Search

Higher body mass index (BMI) increases the risk of developing primary graft dysfunction (PGD) after lung transplantation; whether BMI is associated with decreased survival after PGD is unknown. We utilized the Lung Transplant Outcomes Group cohort of 1,538 subjects from 2011-2018. We evaluated the association between preoperative BMI and graft survival among subjects with severe PGD using Cox proportional hazards models with linear splines. Models were stratified by center and adjusted for sex, age, Lung Allocation Score, and diagnosis. PGD developed in 383 subjects. Among subjects with PGD, low BMI was associated with increased mortality while high BMI was not associated with differential mortality, compared to normal BMI. Results were similar for 90-day and 1-year survival. While high BMI increases the risk of developing PGD, it does not appear to be associated with survival after PGD. Future work should focus on PGD prevention rather than PGD management in patients with obesity.

Background: Tacrolimus therapy is standard of care for immunosuppression after lung transplantation. However, tacrolimus exposure variability during the early postoperative period may contribute to poor outcomes in this population. Few studies have examined tacrolimus pharmacokinetics (PK) during this high-risk period. Methods: We conducted a retrospective pharmacokinetic study in lung transplant recipients at the University of Pennsylvania who were enrolled in the Lung Transplant Outcomes Group cohort. We used nonlinear mixed-effects regression to derive a population PK model in 270 patients and examined validity in a separate cohort of 114 patients. Covariates were examined with univariate analysis and a multivariable model was developed using forward and backward stepwise selection. The performance of the final model in the validation cohort was examined with calculation of prediction error (PE). Results: We developed a 1-compartment base model with a fixed rate absorption constant. Covariates improving model fit were postoperative day, hematocrit, transplant type, CYP3A5 genotype, weight, and exposure to cytochrome p450 enzyme (CYP) inhibitor drugs. The strongest predictor of tacrolimus clearance was postoperative day, with median predicted clearance increasing more than 3-fold over the 14-day study period. In the validation cohort, the final model showed a mean PE of 36.4% (95% confidence interval 30.8%-41.9%) and a median PE of 7.2% (interquartile range −29.3% to 70.53%). Conclusions: Tacrolimus clearance is highly dynamic during the early postlung transplant period. Population PK models that include lung-transplant–specific covariates may enable precision dosing algorithms that account for this highly dynamic clearance. Future multicenters studies including a broader set of covariates are warranted.

Objective: To assess the effect of intraoperative cryoablation on postoperative patient-reported pain, opioid use, and clinical outcomes in lung transplantation. Methods: We performed a single-center retrospective cohort study of adult lung transplant recipients from August 2017 to September 2018. We compared outcomes of patients who received intraoperative cryoablation of the intercostal nerves with those who did not. Primary outcomes were postoperative patient-reported pain scores and opioid use. Secondary outcomes included postoperative sedation and agitation levels and perioperative outcomes. Data were abstracted from patients' electronic health records. Results: Of the 102 patients transplanted, 45 received intraoperative cryoablation (intervention group) and 57 received the standard of care, which did not include intercostal or serratus blocks or immediate postoperative epidural placement (control group). The intervention group had significantly lower median and maximum postoperative pain scores at days 3 and 7 and significantly lower oral opioid use at days 3, 7, and 14 compared with the control group. Chronic opioid use at 3 and 6 months' posttransplant was lower in the intervention group. Differences in perioperative outcomes, including length of mechanical ventilation, sedation and agitation levels, and hospital stay, were not clinically meaningful. Survival at 30 days and 1 year was superior in the intervention compared with the control group. Conclusions: Findings suggest that use of intraoperative cryoablation is an effective approach for treating pain and reducing opioid use in patients who undergo lung transplant, but a randomized study across multiple institutions is needed to confirm these findings.

Fournier’s gangrene is a rapidly progressive necrotizing fasciitis of the perineum and external genital organs that is uncommon in the pediatric age group. We present a case report of a 17-year-old obese male with comorbidities of type II diabetes, hypertension, and tobacco use, who presented to the hospital with vague systemic symptoms and pain in the gluteal area. On examination, he was febrile and had erythema and induration of his left scrotum, perineum, and gluteal region. Imaging obtained due to rapid progression of symptoms was consistent with a diagnosis of Fournier’s gangrene. He was managed with broad-spectrum antibiotics, aggressive surgical debridement, and a diverting colostomy. This case brings to light to a classically adult diagnosis that should be considered in adolescents, especially given the rising numbers of risk factors in this population, such as diabetes, obesity, and smoking.

Undiagnosed concussions increase risk of additional injuries and can prolong recovery. Because of the difficulties recognizing concussive symptoms, concussion education must specifically target improving athlete concussion reporting. Many concussion education programs are designed without significant input from athletes, resulting in a less enjoyable athlete experience, with potential implications on program efficacy. Athlete enjoyment of previous concussion education programs moderates the improvement in concussion-reporting intention after experiencing the research version of CrashCourse (CC) concussion education. Prospective cohort study. Level of evidence: Level IV. Quantitative assessment utilizing ANOVA with moderation analysis of 173 male high school football players, aged 13 to 17, who completed baseline assessments of concussion knowledge, concussion reporting, and attitudes about prior educational interventions. Athletes were subsequently shown CC, before a follow-up assessment was administered assessing the same domains. At baseline, only 58.5% of athletes reported that they enjoyed their previous concussion education. After CC, athletes were significantly more likely to endorse that they would report a suspected concussion (from 69.3% of athletes to 85.6%; P

A group of gene mutations has been identified to be strongly associated with secondary acute myeloid leukemias (AML) arising from prior myeloid neoplasms. The International Consensus Classification (ICC) and proposed 5th edition of the World Health Organization (WHO) classification differ by inclusion of RUNX1 . A recent study suggested that having two or more secondary mutations is associated with a particularly poor prognosis. In a study of 294 de novo AML patients, we found that patients with at least one ICC-defined secondary mutation had shorter survival when compared to those without secondary mutations, and ICC/WHO groups of two or more mutations did not predict for worse outcomes., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Therapy-related myeloid neoplasms (t-MN) are a heterogeneous group of aggressive myeloid neoplasms that arise following exposure to various cytotoxic therapeutic agents and/or ionizing radiation for treatment of prior non-myeloid malignancy or autoimmune disease. Each therapeutic group has been associated with varying latency intervals from the time of therapy exposure to onset of t-MN, as well as certain recurrent genetic alterations. This review will focus on the molecular genetic alterations that have been described in t-MNs, as well as recent updates regarding diagnostic classification., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Therapy-related acute myeloid leukemias (t-AML) are a heterogenous group of aggressive neoplasms that arise following exposure to cytotoxic chemotherapy and/or ionizing radiation. Many therapy-related myeloid neoplasms (t-MN) are associated with distinct chromosomal aberrations and/or TP53 alterations, but little is known about the clinicopathologic and molecular features of normal karyotype t-AML (NK-t-AML) and whether this t-MN subtype is distinctly different from NK de novo AML (NK-dn-AML)., Methods: This multi-institutional study by the Bone Marrow Pathology Group retrospectively evaluated clinicopathologic and molecular characteristics of 335 patients with NK-AML, comprising 105 t-AML and 230 dn-AML cases., Results: Patients with t-AML compared with dn-AML exhibit significantly shorter overall survival (OS; median months: 17.6 v 44.2; P < .0001) and relapse-free survival (RFS; median months: 9.1 v 19.2; P = .0018). Frequency of NPM1 , FLT3 , KRAS , and GATA2 mutations were significantly different in NK-t-AML compared with NK-dn-AML ( NPM1 35% v 49%; P = .0493; FLT3 23% v 36%; P = 0494; KRAS 12% v 5%; P = .0465; GATA2 9% v 2% P = .0105), while TP53 mutations were rare. Patients with t-AML more often stratified into intermediate or adverse 2017 ELN genetic risk groups. Favorable ELN risk predicted favorable OS (hazard ratio [HR], 0.4056; 95% CI, 0 to 0.866; P = .020) and RFS (HR, 0.355; 95% CI, 0 to 0.746; P = .006). Among all patients with NK-AML, stem-cell transplant and favorable ELN risk both significantly affected RFS, while therapy-relatedness and age had a borderline significant impact on OS (HR, 1.355; 95% CI, 0.975 to 1.882; P = .070)., Conclusion: To our knowledge, this is the largest study to date to comprehensively evaluate NK-t-AML and provides a framework that may inform our understanding of NK-t-AML disease biology and could potentially help guide therapeutic management and improved disease classification in t-MNs that lack cytogenetic aberrations.

This multi-institutional study retrospectively evaluated clinicopathologic and genetic characteristics in 351 patients with core-binding-factor acute myeloid leukemia (CBF-AML), comprising 69 therapy-related (t-CBF-AML) and 282 de novo cases. The T-CBF-AML patients were older, had lower WBC counts, and slightly higher hemoglobin than patients with de novo disease. Secondary cytogenetic abnormalities were more frequent in patients with de novo disease than t-CBF-AML (57.1% vs 41.1%, P = .026). Patients with secondary cytogenetic abnormalities had longer overall survival (OS) than those without abnormalities (median 190 vs 87 months, P = .021); trisomy 8, trisomy 22, and loss of the X or Y chromosome were associated with longer OS. In the 165 cases performed of targeted gene sequencing, pathogenic mutations were detected in 75.7% of cases, and were more frequent in de novo than in therapy-related disease (P = .013). Mutations were found in N/KRAS (37.0%), FLT3 (27.8%), KIT (17.2%), TET2 (4.9%), and ASXL1 (3.9%). The TET2 mutations were associated with shorter OS (P = .012) while N/KRAS mutation was associated with longer OS in t(8;21) AML patients (P = .001). The KIT mutation did not show prognostic significance in this cohort. Although they received similar therapy, t-CBF-AML patients had shorter OS than de novo patients (median 69 vs 190 months, P = .038). In multivariate analysis of all patients, older age and absence of any secondary cytogenetic abnormalities were significant predictors of shorter OS. Among the t-CBF-AML subset, age and hemoglobin were significant on multivariate analysis. This study demonstrated that although de novo and t-CBF-AML patients share many features, t-CBF-AML patients have worse clinical outcome than de novo patients., (© 2020 Wiley Periodicals, Inc.)

Purpose: We retrospectively investigated the Genomic Prostate Score® assay in clinical practice at an urban tertiary care academic center., Materials and Methods: We reviewed all Genomic Prostate Score results acquired during a 3-year period. Changes in patient NCCN® (National Comprehensive Cancer Network®) risk group, including very low, low, intermediate or high risk, and ultimate management decisions were recorded., Results: Genomic Prostate Score risk stratification was performed in 134 men. According to the NCCN Guidelines®, 31 of the 134 men (23.1%) were at very low risk, 45 (33.6%) were at low risk and 58 (43.3%) were at intermediate risk. After adding the score the risk group changed in 32 of 134 patients (23.9%). The risk group did not change in the 31 men at very low risk. However, in the low risk group the risk changed in 19 of the 45 men (42.2%), including in 15 to very low and in 4 to intermediate risk. Also, in the intermediate risk group the risk changed in 13 of the 58 men (22.4%), including to low in 12 and to high risk in 1. Nine of the 15 men (60%) in whom risk changed from low to very low elected active surveillance. Nine of the 12 patients (75%) at intermediate risk in whom risk changed to low risk elected active surveillance, 2 (16.7%) elected definitive therapy and in 1 (8.3%) the choice was unknown. Of the 45 men at intermediate risk in whom risk was unchanged 28 (62.2%) elected definitive therapy, 12 (26.0%) elected active surveillance and in 5 (11.1%) the choice was unknown. Of the 4 men upgraded from low to intermediate risk after adding the genomic prostate score 2 elected definitive therapy and 2 chose active surveillance., Conclusions: The Genomic Prostate Score has limited clinical usefulness in patients at very low risk since the NCCN risk group did not change. While it may be more useful for men at low and intermediate risk, for 32 (31%) of whose risk group was reclassified, clinical management decisions did not always appear to reflect these changes.

BRAF p.V600E mutations are detected in greater than 50% of pediatric Langerhans cell histiocytosis (LCH) lesions. However, the use of mutation-specific BRAF V600E immunohistochemistry (IHC) as a surrogate for molecular testing in pediatric LCH is unknown. We tested the mutation-specific BRAF V600E monoclonal antibody (clone VE1) in formalin-fixed, paraffin-embedded LCH samples from 26 pediatric patients (14 males and 12 females, ages 7 mo-17 y) using allele-specific real-time polymerase chain reaction (PCR) with a limit of detection of 0.5% as the comparative gold standard. BRAF VE1 staining was scored for both intensity (0-3+) and percentage of immunoreactive tumor cells (0%-100%). BRAF VE1 immunoreactivity was determined using both lenient (≥1+, ≥1%) and stringent (≥2+, ≥10%) scoring criteria. Using lenient-scoring criteria, we found that the sensitivity and specificity of IHC compared with allele-specific real-time PCR were 100.0% and 18.2%, respectively. The poor specificity of lenient IHC analysis was attributable to weak, 1+ staining in both BRAF-mutated and wild-type LCH. Using stringent-scoring criteria, we found that specificity improved to 100.0% at the expense of sensitivity that decreased to 80.0%. Stringent scoring generated 3 false-negative results, but in all cases, neoplastic tissue comprised less than 5% of the stained section and/or the specimen was decalcified. In conclusion, highly sensitive molecular assays remain the gold standard for BRAF mutation analysis in LCH paraffin-embedded lesions. To avoid false-positive results, unequivocal VE1 staining of 2+ intensity in greater than or equal to 10% neoplastic histiocytes is required. However, negative VE1 results require additional studies to exclude false-negatives, and stringent-scoring criteria may not be optimal for scant or decalcified specimens., (Copyright © 2017 John Wiley & Sons, Ltd.)

Non-aqueous capillary electrophoresis (NACE) may provide a selectivity enhancement in separations since the analyte dissociation constants (pKa) in organic media are different from those in aqueous solutions. In this work, we have studied the inversion in mobility order observed in the separation of tertiary (imipramine (IMI) and amitryptiline (AMI)) and secondary amines (desipramine (DES) and nortryptiline (NOR)) in water, methanol, and acetonitrile. We have determined the pKa values in those solvents and the variation of dissociation constants with the temperature. From these data, and applying the Van't Hoff equation, we have calculated the thermodynamic parameters deltaH and deltaS. The pKa values found in methanol for DES, NOR, IMI, and AMI were 10.80, 10.79, 10.38, and 10.33, respectively. On the other hand, in acetonitrile an opposite relation was found since the values were 20.60, 20.67, 20.74, and 20.81 for DES, NOR, IMI, and AMI. This is the reason why a migration order inversion is observed in NACE for these solvents. The thermodynamic parameters were evaluated and presented a tendency that can be correlated with that observed for pKa values.