Thoracic radiotherapy (TRT) is increasingly used in patients receiving osimertinib for advanced NSCLC, and the risk of pneumonitis is not established. We investigated the risk of pneumonitis and ...potential risk factors in this population.
We performed a multi-institutional retrospective analysis of patients under active treatment with osimertinib who received TRT between April 2016 and July 2022 at two institutions. Clinical characteristics, including whether osimertinib was held during TRT and pneumonitis incidence and grade (Common Terminology Criteria for Adverse Events version 5.0) were documented. Logistic regression analysis was performed to identify risk factors associated with grade 2 or higher (2+) pneumonitis.
The median follow-up was 10.2 months (range: 1.9–53.2). Of 102 patients, 14 (13.7%) developed grade 2+ pneumonitis, with a median time to pneumonitis of 3.2 months (range: 1.5–6.3). Pneumonitis risk was not significantly increased in patients who continued osimertinib during TRT compared with patients who held osimertinib during TRT (9.1% versus 15.0%, p = 0.729). Three patients (2.9%) had grade 3 pneumonitis, none had grade 4, and two patients had grade 5 events (2.0%, diagnosed 3.2 mo and 4.4 mo post-TRT). Mean lung dose was associated with the development of grade 2+ pneumonitis in multivariate analysis (OR = 1.19, p = 0.021).
Although the overall rate of pneumonitis in patients receiving TRT and osimertinib was relatively low, there was a small risk of severe toxicity. The mean lung dose was associated with an increased risk of developing pneumonitis. These findings inform decision-making for patients and providers.
Objectives We sought to determine the incremental prognostic value of 64 multi-slice coronary computed tomography angiography (CCTA) in coronary artery bypass graft (CABG) patients. Background ...Prognostication in CABG patients can be difficult. Anatomical assessment of native coronary artery disease and graft patency might provide useful information, but the utility of CCTA in the assessment of CABG patients is unknown. Methods Six hundred fifty-seven CABG patients with all-cause mortality follow-up were identified from a multicenter CCTA registry, of 10,628 patients from 5 CCTA centers. Clinical risk was profiled with modified logistic and additive EuroSCOREs (European Systems for Cardiac Operative Risk Evaluations). The CCTA defined coronary anatomy. Patients were classified by unprotected coronary territory (UCT) or a summary of native vessel disease and graft patency: the coronary artery protection score (CAPS). Results Forty-four deaths occurred during a mean follow-up of 20 months. Left ventricular ejection fraction, creatinine, age, severity of native vessel disease, UCT, CAPS, and EuroSCOREs were univariate predictors of mortality (p < 0.001). In multivariate analysis with additive EuroSCORE, UCT (p = 0.004) and CAPS were predictive of events (p < 0.001). In comparison with additive EuroSCORE, CAPS score was associated with a 27% net reclassification index. Conclusions Coronary computed tomography angiography provides incremental anatomical data to clinical risk assessment to help determine the prognosis of patients after CABG. The CAPS evaluation with CCTA might help identify those patients at highest risk.
Background Computer-assisted diagnosis of dermoscopic images of skin lesions has the potential to improve melanoma early detection. Objective We sought to evaluate the performance of a novel ...classifier that uses decision forest classification of dermoscopic images to generate a lesion severity score. Methods Severity scores were calculated for 173 dermoscopic images of skin lesions with known histologic diagnosis (39 melanomas, 14 nonmelanoma skin cancers, and 120 benign lesions). A threshold score was used to measure classifier sensitivity and specificity. A reader study was conducted to compare the sensitivity and specificity of the classifier with those of 30 dermatology clinicians. Results The classifier sensitivity for melanoma was 97.4%; specificity was 44.2% in a test set of images. In the reader study, the classifier's sensitivity to melanoma was higher ( P < .001) and specificity was lower ( P < .001) than that of clinicians. Limitations This is a retrospective study using existing images primarily chosen for biopsy by a dermatologist. The size of the test set is small. Conclusions Our classifier may aid clinicians in deciding if a skin lesion should be biopsied and can easily be incorporated into a portable tool (that uses no proprietary equipment) that could aid clinicians in noninvasively evaluating cutaneous lesions.
Dose to normal lung has commonly been linked with radiation-induced lung toxicity (RILT) risk, but incorporating functional lung metrics in treatment planning may help further optimize dose delivery ...and reduce RILT incidence. The purpose of this study was to investigate the impact of the dose delivered to functional lung regions by analyzing perfusion (Q), ventilation (V), and combined V/Q single-photon-emission computed tomography (SPECT) dose-function metrics with regard to RILT risk in patients with non-small cell lung cancer (NSCLC) patients who received radiation therapy (RT).
SPECT images acquired from 88 patients with locally advanced NSCLC before undergoing conventionally fractionated RT were retrospectively analyzed. Dose was converted to the nominal dose equivalent per 2 Gy fraction, and SPECT intensities were normalized. Regional lung segments were defined, and the average dose delivered to each lung region was quantified. Three functional categorizations were defined to represent low-, normal-, and high-functioning lungs. The percent of functional lung category receiving ≥20 Gy and mean functional intensity receiving ≥20 Gy (iV20) were calculated. RILT was defined as grade 2+ radiation pneumonitis and/or clinical radiation fibrosis. A logistic regression was used to evaluate the association between dose-function metrics and risk of RILT.
By analyzing V/Q normalized intensities and functional distributions across the population, a wide range in functional capability (especially in the ipsilateral lung) was observed in patients with NSCLC before RT. Through multivariable regression models, global lung average dose to the lower lung was found to be significantly associated with RILT, and Q and V iV20 were correlated with RILT when using ipsilateral lung metrics. Through a receiver operating characteristic analysis, combined V/Q low-function receiving ≥20 Gy (low-functioning V/Q20) in the ipsilateral lung was found to be the best predictor (area under the curce: 0.79) of RILT risk.
Irradiation of the inferior lung appears to be a locational sensitivity for RILT risk. The multivariable correlation between ipsilateral lung iV20 and RILT, as well as the association of low-functioning V/Q20 and RILT, suggest that irradiating low-functioning regions in the lung may lead to higher toxicity rates.
Although family history (FH) of coronary artery disease (CAD) is considered a risk factor for future cardiovascular events, the prevalence, extent, severity, and prognosis of young patients with FH ...of CAD have been inadequately studied. From 27,125 consecutive patients who underwent coronary computed tomographic angiography, 6,308 young patients (men aged <55 years and women aged <65 years) without known CAD were identified. Obstructive CAD was defined as >50% stenosis in a coronary artery >2 mm diameter. Risk-adjusted logistic regression, Kaplan-Meier, and Cox proportional-hazards models were used to compare patients with and without FH of CAD. Compared with subjects without FH of CAD, those with FH of CAD (FH+) had higher prevalences of any CAD (40% vs 30%, p <0.001) and obstructive CAD (11% vs 7%, p <0.001), with multivariate odds of FH+ increasing the likelihood of obstructive CAD by 71% (p <0.001). After a mean follow-up period of 2 ± 1 years (42 myocardial infarctions and 39 all-cause deaths), FH+ patients experienced higher annual rates of myocardial infarction (0.5% vs 0.2%, log-rank p = 0.001), with a positive FH the strongest predictor of myocardial infarction (hazard ratio 2.6, 95% confidence interval 1.4 to 4.8, p = 0.002). In conclusion, young FH+ patients have higher presence, extent, and severity of CAD, which are associated with increased risk for myocardial infarction. Compared with other clinical CAD risk factors, positive FH in young patients is the strongest clinical predictor of future unheralded myocardial infarction.
Objective To evaluate the relationship between ampicillin dosing, exposure, and seizures. Study design This was a retrospective observational cohort study of electronic health record (EHR) data ...combined with pharmacokinetic model derived drug exposure predictions. We used the EHR from 348 Pediatrix Medical Group neonatal intensive care units from 1997 to 2012. We included all infants 24-41 weeks gestational age, 500-5400 g birth weight, first exposed to ampicillin prior to 25 days postnatal age. Using a 1-compartment pharmacokinetic model and EHR data, we simulated maximum ampicillin concentration at steady state (Cmaxss, µg/mL) and area under the concentration time curve from 0 to 24 hours (AUC24, µg*h/dL). Using multivariable logistic regression, we evaluated association between ampicillin dosing, exposure, and seizures as documented in the EHR. Results We identified 131 723 infants receiving 134 041 courses of ampicillin for 653 506 infant-days of exposure. The median daily dose was 200 mg/kg/d (25th, 75th percentile; 100, 200). Median Cmaxss and AUC24 were 256.6 µg/mL (164.3, 291.5) and 2593 µg*h/dL (1917, 3334). On multivariable analysis, dosing was not associated with seizures. However increasing Cmaxss (OR = 1.10, 95% CI 1.03, 1.17) and AUC24 (OR 1.11, 95% CI 1.05, 1.18) were associated with increased odds of seizures. Conclusions In this cohort of hospitalized infants, higher ampicillin exposure was associated with seizures as documented in the EHR.
To evaluate non-research-related, physician-industry financial relationships in the United States, in 2013, as reported pursuant to the Physician Payments Sunshine Act (a provision of the Affordable ...Care Act).
In September 2014, CMS released the first five months (August 2013 to December 2013) of data disclosing physician-industry financial relationships. The frequency and value of non-research-related transfers in radiology were calculated and compared with those for 19 other specialties. Subanalyses of the frequency and value of such transfers in radiology were performed, based on state of licensure, radiologic subspecialty, nature of payment, manufacturer identity, and drug or device involved.
A total of 7.4% (2,654 of 35,768) of radiologists from the United States had reportable non-research-related financial relationship(s) with industry during the 5-month period, the second-lowest level among the medical specialties evaluated. The average value of non-research-related transfers of value to radiologists, excluding royalties and licenses, was low ($438.71; SD: $2,912.15; median: $43.85), with <4% of radiologists receiving >$10 per month. Of all categories, that of food and beverage had the most transfers of value (86.0%; 5,655 of 6,577); royalties and licensure were associated with the greatest average value ($27,072.34; SD: $67,524.92). Although high-value relationships were rare, 57.8% (26 of 45) of radiologists who received a value >$1,000 per month held leadership positions in imaging enterprises.
Less than 4% of radiologists have non-research-related financial relationships with industry that are valued at >$10 per month, suggesting that meaningful, deleterious effects of such relationships on radiology practice, if present, are infrequent.
Background An emerging paradigm holds that resistance to the development of allergic diseases, including allergic rhinoconjunctivitis, relates to an intact epithelial/epidermal barrier during early ...childhood. Conceivably, the immunologic and genomic footprint of this resistance is preserved in nonatopic, nonallergic adults and is unmasked during exposure to an aeroallergen. Objective The aim of this study was to obtain direct support of the epithelial/epidermal barrier model for allergic rhinoconjunctivitis. Methods Twenty-three adults allergic to house dust mites (HDMs) (M+) and 15 nonsensitive, nonallergic (M−) participants completed 3-hour exposures to aerosolized HDM ( Dermatophagoides pteronyssinus ) powder on 4 consecutive days in an allergen challenge chamber. We analyzed: (1) peripheral blood leukocyte levels and immune responses; and (2) RNA sequencing–derived expression profiles of nasal cells, before and after HDM exposure. Results On HDM challenge: (1) only M+ persons developed allergic rhinoconjunctivitis symptoms; and (2) peripheral blood leukocyte levels/responses and gene expression patterns in nasal cells were largely concordant between M+ and M− participants; gross differences in these parameters were not observed at baseline (pre-exposure). Two key differences were observed. First, peripheral blood CD4+ and CD8+ T-cell activation levels initially decreased in M− participants versus increased in M+ participants. Second, in M− compared with M+ participants, genes that promoted epidermal/epithelial barrier function (eg, filament-aggregating protein filaggrin) versus inflammation (eg, chemokines) and innate immunity (interferon) were upregulated versus muted, respectively. Conclusion An imprint of resistance to HDM challenge in nonatopic, nonallergic adults was muted T-cell activation in the peripheral blood and inflammatory response in the nasal compartment, coupled with upregulation of genes that promote epidermal/epithelial cell barrier function.
Background Despite providing superb excess weight loss and increased resolution of comorbid diseases, such as type 2 diabetes mellitus, compared to other bariatric procedures, the duodenal switch/ ...biliopancreatic diversion (DS/BD) has not gained widespread acceptance among patients and physicians. In this study, we investigated outcomes, symptoms and complications among postsurgical DS patients compared to RYGB patients. Methods We used propensity scores to retrospectively match patients who underwent DS/BD between 2005 and 2010 to comparable Roux-en-Y gastric bypass (RYGB) patients. We then reviewed patient charts, and surveyed patients using the University of Minnesota Bariatric Surgery Outcomes Survey tool to track outcomes, comorbid illnesses and complications. Results One hundred ninety consecutive patients underwent primary DS/BD between 2005 and 2010 at the University of Minnesota Medical Center. There were 178 patients available for follow-up (93.7%) who were matched to 139 RYGB patients. Type 2 diabetes, hypertension, and hyperlipidemia all significantly improved in each group. Improvements were significantly higher in the DS/BD group. Percent total weight loss was not different between groups. Loose stools and bloating symptoms were more frequently reported among DS/BD patients. With the exception of increased emergency department visits among DS/BD patients ( P < .01), overall complication rates were not significantly different between DS/BD and RYGB. There was no difference in mortality rates between the groups. Conclusion The DS/BD is a robust procedure that engenders both superior weight loss and improvement of major comorbidities. Complication and adverse event rates are similar to those of RYGB.
Abstract Purpose Over the last decade, few new antibiotics have been approved by the Food and Drug Administration (FDA) for pediatric use. For most anti-infective agents, including antibiotics, ...extrapolation of efficacy from adults to children is possible if the disease and therapeutic exposures are similar between the 2 populations. This approach reduces the number of studies required in children, but relies heavily on exposure matching between children and adults. Failures in exposure matching can lead to delays in pediatric approvals of new anti-infective agents. We sought to determine the extent of exposure matching, defined by a comparison of area under the concentration-time curve, between children and adults, for anti-infective drug products submitted to the FDA for approval. Methods We reviewed anti-infective submissions to the FDA (2002–2014) for pediatric indication. We included drug products administered via oral, intravenous, or intramuscular administration routes, and those with AUC estimates for children in available FDA reports. Our main outcome of interest was the proportion of drugs with median (or mean) pediatric AUC within 20% of the median (or mean) reported adult value. Findings We identified 29 drug products that met inclusion criteria, 14 (48%) of which had mean (or median) AUCs of all submitted age groups within 20% of that in adults. Only route of administration and drug class were associated with pediatric AUC within 20% of adult AUC. Implications Future research is needed to define criteria for and predictors of successful exposure matching of anti-infectives between children and adults.
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