GNOSIS: an R Shiny app supporting cancer genomics survival analysis with cBioPortal.

Exploratory analysis of cancer consortia data curated by the cBioPortal repository typically requires advanced programming skills and expertise to identify novel genomic prognostic markers that have the potential for both diagnostic and therapeutic exploitation. We developed GNOSIS (GeNomics explOrer using StatistIcal and Survival analysis in R), an R Shiny App incorporating a range of R packages enabling users to efficiently explore and visualise such clinical and genomic data. GNOSIS provides an intuitive graphical user interface and multiple tab panels supporting a range of functionalities, including data upload and initial exploration, data recoding and subsetting, data visualisations, statistical analysis, mutation analysis and, in particular, survival analysis to identify prognostic markers. GNOSIS also facilitates reproducible research by providing downloadable input logs and R scripts from each session, and so offers an excellent means of supporting clinician-researchers in developing their statistical computing skills.

Zilovertamab Vedotin Targeting of ROR1 as Therapy for Lymphoid Cancers.

BACKGROUND: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein present on many cancers. Zilovertamab vedotin (ZV) is an antibody­drug conjugate comprising a monoclonal antibody recognizing extracellular ROR1, a cleavable linker, and the anti-microtubule cytotoxin monomethyl auristatin E. METHODS: In this phase 1, first-in-human, dose-escalation study, we accrued patients with previously treated lymphoid cancers to receive ZV every 3 weeks until the occurrence of cancer progression or unacceptable toxicity had occurred. RESULTS: We enrolled 32 patients with tumor histologies of mantle cell lymphoma (MCL) (n=15), chronic lymphocytic leukemia (n=7), diffuse large B-cell lymphoma (DLBCL) (n=5), follicular lymphoma (n=3), Richter transformation lymphoma (n=1), or marginal zone lymphoma (n=1). Patients had received a median of four previous drug and/or cellular therapies. Starting dose levels were 0.5 (n=1), 1.0 (n=3), 1.5 (n=3), 2.25 (n=11), and 2.5 (n=14) mg per kg of body weight (mg/kg). Pharmacokinetic and pharmacodynamic data documented systemic ZV exposure and exposure-dependent ZV targeting of ROR1 on circulating tumor cells. As expected with an monomethyl auristatin E-containing antibody­drug conjugate, adverse events (AEs) included acute neutropenia and cumulative neuropathy resulting in a recommended ZV dosing regimen of 2.5 mg/kg every 3 weeks. No clinically concerning AEs occurred to suggest ROR1-mediated toxicities or nonspecific ZV binding to normal tissues. ZV induced objective tumor responses in 7 of 15 patients with MCL (47%; 4 partial and 3 complete) and in 3 of 5 patients with DLBCL (60%; 1 partial and 2 complete); objective tumor responses were not observed among patients with other tumor types. CONCLUSIONS: In heavily pretreated patients, ZV demonstrated no unexpected toxicities and showed evidence of antitumor activity, providing clinical proof of concept for selective targeting of ROR1 as a potential new approach to cancer therapy. (ClinicalTrials.gov number, NCT03833180.)

Survival outcomes are associated with genomic instability in luminal breast cancers.

Breast cancer is the leading cause of cancer related death among women. Breast cancers are generally diagnosed and treated based on clinical and histopathological features, along with subtype classification determined by the Prosigna Breast Cancer Prognostic Gene Signature Assay (also known as PAM50). Currently the copy number alteration (CNA) landscape of the tumour is not considered. We set out to examine the role of genomic instability (GI) in breast cancer survival since CNAs reflect GI and correlate with survival in other cancers. We focused on the 70% of breast cancers classified as luminal and carried out a comprehensive survival and association analysis using Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data to determine whether CNA Score Quartiles derived from absolute CNA counts are associated with survival. Analysis revealed that patients diagnosed with luminal A breast cancer have a CNA landscape associated with disease specific survival, suggesting that CNA Score can provide a statistically robust prognostic factor. Furthermore, stratification of patients into subtypes based on gene expression has shown that luminal A and B cases overlap, and it is in this region we largely observe luminal A cases with reduced survival outlook. Therefore, luminal A breast cancer patients with quantitatively elevated CNA counts may benefit from more aggressive therapy. This demonstrates how individual genomic landscapes can facilitate personalisation of therapeutic interventions to optimise survival outcomes.

Effective radiation dose in computed tomographic angiography of the chest and diagnostic cardiac catheterization in pediatric patients.

Computed tomographic angiography (CTA) and cardiac catheterization are useful adjuncts to echocardiography for delineating cardiovascular anatomy in pediatric patients. These studies require ionizing radiation, and it is paramount to understand the amount of radiation pediatric patients receive when these tests are performed. Modern dosimetry methods facilitate the conversion of radiation doses of varying units into an effective radiation dose. To compare the effective radiation dose between nongated CTA of the chest and diagnostic cardiac catheterization in pediatric patients. This is a retrospective cohort study of patients of patients who underwent either nongated CTA of the chest or diagnostic cardiac catheterization between July 2009 and April 2010. Fifty patients were included in each group as consecutive samples at a single tertiary care center. An effective radiation dose (mSv) was formulated using conversion factors for each group. The median effective dose (ED) for the CTA group was 0.74 mSv compared with 10.8 mSv for the catheterization group (p < 0.0001). The median ED for children <1 year of age in the CTA group was 0.76 mSv compared with 13.4 mSv for the catheterization group (p < 0.0001). Nongated CTA of the chest exposes children to 15 times less radiation than diagnostic cardiac catheterization. Unless hemodynamic data are necessary, CTA of the chest should be considered in lieu of diagnostic cardiac catheterization in patients with known or presumed cardiac disease who need additional imaging beyond echocardiography.

Changes in autism spectrum disorder prevalence in 4 areas of the United States.

BACKGROUND: We sought to describe autism spectrum disorder (ASD) population characteristics and changes in identified prevalence across 3 time periods. METHODS: Children with a potential ASD were identified through records abstraction at multiple sources with clinician review based on Diagnostic and Statistical Manual (DSM-IV-TR) criteria. Multisite, population-based data from the Autism and Developmental Disabilities Monitoring (ADDM) Network were analyzed from areas of Arizona (AZ), Georgia (GA), Maryland (MD), and South Carolina (SC). Participants were 8-year-old children (born in 1992, 1994, or 1996) in 2000, 2002, or 2004 (and children born in 1988 residing in metropolitan Atlanta in 1996) who had been evaluated for a variety of developmental concerns at education and/or health sources. RESULTS: From 2000 to 2004, the identified prevalence of the ASDs per 1,000 8-year-old children showed significant increases of 38% in GA and 72% in MD and a nonsignificant increase of 26% in AZ. ASD prevalence was relatively stable in SC with a nonsignificant decrease of 17%. Males had a higher identified prevalence of ASD in all years. Increases among racial, ethnic, and cognitive functioning subgroups varied by site and surveillance year. More children were classified with an ASD by community professionals over time, except in AZ. CONCLUSIONS: There was a trend toward increase in identified ASD prevalence among 8-year-old children who met the surveillance case definition in 3 of the 4 study sites from 2000 to 2004. Some of the observed increases are due to improved ascertainment; however, a true increase in ASD symptoms cannot be ruled out. These data confirm that the prevalence of ASDs is undergoing significant change in some areas of the United States and that ASDs continue to be of urgent public health concern.

Pleural effusions in a series of 181 outpatients with sarcoidosis.

OBJECTIVES: Pleural effusion (PE) is considered to be a rare manifestation of pulmonary sarcoidosis. We performed thoracic ultrasonography prospectively in consecutive outpatients with sarcoidosis to determine the frequency of PEs caused by sarcoidosis and to define their pleural fluid characteristics. DESIGN: Consecutive outpatients aged >/= 18 years with biopsy-proven sarcoidosis underwent ultrasonography. SETTING: University hospital, outpatient sarcoidosis clinic. RESULTS: One hundred eighty-one outpatients were enrolled into the study. The subjects were predominately African-American and female. Most were between 30 and 60 years of age. The Scadding radiograph stages were fairly evenly distributed across all five stages (0 through 4). Five (2.8%) of 181 patients were found to have pleural fluid. Two patients had a unilateral left-sided PE, and three patients had bilateral PEs. Pleural fluid analysis (PFA) was performed in four patients. The PFA showed a lymphocyte-predominant exudate using protein criterion in only two patients, which is consistent with sarcoidosis-related PE; one patient underwent pleural biopsy, which was consistent with the diagnosis of sarcoidosis. A sarcoidosis-related PE was seen in 1 of 9 patients (11.1%) who had an exacerbation of pulmonary sarcoidosis compared to 1 of 172 patients (0.6%) who did not have an exacerbation (p < 0.4). CONCLUSION: PEs are rare in outpatients with sarcoidosis, even when a sensitive technique, such as ultrasonography, is used. The frequency of PEs was 2.8% (5 of 181 patients) with only 2 of the 181 PEs (1.1%) caused by sarcoid pleural involvement. PE in patients with sarcoidosis should not be assumed to be related to sarcoidosis. Discordance between levels of pleural fluid total protein and lactate dehydrogenase may be a characteristic finding in patients with sarcoid PE. An exacerbation of pulmonary sarcoidosis was not an independent risk factor for the development of sarcoid-related PE.

Pulmonary complications after esophagectomy.

BACKGROUND: Pulmonary complications are common in patients who have undergone esophagectomy. There are no good predictive variables for these complications. In addition, the role that preoperative treatment with chemotherapy and radiation may play in postoperative complications remains unclear. METHODS: We performed a retrospective review of all patients who underwent esophagectomy by a single surgeon at our institution over a 6-year period. Data were analyzed for a correlation between patient risk factors and pulmonary complications, including mortality, prolonged mechanical ventilation, and hospital length of stay. RESULTS: Complete data were available on 61 patients. Nearly all patients had some pulmonary abnormality (eg, pleural effusion), although most of these were clinically insignificant. Pneumonia was the most common clinically important complication, and 19.7% of patients required prolonged ventilatory support. Significant risk factors identified included impaired pulmonary function, especially for patients with forced expiratory volume in 1 second (FEV1) less than 65% of predicted, preoperative chemoradiotherapy, and age. CONCLUSIONS: Impaired lung function is a significant risk factor for pulmonary complications after esophagectomy. Patients with FEV1 less than 65% of predicted appear to be at greatest risk. There also seems to be an associated risk of preoperative chemoradiotherapy for pulmonary complications after esophagectomy.