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Abstract OBJECTIVE Immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) are commonly utilized in the management of brain metastases. Treatment-related imaging changes (TRIC) are a frequently observed clinical manifestation and are commonly classified as radiographic radiation necrosis. However, these findings are not well characterized and may predict for response to SRS and ICI. METHODS The diagnosis-specific graded prognostic assessment was used to guide variable selection. TRIC were determined based upon MRI, PET/CT, or MR spectroscopy and a consensus by local clinical providers was required. RESULTS The analysis included 697 patients with 4,536 brain metastases across 11 institutions in 4 countries. The median follow-up after SRS was 13.6 months. The median age was 66 years, 54.1% of patients were male, and 57.3%, 36.3%, and 6.4% were non-small cell lung cancer, melanoma, and renal cell carcinoma (RCC) histology, respectively. TRIC were observed in 9.8%. On univariable analysis, Karnofsky Performance Status (KPS) (hazard ratio [HR]: 0.98; p < 0.001), presence of TRIC (HR: 0.67; p = 0.03), female sex (HR: 0.67; p < 0.001), and prior resection (HR: 0.60; p = 0.03) were associated with improved OS. On multivariable analysis, KPS (HR: 0.98; p < 0.001) and the presence of TRIC (HR: 0.66; p = 0.03) were associated with improved OS. A V12 Gy ≥ 10 cm3 (Odds Ratio [OR]: 2.78; p < 0.001), prior whole brain radiation therapy (OR: 3.46; p = 0.006), and RCC histology (OR: 3.10; p = 0.01) were associated with an increased probability of developing TRIC. The median OS in patients with and without TRIC was 29.0 and 23.1 months, respectively (log-rank p = 0.03). CONCLUSION TRIC following ICI and SRS are associated with a median OS benefit of approximately 6 months. Further prospective study is warranted to further elucidate the role and etiology of this common clinical scenario.

Abstract Objectives The COVID-19 vaccination in autoimmune diseases (COVAD) study aimed to assess short-term COVID-19 vaccination-related adverse events (AEs) in RA patients. Methods An online self-reported questionnaire (March–December 2021) was used to capture data related to COVID-19 vaccination-related AEs in RA, other autoimmune rheumatic diseases (AIRDs) (excluding RA and inflammatory myositis), non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs). Descriptive and multivariable regression analyses were performed. Results Of the 9462 complete respondents, 14.2% (n = 1347) had been diagnosed with RA; they had a mean (s.d.) age of 50.7 (13.7) years, 74.2% were women and 49.3% were Caucasian. In total, 76.9% and 4.2% of patients with RA reported minor and major AEs, respectively. Patients with active and inactive RA had similar AE and hospitalization frequencies. Overall, AEs were reported more frequently by BNT162b2 and mRNA-1273 recipients and less frequently by BBV152 recipients compared with the rest. Major AE and hospitalization frequencies were similar across recipients of different vaccines. Patients receiving methotrexate and hydroxychloroquine reported fewer minor AEs than those patients not on them. Compared with HCs and patients with other AIRDs, patients with RA reported similar total AEs, overall minor AEs, and hospitalizations. Compared with nrAIDs, patients with RA reported lower frequencies of overall AEs, minor AEs (both odds ratio [OR] = 0.7; 95% CI: 0.5, 0.9), and injection site pain (OR = 0.6; 95% CI: 0.5, 0.8) with similar major AE and hospitalization frequencies. Conclusion Despite the differences in AE frequency across different COVID-19 vaccines, all were well tolerated in patients with RA and were comparable to HCs, providing reassurance as to the safety of COVID-19 vaccination.

PURPOSE The sequencing of androgen-deprivation therapy (ADT) with radiotherapy (RT) may affect outcomes for prostate cancer in an RT-field size-dependent manner. Herein, we investigate the impact of ADT sequencing for men receiving ADT with prostate-only RT (PORT) or whole-pelvis RT (WPRT). MATERIALS AND METHODS Individual patient data from 12 randomized trials that included patients receiving neoadjuvant/concurrent or concurrent/adjuvant short-term ADT (4-6 months) with RT for localized disease were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate consortium. Inverse probability of treatment weighting (IPTW) was performed with propensity scores derived from age, initial prostate-specific antigen, Gleason score, T stage, RT dose, and mid-trial enrollment year. Metastasis-free survival (primary end point) and overall survival (OS) were assessed by IPTW-adjusted Cox regression models, analyzed independently for men receiving PORT versus WPRT. IPTW-adjusted Fine and Gray competing risk models were built to evaluate distant metastasis (DM) and prostate cancer–specific mortality. RESULTS Overall, 7,409 patients were included (6,325 neoadjuvant/concurrent and 1,084 concurrent/adjuvant) with a median follow-up of 10.2 years (interquartile range, 7.2-14.9 years). A significant interaction between ADT sequencing and RT field size was observed for all end points ( P interaction < .02 for all) except OS. With PORT (n = 4,355), compared with neoadjuvant/concurrent ADT, concurrent/adjuvant ADT was associated with improved metastasis-free survival (10-year benefit 8.0%, hazard ratio [HR], 0.65; 95% CI, 0.54 to 0.79; P < .0001), DM (subdistribution HR, 0.52; 95% CI, 0.33 to 0.82; P = .0046), prostate cancer–specific mortality (subdistribution HR, 0.30; 95% CI, 0.16 to 0.54; P < .0001), and OS (HR, 0.69; 95% CI, 0.57 to 0.83; P = .0001). However, in patients receiving WPRT (n = 3,049), no significant difference in any end point was observed in regard to ADT sequencing except for worse DM (HR, 1.57; 95% CI, 1.20 to 2.05; P = .0009) with concurrent/adjuvant ADT. CONCLUSION ADT sequencing exhibits a significant impact on clinical outcomes with a significant interaction with field size. Concurrent/adjuvant ADT should be the standard of care where short-term ADT is indicated in combination with PORT.

BACKGROUND: Melanoma brain metastases are commonly treated with stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICIs). However, the toxicity of these 2 treatments is largely unknown when administered concurrently. OBJECTIVE: To evaluate the risk of radiation necrosis (RN) with concurrent and nonconcurrent SRS and ICIs. METHODS: The guidelines from the Strengthening the Reporting of Observational Studies in Epidemiology checklist were used. Inverse probability of treatment weighting, univariable and multivariable logistic regression, and the Kaplan-Meier method was utilized. RESULTS: There were 203 patients with 1388 brain metastases across 11 international institutions in 4 countries with a median follow-up of 15.6 months. The rates of symptomatic RN were 9.4% and 8.2% in the concurrent and nonconcurrent groups, respectively ( P =.766). On multivariable logistic regression, V12 ≥ 10 cm 3 (odds ratio [OR]: 2.76; P =.006) and presence of BRAF mutation (OR: 2.20; P =.040) were associated with an increased risk of developing symptomatic RN; the use of concurrent over nonconcurrent therapy was not associated with an increased risk (OR: 1.06; P =.877). There were 20 grade 3 toxic events reported, and no grade 4 events reported. One patient experienced a grade 5 intracranial hemorrhage. The median overall survival was 36.1 and 19.8 months for the concurrent and nonconcurrent groups (log-rank P =.051), respectively. CONCLUSION: Concurrent administration of ICIs and SRS are not associated with an increased risk of RN. Tumors harboring BRAF mutation, or perhaps prior exposure to targeted agents, may increase this risk. Radiosurgical optimization to maintain V12 < 10 cm 3 is a potential strategy to reduce the risk of RN.

Abstract Background Carotid intraplaque hemorrhage (IPH) is considered a strong marker of histologically defined plaque vulnerability leading to cerebrovascular ischemic events. Cerebral microbleeds (CMBs) represent hemorrhage-prone small vessel disease and they are a common finding on brain MRI in patients with cerebrovascular disease. However, the potential mechanism and the risk for CMBs are not clear. The characteristics of carotid lesions have been considered relevant in the relationship between carotid artery atherosclerosis and the presence of CMBs. The potential association between carotid IPH histologically defined and CMBs has not been investigated yet. Purpose We have previously reported the prevalence of IPH in patients with non-obstructive carotid disease in patients who underwent carotid endarterectomy (CEA). In this study, we aimed to investigate whether the presence and the extent of carotid IPH are related to the existence of CMBs. We hypothesized that patients with carotid IPH would have a higher risk of CMBs. Methods This retrospective study enrolled 101 consecutive patients undergoing CEA with symptomatic (including ischemic stroke, TIA, and amaurosis fugax) or asymptomatic ipsilateral carotid artery disease. Carotid plaque specimens were collected at CEA from all the patients and stained with Movat Pentachrome to identify the presence and the extent (%) of IPH. Neck CTA was obtained to measure the degree of carotid stenosis. Brain MRI was pre-surgically performed and CMBs were studied using T2*-weighted gradient-recalled echo (GRE) or susceptibility-weighted imaging (SWI) sequence. The CMBs were counted and localized. Clinical and biochemical data, comorbidities, and medications were recorded. The association between carotid IPH and CMBs was examined adjusted for other risk factors. Results The presence of carotid IPH was in 57 (56.4%) patients. CMBs were more observed in patients with carotid IPH compared to those without IPH [19 (33.3%) vs 5 (11.4%); p=0.010]. Logistic regression analysis demonstrated an association between the extent of IPH in the carotid atheroma and the presence of CMBs [OR 1.051 (95% CI 1.012–1.090); p=0.009]. Moreover, the carotid IPH extent was associated with the number of CMBs (p=0.004). In patients with CMBs, the median degree of ipsilateral carotid stenosis was 40% (35–65%) and it was 70% (50–80%) in those without CMBs, with a significant difference between the two groups (p=0.049). Conclusions In patients undergoing CEA, the histologically defined presence of carotid IPH and its extent are associated with CMBs on brain MR imaging. CMBs may be a potential mechanism for cerebrovascular events in patients with carotid atherosclerotic IPH and they may be an imaging marker that can distinguish the severity of the carotid artery disease. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Mayo Clinic Foundation

Objective To develop a standardised tool to evaluate flexible ureterorenoscopes (fURS). Materials and Methods A three‐stage consensus building approach based on the modified Delphi technique was performed under guidance of a steering group. First, scope‐ and user‐related parameters used to evaluate fURS were identified through a systematic scoping review. Then, the main categories and subcategories were defined, and the expert panel was selected. Finally, a two‐step modified Delphi consensus project was conducted to firstly obtain consensus on the relevance and exact definition of each (sub)category necessary to evaluate fURS, and secondly on the evaluation method (setting, used tools and unit of outcome) of those (sub)categories. Consensus was reached at a predefined threshold of 80% high agreement. Results The panel consisted of 30 experts in the field of endourology. The first step of the modified Delphi consensus project consisted of two questionnaires with a response rate of 97% ( n = 29) for both. Consensus was reached for the relevance and definition of six main categories and 12 subcategories. The second step consisted of three questionnaires (response rate of 90%, 97% and 100%, respectively). Consensus was reached on the method of measurement for all (sub)categories. Conclusion This modified Delphi consensus project reached consensus on a standardised grading tool for the evaluation of fURS – The Uniform grading tooL for flexIble ureterorenoscoPes (TULIP) tool. This is a first step in creating uniformity in this field of research to facilitate future comparison of outcomes of the functionality and handling of fURS.

AbstractBackgroundPatients with prostate cancer suffer significant sexual dysfunction after treatment which negatively affects them and their partners psychologically, and strain their relationships.AimWe convened an international panel with the aim of developing guidelines that will inform clinicians, patients and partners about the impact of prostate cancer therapies (PCT) on patients’ and partners’ sexual health, their relationships, and about biopsychosocial rehabilitation in prostate cancer (PC) survivorship.MethodsThe guidelines panel included international expert researchers and clinicians, and a guideline methodologist. A systematic review of the literature, using the Ovid MEDLINE, Scopus, CINAHL, PsychINFO, LGBT Life, and Embase databases was conducted (1995–2022) according to the Cochrane Handbook for Systematic Reviews of Interventions. Study selection was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Each statement was assigned an evidence strength (A-C) and a recommendation level (strong, moderate, conditional) based on benefit/risk assessment, according to the nomenclature of the American Urological Association (AUA). Data synthesis included meta-analyses of studies deemed of sufficient quality (3), using A Measurement Tool to Assess Systematic Reviews (AMSTAR).OutcomesGuidelines for sexual health care for patients with prostate cancer were developed, based on available evidence and the expertise of the international panel.ResultsThe guidelines account for patients’ cultural, ethnic, and racial diversity. They attend to the unique needs of individuals with diverse sexual orientations and gender identities. The guidelines are based on literature review, a theoretical model of sexual recovery after PCT, and 6 principles that promote clinician-initiated discussion of realistic expectations of sexual outcomes and mitigation of sexual side-effects through biopsychosocial rehabilitation. Forty-seven statements address the psychosexual, relationship, and functional domains in addition to statements on lifestyle modification, assessment, provider education, and systemic challenges to providing sexual health care in PC survivorship.Clinical ImplicationsThe guidelines provide clinicians with a comprehensive approach to sexual health care for patients with prostate cancer.Strengths & LimitationsThe strength of the study is the comprehensive evaluation of existing evidence on sexual dysfunction and rehabilitation in prostate cancer that can, along with available expert knowledge, best undergird clinical practice. Limitation is the variation in the evidence supporting interventions and the lack of research on issues facing patients with prostate cancer in low and middle-income countries.ConclusionThe guidelines document the distressing sexual sequelae of PCT, provide evidence-based recommendations for sexual rehabilitation and outline areas for future research.

AbstractObjectiveTo profile clinically non‐aggressive and aggressive pituitary adenomas (PAs)/pituitary neuroendocrine tumours (PitNETs) and pituitary carcinomas for somatic mutations and epigenetic alterations of genes involved in cell proliferation/differentiation, microRNAs (miRNA)/long noncoding RNA (LncRNA)‐post‐transcriptional regulators and therapy targets.DesignRetrospective observational study.Patients and MeasurementsA total of 64 non‐aggressive and 41 aggressive PAs/PitNETs and 6 pituitary carcinomas treated by endoscopic surgery with ≥1‐year follow‐up were included. Somatic mutations of 17 genes and DNA methylation of 22 genes were assessed. Ten normal pituitaries were used as control.ResultsWe found at least one mutation in 17 tumours, including 6/64 non‐aggressive, 10/41 aggressive PAs/PitNETs, and 1/6 pituitary carcinoma. AIP (N = 6) was the most frequently mutated gene, followed by NOTCH (4), and TP53 (3). Hypermethylation of PARP15, LINC00599, ZAP70 was more common in aggressive than non‐aggressive PAs/PITNETs (p < .05). Lower levels of methylation of AIP, GNAS and PDCD1 were detected in aggressive PAs/PITNETs than non‐aggressive ones (p < .05). For X‐linked genes, males presented higher level of methylation of FLNA, UXT and MAGE family (MAGEA11, MAGEA1, MAGEC2) genes in aggressive vs. non‐aggressive PAs/PITNETs (p < .05).In pituitary carcinomas, methylation of autosomal genes PARP15, LINC00599, MIR193 and ZAP70 was higher than in PAs/PITNETs, while X‐linked genes methylation level was lower.ConclusionsSomatic mutations and methylation levels of genes involved in cell proliferation/differentiation, miRNA/LncRNA‐post‐transcriptional regulators and targets of antineoplastic therapies are different in non‐aggressive and in aggressive PAs/PitNETs. Methylation profile also varies according to gender. Combined genetic‐epigenetic analysis, in association with clinico‐radiological‐pathological data, may be of help in predicting PA/PitNET behaviour.

Background Corticosteroids are the mainstay of treatment for immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI), but the optimal duration of therapy has not been established. Prolonged use of corticosteroids can cause numerous adverse effects and may decrease progression-free survival among patients treated with ICPis. We sought to determine whether a shorter duration of corticosteroids was equally efficacious and safe as compared with a longer duration. Methods We used data from an international multicenter cohort study of patients diagnosed with ICPi-AKI from 29 centers across nine countries. We examined whether a shorter duration of corticosteroids (28 days or less) was associated with a higher rate of recurrent ICPi-AKI or death within 30 days following completion of corticosteroid treatment as compared with a longer duration (29–84 days). Results Of 165 patients treated with corticosteroids, 56 (34%) received a shorter duration of treatment and 109 (66%) received a longer duration. Patients in the shorter versus longer duration groups were similar with respect to baseline and ICPi-AKI characteristics. Five of 56 patients (8.9%) in the shorter duration group and 12 of 109 (11%) in the longer duration group developed recurrent ICPi-AKI or died (p=0.90). Nadir serum creatinine in the first 14, 28, and 90 days following completion of corticosteroid treatment was similar between groups (p=0.40, p=0.56, and p=0.89, respectively). Conclusion A shorter duration of corticosteroids (28 days or less) may be safe for patients with ICPi-AKI. However, the findings may be susceptible to unmeasured confounding and further research from randomized clinical trials is needed.