A Phase II Prospective Blinded Trial of Magnetic Resonance Imaging and In-Bore Biopsy in Active Surveillance for Prostate Cancer.

OBJECTIVE: To demonstrate the added benefit of multiparametric (mp)MRI risk stratification during active surveillance. METHODS: This prospective, single-arm, nonrandomized study included 82 men with low-risk prostate cancer (PCa). We compared two biopsy strategies in parallel. The first biopsy strategy was an in-bore and transrectal ultrasound (TRUS) biopsy in men with suspicious mpMRI findings. The second was a TRUS biopsy in all 82 men, blinded to the results of the previously performed mpMRI. RESULTS: We identified 27/82 men with suspicious mpMRI. Of those 27 men, we detected 8/27 with csPCa on biopsy, and we identified two men with in-bore biopsy exclusively, three men with TRUS biopsy exclusively, and three men with both biopsy strategies. Of the 55/82 men with nonsuspicious mpMRI (who only received TRUS biopsies), two men had csPCa. TRUS biopsy of the entire cohort of 82 men would have led to the correct diagnosis of 80% men with csPCa, requiring all 82 men to receive biopsies (csPCa in 10% of the 82 biopsies). Conducting in-bore biopsies plus TRUS biopsies in men with suspicious mpMRI would have also led to the detection of 80% of men with csPCa, requiring only 27 men to receive biopsies (csPCa in 30% of the 27 biopsies). CONCLUSION: The combination of TRUS and in-bore biopsies, limited to men with suspicious mpMRI, resulted in a similar detection rate of csPCa compared to TRUS biopsies of all men but required only one-third of men to undergo biopsy. Our results indicate that in-bore and TRUS biopsies continue to complement each other.

Impact of pain and adverse health outcomes on long-term US testicular cancer survivors.

BACKGROUND: No study has quantified the impact of pain and other adverse health outcomes on global physical and mental health in long-term US testicular cancer survivors or evaluated patient-reported functional impairment due to pain. METHODS: Testicular cancer survivors given cisplatin-based chemotherapy completed validated surveys, including Patient-Reported Outcomes Measurement Information System v1.2 global physical and mental health, Patient-Reported Outcomes Measurement Information System pain questionnaires, and others. Multivariable linear regression examined relationships between 25 adverse health outcomes with global physical and mental health and pain-interference scores. Adverse health outcomes with a ß^ of more than 2 are clinically important and reported below. RESULTS: Among 358 testicular cancer survivors (median age = 46 years, interquartile range [IQR] = 38-53 years; median time since chemotherapy = 10.7 years, IQR = 7.2-16.0 years), median adverse health outcomes number was 5 (IQR = 3-7). A total of 12% testicular cancer survivors had 10 or more adverse health outcomes, and 19% reported chemotherapy-induced neuropathic pain. Increasing adverse health outcome numbers were associated with decreases in physical and mental health (P < .0001 each). In multivariable analyses, chemotherapy-induced neuropathic pain (ß^ = -3.72; P = .001), diabetes (ß^ = -4.41; P = .037), obesity (ß^ = -2.01; P = .036), and fatigue (ß^ = -8.58; P < .0001) were associated with worse global mental health, while being married or living as married benefited global mental health (ß^ = 3.63; P = .0006). Risk factors for pain-related functional impairment included lower extremity location (ß^ = 2.15; P = .04) and concomitant peripheral artery disease (ß^ = 4.68; P < .001). Global physical health score reductions were associated with diabetes (ß^ = -3.81; P = .012), balance or equilibrium problems (ß^ = -3.82; P = .003), cognitive dysfunction (ß^ = -4.43; P < .0001), obesity (ß^ = -3.09; P < .0001), peripheral neuropathy score (ß^ = -2.12; P < .0001), and depression (ß^ = -3.17; P < .0001). CONCLUSIONS: Testicular cancer survivors suffer adverse health outcomes that negatively impact long-term global mental health, global physical health, and pain-related functional status. Clinically important factors associated with worse physical and mental health identify testicular cancer survivors requiring closer monitoring, counseling, and interventions. Chemotherapy-induced neuropathic pain must be addressed, given its detrimental impact on patient-reported functional status and mental health 10 or more years after treatment.

Stereotactic Magnetic Resonance-guided Adaptive Radiation Therapy for Localized Kidney Cancer: Early Outcomes from a Prospective Phase 1 Trial and Supplemental Cohort.

Stereotactic magnetic resonance (MR)-guided adaptive radiotherapy (SMART) for renal cell carcinoma may result in more precise treatment delivery through the capabilities for improved image quality, daily adaptive planning, and accounting for respiratory motion during treatment with real-time MR tracking. In this study, we aimed to characterize the safety and feasibility of SMART for localized kidney cancer. Twenty patients with localized kidney cancer (ten treated in a prospective phase 1 trial and ten in the supplemental cohort) were treated to 40 Gy in five fractions on a 0.35 T MR-guided linear accelerator with daily adaptive planning and a cine MR-guided inspiratory breath hold technique. The median follow-up time was 17 mo (interquartile range: 13-20 months). A single patient developed local failure at 30 mo. No grade ≥3 adverse events were reported. The mean decrease in estimated glomerular filtration rate was -1.8 ml/min/1.73 m2 (95% confidence interval or CI [-6.6 to 3.1 ml/min/1.73 m2]), and the mean decrease in tumor diameter was -0.20 cm (95% CI [-0.6 to 0.2 cm]) at the last follow-up. Anterior location and overlap of the 25 or 28 Gy isodose line with gastrointestinal organs at risk were predictive of the benefit from online adaptive planning. Kidney SMART is feasible and, at the early time point evaluated in this study, was well tolerated with minimal decline in renal function. More studies are warranted to further evaluate the safety and efficacy of this technique. PATIENT SUMMARY: For patients with localized renal cell carcinoma who are not surgical candidates, stereotactic magnetic resonance--guided adaptive radiotherapy is a feasible and safe noninvasive treatment option that results in minimal impact on kidney function.

Clinical Outcomes of De Novo Versus Relapsed Early Metastatic Testicular Seminoma Treated With Contemporary Radiation Therapy.

PURPOSE: Chemotherapy (CHT) or radiation therapy (RT) are first-line treatments for clinical stage II (CS-II) testicular seminoma. Historically, clinical stage I (CS-I) seminoma was also treated with CHT or RT, but in the past 2 decades practice has shifted toward active surveillance for CS-I with RT or CHT reserved for patients with progression to CS-II. Limited data exist on contemporary RT techniques and patient stratification (ie, de novo [CS-II at orchiectomy] vs relapsed [CS-II diagnosed during surveillance after orchiectomy for CS-I]). We investigated outcomes in CS-II patients treated with RT in the modern era across 2 institutions. METHODS AND MATERIALS: A retrospective review identified 73 patients treated with RT for CS-II A or B seminoma between 2001 and 2022. Recurrence-free survival (RFS) was calculated by the Kaplan-Meier method and univariate analyses were performed with log-rank or Cox proportional hazard regression. Recurrence was defined as biopsy-proven metastatic seminoma after RT completion. Second malignancies were defined as a biopsy-proven malignancy originating in the prior RT field. RESULTS: Thirty-eight (52%) patients presented with de novo CS-II and 35 (48%) patients had relapsed CS-II. Median follow-up was 4.8 years (IQR: 2.3-8.1). Five-year RFS was 82% overall (92% in relapsed patients and 73% in de novo patients). Relapsed CS-II disease had lower recurrence rates after RT compared with de novo CS-II disease. All recurrences occurred outside the prior RT field and were salvaged. Disease-specific survival was 100%. Two second malignancies occurred (prostate, colorectal cancer at 67 months and 119 months post-RT, respectively). CONCLUSIONS: In patients with CS-II seminoma treated with modern RT, there were no in-field recurrences. Presentation with de novo CS-II is associated with out-of-field recurrence. Subject to further larger-scale validation, our results suggest that compared with CS-II at time of relapse, de novo CS-II may portend more aggressive or micrometastatic disease beyond the retroperitoneum, raising the possibility of benefit from CHT after radiation.

Combined effects of green tea supplementation and eccentric exercise on nuclear factor erythroid 2-related factor 2 activity.

PURPOSE: This study investigated whether combining eccentric exercise and green tea supplementation synergistically increased nuclear factor erythroid 2-related factor 2 (NRF2) activity, a transcription factor responsible for coordinating endogenous antioxidant expression. METHODS: In a double-blinded, randomized, between-subjects design, 24 males (mean [SD]; 23 [3] years, 179.6 [6.1] cm, 78.8 [10.6] kg) performed 100 drop jumps following a 6 days supplementation period with either green tea (poly)phenols (n = 12; 500 mg·d-1) or a placebo (n = 12; inulin). NRF2/antioxidant response element (ARE) binding in peripheral blood mononuclear cells (PBMCs), catalase (CAT) and glutathione reductase (GR) activity, 8-hydroxy-2'-deoxyguanosine (8-OHdG) excretion, and differential leukocyte counts were measured pre-, post-, 1 h and 24 h post-exercise. RESULTS: Exercise did not increase NRF2/ARE binding (p = 0.12) (fold change vs rest: green tea = [post] 0.78 ± 0.45, [1 h] 1.17 ± 0.54, [24 h] 1.06 ± 0.56; placebo = [post] 1.40 ± 1.50, [1 h] 2.98 ± 3.70, [24 h] 1.04 ± 0.45). Furthermore, CAT activity (p = 0.12) and 8-OHdG excretion (p = 0.42) were unchanged in response to exercise and were not augmented by green tea supplementation (p > 0.05 for all). Exercise increased GR activity by 30% (p = 0.01), however no differences were found between supplement groups (p = 0.51). Leukocyte and neutrophil concentrations were only elevated post-exercise (p < 0.001 for all). CONCLUSION: Eccentric exercise, either performed alone or in conjunction with green tea supplementation, did not significantly increase NRF2 activity in PBMCs. TRIAL REGISTRATION NUMBER: osf.io/kz37g (registered: 15/09/21).

Analysis of comorbidities and multimorbidity in adult patients in the International Severe Asthma Registry.

BACKGROUND: Investigation for the presence of asthma comorbidities is recommended by the Global Initiative for Asthma because their presence can complicate asthma management. OBJECTIVE: To understand the prevalence and pattern of comorbidities and multimorbidity in adults with severe asthma and their association with asthma-related outcomes. METHODS: This was a cross-sectional study using data from the International Severe Asthma Registry from 22 countries. A total of 30 comorbidities were identified and categorized a priori as any of the following: (1) potentially type 2-related comorbidities, (2) potentially oral corticosteroid (OCS)-related comorbidities, or (3) comorbidities mimicking or aggravating asthma. The association between comorbidities and asthma-related outcomes was investigated using multivariable models adjusted for country, age at enrollment, and sex (ie male or female). RESULTS: Of the 11,821 patients, 69%, 67%, and 55% had at least 1 potentially type 2-related, potentially OCS-related, or mimicking or aggravating comorbidities, respectively; 57% had 3 or more comorbidities, and 33% had comorbidities in all 3 categories. Patients with allergic rhinitis, nasal polyposis, and chronic rhinosinusitis experienced 1.12 (P = .003), 1.16 (P < .001), and 1.29 times (P < .001) more exacerbations per year, respectively, than those without. Patients with nasal polyposis and chronic rhinosinusitis were 40% and 46% more likely (P < .001), respectively, to have received long-term (LT) OCS. All assessed potential OCS-related comorbidities (except obesity) were associated with a greater likelihood of LTOCS use (odds ratios [ORs]: 1.23-2.77) and, except for dyslipidemia, with a greater likelihood of uncontrolled asthma (ORs: 1.29-1.68). All mimicking or aggravating comorbidities assessed were associated with more exacerbations (1.24-1.68 times more), all (except bronchiectasis) with increased likelihood of uncontrolled asthma (ORs: 1.57-1.81), and all (except chronic obstructive pulmonary disease) with increased likelihood of LTOCS use (ORs: 1.37-1.57). A greater number of comorbidities was associated with worse outcomes. CONCLUSION: In a global study, comorbidity or multimorbidity is reported in most adults with severe asthma and is associated with poorer asthma-related outcomes. CLINICAL TRIAL REGISTRATION: The International Severe Asthma Registry database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization Studies (European Network Centres for Pharmacoepidemiology and Pharmacovigilance [ENCEPP]/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EMA 2014; EUPAS44024) and with all applicable local and international laws and regulations, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=48848). Governance was provided by ADEPT (registration number: ADEPT1121).

Association Between T2-related Comorbidities and Effectiveness of Biologics in Severe Asthma.

Rationale: Previous studies investigating the impact of comorbidities on the effectiveness of biologic agents have been relatively small and of short duration and have not compared classes of biologic agents. Objectives: To determine the association between type 2-related comorbidities and biologic agent effectiveness in adults with severe asthma (SA). Methods: This cohort study used International Severe Asthma Registry data from 21 countries (2017-2022) to quantify changes in four outcomes before and after biologic therapy-annual asthma exacerbation rate, FEV1% predicted, asthma control, and long-term oral corticosteroid daily dose-in patients with or without allergic rhinitis, chronic rhinosinusitis (CRS) with or without nasal polyps (NPs), NPs, or eczema/atopic dermatitis. Measurements and Main Results: Of 1,765 patients, 1,257, 421, and 87 initiated anti-IL-5/5 receptor, anti-IgE, and anti-IL-4/13 therapies, respectively. In general, pre- versus post-biologic therapy improvements were noted in all four asthma outcomes assessed, irrespective of comorbidity status. However, patients with comorbid CRS with or without NPs experienced 23% fewer exacerbations per year (95% CI, 10-35%; P < 0.001) and had 59% higher odds of better post-biologic therapy asthma control (95% CI, 26-102%; P < 0.001) than those without CRS with or without NPs. Similar estimates were noted for those with comorbid NPs: 22% fewer exacerbations and 56% higher odds of better post-biologic therapy control. Patients with SA and CRS with or without NPs had an additional FEV1% predicted improvement of 3.2% (95% CI, 1.0-5.3; P = 0.004), a trend that was also noted in those with comorbid NPs. The presence of allergic rhinitis or atopic dermatitis was not associated with post-biologic therapy effect for any outcome assessed. Conclusions: These findings highlight the importance of systematic comorbidity evaluation. The presence of CRS with or without NPs or NPs alone may be considered a predictor of the effectiveness of biologic agents in patients with SA.

Enhanced recovery after brain tumor surgery: pilot protocol implementation in a large healthcare system.

OBJECTIVE: Enhanced recovery after surgery (ERAS) protocols have been used in numerous specialties to improve the safety, efficiency, and cost of surgical interventions. Despite these successes, implementation of ERAS in cranial neurosurgery remains limited. In this study, a comprehensive ERAS protocol was implemented at two pilot sites within the Providence Health & Services system, and groundwork was laid for systemwide adoption. METHODS: An enhanced recovery protocol was developed and implemented through an interdisciplinary team of clinicians, executive leadership, and clinical informatics professionals across preoperative, intraoperative, and postoperative domains. Outcomes including length of stay, discharge destination, and cost were collected through systemwide databases and compared with nonprotocolized sites. RESULTS: During the study period, both pilot sites became top performers across the regional system in all evaluated metrics. The median length of stay for elective craniotomy at site 1 was reduced to 1.25 days, with a home discharge rate of > 90%. The cost per case at the pilot sites was nearly $7000 less on average than that of the nonprotocolized sites. CONCLUSIONS: Implementation of enhanced recovery protocols for brain tumor surgery is feasible and effective, resulting in marked improvements in healthcare efficiency. Future studies, including implementation of the current protocol across the entire Providence system, are needed to maximize the potential benefits of enhanced recovery programs.

MR-guided prostate SBRT in prostate cancer patients with low-volume metastatic disease.

BACKGROUND: Recent data have found an overall survival benefit from prostate-directed radiotherapy in patients with low-volume metastatic prostate cancer. Prostate SBRT is an attractive treatment in this setting and may be optimised with MR-guided adaptive treatment. Here, we share our institutional experience delivering stereotactic MR-guided adaptive prostate SBRT (SMART) for patients with low-volume metastatic disease. METHODS: We reviewed patients with low-volume metastatic disease who received prostate SMART from October 2019 to December 2021 on a 0.35T MR-Linac. The cohort included 14 patients. Genitourinary (GU) and gastrointestinal (GI) toxicities were assessed using CTCAE v 5.0. Progression was defined as a change in systemic or hormonal therapy regimen as a result of PSA rise or disease progression. RESULTS: The median follow-up time was 29 months. Seven patients had hormone sensitive prostate cancer and 7 had castrate resistant prostate cancer (CRPC). 13 patients received 36.25 Gy in 5 fractions and one patient received 33 Gy in 5 fractions. At the time of last follow-up, 11 patients had not experienced progression and three patients, all with CRPC, had experienced progression. No patients developed local progression in the prostate after SMART. One patient experienced acute grade 2 urinary toxicity (7%) and no patients experienced acute grade 2 GI toxicity (0%). No grade 3 + acute toxicities were observed. CONCLUSIONS: Prostate SMART was found to be well tolerated and all patients had local control of disease within the prostate at the time of last follow-up. Prostate SMART may represent a low-risk and well-tolerated approach for delivering prostate-directed radiotherapy for patients with limited metastatic disease.

Adult Severe Asthma Registries: A Global and Growing Inventory.

Aim: The International Severe Asthma Registry (ISAR; http://isaregistries.org/) uses standardised variables to enable multi-country and adequately powered research in severe asthma. This study aims to look at the data countries within ISAR and non-ISAR countries reported collecting that enable global research that support individual country interests. Methods: Registries were identified by online searches and approaching severe asthma experts. Participating registries provided data collection specifications or confirmed variables collected. Core variables (results from ISAR's Delphi study), steroid-related comorbidity variables, biologic safety variables (serious infection, anaphylaxis, and cancer), COVID-19 variables and additional variables (not belonging to the aforementioned categories) that registries reported collecting were summarised. Results: Of the 37 registries identified, 26 were ISAR affiliates and 11 non-ISAR affiliates. Twenty-five ISAR-registries and 4 non-ISAR registries reported collecting >90% of the 65 core variables. Twenty-three registries reported collecting all optional steroid-related comorbidity variables. Twenty-nine registries reported collecting all optional safety variables. Ten registries reported collecting COVID-19 variables. Twenty-four registries reported collecting additional variables including data from asthma questionnaires (10 Asthma Control Questionnaire, 20 Asthma Control Test, 11 Asthma Quality of Life Questionnaire, and 4 EuroQol 5-dimension 5-level Questionnaire). Eight registries are linked to databases such as electronic medical records and national claims or disease databases. Conclusion: Standardised data collection has enabled individual severe asthma registries to collect unified data and increase statistical power for severe asthma research irrespective of ISAR affiliations.

Tezepelumab Efficacy in Patients with Severe, Uncontrolled Asthma with Comorbid Nasal Polyps in NAVIGATOR.

Purpose: Tezepelumab, a human monoclonal antibody, blocks thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab reduced annualized asthma exacerbation rates (AAERs) versus placebo, irrespective of baseline disease characteristics, and improved lung function and symptom control versus placebo in adults and adolescents with severe, uncontrolled asthma. We assessed the efficacy of tezepelumab in patients with severe asthma with or without nasal polyps (NPs) in the 2 years before randomization in NAVIGATOR. Methods: Patients with severe asthma (N=1059) were randomized (1:1) and received tezepelumab 210 mg or placebo every 4 weeks subcutaneously for 52 weeks. Prespecified exploratory analyses included: AAER over 52 weeks and changes from baseline to week 52 in pre-bronchodilator forced expiratory volume in 1 second, Sino-Nasal Outcome Test (SNOT)-22 scores, and asthma control and health-related quality life (HRQoL) outcomes in NP subgroups. Changes from baseline in fractional exhaled nitric oxide (FeNO), blood eosinophil counts, total immunoglobulin E (IgE), eosinophil-derived neurotoxin (EDN), matrix metalloproteinase-10 (MMP-10), and serum interleukin (IL)-5, IL-6, IL-8 and IL-13 were assessed (post hoc). Results: Tezepelumab reduced the AAER over 52 weeks versus placebo by 85% (95% confidence interval [CI]: 72, 92; n=118) and 51% (95% CI: 40, 60; n=941) in patients with and without NPs, respectively. At week 52, tezepelumab improved lung function, asthma control and HRQoL versus placebo in patients with and without NPs. Tezepelumab reduced SNOT-22 total scores (least-squares mean difference versus placebo [95% CI]) in patients with NPs at 28 weeks (-12.57 points [-19.40, -5.73]) and 52 weeks (-10.58 points [-17.75, -3.41]). At week 52, tezepelumab reduced blood eosinophil counts and FeNO, IgE, IL-5, IL-13, EDN and MMP-10 levels versus placebo, irrespective of NP status. Conclusion: Tezepelumab resulted in clinically meaningful improvements in sino-nasal symptoms and asthma outcomes in patients with severe asthma with comorbid NPs.

Acute toxicity comparison of magnetic resonance-guided adaptive versus fiducial or computed tomography-guided non-adaptive prostate stereotactic body radiotherapy: A systematic review and meta-analysis.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is gaining wider adoption for prostate cancer management but there remain significant toxicity risks when delivering prostate SBRT with standard techniques. Magnetic resonance-guided daily adaptive SBRT (MRg-A-SBRT) offers technological advantages in precision of radiation dose delivery, but the toxicity profile associated with MRg-A-SBRT compared to more standardly used fiducial or computed tomography-guided non-adaptive prostate SBRT (CT-SBRT) remains unknown. METHODS: A meta-analysis to compare acute toxicity rates associated with MRg-A-SBRT and CT-SBRT for prostate cancer was performed in compliance with PRISMA guidelines. MEDLINE (PubMed) and Google Scholar were searched for prospective studies of prostate SBRT that were published between January 1, 2018 and August 31, 2022. Random effects and fixed effects models were used to estimate pooled toxicity rates, and meta-regression was performed to compare toxicity between MRg-A-SBRT and CT-SBRT study groups. RESULTS: Twenty-nine prospective studies were identified that met the inclusion criteria and included a total of 2547 patients. The pooled estimates for acute grade 2 or higher (G2+) genitourinary (GU) and gastrointestinal (GI) toxicity for MRg-A-SBRT were 16% (95% confidence interval [CI], 10%-24%) and 4% (95% CI, 2%-7%) and for CT-SBRT they were 28% (95% CI, 23%-33%) and 9% (95% CI, 6%-12%), respectively. On meta-regression, the odds ratios for acute G2+ GU and GI toxicities comparing MRg-A-SBRT and CT-SBRT were 0.56 (95% CI, 0.33-0.97, p = .04) and 0.40 (95% CI, 0.17-0.96, p = .04), respectively. CONCLUSION: MRg-A-SBRT is associated with a significantly reduced risk of acute G2+ GU or GI toxicity compared to CT-SBRT. Longer follow-up will be needed to evaluate late toxicity and disease control outcomes. PLAIN LANGUAGE SUMMARY: Magnetic resonance imaging-guided daily adaptive prostate stereotactic radiation (MRg-A-SBRT) is a treatment that may allow for delivery of prostate radiation more precisely than other radiotherapy techniques, but it is unknown whether this reduces side effects compared to standardly used computed tomography-guided SBRT (CT-SBRT). In this systematic review and meta-analysis combining data from 29 clinical trials including 2547 patients, it was found that the risk of short-term urinary side effects was reduced by 44% and the risk of short-term bowel side effects was reduced by 60% with MRg-A-SBRT compared to CT-SBRT.

Effect of Biologic Therapies on Airway Hyperresponsiveness and Allergic Response: A Systematic Literature Review.

Background: Airway hyperresponsiveness (AHR) is a key feature of asthma. Biologic therapies used to treat asthma target specific components of the inflammatory pathway, and their effects on AHR can provide valuable information about the underlying disease pathophysiology. This review summarizes the available evidence regarding the effects of biologics on allergen-specific and non-allergen-specific airway responses in patients with asthma. Methods: We conducted a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, including risk-of-bias assessment. PubMed and Ovid were searched for studies published between January 1997 and December 2021. Eligible studies were randomized, placebo-controlled trials that assessed the effects of biologics on AHR, early allergic response (EAR) and/or late allergic response (LAR) in patients with asthma. Results: Thirty studies were identified for inclusion. Bronchoprovocation testing was allergen-specific in 18 studies and non-allergen-specific in 12 studies. Omalizumab reduced AHR to methacholine, acetylcholine or adenosine monophosphate (3/9 studies), and reduced EAR (4/5 studies) and LAR (2/3 studies). Mepolizumab had no effect on AHR (3/3 studies), EAR or LAR (1/1 study). Tezepelumab reduced AHR to methacholine or mannitol (3/3 studies), and reduced EAR and LAR (1/1 study). Pitrakinra reduced LAR, with no effect on AHR (1/1 study). Etanercept reduced AHR to methacholine (1/2 studies). No effects were observed for lebrikizumab, tocilizumab, efalizumab, IMA-638 and anti-OX40 ligand on AHR, EAR or LAR; benralizumab on LAR; tralokinumab on AHR; and Ro-24-7472 on AHR or LAR (all 1/1 study each). No dupilumab or reslizumab studies were identified. Conclusion: Omalizumab and tezepelumab reduced EAR and LAR to allergens. Tezepelumab consistently reduced AHR to methacholine or mannitol. These findings provide insights into AHR mechanisms and the precise effects of asthma biologics. Furthermore, findings suggest that tezepelumab broadly targets allergen-specific and non-allergic forms of AHR, and the underlying cells and mediators involved in asthma.

Patient Perception of Education, Care Coordination, and Psychological Distress After Developing Facial Paralysis: A Qualitative Study.

Importance: The management of vestibular schwannoma may include observation, microsurgical resection, or radiation of a tumor near the facial nerve. Injury to the facial nerve can result in facial paralysis with major functional, social, and psychological sequelae, and the experiences of patients after paralysis are not well studied. Objective: To (1) identify patient preparedness for developing facial paralysis and how well their care is coordinated following its development and (2) present in their own words outcomes of facial paralysis in terms of physical health, emotional health, self-perception, and social interactions. Design, Setting, and Participants: A qualitative observational study was performed using semistructured interviews at a tertiary care academic medical center. Semistructured interviews were conducted between January 1, 2018, and June 30, 2019, with adults aged 25 to 70 years who developed facial paralysis after treatment for vestibular schwannoma. Data were analyzed from July 2019 to June 2020. Main Outcomes and Measures: Perceptions of the educational and emotional experiences of individuals who developed complete facial paralysis after surgical treatment of vestibular schwannoma. Results: Overall, 12 participants were interviewed (median age, 54 years [range, 25-70 years]; 11 were female). Saturation was achieved after 12 interviews, indicating that no further information could be elicited from additional interviews. Four major themes were identified: (1) lack of sufficient patient education about the diagnosis of facial paralysis; (2) lack of appropriate care coordination related to facial paralysis; (3) changes in physical and emotional health following facial paralysis; and (4) changes in social interactions and external support following facial paralysis. Conclusions and Relevance: It is well-known that patients with facial paralysis have reduced quality of life, severe psychological and emotional sequelae. However, little is currently done to help prepare patients for this undesirable outcome. In this qualitative study of facial paralysis, patients express, in their own words, their feeling that the education and management of facial paralysis by their clinicians was inadequate. Before patients undergo surgery, and certainly after injury to the facial nerve, clinicians should consider the patient's goals, preferences, and values to ensure that a comprehensive educational program and psychosocial support system are implemented. Facial reanimation research has not adequately captured these key patient factors associated with the quality of communication.

Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial.

BACKGROUND: The interim analysis of the ENZAMET trial of testosterone suppression plus either enzalutamide or standard nonsteroidal antiandrogen therapy showed an early overall survival benefit with enzalutamide. Here, we report the planned primary overall survival analysis, with the aim of defining the benefit of enzalutamide treatment in different prognostic subgroups (synchronous and metachronous high-volume or low-volume disease) and in those who received concurrent docetaxel. METHODS: ENZAMET is an international, open-label, randomised, phase 3 trial conducted at 83 sites (including clinics, hospitals, and university centres) in Australia, Canada, Ireland, New Zealand, the UK, and the USA. Eligible participants were males aged 18 years or older with metastatic, hormone-sensitive prostate adenocarcinoma evident on CT or bone scanning with 99mTc and an Eastern Cooperative Oncology Group performance status score of 0-2. Participants were randomly assigned (1:1), using a centralised web-based system and stratified by volume of disease, planned use of concurrent docetaxel and bone antiresorptive therapy, comorbidities, and study site, to receive testosterone suppression plus oral enzalutamide (160 mg once per day) or a weaker standard oral non-steroidal antiandrogen (bicalutamide, nilutamide, or flutamide; control group) until clinical disease progression or prohibitive toxicity. Testosterone suppression was allowed up to 12 weeks before randomisation and for up to 24 months as adjuvant therapy. Concurrent docetaxel (75 mg/m2 intravenously) was allowed for up to six cycles once every 3 weeks, at the discretion of participants and physicians. The primary endpoint was overall survival in the intention-to-treat population. This planned analysis was triggered by reaching 470 deaths. This study is registered with ClinicalTrials.gov, NCT02446405, ANZCTR, ACTRN12614000110684, and EudraCT, 2014-003190-42. FINDINGS: Between March 31, 2014, and March 24, 2017, 1125 participants were randomly assigned to receive non-steroidal antiandrogen (n=562; control group) or enzalutamide (n=563). The median age was 69 years (IQR 63-74). This analysis was triggered on Jan 19, 2022, and an updated survival status identified a total of 476 (42%) deaths. After a median follow-up of 68 months (IQR 67-69), the median overall survival was not reached (hazard ratio 0·70 [95% CI 0·58-0·84]; p<0·0001), with 5-year overall survival of 57% (0·53-0·61) in the control group and 67% (0·63-0·70) in the enzalutamide group. Overall survival benefits with enzalutamide were consistent across predefined prognostic subgroups and planned use of concurrent docetaxel. The most common grade 3-4 adverse events were febrile neutropenia associated with docetaxel use (33 [6%] of 558 in the control group vs 37 [6%] of 563 in the enzalutamide group), fatigue (four [1%] vs 33 [6%]), and hypertension (31 [6%] vs 59 [10%]). The incidence of grade 1-3 memory impairment was 25 (4%) versus 75 (13%). No deaths were attributed to study treatment. INTERPRETATION: The addition of enzalutamide to standard of care showed sustained improvement in overall survival for patients with metastatic hormone-sensitive prostate cancer and should be considered as a treatment option for eligible patients. FUNDING: Astellas Pharma.

Comparison of MR-soft tissue based versus biliary stent based alignment for image guidance in pancreatic SBRT.

PURPOSE: The role of biliary stents in image-guided localization for pancreatic cancer has been inconclusive. To date, stent accuracy has been largely evaluated against implanted fiducials on cone beam computed tomography. We aim to use magnetic resonance (MR) soft tissue as a direct reference to examine the geometric and dosimetric impacts of stent-based localization on the newly available MR linear accelerator. METHODS: Thirty pancreatic cancer patients (132 fractions) treated on our MR linear accelerator were identified to have a biliary stent. In our standard adaptive workflow, patients were set up to the target using soft tissue for image registration and structures were re-contoured on daily MR images. The original plan was then projected on treatment anatomy and dose predicted, followed by plan re-optimization and treatment delivery. These online predicted plans were soft tissue-based and served as reference plans. Retrospective image registration to the stent was performed offline to simulate stent-based localization and the magnitude of shifts was taken as the geometric accuracy of stent localization. New predicted plans were generated based on stent-alignment for dosimetric comparison. RESULTS: Shifts were within 3 mm for 90% of the cases (mean = 1.5 mm); however, larger shifts up to 7.2 mm were observed. Average PTV coverage dropped by 1.1% with a maximum drop of 26.8%. The mean increase in V35Gy was 0.15, 0.05, 0.02, and 0.02 cc for duodenum, stomach, small bowel and large bowel, respectively. Stent alignment was significantly worse for all metrics except for small bowel (p = 0.07). CONCLUSIONS: Overall discrepancy between stent- and soft tissue-alignment was modest; however, large discrepancies were observed for select cases. While PTV coverage loss may be compensated for by using a larger margin, the increase in dose to gastrointestinal organs at risk may limit the role of biliary stents in image-guided localization.

Non-invasive estimation of muscle fibre size from high-density electromyography.

Because of the biophysical relation between muscle fibre diameter and the propagation velocity of action potentials along the muscle fibres, motor unit conduction velocity could be a non-invasive index of muscle fibre size in humans. However, the relation between motor unit conduction velocity and fibre size has been only assessed indirectly in animal models and in human patients with invasive intramuscular EMG recordings, or it has been mathematically derived from computer simulations. By combining advanced non-invasive techniques to record motor unit activity in vivo, i.e. high-density surface EMG, with the gold standard technique for muscle tissue sampling, i.e. muscle biopsy, here we investigated the relation between the conduction velocity of populations of motor units identified from the biceps brachii muscle, and muscle fibre diameter. We demonstrate the possibility of predicting muscle fibre diameter (R2  = 0.66) and cross-sectional area (R2  = 0.65) from conduction velocity estimates with low systematic bias (∼2% and ∼4% respectively) and a relatively low margin of individual error (∼8% and ∼16%, respectively). The proposed neuromuscular interface opens new perspectives in the use of high-density EMG as a non-invasive tool to estimate muscle fibre size without the need of surgical biopsy sampling. The non-invasive nature of high-density surface EMG for the assessment of muscle fibre size may be useful in studies monitoring child development, ageing, space and exercise physiology, although the applicability and validity of the proposed methodology need to be more directly assessed in these specific populations by future studies. KEY POINTS: Because of the biophysical relation between muscle fibre size and the propagation velocity of action potentials along the sarcolemma, motor unit conduction velocity could represent a potential non-invasive candidate for estimating muscle fibre size in vivo. This relation has been previously assessed in animal models and humans with invasive techniques, or it has been mathematically derived from simulations. By combining high-density surface EMG with muscle biopsy, here we explored the relation between the conduction velocity of populations of motor units and muscle fibre size in healthy individuals. Our results confirmed that motor unit conduction velocity can be considered as a novel biomarker of fibre size, which can be adopted to predict muscle fibre diameter and cross-sectional area with low systematic bias and margin of individual error. The proposed neuromuscular interface opens new perspectives in the use of high-density EMG as a non-invasive tool to estimate muscle fibre size without the need of surgical biopsy sampling.

Patient-Reported Functional Impairment Due to Hearing Loss and Tinnitus After Cisplatin-Based Chemotherapy.

PURPOSE: Cisplatin is widely used and highly ototoxic, but patient-reported functional impairment because of cisplatin-related hearing loss (HL) and tinnitus has not been comprehensively evaluated. PATIENTS AND METHODS: Testicular cancer survivors (TCS) given first-line cisplatin-based chemotherapy completed validated questionnaires, including the Hearing Handicap Inventory for Adults (HHIA) and Tinnitus Primary Function Questionnaire (TPFQ), each of which quantifies toxicity-specific functional impairment. Spearman correlations evaluated associations between HL and tinnitus severity and level of functional handicap quantified with the HHIA and TPFQ, respectively. Associations between HL or tinnitus and five prespecified adverse health outcomes (cognitive dysfunction, fatigue, depression, anxiety, and overall health) were evaluated. RESULTS: HL and tinnitus affected 137 (56.4%) and 147 (60.5%) of 243 TCS, respectively. Hearing aids were used by 10% TCS (14/137). Of TCS with HL, 35.8% reported clinically significant functional impairment. Severe HHIA-assessed functional impairment was associated with cognitive dysfunction (odds ratio [OR], 10.62; P < .001), fatigue (OR, 5.48; P = .003), and worse overall health (OR, 0.19; P = .012). Significant relationships existed between HL severity and HHIA score, and tinnitus severity and TPFQ score (P < .0001 each). TCS with either greater hearing difficulty or more severe tinnitus were more likely to report cognitive dysfunction (OR, 5.52; P = .002; and OR, 2.56; P = .05), fatigue (OR, 6.18; P < .001; and OR, 4.04; P < .001), depression (OR, 3.93; P < .01; and OR, 3.83; P < .01), and lower overall health (OR, 0.39; P = .03; and OR, 0.46; P = .02, respectively). CONCLUSION: One in three TCS with HL report clinically significant functional impairment. Follow-up of cisplatin-treated survivors should include routine assessment for HL and tinnitus. Use of the HHIA and TPFQ permit risk stratification and referral to audiologists as needed, since HL adversely affects functional status and is the single largest modifiable risk factor for cognitive decline and dementia in the general population.

Handgrip Strength Is Related to Hippocampal and Lobar Brain Volumes in a Cohort of Cognitively Impaired Older Adults with Confirmed Amyloid Burden.

BACKGROUND: Strength and mobility are essential for activities of daily living. With aging, weaker handgrip strength, mobility, and asymmetry predict poorer cognition. We therefore sought to quantify the relationship between handgrip metrics and volumes quantified on brain magnetic resonance imaging (MRI). OBJECTIVE: To model the relationships between handgrip strength, mobility, and MRI volumetry. METHODS: We selected 38 participants with Alzheimer's disease dementia: biomarker evidence of amyloidosis and impaired cognition. Handgrip strength on dominant and non-dominant hands was measured with a hand dynamometer. Handgrip asymmetry was calculated. Two-minute walk test (2MWT) mobility evaluation was combined with handgrip strength to identify non-frail versus frail persons. Brain MRI volumes were quantified with Neuroreader. Multiple regression adjusting for age, sex, education, handedness, body mass index, and head size modeled handgrip strength, asymmetry and 2MWT with brain volumes. We modeled non-frail versus frail status relationships with brain structures by analysis of covariance. RESULTS: Higher non-dominant handgrip strength was associated with larger volumes in the hippocampus (p = 0.02). Dominant handgrip strength was related to higher frontal lobe volumes (p = 0.02). Higher 2MWT scores were associated with larger hippocampal (p = 0.04), frontal (p = 0.01), temporal (p = 0.03), parietal (p = 0.009), and occipital lobe (p = 0.005) volumes. Frailty was associated with reduced frontal, temporal, and parietal lobe volumes. CONCLUSION: Greater handgrip strength and mobility were related to larger hippocampal and lobar brain volumes. Interventions focused on improving handgrip strength and mobility may seek to include quantified brain volumes on MR imaging as endpoints.