RATIONALE:Common and rare variants that are associated with the risk of developing idiopathic pulmonary fibrosis (IPF) have been identified predominantly in European ancestry populations. OBJECTIVES:To better understand the genetic variants that contribute to IPF in individuals with Asian ancestry, we conducted a genome-wide association study of IPF in East Asian populations. METHODS:We included 1026 patients with IPF and compared them to 1723 unaffected controls of Japanese and Korean ancestry. Genome-wide association analysis was conducted in the Japanese and Korean ancestry cohorts separately and combined using meta-analysis. Restricted maximum likelihood was used to estimate the SNP-based heritability and local ancestry of chromosome 11 was inferred for each subject. MEASUREMENTS AND MAIN RESULTS:We identified loci on chromosomes 4 (FAM13A; rs7690839), 5 (TERT; rs7734992), 6 (DSP; rs2076295), and 11 (MUC5B; rs35705950) that were significantly associated with risk of IPF. Importantly, the sentinel variants in each of these loci are the same as, or in strong linkage disequilibrium with, the risk variants that have been observed in studies of European ancestry populations. In aggregate, common variants (not including the MUC5B promoter variant) account for approximately 25% of the risk of developing IPF in these East Asian ancestry cohorts. Moreover, local ancestry analysis indicates that the presence of MUC5B promoter variant in the East Asian population is not a result of admixture with European ancestry populations. CONCLUSIONS:We conclude that the IPF risk loci in East Asian populations are shared with those of European ancestry populations, although their risk allele frequencies and effect sizes differ. These findings indicate shared genetic risk factors of IPF across ancestries.

Introduction Interstitial lung abnormalities (ILAs) are early imaging markers of interstitial lung disease and pulmonary fibrosis. Occupational exposures to fumes and dusts are widespread and may especially impact individuals with familial susceptibility. We aimed to investigate the associations between occupational inhaled exposures and the risk of ILAs in individuals with potential familial susceptibility to pulmonary fibrosis.Methods We analysed data from 266 relatives of patients with familial or sporadic pulmonary fibrosis, enrolled in two cohorts: the Clinical Genetics and Screening for Pulmonary Fibrosis (n=184) and the Genetics of Pulmonary Fibrosis Study (n=82). Occupational exposures were determined through standardised questionnaires and categorised as vehicle fumes, non-vehicle fumes, mineral dusts, organic dusts, any fumes, any dusts or any dusts or fumes. Risk of ILAs was evaluated using modified Poisson models adjusted for age, sex and smoking status.Results The mean age of participants was 59.7 years and 23.7% had ILAs. Any occupational inhalational exposure was more common among participants with ILAs (27.0% for any fume) than among those without ILAs (16.7% for any fume). Exposure to any fumes, encompassing both vehicle and non-vehicle fumes, was associated with increased risk of ILAs (risk ratio (RR): 1.59, 95% CI 1.02 to 2.49). Similar positive but non-significant associations were observed for other exposures, including organic dusts, vehicle fumes, non-vehicle fumes and composite exposure.Discussion Occupational inhaled fume exposure is associated with higher risk of ILAs in individuals with potential familial susceptibility to pulmonary fibrosis. This highlights the potential value of considering occupational exposures in screening at-risk populations.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex and heterogeneous disease. Given this, we reasoned that differences in genetic profiles may be associated with unique clinical and radiologic features. Computational image analysis, sometimes referred to as radiomics, provides objective, quantitative assessments of radiologic features in subjects with pulmonary fibrosis. Objectives: To determine if the genetic risk profile of patients with IPF identifies unique computational imaging phenotypes. Methods: Participants with IPF were included in this study if they had genotype data and computed tomography (CT) scans of the chest available for computational image analysis. The extent of lung fibrosis and the likelihood of a usual interstitial pneumonia (UIP) pattern were scored automatically using two separate, previously validated deep learning techniques for CT analysis. UIP pattern was also classified visually by radiologists according to established criteria. Results: Among 329 participants with IPF, MUC5B and ZKSCAN1 were independently associated with the deep learning-based UIP score. None of the common variants were associated with fibrosis extent by computational imaging. We did not find an association between MUC5B or ZKSCAN1 and visually assessed UIP pattern. Conclusions: Select genetic variants are associated with computer-based classification of UIP on CT in this IPF cohort. Analysis of radiologic features using deep learning may enhance our ability to identify important genotype-phenotype associations in fibrotic lung diseases.

Rational: Interstitial lung abnormalities (ILA) are increasingly recognized as early imaging markers of potential interstitial lung disease or pulmonary fibrosis (PF). Occupational exposures to inhaled agents, such as fumes and dusts, are common and may contribute to the development of these abnormalities. This study aims to evaluate the association between occupational inhaled exposures and the risk of ILA. Methods: The study included 266 participants from two cohorts: the Clinical Genetics and Screening for Pulmonary Fibrosis (CGS-PF) cohort based in Boston (184 participants) and the Genetics of Pulmonary Fibrosis Study (G-PFS) cohort based in Denver (82 participants) which included relatives of patients with both familial and sporadic PF (CGS-PF) or just sporadic PF (G-PFS). Occupational exposure histories were collected via questionnaire and categorized as exposure to vehicle fumes, non-vehicle fumes, mineral dusts, organic dusts, and combined categories such as any fumes (encompassing both vehicle and non-vehicle), any dusts (encompassing both mineral and organic), and any dusts or fumes. The risk of developing ILA was assessed using Poisson models, adjusting for potential confounders such as age, sex, and smoking status. Relative risk (RR) and 95% confidence intervals (CIs) were calculated to quantify associations. Results: The mean (SD) age of participants was 59.7 (10.0) years. Among participants, 16.9% had ever exposure to mineral dusts, 16.5% to organic dusts, 10.2% to vehicle fumes, and 15% to non-vehicle fumes. Additionally, 27.4% reported exposure to any dusts, 19.2% to any fumes, and 33.8% to either any fumes or dusts. Our analysis revealed that ever exposure to any fumes, encompassing both vehicle and non-vehicle fumes, was associated with a significantly increased risk of ILA, with a RR of 1.59 (95% CI: 1.02 – 2.49) (Figure 1). Similar positive trends were observed for other exposures, including mineral dusts, organic dusts, vehicle fumes, and non-vehicle fumes, as well as the composite exposure to any dusts or fumes; however, these did not reach statistical significance. Conclusion: The findings support the hypothesis that occupational exposure to inhaled fumes is associated with an increased risk of ILA. While the trend for other exposures did not meet significance thresholds, these results underscore the potential respiratory health risks associated with occupational inhaled exposures. Further research is warranted to elucidate these relationships, identify at higher-risk for exposure-associated ILA, and to inform protective occupational health policies. Keywords: Interstitial lung abnormalities, occupational exposure, fumes, dusts, pulmonary fibrosis, respiratory health

Rationale First-degree relatives of patients with pulmonary fibrosis (referred to here as relatives) are at high risk for interstitial lung abnormalities (ILA), highlighting the need for biomarkers for risk prediction. We aimed to identify blood proteins associated with and predictive of ILA among relatives of patients with pulmonary fibrosis. Methods Relatives enrolled in two independent cohorts had protein levels measured using an aptamer-based proteomic platform. ILA were assessed with computed tomography scans as per Fleischner Society recommendations. Protein associations with ILA were assessed using regression. Significant proteins were used with clinical variables to detect ILA. Results Of 237 relatives from two independent cohorts, 26% had ILA. Seven proteins were associated with ILA in the discovery cohort after false discovery rate adjustment, and all remained significant after adjusting for age, gender and smoking status. Six of the seven proteins were significantly associated in the validation cohort, including growth differentiation factor 15, surfactant protein D and surfactant protein B. In a multivariable model, six proteins combined with basic demographics in the discovery cohort had an area under the curve of 0.92 (0.88 in the validation cohort). Least absolute shrinkage and selection operator modelling identified three proteins and age as predictors, with an area under the curve of 0.89 in the validation cohort. When applied to the combined cohorts, this simple model would reduce the need for computed tomography imaging in one of every three relatives screened. Conclusion Peripheral blood proteins are associated with ILA in relatives of patients with pulmonary fibrosis and can be used to detect them. Our findings demonstrate the potential use of blood biomarkers in this high-risk group and suggest molecular targets for future investigation.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that is associated with common genetic variants, rare variants, and environmental risk factors. Genome-wide association studies of IPF have included more than 5,000 unique patients with IPF and identified approximately two dozen common genetic variants that are associated with the risk of disease. However, the vast majority of these patients were of European ancestry. Thus, the genetic risk of IPF in ancestries other than European populations is largely unknown. To better understand which genetic variants contribute to IPF in individuals with East Asian ancestry, we conducted a genome-wide association study of IPF in Japanese and Korean populations. Methods: Among individuals of Japanese and Korean ancestry, we genotyped 1,026 patients with IPF and compared them to 1,723 unaffected controls. Genome-wide association analyses were conducted in the Japanese and Korean cohorts separately, which were then combined using a fixed-effects meta-analysis. Ancestry deconvolution was used to infer the local ancestry of each region of chromosome 11 for each subject.Results: We identified loci on chromosomes 4 (FAM13A; rs7690839), 5 (TERT; rs7734992), 6 (DSP; rs2076295), and 11 (MUC5B; rs35705950) that were significantly associated with risk of IPF. Importantly, the sentinel genetic variant indentified in each of these loci are the same as, or in strong linkage disequilibrium with, the common risk variants observed in genetic association studies of European populations. Local ancestry analysis indicates that the presence of the MUC5B promoter variant in the East Asian population is not a result of admixture with European populations.Conclusion: We conclude that the IPF risk loci in East Asian populations are shared with those of European populations. However, some of the frequencies and effect sizes of the associated variants differ. These findings indicate a common etiology of IPF across ancestries that may experience different degrees of genetic selection.

PurposeThe purpose of this study was to evaluate the correlation between longitudinal monitoring of donor-derived cell free DNA (dd-cfDNA) in lung transplant recipients and a “gold standard” of existing tools (pulmonary function testing, radiographic imaging, laboratory and bronchoscopy data, clinical judgment) to assess allograft function.Methods24 consecutive transplant recipients were prospectively enrolled in this study measuring dd-cfDNA levels monthly in the first year after bilateral lung transplant. Blinded clinical adjudications were performed at the same timepoints to categorize allograft function as stable (FEV1 within 10% of prior value or when compared to best two averaged post-transplant values) or unstable. When deemed unstable, etiology of unstable graft function was elicited based on available clinical data. We then evaluated the association between dd-cfDNA and the clinical impression of allograft function using linear mixed models which adjusted for patient-level covariates and time since transplant.ResultsUnstable allografts were associated with 54.4% higher measures of dd-cfDNA, controlling for time since transplant and demographic covariates [adjusted mean ratio (aMR) = 1.54, 95% CI: 1.25–1.91]. Females tended to have higher measures of dd-cfDNA (aMR = 1.90 95%CI: 1.14–3.16). A two-fold increase in dd-cfDNA was associated with declines in FEV1 and FVC of 0.047 and 0.066 L, respectively, controlling for time since transplant and demographic covariates (slope: −0.047 95%CI: −0.076 to −0.019, and slope: −0.066 95%CI: −0.097 to −0.035, respectively). Discussion: Donor derived cell free DNA presents a potential additional minimally invasive clinical tool in lung transplant allograft monitoring within the first year of transplant, with unstable allografts correlating with higher dd-cfDNA values.

RATIONALE Relatives of patients with familial interstitial pneumonia are at increased risk for pulmonary fibrosis, and develop preclinical pulmonary fibrosis (PrePF). OBJECTIVES We defined the incidence and progression of new onset PrePF; its relationship to survival among first degree relatives of families with familial interstitial pneumonia. METHODS This is a cohort study of family members with familial interstitial pneumonia who were initially screened with a questionnaire and chest HRCT scan, and approximately 4 years later, the evaluation was repeated. 493 asymptomatic first-degree relatives of patients with familial interstitial pneumonia were evaluated at baseline, and 296 (60%) of the original subjects participated in subsequent evaluation. RESULTS The median interval between HRCTs was 3.9 years (IQ range 3.5-4.4). 252 subjects who agreed to repeat evaluation were originally determined not to have PrePF at baseline; 16 developed PrePF. A conservative estimate of the annual incidence of PrePF is 1,023 per 100, 000 person years (95% CI 511-1831). Of 44 subjects with PrePF at baseline, 38.4% subjects had worsening dyspnea compared to 15.4% of those without PrePF (P=0.002). Usual interstitial pneumonia (UIP) by HRCT (P< 0.0002) and baseline quantitative fibrosis score (P<0.001) are also associated with worsening dyspnea. PrePF at the initial screen is associated with decreased survival (P< 0.001). CONCLUSIONS The incidence of PrePF in this at-risk population is at least 100-fold higher than that reported for sporadic idiopathic pulmonary fibrosis (IPF). While PrePF and IPF represent distinct entities, our study demonstrates that PrePF, like IPF, is progressive and associated with decreased survival.

RATIONALE Idiopathic pulmonary fibrosis is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to non-genetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants genome-wide may contribute to the risk of IPF remains unknown. OBJECTIVES We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. METHODS As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ≤0.01) within genes or regions. We also identified individual variants that are influential within genes and estimated the heritability of IPF based on rare and common variants. MEASUREMENTS AND MAIN RESULTS Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP-heritability of IPF was estimated to be 32% (s.e. 3%). CONCLUSIONS Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

A 23-month-old male with known T-ALL had G-banding finding of monosomy 7 in 13 (59%) of the 22 metaphases analyzed from the bone marrow (BM). This, together with pathologic findings, confirmed the diagnosis of Juvenile myelomonocytic leukemia (infantile monosomy 7 syndrome). BM studies of microsatellites statues and tumor mutational burden showed no findings of therapy or clinical trial options. BM NGS identified gene alterations, including 1) ASXL1-G646fs*12 (NM_015338; 1934_1935insG), with uncertain significance in treatment; and 2) NOTCH1-Q2459fs*18(NM_017617; 73775delC); mutation of the gene commonly seen in T-ALL with a poor prognosis. Optical genome mapping studies of the BM confirmed monosomy 7 with 2 additional findings. 1). t(1;14)(q42.3;q22.1) had VAF=0.52, suggestive of germline translocation. The breakpoint at 14q22.1 involves the tumor suppressor gene GNG2; its expression was downregulated in multiple cancers (e.g. breast cancer, cervical squamous cell carcinoma, colonic adenocarcinoma). 2). ∼5 Kb deletion in PMS2 gene at 7p22.1 with VAF=0.73. Testing of gDNA from cultured fibroblasts confirmed germline heterozygous deletion of exons 9-10 in PMS2; indicative of an increased risk of autosomal dominant HNPCC (Lynch) syndrome and autosomal recessive mismatch repair deficiency syndrome. This case study emphasizes the significance of the application of comprehensive cytogenomic methods for studies of pediatric cancer cases with potential implications in germline alternations and management of both acquired and inherited disorders. A 23-month-old male with known T-ALL had G-banding finding of monosomy 7 in 13 (59%) of the 22 metaphases analyzed from the bone marrow (BM). This, together with pathologic findings, confirmed the diagnosis of Juvenile myelomonocytic leukemia (infantile monosomy 7 syndrome). BM studies of microsatellites statues and tumor mutational burden showed no findings of therapy or clinical trial options. BM NGS identified gene alterations, including 1) ASXL1-G646fs*12 (NM_015338; 1934_1935insG), with uncertain significance in treatment; and 2) NOTCH1-Q2459fs*18(NM_017617; 73775delC); mutation of the gene commonly seen in T-ALL with a poor prognosis. Optical genome mapping studies of the BM confirmed monosomy 7 with 2 additional findings. 1). t(1;14)(q42.3;q22.1) had VAF=0.52, suggestive of germline translocation. The breakpoint at 14q22.1 involves the tumor suppressor gene GNG2; its expression was downregulated in multiple cancers (e.g. breast cancer, cervical squamous cell carcinoma, colonic adenocarcinoma). 2). ∼5 Kb deletion in PMS2 gene at 7p22.1 with VAF=0.73. Testing of gDNA from cultured fibroblasts confirmed germline heterozygous deletion of exons 9-10 in PMS2; indicative of an increased risk of autosomal dominant HNPCC (Lynch) syndrome and autosomal recessive mismatch repair deficiency syndrome. This case study emphasizes the significance of the application of comprehensive cytogenomic methods for studies of pediatric cancer cases with potential implications in germline alternations and management of both acquired and inherited disorders.

Purpose To evaluate if therapeutic tacrolimus (TAC) levels in first 14 days impact early biopsy-proven acute rejection (BPAR) rates in lung transplant recipients (LTR) treated with basiliximab (BAS) induction therapy. Methods This was a retrospective review of all adults who underwent lung transplant between 01/01/2019 - 04/01/2021 at University of Colorado Hospital and received BAS induction. Study cohort stratified subjects diagnosed with ≥1 episode of BPAR at 6 months PT vs without BPAR. Primary outcome was the number of days with a therapeutic TAC level (≥ 8 ng/mL) during the first 2 weeks post-transplant. Mann Whitney U Test was used for continuous outcomes. Fisher's Exact Test was utilized for categorical outcomes. Results There were 93 LTR during the study period. 78 patients met inclusion for analysis, 26 had ≥1 incidence of BPAR ≤6 months PT while 52 patients did not. Baseline characteristics were similar between groups (Table 1). The primary outcome, median days with a therapeutic TAC trough during the first 14 days PT, did not differ significantly (p=0.924; Figure 1). Secondary outcomes also did not differ regarding the days to two consecutive therapeutic levels (No BPAR: 8 [IQR 6-12] vs BPAR: 8.5 [IQR 6-12]; P=0.941) or for patients with BPAR at 1 month vs those without (7 [IQR 4-9] vs 6 [4-8]; P=0.555). Conclusion In this cohort of LTR treated with BAS induction, there was no difference in the days with a therapeutic TAC level in the first 14 days between those with and without BPAR in the first 6 months PT. This suggests other factors may be more important in modulating early rejection risk.

Introduction Reactivation of latent mycobacterium tuberculosis (MTB) infection in lung transplant recipients is common, which is why pre-transplant screening is recommended to guide treatment. However, MTB transmission from a donor organ is much rarer and there is no consistent screening process of donors. We describe a consequence of this, a rare case of donor-derived disseminated MTB infection in a bilateral lung transplant (BLTx) recipient. Case Report A 61-year-old female three months post BLTx complicated by post-operative right lung torsion requiring pneumonectomy presented with a swollen and tender right index finger, tender nodules along her occiput, and a recurrent left sided pleural effusion, which was drained on presentation and culture negative. She improved initially with linezolid and ceftriaxone for presumed septic arthritis, however re-presented two weeks later with similar features, which prompted further evaluation. CT and subsequently MRI of the abdomen demonstrated multiple rim-enhancing liver lesions. A finger aspirate and liver biopsy were obtained that were both culture and smear positive for MTB. Sputum acid fast bacilli samples were negative, and she was started on quadruple therapy with rifabutin, isoniazid, pyrazinamide, and ethambutol with clinical improvement, including resolution of her culture-negative pleural effusion. We suspect that this was a donor-derived infection as the donor lived in an endemic region for many years and the recipient was latent TB negative pre-transplant. Summary Donor-derived MTB infection can be difficult to diagnosis due to the atypical way it can present, especially in patients who reside in non-endemic areas. As the world becomes more globalized, and access to lung transplant more accessible, we believe that more donor organs will come from individuals who have lived in endemic areas increasing the risk of donor-derived MTB infections making this an important diagnosis to consider.

Introduction There are no universal guidelines on screening donors for coccidioides. We describe a fatal case of coccidioides empyema from a donor previously residing in an endemic region. Case Report This is a 72 year old male, status post right single lung transplantation 3 weeks prior for chronic hypersensitivity pneumonitis, who presents to clinic with a productive cough. The donor was a 31 year old male with no medical history from the southern inland region of California. A chest X-ray in clinic demonstrated a right pleural effusion. He underwent thoracentesis and bronchoscopy on post-operative day (POD) 22. Pleural fluid was lymphocytic and exudative with negative cultures, and transbronchial biopsies showed mild acute cellular rejection. He was treated with pulse dose steroids. His symptoms worsened one week later when he was seen in the emergency department. Chest CT showed a large right loculated pleural effusion. The patient was started on broad spectrum antibiotics, and a thoracostomy tube was placed, demonstrating a neutrophil predominant exudate. Repeat chest CT showed the effusion extending through the chest wall, and an additional thoracostomy tube was placed. The patient became more hypoxemic requiring mechanical ventilation and VV-ECMO. Pleural cultures taken two-days prior demonstrated mold and the patient underwent irrigation with amphotericin in the operating room, along with intravenous amphotericin. Ultimately, the patient had multi-organ failure and cardiac arrest. Following his passing, pleural fluid cultures confirmed growth of Coccidioides immitis. Summary This case describes a patient with initial negative serologies to coccidioides and a donor from the southern inland region of California, where the incidence of coccidioides is increasing. Transmission of donor-derived coccidioides has been shown to be 43% within 30 days post-transplant, with a 29% mortality. Given the high mortality and treatment availability, screening donors in endemic areas with serologies may prevent post-transplant complications.

BACKGROUND:Invasive candidiasis (IC) is a substantial cause of morbidity and mortality among lung transplant recipients (LTRs). Postoperative factors include prolonged hospital stay, central lines, delayed chest closure, and dehiscence increase IC risk. Correspondingly, current guidelines propose targeted IC coverage early posttransplant with fluconazole or an echinocandin.METHODS:This retrospective analysis was performed on LTRs from January 2016 to January 2020 and evaluated effectiveness of a recent protocol utilizing perioperative anidulafungin for early IC prevention in addition to long-term triazole antifungal prophylaxis. Prior to this protocol, patients were primarily established on itraconazole prophylaxis alone. The primary endpoint was proven or probable IC within 90 days after transplant. Multivariable logistic regression modeling was used to assess risk factors for invasive fungal infection (IFI).RESULTS:Among 144 LTRs, there was a numerically lower incidence of IC in the protocol group, although not statistically significant (6% vs. 13%, p = 0.16). Incidence of proven or probable IFI was 7.5% in the protocol cohort and 19.5% in the pre-protocol cohort (p = 0.038). In multivariable analysis, when controlling for lung allocation score (OR 1.04, 95% CI 1.01-1.08), donor perioperative culture with fungal growth (OR 2.92, 95% CI 1.02-8.92), and dehiscence (OR 3.54, 95% CI 1.14-10.85), protocol cohort was not significantly associated with IFI (OR 0.41, 95% CI 0.12-1.23).CONCLUSIONS:To our knowledge, this is the first study investigating combination triazole/echinocandin use in the early post-lung transplant period. These findings demonstrate that in-hospital anidulafungin offers unclear benefit for early IC prevention when used in combination with triazole prophylaxis.

Purpose The purpose of this study is to determine to what extent longitudinal monitoring of donor-derived cell free DNA (dd-cfDNA) in lung transplant recipients can be used as a marker of lung injury and stability. Methods 21 out of a planned cohort of 24 subjects have been enrolled in this study measuring dd-cfDNA levels on a monthly basis in the first year after bilateral lung transplant. A blinded clinical adjudication is performed at the same timepoints to categorize allograft function as stable (FEV1 within 10% of prior value) or unstable. When deemed unstable, etiology of unstable graft function is elicited. We then evaluate correlation between dd-cfDNA results and the clinical impression of allograft function. Results At present, we have 5 months of data on 6 patients. Median dd-cfDNA levels in those with clinically stable graft function was 0.41 (IQR 0.6), and unstable graft function was 0.88 (IQR 1.0). There was little within patient variability with the exception of one subject who experienced an A2 rejection at month 3. There also did not appear to be a consistent increase in dd-cfDNA levels in the time directly before recording unstable graft function. Conclusion Decreasing dd-cfDNA values post-transplant may relate to delayed resolution of graft injury due to ischemia-reperfusion. The sample median dd-cfDNA value was 2X higher during adjudicated "unstable graft function" versus "stable". We speculate that serial trends in dd-cfDNA may detect unstable graft function with higher precision than a dd-cfDNA threshold. Further analysis with ongoing patient enrollment and utilization of the enriched dataset regarding etiology of "unstable graft function" will further refine the utility of this clinical tool.

Rhabdomyosarcoma is the most common sarcoma diagnosed in childhood and adolescence, arising from the bladder/prostate in only 5%-10% of cases. Treatment-induced cytodifferention of tumor cells into mature rhabdomyoblasts has been reported following chemoradiation and is thought to suggest a more favorable outcome. We report a case of embryonal rhabdomyosarcoma of the bladder/prostate that exhibited extensive cytodifferentiation with downregulation of myogenin and MyoD1 gene expression in rhabdomyoblasts following treatment with chemoradiation therapy. The downregulation of myogenin and MyoD1 expression in rhabdomyoblasts following chemoradiation treatment has not previously been described in the literature and its significant remains uncertain. (C) 2020 Elsevier Inc.