A Multicenter Evaluation of Different Chemotherapy Regimens in Older Adults With Head and Neck Squamous Cell Carcinoma Undergoing Definitive Chemoradiation.

PURPOSE: The number of older adults with head and neck squamous cell carcinoma (HNSCC) is increasing, and treatment of these patients is challenging. Although cisplatin-based chemotherapy concomitantly with radiation therapy is considered the standard regimen for patients with locoregionally advanced HNSCC, there is substantial real-world heterogeneity regarding concomitant chemotherapy in older patients with HNSCC. METHODS AND MATERIALS: The SENIOR study is an international multicenter cohort study including older patients (≥65 years) with HNSCC treated with definitive radiation therapy at 13 academic centers in the United States and Europe. Patients with concomitant chemoradiation were analyzed regarding overall survival (OS) and progression-free survival (PFS) via Kaplan-Meier analyses. Fine-Gray competing risk regressions were performed regarding the incidence of locoregional failures and distant metastases. RESULTS: Six hundred ninety-seven patients with a median age of 71 years were included in this analysis. Single-agent cisplatin was the most common chemotherapy regimen (n = 310; 44%), followed by cisplatin plus 5-fluorouracil (n = 137; 20%), carboplatin (n = 73; 10%), and mitomycin C plus 5-fluorouracil (n = 64; 9%). Carboplatin-based regimens were associated with diminished PFS (hazard ratio [HR], 1.39 [1.03-1.89]; P < .05) and a higher incidence of locoregional failures (subdistribution HR, 1.54 [1.00-2.38]; P = .05) compared with single-agent cisplatin, whereas OS (HR, 1.15 [0.80-1.65]; P = .46) was comparable. There were no oncological differences between single-agent and multiagent cisplatin regimens (all P > .05). The median cumulative dose of cisplatin was 180 mg/m2 (IQR, 120-200 mg/m2). Cumulative cisplatin doses ≥200 mg/m2 were associated with increased OS (HR, 0.71 [0.53-0.95]; P = .02), increased PFS (HR, 0.66 [0.51-0.87]; P = .003), and lower incidence of locoregional failures (subdistribution HR, 0.50 [0.31-0.80]; P = .004). Higher cumulative cisplatin doses remained an independent prognostic variable in the multivariate regression analysis for OS (HR, 0.996 [0.993-0.999]; P = .009). CONCLUSIONS: Single-agent cisplatin can be considered in the standard chemotherapy regimen for older patients with HNSCC who can tolerate cisplatin. Cumulative cisplatin doses are prognostically relevant in older patients with HNSCC.

Outcomes of definitive local therapy with intensity-modulated radiation therapy in elderly patients ≥70 years with HPV-associated oropharyngeal cancer.

The incidence of human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing among elderly (≥70 years) patients and the optimal treatment approach is not known. In this study, we aimed to determine disease and toxicity outcomes in an elderly HPV-OPSCC population primarily treated with a chemoradiation (CRT) approach. We identified 70 elderly HPV-OPSCC patients who were treated with either surgery, radiotherapy, or CRT between 2011 and 2021. Time-to-event analysis for overall survival (OS), progression-free survival (PFS), and local control (LC) were conducted using the Kaplan-Meier method. Univariate and multivariable cox regression models were used to estimate the hazard ratio associated with covariates. The median follow-up for our cohort was 43.9 months. Of the 70 elderly patients, 55 (78.6%) receive CRT and 15 (22.4%) received RT alone. Two patients underwent TORS resection. Of the 55 patients treated with CRT, the most common systemic agents were weekly carboplatin/taxol (n = 18), cetuximab (n = 17), and weekly cisplatin (n = 11). The 5-year OS, PFS, and LC were 57%, 52%, and 91%, respectively. On univariate analysis, Eastern Cooperative Oncology Group performance status and Charlson Comorbidity Index (CCI) were significant predictors of OS, while on multivariate analysis only CCI was a significant predictor of OS (p = 0.006). The rate of late peg tube dependency, osteoradionecrosis, and aspiration was 10%, 4%, and 4%, respectively. Definitive local therapy in elderly HPV-OPSCC patients is associated with excellent LC and a low rate of late toxicities. Prospective studies are needed to further stratify subgroups of elderly patients who may benefit from aggressive definitive local therapy.

Large Adult Spinal Diffuse Midline Histone H3 Lysine27-to-Methionine-Mutant Glioma With Intramedullary and Extramedullary Components Presenting With Progressive Hydrocephalus: A Case Report Highlighting Unique Imaging Findings and Treatment.

Diffuse midline glioma with histone H3 lysine27-to-methionine mutation (H3 K27M mutation) is a rare, aggressive tumor that is designated as World Health Organization (WHO) grade IV regardless of histologic features. Preoperative diagnosis remains challenging due to limited evidence regarding distinctive clinical and imaging characteristics. We describe the case of a young woman who presented with progressively worsening headaches due to communicating hydrocephalus. MR imaging with contrast of the cervical and thoracic spine revealed diffuse leptomeningeal enhancement with focal areas of intramedullary and subarachnoid T2 hyperintensity and enhancement, suggestive of a potential infectious process. Intraoperatively, no epidural pathology was identified, and with the differential diagnosis remaining broad, a second procedure was conducted involving intradural exploration and biopsy of a lesion. This was then identified as a diffuse midline glioma with H3 K27M mutation. The nonfocal clinical presentation in the setting of communicating hydrocephalus as well as the significant exophytic tumor growth and imaging findings made the initial diagnosis unique and challenging. This case, therefore, emphasizes the rare presentation of this tumor, and the need for further understanding of the clinical and imaging characteristics of this disease as well as the need for effective therapeutics.

Transcriptomic abnormalities in peripheral blood in bipolar disorder, and discrimination of the major psychoses.

We performed a transcriptome-wide meta-analysis and gene co-expression network analysis to identify genes and gene networks dysregulated in the peripheral blood of bipolar disorder (BD) cases relative to unaffected comparison subjects, and determined the specificity of the transcriptomic signatures of BD and schizophrenia (SZ). Nineteen genes and 4 gene modules were significantly differentially expressed in BD cases. Thirteen gene modules were shown to be differentially expressed in a combined case-group of BD and SZ subjects called "major psychosis", including genes biologically linked to apoptosis, reactive oxygen, chromatin remodeling, and immune signaling. No modules were differentially expressed between BD and SZ cases. Machine-learning classifiers trained to separate diagnostic classes based solely on gene expression profiles could distinguish BD cases from unaffected comparison subjects with an area under the curve (AUC) of 0.724, as well as BD cases from SZ cases with AUC = 0.677 in withheld test samples. We introduced a novel and straightforward method called "polytranscript risk scoring" that could distinguish BD cases from unaffected subjects (AUC = 0.672) and SZ cases (AUC = 0.607) significantly better than expected by chance. Taken together, our results highlighted gene expression alterations common to BD and SZ that involve biological processes of inflammation, oxidative stress, apoptosis, and chromatin regulation, and highlight disorder-specific changes in gene expression that discriminate the major psychoses.

Blood transcriptomic comparison of individuals with and without autism spectrum disorder: A combined-samples mega-analysis.

Blood-based microarray studies comparing individuals affected with autism spectrum disorder (ASD) and typically developing individuals help characterize differences in circulating immune cell functions and offer potential biomarker signal. We sought to combine the subject-level data from previously published studies by mega-analysis to increase the statistical power. We identified studies that compared ex vivo blood or lymphocytes from ASD-affected individuals and unrelated comparison subjects using Affymetrix or Illumina array platforms. Raw microarray data and clinical meta-data were obtained from seven studies, totaling 626 affected and 447 comparison subjects. Microarray data were processed using uniform methods. Covariate-controlled mixed-effect linear models were used to identify gene transcripts and co-expression network modules that were significantly associated with diagnostic status. Permutation-based gene-set analysis was used to identify functionally related sets of genes that were over- and under-expressed among ASD samples. Our results were consistent with diminished interferon-, EGF-, PDGF-, PI3K-AKT-mTOR-, and RAS-MAPK-signaling cascades, and increased ribosomal translation and NK-cell related activity in ASD. We explored evidence for sex-differences in the ASD-related transcriptomic signature. We also demonstrated that machine-learning classifiers using blood transcriptome data perform with moderate accuracy when data are combined across studies. Comparing our results with those from blood-based studies of protein biomarkers (e.g., cytokines and trophic factors), we propose that ASD may feature decoupling between certain circulating signaling proteins (higher in ASD samples) and the transcriptional cascades which they typically elicit within circulating immune cells (lower in ASD samples). These findings provide insight into ASD-related transcriptional differences in circulating immune cells. © 2016 Wiley Periodicals, Inc.

Transcriptome-wide mega-analyses reveal joint dysregulation of immunologic genes and transcription regulators in brain and blood in schizophrenia.

The application of microarray technology in schizophrenia research was heralded as paradigm-shifting, as it allowed for high-throughput assessment of cell and tissue function. This technology was widely adopted, initially in studies of postmortem brain tissue, and later in studies of peripheral blood. The collective body of schizophrenia microarray literature contains apparent inconsistencies between studies, with failures to replicate top hits, in part due to small sample sizes, cohort-specific effects, differences in array types, and other confounders. In an attempt to summarize existing studies of schizophrenia cases and non-related comparison subjects, we performed two mega-analyses of a combined set of microarray data from postmortem prefrontal cortices (n=315) and from ex-vivo blood tissues (n=578). We adjusted regression models per gene to remove non-significant covariates, providing best-estimates of transcripts dysregulated in schizophrenia. We also examined dysregulation of functionally related gene sets and gene co-expression modules, and assessed enrichment of cell types and genetic risk factors. The identities of the most significantly dysregulated genes were largely distinct for each tissue, but the findings indicated common emergent biological functions (e.g. immunity) and regulatory factors (e.g., predicted targets of transcription factors and miRNA species across tissues). Our network-based analyses converged upon similar patterns of heightened innate immune gene expression in both brain and blood in schizophrenia. We also constructed generalizable machine-learning classifiers using the blood-based microarray data. Our study provides an informative atlas for future pathophysiologic and biomarker studies of schizophrenia.

Endoscopic gallbladder drainage compared with percutaneous drainage.

BACKGROUND: High-risk patients with cholecystitis have conventionally been offered percutaneous gallbladder drainage (PGBD) for treatment. A growing experience of endoscopic gallbladder drainage (EGBD) has been reported to be effective and safe. OBJECTIVE: To compare the short- and long-term outcomes of EGBD and PGBD. DESIGN: A retrospective review. SETTING: Single academic tertiary care center. PATIENTS: Inpatients diagnosed with cholecystitis. INTERVENTIONS: Any patient deemed a nonsurgical candidate and who has undergone either PGBD or EGBD was included in the analysis. MAIN OUTCOME MEASUREMENTS: Patient demographics along with procedural and clinical outcomes were recorded for each group. RESULTS: Forty-three patients underwent PGBD and 30 underwent EGBD (24 transpapillary, 6 transmural). Technical (97.6% vs 100%) and clinical (97.6% vs 86.7%) success rates of PGBD and EGBD were similar. However, postprocedure hospital length of stay (16.3 vs 7.6 days), time to clinical resolution (4.6 vs 3.0 days), adverse event rate (39.5% vs 13.3%), number of sessions (2.0 vs 1.0), number of repeat interventions (53.4% vs 13.3%), and postprocedure pain scores (3.8 vs 2.1) were significantly higher for PGBD than EGBD. LIMITATIONS: Retrospective analysis. CONCLUSION: Although EGBD has similar technical and clinical success compared with PGBD, it uses fewer hospital resources and results in fewer adverse events, improved pain scores, and decreased need for repeat gallbladder drainage. EGBD may provide a less-invasive, safer, cost-effective option for gallbladder drainage than PGBD with improved clinical outcomes.