Citations

Abstract Introduction Peyronie’s disease (PD) is traditionally categorized into 2 phases: acute (active) and chronic (stable) phase; however, clinical definitions and distinction between the phases vary in the literature and remain blurred.[1] The American Urological Association guidelines outline changing symptoms with the presence of pain as a defining symptom of acute disease, but provide little guidance about timeframe.[2] Historically, acute-phase characteristics include presence of penile pain and progressing deformity (eg, worsening penile curvature), with time from symptom onset to acute phase completion being <3–18 months.[1] While there may be academic utility in temporally categorizing PD, it may limit or postpone the treatment options for patients suffering from the condition. Collagenase clostridium histolyticum (CCH) is an approved nonsurgical PD treatment option and several studies suggest its safety and efficacy in acute phase PD.[3-6] In light of these studies and ambiguity in dichotomizing phases, previous clinical trial data were reanalyzed to investigate the potential for opening the gamut of treatment options at earlier timepoints in the disease process. Objective This analysis examines CCH treatment efficacy on improving penile curvature in participants presenting with/without penile pain at baseline and disease duration of 12–18 months or >18 months from the CCH clinical trial program. Methods Literature related to CCH treatment of acute phase PD was compiled and treatment outcomes assessed. Additionally, a post hoc analysis of pooled data from two phase 3 randomized, double-blind trials of CCH in PD (IMPRESS I, NCT01221597; IMPRESS II, NCT01221623) was conducted. CCH-treated participants were stratified by the reporting of moderate-severe pain or no pain at baseline based on the following study measures: penile pain on palpation, penile pain on erection, PD questionnaire (PDQ) combined questions 7–9, and PDQ question 10 only. Additional subgroup analyses stratified participants by presence of pain and disease duration (12–18 or >18 months). The primary efficacy endpoint was the percentage change in penile curvature at week 52 from baseline. Results The IMPRESS I/II data analysis found that participants who experienced moderate-severe pain at baseline had penile curvature improvements by week 52 similar to participants with no pain at baseline. Across all pain measures, the percentage decreases in mean penile curvature from baseline ranged from 29%–42% for moderate-severe pain groups and 35%–37% for no penile pain groups. There were no clear differences in mean penile curvature improvement between groups for any specific pain measure when stratified by disease duration of 12–18 months (moderate-severe pain, 32%–40% improvement; no pain, 23%–29% improvement) versus >18 months (moderate-severe pain, 24%–44% improvement; no pain, 37%–40% improvement). Outcomes from the IMPRESS trials were comparable in context with published literature. Conclusions Based on a subanalysis of IMPRESS data, there were no clear differences identified in CCH treatment outcomes between participants experiencing moderate-severe pain or no pain at baseline regardless of disease duration (12–18 versus >18 months). These analyses are consistent with other literature evaluating the efficacy of CCH in the acute phase of disease and suggest that ongoing pain is not a contraindication to CCH therapy. Disclosure Yes, this is sponsored by industry/sponsor: Endo Pharmaceuticals Inc. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Endo Pharmaceuticals Inc; Boston Scientific Corporation; Antares Pharma, Inc; PathRight Medical.

BACKGROUND: Up to 85% of patients with sickle cell disease (SCD) will develop gallstones by their third decade. Cholecystectomy is the most commonly performed procedure in these patients. Cholecystectomy is recommended for patients with SCD with symptomatic cholelithiasis and leads to lower morbidity. No contemporary large studies have evaluated this recommendation or associated clinical outcomes. This study evaluates clinical outcomes after cholecystectomy in patients with SCD and cholelithiasis with specific advanced clinical presentations. STUDY DESIGN: The Nationwide Inpatient Sample was queried for patients with SCD and gallbladder disease between 2006 and 2015. Patients were divided into groups based on their disease presentation, including uncomplicated cholelithiasis, acute and chronic cholecystitis, and gallstone pancreatitis. Clinical outcomes associated with disease presentation were analyzed. Statistical analysis was performed using the Student’s t-test, chi-square test, ANOVA, and logistic regression. RESULTS: There were 6,662 patients with SCD who presented with cholelithiasis. Median age was 20 (interquartile range 16 to 34) years and 54% were female patients. Cholecystectomy was performed in 1,779 patients with SCD with the most common indication being chronic cholecystitis (44%), followed by uncomplicated cholelithiasis (27%), acute cholecystitis (21%), and choledocholithiasis or gallstone pancreatitis (8%). On multivariable regression, advanced clinical presentation was the strongest predictor of perioperative vaso-occlusive crisis, which was the most common complication. Patients undergoing cholecystectomy for uncomplicated cholelithiasis were at lower risk than those with acute cholecystitis (odds ratio [OR] 2.37; 95% CI 1.64 to 3.41), chronic cholecystitis (OR 1.74; 95% CI 1.26 to 2.4), and choledocholithiasis or gallstone pancreatitis (OR 2.24; 95% CI 1.41 to 3.57). CONCLUSIONS: Seventy-three percent of patients with SCD have advanced clinical presentation at the time of their cholecystectomy. After cholecystectomy, perioperative vaso-occlusive events were significantly increased in patients with advanced clinical presentation. These data support screening abdominal ultrasounds and early cholecystectomy for cholelithiasis in patients with SCD.

High-grade gliomas are the most common and aggressive adult primary brain tumors with a median survival of only 12–15 months. Current standard therapy consists of maximal safe surgical resection followed by DNA-damaging agents, such as irradiation and chemotherapy that can delay but not prevent inevitable recurrence. Some have interpreted glioma recurrence as evidence of glioma stem cells which persist in a relatively quiescent state after irradiation and chemotherapy, before the ultimate cell cycle re-entry and glioma recurrence. Conversely, latent cancer cells with a therapy-induced senescent phenotype have been shown to escape senescence, giving rise to more aggressive stem-like tumor cells than those present in the original tumor. Therefore, approaches are needed to either eliminate or keep these glioma initiating cells in a senescent state for a longer time to prolong survival. In our current study, we demonstrate that the radiation-induced cell cycle inhibitor P21 can provide a powerful route to induce cell death in short-term explants of PDXs derived from three molecularly diverse human gliomas. Additionally, cells not killed by P21 overexpression were maintained in a stable senescent state for longer than control cells. Collectively, these data suggest that P21 activation may provide an attractive therapeutic target to improve therapeutic outcomes.

Abstract Glioblastoma (GBM) remains the most common and lethal adult primary brain cancer. Two of the most significant issues preventing the development of effective GBM treatments are inter- and intra-tumor heterogeneity. To address these issues, we developed a novel platform termed ISOSCELES (Inferred cell Sensitivity Operating on the integration of Single-Cell Expression and L1000 Expression Signatures). ISOSCELES integrates single-cell gene expression data in individual GBM tumors with perturbation-response data derived from the NIH Library of Integrated Network-Based Cellular Signatures (LINCS) L1000 dataset to predict sensitive and resistant tumor cell populations. Importantly, we analyzed the predictive power of ISOSCELES in an in vivo xenograft model and demonstrated that ISOSCELES reveals the GBM cell identities primed for lineage expansion during treatment with the aurora kinase inhibitor alisertib. These studies suggest that ISOSCELES can be used to identify sensitive and resistant cell populations to targeted therapies in GBM, which can inform treatment decisions in ongoing and future clinical trials.

Abstract Glioblastoma (GBM) remains the most common adult brain cancer, with a dismal average patient survival of less than two years. No new treatments have been approved for GBM since the introduction of the alkylating agent temozolomide in 2005. Even then, temozolomide treatment only increases the average survival of GBM patients by a few months. Thus, novel therapeutic options are direly needed. The aurora kinases A and B are targetable and overexpressed in GBM, and their expression is highly correlated with patient survival outcomes. Our lab has found that small molecule aurora kinase inhibition reduces GBM tumor growth in vitro and in vivo, however, eventually tumors still grow. Computational analysis integrating compound transcriptional response signatures from the LINCS L1000 dataset with the single-cell RNA-sequencing data of patient GBM tumors resected at the University of Miami predicts that aurora inhibition targets a subset of cells present within any GBM tumor. Results of in vivo single-cell perturbation experiments with the aurora kinase inhibitor alisertib coincide with our predictions and reveal a cellular transcriptional phenotype resistant to aurora kinase inhibition, characterized by a mesenchymal expression program. We find that small molecules that are predicted to target different cell populations from alisertib, including this resistant mesenchymal population, synergize with alisertib to kill GBM cells. As a whole, we have identified the cellular population resistant to aurora kinase inhibition and have developed an analytical framework that identifies synergistic small molecule combinations by identifying compounds that target transcriptionally distinct cellular populations within GBM tumors.

BACKGROUND: Opioid-related adverse events are a serious problem in hospitalized patients. Little is known about patients who are likely to experience opioid-induced respiratory depression events on the general care floor and may benefit from improved monitoring and early intervention. The trial objective was to derive and validate a risk prediction tool for respiratory depression in patients receiving opioids, as detected by continuous pulse oximetry and capnography monitoring. METHODS: PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) was a prospective, observational trial of blinded continuous capnography and oximetry conducted at 16 sites in the United States, Europe, and Asia. Vital signs were intermittently monitored per standard of care. A total of 1335 patients receiving parenteral opioids and continuously monitored on the general care floor were included in the analysis. A respiratory depression episode was defined as respiratory rate ≤5 breaths/min (bpm), oxygen saturation ≤85%, or end-tidal carbon dioxide ≤15 or ≥60 mm Hg for ≥3 minutes; apnea episode lasting >30 seconds; or any respiratory opioid-related adverse event. A risk prediction tool was derived using a multivariable logistic regression model of 46 a priori defined risk factors with stepwise selection and was internally validated by bootstrapping. RESULTS: One or more respiratory depression episodes were detected in 614 (46%) of 1335 general care floor patients (43% male; mean age, 58 ± 14 years) continuously monitored for a median of 24 hours (interquartile range [IQR], 17–26). A multivariable respiratory depression prediction model with area under the curve of 0.740 was developed using 5 independent variables: age ≥60 (in decades), sex, opioid naivety, sleep disorders, and chronic heart failure. The PRODIGY risk prediction tool showed significant separation between patients with and without respiratory depression ( P < .001) and an odds ratio of 6.07 (95% confidence interval [CI], 4.44–8.30; P < .001) between the high- and low-risk groups. Compared to patients without respiratory depression episodes, mean hospital length of stay was 3 days longer in patients with ≥1 respiratory depression episode (10.5 ± 10.8 vs 7.7 ± 7.8 days; P < .0001) identified using continuous oximetry and capnography monitoring. CONCLUSIONS: A PRODIGY risk prediction model, derived from continuous oximetry and capnography, accurately predicts respiratory depression episodes in patients receiving opioids on the general care floor. Implementation of the PRODIGY score to determine the need for continuous monitoring may be a first step to reduce the incidence and consequences of respiratory compromise in patients receiving opioids on the general care floor.

Significance Glioblastoma Multiforme (GBM) is the most common and deadliest primary brain tumor in adults. As the median survival is approximately 14 mo there is an urgent need for novel therapies. Epigenetic modulators such as bromodomain and extraterminal (BET) proteins are important therapeutic targets in GBM. Bromodomain inhibitors (including I-BET151) suppress proliferation by repressing oncogenes and inducing tumor suppressor genes through unidentified pathways. Here we demonstrate that HOTAIR (HOX transcript antisense RNA) is overexpressed in GBM, where it is crucial to sustain tumor cell proliferation, and that inhibition of HOTAIR by I-BET151 is necessary to induce cell cycle arrest in GBM cells. Our study outlines the mechanism of action underlying the antiproliferative activity of I-BET151, showing for the first time, to our knowledge, that the oncogenic long noncoding RNA HOTAIR is a major target.