Jejunal or Ileal Exocrine Drainage in Pancreas Transplantation: Impact on Gastrointestinal Function.

OBJECTIVES: Pancreas transplant can have serious complications requiring salvage pancreatectomy, and surgical approaches should be carefully considered, with jejunal or ileal anastomoses most often employed. The jejunum may reduce gastrointestinal disturbance, whereas the ileum is more immunogenic. Proximal gastrointestinal anastomoses pose challenges with salvage pancreatectomy and creation of high-output stoma, often in the context of end-stage renal failure. Here, we compared outcomes between these techniques. MATERIALS AND METHODS: We retrospectively analyzed patient records of simultaneous pancreas and kidney transplants at a single center between 2013 and 2015, with follow-up to 2020. RESULTS: Our center performed 86 simultaneous pancreas and kidney transplants during the study period; 10 patients were excluded because of incomplete records of anastomosis type. Of included recipients, 59.2% were men (mean age 41.5 ± 8.4 y), 72.4% were donors after brain death, and 98.7% had received a first pancreas transplant. Forty-three simultaneous pancreas and kidney transplants were performed with ileal anastomosis and 33 with jejunal anastomosis. We found no significant differences in recipient or donor factors or immunosuppression regimen between anastomosis groups and no significant differences in overall patient, pancreas, or kidney graft survival or in gastrointestinal complications. Hospital length of stay was higher with ileal anastomosis (median 14 vs 19 days; P < .05), as was cold ischemic time (median 8:48 vs 9:31 hours; P < .05). Three patients required salvage pancre-atectomy and loop ileostomy formation with multiorgan support, prolonged intensive care unit stay, relaparotomy, and/or laparostomy. CONCLUSIONS: Long-term outcomes were comparable between our patient groups. Catastrophic complica-tions occur in a minority of cases, requiring salvage surgery. More complications occurred with ileal anastomosis, but this approach allows graft pancreatectomy and formation of loop ileostomy, avoiding a more proximal stoma in clinically unstable patients. Further studies are needed to examine the impact of enteric anastomosis site.

Neoadjuvant Intravenous Oncolytic Vaccinia Virus Therapy Promotes Anticancer Immunity in Patients.

Improving the chances of curing patients with cancer who have had surgery to remove metastatic sites of disease is a priority area for cancer research. Pexa-Vec (Pexastimogene Devacirepvec; JX-594, TG6006) is a principally immunotherapeutic oncolytic virus that has reached late-phase clinical trials. We report the results of a single-center, nonrandomized biological end point study (trial registration: EudraCT number 2012-000704-15), which builds on the success of the presurgical intravenous delivery of oncolytic viruses to tumors. Nine patients with either colorectal cancer liver metastases or metastatic melanoma were treated with a single intravenous infusion of Pexa-Vec ahead of planned surgical resection of the metastases. Grade 3 and 4 Pexa-Vec-associated side effects were lymphopaenia and neutropaenia. Pexa-Vec was peripherally carried in plasma and was not associated with peripheral blood mononuclear cells. Upon surgical resection, Pexa-Vec was found in the majority of analyzed tumors. Pexa-Vec therapy associated with IFNα secretion, chemokine induction, and resulted in transient innate and long-lived adaptive anticancer immunity. In the 2 patients with significant and complete tumor necrosis, a reduction in the peripheral T-cell receptor diversity was observed at the time of surgery. These results support the development of presurgical oncolytic vaccinia virus-based therapies to stimulate anticancer immunity and increase the chances to cure patients with cancer.

Differential and longitudinal immune gene patterns associated with reprogrammed microenvironment and viral mimicry in response to neoadjuvant radiotherapy in rectal cancer.

BACKGROUND: Rectal cancers show a highly varied response to neoadjuvant radiotherapy/chemoradiation (RT/CRT) and the impact of the tumor immune microenvironment on this response is poorly understood. Current clinical tumor regression grading systems attempt to measure radiotherapy response but are subject to interobserver variation. An unbiased and unique histopathological quantification method (change in tumor cell density (ΔTCD)) may improve classification of RT/CRT response. Furthermore, immune gene expression profiling (GEP) may identify differences in expression levels of genes relevant to different radiotherapy responses: (1) at baseline between poor and good responders, and (2) longitudinally from preradiotherapy to postradiotherapy samples. Overall, this may inform novel therapeutic RT/CRT combination strategies in rectal cancer. METHODS: We generated GEPs for 53 patients from biopsies taken prior to preoperative radiotherapy. TCD was used to assess rectal tumor response to neoadjuvant RT/CRT and ΔTCD was subjected to k-means clustering to classify patients into different response categories. Differential gene expression analysis was performed using statistical analysis of microarrays, pathway enrichment analysis and immune cell type analysis using single sample gene set enrichment analysis. Immunohistochemistry was performed to validate specific results. The results were validated using 220 pretreatment samples from publicly available datasets at metalevel of pathway and survival analyses. RESULTS: ΔTCD scores ranged from 12.4% to -47.7% and stratified patients into three response categories. At baseline, 40 genes were significantly upregulated in poor (n=12) versus good responders (n=21), including myeloid and stromal cell genes. Of several pathways showing significant enrichment at baseline in poor responders, epithelial to mesenchymal transition, coagulation, complement activation and apical junction pathways were validated in external cohorts. Unlike poor responders, good responders showed longitudinal (preradiotherapy vs postradiotherapy samples) upregulation of 198 immune genes, reflecting an increased T-cell-inflamed GEP, type-I interferon and macrophage populations. Longitudinal pathway analysis suggested viral-like pathogen responses occurred in post-treatment resected samples compared with pretreatment biopsies in good responders. CONCLUSION: This study suggests potentially druggable immune targets in poor responders at baseline and indicates that tumors with a good RT/CRT response reprogrammed from immune "cold" towards an immunologically "hot" phenotype on treatment with radiotherapy.

Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C.

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.

Non-native honey bees disproportionately dominate the most abundant floral resources in a biodiversity hotspot.

Most plant-pollinator mutualisms are generalized. As such, they are susceptible to perturbation by abundant, generalist, non-native pollinators such as the western honey bee ( Apis mellifera), which can reach high abundances and visit flowers of many plant species in their expansive introduced range. Despite the prevalence of non-native honey bees, their effects on pollination mutualisms in natural ecosystems remain incompletely understood. Here, we contrast community-level patterns of floral visitation by honey bees with that of the diverse native pollinator fauna of southern California, USA. We show that the number of honey bees visiting plant species increases much more rapidly with flower abundance than does that of non-honey bee insects, such that the percentage of all visitors represented by honey bees increases with flower abundance. Thus, honey bees could disproportionately impact the most abundantly blooming plant species and the large numbers of both specialized and generalized pollinator species that they sustain. Honey bees may preferentially exploit high-abundance floral resources because of their ability to recruit nest-mates; these foraging patterns may cause native insect species to forage on lower-abundance resources to avoid competition. Our results illustrate the importance of understanding foraging patterns of introduced pollinators in order to reveal their ecological impacts.

The worldwide importance of honey bees as pollinators in natural habitats.

The western honey bee (Apis mellifera) is the most frequent floral visitor of crops worldwide, but quantitative knowledge of its role as a pollinator outside of managed habitats is largely lacking. Here we use a global dataset of 80 published plant-pollinator interaction networks as well as pollinator effectiveness measures from 34 plant species to assess the importance of A. mellifera in natural habitats. Apis mellifera is the most frequent floral visitor in natural habitats worldwide, averaging 13% of floral visits across all networks (range 0-85%), with 5% of plant species recorded as being exclusively visited by A. mellifera For 33% of the networks and 49% of plant species, however, A. mellifera visitation was never observed, illustrating that many flowering plant taxa and assemblages remain dependent on non-A. mellifera visitors for pollination. Apis mellifera visitation was higher in warmer, less variable climates and on mainland rather than island sites, but did not differ between its native and introduced ranges. With respect to single-visit pollination effectiveness, A. mellifera did not differ from the average non-A. mellifera floral visitor, though it was generally less effective than the most effective non-A. mellifera visitor. Our results argue for a deeper understanding of how A. mellifera, and potential future changes in its range and abundance, shape the ecology, evolution, and conservation of plants, pollinators, and their interactions in natural habitats.

Mitral valve endocarditis in a patient with Ehlers-Danlos syndrome.

We report a patient with Ehlers-Danlos syndrome and mitral valve endocarditis. The case was complicated due to the initial septic status of the patient and the fragility of the mitral valve both of which required further early operative intervention. The patient also had pre-existing pulmonary septic emboli, the significance of which was missed prior to the admission to our Unit. Two peripheral arterial aneurysms were identified and corrected surgically on same admission. Possible complications of the syndrome and surgical implications are discussed along with review of the literature.