Surgical Outcomes and Genomic Insights of Nonclear Cell Renal Cell Carcinoma with Synchronous and Metachronous Nodal Disease.

INTRODUCTION: Oncological outcomes in patients with nonclear cell renal cell carcinoma (non-ccRCC) treated with surgery for locoregional nodal disease (ND) remain incompletely characterized. The objective was to investigate the characteristics and outcomes of non-ccRCC patients treated with lymph node dissection (LND) and salvage-LND (S-LND). METHODS: A total of 1627 patients underwent nephrectomy for nonmetastatic non-ccRCC at Memorial Sloan Kettering Cancer Center between 2007 and 2023. Histology was grouped as papillary, chromophobe, unclassified, and rare subtypes. Retrospective evaluation identified 2.5% (n = 40) of patients with nodal disease at time of nephrectomy (synchronous-ND) and 1.1% (n = 18) with metachronous nodal disease limited to the retroperitoneum (metachronous-ND). Patients' demographics and tumor characteristics were recorded and evaluated by univariate and multivariate cox regression models. Recurrence-free survival (RFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Patients who underwent tumor DNA sequencing during their clinical course were considered for genomic analysis. RESULTS: OS trended toward longer in metachronous-ND (51 vs 105 months; P = .2), though 23% of patients with synchronous-ND were recurrence-free at 45 months median follow-up. In multivariate analysis, rare histologies were associated with decreased OS (P = .030) and metachronous-ND with improved OS (P = .036). RFS and OS after S-LND was 15 and 96 months, respectively. Late onset of metachronous-ND/recurrence was associated with improved OS (P = .008). Genetic alterations in SETD2, TP53, B2M, and FGFR3 were exclusively seen in synchronous-ND, and tumor mutation burden (TMB) was also higher in patients with synchronous-ND (P = .016). CONCLUSIONS: Patients with metachronous-ND tend to have prolonged OS compared to synchronous-ND, but a substantial portion of patients with synchronous-ND still enter a durable disease-free state following LND. S-LND can likewise provide long-term survival, particularly in patients with longer time to metachronous nodal recurrence. Synchronous-ND was associated with SETD2, TP53, and NF2 alteration as well as higher TMB.

A Phase 2 Trial of Talazoparib and Avelumab in Genomically Defined Metastatic Kidney Cancer.

BACKGROUND: Although different kidney cancers represent a heterogeneous group of malignancies, multiple subtypes including Von Hippel-Lindau (VHL)-altered clear cell renal cell carcinoma (ccRCC), fumarate hydratase (FH)- and succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC), and renal medullary carcinoma (RMC) are affected by genomic instability. Synthetic lethality with poly ADP-ribose polymerase inhibitors (PARPis) has been suggested in preclinical models of these subtypes, and paired PARPis with immune checkpoint blockade (ICB) may achieve additive and/or synergistic effects in patients with previously treated advanced kidney cancers. OBJECTIVE: To evaluate combined PARPi + ICB in treatment-refractory metastatic kidney cancer. DESIGN, SETTING, AND PARTICIPANTS: We conducted a single-center, investigator-initiated phase 2 trial in two genomically selected advanced kidney cancer cohorts: (1) VHL-altered RCC with at least one prior ICB agent and one vascular endothelial growth factor (VEGF) inhibitor, and (2) FH- or SDH-deficient RCC with at least one prior ICB agent or VEGF inhibitor and RMC with at least one prior line of chemotherapy. INTERVENTION: Patients received talazoparib 1 mg daily plus avelumab 800 mg intravenously every 14 d in 28-d cycles. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was objective response rate (ORR) by Immune Response Evaluation Criteria in Solid Tumors at 4 mo, and the secondary endpoints included progression-free survival (PFS), overall survival, and safety. RESULTS AND LIMITATIONS: Cohort 1 consisted of ten patients with VHL-altered ccRCC. All patients had previously received ICB. The ORR was 0/9 patients; one patient was not evaluable due to missed doses. In this cohort, seven patients achieved stable disease (SD) as the best response. The median PFS was 3.5 mo (95% confidence interval [CI] 1.0, 3.9 mo). Cohort 2 consisted of eight patients; four had FH-deficient RCC, one had SDH-deficient RCC, and three had RMC. In this cohort, six patients had previously received ICB. The ORR was 0/8 patients; two patients achieved SD as the best response and the median PFS was 1.2 mo (95% CI 0.4, 2.9 mo). The most common treatment-related adverse events of all grades were fatigue (61%), anemia (28%), nausea (22%), and headache (22%). There were seven grade 3-4 and no grade 5 events. CONCLUSIONS: The first clinical study of combination PARPi and ICB therapy in advanced kidney cancer did not show clinical benefit in multiple genomically defined metastatic RCC cohorts or RMC. PATIENT SUMMARY: We conducted a study to look at the effect of two medications, talazoparib and avelumab, in patients with metastatic kidney cancer who had disease progression on standard treatment. Talazoparib blocks the normal activity of molecules called poly ADP-ribose polymerase, which then prevents tumor cells from repairing themselves and growing, while avelumab helps the immune system recognize and kill cancer cells. We found that the combination of these agents was safe but not effective in specific types of kidney cancer.

Molecular Characterization of the Tumor Microenvironment in Renal Medullary Carcinoma.

Renal medullary carcinoma (RMC) is a highly aggressive disease associated with sickle hemoglobinopathies and universal loss of the tumor suppressor gene SMARCB1. RMC has a relatively low rate of incidence compared with other renal cell carcinomas (RCCs) that has hitherto made molecular profiling difficult. To probe this rare disease in detail we performed an in-depth characterization of the RMC tumor microenvironment using a combination of genomic, metabolic and single-cell RNA-sequencing experiments on tissue from a representative untreated RMC patient, complemented by retrospective analyses of archival tissue and existing published data. Our study of the tumor identifies a heterogenous population of malignant cell states originating from the thick ascending limb of the Loop of Henle within the renal medulla. Transformed RMC cells displayed the hallmarks of increased resistance to cell death by ferroptosis and proteotoxic stress driven by MYC-induced proliferative signals. Specifically, genomic characterization of RMC tumors provides substantiating evidence for the recently proposed dependence of SMARCB1-difficient cancers on proteostasis modulated by an intact CDKN2A-p53 pathway. We also provide evidence that increased cystine-mTORC-GPX4 signaling plays a role in protecting transformed RMC cells against ferroptosis. We further propose that RMC has an immune landscape comparable to that of untreated RCCs, including heterogenous expression of the immune ligand CD70 within a sub-population of tumor cells. The latter could provide an immune-modulatory role that serves as a viable candidate for therapeutic targeting.

Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates.

PURPOSE: To assess the efficacy and safety of cabozantinib plus nivolumab in a phase II trial in patients with non-clear-cell renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients had advanced non-clear-cell renal carcinoma who underwent 0-1 prior systemic therapies excluding prior immune checkpoint inhibitors. Patients received cabozantinib 40 mg once daily plus nivolumab 240 mg once every 2 weeks or 480 mg once every 4 weeks. Cohort 1 enrolled patients with papillary, unclassified, or translocation-associated RCC; cohort 2 enrolled patients with chromophobe RCC. The primary end point was objective response rate (ORR) by RECIST 1.1; secondary end points included progression-free survival, overall survival, and safety. Next-generation sequencing results were correlated with response. RESULTS: A total of 47 patients were treated with a median follow-up of 13.1 months. Objective response rate for cohort 1 (n = 40) was 47.5% (95% CI, 31.5 to 63.9), with median progression-free survival of 12.5 months (95% CI, 6.3 to 16.4) and median overall survival of 28 months (95% CI, 16.3 to not evaluable). In cohort 2 (n = 7), no responses were observed; one patient had stable disease > 1 year. Grade 3/4 treatment-related adverse events were observed in 32% treated patients. Cabozantinib and nivolumab were discontinued because of toxicity in 13% and 17% of patients, respectively. Common mutations included NF2 and FH in cohort 1 and TP53 and PTEN in cohort 2. Objective responses were seen in 10/12 patients with either NF2 or FH mutations. CONCLUSION: Cabozantinib plus nivolumab showed promising efficacy in most non-clear-cell RCC variants tested in this trial, particularly those with prominent papillary features, whereas treatment effects were limited in chromophobe RCC. Genomic findings in non-clear-cell RCC variants warrant further study as predictors of response.

Genomic and Metabolic Hallmarks of SDH- and FH-deficient Renal Cell Carcinomas.

BACKGROUND: Succinate dehydrogenase-deficient and fumarate hydratase-deficient renal cell carcinomas (SDHRCC and FHRCC) are rare kidney cancers driven by loss of TCA cycle enzymes. OBJECTIVE: To define and compare the genomic and metabolomic hallmarks of SDHRCC and FHRCC. DESIGN, SETTING, AND PARTICIPANTS: We analyzed SDHRCC and FHRCC tumors with either immunohistochemical evidence of loss of protein expression or genomically confirmed biallelic inactivation of SDHA/B/C/D/AF2 or FH. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Somatic alterations were identified using clinical pipelines, with allele-specific copy number alterations (CNAs) identified using FACETS. Mass spectrometry-based metabolomic profiling was performed on available SDHRCC and FHRCC tumors. RESULTS AND LIMITATIONS: Tumors were analyzed for 42 patients (25 FHRCC, 17 SDHRCC). In the germline analysis, 16/17 SDHRCCs harbored a germline alteration in SDHB, whereas only 17/22 FHRCCs had pathogenic germline FH variants. SDHRCCs had a lower mutation burden (p = 0.02) and CNA burden (p = 0.0002) than FHRCCs. All SDHRCCs presented with deletion of chromosome 1p (overlapping SDHB), whereas FHRCCs demonstrated high but not ubiquitous loss of 1q (FH locus). Both SDHRCCs and FHRCCs exhibited significant idiopathic accumulation of the metabolite guanine. FHRCC tumors had elevated levels of urea cycle metabolites (argininosuccinate, citrulline, and fumarate), whereas SDHRCC tumors had elevation of numerous acylcarnitines. These characteristic metabolic changes allowed identification of a previously unrecognized SDH-deficient RCC. CONCLUSIONS: Despite sharing similar genetic etiology, SDHRCC and FHRCC represent distinct molecular entities with unique genetic and metabolic abnormalities. PATIENT SUMMARY: Kidney cancers driven by loss of the gene encoding either the succinate dehydrogenase or fumarate hydratase enzyme are rare. We sought to define and compare the genetic and metabolic features of these cancer entities.

Diverse tumorigenic consequences of human papillomavirus integration in primary oropharyngeal cancers.

Human papillomavirus (HPV) causes 5% of all cancers and frequently integrates into host chromosomes. The HPV oncoproteins E6 and E7 are necessary but insufficient for cancer formation, indicating that additional secondary genetic events are required. Here, we investigate potential oncogenic impacts of virus integration. Analysis of 105 HPV-positive oropharyngeal cancers by whole-genome sequencing detects virus integration in 77%, revealing five statistically significant sites of recurrent integration near genes that regulate epithelial stem cell maintenance (i.e., SOX2, TP63, FGFR, MYC) and immune evasion (i.e., CD274). Genomic copy number hyperamplification is enriched 16-fold near HPV integrants, and the extent of focal host genomic instability increases with their local density. The frequency of genes expressed at extreme outlier levels is increased 86-fold within ±150 kb of integrants. Across 95% of tumors with integration, host gene transcription is disrupted via intragenic integrants, chimeric transcription, outlier expression, gene breaking, and/or de novo expression of noncoding or imprinted genes. We conclude that virus integration can contribute to carcinogenesis in a large majority of HPV-positive oropharyngeal cancers by inducing extensive disruption of host genome structure and gene expression.

Comprehensive Molecular Characterization and Response to Therapy in Fumarate Hydratase-Deficient Renal Cell Carcinoma.

PURPOSE: Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive form of RCC associated with hereditary leiomyomatosis and RCC syndrome. Evidence for systemic therapy efficacy is lacking. EXPERIMENTAL DESIGN: We studied clinical and genomic characteristics of FH-RCC, including response [objective response rate (ORR)] to systemic therapies and next-generation sequencing (NGS). Patients with metastatic FH-RCC, defined by presence of pathogenic germline or somatic FH mutation plus IHC evidence of FH loss, were included. RESULTS: A total of 28 of 32 included patients (median age 46; range, 20-74; M:F, 20:12) underwent germline testing; 23 (82%) harbored a pathogenic FH germline variant. Five (16%) were negative for germline FH mutations; all had biallelic somatic FH loss. Somatic NGS (31/32 patients) revealed co-occurring NF2 mutation most frequently (n = 5). Compared with clear-cell RCC, FH-RCC had a lower mutation count (median 2 vs. 4; P < 0.001) but higher fraction of genome altered (18.7% vs. 10.3%; P = 0.001). A total of 26 patients were evaluable for response to systemic therapy: mTOR/VEGF combination (n = 18, ORR 44%), VEGF monotherapy (n = 15, ORR 20%), checkpoint inhibitor therapy (n = 8, ORR 0%), and mTOR monotherapy (n = 4, ORR 0%). No complete responses were seen. Median overall and progression-free survival were 21.9 months [95% confidence interval (CI): 14.3-33.8] and 8.7 months (95% CI: 4.8-12.3), respectively. CONCLUSIONS: Although most FH-RCC tumors are due to germline FH alterations, a significant portion result from biallelic somatic FH loss. Both somatic and germline FH-RCC have similar molecular characteristics, with NF2 mutations, low tumor mutational burden, and high fraction of genome altered. Although immunotherapy alone produced no objective responses, combination mTOR/VEGF therapy showed encouraging results.

Emergent TandemHeart-ECMO for acute severe mitral regurgitation with cardiogenic shock and hypoxaemia: a case series.

BACKGROUND: Acute severe mitral regurgitation (MR) associated with cardiogenic shock is a life-threatening emergency. Traditional teaching has focused on the need for emergent coronary angiography and/or intra-aortic balloon counterpulsation in preparation for emergent open-heart surgery for repair/replacement. Unfortunately, emergent open-heart surgery in patients with acute MR complicated by cardiogenic shock is associated with 25-46% perioperative mortality. New devices have provided additional options for stabilization prior to emergent surgery which facilitate improved outcomes. CASE SUMMARY: We present two cases of acute severe MR resulting in cardiogenic shock and profound hypoxaemia. TandemHeart® mechanical circulatory support with an oxygenator spliced into the circuit, akin to veno-arterial extracorporeal membrane oxygenation (ECMO), facilitated haemodynamic stabilization and decongestion of the lungs facilitating successful bridge to mitral valve surgery. Successful discharge to home was achieved in both patients with good neurological outcomes and sustained long-term functional recovery at 18 and 14 months, respectively. DISCUSSION: Selective use of the TandemHeart®, with or without ECMO, facilitates management of the critically ill cardiogenic shock patient with acute severe MR.

Inferring clonal heterogeneity in cancer using SNP arrays and whole genome sequencing.

MOTIVATION: Clonal heterogeneity is common in many types of cancer, including chronic lymphocytic leukemia (CLL). Previous research suggests that the presence of multiple distinct cancer clones is associated with clinical outcome. Detection of clonal heterogeneity from high throughput data, such as sequencing or single nucleotide polymorphism (SNP) array data, is important for gaining a better understanding of cancer and may improve prediction of clinical outcome or response to treatment. Here, we present a new method, CloneSeeker, for inferring clinical heterogeneity from sequencing data, SNP array data, or both. RESULTS: We generated simulated SNP array and sequencing data and applied CloneSeeker along with two other methods. We demonstrate that CloneSeeker is more accurate than existing algorithms at determining the number of clones, distribution of cancer cells among clones, and mutation and/or copy numbers belonging to each clone. Next, we applied CloneSeeker to SNP array data from samples of 258 previously untreated CLL patients to gain a better understanding of the characteristics of CLL tumors and to elucidate the relationship between clonal heterogeneity and clinical outcome. We found that a significant majority of CLL patients appear to have multiple clones distinguished by copy number alterations alone. We also found that the presence of multiple clones corresponded with significantly worse survival among CLL patients. These findings may prove useful for improving the accuracy of prognosis and design of treatment strategies. AVAILABILITY AND IMPLEMENTATION: Code available on R-Forge: https://r-forge.r-project.org/projects/CloneSeeker/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Human papillomavirus and the landscape of secondary genetic alterations in oral cancers.

Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCCs) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCCs, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. In contrast, in HPV-negative OSCCs, T>C substitutions in the sequence context 5'-ATN-3' correlated with tobacco exposure. Universal expression of HPV E6*1 and E7 oncogenes was a sine qua non of HPV-positive OSCCs. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D, FGFR3, FBXW7, DDX3X, PTEN, TRAF3, RB1, CYLD, RIPK4, ZNF750, EP300, CASZ1, TAF5, RBL1, IFNGR1, and NFKBIA Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon (IFN) and nuclear factor kappa B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr 11q (including CCND1) and 14q (including DICER1 and AKT1) were recurrently lost in HPV-positive OSCCs, in contrast to their gains in HPV-negative OSCCs. High-ranking variant allele fractions implicated ZNF750, PIK3CA, and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.

Thirty biologically interpretable clusters of transcription factors distinguish cancer type.

BACKGROUND: Transcription factors are essential regulators of gene expression and play critical roles in development, differentiation, and in many cancers. To carry out their regulatory programs, they must cooperate in networks and bind simultaneously to sites in promoter or enhancer regions of genes. We hypothesize that the mRNA co-expression patterns of transcription factors can be used both to learn how they cooperate in networks and to distinguish between cancer types. RESULTS: We recently developed a new algorithm, Thresher, that combines principal component analysis, outlier filtering, and von Mises-Fisher mixture models to cluster genes (in this case, transcription factors) based on expression, determining the optimal number of clusters in the process. We applied Thresher to the RNA-Seq expression data of 486 transcription factors from more than 10,000 samples of 33 kinds of cancer studied in The Cancer Genome Atlas (TCGA). We found that 30 clusters of transcription factors from a 29-dimensional principal component space were able to distinguish between most cancer types, and could separate tumor samples from normal controls. Moreover, each cluster of transcription factors could be either (i) linked to a tissue-specific expression pattern or (ii) associated with a fundamental biological process such as cell cycle, angiogenesis, apoptosis, or cytoskeleton. Clusters of the second type were more likely also to be associated with embryonically lethal mouse phenotypes. CONCLUSIONS: Using our approach, we have shown that the mRNA expression patterns of transcription factors contain most of the information needed to distinguish different cancer types. The Thresher method is capable of discovering biologically interpretable clusters of genes. It can potentially be applied to other gene sets, such as signaling pathways, to decompose them into simpler, yet biologically meaningful, components.

The Effect of Continuous-Flow Left Ventricular Assist Device Duration on Postoperative Outcomes.

BACKGROUND: This study evaluated the effect of continuous-flow left ventricular assist device (CF-LVAD) duration on postoperative outcomes in heart transplant patients. METHODS: United Network of Organ Sharing heart transplant follow-up data from 2005 to 2015 were obtained. Patients supported by CF-LVADs who subsequently underwent cardiac transplantation were studied. The study population was divided into three groups by CF-LVAD duration of less than 1 year, 1 to 2 years, and more than 2 years. Multivariable Cox regression analysis was used to identify predictors of overall postoperative graft survival. Kaplan-Meier survival functions were used to estimate actuarial survival at 1, 2, and 5 years after transplant. The association between CF-LVAD duration and postoperative acute rejection episodes before and after hospital discharge was assessed. RESULTS: Of 21,336 recipients, 4,382 had CF-LVADs before cardiac transplantation: 2,603 (59.4%) had CF-LVADs for less than 1 year, 1,178 (26.9%) for 1 to 2 years, and 601 (13.7%) for more than 2 years. Donor age, high body mass index, dialysis dependence, and poor functional status at transplant were significant predictors of poor posttransplant graft survival. CF-LVAD duration was associated with increased incidence of acute rejection before hospital discharge (odds ratio, 1.14; 95% confidence interval, 1.02 to 1.28; p = 0.019). Duration was not related to acute rejection episodes after discharge. There was no difference in survival among patients with increasing time durations (hazard ratio, 1.01; 95% CI, 0.89 to 1.15; p = 0.824). Graft survival at 1, 2, and 5 years among patient groups was not significantly different (p = 0.824 by log-rank test) CONCLUSIONS: Duration of CF-LVAD support does not affect posttransplant graft survival. Longer duration of support increases acute rejection episodes; however, this may not translate into diminished survival.

Impact of Left-Ventricular Assist Device-Related Complications on Posttransplant Graft Survival.

BACKGROUND: This study describes the impact of continuous-flow left-ventricular-assist device (CF-LVAD)-related complications on postoperative outcomes. METHODS: The United Network for Organ Sharing (UNOS) heart transplant follow-up data from 2005 to 2015 were obtained. CF-LVAD patients who were bridged to transplant were studied. Device-related complications (DRCs) at patient's last follow-up before transplantation were reported in 5 categories: device thrombosis (B1), infection (B2), device malfunction (B3), life-threatening arrhythmias (B4), and others (B5). Multivariable Cox regression models were used to evaluate the association of each category of complications and number of complications with postoperative graft survival. RESULTS: Of 3,877 patients analyzed, incidence of DRCs was as following: 374 (9.65%) for thrombosis (B1), 869 (22.41%) for device-related infection (B2), 400 (10.32%) for device malfunction (B3), 135 (3.48%) for life-threatening arrhythmias (B4), and 510 (13.15%) for others (B5). A total of 2,018 (52.05%) patients did not have any DRC at last follow-up; 1,482 (38.23%) patients had 1 DRC and 377 (9.72%) patients had 2 or more DRCs. Mean time from last preoperative follow-up to transplant in patients with 0, 1, and 2 or more DRCs was 93, 18, and 11 days, respectively. Multivariate analysis showed that none of the complications (from B1 to B5) were independent risk factors for poor graft survival after cardiac transplantation. Independent predictors of postoperative graft failure were increasing donor age, inpatient status, increasing body mass index, poor functional status, ventilator dependence, and extracorporeal membrane oxygenation at the time of transplant. CONCLUSIONS: DRCs are common among advanced heart failure patients bridged to transplant with CF-LVADs. Contrary to popular belief, DRCs are not associated with poor postoperative graft survival.

Post-transplant survival in idiopathic pulmonary fibrosis patients concurrently listed for single and double lung transplantation.

BACKGROUND: Lung transplantation is a widely accepted treatment for patients with end-stage lung disease related to idiopathic pulmonary fibrosis (IPF). However, there are conflicting data on whether double lung transplant (DLT) or single lung transplant (SLT) is the superior therapy in these patients. The purpose of this study was to determine whether actuarial post-transplant graft survival among IPF patients concurrently listed for DLT and SLT is greater for recipients undergoing the former or the latter. METHODS: The United Network for Organ Sharing provided de-identified patient-level data. Analysis included lung transplant candidates with IPF listed between January 1, 2001 and December 31, 2009 (n = 3,411). The study population included 1,001 (29.3%) lung transplant recipients concurrently listed for DLT and SLT, all ≥18 years of age. The primary outcome measure was actuarial post-transplant graft survival, expressed in years. RESULTS: Among the study population, 433 (43.26%) recipients underwent SLT and 568 (56.74%) recipients underwent DLT. The analysis included 2,722.5 years at risk, with median graft survival of 5.31 years. On univariate (p = 0.317) and multivariate (p = 0.415) regression analyses, there was no difference in graft survival between DLT and SLT. CONCLUSIONS: Among IPF recipients concurrently listed for DLT and SLT, there is no statistical difference in actuarial graft survival between recipients undergoing DLT vs SLT. This analysis suggests that increased use of SLT for IPF patients may increase the availability of organs to other candidates, and thus increase the net benefit of these organs, without measurably compromising outcomes.

E3 Ubiquitin Ligase Cbl-b Regulates Thymic-Derived CD4+CD25+ Regulatory T Cell Development by Targeting Foxp3 for Ubiquitination.

CD28 costimulation is essential for the development of thymic-derived CD4(+)CD25(+)Foxp3(+) regulatory T cells ("tTregs"). E3 ubiquitin ligase Cbl-b has been shown to regulate CD28 dependence of T cell activation. In this paper, we report that the loss of Cbl-b partially but significantly rescues the defective development of tTregs in Cd28(-/-) mice. This partial rescue is independent of IL-2. Mechanistically, Cbl-b binds to Foxp3 upon TCR stimulation and, together with Stub1, targets Foxp3 for ubiquitination and subsequently degradation in the proteasome. As Cbl-b self-ubiquitination and proteasomal degradation is impaired in Cd28(-/-) T cells, the defective development of tTregs in Cd28(-/-) mice may in part be due to increased Foxp3 ubiquitination and degradation targeted by Stub1 and Cbl-b. Treating Cd28(-/-) mice with a proteasome inhibitor completely rescues defective tTreg development in these mice. Therefore, Cbl-b, together with Stub1, ubiquitinate Foxp3, and regulate tTreg development.

Mixed group of Rhizobiales microbes in lung and blood of a patient with fatal pulmonary illness.

We examined the microbial composition in the diseased lung and early-phase microbial cultures from the blood of a patient with a rapidly progressing fatal pulmonary illness. Although no microbes could be isolated from such cultures during the initial study, the HTS-microbiome study revealed the presence of a unique mixture of alphaproteobacteria, composed mainly of different families of Rhizobiales microbes. Microbial 16S rDNA sequences matching closely to Afipia cberi were identified mainly in the patient's diseased lung tissue, but only rarely in the early-phase blood cultures. Conversely, the high abundance of sequences found in early-phase blood cultures of different broth media matched closely with those of the families Methylobacteriaceae, Phyllobacteriaceae and Sphingomonadaceae. The two species that successfully adapted to grow in a laboratory culture system were A. cberi and Mesorhizobium hominis, which eventually were isolated from a previously cryopreserved blood culture of SP4 broth. Many other species, including members of the Bradyrhizobiaceae and Phyllobacteriaceae families, and all members of the Methylobacteriaceae and Sphingomonadaceae families identified by HTS remained non-cultivated. We developed specific PCR primers and FISH probes, which detected the target Rhizobiales microbes in former blood cultures and autopsy lung tissues. It is unclear what role these Rhizobiales microbes might have played in the patient's complex disease process. However, the above mentioned assays should help in rapidly detecting and identifying these previously unrecognized Rhizobiales microbes in patients.

Concomitant Kaposi sarcoma and multicentric Castleman's disease in a heart transplant recipient.

Post-transplant human herpes virus -8 (HHV-8)/Kaposi sarcoma herpes virus (KSHV) infection is associated with neoplastic and non-neoplastic diseases. Kaposi sarcoma (KS), multicentric Castleman's disease (MCD), and primary effusion lymphomas (PEL) are the most common HHV-8-associated neoplastic complications described in solid organ transplant (SOT) patients. Concurrent KS and MCD have been previously described after transplantation only twice - once after liver transplantation and once after renal transplantation. We describe a unique heart transplant patient who also developed concurrent KS and MCD. To our knowledge this is the first documented case of a heart transplant recipient presenting with these two HHV-8-mediated complications at the same time.

Lessons learned from the first fully magnetically levitated centrifugal LVAD trial in the United States: the DuraHeart trial.

BACKGROUND: The DuraHeart is a continuous centrifugal-flow left ventricular assist device that uses active magnetic levitation for impeller positioning designed for improved hemocompatibility and durability. This study reviews the results of the US trial with specific attention to hemolysis, thrombotic complications, and pump failure. METHODS: The US SUSTAIN trial was a multicenter, prospective, single-arm observational study in advanced heart failure patients listed for transplantation. Follow-up was complete in 100% of the patients at 6 months. RESULTS: Sixty-three patients were enrolled at 23 centers. Forty-six patients (73%) reached the primary end points of survival to transplantation, alive on the original device at 180 days and listed for transplantation, or explant for recovery. Median duration of support was 267 days (range, 10 to 952 days) with a total support time of 46 patient-years. There was no clinical hemolysis reported during the study. Mean lactate dehydrogenase values peaked at day 4 and significantly decreased during support (435±236 U/L and 297±142 U/L on day 3 and day 180, respectively). There were no cases of pump thrombosis reported, and 3 cases of pump thrombus "in transit" (0.06 events/patient-year) were observed. There were 6 (10%) cases of magnetic levitation system failure, all secondary to cable wire fractures (0.12 events/patient-year). All patients were hemodynamically stable with the backup hydrodynamic mode. Major adverse events included gastrointestinal bleeding (0.52 events/patient-year), ischemic and hemorrhagic strokes (0.17 events/patient-year and 0.09 events/patient-year, respectively), and driveline infections (0.67 events/patient-year). CONCLUSIONS: The DuraHeart demonstrated good hemocompatibility; however, the reliability of full magnetic levitation systems should be a high priority in future pump designs.