Citations

AbstractBackground and objectivesWe aimed to determine outcomes with transplanting kidneys from deceased donors with severe acute kidney injury requiring acute renal replacement therapy (RRT).Materials and methodsA total of 172 recipients received a kidney from donors with acute kidney injury stage 3 (AKIN3) requiring RRT. We compared the study group to 528 recipients who received a kidney from donors with AKIN stage 3 not on RRT and 463 recipients who received < 85% Kidney Donor Profile Index (KDPI) AKIN stage 0 kidney.ResultsThe study group donors were younger compared to the 2 control groups. Despite higher DGF in the study group, the length of hospital stay and acute rejection were similar. Death censored graft survival (96% AKIN3‐RRT vs. 97%AKIN3 no RRT vs. 96% KDPI < 85% AKIN0,P = 0.26) and patient survival with functioning graft at 1 year (95% across all groups,P = 0.402) were similar. The estimated glomerular filtration rate were similar across the 3 groups after first month. Interstitial fibrosis and tubular atrophy score ≥ 2 on protocol biopsy at time 0, 4 and 12 months were similar. Primary nonfunction was rare and associated with high KDPI.ConclusionsTransplanting selected kidneys from deceased donors with AKIN3 requiring RRT is safe and has good outcomes.

Abstract Rationale Early, accurate diagnosis of interstitial lung disease (ILD) informs prognosis and therapy, especially in idiopathic pulmonary fibrosis (IPF). Current diagnostic methods are imperfect. High-resolution computed tomography has limited resolution, and surgical lung biopsy (SLB) carries risks of morbidity and mortality. Endobronchial optical coherence tomography (EB-OCT) is a low-risk, bronchoscope-compatible modality that images large lung volumes in vivo with microscopic resolution, including subpleural lung, and has the potential to improve the diagnostic accuracy of bronchoscopy for ILD diagnosis. Objectives We performed a prospective diagnostic accuracy study of EB-OCT in patients with ILD with a low-confidence diagnosis undergoing SLB. The primary endpoints were EB-OCT sensitivity/specificity for diagnosis of the histopathologic pattern of usual interstitial pneumonia (UIP) and clinical IPF. The secondary endpoint was agreement between EB-OCT and SLB for diagnosis of the ILD fibrosis pattern. Methods EB-OCT was performed immediately before SLB. The resulting EB-OCT images and histopathology were interpreted by blinded, independent pathologists. Clinical diagnosis was obtained from the treating pulmonologists after SLB, blinded to EB-OCT. Measurements and Main Results We enrolled 31 patients, and 4 were excluded because of inconclusive histopathology or lack of EB-OCT data. Twenty-seven patients were included in the analysis (16 men, average age: 65.0 yr): 12 were diagnosed with UIP and 15 with non-UIP ILD. Average FVC and Dl CO were 75.3% (SD, 18.5) and 53.5% (SD, 16.4), respectively. Sensitivity and specificity of EB-OCT was 100% (95% confidence interval, 75.8–100.0%) and 100% (79.6–100%), respectively, for both histopathologic UIP and clinical diagnosis of IPF. There was high agreement between EB-OCT and histopathology for diagnosis of ILD fibrosis pattern (weighted κ: 0.87 [0.72–1.0]). Conclusions EB-OCT is a safe, accurate method for microscopic ILD diagnosis, as a complement to high-resolution computed tomography and an alternative to SLB.

Study Design: Retrospective cohort study. Objective: The influence that race has on mortality rates in patients with spinal cord tumors is relatively unknown. The aim of this study was to investigate the influence of race on the outcomes of patients with primary malignant or nonmalignant tumors of the spinal cord or spinal meninges. Methods: The Surveillance, Epidemiology, and End Results (SEER) Registry was used to identify all patients with a code for primary malignant or nonmalignant tumor of the spinal cord (C72.0) or spinal meninges (C70.1) from 1973 through 2016. Racial groups (African-American/Black vs. White) were balanced using propensity-score (PS) matching using a non-parsimonious 1:1 nearest neighbor matching algorithm. Overall survival (OS) estimates were obtained using the Kaplan-Meier method and compared across non-PS-matched and PS-matched groups using log-rank tests. Associations of survival with clinical variables was assessed using doubly robust Cox proportional-hazards (CPH) regression analysis. Results: There were a total of 7,498 patients identified with 648 (6.8%) being African American. African-American patients with primary intradural spine tumors were more likely to die of all causes than were White patients in both the non-PS-matched [HR: 1.26, 95% CI: (1.04, 1.51), P = 0.01] and PS-matched cohorts [HR: 1.64, 95% CI: (1.28, 2.11), P < 0.0001]. On multivariate CPH regression analysis age at diagnosis [HR: 1.03, 95% CI: (1.02, 1.05), P < 0.0001], race [HR: 1.82, 95% CI: (1.22, 2.74), P = 0.004), and receipt of RT [HR: 2.62, 95% CI: (1.56, 4.37), P = 0.0002) were all significantly associated with all-cause mortality, when controlling for other demographic, tumor, and treatment variables. Conclusions: Our study provides population-based estimates of the prognosis for patients with primary malignant or nonmalignant tumors of the spinal cord or spinal meninges and suggests that race may impact all-cause mortality.

AbstractBackgroundRecent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.Methods483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)–negative (PRSER-), or ER-positive (PRSER+) breast cancer risk.ResultsPRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.ConclusionsPopulation-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.

Tailoring stress responses When faced with environmental stress, cells respond by shutting down cellular processes such as translation and nucleocytoplasmic transport. At the same time, cells preserve cytoplasmic messenger RNAs in structures known as stress granules, and many cellular proteins are modified by the covalent addition of ubiquitin, which has long been presumed to reflect degradation of stress-damaged proteins (see the Perspective by Dormann). Maxwell et al. show that cells generate distinct patterns of ubiquitination in response to different stressors. Rather than reflecting the degradation of stress-damaged proteins, this ubiquitination primes cells to dismantle stress granules and reinitiate normal cellular activities once the stress is removed. Gwon et al. show that persistent stress granules are degraded by autophagy, whereas short-lived granules undergo a process of disassembly that is autophagy independent. The mechanism of this disassembly depends on the initiating stress. Science , abc3593 and abf6548, this issue p. eabc3593 and p. eabf6548 ; see also abj2400, p. 1393

Significance Statement A higher percentage of the kidney cortex area that exhibits interstitial fibrosis/tubular atrophy (IF/TA) is a feature of poor prognosis on biopsy. This study describes IF/TA density (the number of IF/TA foci per area of cortex) and shows it predicts progressive CKD, independent of both percentage IF/TA and clinical characteristics among patients who have undergone nephrectomy. Other patterns of IF/TA and inflammation were not predictive for progressive CKD and mortality beyond percentage IF/TA and clinical characteristics. At the same percentage IF/TA, a higher IF/TA density suggests more scattered and widespread damage to the nephrons, with a worse kidney prognosis. This information may be helpful for accurate interpretation of the severity of “chronic changes” observed on a kidney biopsy. Background Chronic tubulointerstitial injury on kidney biopsy is usually quantified by the percentage of cortex with interstitial fibrosis/tubular atrophy (IF/TA). Whether other patterns of IF/TA or inflammation in the tubulointerstitium have prognostic importance beyond percentage IF/TA is unclear. Methods We obtained, stained, and digitally scanned full cortical thickness wedge sections of renal parenchyma from patients who underwent a radical nephrectomy for a tumor over 2000–2015, and morphometrically analyzed the tubulointerstitium of the cortex for percentage IF/TA, IF/TA density (foci per mm 2 cortex), percentage subcapsular IF/TA, striped IF/TA, percentage inflammation (both within and outside IF/TA regions), and percentage subcapsular inflammation. Patients were followed with visits every 6–12 months. Progressive CKD was defined as dialysis, kidney transplantation, or 40% decline from the postnephrectomy eGFR. Cox models assessed the risk of CKD or noncancer mortality with morphometric measures of tubulointerstitial injury after adjustment for the percentage IF/TA and clinical characteristics. Results Among 936 patients (mean age, 64 years; postnephrectomy baseline eGFR, 48 ml/min per 1.73m 2 ), 117 progressive CKD events and 183 noncancer deaths occurred over a median 6.4 years. Higher IF/TA density predicted both progressive CKD and noncancer mortality after adjustment for percentage IF/TA and predicted progressive CKD after further adjustment for clinical characteristics. Independent of percentage IF/TA, age, and sex, higher IF/TA density correlated with lower eGFR, smaller nonsclerosed glomeruli, more global glomerulosclerosis, and smaller total cortical volume. Conclusions Higher density of IF/TA foci (a more scattered pattern with more and smaller foci) predicts higher risk of progressive CKD after radical nephrectomy compared with the same percentage of IF/TA but with fewer and larger foci.

Abstract PURPOSE: Ovarian cancer remains the most lethal gynecological malignancy in the United States even though there are a number of treatment options. For the newly diagnosed ovarian cancer patient, treatment is standard with the majority of patients receiving first-line platinum/taxol treatment following surgical debulking or as part of a neo-adjuvant treatment regimen. Standard response assessment to this chemotherapy combination depends on lengthy clinical follow-up of at least 6 months following the conclusion of the chemotherapy. This course is initially effective in 70-80% of patients, but 20-30% will relapse within the 6 months post-chemotherapy or not respond at all. Additionally, most of the initial responders will also relapse. Early prediction of the patients whose cancers do not respond could lead to earlier intervention with more effective therapy. RESULTS: To perform this prediction, we developed a test utilizing live tumor tissue and 3D cell culture to predict the response of ovarian cancer patients to standard platinum and taxol chemotherapy along with the standard agents used for relapse patients. To validate the assay, we performed a prospective trial involving 86 women with newly diagnosed ovarian cancer from whom live tumor tissue was recovered at surgical resection prior to chemotherapy. Of the 79 patients whose tissues yielded a successful assay result, 27 had sufficient clinical follow-up to determine the accuracy of the response predictions made by the assay. Assay response predictions were made within 7 days following surgery while clinical response was not determined until 6 months or more following the conclusion of first-line chemotherapy. Assay results predicted first-line chemotherapy response in 100% of clinical responders (19 of 19) and first-line chemotherapy non-response in 62.5% of clinical non-responders (5 of 8) as defined by CA-125 and radiographic surveillance. This response prediction was statistically significant by Fisher's Exact test, p &lt; 0.001. The sensitivity of the assay was 86% while the specificity was 100%. When the assay results were examined in terms of progression free survival, 19 of 19 patients identified as responders by the assay remained progression free at least 6 months post-chemotherapy with 14 remaining progression free 10 or more months post-chemotherapy. In contrast, of the 8 assay non-responders, 3 were refractory with progression within 3 months of chemotherapy conclusion and 2 progressed less than 6 months post-chemotherapy with a mean progression free survival of 4.5 months. CONCLUSIONS: Our rapid, ex vivo, 3D cellular assay is capable of accurate patient specific response prediction of first-line combination therapy in newly diagnosed ovarian cancer patients and can serve as a prognostic indicator of progression free survival. This preliminary clinical validation shows the significant potential of this assay as a future tool in personalized cancer care for ovarian cancer patients. Citation Format: Stephen Shuford, Jeffrey Elder, Larry Puls, John Weroha, Xiaonan Hou, Valentina Zanfagnin, Alpa Nick, Michael P. Stany, Larry Maxwell, Thomas Conrads, Chris Corless, Anil K. Sood, Matthew Gevaert, Howland E. Crosswell, and Teresa M. DesRochers. PROSPECTIVE CLINICAL VALIDATION OF EX VIVO, PATIENT-SPECIFIC RESPONSE PREDICTION TO FIRST-LINE CHEMOTHERAPY [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-069.

Abstract CRLF2-rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) accounts for more than half of Philadelphia chromosome-like (Ph-like) ALL and is associated with a poor outcome in children and adults. Overexpression of CRLF2 results in activation of Janus kinase (JAK)-STAT and parallel signaling pathways in experimental models, but existing small molecule inhibitors of JAKs show variable and limited efficacy. Here, we evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) directed against JAKs. Solving the structure of type I JAK inhibitors ruxolitinib and baricitinib bound to the JAK2 tyrosine kinase domain enabled the rational design and optimization of a series of cereblon (CRBN)-directed JAK PROTACs utilizing derivatives of JAK inhibitors, linkers, and CRBN-specific molecular glues. The resulting JAK PROTACs were evaluated for target degradation, and activity was tested in a panel of leukemia/lymphoma cell lines and xenograft models of kinase-driven ALL. Multiple PROTACs were developed that degraded JAKs and potently killed CRLF2r cell lines, the most active of which also degraded the known CRBN neosubstrate GSPT1 and suppressed proliferation of CRLF2r ALL in vivo, e.g. compound 7 (SJ988497). Although dual JAK/GSPT1-degrading PROTACs were the most potent, the development and evaluation of multiple PROTACs in an extended panel of xenografts identified a potent JAK2-degrading, GSPT1-sparing PROTAC that demonstrated efficacy in the majority of kinase-driven xenografts that were otherwise unresponsive to type I JAK inhibitors, e.g. compound 8 (SJ1008030). Together, these data show the potential of JAK-directed protein degradation as a therapeutic approach in JAK-STAT–driven ALL and highlight the interplay of JAK and GSPT1 degradation activity in this context.

Background: Quality of life (QOL) and psychological health has been reported to be decreased among women with gynecological conditions such as uterine fibroids (UFs). Materials and Methods: Women enrolled in the Comparing Options for Management: PAtient-centered REsults for Uterine Fibroids (COMPARE-UF) registry, receiving procedural therapy for symptomatic UFs, were eligible for this analysis if they completed a series of health-related QOL surveys administered at three time points (baseline, 6–12 weeks postprocedure, and 1 year postprocedure; n = 1486). Ethical approval for this study was obtained at each recruiting site and the coordinating center (NCT02260752, clinicaltrials.gov ). Results: More than 26% ( n = 393) of women reported moderate anxiety/depression on the baseline anxiety/depression domain of the Euro-QOL 5-dimension instrument. At both the 6–12 weeks and 1-year postprocedural follow-up, there was significant improvement in the UF QOL symptom severity score ( p < 0.001, p < 0.001), the total UF symptom QOL score ( p < 0.001, p < 0.001), and the Euro-QOL 5-dimension visual analog scale ( p < 0.001, p = 0.004) compared with the preprocedural baseline scores. The reporting of anxiety/depression decreased by 66.4% among women who were at baseline, whereas 5.6% of women previously reporting no anxiety/depression reported anxiety/depression at the 1-year follow-up. Conclusion: UF symptoms were more severe among women reporting anxiety/depression at baseline. At the 1-year follow-up, health-related QOL scores improved among all women and the prevalence of anxiety/depression decreased in most, but not all women, whereas severity of anxiety/depression worsened in a small percentage of women (5.6%). Overall, these results suggest that UF treatment improves symptoms of anxiety/depression associated with symptomatic UFs.

Context.— It is unclear if preimplantation frozen section biopsy correlates with outcomes after deceased donor kidney transplantation. Objective.— To assess if chronic histologic changes on the preimplant frozen section correlates with graft loss and estimated glomerular filtration rate independently of kidney donor profile index (KDPI). Design.— Seven hundred three preimplantation biopsies were reviewed and a Banff sum score was calculated using glomerular sclerosis, interstitial fibrosis, vascular intimal thickening, and arteriolar hyalinosis. The posttransplant outcomes were compared for preimplantation biopsy Banff sum 0-1, 2-3, and 4-9. The cohort was also stratified by KDPI 85 or less versus more than 85. Results.— For the entire biopsy cohort, graft survival, estimated glomerular filtration rate at 1 year, and chronic changes on a 1-year posttransplant biopsy were superior in the group with preimplantation Banff sum 0-1. After stratifying by KDPI, the Banff sum no longer correlated with graft survival. In a univariate mode, using the Banff sum score as a continuous variable, a higher Banff sum score was significantly associated with graft failure (P = .03); however, after adjusting the KDPI, the Banff sum score no longer correlated with graft failure (P = .45). The 1-year estimated glomerular filtration rate and 1-year biopsy changes were superior in the group with Banff sum 0-1 only in the cohort with KDPI 85 or less. Conclusions.— In donor kidneys used for transplant, preimplantation biopsy chronic changes correlate with estimated glomerular filtration rate and biopsy findings at 1 year, but biopsies with mostly mild chronicity and Banff sum scores less than or equal to 5 did not impact graft survival beyond KDPI.