Laryngeal dystonia is a chronic neurologic disorder characterized by intention-induced spasms of the vocal folds driven by aberrant central motor processing. The use of in-office transcervical ...botulinum toxin injection for the treatment of laryngeal disorders, such as laryngeal dystonia, has been deemed safe and efficacious. There is, however, no available data outlining the hemodynamic changes experienced by patients undergoing this frequently performed procedure.
One hundred and one patients diagnosed with laryngeal dystonia were enrolled in this prospective study. These patients underwent transcervical laryngeal botulinum toxin injection to address their dysphonia. Vital signs where acquired prior to, and at the time of injection. Alterations in these parameters were then evaluated for statistical significance.
Statistically significant increases in mean heart rate (5.8 ± 10.8 bpm, P < 0.0001), systolic blood pressure and diastolic blood pressure (7.0 ± 9.5 mm Hg, P < 0.0001; 8.7 ± 14.7 mm Hg, P < 0.0001) were discovered. No statistically significant difference in oxygen saturation was noted and no patients in the study faced major adverse outcomes.
Though these findings may not have related to clinically significant complication, our study demonstrates the importance of understanding potential stressors in a procedure routinely performed by laryngologists. This may result in more careful patient selection, alterations in procedure, and improved safety by acting in a timely fashion if alarming changes in hemodynamic parameters are noted.
Cancer patients with advanced disease routinely exhaust available clinical regimens and lack actionable genomic medicine results, leaving a large patient population without effective treatments ...options when their disease inevitably progresses. To address the unmet clinical need for evidence-based therapy assignment when standard clinical approaches have failed, we have developed a probabilistic computational modeling approach which integrates molecular sequencing data with functional assay data to develop patient-specific combination cancer treatments.
Tissue taken from a murine model of alveolar rhabdomyosarcoma was used to perform single agent drug screening and DNA/RNA sequencing experiments; results integrated via our computational modeling approach identified a synergistic personalized two-drug combination. Cells derived from the primary murine tumor were allografted into mouse models and used to validate the personalized two-drug combination. Computational modeling of single agent drug screening and RNA sequencing of multiple heterogenous sites from a single patient's epithelioid sarcoma identified a personalized two-drug combination effective across all tumor regions. The heterogeneity-consensus combination was validated in a xenograft model derived from the patient's primary tumor. Cell cultures derived from human and canine undifferentiated pleomorphic sarcoma were assayed by drug screen; computational modeling identified a resistance-abrogating two-drug combination common to both cell cultures. This combination was validated in vitro via a cell regrowth assay.
Our computational modeling approach addresses three major challenges in personalized cancer therapy: synergistic drug combination predictions (validated in vitro and in vivo in a genetically engineered murine cancer model), identification of unifying therapeutic targets to overcome intra-tumor heterogeneity (validated in vivo in a human cancer xenograft), and mitigation of cancer cell resistance and rewiring mechanisms (validated in vitro in a human and canine cancer model).
These proof-of-concept studies support the use of an integrative functional approach to personalized combination therapy prediction for the population of high-risk cancer patients lacking viable clinical options and without actionable DNA sequencing-based therapy.
Chest tube management protocols, particularly in patients with alveolar-pleural air leak due to recent surgery or trauma, are limited by concerns over safety, especially concerns about rapid and ...occult development of pneumothorax. A continuous, real-time monitor of pneumothorax could improve the quality and safety of chest tube management. We developed a rat model of pneumothorax to test a novel approach of measuring electrical impedance within the pleural space as a monitor of lung expansion.
Anesthetized Sprague–Dawley rats underwent right thoracotomy. A novel impedance sensor and a thoracostomy tube were introduced into the right pleural space. Pneumothorax of varying volumes ranging from 0.2 to 20 mL was created by syringe injection of air via the thoracostomy tube. Electrical resistance measurements from the pleural sensor and fluoroscopic images were obtained at baseline and after the creation of pneumothorax and results compared.
A statistically significant, dose-dependent increase in electrical resistance was observed with increasing volume of pneumothorax. Resistance measurement allowed for continuous, real-time monitoring of pneumothorax development and the ability to track pneumothorax resolution by aspiration of air via the thoracostomy tube. Pleural resistance measurement demonstrated 100% sensitivity and specificity for all volumes of pneumothorax tested and was significantly more sensitive for pneumothorax detection than fluoroscopy.
The electrical impedance-based pleural space sensor described in this study provided sensitive and specific pneumothorax detection, which was superior to radiographic analysis. Real-time, continuous monitoring for pneumothorax has the potential to improve the safety, quality, and efficiency of postoperative chest tube management.
Background:
Code selection is crucial to the accuracy and reproducibility of studies using administrative data, however a comprehensive assessment of coding trends for major cardiac diagnoses and ...procedures is lacking. We aimed to evaluate trends in administrative code utilization for major cardiac diagnoses and procedures, and adherence to required methodological practices in cardiac research using the National Inpatient Sample (NIS).
Methods:
In this observational study of 445 articles, ICD-9-CM codes corresponding to acute myocardial infarction (AMI), heart failure, atrial fibrillation, percutaneous coronary intervention, and coronary artery bypass grafting were collected and analyzed. The NIS was used to compare the number of hospitalizations between the most frequently encountered AMI case definitions. Key elements were abstracted from each article to evaluate adherence to required methodological practices.
Results:
Variation in code utilization was observed for each diagnosis and procedure assessed, and the number of unique case definitions published per year increased throughout the study period (
P
< 0.001), driven largely by the significant increase in articles per year (
P
< 0.001). Off-target codes were observed in 39 (8.8%) studies. Upon reintroduction into the NIS for 2008–2012, the most commonly encountered case definitions for AMI were found to yield significantly different estimates of AMI hospitalizations and hospitalization trends over time. Three hundred and ninety-nine articles (84%) did not adhere to one or more required research practices. Overall adherence was superior for publications in higher-impact journals (
P
= 0.002).
Conclusions:
Substantial variation in code selection exists for major cardiac diagnoses and procedures, and non-adherence to methodological standards is widespread. These data have important implications for the accuracy and generalizability of analyses using the NIS.
Nonrhabdomyosarcoma soft-tissue sarcomas (STSs) are a class of 50+ cancers arising in muscle and soft tissues of children, adolescents, and adults. Rarity of each subtype often precludes ...subtype-specific preclinical research, leaving many STS patients with limited treatment options should frontline therapy be insufficient. When clinical options are exhausted, personalized therapy assignment approaches may help direct patient care. Here, we report the results of an adult female STS patient with relapsed undifferentiated pleomorphic sarcoma (UPS) who self-drove exploration of a wide array of personalized Clinical Laboratory Improvement Amendments (CLIAs) level and research-level diagnostics, including state of the art genomic, proteomic, ex vivo live cell chemosensitivity testing, a patient-derived xenograft model, and immunoscoring. Her therapeutic choices were also diverse, including neoadjuvant chemotherapy, radiation therapy, and surgeries. Adjuvant and recurrence strategies included off-label and natural medicines, several immunotherapies, and N-of-1 approaches. Identified treatment options, especially those validated during the in vivo study, were not introduced into the course of clinical treatment but did provide plausible treatment regimens based on FDA-approved clinical agents.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously ...identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models. In this study, we investigated whether ENT also has antitumor activity in fusion-negative eRMS orthotopic allografts and PDX models either as a single agent or in combination with vincristine (VCR).
We tested the efficacy of ENT and VCR as single agents and in combination in orthotopic allograft and PDX mouse models of eRMS. We then performed CRISPR screening to identify which HDAC among the class I HDACs is responsible for tumor growth inhibition in eRMS. To analyze whether ENT treatment as a single agent or in combination with VCR induces myogenic differentiation, we performed hematoxylin and eosin (H&E) staining in tumors.
ENT in combination with the chemotherapy VCR has synergistic antitumor activity in a subset of fusion-negative eRMS in orthotopic "allografts," although PDX mouse models were too hypersensitive to the VCR dose used to detect synergy. Mechanistic studies involving CRISPR suggest that HDAC3 inhibition is the primary mechanism of cell-autonomous cytoreduction in eRMS. Following cytoreduction in vivo, residual tumor cells in the allograft models treated with chemotherapy undergo a dramatic, entinostat-induced (70-100%) conversion to non-proliferative rhabdomyoblasts.
Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS.
Risk or presence of metastasis in medulloblastoma causes substantial treatment-related morbidity and overall mortality. Through the comparison of cytokines and growth factors in the cerebrospinal ...fluid (CSF) of metastatic medulloblastoma patients with factors also in conditioned media of metastatic MYC amplified medulloblastoma or leptomeningeal cells, we were led to explore the bioactivity of IGF1 in medulloblastoma by elevated CSF levels of IGF1, IGF-sequestering IGFBP3, IGFBP3-cleaving proteases (MMP and tPA), and protease modulators (TIMP1 and PAI-1). IGF1 led not only to receptor phosphorylation but also accelerated migration/adhesion in MYC amplified medulloblastoma cells in the context of appropriate matrix or meningothelial cells. Clinical correlation suggests a peri-/sub-meningothelial source of IGF-liberating proteases that could facilitate leptomeningeal metastasis. In parallel, studies of key factors responsible for cell autonomous growth in MYC amplified medulloblastoma prioritized IGF1R inhibitors. Together, our studies identify IGF1R as a high value target for clinical trials in high risk medulloblastoma.
A model was built that characterized effects of individual factors on five-year prostate cancer (PCa) risk in the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial (PLCO) and the Selenium and ...Vitamin E Cancer Prevention Trial (SELECT). This model was validated in a third San Antonio Biomarkers of Risk (SABOR) screening cohort.
A prediction model for 1- to 5-year risk of developing PCa and Gleason > 7 PCa (HG PCa) was built on PLCO and SELECT using the Cox proportional hazards model adjusting for patient baseline characteristics. Random forests and neural networks were compared to Cox proportional hazard survival models, using the trial datasets for model building and the SABOR cohort for model evaluation. The most accurate prediction model is included in an online calculator.
The respective rates of PCa were 8.9%, 7.2%, and 11.1% in PLCO (n = 31,495), SELECT (n = 35,507), and SABOR (n = 1790) over median follow-up of 11.7, 8.1 and 9.0 years. The Cox model showed higher prostate-specific antigen (PSA), BMI and age, and African American race to be associated with PCa and HGPCa. Five-year risk predictions from the combined SELECT and PLCO model effectively discriminated risk in the SABOR cohort with C-index 0.76 (95% CI 0.72, 0.79) for PCa, and 0.74 (95% CI 0.65,0.83) for HGPCa.
A 1- to 5-year PCa risk prediction model developed from PLCO and SELECT was validated with SABOR and implemented online. This model can individualize and inform shared screening decisions.
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