Selection criteria for lung-cancer screening Tammemägi, Martin C; Katki, Hormuzd A; Hocking, William G ...
The New England journal of medicine,
02/2013, Volume:
368, Issue:
8
Journal Article
Peer reviewed
Open access
The National Lung Screening Trial (NLST) used risk factors for lung cancer (e.g., ≥30 pack-years of smoking and <15 years since quitting) as selection criteria for lung-cancer screening. Use of an ...accurate model that incorporates additional risk factors to select persons for screening may identify more persons who have lung cancer or in whom lung cancer will develop.
We modified the 2011 lung-cancer risk-prediction model from our Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to ensure applicability to NLST data; risk was the probability of a diagnosis of lung cancer during the 6-year study period. We developed and validated the model (PLCO(M2012)) with data from the 80,375 persons in the PLCO control and intervention groups who had ever smoked. Discrimination (area under the receiver-operating-characteristic curve AUC) and calibration were assessed. In the validation data set, 14,144 of 37,332 persons (37.9%) met NLST criteria. For comparison, 14,144 highest-risk persons were considered positive (eligible for screening) according to PLCO(M2012) criteria. We compared the accuracy of PLCO(M2012) criteria with NLST criteria to detect lung cancer. Cox models were used to evaluate whether the reduction in mortality among 53,202 persons undergoing low-dose computed tomographic screening in the NLST differed according to risk.
The AUC was 0.803 in the development data set and 0.797 in the validation data set. As compared with NLST criteria, PLCO(M2012) criteria had improved sensitivity (83.0% vs. 71.1%, P<0.001) and positive predictive value (4.0% vs. 3.4%, P=0.01), without loss of specificity (62.9% and. 62.7%, respectively; P=0.54); 41.3% fewer lung cancers were missed. The NLST screening effect did not vary according to PLCO(M2012) risk (P=0.61 for interaction).
The use of the PLCO(M2012) model was more sensitive than the NLST criteria for lung-cancer detection.
Deep learning is a family of computational methods that allow an algorithm to program itself by learning from a large set of examples that demonstrate the desired behavior, removing the need to ...specify rules explicitly. Application of these methods to medical imaging requires further assessment and validation.
To apply deep learning to create an algorithm for automated detection of diabetic retinopathy and diabetic macular edema in retinal fundus photographs.
A specific type of neural network optimized for image classification called a deep convolutional neural network was trained using a retrospective development data set of 128 175 retinal images, which were graded 3 to 7 times for diabetic retinopathy, diabetic macular edema, and image gradability by a panel of 54 US licensed ophthalmologists and ophthalmology senior residents between May and December 2015. The resultant algorithm was validated in January and February 2016 using 2 separate data sets, both graded by at least 7 US board-certified ophthalmologists with high intragrader consistency.
Deep learning-trained algorithm.
The sensitivity and specificity of the algorithm for detecting referable diabetic retinopathy (RDR), defined as moderate and worse diabetic retinopathy, referable diabetic macular edema, or both, were generated based on the reference standard of the majority decision of the ophthalmologist panel. The algorithm was evaluated at 2 operating points selected from the development set, one selected for high specificity and another for high sensitivity.
The EyePACS-1 data set consisted of 9963 images from 4997 patients (mean age, 54.4 years; 62.2% women; prevalence of RDR, 683/8878 fully gradable images 7.8%); the Messidor-2 data set had 1748 images from 874 patients (mean age, 57.6 years; 42.6% women; prevalence of RDR, 254/1745 fully gradable images 14.6%). For detecting RDR, the algorithm had an area under the receiver operating curve of 0.991 (95% CI, 0.988-0.993) for EyePACS-1 and 0.990 (95% CI, 0.986-0.995) for Messidor-2. Using the first operating cut point with high specificity, for EyePACS-1, the sensitivity was 90.3% (95% CI, 87.5%-92.7%) and the specificity was 98.1% (95% CI, 97.8%-98.5%). For Messidor-2, the sensitivity was 87.0% (95% CI, 81.1%-91.0%) and the specificity was 98.5% (95% CI, 97.7%-99.1%). Using a second operating point with high sensitivity in the development set, for EyePACS-1 the sensitivity was 97.5% and specificity was 93.4% and for Messidor-2 the sensitivity was 96.1% and specificity was 93.9%.
In this evaluation of retinal fundus photographs from adults with diabetes, an algorithm based on deep machine learning had high sensitivity and specificity for detecting referable diabetic retinopathy. Further research is necessary to determine the feasibility of applying this algorithm in the clinical setting and to determine whether use of the algorithm could lead to improved care and outcomes compared with current ophthalmologic assessment.
Summary Background Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. We assessed the effects of meningococcal ...quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in 18–24-year-olds. Methods In this phase 3, observer-blind, randomised controlled trial, university students aged 18–24 years from ten sites in England were randomly assigned (1:1:1, block size of three) to receive two doses 1 month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. Participants were randomised with a validated computer-generated random allocation list. Participants and outcome-assessors were masked to the treatment group. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over 1 year. Primary outcomes were cross-sectional carriage 1 month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination. Reactogenicity and adverse events were monitored throughout the study. Analysis was done on the modified intention-to-treat population, which included all enrolled participants who received a study vaccination and provided at least one assessable swab after baseline. This trial is registered with ClinicalTrials.gov , registration number NCT01214850. Findings Between Sept 21 and Dec 21, 2010, 2954 participants were randomly assigned (987 assigned to control 984 analysed, 979 assigned to 4CMenB 974 analysed, 988 assigned to MenACWY-CRM 983 analysed); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1·2, 95% CI 0·8–1·7) or MenACWY-CRM (0·9, 0·6–1·3) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18·2% 95% CI 3·4–30·8 carriage reduction), capsular groups BCWY (26·6% 10·5–39·9 carriage reduction), capsular groups CWY (29·6% 8·1–46·0 carriage reduction), and serogroups CWY (28·5% 2·8–47·5 carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39·0% (95% CI 17·3–55·0) carriage reduction for serogroup Y and 36·2% (15·6–51·7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified. Interpretation Although we detected no significant difference between groups at 1 month after vaccine course, MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates during 12 months after vaccination and therefore might affect transmission when widely implemented. Funding Novartis Vaccines.
The unique acute effects of the large fractional doses that characterize stereotactic radiosurgery (SRS) or radiotherapy (SRT), specifically in terms of antitumor immune cellular processes, vascular ...damage, tumor necrosis, and apoptosis on brain metastasis have yet to be empirically demonstrated. The objective of this study is to provide the first in-human evaluation of the acute biological effects of SRS/SRT in resected brain metastasis. Tumor samples from patients who underwent dose-escalated preoperative SRT followed by resection with available non-irradiated primary tumor tissues were retrieved from our institutional biorepository. All primary tumors and irradiated metastases were evaluated for the following parameters: tumor necrosis, T-cells, natural killer cells, vessel density, vascular endothelial growth factor, and apoptotic factors. Twenty-two patients with irradiated and resected brain metastases and paired non-irradiated primary tumor samples met inclusion criteria. Patients underwent a median preoperative SRT dose of 18 Gy (Range: 15-20 Gy) in 1 fraction, with 3 patients receiving 27-30 Gy in 3-5 fractions, followed by resection within median interval of 67.8 h (R: 18.25-160.61 h). The rate of necrosis was significantly higher in irradiated brain metastases than non-irradiated primary tumors (p < 0.001). Decreases in all immunomodulatory cell populations were found in irradiated metastases compared to primary tumors: CD3 + (p = 0.003), CD4 + (p = 0.01), and CD8 + (p = 0.01). Pre-operative SRT is associated with acute effects such as increased tumor necrosis and differences in expression of immunomodulatory factors, an effect that does not appear to be time dependent, within the limited intervals explored within the context of this analysis.
We developed a quantitative description of the circuits formed in cat area 17 by estimating the "weight" of the projections between different neuronal types. To achieve this, we made ...three-dimensional reconstructions of 39 single neurons and thalamic afferents labeled with horseradish peroxidase during intracellular recordings in vivo. These neurons served as representatives of the different types and provided the morphometrical data about the laminar distribution of the dendritic trees and synaptic boutons and the number of synapses formed by a given type of neuron. Extensive searches of the literature provided the estimates of numbers of the different neuronal types and their distribution across the cortical layers. Applying the simplification that synapses between different cell types are made in proportion to the boutons and dendrites that those cell types contribute to the neuropil in a given layer, we were able to estimate the probable source and number of synapses made between neurons in the six layers. The predicted synaptic maps were quantitatively close to the estimates derived from the experimental electron microscopic studies for the case of the main sources of excitatory and inhibitory input to the spiny stellate cells, which form a major target of layer 4 afferents. The map of the whole cortical circuit shows that there are very few "strong" but many "weak" excitatory projections, each of which may involve only a few percentage of the total complement of excitatory synapses of a single neuron.
The purpose of this study was to critically analyze the risk of unplanned readmission following resection of brain metastasis and to identify key risk factors to allow for early intervention ...strategies in high-risk patients. We analyzed data from the Nationwide Readmissions Database (NRD) from 2010-2014, and included patients who underwent craniotomy for brain metastasis, identified using ICD-9-CM diagnosis (198.3) and procedure (01.59) codes. The primary outcome of the study was unplanned 30-day all-cause readmission rate. Secondary outcomes included reasons and costs of readmissions. Hierarchical logistic regression model was used to identify the factors associated with 30-day readmission following craniotomy for brain metastasis. During the study period, 44,846 index hospitalizations occurred for patients who underwent resection of brain metastasis. In this cohort, 17.8% (n = 7,965) had unplanned readmissions within the first 30 days after discharge from the index hospitalization. The readmission rate did not change significantly during the five-year study period (p-trend = 0.286). The median per-patient cost for 30-day unplanned readmission was $11,109 and this amounted to a total of $26.4 million per year, which extrapolates to a national expenditure of $269.6 million. Increasing age, male sex, insurance status, Elixhauser comorbidity index, length of stay, teaching status of the hospital, neurological complications and infectious complications were associated with 30-day readmission following discharge after an index admission for craniotomy for brain metastasis. Unplanned readmission rates after resection of brain metastasis remain high and involve substantial healthcare expenditures. Developing tools and interventions to prevent avoidable readmissions could focus on the high-risk patients as a future strategy to decrease substantial healthcare expense.
Malignant transformation (MT) of adult grade 2 glioma (low-grade glioma LGG) is associated with adverse survival. We sought to describe the incidence, outcomes, and risk factors for MT of molecularly ...classified LGG.
We reviewed a single-institutional database of adults who received a diagnosis of LGG with data allowing for molecular classification from 1980 to 2018 to evaluate time to MT and its associated risk factors. MT was defined as pathologic confirmation of grade 3-4 glioma and/or imaging characteristics consistent with MT by multidisciplinary consensus.
Among the included 486 adults with molecularly classified LGG, median age was 39 years (range, 18-78), median tumor size was 3.9 cm (range, 0.3-13.0), and 262 (54%) were male. Molecular classification was IDH
1p/19q
in 169 (35%), IDH
1p/19q
in 125 (26%), and IDH
in 192 (40%) patients. Adjuvant management was observation in 246 (51%) patients, temozolomide alone in 82 (16%), radiation therapy alone in 63 (13%), and radiation therapy concurrent with temozolomide in 81 (17%). Temozolomide monotherapy was more likely to be given to IDH
1p/19q
patients (P < .001). Median follow-up was 5.3 years. MT occurred in 84 (17%) patients, with a 5-year freedom from MT of 86% (95% confidence interval CI, 82%-90%). Median overall survival after MT was 2.4 years (95% CI, 1.5-3.3) and was associated with molecular classification (P = .03) and grade at MT (P < .001). Factors associated with MT were male sex (hazard ratio HR, 2.1; 95% CI, 1.2-3.6; P = .009), tumor size ≥5 cm (HR, 3.5; 95% CI, 2.0-6.2; P < .001), IDH
1p/19q
(HR, 2.7; 95% CI, 1.3-5.6; P = .009) or IDH
classification (HR, 5.5; 95% CI, 2.5-11.8; P < .001), and adjuvant temozolomide monotherapy (HR, 3.8; 95% CI, 1.4-10.3; P = .008).
MT of LGG has a poor prognosis associated with unfavorable molecular groups. Analysis of our large cohort identified adjuvant temozolomide monotherapy as the only modifiable risk factor for MT and provides the first clinical evidence of temozolomide-associated MT among molecularly classified adult LGG. This novel finding supplements our understanding of temozolomide-induced hypermutation and informs precision management of LGG.
Subcutaneous or Transvenous Defibrillator Therapy Knops, Reinoud E; Olde Nordkamp, Louise R A; Delnoy, Peter-Paul H M ...
The New England journal of medicine,
08/2020, Volume:
383, Issue:
6
Journal Article
Peer reviewed
Open access
The subcutaneous implantable cardioverter-defibrillator (ICD) was designed to avoid complications related to the transvenous ICD lead by using an entirely extrathoracic placement. Evidence comparing ...these systems has been based primarily on observational studies.
We conducted a noninferiority trial in which patients with an indication for an ICD but no indication for pacing were assigned to receive a subcutaneous ICD or transvenous ICD. The primary end point was the composite of device-related complications and inappropriate shocks; the noninferiority margin for the upper boundary of the 95% confidence interval for the hazard ratio (subcutaneous ICD vs. transvenous ICD) was 1.45. A superiority analysis was prespecified if noninferiority was established. Secondary end points included death and appropriate shocks.
A total of 849 patients (426 in the subcutaneous ICD group and 423 in the transvenous ICD group) were included in the analyses. At a median follow-up of 49.1 months, a primary end-point event occurred in 68 patients in the subcutaneous ICD group and in 68 patients in the transvenous ICD group (48-month Kaplan-Meier estimated cumulative incidence, 15.1% and 15.7%, respectively; hazard ratio, 0.99; 95% confidence interval CI, 0.71 to 1.39; P = 0.01 for noninferiority; P = 0.95 for superiority). Device-related complications occurred in 31 patients in the subcutaneous ICD group and in 44 in the transvenous ICD group (hazard ratio, 0.69; 95% CI, 0.44 to 1.09); inappropriate shocks occurred in 41 and 29 patients, respectively (hazard ratio, 1.43; 95% CI, 0.89 to 2.30). Death occurred in 83 patients in the subcutaneous ICD group and in 68 in the transvenous ICD group (hazard ratio, 1.23; 95% CI, 0.89 to 1.70); appropriate shocks occurred in 83 and 57 patients, respectively (hazard ratio, 1.52; 95% CI, 1.08 to 2.12).
In patients with an indication for an ICD but no indication for pacing, the subcutaneous ICD was noninferior to the transvenous ICD with respect to device-related complications and inappropriate shocks. (Funded by Boston Scientific; PRAETORIAN ClinicalTrials.gov number, NCT01296022.).
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