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Importance The impact of patient-specific, disease-related, and social factors on outcomes in limited-stage small cell lung cancer (LS-SCLC) is not well defined. A post hoc secondary analysis of such factors from the Cancer and Leukemia Group B (CALGB) 30610–Radiation Therapy Oncology Group (RTOG) 0538 trial may impact future trial design. Objective To assess the comprehensive demographic, disease-related, treatment-related, and social factors for potential associations with survival outcomes and understand whether specific subpopulations may benefit from radiotherapy (RT) dose escalation in LS-SCLC. Design, Setting, and Participants This post hoc secondary analysis of a randomized clinical trial included 638 adults with LS-SCLC treated at 186 unique treatment sites with at least 1 accrual for all patients from March 15, 2008, to December 1, 2019; 313 patients were randomized to receive RT twice daily to a dosage of 45 Gy for 3 weeks and 325 to receive RT once daily to a dosage of 70 Gy for 7 weeks. Data were locked February 28, 2022, and analyzed from November 28, 2022, to June 4, 2024. Interventions Twice-daily RT or once-daily RT. Main Outcomes and Measures Multivariable Cox proportional hazards models evaluated the association of treatment groups and other risk factors with progression-free survival (PFS) and overall survival (OS). Patient-specific factors included age, sex, and Eastern Cooperative Oncology Group performance status. Disease-related factors included tumor, nodal, and overall cancer stages. Treatment-related factors included type of chemotherapy, timing of concurrent RT, RT technique, and prophylactic cranial irradiation. Social factors included marital status and treatment center accrual volume. Results Among 507 patients (260 [51.3%] female and 247 [48.7%] male; mean [SD] age, 62.6 [7.9] years) included in the multivariate survival analysis, with a median follow-up of 4.7 (IQR, 3.7-7.1) years, female sex was associated with improved OS (hazard ratio [HR], 0.73 [95% CI, 0.58-0.91]; P = .006), while being 70 years or older was associated with decreased OS (HR, 1.50 [95% CI, 1.14-1.98]; P = .004). Neither age nor sex was associated with PFS. When compared with those with N1 disease, OS and PFS were worse in patients with N2 (HRs, 1.64 [95% CI, 1.19-2.26]; P = .002 and 1.36 [95% CI, 1.02-1.81]; P = .04, respectively) and N3 (HRs, 2.03 [95% CI, 1.40-2.93]; P < .001 and 1.63 [95% CI, 1.17-2.26]; P = .004) disease. Compared with stage II cancer, OS was worse for stage IIIA (HR, 1.65 [95% CI, 1.17-2.31]; P = .004) and stage IIIB (HR, 1.94 [95% CI, 1.34-2.83]; P < .001). Compared with high-volume accrual centers, treatment at low- or middle-volume accrual centers was associated with worse PFS (HRs, 1.94 [95% CI, 1.33-2.82; P < .001] and 1.44 [95% CI, 1.15-1.82; P = .002], respectively) and worse OS (HRs, 1.55 [95% CI, 1.03-2.32; P = .03] and 1.33 [95% CI, 1.04-1.70; P = .02], respectively). Conclusions and Relevance This secondary analysis of the CALGB 30610–RTOG 0538 randomized clinical trial of patients with LS-SCLC found associations between female sex or being younger than 70 years and improved overall survival and between advanced nodal stage or treatment at low- or middle-volume accrual centers and worse outcomes. These findings suggest that stratification by nodal stage, clinical stage, and age should be considered in future randomized trials. Trial Registration ClinicalTrials.gov Identifier: NCT00632853

Background SynthesiZed Improved Resolution and Concurrent nOise reductioN (ZIRCON) is a multi-kernel synthesis method that creates a single series of thin-slice computed tomography (CT) images displaying low noise and high spatial resolution, increasing reader efficiency and minimizing partial volume averaging. Purpose To compare the diagnostic performance of a single set of ZIRCON images to two routine clinical image series using conventional CT head and bone reconstruction kernels for diagnosing intracranial findings and fractures in patients with trauma or suspected acute neurologic deficit. Material and Methods In total, 50 patients underwent clinically indicated head CT in the ER (15 normal, 35 abnormal cases). A non-reader neuroradiologist established the reference standard. Three neuroradiologists reviewed two routine clinical series (head and bone kernels) and a single ZIRCON series, detecting intracranial findings or fractures and rating confidence (0–100). Sensitivity, specificity, and jackknife free-response receiver operating characteristic (JAFROC) figure of merit (FOM) were compared (limit of non-inferiority: −0.10). Results ZIRCON and conventional images demonstrated comparable performance for fractures (sensitivity: 51.5% vs. 54.5%; specificity: 40.2% vs. 34.2%) and intracranial findings (sensitivity: 88.2% vs. 91.4%; specificity: 77.2% vs. 73.7%).The estimated difference of JAFROC FOM demonstrated ZIRCON non-inferiority for acute pathologies overall (0.003 [95% CI=−0.051–0.057]) and fractures (0.048 [95% CI=−0.050–0.145]) but not for intracranial findings alone (−0.024 [95% CI=−0.100–0.052]). Conclusion Thin-slice, low noise, and high spatial resolution images can be created to display intracranial findings and fractures replacing multiple images series in head CT with similar performance. Future studies in more patients and further algorithmic development are warranted.

Abstract Background Radiotherapy of breast cancer can be associated with dermatitis. Grade ≥ 2 radiation dermatitis can be painful and impair the patients’ quality of life. To reduce the risk of this complication, patients have to perform skin care several times each day. This may require a considerable level of compliance. This randomized DAI-BREAC trial investigates whether a mobile application reminding the patients four times per day to perform skin care (reminder app) will contribute to reduction of grade ≥ 2 radiation dermatitis. Methods This multinational, randomized, active-controlled, parallel-group, multicenter trial compares standard skin care supported by a reminder app (Arm A) versus standard skin care alone (Arm B) regarding grade ≥ 2 radiation dermatitis in patients receiving adjuvant radiotherapy for breast cancer. The effect of the app will be considered clinically relevant, if the rate of grade ≥ 2 radiation dermatitis is reduced from 25.4% (rate identified in a preceding study) to 15%. A total of 134 patients per arm including drop-outs are required. Secondary aims include pain (visual analogue scale), patient satisfaction with the app (questionnaire), impact of the app on the use of health technology (questionnaire), and benefit from support (coaching) by staff members regarding the use of the app (questionnaire). Discussion If reminder app contributes to a decrease of grade ≥ 2 radiation dermatitis in patients irradiated for breast cancer, it will likely become a useful instrument for these patients. Trial registration: clinicaltrials.gov (NCT06483477; URL: https://clinicaltrials.gov/show/NCT06483477). Registered on 1st of July, 2024. First patient is planned to be included in September 2024.

Background: Recent literature demonstrated a 24-hour reduction in vancomycin duration of therapy (DOT) for skin and soft tissue infections (SSTIs) with a negative methicillin-resistant staphylococcus aureus (MRSA) nasal screening versus a positive nasal screening. Objective of this study was to investigate vancomycin DOT in patients with SSTIs who received MRSA nasal polymerase chain reaction (PCR) screening versus those who did not receive MRSA nasal PCR screening. Methods: A retrospective, multi-center, cohort study was completed in admitted adult patients on vancomycin for SSTI from 01/01/2020 to 09/30/2022. Hospital policy permits any clinician to order a MRSA nasal PCR screening test for various indications, including SSTIs, pneumonia and sepsis. Results: One-hundred-fifty-one patients were included, of which 71 had MRSA nasal PCR screening tests obtained, and 80 did not. The median vancomycin DOT in patients with MRSA nasal PCR screening tests was 19.9 versus 36.7 hours ( P = .014) in patients without screening tests. Conclusion: Patients with SSTIs who receive MRSA nasal PCR screening tests have a shortened vancomycin DOT. These results contribute to current data in support of the efficacy and clinical utility of obtaining MRSA nasal PCR screening tests for SSTIs.

Abstract Many patients in the emergency department present with signs and symptoms that arouse concern for sepsis; however, other explanations are also possible. There are currently no rapid tests used in clinical practice that reliably distinguish the presence of a bacterial or viral infection vs. a non-infectious etiology and can predict a patient’s likelihood to decompensate. The diagnostic and prognostic uncertainty in “gray zone” patients complicates the decision to begin therapy as clinicians need to balance the risk of withholding therapy vs. the risk of the therapy itself (e.g., overtreatment with antibiotics and hospitalization, which is costly, potentially harmful, and contributes to antibiotic resistance). The TriVerity™ Test uses isothermal amplification and machine-learning algorithms to quantify and interpret mRNA expression levels to determine both likelihood of bacterial infection, viral infection, or no infection, and whether the patient will likely require one or more critical interventions within 7 days. The three scores each fall into one of five interpretation bands ranging from Very high to Very low. Testing takes approximately 30 minutes using the proprietary Myrna™ Instrument with an operator hands-on-time of under one minute. We enrolled 1,222 patients from 22 emergency departments (ED) to validate the performance of the TriVerity Test. Patients were treated as per local standard of care and were followed for 28 days. Bacterial and viral TriVerity results were validated against clinically adjudicated infection status; the illness severity TriVerity result was validated against the need for at least one critical interventions within 7 days. The bacterial TriVerity result had high AUROC for the diagnosis of bacterial infection (0.83; 80% CI 0.81–0.85) and divided bacterial infection likelihood scores into five interpretation bands with increasing likelihood ratios of infection ranging from Very low (LR- 0.08, 80% CI 0.06–0.11) to Very high (LR + 8.04, 80% CI 5.72–11.78). The AUROC for the bacterial TriVerity result was significantly higher compared to AUROCs for C-reactive protein, procalcitonin or white blood cell count. Similarly, the viral TriVerity score showed high AUROC for the diagnosis of viral infection (0.91; 80% CI 0.90–0.93) and likelihood ratios from Very low (LR- 0.09, 80% CI 0.05–0.14) to Very high (LR + 40.93; 80% CI 29.11–79.23). The TriVerity Illness Severity score showed a high AUROC for the prediction of illness severity (0.77; 80% CI 0.77–0.81) with scores divided into five interpretation bands with increasing likelihood ratios ranging from Very low (LR- 0.22; 80% CI 0.14–0.33) to Very high (LR + 11.33; 80% CI 7.31–17.00). TriVerity illness severity results allowed marked re-classification of the risk for “ICU-level care” as compared to clinical assessment (qSOFA scores) alone. In conclusion, TriVerity provides rapid, highly accurate and actionable results for the diagnosis and prognosis of patients with suspected acute infection and/or sepsis, supporting a major unmet medical need. TriVerity may improve personalized management of patients with suspected acute infections and suspected sepsis for improved overall healthcare outcomes.

Many patients with malignant spinal cord compression (MSCC) who are not candidates for neurosurgery receive radiotherapy alone. This study compared 15 × 2.633 Gy over three weeks to 20 × 2.0 Gy over four weeks in patients with favorable survival prognoses. The outcomes of 34 patients treated with 15 × 2.633 Gy (equivalent dose 41.6 Gy10) in the RAMSES-01 trial were compared to 239 patients from an existing database receiving 20 × 2.0 Gy using propensity-score-adjusted Cox and logistic regression models. All patients had favorable survival prognoses. Endpoints included local progression-free survival (LPFS), improvement of motor function, post-treatment ambulatory status, and overall survival (OS). After propensity score adjustment, the 12-month rates of LPFS and OS were 98.1% (RAMSES-01 cohort) vs. 91.6% (p = 0.265) and 79.1% vs. 82.2% (p = 0.704), respectively. Regarding improvement of motor function, 15 × 2.633 Gy appeared superior (p = 0.073). No significant difference was observed regarding ambulatory status (p = 0.822). The three-week regimen for MSCC has similar outcomes and reduces treatment time when compared to a four-week regimen.

Objectives: Based in part on the results of randomized controlled trials (RCTs) that suggest a beneficial effect over alternative treatment options, the use of platelet-rich plasma (PRP) for the management of knee osteoarthritis (OA) is widespread and increasing. However, the extent to which these studies are vulnerable to slight variations in the outcomes of patients remains unknown. The purpose of this study is to evaluate the statistical fragility of conclusions from RCTs that reported outcomes of patients with knee OA who were treated with PRP versus alternative nonoperative management strategies. Methods: All RCTs comparing PRP to alternative nonoperative treatment options for knee OA were identified. The fragility index (FI) and reverse fragility index (RFI) were applied to assess the robustness of conclusions regarding the efficacy of PRP for knee OA. Meta-analyses were performed to determine the minimum number of patients from one or more trials included in the meta-analysis for which a modification on the event status would change the statistical significance of the pooled treatment effect. Results: In total, this analysis included outcomes from 1993 patients with a mean (± standard deviation) age of 58.0 ± 3.8 years. The mean number of events required to reverse significance (FI) was 4.57 ± 5.85. This corresponded to a fragility quotient of 0.060 ± 0.075, meaning the significance of the results was contingent on 6 events per 100 participants. For non-significant outcome events, the mean number of events required to reverse statistical nonsignificance (RFI) was 4.41 ± 2.22. This corresponded to a reverse fragility quotient of 0.065 ± 0.056, meaning the non-significance of the results was contingent on 6.5 events per 100 participants (Figure 1). Based on random-effects meta-analyses, PRP demonstrated a significantly higher rate of successful outcomes when compared to hyaluronic acid (p = 0.002, odds ratio 95% CI = 2.19 [1.33-3.62]) (Figure 2) as well as higher rates of patient-reported symptom relief (p = 0.019, odds ratio [95% CI] = 1.55 [1.07-2.24]) (Figure 3), not requiring a reintervention after the initial injection treatment (p = 0.002, odds ratio [95% CI] = 2.17 [1.33-3.53]) (Figure 4), and achieving the minimal clinically important difference (MCID) for pain improvement (p = 0.007, odds ratio [95% CI] = 6.19[1.63-23.42]) when compared to all alternative nonoperative treatments. Overall, the mean number of events per meta-analysis required to change the statistical significance of the pooled treatment effect was 8.67 ± 4.50. Conclusions: Individual RCTs evaluating PRP for knee OA possess slight robustness. Upon meta-analysis, PRP demonstrated a significant advantage over HA as well as improved symptom relief, lower rates of reintervention, and more frequent achievement of the MCID for pain improvement when compared to alternative, nonoperative treatment options. Statistically significant pooled treatment effects evaluating PRP for knee OA are more robust than approximately half of all comparable meta-analyses in medicine and healthcare. Future RCTs and meta-analyses should consider reporting fragility indices and quotients to facilitate interpretation of results in their proper context. In addition, the robustness of these findings suggests that reconsideration of the American Academy of Orthopaedic Surgeons clinical practice guidelines around the use of PRP for knee OA may be warranted.

We performed 6-yr follow-up testing on a world record-breaking master marathon runner. We determined that his performance declined since his record-breaking marathon in 2018 primarily due to a reduction in V̇o2max. His max heart rate (HR) changed minimally, but his peak O2 pulse decreased, suggesting that his maximal stroke volume and/or arteriovenous O2 difference decreased. These changes likely reflect primarily age-related effects in the absence of an overt pathological disease process.

Background In this open-label, randomized, non-comparative, multicenter phase II study (Alliance A091401) we report on three expansion cohorts treated with nivolumab (N) with and without ipilimumab (N+I) and provide a multi-omic correlative analysis of actionable biomarkers. Methods Patients were randomized (non-comparative) to receive either N or N+I. The primary endpoint was a 6-month confirmed response rate (CRR) defined by Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included treatment-related adverse events (TRAEs), progression-free survival, and overall survival. Multi-omic correlative analyses were conducted using samples from both the primary and expansion cohorts. Results A total of 66 patients were evaluated for the primary endpoint with disease including gastrointestinal stromal tumor (GIST, n=18), undifferentiated pleomorphic sarcoma (UPS, n=24), and dedifferentiated liposarcoma (DDLPS, n=24). Neither N nor N+I achieved a complete or partial response in the GIST expansion cohort. In DDLPS and UPS, the primary response endpoint of CRR was met with N+I (both 16.6%, 2/12) but not with N alone (both 8.3%, 1/12). In the GIST cohort, TRAE was higher with N+I treatment, halting enrollment as required per protocol. In a correlative analysis of patients for the expansion cohort and the original cohort (n=86), traditional biomarkers of immunotherapy response were not correlated with response in any histological subtype. Markers of genomic instability including the presence of gene fusions and increased subclonal mutations correlated with improved clinical outcomes. Conclusions This expansion cohort reaffirms the outcomes of A091401. There remains a pressing need to determine the role of and predictive biomarkers for immunotherapy in sarcoma. Trial registration number NCT02500797.

Context: Epidemiological studies have shown an increased risk of musculoskeletal injury after concussion. The purpose of this study was to determine whether the reverse relationship exists, specifically whether there is an increased risk of concussion after an anterior cruciate ligament (ACL) injury in a population-based cohort. Design: Retrospective cohort. Methods: The Rochester Epidemiology Project was searched between 2000 and 2017 for International Classification of Diseases, 9th and 10th Revision codes relevant to the diagnosis and treatment of concussion and ACL tear. A total of 1294 unique patients with acute, isolated ACL tears and no previous history of concussion were identified. Medical records for cases were reviewed to confirm ACL tear diagnosis and to determine history of concussion after the ACL injury. Cases were matched by age, sex, and Rochester Epidemiology Project availability to patients without an ACL tear (1:3 match), resulting in 3882 controls. Medical records of matched control patients were reviewed to rule out history of ACL injury. The hazard ratio of concussion injury following an ACL injury was determined. Results: Nine patients with an ACL injury suffered concussion up to 3 years after the ACL injury. The rate of concussion was no different between ACL-injured cases (0.7%) compared with matched controls with no ACL injury (1.2%), which corresponded to a hazard ratio of 0.55 (95% confidence interval, 0.3–1.1; P = .10). Conclusions: Based on the current evidence, there does not appear to be a significant association between ACL injury and subsequent concussion, which suggests that a concussion uniquely affects the risk of future subsequent musculoskeletal injury.