Citations

Background: The objective of this study was to describe inpatient prevalence, characteristics, outcomes, and resource use for acute salicylate intoxication hospitalizations in the United States. Methods: A total of 13,805 admissions with a primary diagnosis of salicylate intoxication from 2003 to 2014 in the National Inpatient Sample database were analyzed. Prognostic factors for in-hospital mortality were determined using multivariable logistic regression. Results: The overall inpatient prevalence of salicylate intoxication among hospitalized patients was 147.8 cases per 1,000,000 admissions in the United States. The average age was 34 ± 19 years. Of these, 35.0% were male and 65.4% used salicylate for suicidal attempts. Overall, 6% required renal replacement therapy. The most common complications of salicylate intoxication were electrolyte and acid-base disorders, including hypokalemia (25.4%), acidosis (19.1%), and alkalosis (11.1%). Kidney failure (9.3%) was the most common observed organ dysfunction. In-hospital mortality was 1.0%. Increased in-hospital mortality was associated with age ≥30, Asian/Pacific Islander race, diabetes mellitus, hyponatremia, ventricular arrhythmia, kidney failure, respiratory failure, and neurological failure, while decreased in-hospital mortality was associated with African American and Hispanic race. Conclusion: hospitalization for salicylate intoxication occurred in 148 per 1,000,000 admissions in the United States. Several factors were associated with in-hospital mortality.

Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but to the authors' knowledge, limited data exist regarding the safety and efficacy of these agents in transplant recipients. Herein, the authors have reported their experience with 17 patients who were treated with ICIs for metastatic malignancies after undergoing solid organ transplantation. Methods Data were abstracted for solid organ transplant recipients who received ICIs for the treatment of malignancy between January 1, 2016, and September 30, 2019. The authors identified 7 kidney, 8 liver, and 2 heart transplant recipients. Outcomes of interest were adverse drug reactions, cancer progression, and patient survival. Results The most common malignancies treated with ICIs were metastatic squamous cell carcinoma (5 patients; 29%) and hepatocellular carcinoma (5 patients; 29%), which were noted exclusively among liver transplant recipients. The median duration on ICIs was 1.7 months (interquartile range, 0.4‐7.6 months). Five patients (29%) developed adverse reactions, including 4 patients (24%) with immune‐related adverse events(irAEs), 3 patients (18%) with acute allograft rejections, 1 patient (6%) with autoimmune colitis, and 1 patient (6%) with ICI‐induced cardiotoxicity (the patient was a heart transplant recipient). The cumulative incidence of cancer progression was 50% and 69%, respectively, at 6 months and 12 months. Eleven patients (65%) died over the median follow‐up period of 4.6 months (interquartile range, 1.5‐13.2 months) from the time of ICI initiation, with cancer progression being the most common cause of death. Conclusions ICIs can be used as individualized therapy in selected patients who have undergone solid organ transplantation but more studies are needed to determine how best to use these agents to improve outcomes further.

Abstract Background Parity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated. Methods A pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses. Results Ever having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend < .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer. Conclusions Incomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.

Background: This study aimed to evaluate the risk factors and the association of acute kidney injury (AKI) with outcomes, and resource utilization in patients hospitalized due to salicylate intoxication in the United States. Methods: Hospitalized patients with a primary diagnosis of salicylate intoxication from 2003 to 2014 were identified in the National Inpatient Sample (NIS) database. End-stage kidney disease patients were excluded. The occurrence of AKI was identified using hospital diagnosis code. Clinical characteristics, in-hospital treatment, outcomes and resource utilization were compared between patients with and without AKI. Results: A total of 13,787 eligible hospital admissions were included in the analysis. AKI occurred in 1,279 (9.3%) admissions. Older age, male sex, more recent year of hospitalization, anemia, hypertension, congestive heart failure, chronic kidney disease, volume depletion, sepsis, and ventricular arrhythmia/cardiac arrest were significantly associated with increased risk of AKI, whereas Hispanic race was associated with decreased risk. AKI was significantly associated with increased risk of organ failure, and in-hospital mortality. In addition, the need for ventilation support, blood component transfusion, renal replacement therapy, length of hospital stay, and hospitalization cost were higher in AKI patients. Conclusion: Approximately one tenth of salicylate intoxication patients developed AKI during hospitalization. AKI was associated with higher morbidity, mortality, and resource utilizations.

Tacrolimus is a first-line calcineurin inhibitor (CNI) and an integral part of the immunosuppressive strategy in solid organ transplantation. Being a dose-critical drug, tacrolimus has a narrow therapeutic index that necessitates periodic monitoring to maintain the drug’s efficacy and reduce the consequences of overexposure. Tacrolimus is characterized by substantial intra- and inter-individual pharmacokinetic variability. At steady state, the tacrolimus blood concentration to daily dose ratio (C/D ratio) has been described as a surrogate for the estimation of the individual metabolism rate, where a low C/D ratio reflects a higher rate of metabolism. Fast tacrolimus metabolism (low C/D ratio) is associated with the risk of poor outcomes after transplantation, including reduced allograft function and survival, higher allograft rejection, CNI nephrotoxicity, a faster decline in kidney function, reduced death-censored graft survival (DCGS), post-transplant lymphoproliferative disorders, dyslipidemia, hypertension, and cardiovascular events. In this article, we discuss the potential role of the C/D ratio in a noninvasive monitoring strategy for identifying patients at risk for potential adverse events post-transplant.

Abstract Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271

Abstract INTRODUCTION: Type 1 Diabetes (T1D) patients have an increased risk for major adverse cardiovascular events (MACE). Pancreas Transplantation Alone (PTA) in patients with T1D achieves near normal glucose control for a prolonged period but limited data are available to date regarding MACE during a 10 year follow up period after the procedure. OBJECTIVE: We studied incidence of MACE after PTA in T1D patients over a 10 year follow-up period. METHODS: Retrospectively, we studied 113 T1D recipients of PTA at Mayo Clinic, Rochester with the procedure performed between January 1998 and August 2018 and follow up of at least 1 year. Data were collected before transplantation and up to 10 year follow up after the first PTA. MACE data were gathered until primary non function, re-transplantation, or complete loss of c-peptide (<0.01ng/ml). We report vascular risk factors including hypertension, hyperlipidemia, smoking and BMI along with MACE (defined as cardiac events as unstable angina, Myocardial Infarction (MI), need for re-vascularization, cardiac death, cerebral events as Transient ischemic attack (TIA), stroke, need for re-vascularization and peripheral arterial disease as need for re-vascularization, gangrene and amputation). RESULTS: Eighteen subjects had pre-transplant MACE. A total of 14 subjects had graft failure within 24 to 36 hours due to thrombosis, with 3 in pre-transplant MACE cohort and 11 in no MACE cohort. Thus, we followed 99 subjects for the development of post-transplant MACE for a period of 6.3 ± 3.6 years. T1D subjects with MACE (n=15) had baseline characteristics: Age 48± 7.8 years, gender F/M 9/6,, duration of diabetes 33 ± 12 years, BMI 26± 3.1(Kg/m2), HbA1c 9.3 ± 1.5% and C-peptide 0.09 ng/ml. 84 T1D patients without MACE were age 42 ± 10.6 years, gender F/M 55/29, duration of diabetes 26.5 ± 10.7 years, BMI 26 ± 5.2(Kg/m2), HbA1c 6.7 ± 2.5 and C-peptide 0.09 ng/ml. There are a total of 584 person-years of follow up to first MACE event and 632 person-years of graft failure, death or last follow-up. Nine patients developed 11 MACE events post-PTA. Therefore, the event rate is 1.5 MACE events per 100 person-years for first MACE event and the total event rate is 1.7 MACE events per 100 person-years of follow-up. Age, smoking (yes), gender, duration of diabetes, HTN and Hyperlipidemia presence did not show any significant impact on post-transplant MACE outcome based on univariate Cox regression but the pre-transplant BMI (HR = 1.14; CI = (1.04, 1.26); p = 0.008) and pre-transplant HbA1c (HR = 1.26; CI = (1.06, 1.51); p = 0.01) showed statistically significant impact. CONCLUSIONS: At our center, MACE is low in PTA recipients. There is no impact of presence of pre-transplant MACE on development of post-transplant MACE but pre-transplant BMI and HbA1c account for risk of MACE.

Abstract Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene, leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. We report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers from 2005 through 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs ≥5 years of age at the time of HCT (94% vs 66%; overall P = .0008). OS was excellent regardless of donor type, even in cord blood recipients (90%). Conditioning intensity did not affect OS, but was associated with donor T-cell and myeloid engraftment after HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early after HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) vs low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005, compared with prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution after either myeloablative or busulfan-containing reduced intensity conditioning. (This trial was registered at www.clinicaltrials.gov as #NCT02064933.)

Abstract Introduction: Male breast cancer (BCa) is a rare disease accounting for less than 1% of all breast cancers (BC) and 1% of all cancers in males. The clinical management is largely extrapolated from female BCa. Few studies have examined the genomic landscape of male BCas, with six male BCas included in The Cancer Genome Atlas (TCGA). Familial studies of male BCas have shown genomic changes similar to female BCa, while a larger targeted sequencing study of 59 male breast cancers identified recurrent mutations affecting PIK3CA and GATA3. To date, there is still limited information regarding the genomic landscape of male BCas; particularly in the context of identifying targeted treatments. To reveal genomic changes that characterize male BCas in the context of known cancer driver genes linked to prognosis and targeted agents, we performed a targeted sequencing study on 248 male BCas from the International Male Breast Cancer Program. Methods: 248 primary M0, ER+ve, HER2-ve male BCas enrolled in the Part 1 (retrospective joint analysis) International Male Breast Cancer Program of 1483 patients diagnosed between 1990-2010 (Cardoso et al. Annals of Oncology, 2018) were processed for nucleic acid extraction from formalin-fixed paraffin embedded (FFPE) tissues. Using the Thermo Fisher Scientific Oncomine Comprehensive Assay v3 (OCAv3), a validated targeted sequencing panel currently used in the NCI-MATCH trial (NCT02465060), we evaluated mutational and copy number variations (CNVs) of genes that are prognostic or predictive to targeted therapies currently in use in the clinic or late-stage clinical trials. The OCAv3 DNA pan-cancer panel assays 115 genes for determining mutational status (48 full coding and 67 hotspot) as well as copy-number assessment in 43 genes. The OCAv3 uses Ampliseq-based technology linked to the Oncomine NGS workflow to identify actionable mutations and CNVs Results: Of the 248 samples assayed, 216 passed strict quality control parameters (87.1%). Using the Oncomine NGS workflow, actionable mutations at ≥5% variant allele frequency (VAF) were most frequently identified in PIK3CA (29.2%), BRCA2 (11.1%), NF1 (11.6%), indels in TP53 (10.6%), ATR (5.6%), ATRX (5.1%), indel BRCA2 (5.1%), TP53 point mutations (4.6%), MET (4.6%), ATM (4.6%), NOTCH2 (4.6%), CHEK1 (4.2%), FANCI (4.2%), PTEN (3.2%) with a number of additional genes identified at lower frequencies. Gene amplifications were most frequently detected in MYC (24.5%), FGFR1 (14.8%), CCND1 (12%), FGF3 (9.7%), FGF19 (9.7%), MDM2 (6.5%), CDK4 (1.4%), FGFR3, MDM4, ERBB2 (0.9% each), and FLT3, AR, MYCL, CDK6, IGF1R, FGFR4, KRAS, AKT3 and ESR1 (0.5% each). Although the results here describe the mutations and copy-number changes deemed to be actionable, further analysis of all non-actionable somatic mutations and CNVs will be presented and compared to female BCas previously assayed using the same panel. Conclusion: In this targeted sequencing study of the largest series of male BCas to our knowledge, we have revealed that PIK3CA continues to be a frequently altered gene in both male and female BCas. However, there is an enrichment of mutations in genes related to DNA repair in male BCs. Interestingly, while MYC is commonly amplified in female BCa, a higher frequency of amplified cases were seen in male BCas, in contrast to female BCas. Together with our previously generated transcriptional profiling data in this data set, we believe that both common and unique biological processes comprising male and female BCas will ultimately improve their clinical management and move towards the goal of precision medicine. This work has been funded by the Breast Cancer Research Foundation (BCRF). Citation Format: Jane Bayani, Coralie Poncet, Cheryl Crozier, Quang M Trinh, Megan Hopkins, Aime Lambert Uwimana, Tammy Piper, Carrie Cunningham, Monika Sobol, Stefan Aebi, Kim Benstead, Oliver Bogler, Lissandra Dal Lago, Florentine Hilbers, Ingrid Hedenfalk, Larissa Korde, Barbro Linderholm, John Martens, Lavinia Middleton, Melissa Murray, Catherine Kelly, Cecilia Nilsson, Monika Nowaczyk, Stephanie Peeters, Aleksandra Peric, Peggy Porter, Carolien Schröder, Isabel T Rubio, Kathryn J Ruddy, Christi van Asperen, Danielle Van Den Weyngaert, Carolien HM van Deurzen, Elise van Leeuwen-Stok, Joanna Vermeij, Eric Winer, Lincoln D Stein, Sharon H Giordano, Fatima Cardoso, John MS Bartlett. The genomic landscape of male breast cancers using the oncomine comprehensive assay for actionable mutations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-03.