efficacy of a novel, case-based virtual surgery clerkship curriculum to determine its impact on student experience during quarantine. Study Design Sixteen third-year medical students enrolled in the General Surgery clerkship between April through June 2020 during COVID-19 distancing at a quaternary medical center (Cleveland Clinic, Cleveland, OH) participated in this study. Course surveys, including a 10-question curriculum-based multiple-choice assessment, were administered before and after the clerkship. Analyses include student self-perception of readiness to see a surgical consult independently, students’ interest in pursuing a General Surgery residency, and improvement of surgical knowledge. Results and Conclusion On a 5-point Likert scale, students felt significantly more assured in their ability to independently assess a surgical consult by the end of the course. Five (31%) students reported an influence of the curriculum on their personal interest in a career in General Surgery. Mean scores on the curriculum-based knowledge assessment increased. These findings highlight that a virtual platform can be a reliable alternative adjunct that delivers surgical content and positively impacts student experience. Supplementary Information The online version contains supplementary material available at 10.1007/s40670-020-01126-5.

Tumor lysis syndrome is a life-threatening complication comprising hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia attributed to release of intracellular contents. Although traditionally associated with leukemia and lymphoma after chemotherapy, it is known to occur in solid malignancies. We herein report a rare case of this syndrome after resection of bulky carcinoid tumor of the lung.

Laparoscopy provides a minimally invasive alternative to open abdominal surgery. Current data describing its association with hospital readmission and costs in relation to surgeon laparoscopic case volume is limited to smaller databases and subsets of operations. This retrospective cohort study of 23,285 adult abdominal operations from 2007 to 2015 compares 30-day readmission rate and costs between laparoscopic and open abdominal operations and examines effect modification by surgeon laparoscopic case volume. Outcomes were all-cause hospital readmission within 30 days after discharge and index hospital admission cost. All-cause hospital readmission rates were significantly lower after laparoscopic abdominal operations compared with open operations (adjusted odds ratio [aOR] 0.56, 95% CI 0.46–0.69, p

High levels of human telomerase reverse transcriptase (hTERT) are detected in more than 85% of human cancers. Immunologic analysis supports that hTERT is a widely applicable target recognized by T cells and can be potentially studied as a broad cancer immunotherapeutic, or a unique line of defense against tumor recurrence. There remains an urgent need to develop more potent hTERT vaccines. Here, a synthetic highly optimized full-length hTERT DNA vaccine (phTERT) was designed and the induced immunity was examined in mice and non-human primates (NHP). When delivered by electroporation, phTERT elicited strong, broad hTERT-specific CD8 T-cell responses including induction of T cells expressing CD107a, IFN-γ, and TNF-α in mice. The ability of phTERT to overcome tolerance was evaluated in an NHP model, whose TERT is 96% homologous to that of hTERT. Immunized monkeys exhibited robust [average 1,834 spot forming unit (SFU)/106 peripheral blood mononuclear cells (PBMC)], diverse (multiple immunodominant epitopes) IFN-γ responses and antigen-specific perforin release (average 332 SFU/106 PBMCs), suggesting that phTERT breaks tolerance and induces potent cytotoxic responses in this human-relevant model. Moreover, in an HPV16-associated tumor model, vaccination of phTERT slows tumor growth and improves survival rate in both prophylactic and therapeutic studies. Finally, in vivo cytotoxicity assay confirmed that phTERT-induced CD8 T cells exhibited specific cytotoxic T lymphocyte (CTL) activity, capable of eliminating hTERT-pulsed target cells. These findings support that this synthetic electroporation-delivered DNA phTERT may have a role as a broad therapeutic cancer vaccine candidate. Cancer Immunol Res; 1(3); 179–89. ©2013 AACR.

The presence of AML1-ETO (RUNX1-CBF2T1), a fusion oncoprotein resulting from a t(8;21) chromosomal translocation, has been implicated as a necessary but insufficient event in the development of a subset of acute myeloid leukemias (AML). While AML1-ETO prolongs survival and inhibits differentiation of hematopoietic stem cells (HSC), other contributory events are needed for cell proliferation and leukemogenesis. We have postulated that specific tumor suppressor genes keep the leukemic potential of AML1-ETO in check. In studying del(9q), one of the most common concomitant chromosomal abnormalities with t(8;21), we identified the loss of an apparent tumor suppressor, TLE4, that appears to cooperate with AML1-ETO to confer a leukemic phenotype. This study sought to identify the molecular basis of this cooperation. We show that the loss of TLE4 confers proliferative advantage to leukemic cells, simultaneous with an upregulation of a pro- inflammatory signature mediated through aberrant increases in Wnt signaling activity. We further demonstrate that inhibition of cyclooxygenase (COX) activity partly reverses the pro-leukemic phenotype due to TLE4 knockdown, pointing towards a novel therapeutic approach for myeloid leukemia.

Due to the strong relationship between the Human Papillomavirus (HPV) "high-risk" subtypes and cervical cancers, most HPV-related studies have been focusing on the "high-risk" HPV subtypes 16 and 18. However, it has been suggested that the "low-risk" subtypes of HPV, HPV6 and HPV11, are the major cause of recurrent respiratory papillomatosis and genital warts. In addition, HPV 6 and 11 are also associated with otolaryngologic malignancies, carcinoma of the lung, tonsil, larynx and low-grade cervical lesions. Therefore, development of HPV therapeutic vaccines targeting on subtypes 6 and 11 E6 or E7 are in great need. In this report, we describe two novel engineered DNA vaccines that encode HPV 6 and 11 consensus E6/E7 fusion proteins (p6E6E7 and p11E6E7) by utilizing a multi-phase strategy. Briefly, after generating consensus sequences, several modifications were performed to increase the expression of both constructs, including codon/RNA optimization, addition of a Kozak sequence and a highly efficient leader sequence. An endoproteolytic cleavage site was also introduced between E6 and E7 protein for proper protein folding and for better CTL processing. The expressions of both constructs were confirmed by western blot analysis and immunofluorescence assay. Vaccination with these DNA vaccines could elicit robust cellular immune responses. The epitope mapping assay was performed to further characterize the cellular immune responses induced by p6E6E7 and p11E6E7. The HPV 6 and 11 E6 or E7-specific immunodominant and subdominant epitopes were verified, respectively. The intracellular cytokine staining revealed that the magnitude of IFN-γ and TNF-α secretion in antigen-specific CD8(+) cells was significantly enhanced, indicating that the immune responses elicited by p6E6E7 and p11E6E7 was heavily skewed toward driving CD8(+) T cells. Such DNA immunogens are interesting candidates for further studies on HPV 6 and 11-associated diseases.

DNA vaccines require significant engineering in order to generate strong CTL responses in both non-human primates and humans. In this study, we designed a clade C env gene (EY3E1-C) to decrease the genetic distances of virus isolates within clade C and focus the induced T cell responses to conserved clade C epitopes. After generating a consensus sequence by analyzing full-length clade C env early transmitter sequences, several modifications were performed to increase the expression of the EY3E1-C, including codon/RNA optimization, addition of Kozak sequence and addition of an IgE leader sequence. We also shortened the V1 and V2 loops to approximate early transmitter isolate sequences and the cytoplasmic tail was truncated to prevent envelope recycling. When studied as a DNA vaccine in Balb/c mice, compared to a primary codon-optimized clade C envelope DNA vaccine (p96ZM651gp140-CD5), this novel construct is up to three times more potent in driving CTL responses. Importantly this construct not only induces stronger cross-reactive cellular responses within clade C, it also induces stronger immune responses against clade B and group M envelope peptide pools than p96ZM651gp140-CD5. Epitope mapping demonstrated that EY3E1-C was able to induce clade C envelope-specific immune responses against 15 peptide pools, clade B envelope-specific immune responses against 19 peptide pools and group M envelope-specific immune responses against 16 peptide pools out of 29, respectively, indicating that a significant increase in the breadth of induced immune responses. The analysis of antibody responses suggested that vaccination of pEY3E1-C could induce a clade C envelope-specific antibody response. The cellular immune responses of pEY3E1-C could be further enhanced when the DNA was delivered by using electroporation (EP). Thus, the synthetic engineered consensus EY3E1-C gene is capable of eliciting stronger and broader CTL responses than primary clade C envelopes. This finding suggests that such synthetic immunogens could be important for examination of their potential as part of an efficient HIV DNA vaccine.

It was discovered almost 20 years ago that plasmid DNA, when injected into the skin or muscle of mice, could induce immune responses to encoded antigens. Since that time, there has since been much progress in understanding the basic biology behind this deceptively simple vaccine platform and much technological advancement to enhance immune potency. Among these advancements are improved formulations and improved physical methods of delivery, which increase the uptake of vaccine plasmids by cells; optimization of vaccine vectors and encoded antigens; and the development of novel formulations and adjuvants to augment and direct the host immune response. The ability of the current, or second-generation, DNA vaccines to induce more-potent cellular and humoral responses opens up this platform to be examined in both preventative and therapeutic arenas. This review focuses on these advances and discusses both preventive and immunotherapeutic clinical applications.

Associated with approximately 8-13% cases of acute myeloid leukemia (AML), t (8;21) results in the formation of the fusion oncoprotein AML1-ETO (AE), which appears to promote hematopoietic precursor expansion through aberrant regulation of canonical AML1 targets. Multiple lines of evidence indicate AE is insufficient for leukemogenesis and requires cooperative secondary mutations. Interstitial deletions of chromosome 9 are one of the more frequent associated cytogenetic abnormalities seen with t(8;21). We previously identified that knockdown of TLE1 and TLE4, members of the Groucho/TLE family of co-repressors residing in a commonly deleted region of chromosome 9 in t (8;21) del (9q) AML cooperates with AE to drive myeloblastic proliferation and cause a leukemic phenotype. In this study, we show how TLE4 loss in the context of AML1-ETO expression results in cell proliferation, decreased apoptosis, blocked differentiation, and increased resistance to chemotherapy and that these effects are mediated through an upregulation of cyclooxygenase (COX)-dependent inflammation. TLE4 knockdown via shRNA (shTLE4) in Kasumi-1 cells (derived from a patient with t (8;21) AML) resulted in increased cell cycling and decreased cell death that is concomitant with significantly lower levels of p16Ink4 and p27Kip1 expression, both major regulators of the G1/S cell cycle checkpoint. RNAseq with GSEA analysis identified enrichment of pathways related to IFN signaling and inflammation within upregulated genes in shTLE4 cells compared to control. Filtering for genes with log2 fold change greater than 0.6, we identified three genes related to inflammation (PTGER4, CEBPb, FOS). As demonstration of the relevance of these findings, we showed these expression levels were also higher in primary human del (9q) and t (8;21) del (9q) leukemia samples compared to normal CD34+ cells; revealing a potential leukemogenic role for inflammatory pathways in del (9q) and t (8;21) del (9q) AML. Using a sub-lethal dose of indomethacin (50uM INDM), we found modulating the COX-dependent inflammatory axis decreased growth of shTLE4 Kasumi-1 cells, decreased cell cycling, and increased dead populations. Concomitantly, INDM treatment was able to reverse shTLE4-induced increases in PTGER4, CEBPb, FOS, and IL1b expression to levels similar to those in control cells. Given the ability to induce myeloblastic proliferation with TLE knockdown and AE expression in zebrafish, we investigated whether shTLE4 causes changes in key myeloid differentiation regulators in Kasumi-1 cells. qPCR analysis demonstrated significantly repressed ELANE, MPO, and PU.1 expression in shTLE4-treated cells, which is relieved with the addition of INDM. TLE4 knockdown in HL60 cells (derived from t (15;17) PML/RARA leukemia) increased levels of FOS, IL1b, CEBPb, and PTGER4. At the same time, shTLE4 significantly reduced CD11b+ and CD11b+ CD14+ populations while decreasing expression of PU.1 and MYB - demonstrating a similar inflammatory gene signature associated with a myeloid differentiation block found in the Kasumi-1 model. We next wanted to examine whether inhibiting COX-dependent inflammation can be synergistic with existing therapies. INDM significantly increased the cell death and apoptosis seen in both control cells as well as cells with TLE4 knockdown treated with AraC. The loss of TLE4 conferred resistance to combination treatment with indomethacin and AraC as evidenced by increased cell proliferation and decreased cell death. However, we observed that cells with TLE4 knockdown were significantly more sensitive to the combination of sunitinib and INDM, pointing to a potentially more therapeutic and less toxic treatment regimen for this otherwise resistant cell population. In this study, we have demonstrated that loss of TLE4 appears to contribute to leukemogenesis through differentiation arrest and increased proliferation mediated through upregulation of COX-dependent inflammatory pathways. Our findings suggest that COX inhibition may serve as an effective adjuvant therapy for AML. Disclosures No relevant conflicts of interest to declare.