Effect of Radiation Doses to the Heart on Survival for Stereotactic Ablative Radiotherapy for Early-stage Non-Small-cell Lung Cancer: An Artificial Neural Network Approach.

INTRODUCTION: The cardiac radiation dose is an important predictor of cardiac toxicity and overall survival (OS) for patients with locally advanced non-small-cell lung cancer (NSCLC). However, radiation-induced cardiac toxicity among patients with early-stage NSCLC who have undergone stereotactic ablative radiotherapy (SABR) has been less well-characterized. Our objective was to assess the associations between cardiac radiation dosimetry and OS in patients with early-stage NSCLC undergoing SABR. MATERIALS AND METHODS: From 2009 to 2014, 153 patients with early-stage NSCLC had undergone SABR at a single institution. The maximum dose, mean dose, V10Gy, V25Gy, and V50Gy to 15 cardiac substructures and the whole heart were analyzed for their association with OS using the Kaplan-Meier method. An artificial neural network (ANN) analysis was performed to modulate confounding behaviors of dosimetric variables to predict for OS. RESULTS: A total of 112 patients were included in the present analysis. The right ventricle (RV) V10Gy most negatively predicted for OS, such that patients who had received a RV V10Gy dose < 4% had significantly longer OS than patients who had received a RV V10Gy does > 4% (5.3 years vs. 2.4 years). On ANN analysis, 74 input features, including cardiac dosimetry parameters, predicted for survival with a test accuracy of 64.7%. A repeat ANN analysis using dosimetry to dose neutral structure confirmed the predictive power of cardiac dosimetry. CONCLUSION: Cardiac dosimetry to subvolumes of the heart was associated with decreased OS in patients with early-stage NSCLC undergoing SABR. These data support the importance of minimizing the radiation dose to cardiac substructures. Further prioritizing the heart as an organ at risk might be warranted. Additionally, cardiac follow-up should be considered.

Psychiatric drugs impact mitochondrial function in brain and other tissues.

Mitochondria have been linked to the etiology of schizophrenia (SZ). However, studies of mitochondria in SZ might be confounded by the effects of pharmacological treatment with antipsychotic drugs (APDs) and other common medications. This review summarizes findings on relevant mitochondria mechanisms underlying SZ, and the potential impact of psychoactive drugs including primarily APDs, but also antidepressants and anxiolytics. The summarized data suggest that APDs impair mitochondria function by decreasing Complex I activity and ATP production and dissipation of the mitochondria membrane potential. At the same time, in the brains of patients with SZ, antipsychotic drug treatment normalizes gene expression modules enriched in mitochondrial genes that are decreased in SZ. This indicates that APDs may have both positive and negative effects on mitochondria. The available evidence suggests three conclusions i) alterations in mitochondria functions in SZ exist prior to APD treatment, ii) mitochondria alterations in SZ can be reversed by APD treatment, and iii) APDs directly cause impairment of mitochondria function. Overall, the mechanisms of action of psychiatric drugs on mitochondria are both direct and indirect; we conclude the effects of APDs on mitochondria may contribute to both their therapeutic and metabolic side effects. These studies support the hypothesis that neuronal mitochondria are an etiological factor in SZ. Moreover, APDs and other drugs must be considered in the evaluation of this pathophysiological role of mitochondria in SZ. Considering these effects, pharmacological actions on mitochondria may be a worthwhile target for further APD development.

Personalized TMS: role of RNA genotyping.

PURPOSE: Noninvasive brain stimulation (NIBS) such a transcranial magnetic stimulation, intermittent theta burst stimulation, transcranial direct current stimulation and electroconvulsive therapy have emerged as an efficacious and well-tolerated therapy for treatment-resistant psychiatric disorders. While novel NIBS techniques are an exciting addition to the current repertoire of neuropsychiatric therapies, their success is somewhat limited by the wide range of treatment responses seen among treated patients. DESIGN/METHODOLOGY/APPROACH: In this study, the authors will review the studies on relevant genetic polymorphisms and discuss the role of RNA genotyping in personalizing NIBS. FINDINGS: Genome studies have revealed several genetic polymorphisms that may contribute for the heterogeneity of treatment response to NIBS where the presence of certain single nucleotide polymorphisms (SNPs) are associated with responders versus nonresponders. ORIGINALITY/VALUE: Historically, mental illnesses have been arguably some of the most challenging disorders to study and to treat because of the degree of biological variability across affected individuals, the role of genetic and epigenetic modifications, the diversity of clinical symptomatology and presentations and the interplay with environmental factors. In lieu of these challenges, there has been a push for personalized medicine in psychiatry that aims to optimize treatment response based on one's unique characteristics.

Comparing Outcomes of Patients With Early-Stage Non-Small-Cell Lung Cancer Treated With Stereotactic Body Radiotherapy Based on Frailty Status.

INTRODUCTION: Frailty of surgical patients has been associated with worse outcomes. There is limited literature discussing frailty in patients with lung cancer treated with stereotactic body radiotherapy (SBRT). This study assesses the relationship between frailty and overall survival (OS), tumor control, and toxicity in patients with early-stage non-small-cell lung cancer (NSCLC) treated with SBRT. PATIENTS AND METHODS: A retrospective review of patients with early-stage NSCLC treated with SBRT at a single institution between February 2009 and September 2014 was performed. A modified frailty index (mFI) of 8 variables was created, and patients were categorized as nonfrail (mFI ≤ 2) and frail (mFI > 2). OS, recurrence-free survival (RFS), local control (LC), regional control, and distant control (DC) were compared between frail and nonfrail patients by Kaplan-Meier analysis and log-rank tests. Univariate and multivariable analyses were conducted. RESULTS: One hundred forty cases of early-stage NSCLC were included, with 49 frail (35.0%) and 91 nonfrail (65.0%) subjects. OS was significantly lower in frail than nonfrail patients (P = .01) with 3-year OS of 59.3% versus 82.0%. LC and DC were significantly lower in frail than nonfrail patients (LC: P = .02, 3-year LC of 85.3% vs. 97.0%; DC: P = .03, 3-year DC of 80.6% vs. 93.4%), as was RFS (P = .01, 3-year RFS of 53.4% vs. 74.5%). Frailty remained a significant predictor for shorter OS on multivariable analysis (hazard ratio = 1.98; 95% confidence interval, 1.02-3.85; P = .04). CONCLUSION: Frailty is associated with reduced OS in early-stage NSCLC patients treated with SBRT. Characterizing frailty using an mFI before treatment could help guide treatment decision making and patient counseling.

Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures.

Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including 18F-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation. The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes. A pan-cancer and cross-species comparison of CNAs highlighted 26 consistently altered DNA regions, containing 11 enzymes in the glycolysis pathway in addition to known cancer-driving genes. Furthermore, exogenous expression of hexokinase and enolase enzymes in an experimental immortalization system altered the subsequent copy number status of the corresponding endogenous loci, supporting the hypothesis that these metabolic genes act as drivers within the conserved CNA amplification regions. Taken together, these results demonstrate that metabolic stress acts as a selective pressure underlying the recurrent CNAs observed in human tumors, and further cast genomic instability as an enabling event in tumorigenesis and metabolic evolution.

The clinical impact of cytomegalovirus infection following allogeneic hematopoietic cell transplantation: Why the quest for meaningful prophylaxis still matters.

Latent infection with human cytomegalovirus (CMV) is common. Functional immunity effectively contains such latent infections; however, CMV reactivation may cause significant complications in patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). In spite of the universal implementation of post-transplant screening for CMV viremia and the institution of pre-emptive antiviral management, CMV disease still occurs in a small portion of patients. Moreover, interactions between CMV and the immune system have significant implications for the incidence of graft-versus-host disease, the recurrence of malignancy, and non-relapse mortality following alloHCT, even in the era of pre-emptive antiviral management. CMV serostatus thus remains an important consideration for patients undergoing alloHCT. We review the clinical impact of CMV in the setting of alloHCT, interactions between CMV serostatus, viral reactivation, and transplant outcomes, as well as current and evolving strategies for prevention and treatment of CMV-related complications that may have significant impact for alloHCT recipients.