Study objective: To evaluate the efficacy and safety of tobramycin solution for inhalation (TSI) in patients with severe bronchiectasis.
Design: Open-label clinical trial consisting of three ...treatment cycles (14 days of drug therapy, and 14 days off drug) and an additional
40-week follow-up by chart review.
Setting: Nine clinical sites throughout the United States.
Subjects: Forty-one adult patients (⥠18 years old) with diffuse bronchiectasis affecting two or more lung segments and a history of
Pseudomonas aeruginosa infection.
Interventions: TSI, 300 mg tobramycin per dose bid.
Measurements and results: During the 12-week treatment period, significant improvements (reduction of 1.5 U p = 0.006) occurred in mean pulmonary
total symptom severity score, a composite score that assesses the severity of cough, shortness of breath, sputum production,
fatigue, and wheezing. Significant improvements (reduction of 9.8 U p < 0.001) were also observed in St. George Respiratory
Questionnaire scores, which measure health-related quality of life. Eradication or presumed eradication of P aeruginosa occurred in 6 of 27 evaluable subjects (22.2%). Tobramycin-resistant P aeruginosa developed in two subjects (minimal inhibitory concentration ⥠16 μg/mL). Ten subjects withdrew from the study due to adverse
events; in nine of these subjects, adverse events were considered probably or possibly related to treatment. The most common
adverse events were cough, wheezing, and dyspnea.
Conclusions: TSI therapy resulted in significant improvements in respiratory symptoms and health-related quality of life in subjects with
severe bronchiectasis, but some subjects did not tolerate TSI therapy. Bronchiectasis patients receiving this therapy should
be monitored for signs of intolerance.
OBJECTIVE. Appropriate radiologic interpretation of screening CT can minimize unnecessary workup and intervention. This is particularly challenging in the baseline round. We report on the quality ...assurance process we developed for the International Early Lung Cancer Action Program. MATERIALS AND METHODS. After initial training at the coordinating center, radiologists at 10 participating institutions and at the center independently interpreted the first 100 baseline screenings. The radiologist at the institutions had access to the center interpretations before issuing the final reports. After the first 100 screenings, the interpretations were jointly discussed. This report summarizes the results of the initial 100 dual interpretations at the 10 institutions. RESULTS. The final institution interpretations agreed with the center in 895 of the 1000 interpretations. Compared with the center, the frequency of positive results was higher at eight of the 10 institutions. The most frequent reason of discrepant interpretations was not following the protocol (n = 55) and the least frequent was not identifying a nodule (n = 3). CONCLUSION. The quality assurance process helped focus educational programs and provided an excellent vehicle for review of the protocol with participating physicians. It also suggests that the rate of positive results can be reduced by such measures.
To evaluate the efficacy and safety of tobramycin solution for inhalation (TSI) in patients with severe bronchiectasis
Open-label clinical trial consisting of three treatment cycles (14 days of drug ...therapy, and 14 days off drug) and an additional 40-week follow-up by chart review
Nine clinical sites throughout the United States
Forty-one adult patients (≥ 18 years old) with diffuse bronchiectasis affecting two or more lung segments and a history of Pseudomonas aeruginosa infection
TSI, 300 mg tobramycin per dose bid
During the 12-week treatment period, significant improvements (reduction of 1.5 U p = 0.006) occurred in mean pulmonary total symptom severity score, a composite score that assesses the severity of cough, shortness of breath, sputum production, fatigue, and wheezing. Significant improvements (reduction of 9.8 U p < 0.001) were also observed in St. George Respiratory Questionnaire scores, which measure health-related quality of life. Eradication or presumed eradication of P aeruginosa occurred in 6 of 27 evaluable subjects (22.2%). Tobramycin-resistant P aeruginosa developed in two subjects (minimal inhibitory concentration ≥ 16 μg/mL). Ten subjects withdrew from the study due to adverse events; in nine of these subjects, adverse events were considered probably or possibly related to treatment. The most common adverse events were cough, wheezing, and dyspnea
TSI therapy resulted in significant improvements in respiratory symptoms and health-related quality of life in subjects with severe bronchiectasis, but some subjects did not tolerate TSI therapy. Bronchiectasis patients receiving this therapy should be monitored for signs of intolerance
Tumor-infiltrating immune cells have been linked to prognosis and response to immunotherapy; however, the levels of distinct immune cell subsets and the signals that draw them into a tumor, such as ...the expression of antigen presenting machinery genes, remain poorly characterized. Here, we employ a gene expression-based computational method to profile the infiltration levels of 24 immune cell populations in 19 cancer types.
We compare cancer types using an immune infiltration score and a T cell infiltration score and find that clear cell renal cell carcinoma (ccRCC) is among the highest for both scores. Using immune infiltration profiles as well as transcriptomic and proteomic datasets, we characterize three groups of ccRCC tumors: T cell enriched, heterogeneously infiltrated, and non-infiltrated. We observe that the immunogenicity of ccRCC tumors cannot be explained by mutation load or neo-antigen load, but is highly correlated with MHC class I antigen presenting machinery expression (APM). We explore the prognostic value of distinct T cell subsets and show in two cohorts that Th17 cells and CD8
T/Treg ratio are associated with improved survival, whereas Th2 cells and Tregs are associated with negative outcomes. Investigation of the association of immune infiltration patterns with the subclonal architecture of tumors shows that both APM and T cell levels are negatively associated with subclone number.
Our analysis sheds light on the immune infiltration patterns of 19 human cancers and unravels mRNA signatures with prognostic utility and immunotherapeutic biomarker potential in ccRCC.
Acute-on-chronic liver failure (ACLF) is characterized by abrupt decompensation in a patient with chronic liver disease with extrahepatic organ dysfunction and is implicated in an increased risk of ...mortality. ACLF may be present in approximately 20% to 40% of hospitalized cirrhosis. There are several diagnostic scoring systems for ACLF; one defined by the North American Consortium for Study of End-stage Liver Disease is the presence of acutely decompensated cirrhosis complicated by failure of two or more organ systems: circulatory, renal, neurological, coagulopathy, and/or pulmonary.
Public neoantigens (NeoAgs) represent an elite class of shared cancer-specific epitopes derived from recurrently mutated driver genes. Here we describe a high-throughput platform combining ...single-cell transcriptomic and T cell receptor (TCR) sequencing to establish whether mutant PIK3CA, among the most frequently genomically altered driver oncogenes, generates an immunogenic public NeoAg. Using this strategy, we developed a panel of TCRs that recognize an endogenously processed neopeptide encompassing a common PIK3CA hotspot mutation restricted by the prevalent human leukocyte antigen (HLA)-A*03:01 allele. Mechanistically, immunogenicity to this public NeoAg arises from enhanced neopeptide/HLA complex stability caused by a preferred HLA anchor substitution. Structural studies indicated that the HLA-bound neopeptide presents a comparatively 'featureless' surface dominated by the peptide's backbone. To bind this epitope with high specificity and affinity, we discovered that a lead TCR clinical candidate engages the neopeptide through an extended interface facilitated by an unusually long CDR3β loop. In patients with diverse malignancies, we observed NeoAg clonal conservation and spontaneous immunogenicity to the neoepitope. Finally, adoptive transfer of TCR-engineered T cells led to tumor regression in vivo in mice bearing PIK3CA-mutant tumors but not wild-type PIK3CA tumors. Together, these findings establish the immunogenicity and therapeutic potential of a mutant PIK3CA-derived public NeoAg.
In people living with HIV, Kaposi Sarcoma (KS), a vascular neoplasm caused by KS herpesvirus (KSHV/HHV-8), remains one of the most common malignancies worldwide. Individuals living with HIV, ...receiving otherwise effective antiretroviral therapy, may present with extensive disease requiring chemotherapy. Hence, new therapeutic approaches are needed. The Wilms' tumor 1 (WT1) protein is overexpressed and associated with poor prognosis in several hematologic and solid malignancies and has shown promise as an immunotherapeutic target. We found that WT1 was overexpressed in >90% of a total 333 KS biopsies, as determined by immunohistochemistry and image analysis. Our largest cohort from ACTG, consisting of 294 cases was further analyzed demonstrating higher WT1 expression was associated with more advanced histopathologic subtypes. There was a positive correlation between the proportion of infected cells within KS tissues, assessed by expression of the KSHV-encoded latency-associated nuclear antigen (LANA), and WT1 positivity. Areas with high WT1 expression showed sparse T-cell infiltrates, consistent with an immune evasive tumor microenvironment. We show that major oncogenic isoforms of WT1 are overexpressed in primary KS tissue and observed WT1 upregulation upon de novo infection of endothelial cells with KSHV. KSHV latent viral FLICE-inhibitory protein (vFLIP) upregulated total and major isoforms of WT1, but upregulation was not seen after expression of mutant vFLIP that is unable to bind IKKƴ and induce NFκB. siRNA targeting of WT1 in latent KSHV infection resulted in decreased total cell number and pAKT, BCL2 and LANA protein expression. Finally, we show that ESK-1, a T cell receptor-like monoclonal antibody that recognizes WT1 peptides presented on MHC HLA-A0201, demonstrates increased binding to endothelial cells after KSHV infection or induction of vFLIP expression. We propose that oncogenic isoforms of WT1 are upregulated by KSHV to promote tumorigenesis and immunotherapy directed against WT1 may be an approach for KS treatment.
Successful liver transplantation offers the possibility of improved survival among patients with decompensated cirrhosis. However, there is wide variability in access to care and promptness of the ...transplant evaluation process in the United States.
We performed a multicenter retrospective study of 1118 patients who underwent evaluation for liver transplantation at the 6 Veterans Affairs' transplant centers from 2013 to 2018. Of these, 832 patients were evaluated within 30 d and 286 > 30 d after referral. We studied the differential effects of the time from referral to evaluation on pretransplant and posttransplant mortality and transplant list dropout and explored predictors of early transplant evaluation.
Patients in the early evaluation group had a shorter adjusted time from referral to listing by 29.5 d (95% confidence interval CI -50.4, -8.5, P < 0.006), and referral to transplantation by 115.1 d (95% CI -179.5, -50.7, P < 0.0001). On a multivariable Cox hazard model, evaluation within 30 d of referral was associated with a significantly lower pretransplant mortality (adjusted hazard ratio aHR 0.70, 95% CI 0.54-0.91, P < 0.01), but not associated with transplant list dropout (aHR 0.95, 95% CI 0.65-1.39, P = 0.79) or posttransplant death (aHR 1.88, 95% CI 0.72-4.9, P = 0.20). An early evaluation within 30 d was positively associated with a higher MELD at referral (aHR 1.03, 95% CI 1.01-1.06, P = 0.006) and negatively associated with distance from the transplant center (aHR 0.99, 95% CI 0.99-0.99, P = 0.045).
Evaluation of patients referred for liver transplantation within 30 d is associated with a reduction in pretransplant mortality.
Batched linear solvers, which solve many small related but independent problems, are increasingly important for highly parallel processors such as graphics processing units (GPUs). GPUs need a ...substantial amount of work to keep them operating efficiently and it is not an option to solve smaller problems one-by-one. Because of the small size of each problem, the task of implementing a parallel partitioning scheme and mapping the problem to hardware is not trivial. In recent history, significant attention has been given to batched dense linear algebra. However, there is also an interest in utilizing sparse iterative solvers in a batched form.
An example use case is found in a gyrokinetic Particle-In-Cell (PIC) code used for modeling magnetically confined fusion plasma devices. The collision operator has been identified as a bottleneck, and a proxy app has been created for facilitating optimizations and porting to GPUs. The current collision kernel linear solver does not run on the GPU—a major bottleneck. As these matrices are sparse and well-conditioned, batched iterative sparse solvers are an attractive option.
A batched sparse iterative solver capability has recently been developed in the Ginkgo library. In this paper, we describe how Ginkgo's batched solver technology can integrate into the XGC collision kernel and accelerate the simulation process. Comparisons for the solve times on NVIDIA V100 and A100 GPUs and AMD MI100 GPUs with one dual-socket Intel Xeon Skylake CPU node with 40 cores are presented for matrices from the collision kernel of XGC. Further, the speedups observed for the overall collision kernel are presented in comparison to different modern CPUs on multiple supercomputer systems. The results suggest that Ginkgo's batched sparse iterative solvers are well suited for efficient utilization of the GPU for this problem, and the performance portability of Ginkgo in conjunction with Kokkos (used within XGC as the heterogeneous programming model) allows seamless execution on exascale-oriented heterogeneous architectures.
•Fast batched sparse iterative linear solvers for modern graphics processing units.•Implementation of different batched sparse matrix formats.•Automatic tuning of shared memory utilization on the GPU.•Strategy for integration into the plasma simulation code XGC via Kokkos.•Performance results on various CPUs and V100, A100 and MI100 GPUs.
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