Summary Background Head and neck cancers positive for human papillomavirus (HPV) are exquisitely radiosensitive. We investigated whether chemoradiotherapy with reduced-dose radiation would maintain ...survival outcomes while improving tolerability for patients with HPV-positive oropharyngeal carcinoma. Methods We did a single-arm, phase 2 trial at two academic hospitals in the USA, enrolling patients with newly diagnosed, biopsy-proven stage III or IV squamous-cell carcinoma of the oropharynx, positive for HPV by p16 testing, and with Zubrod performance status scores of 0 or 1. Patients received two cycles of induction chemotherapy with 175 mg/m2 paclitaxel and carboplatin (target area under the curve of 6) given 21 days apart, followed by intensity-modulated radiotherapy with daily image guidance plus 30 mg/m2 paclitaxel per week concomitantly. Complete or partial responders to induction chemotherapy received 54 Gy in 27 fractions, and those with less than partial or no responses received 60 Gy in 30 fractions. The primary endpoint was progression-free survival at 2 years, assessed in all eligible patients who completed protocol treatment. This study is registered with ClinicalTrials.gov , numbers NCT02048020 and NCT01716195. Findings Between Oct 4, 2012, and March 3, 2015, 45 patients were enrolled with a median age of 60 years (IQR 54–67). One patient did not receive treatment and 44 were included in the analysis. 24 (55%) patients with complete or partial responses to induction chemotherapy received 54 Gy radiation, and 20 (45%) with less than partial responses received 60 Gy. Median follow-up was 30 months (IQR 26–37). Three (7%) patients had locoregional recurrence and one (2%) had distant metastasis; 2-year progression-free survival was 92% (95% CI 77–97). 26 (39%) of 44 patients had grade 3 adverse events, but no grade 4 events were reported. The most common grade 3 events during induction chemotherapy were leucopenia (17 39%) and neutropenia (five 11%), and during chemoradiotherapy were dysphagia (four 9%) and mucositis (four 9%). One (2%) of 44 patients was dependent on a gastrostomy tube at 3 months and none was dependent 6 months after treatment. Interpretation Chemoradiotherapy with radiation doses reduced by 15–20% was associated with high progression-free survival and an improved toxicity profile compared with historical regimens using standard doses. Radiotherapy de-escalation has the potential to improve the therapeutic ratio and long-term function for these patients. Funding University of California.
Background
Radiation Therapy Oncology Group (RTOG)‐0129 recursive partitioning analysis was the basis for risk‐based therapeutic intensification trials for oropharyngeal cancer (OPC). To the authors’ ...knowledge, the question of whether RTOG‐0129 overall survival (OS) estimates for low‐risk, intermediate‐risk, and high‐risk groups are similar in other data sets or applicable to progression‐free survival (PFS) is unknown. Therefore, the authors evaluated whether survival differences between RTOG‐0129 risk groups persist at 5 years, are reproducible in an independent clinical trial, and are applicable to PFS, and whether toxicities differ across risk groups.
Methods
Prospective randomized clinical trials were analyzed retrospectively. RTOG‐0129 evaluated standard versus accelerated fractionation radiotherapy concurrent with cisplatin. RTOG‐0522 compared the combination of cisplatin and accelerated fractionation with or without cetuximab. Patients with OPC with available p16 status and tobacco history were eligible.
Results
There was a total of 260 patients and 287 patients, respectively, from RTOG‐0129 and RTOG‐0522, with median follow‐ups for surviving patients of 7.9 years (range, 1.7‐9.9 years) and 4.7 years (range, 0.1‐7.0 years), respectively. Previous OS differences in RTOG‐0129 persisted at 5 years. In RTOG‐0522, the 5‐year OS rates for the low‐risk, intermediate‐risk, and high‐risk groups were 88.1%, 69.9%, and 45.1%, respectively (P for trend, <.001). The 5‐year PFS rates for the same 3 groups were 72.9%, 56.1%, and 42.2%, respectively. In RTOG‐0522 among a subgroup of patients considered to be at very good risk (p16‐positive disease, smoking history of ≤10 pack‐years, and classified with T1‐T2 disease with ipsilateral lymph nodes measuring ≤6 cm or T3 disease without contralateral or >6 cm lymph nodes), the 5‐year OS and PFS rates were 93.8% and 82.2%, respectively. Overall rates of acute and late toxicities were similar by risk group.
Conclusions
RTOG‐0129 risk groups persisted at 5 years and were reproducible in RTOG‐0522. However, there was variability in the estimates. These data underscore the importance of long‐term follow‐up and appropriate patient selection in therapeutic deintensification trials.
To the authors’ knowledge, the issue of whether Radiation Therapy Oncology Group (RTOG)‐0129 overall survival estimates for low‐risk, intermediate‐risk, and high‐risk groups are similar in other data sets or applicable to progression‐free survival is unknown. In the current study, RTOG‐0129 risk groups appear to persist at 5 years, are reproducible in RTOG‐0522, and can be applied to progression‐free survival. However, there is variability in the estimates, which underscores the importance of long‐term follow‐up in therapeutic deintensification.
Purpose Treatment of oropharyngeal squamous cell carcinoma (OPSCC) is evolving toward risk-based modification of therapeutic intensity, which requires patient-specific estimates of overall survival ...(OS) and progression-free survival (PFS). Methods To develop and validate nomograms for OS and PFS, we used a derivation cohort of 493 patients with OPSCC with known p16 tumor status (surrogate of human papillomavirus) and cigarette smoking history (pack-years) randomly assigned to clinical trials using platinum-based chemoradiotherapy (NRG Oncology Radiation Therapy Oncology Group RTOG 0129 and 0522). Nomograms were created from Cox models and internally validated by use of bootstrap and cross-validation. Model discrimination was measured by calibration plots and the concordance index. Nomograms were externally validated in a cohort of 153 patients with OPSCC randomly assigned to a third trial, NRG Oncology RTOG 9003. Results Both models included age, Zubrod performance status, pack-years, education, p16 status, and T and N stage; the OS model also included anemia and age × pack-years interaction; and the PFS model also included marital status, weight loss, and p16 × Zubrod interaction. Predictions correlated well with observed 2-year and 5-year outcomes. The uncorrected concordance index was 0.76 (95% CI, 0.72 to 0.80) for OS and 0.70 (95% CI, 0.66 to 0.74) for PFS, and bias-corrected indices were similar. In the validation set, OS and PFS models were well calibrated, and OS and PFS were significantly different across tertiles of nomogram scores (log-rank P = .003;< .001). Conclusion The validated nomograms provided useful prediction of OS and PFS for patients with OPSCC treated with primary radiation-based therapy.
Epilepsy is a commonly observed long-term neurological disorder that impairs nerve cell activity in the brain and has a severe impact on people’s daily lives. Accurate seizure detection in the ...long-term electroencephalogram (EEG) signals has gained vital importance in the diagnosis of patients with epilepsy. Visual interpretation and detection of epileptic seizures in long-term EEG is a time-consuming and burdensome task for neurologists. Therefore, in this study, we propose a computationally efficient automated seizure detection model using a novel feature called successive decomposition index (SDI). We observed that the SDI feature was significantly higher during the epileptic seizure as compared to normal EEG. The performance of the proposed method was evaluated using three databases, namely the Ramaiah Medical College and Hospital (DB1), CHB-MIT (DB2) and the Temple University Hospital (DB3) consisting of 58 h, 884 h, and 408 h of EEG, respectively. Experimental results revealed the sensitivity–false detection rate–median detection delay of 97.53%–0.4/h–1.5 s, 97.28%–0.57/h–1.7 s, and 95.80%–0.49/h–1.5 s for DB1, DB2, and DB3, respectively, using the support vector machine classifier. The proposed method significantly outperformed previously presented methods (wavelets and other feature extraction methods) while being computationally more efficient. Further, to the best of the author’s knowledge, present study is the first study that was tested on three different EEG databases and showed consistent results leading to the generalization and robustness of the algorithm. Hence, the proposed method is an efficient tool for neurologists to detect epileptic seizures in long-term EEG.
Recognition of epileptic seizure type is essential for the neurosurgeon to understand the cortical connectivity of the brain. Though automated early recognition of seizures from normal ...electroencephalogram (EEG) was existing, no attempts have been made towards the classification of variants of seizures. Therefore, this study attempts to classify seven variants of seizures with non-seizure EEG through the application of convolutional neural networks (CNN) and transfer learning by making use of the Temple University Hospital EEG corpus. The objective of our study is to perform a multi-class classification of epileptic seizure type, which includes simple partial, complex partial, focal non-specific, generalized non-specific, absence, tonic, and tonic–clonic, and non-seizures. The 19 channels EEG time series was converted into a spectrogram stack before feeding as input to CNN. The following two different modalities were proposed using CNN: (1) Transfer learning using pretrained network, (2) Extract image features using pretrained network and classify using the support vector machine classifier. The following ten pretrained networks were used to identify the optimal network for the proposed study: Alexnet, Vgg16, Vgg19, Squeezenet, Googlenet, Inceptionv3, Densenet201, Resnet18, Resnet50, and Resnet101. The highest classification accuracy of 82.85% (using Googlenet) and 88.30% (using Inceptionv3) was achieved using transfer learning and extract image features approach respectively. Comparison results showed that CNN based approach outperformed conventional feature and clustering based approaches. It can be concluded that the EEG based classification of seizure type using CNN model could be used in pre-surgical evaluation for treating patients with epilepsy.
•We propose a CNN and transfer learning-based 8-class seizure type classification using the Temple University Hospital EEG corpus.•We propose a CNN and transfer learning-based 8-class seizure type classification•ReLU layer showed the highest accuracy using extract image feature approach•The highest accuracy of 82.85% and 88.30% was achieved using Googlenet and Inceptionv3 respectively•Extract image features approach outperformed transfer learning approach
Aim
Evidence suggests microvascular dysfunction (wider retinal venules and narrower arterioles) in schizophrenia (SCZ) and bipolar disorder (BD). The vascular development is synchronous with neuronal ...development in the retina and brain. The retinal vessel trajectory is related to retinal nerve fiber layer thinning and cerebrovascular abnormalities in SCZ and BD and has not yet been examined. Hence, in this study we examined the retinal vascular trajectory in SCZ and BD in comparison with healthy volunteers (HV).
Methods
Retinal images were acquired from 100 HV, SCZ patients, and BD patients, respectively, with a non‐mydriatic fundus camera. Images were quantified to obtain the retinal arterial and venous trajectories using a validated, semiautomated algorithm. Analysis of covariance and regression analyses were conducted to examine group differences. A supervised machine‐learning ensemble of bagged‐trees method was used for automated classification of trajectory values.
Results
There was a significant difference among groups in both the retinal venous trajectory (HV: 0.17 ± 0.08; SCZ: 0.25 ± 0.17; BD: 0.27 ± 0.20; P < 0.001) and the arterial trajectory (HV: 0.34 ± 0.15; SCZ: 0.29 ± 0.10; BD: 0.29 ± 0.11; P = 0.003) even after adjusting for age and sex (P < 0.001). On post‐hoc analysis, the SCZ and BD groups differed from the HV on retinal venous and arterial trajectories, but there was no difference between SCZ and BD patients. The machine learning showed an accuracy of 86% and 73% for classifying HV versus SCZ and BD, respectively.
Conclusion
Smaller trajectories of retinal arteries indicate wider and flatter curves in SCZ and BD. Considering the relation between retinal/cerebral vasculatures and retinal nerve fiber layer thinness, the retinal vascular trajectory is a potential marker for SCZ and BD. As a relatively affordable investigation, retinal fundus photography should be further explored in SCZ and BD as a potential screening measure.
Objectives
The examination of retinal microvascular abnormalities through fundus photography is currently the best available non‐invasive technique for assessment of cerebral vascular status. Several ...studies in the last decade have reported higher incidences of adverse cerebrovascular events in Schizophrenia (SCZ) and bipolar disorder (BD). However, retinal microvasculature abnormalities in SCZ and BD have remained under‐explored, and no study has compared this aspect of SCZ and BD till date.
Methods
Retinal Images of 100 SCZ patients, BD patients, and healthy volunteers each were acquired by trained individuals using a non‐mydriatic camera with a 40‐degree field of view. The retinal images were quantified using a valid semi‐automated method. The average of left and right eye diameters of the venules and arterioles passing through the extended zone between 0.5 and 2 disc diameters from the optic disc were calculated.
Results
The groups differed significantly with respect to average diameters of both retinal venules (P < 0.001) and retinal arterioles (P < 0.001), after controlling for age and sex. Both SCZ and BD patients had significantly narrower arterioles and wider venules compared to HV. There were also significant differences between SCZ and BD patients; patients with BD had narrower arterioles and wider venules.
Conclusion
Considering the affordability and easy accessibility of the investigative procedure, retinal microvascular examination could serve as a potential screening tool to identify individuals at risk for adverse cerebrovascular events. The findings of the current study also provide a strong rationale for further systematic examination of retinal vascular abnormalities in SCZ and BD.
Tumor cure with conventional fractionated radiotherapy is 65%, dependent on tumor cell-autonomous gradual buildup of DNA double-strand break (DSB) misrepair. Here we report that single-dose ...radiotherapy (SDRT), a disruptive technique that ablates more than 90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase-mediated (ASMase-mediated) microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality. ASMase-mediated microcirculatory vasoconstriction after SDRT conferred an ischemic stress response within parenchymal tumor cells, with ROS triggering the evolutionarily conserved SUMO stress response, specifically depleting chromatin-associated free SUMO3. Whereas SUMO3, but not SUMO2, was indispensable for homology-directed repair (HDR) of DSBs, HDR loss of function after SDRT yielded DSB unrepair, chromosomal aberrations, and tumor clonogen demise. Vasoconstriction blockade with the endothelin-1 inhibitor BQ-123, or ROS scavenging after SDRT using peroxiredoxin-6 overexpression or the SOD mimetic tempol, prevented chromatin SUMO3 depletion, HDR loss of function, and SDRT tumor ablation. We also provide evidence of mouse-to-human translation of this biology in a randomized clinical trial, showing that 24 Gy SDRT, but not 3×9 Gy fractionation, coupled early tumor ischemia/reperfusion to human cancer ablation. The SDRT biology provides opportunities for mechanism-based selective tumor radiosensitization via accessing of SDRT/ASMase signaling, as current studies indicate that this pathway is tractable to pharmacologic intervention.
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