Citations

Abstract Purpose: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) interaction has led to durable responses in fewer than half of patients with mismatch repair–deficient (MMR-d) advanced colorectal cancers. Immune contexture, including spatial distribution of immune cells in the tumor microenvironment (TME), may predict immunotherapy outcome. Experimental Design: Immune contexture and spatial distribution, including cell-to-cell distance measurements, were analyzed by multiplex immunofluorescence (mIF) in primary colorectal cancers with d-MMR (N = 33) from patients treated with anti–PD-1 antibodies. By digital image analysis, density, ratio, intensity, and spatial distribution of PD-L1, PD-1, CD8, CD3, CD68, LAG3, TGFβR2, MHC-I, CD14, B2M, and pan-cytokeratin were computed. Feature selection was performed by regularized Cox regression with LASSO, and a proportional hazards model was fitted to predict progression-free survival (PFS). Results: For predicting survival among patients with MMR-d advanced colorectal cancer receiving PD-1 blockade, cell-to-cell distance measurements, but not cell densities or ratios, achieved statistical significance univariately. By multivariable feature selection, only mean number of PD-1+ cells within 10 μm of a PD-L1+ cell was significantly predictive of PFS. Dichotomization of this variable revealed that those with high versus low values had significantly prolonged PFS [median not reached (>83 months) vs. 8.5 months (95% confidence interval (95% CI), 4.7–NR)] with a median PFS of 28.4 months for all patients [adjusted HR (HRadj) = 0.14; 95% CI, 0.04–0.56; P = 0.005]. Expression of PD-1 was observed on CD8+ T cells; PD-L1 on CD3+ and CD8+ T lymphocytes, macrophages (CD68+), and tumor cells. Conclusions: In d-MMR colorectal cancers, PD-1+ to PD-L1+ receptor to ligand proximity is a potential predictive biomarker for the effectiveness of PD-1 blockade.

Abstract Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections and inflammatory conditions. Hematopoietic cell transplantation (HCT) is the definitive treatment for CGD, but questions remain regarding patient selection and impact of active disease on transplant outcomes. We performed a multi-institutional retrospective and prospective study of 391 patients with CGD treated either conventionally (non-HCT) enrolled from 2004 to 2018 or with HCT from 1996 to 2018. Median follow-up after HCT was 3.7 years with a 3-year overall survival of 82% and event-free survival of 69%. In a multivariate analysis, a Lansky/Karnofsky score <90 and use of HLA-mismatched donors negatively affected survival. Age, genotype, and oxidase status did not affect outcomes. Before HCT, patients had higher infection density, higher frequency of noninfectious lung and liver diseases, and more steroid use than conventionally treated patients; however, these issues did not adversely affect HCT survival. Presence of pre-HCT inflammatory conditions was associated with chronic graft-versus-host disease. Graft failure or receipt of a second HCT occurred in 17.6% of the patients and was associated with melphalan-based conditioning and/or early mixed chimerism. At 3 to 5 years after HCT, patients had improved growth and nutrition, resolved infections and inflammatory disease, and lower rates of antimicrobial prophylaxis or corticosteroid use compared with both their baseline and those of conventionally treated patients. HCT leads to durable resolution of CGD symptoms and lowers the burden of the disease. Patients with active infection or inflammation are candidates for transplants; HCT should be considered before the development of comorbidities that could affect performance status. This trial was registered at www.clinicaltrials.gov as #NCT02082353.

PURPOSE Increased awareness of the distinct tumor biology for adolescents and young adults (AYAs) with cancer has led to improvement in outcomes for this population. However, in cholangiocarcinoma (CCA), a paucity of data exist on the AYA population. To our knowledge, we present the largest study to date on AYA disease biology, treatment patterns, and survival outcomes in CCA. METHODS A multi-institutional cohort of patients with CCA diagnosed with intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma (ECC) was used for analysis. Retrospective chart review was conducted on patients who were 50 years old and younger (young; n = 124) and older than 50 years (older; n = 723). RESULTS Among 1,039 patients screened, 847 patients met eligibility (72% ICC, 28% ECC). Young patients had a larger median tumor size at resection compared with older patients (4.2 v 3.6 cm; P = .048), more commonly had N1 disease (65% v 43%; P = .040), and were more likely to receive adjuvant therapy (odds ratio, 4.0; 95% CI, 1.64 to 9.74). Tumors of young patients were more likely to harbor an FGFR2 fusion, BRAF mutation, or ATM mutation ( P < .05 for each). Young patients were more likely to receive palliative systemic therapy (96% v 69%; P < .001), targeted therapy (23% v 8%; P < .001), and treatment on a clinical trial (31% v 19%; P = .004). Among patients who presented with advanced disease, young patients had a higher median overall survival compared with their older counterparts (17.7 v 13.5 months; 95% CI, 12.6 to 22.6 v 11.4 to 14.8; P = .049). CONCLUSION Young patients with CCA had more advanced disease at resection, more commonly received both adjuvant and palliative therapies, and demonstrated improved survival compared with older patients. Given the low clinical trial enrollment and poor outcomes among some AYA cancer populations, data to the contrary in CCA are highly encouraging.

AbstractIntroductionIncreasingly, early‐stage non–small cell lung cancer (NSCLC) is treated with stereotactic body radiation therapy (SBRT). Although treatment is generally effective, a small subset of tumors will recur because of radioresistance. Preclinical studies suggested PI3K‐AKT‐mTOR activation mediates radioresistance. This study sought to validate this finding in tumor samples from patients who underwent SBRT for NSCLC.MethodsPatients with T1‐3N0 NSCLC treated with SBRT at our institution were included. Total RNA of formalin‐fixed paraffin‐embedded tumor biopsy specimens (pretherapy) was isolated and analyzed using the Clariom D assay. Risk scores from a PI3K activity signature and four published NSCLC signatures were generated and dichotomized by the median. Kaplan–Meier curves and Cox regressions were used to analyze their association with recurrence and overall survival (OS). The PI3K signature was also tested in a data set of resected NSCLC for additional validation.ResultsA total of 92 patients were included, with a median follow‐up of 18.3 months for living patients. There was no association of any of the four published gene expression signatures with recurrence or OS. However, high PI3K risk score was associated with higher local recurrence (hazard ratio [HR], 11.72; 95% CI, 1.40–98.0; p = .023) and worse disease‐free survival (DFS) (HR, 3.98; 95% CI, 1.57–10.09; p = .0035), but not OS (p = .49), regional recurrence (p = .15), or distant recurrence (p = .85). In the resected NSCLC data set (n = 361), high PI3K risk score was associated with decreased OS (log‐rank p = .013) but not DFS (p = 0.54).ConclusionsThis study validates that higher PI3K activity, measured by gene expression, is associated with local recurrence and worse DFS in early‐stage NSCLC patients treated with SBRT. This may be useful in prognostication and/or tailoring treatment, and merits further validation.

Abstract We identified the lowest composition necessary to generate a vaccination adjuvant that promotes a Treg response following immunization in mice and named it “complete tolerogenic adjuvant.” This novel adjuvant may allow us to utilize the well-established “antigen plus adjuvant” method of vaccination to induce Treg cell-mediated antigen-specific immunosuppression. The minimal composition is dexamethasone, rapamycin, and monophosphoryl lipid A with the following mass ratios: 8:20:3. We have demonstrated why immunosuppressive and immunogenic substances are both required for the formation of genuine adjuvants for Treg cells by dissecting the roles of each of these components during vaccination. Currently, research is ongoing in our group to begin to assess the usefulness of this adjuvant for antigen immunization in murine models of human autoimmune/inflammatory diseases. Specifically, we are evaluating the tolerogenic efficacy of this adjuvant for vaccination regimen targeting the apolipoprotein B antigen, using the ApoE−/− mouse model of atherosclerosis. These studies are expected to help drive the development of further, perhaps more effective, complete tolerogenic adjuvants that could be used to create a plethora of new, novel vaccines for treating immunological illnesses. Master program and NIH grant

Abstract Despite recent methodology advancements in clinical natural language processing (NLP), the adoption of clinical NLP models within the translational research community remains hindered by process heterogeneity and human factor variations. Concurrently, these factors also dramatically increase the difficulty in developing NLP models in multi-site settings, which is necessary for algorithm robustness and generalizability. Here, we reported on our experience developing an NLP solution for Coronavirus Disease 2019 (COVID-19) signs and symptom extraction in an open NLP framework from a subset of sites participating in the National COVID Cohort (N3C). We then empirically highlight the benefits of multi-site data for both symbolic and statistical methods, as well as highlight the need for federated annotation and evaluation to resolve several pitfalls encountered in the course of these efforts.

Background: Studies suggest that similar clinical results are achieved via arthroscopic and open biceps tenodesis (BT) techniques. Purpose: To quantify the postoperative migration of the BT construct between arthroscopic suprapectoral BT (ASPBT) and open subpectoral BT (OSPBT) techniques via interference screw (IS) or single-suture suture anchor (SSSA) fixation using radiostereometric analysis. Study Design: Cohort study; Level of evidence, 2. Methods: Distal migration of the biceps tendon after OSPBT with a polyetheretherketone IS, OSPBT with 1 SSSA, ASPBT with polyetheretherketone IS, and ASPBT with 2 SSSAs was measured prospectively. Patients with symptomatic biceps tendinopathy and preoperative patient-reported outcome measures (PROMs) including Constant-Murley subjective, Single Assessment Numeric Evaluation, or Patient-Reported Outcomes Measurement Information System–Upper Extremity scores were included. A tantalum bead was sutured on the proximal end of the long head of the biceps tendon before fixation of tendon tissue. Anteroposterior radiographs were performed immediately postoperatively, at 1 week, and at 3 months. Bead migration was measured, and preoperative PROMs were compared with those at latest follow-up. Results: Of 115 patients, 94 (82%) were available for final follow-up. IS fixation yielded the least tendon migration with no difference between the open and arthroscopic approaches (4.31 vs 5.04 mm; P = .70). Fixation with 1 suture anchor demonstrated significantly greater migration than that achieved with an IS at both 1 week (6.47 vs 0.1 mm, 6.47 vs 1.75 mm, P < .001;) and 3 months (14.76 vs 4.31 mm, 14.76 vs 5.04 mm, P < .001) postoperatively. Two-suture anchor fixation yielded significantly greater migration than IS fixation at 1 week (7.02 vs 0.1 mm, P < .001; 7.02 vs 1.75 mm, P = .003) but not 3 months postoperatively (8.06 vs 4.31 mm, P = .10; 8.06 vs 5.04 mm, P = .07). Four patients with suture anchor fixation (3 patients in the OSPBT 1 SSSA group, 9.4%, and 1 patient in the ASPBT 2 SSSAs group, 3.8%) developed a Popeye deformity, whereas no Popeye deformities occurred in the IS groups. Mean 3-month bead migration in patients with and without a Popeye deformity was 60.8 and 11.2 mm, respectively ( P < .0001). PROMs did not differ among groups at final follow-up. Conclusion: Interference screw fixation yielded the least tendon migration whether achieved arthroscopically or open. The available data indicated that fixation with 1 SSSA but not 2 SSSAs resulted in significantly greater migration than that achieved with an IS. Despite variations in tendon migration, PROMs were similar among all groups. When SSSAs are used, tendon migration may be minimized by using ≥2 anchors.

SummaryDespite the availability of evidence‐based interventions to improve binge eating, Black women have some of the lowest rates of access to care for eating disorders. Innovation is needed to offer accessible and culturally relevant treatment options. To this end, using an open trial design, we investigated the feasibility and acceptability of a group‐based, appetite awareness training (AAT) + lifestyle modification (LM) programme in Black women at risk for BED in a primary care setting. Participants (n = 20) were Black women recruited from a family medicine centre affiliated with a local public university, and who reported at least two binge eating episodes in the last 28 days. Participants completed a 16‐session AAT + LM programme over 4 months. Key outcomes were objective binge eating (assessed by the EDE and the EDE‐Q), body dissatisfaction, and weight change, all assessed at baseline, four (post‐treatment) and 6 months (2‐month follow‐up). Ninety‐five percent of participants completed assessments at post‐treatment and attended nearly 60% of intervention sessions. Among completers (n = 19), body dissatisfaction and objective binge eating decreased from baseline to post‐treatment and this decrease was maintained at the 2‐month follow‐up. In exit interviews, participants reported programme satisfaction. Providing training in appetite awareness combined with lifestyle modification principles may be useful in the treatment of body dissatisfaction and binge eating among Black women.

BACKGROUND: Heart failure remains a global health burden, and patients hospitalized are particularly at risk, but genetic associates for subsequent death or rehospitalization are still lacking. METHODS: The genetic substudy of the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) was used to perform genome-wide association study and transethnic meta-analysis. The overall trial included the patients of self-reported European ancestry (n=2173) and African ancestry (n=507). The end point was death or heart failure rehospitalization within 180 days. Cox models adjusted for 11 a priori predictors of rehospitalization and 5 genetic principal components were used to test the association between single-nucleotide polymorphisms and outcome. Summary statistics from the 2 populations were combined via meta-analysis with the significance threshold considered P <5×10 − 8 . RESULTS: Common variants (rs2342882 and rs35850039 in complete linkage disequilibrium) located in FGD5 were significantly associated with the primary outcome in both ancestry groups (European Americans: hazard ratio [HR], 1.38; P =2.42×10 −6 ; African ancestry: HR, 1.51; P =4.43×10 − 3 ; HR in meta-analysis, 1.41; P =4.25×10 −8 ). FGD5 encodes a regulator of VEGF (vascular endothelial growth factor)-mediated angiogenesis, and in silico investigation revealed several previous genome-wide association study hits in this gene, among which rs748431 was associated with our outcome (HR, 1.20; meta P <0.01). Sensitivity analysis proved FGD5 common variants survival association did not appear to operate via coronary artery disease or nesiritide treatment ( P >0.05); and the signal was still significant when changing the censoring time from 180 to 30 days (HR, 1.39; P =1.59×10 −5 ). CONCLUSIONS: In this multiethnic genome-wide association study of ASCEND-HF, single-nucleotide polymorphisms in FGD5 were associated with increased risk of death or rehospitalization. Additional investigation is required to examine biological mechanisms and whether FGD5 could be a therapeutic target. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00475852.