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Background: Body mass index (BMI) both before and after heart transplant (HT) is used to risk stratify in adult HT. Single-center studies identify BMI as a potential predictor of outcome after HT in children; large-scale analyses in pediatric HT have not been performed. Methods: The ISHLT pediatric heart transplant registry was queried for HT recipients >2 years old between 1996 and 2006 with data for BMI percentile (BMI%ile) at HT. Survival and morbidity rates post-HT were compared between BMI%ile cohorts defined as: wasted, <5th BMI%ile; normal, 5th to 95th BMI%ile; and obese, >95th BMI%ile at HT. Results: Data from 2,333 pediatric HT patients were available for analysis. Incidence of abnormal BMI%ile at HT was: wasted = 23% and obese = 8%. Wasting and obesity were similar in patients with congenital or cardiomyopathic diagnoses. Wasted or obese patients at HT did not differ from patients with normal BMI in survival on Kaplan–Meier or multivariate analyses. There were no significant differences in pre-, peri- or post-operative adverse events between patients with wasting or obesity and those with normal BMI%ile at HT. Conclusions: In contrast to adults, abnormal body mass at time of transplant was not associated with decreased survival in pediatric HT recipients. Potential pediatric transplant candidates should not be excluded based on the perception that wasting or obesity will increase the risk of adverse outcomes. [Copyright &y& Elsevier]

Histone lysine methyltransferase NSD2 (WHSC1/MMSET) is overexpressed frequently in multiple myeloma due to the t(4;14) translocation associated with 15% to 20% of cases of this disease. NSD2 has been found to be involved in myelomagenesis, suggesting it may offer a novel therapeutic target. Here we show that NSD2 methyltransferase activity is crucial for clonogenicity, adherence, and proliferation of multiple myeloma cells on bone marrow stroma in vitro and that NSD2 is required for tumorigenesis of t(4;14)+ but not t(4;14)- multiple myeloma cells in vivo. The PHD domains in NSD2 were important for its cellular activity and biological function through recruiting NSD2 to its oncogenic target genes and driving their transcriptional activation. By strengthening its disease linkage and deepening insights into its mechanism of action, this study provides a strategy to therapeutically target NSD2 in multiple myeloma patients with a t(4;14) translocation. [ABSTRACT FROM AUTHOR]

OBJECTIVE To examine interactions between demographic, pain, urinary, psychological and environmental predictors of quality of life (QOL) in men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). PATIENTS AND METHODS In all, 253 men previously enrolled in the National Institutes of Health Chronic Prostatitis Cohort study in North American tertiary-care clinical centres (six in the USA and one in Canada) self-reported with validated instruments, including the QOL subscales of the Short Form-12 (physical, SF12-PCS; and mental, SF12-MCS), demographics, urinary symptoms, depression, current pain, pain coping, ‘catastrophising’ (catastrophic thinking about pain), pain control, social support and solicitous responses from a partner. Data were collected through a one-time survey. Covariates determined to be significant were entered into a multivariable regression model predicting SF12-PCS and SF12-MCS. RESULTS Adjusting for covariates, regression models showed that poorer SF12-PCS scores were predicted by worse urinary function ( P < 0.001) and increased use of pain-contingent resting as a coping strategy ( P = 0.026). Further, poorer SF12-MCS scores were predicted by greater pain catastrophizing ( P = 0.002) and lower perceptions of social support ( P< 0.001). In separate follow-up analyses, helplessness was the significant catastrophizing subscale ( P < 0.001), while support from family and friends were the significant social support subscales ( P = 0.002 and <0.001). CONCLUSIONS These data suggest that specific coping and environmental factors (i.e. catastrophizing, pain-contingent resting, social support) are significant in understanding how patients with CP/CPPS adjust. These data can be used to develop specific cognitive-behavioural programmes for men with CP/CPPS who are refractory to standard medical therapy. [ABSTRACT FROM AUTHOR]

We report a personalized tumor-informed technology, Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (PROPHET) using deep sequencing of 50 patient-specific variants to detect molecular residual disease (MRD) with a limit of detection of 0.004%. PROPHET and state-of-the-art fixed-panel assays were applied to 760 plasma samples from 181 prospectively enrolled early stage non-small cell lung cancer patients. PROPHET shows higher sensitivity of 45% at baseline with circulating tumor DNA (ctDNA). It outperforms fixed-panel assays in prognostic analysis and demonstrates a median lead-time of 299 days to radiologically confirmed recurrence. Personalized non-canonical variants account for 98.2% with prognostic effects similar to canonical variants. The proposed tumor-node-metastasis-blood (TNMB) classification surpasses TNM staging for prognostic prediction at the decision point of adjuvant treatment. PROPHET shows potential to evaluate the effect of adjuvant therapy and serve as an arbiter of the equivocal radiological diagnosis. These findings highlight the potential advantages of personalized cancer techniques in MRD detection. [Display omitted] • PROPHET outperforms fixed-panel MRD assays in head-to-head comparison in NSCLC • TNMB stage, integrating landmark ctDNA MRD and TNM, improves prognosis prediction • PROPHET illustrates a median lead time of 299 days to radiological recurrence • Post-relapse ctDNA status facilitates decision on later lines of treatment Chen et al. introduce personalized Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (PROPHET) for detecting molecular residual disease (MRD) in NSCLC, featuring a notably low limit of detection (LOD). It exhibits elevated sensitivity and extended lead time than radiologically confirmed recurrence. It also facilitates prognostic accuracy and postoperative treatment evaluation. [ABSTRACT FROM AUTHOR]

Highlights • De novo T790 M is significantly more likely to coexist with EGFR L858R than with 19del in NSCLC. • The relative allele frequency of T790 M mutation may serve as a predictive biomarker for treatment response to EGFR-TKIs. • Osimertinib is potentially an effective drug for the treatment of advanced NSCLC with de novo T790 M. Abstract Introduction De novo T790 M mutation in EGFR has been reported in various studies. However, its genetic characteristics and association with EGFR tyrosine kinase inhibitors (TKIs) treatment response remain poorly studied. Methods We retrospectively screened 1228 consecutive non-small cell lung cancer (NSCLC) patients and identified 29 de novo T790 M carriers. Capture-based targeted deep sequencing was conducted on 21 eligible samples as well as a 20-sample cohort with acquired T790 M mutation after EGFR-TKIs treatment. We characterized and compared their mutational profiles using a panel consisting of 168 lung cancer-related genes. Results De novo T790 M mutation was found in 5.8% of the TKI-naive patients harboring EGFR activating mutations. Among the de novo T790 M samples, T790 M was significantly more likely to coexist with L858R than with 19del (76.2% vs. 23.8%) compared to the acquired T790 M cohort (30.0% vs. 70.0%) (p = 0.003). These two groups harbored different concurrent gene mutations as well. Notably, the ratio of allele frequency (AF) of the T790 M mutation to the EGFR activating mutation in each patient, defined as the T790 M relative AF (RAF), differed significantly between the de novo and acquired T790 M cohorts (86.1% vs. 22.3%, p < 0.0001). Among the 10 patients with de novo T790 M who received the 1st-generation EGFR-TKIs treatment, interestingly, the only one who achieved partial response (PR) had the lowest T790 M RAF of 19.7%. The other 9 patients with an average T790 M RAF of 85.9% (±22.6%) achieved stable disease or progressive disease as the best response. One patient, treated with osimertinib after erlotinib failure, achieved PR and the therapeutic response sustained for more than 14.5 months. Conclusion The molecular characteristics of de novo T790 M carriers differ distinctly from acquired T790 M carriers. The RAF of EGFR T790 M mutation may serve as a predictive biomarker for treatment response to EGFR-TKIs. Osimertinib is potentially an effective drug for the treatment of NSCLC with de novo T790 M. [ABSTRACT FROM AUTHOR]

Introduction Anaplastic lymphoma kinase ( ALK ) rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). NSCLCs with ALK -rearrangement can be effectively treated with crizotinib. However, magnitude and duration of responses are found to be heterogeneous. This study explored the clinical efficacy of crizotinib in different ALK variants. Methods Among 96 ALK -rearrangement patients treated with crizotinib, 60 patients were identified with tumor specimens that could be evaluated by next-generation sequencing (NGS). We retrospectively evaluated the efficacy of crizotinib in different ALK variants. Results The median Progression-free survival (PFS) of the 96 ALK -rearrangement patients was 14.17 months. Among the 60 patients with NGS results, the most frequent variants were variant 3a/b (33.33%), variant 1 (23.33%) and variant 2 (15.00%). The percentage of rare EML4 - ALK variants and non EML4 - ALK variants were 10.00% and 18.33%. Survival analysis showed that patients with variant 2 appeared to have longer PFS than others (P = .021); also, patients with TP53 mutation seemed to have an unfavorable PFS than those with TP53 wild-type with a borderline p value (P = .068). After adjusting for other baseline characteristics, EML4 - ALK variant 2 was identified as an important factor for a better PFS of crizotinib. We also found that patients with variant 3a/b had shorter duration of response to crizotinib; however, no significant difference of PFS was observed between the PFS of variant3a/b and non-v3 EML4 - ALK variants. Conclusions Our results indicate prolonged PFS in patients with EML4 - ALK variant 2. [ABSTRACT FROM AUTHOR]

Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses. [ABSTRACT FROM AUTHOR]

Ezh2 (Enhancer of zeste homolog 2) protein is the enzymatic component of the Polycomb repressive complex 2 (PRC2), which represses gene expression by methylating lysine 27 of histone H3 (H3K27) and regulates cell proliferation and differentiation during embryonic development. Recently, hot-spot mutations of Ezh2 were identified in diffused large B-cell lymphomas and follicular lymphomas. To investigate if tumor growth is dependent on the enzymatic activity of Ezh2, we developed a potent and selective small molecule inhibitor, EI1, which inhibits the enzymatic activity of Ezh2 through direct binding to the enzyme and competing with the methyl group donor S-Adenosyl methionine. EI1-treated cells exhibit genome-wide loss of H3K27 methylation and activation of PRC2 target genes. Furthermore, inhibition of Ezh2 by EI1 in diffused large B-cell lymphomas cells carrying the Y641 mutations results in decreased proliferation, cell cycle arrest, and apoptosis. These results provide strong validation of Ezh2 as a potential therapeutic target for the treatment of cancer. [ABSTRACT FROM AUTHOR]

The article presents a clinical trial which determines whether pregabalin therapy reduces symptoms in men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Men who were recruited from ten tertiary clinical centers aged at least 18 years with reported symptoms of discomfort or pain in the pelvic region were eligible to participate in the study. The article mentions that the six weeks of treatment with an increasing dosage of pregabalin did not show any clinically significant decrease in CP/CPPS condition as compared with placebo therapy.

Background: In men with chronic prostatitis–chronic pelvic pain syndrome, treatment with alpha-adrenergic receptor blockers early in the course of the disorder has been reported to be effective in some, but not all, relatively small randomized trials. Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of alfuzosin, an alpha-adrenergic receptor blocker, in reducing symptoms in men with chronic prostatitis–chronic pelvic pain syndrome. Participation in the study required diagnosis of the condition within the preceding 2 years and no previous treatment with an alpha-adrenergic receptor blocker. Men were randomly assigned to treatment for 12 weeks with either 10 mg of alfuzosin per day or placebo. The primary outcome was a reduction of at least 4 points (from baseline to 12 weeks) in the score on the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) (range, 0 to 43; higher scores indicate more severe symptoms). A 4-point decrease is the minimal clinically significant difference in the score. Results: A total of 272 eligible participants underwent randomization, and in both study groups, 49.3% of participants had a decrease of at least 4 points in their total NIH-CPSI score (rate difference associated with alfuzosin, 0.1%; 95% confidence interval, −11.2 to 11.0; P=0.99). In addition, a global response assessment showed similar response rates at 12 weeks: 33.6% in the placebo group and 34.8% in the alfuzosin group (P=0.90). The rates of adverse events in the two groups were also similar. Conclusions: Our findings do not support the use of alfuzosin to reduce the symptoms of chronic prostatitis–chronic pelvic pain syndrome in men who have not received prior treatment with an alpha-blocker. (ClinicalTrials.gov number, NCT00103402.) N Engl J Med 2008;359:2663-73. [ABSTRACT FROM AUTHOR]

The performance of next generation sequencing in profiling somatic mutations from plasma samples, especially in early‐stage cancer, is limited by its sensitivity due to the extremely low amount of cell‐free DNA (cfDNA). Polymerase‐chain reaction amplification of limited amounts of DNA often results in product redundancy and the amplification of contaminant DNA. Numerous methods have been developed to detect and quantify ultralow frequency mutations. In this study, the potential of tagging each DNA molecule with a unique molecular identifier (UMI) is explored to detect ultralow frequency mutations in early‐stage lung cancer patients. Paired tissue and blood samples from 32 patients with early‐stage (stage IA‐IIB) nonsmall cell lung cancer are sequenced using a panel consisting of 168 cancer‐related genes. Collectively, 93.8% of tissue samples and 59.4% of plasma samples have mutations detected. The concordance rates are acceptable for all patients except for stage IA. Notably, mutations at an alleleic frequency as low as 0.1% are detected in UMI‐tagged cfDNA samples. Moreover, patients with nonadenocarcinoma histology have a significantly higher detection rate than patients with adenocarcinoma (92.9% vs 33.3%, P = 0.002). The study demonstrates the potential of UMI in early detection of lung cancer from plasma samples. [ABSTRACT FROM AUTHOR]

Background: Detection of circulating tumor DNA (ctDNA) is a promising method for postoperative surveillance of lung cancer. However, relatively low positive rate in early stage patients restricts its application. Aberrant methylation of ctDNA can be detected in blood samples, and may provide a more sensitive method. This study is designed to systematically evaluate and compare the detection of aberrant methylation and mutations in ctDNA among surgical non-small cell lung cancer (NSCLC) patients, aiming to investigate the feasibility of ctDNA detection as a means of lung cancer surveillance.Methods: This is a prospective observational study. Consecutive surgical NSCLC patients will be recruited. Blood samples will be collected both before and after surgery (during the follow-up period), while matching tumor tissues and tumor-adjacent normal tissues will be collected during surgery. Quantitative analysis of aberrant methylation and mutations of ctDNA will be conducted in combination with a three-year follow-up data.Discussion: This is the first registered prospective study designed to investigate the feasibility of ctDNA methylation detection as a means of postoperative lung cancer surveillance. We will systematically evaluate and compare the quantitative detection of ctDNA mutations and ctDNA methylation in surgical NSCLC patients, combining with the follow-up information. By integrating genetic and epigenetic information of ctDNA, more effective strategies for postoperative surveillance may be defined.Trial Registration: This study (MEDAL, MEthylation based Dynamic Analysis for Lung cancer) was registered on ClinicalTrials.gov on 08/05/2018 (NCT03634826; Pre-results). [ABSTRACT FROM AUTHOR]

SETDB1 is a histone H3K9 methyltransferase that has a critical role in early development. It is located within a melanoma susceptibility locus and facilitates melanoma formation. However, the mechanism by which SETDB1 regulates tumorigenesis remains unknown. Here we report the molecular interplay between SETDB1 and the well-known hotspot gain-of-function (GOF) TP53 R249S mutation. We show that in hepatocellular carcinoma (HCC) SETDB1 is overexpressed with moderate copy number gain, and GOF TP53 mutations including R249S associate with this overexpression. Inactivation of SETDB1 in HCC cell lines bearing the R249S mutation suppresses cell growth. The TP53 mutation status renders cancer cells dependent on SETDB1. Moreover, SETDB1 forms a complex with p53 and catalyses p53K370 di-methylation. SETDB1 attenuation reduces the p53K370me2 level, which subsequently leads to increased recognition and degradation of p53 by MDM2. Together, we provide both genetic and biochemical evidence for a mechanism by which SETDB1 regulates cancer cell growth via methylation of p53. [ABSTRACT FROM AUTHOR]