Citations

SummaryFimepinostat (CUDC‐907), a first‐in‐class oral small‐molecule inhibitor of histone deacetylase and phosphatidylinositol 3‐kinase, demonstrated efficacy in a phase 1 study of patients with relapsed/refractory (R/R) diffuse large and high‐grade B‐cell lymphomas (DLBCL/HGBL), particularly those with increased MYC protein expression and/orMYCgene rearrangement/copy number gain (MYC‐altered disease). Therefore, a phase 2 study of fimepinostat was conducted in this patient population with 66 eligible patients treated. The primary end‐point of overall response (OR) rate for patients with MYC‐IHC ≥40% (n = 46) was 15%. Subsequently, exploratory pooled analyses were performed including patients treated on both the phase 1 and 2 studies based upon the presence of MYC‐altered disease as well as a biomarker identified by Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER). For these patients with MYC‐altered disease (n = 63), the overall response (OR) rate was 22% with seven responding patients remaining on treatment for approximately two years or longer, and VIPER yielded a three‐protein biomarker classification with positive and negative predictive values of ≥85%. Prolonged durations of response were achieved by patients with MYC‐altered R/R DLBCL/HGBL treated with single‐agent fimepinostat. Combination therapies and/or biomarker‐based patient selection strategies may lead to higher response rates in future clinical trials.

Reactive intralymphovascular immunoblastic proliferations (ILVIPs) may mimic aggressive lymphomas and are rarely reported. Herein, we characterize the clinicopathologic features of 8 patients with ILVIPs. No patients had lymphadenopathy, hepatosplenomegaly, or other findings suggestive of lymphoma. The ILVIPs involved the small or large intestine (n=5) and appendix (n=3). Patients were evaluated for abdominal pain, suspected appendicitis, intestinal obstruction, diverticulitis, volvulus, or tumor resection. Histologic sections showed expanded lymphovascular spaces filled by intermediate to large immunoblasts, positive for CD38, CD43, CD45, CD79a, and MUM1/IRF4 in all cases tested. Five of 6 (83%) cases were positive for CD30. CD20 was weakly positive in a subset of cells in 2 (25%) cases, and PAX5 was weakly positive in 4 (50%) cases. The immunoblasts expressed polytypic light chains in all cases tested. In 1 case, a subset of immunoblasts expressed T-cell markers indicating the presence of a T-cell component. The immunoblasts were negative for ALK, BCL-2, BCL-6, CD10, CD56, CD138, and Epstein-Barr virus–encoded small RNA in all cases assessed. The proliferation index shown by Ki-67 was high with a median of 80%. In all 6 cases tested, the immunoblasts were shown within lymphatic channels highlighted by D2-40. In conclusion, ILVIPs can be rarely observed in patients with inflammatory or infectious conditions, especially in gastrointestinal tract surgical specimens. The immunoblasts are predominantly of B-lineage with a postgerminal center immunophenotype and are located within lymphatic channels. It is essential to distinguish reactive ILVIPs from aggressive lymphomas to avoid unnecessary therapy.

Abstract There is growing evidence showing that sex disparity in lung cancer risk cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene-sex interaction analysis using genotype from a lung cancer cohort including ~ 47,000 individuals with European ancestry. Three low-frequency variants (minor allele frequency < 0.05), rs17662871 (OR=0.71, p=4.29x10-8); rs79942605 (OR=2.17, p=2.81x10-8); and rs208908 (OR=0.70, p=4.54x10-8), were identified with different risk effect of lung cancer between men and women. Further eQTL and functional annotation analysis suggested rs208908 affect lung cancer risk through differential regulation of CXADR (Coxsackie Virus And Adenovirus Receptor) gene expression in lung tissues between men and women. Our study is one of the first studies to provide novel insights about the genetic and molecular basis for sex disparity in lung cancer development.

Background : Lipid lowering therapy reduces mortality in patients with both ischemic and nonischemic cardiomyopathies and recently has been shown to decrease ICD shocks. Radiofrequency ablation (RFA) of recurrent VT in patients with an ICD also reduces shocks following intervention. It is unclear if statin therapy after VT RFA will further impact ICD shock rates. Methods : All patients from 1993–2005 who underwent a RFA procedure for recurrent VT at the Mayo Clinic with an ICD were included. Patient records were extracted for medical and procedural details and all ICD interrogations were reviewed for VT recurrence and therapies. Results: 63 patients (age 62±15 years) were followed over 3.9±3.6 years. Comorbid diseases included: coronary artery disease 37(58%, 34 prior myocardial infarction), ARVD/C 6(10%), nonischemic dilated cardiomyopathy 7(11%), moderate-severe valve disease 14(22%), hypertension 34(54%), and hyperlipidemia 35(56%). Ejection fraction was <0.35 in 34(56%). VT was induced in all patients (LV 55 (LVOT 1), RV 8 (RVOT 3) with multiple inducible VTs in 21(33%). VT was noninducible after RFA in 39(62%) patients. Dismissal medications included: statins 19(30%), beta blockers 40(66%), ACE/ARB 37(61%), diuretics 34(55%), and digoxin 23(37%). 5-year overall survival was 63%(95% CI 55–71). Age, diabetes, and renal insufficiency were associated with increased post ablation mortality, with no medication improving survival. 5-year survival free of ICD shocks was 31%(95% CI 24–38). Only statin therapy at discharge was associated with a decreased risk of ICD shocks [5(26%) versus 26(59%), p=0.020]. 7 additional patients received statins during follow-up, but not at discharge, of these 5(71%) had shocks. Conclusion : Statin use at discharge in patients with an ICD undergoing RFA for refractory VT significantly reduced recurrent ventricular arrhythmias and ICD shocks. Although the mechanism underlying the effects of statins on arrhythmic recurrence early after RFA requires further study, these data support aggressive therapy of the underlying substrate responsible for the VT.

Background: The hallmark of Long QT Syndrome (LQTS) is a prolongation of the ventricular electrical action potential caused by mutations involving key cardiac ion channels on the surface membrane of ventricular myocytes. Different mutations are associated with specific modes of arrhythmia initiation and distinct changes in cardiac rhythm prior to these events. We hypothesized that some LQTS-causing mutations might involve the sinus node, leading to aberrations in cardiac rhythm. To test this hypothesis, we examined the features of cardiac rhythm in 23 genotyped patients with LQTS and 14 matched controls (C) using Holter ECG data (6hrs). Methods: QRS-complexes were identified using custom software and verified by an experienced ECG reader; series of sinus beats were extracted and gaps in time series were linearly interpolated. The mean, max, and min heart rate (HR), the time (SD, SDNN, SDANN, RMSSD, pNN50) and frequency-domain (Total (TP), Very low (VLF), Low (LF), High (HF) frequency powers, and LF/HF) indices of heart rate variability (HRV) were calculated in each 5-min interval and over the entire recording. The short-long-short irregularity was examined using the novel multiscale rhythmogenetic analysis (MRA), which quantifies changes in the HRV indices during the transition from one time-scale window to another. Results: The maximum heart rate was slower in LQTS than in C (101±13 and 119±19bpm, p=0.001). The high-frequency power (HF) was lower in LQTS than in C (80±76 and 113±58ms 2 , p<0.05). However, the short-term irregularity (quantified by the difference in RMSSD between the 75ms and 2000ms time scales) was 4 times greater in LQTS compared to C (p=0.003). Inclusion or exclusion of two patents who were on β-blockers did not change the results. Conclusions: LQTS is associated with specific changes in cardiac rhythm, including: diminished acceleration capacity, decreased high-frequency power, and enhanced short-long-short irregularity. This suggests that LQTS involves channel modifications in the sinus node, which might contribute to arrhythmogenesis. Rhythm characterization in genetic sub-types of LQTS might improve arrhythmia risk stratification in this heterogeneous patient population.

Objectives To investigate the genetic alterations of patients with prostate cancer (PCa) with and without intraductal carcinoma of the prostate (IDC‐P). Patients and Methods We performed targeted sequencing of plasma cell‐free DNA on 161 patients with prostate adenocarcinoma (PAC) with IDC‐P and 84 without IDC‐P. Genomic alterations were compared between these two groups. The association between genetic alterations and patients’ survival outcomes was also explored. Results We identified that 29.8% (48/161) and 21.4% (18/84) of patients with and without IDC‐P harboured genomic alterations in DNA repair pathways, respectively ( P = 0.210). Pathogenic germline DNA repair alterations were frequently detected in IDC‐P carriers compared to IDC‐P non‐carriers (11.8% [19/161] vs 2.4% [two of 84], P = 0.024). Germline BReast CAncer type 2 susceptibility protein ( BRCA2 ) and somatic cyclin‐dependent kinase 12 ( CDK12 ) defects were specifically identified in IDC‐P carriers relative to PAC ( BRCA2 : 8.7% [14/161] vs 0% and CDK12 : 6.8% [11/161] vs 1.2% [one of 84]). Patients with IDC‐P had a distinct androgen receptor (AR) pathway alteration, characterised by an enrichment of nuclear receptor corepressor 2 ( NCOR2 ) mutations compared with patients with pure PAC (21.1% [34/161] vs 6.0% [five of 84], P = 0.004). Increased AR alterations were detected in patients harbouring tumours with an IDC‐P proportion of ≥10% vs those with an IDC‐P proportion of <10% (6.4% [five of 78] vs 18.1% [15/83], P = 0.045). For IDC‐P carriers, tumour protein p53 ( TP53 ) mutation was associated with shorter castration‐resistant‐free survival (median 10.9 vs 28.9 months, P = 0.026), and BRCA2 alteration was related to rapid prostate‐specific antigen progression for those receiving abiraterone treatment (median 9.1 vs 11.9 months, P = 0.036). Conclusion Our findings provide genomic evidence explaining the aggressive phenotype of tumours with IDC‐P, highlighting the potential therapeutic strategies for this patient population.

Abstract Purpose The multiple energy extraction (MEE) delivery technique for synchrotron‐based proton delivery systems reduces beam delivery time by decelerating the beam multiple times during one accelerator spill, but this might cause additional plan quality degradation due to intrafractional motion. We seek to determine whether MEE causes significantly different plan quality degradation compared to single energy extraction (SEE) for lung cancer treatments due to the interplay effect. Methods Ten lung cancer patients treated with IMPT at our institution were nonrandomly sampled based on a representative range of tumor motion amplitudes, tumor volumes, and respiratory periods. Dose‐volume histogram (DVH) indices from single‐fraction SEE and MEE four‐dimensional (4D) dynamic dose distributions were compared using the Wilcoxon signed‐rank test. Distributions of monitor units (MU) to breathing phases were investigated for features associated with plan quality degradation. SEE and MEE DVH indices were compared in fractionated deliveries of the worst‐case patient treatment scenario to evaluate the impact of fractionation. Results There were no clinically significant differences in target mean dose, target dose conformity, or dose to organs‐at‐risk between SEE and MEE in single‐fraction delivery. Three patients had significantly worse dose homogeneity with MEE compared to SEE (single‐fraction mean D 5% ‐D 95% increased by up to 9.6% of prescription dose), and plots of MU distribution to breathing phases showed synchronization patterns with MEE but not SEE. However, after 30 fractions the patient in the worst‐case scenario had clinically acceptable target dose homogeneity and coverage with MEE (mean D 5% –D 95% increased by 1% compared to SEE). Conclusions For some patients with breathing periods close to the mean spill duration, MEE resulted in significantly worse single‐fraction target dose homogeneity compared to SEE due to the interplay effect. However, this was mitigated by fractionation, and target dose homogeneity and coverage were clinically acceptable after 30 fractions with MEE.

Introduction Optivol (Medtronic Inc.) thoracic impedance (ZT) provides preemptive disease status information in heart failure (HF). It remains unclear how pulmonary‐capillary blood volume (Vc), lung volume (Lvol), and interstitial fluid influence ZT. Hypothesis Positional change and exercise result in increased Vc and/or lung interstitial fluid and ZT tracks fluctuation in these variables. Methods 12 HF patients (age 63±8yr, LVEF 41±14%) were recruited. Measures were taken at rest, exercise, recovery. This included: spirometry, ZT, diffusing capacity of the lungs for CO and NO (DLCO, DLNO), alveolar‐capillary conductance (Dm, interstitial fluid index), and Vc. Inspiratory capacity was obtained to provide consistent lung volumes for assessing ZT. Results Positional change (upright‐supine) resulted in an increased ZT (5±4%, p<0.01), while the change in Lvol (RV‐TLC) resulted in a 7±2 ohm swing in ZT (0.2±0.1ohm change/100ml change in Lvol). After 30min supine, Vc increased 28±39% (p<0.05) while Dm/Vc and Lvol decreased (29±11% and 17±3%, p<0.05). During exercise compared to baseline, Vc increased 56±44% (p<0.01), DmCO/Vc decreased 25±7% (p<0.05), and ZT did not change. During recovery measures normalized except DmCO/Vc. Conclusion Positional changes and fluctuations in Lvol influence ZT yet measures of lung fluid minimally impact this measure despite significant fluctuations.