Purpose Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumor (GIST), but often are of transient benefit as resistance commonly develops. Immunotherapy, particularly blockade of the inhibitory receptor programmed death 1 (PD-1) or the ligand programmed death ligand 1 (PD-L1), has shown effectiveness in a variety of cancers. The functional effects of PD-1/PD-L1 blockade are unknown in GIST. Experimental Design We analyzed tumor and matched blood samples from 85 patients with GIST and determined the expression of immune checkpoint molecules using flow cytometry. We investigated the combination of imatinib with PD-1/PD-L1 blockade in KitV558Δ/+ mice that develop GIST. Results The inhibitory receptors PD-1, lymphocyte activation gene 3 (LAG-3), and T cell immunoglobulin mucin-3 (TIM-3) were upregulated on tumor-infiltrating T cells compared to T cells from matched blood. PD-1 expression on T cells was highest in imatinib-treated human GISTs. Meanwhile, intratumoral PD-L1 expression was variable. In human GIST cell lines, treatment with imatinib abrogated the IFN-γ–induced upregulation of PD-L1 via STAT1 inhibition. In KitV558Δ/+ mice imatinib downregulated IFN-γ–related genes and reduced PD-L1 expression on tumor cells. PD-1 and PD-L1 blockade in vivo each had no efficacy alone, but enhanced the antitumor effects of imatinib by increasing T cell effector function in the presence of KIT and IDO inhibition. Conclusions PD-1/PD-L1 blockade is a promising strategy to improve the effects of targeted therapy in GIST. Collectively, our results provide the rationale to combine these agents in human GIST.

Sinorhizobium meliloti forms symbiotic, nitrogen-fixing nodules on the roots of Medicago truncatula. The bacteria invade and colonize the roots through structures called infection threads. S. meliloti unable to produce the exopolysaccharide succinoglycan are unable to establish a symbiosis because they are defective in initiating the production of infection threads and in invading the plant. Here, we use microarrays representing 16,000 M. truncatula genes to compare the differential transcriptional responses of this host plant to wild-type and succinoglycan-deficient S. meliloti at the early time point of 3 days postinoculation. This report describes an early divergence in global plant gene expression responses caused by a rhizobial defect in succinoglycan production, rather than in Nod factor production. The microarray data show that M. truncatula inoculated with wild-type, succinoglycan-producing S. meliloti more strongly express genes encoding translation components, protein degradation machinery, and some nodulins than plants inoculated with succinoglycan-deficient bacteria. This finding is consistent with wild-type-inoculated plants having received a signal, distinct from the well characterized Nod factor, to alter their metabolic activity and prepare for invasion. In contrast, M. truncatula inoculated with succinoglycan-deficient S. meliloti more strongly express an unexpectedly large number of genes in two categories: plant defense responses and unknown functions. One model consistent with our results is that appropriate symbiotically active exopolysaccharides act as signals to plant hosts to initiate infection thread formation and that, in the absence of this signal, plants terminate the infection process, perhaps via a defense response.nitrogen fixation ͉ nodule ͉ succinoglycan ͉ microarray ͉ legume

Objectives Readmission is associated with high mortality, morbidity, and cost. We used the ACS-NSQIP to determine risk factors for readmission following lower extremity bypass (LEB). Methods We identified all patients who received LEB in the 2011 ACS-NSQIP database. Multivariable logistic regression was used to assess independent predictors of 30-day readmission. We also identified our institutional contribution of LEB patients to the ACS-NSQIP from 2005–2011 to determine our institution’s rate of readmission and readmission indications. Results Among 5018 patients undergoing LEB, ACS-NSQIP readmission analysis was performed on 4512, excluding those whose readmission data was unavailable, suffered a death on index admission, or remained in the hospital at 30 days. Overall readmission rate was 18%, and readmission rate of those with NSQIP captured complications was 8%. Multivariable predictors of readmission were dependent functional status (OR 1.40, 95% CI: 1.08–1.79), dyspnea (OR 1.28, 95% CI: 1.02–1.60), cardiac comorbidity (OR 1.46, 95% CI: 1.16–1.84), dialysis dependence (OR 1.44, 95% CI: 1.05–1.97), obesity (OR 1.28, 95% CI: 1.07–1.53), malnutrition (OR 1.42, 95% CI 1.12–1.79), CLI operative indication (OR 1.40, 95% CI: 1.10–1.79), and return to the operating room on index admission (OR 8.0, 95% CI: 6.68–9.60). The most common post-discharge complications occurring in readmitted patients included wound complications (56%), multiple complications (22%), and graft failure (5%). Our institutional data contributed 465 LEB patients to the ACS-NSQIP from 2005–2012, with an overall readmission rate of 14%. Unplanned readmissions related to the original LEB (related unplanned) made up 75% of cases. The remainder 25% included readmissions that were planned staged procedures related to the original LEB (related planned, 11%) and admissions for a completely unrelated reason (unrelated unplanned, 14%). The most common readmission indications included wound infection (40%) and graft failure (13%). Readmissions were attributable to NSQIP captured post-discharge complications in 44% of cases, an additional 44% had a non-NSQIP defined reason for readmission, and the remainder (12%) included patients admitted for complications described in NSQIP but not meeting strict NSQIP criteria. Discussion Readmissions are common after lower extremity bypass. Optimization of select chronic conditions, closer follow-up of patients in poor health and those who required return to the OR, and early detection of surgical site infections may improve readmission rates. Our finding that 25% of readmissions after LEB are not procedure related informs the broader discussion on how a readmission penalty affects vascular surgery in particular.

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Background It remains unclear if patients with clinical stage T2 N0 (cT2 N0) esophageal cancer should be offered induction therapy vs surgical intervention alone. Methods This was a retrospective cohort study of cT2 N0 patients undergoing induction therapy, followed by surgical resection, or resection alone, at the Johns Hopkins Hospital from 1989 to 2009. Kaplan-Meier analysis was used to compare all-cause mortality in cT2 N0 patients who had resection alone vs those who had induction chemoradiation therapy, followed by resection. Results A study cohort of 69 patients was identified and divided into two groups: 55 patients (79.7%) received induction therapy and 14 (20.3%) did not. No statistically significant difference in 5-year survival rate was observed for the two groups: 49.5% for the resection-only group and 53.8% for the induction group. More than 50% of cT2 N0 patients were understaged. Conclusions For cT2 N0 esophageal cancer patients, the benefit of neoadjuvant therapy is still unclear. Induction therapy for cT2 N0 did not translate into a statistically significant improvement in survival. However, due to the significant understaging of T2 N0 patients, we recommend neoadjuvant therapy to all cT2N0 patients before operation.