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Background Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce. Methods In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT). Results Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58–74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7–3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4–3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS. Conclusions Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS.

OBJECTIVE Aneurysm occlusion has been used as surrogate marker of aneurysm treatment efficacy. Aneurysm occlusion scales are used to evaluate the outcome of endovascular aneurysm treatment and to monitor recurrence. These scales, however, require subjective interpretation of imaging data, which can reduce the utility and reliability of these scales and the validity of clinical studies regarding aneurysm occlusion rates. Use of a core lab with independent blinded reviewers has been implemented to enhance the validity of occlusion rate assessments in clinical trials. The degree of agreement between core labs and treating physicians has not been well studied with prospectively collected data. METHODS In this study, the authors analyzed data from the Hydrogel Endovascular Aneurysm Treatment (HEAT) trial to assess the interrater agreement between the treating physician and the blinded core lab. The HEAT trial included 600 patients across 46 sites with intracranial aneurysms treated with coiling. The treating site and the core lab independently reviewed immediate postoperative and follow-up imaging (3–12 and 18–24 months, respectively) using the Raymond-Roy occlusion classification (RROC) scale, Meyer scale, and recanalization survey. A post hoc analysis was performed to calculate interrater reliability using Cohen’s kappa. Further analysis was performed to assess whether degree of agreement varied on the basis of various factors, including scale used, timing of imaging, size of the aneurysm, imaging modality, location of the aneurysm, dome-to-neck ratio, and rupture status. RESULTS Minimal interrater agreement was noted between the core lab reviewers and the treating physicians for assessing aneurysm occlusion using the RROC grading scale (k = 0.39, 95% CI 0.38–0.40) and Meyer scale (k = 0.23, 95% CI 0.14–0.38). The degree of agreement between groups was slightly better but still weak for assessing recanalization (k = 0.45, 95% CI 0.38–0.52). Factors that significantly improved degree of agreement were scales with fewer variables, greater time to follow-up, imaging modality (digital subtraction angiography), and wide-neck aneurysms. CONCLUSIONS Assessment of aneurysm treatment outcome with commonly used aneurysm occlusion scales suffers from risk of poor interrater agreement. This supports the use of independent core labs for validation of outcome data to minimize reporting bias. Use of outcome tools with fewer point categories is likely to provide better interrater reliability. Therefore, the outcome assessment tools are ideal for clinical outcome assessment provided that they are sensitive enough to detect a clinically significant change.

AbstractBackgroundIntegrating shared decision making between patients and physicians and incorporating their values and preferences in the development of clinical practice guidelines (CPGs) is of critical importance to optimize CPG implementation and treatment adherence. This applies to many debilitating diseases, including hypercalcemia of malignancy (HCM).ObjectiveEvaluate patient and physician values, preferences, and attitudes to better inform CPGs to treat HCM in adults.MethodsWe followed a mixed-methods approach. We conducted a systematic review using 5 databases to identify studies reporting on patient and physician values, costs and resources, feasibility, acceptability, and equity regarding HCM treatment. We also gathered data from different countries on the cost of multiple treatment modalities. We collected data on outcome prioritization from the CPG Working Group. Similarly, we collected data from patients with HCM regarding outcome prioritization and administered a questionnaire to evaluate their attitudes and perceptions toward treatment as well as treatment acceptability and feasibility.ResultsIn the systematic review, we included 2 cross-sectional surveys conducted on the same population of physicians who agreed that treating HCM alleviates symptoms and improves quality of life; however, harms and benefits should be thoroughly considered when deciding on the duration of treatment. We also included 2 studies on cost showing that intravenous (IV) bisphosphonate is more cost-effective than a combination of IV bisphosphonate and calcitonin and administration of IV zoledronic acid at home is more cost-effective than other IV bisphosphonates. The cost of zoledronic acid, denosumab, and cinacalcet varied widely among countries and types (brand vs generic). Both the CPG Working Group and patients with HCM agreed that the most important outcomes when deciding on treatment were survival and resolution of HCM, but there was some variability in the ratings for other outcomes.ConclusionUsing mixed methods, CPG developers can obtain meaningful information regarding evidence to decision criteria. In the case of HCM CPGs, this approach has provided the required contextual information and supported the development of evidence-based recommendations.

BACKGROUND: Loeys–Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by a classic triad of hypertelorism, bifid uvula and/or cleft palate, and generalized arterial tortuosity. There are limited data on the prevalence and rupture risk of intracranial aneurysms (IAs) in the setting of LDS, with no established guidelines. OBJECTIVE: To analyze the prevalence and rupture risk of IA in LDS. METHODS: Electronic medical records of patients with a confirmed diagnosis of LDS and available cerebrovascular imaging were reviewed. Patients were divided into 2 groups based on the presence of IA. Unmatched and propensity-matched analyses were used to identify potential risk factors for aneurysm formation. RESULTS: Records of 1111 patients were screened yielding a total of 60 patients with a diagnosis of LDS. Eighteen (30%) patients had IA, 4 (22.2%) of whom had multiple aneurysms for a total of 24 IAs. Twenty-three (95.8%) aneurysms were located in the anterior circulation; none of them were ruptured. On unmatched analysis, age ( P = .015), smoking history ( P = .034), hypertension ( P = .035), and number of extracranial aneurysms ( P < .001) were significantly higher in patients with IA. After matching for age, sex, race, stroke history, family history, and extracranial aneurysms, smoking history ( P = .009) remained significant. CONCLUSION: Patients with LDS have an increased risk of IAs, especially with a history of smoking. The prevalence rate of IAs in our series was 30%. Screening imaging should be considered at diagnosis, and patients should be encouraged to abstain from smoking. Further studies are needed to elucidate the risk of IA rupture and treatment considerations in this unique population.

Introduction Hypercalcaemia of malignancy (HCM) is the second most common cause of hypercalcaemia and is associated with significant morbidity and mortality. Several treatment options are available including pharmacological therapy with bisphosphonates, denosumab, glucocorticoids and calcimimetics, as well as conventional therapy with hydration and possibly calcitonin. While guidelines have previously considered treatment effects, no guideline has yet considered a range of contextual factors impacting recommendations for the management. The aim of this study was to summarise the available evidence on important decisional factors for the development of guidelines for the treatment of HCM. These include patient’s values and preferences, cost, acceptability, feasibility and equity. Methods and analysis This protocol is registered in PROSPERO (registration number: CRD42021264371). This is a systematic review of observational studies, case series, trials, reviews and qualitative studies involving treatment of adult patients with HCM. We will develop and execute two independent search strategies using five databases: PubMed, Medline (OVID), Embase.com, CINAHL (EBSCO) and Cochrane, and review their combined output. Two reviewers will screen titles and abstracts and full texts and will implement data abstraction from relevant studies independently and in duplicate. The outcomes of interest are the decisional factors that influence drug selection, with possible subgroup summaries by drug class or aetiology of HCM. We will present the data collected in a narrative and thematic approach. Ethics and dissemination Ethical approval is not applicable for our study, since we will only collect data from available literature. This systematic review will be submitted to a peer-reviewed journal when completed.

Abstract Arteriovenous malformations (AVMs) are highly complex vascular lesions characterized by abnormal connections between arteries and an intervening nidus. Definitive and safe treatment of AVMs may require the combination of multiple treatment modalities to address the various complex features of the AVM. 1 Endovascular embolization can be used as an adjuvant to surgery in order to control deep feeders, reduce flow, and address high-risk features such as aneurysms. In addition, by progressively reducing the AVM flow, staged embolization can lead to normalization of peri-AVM hemodynamics and therefore may decrease the risk of postresection hemorrhage. 2,3 In this operative video, we present a case of a 41-yr-old female who presented with progressively worsening left-sided hemiparesis. Magnetic resonance imaging (MRI) and angiography revealed a complex right fronto-parietal AVM with significant associated edema, likely due to the vascular steal phenomenon. The area of edema, which included the motor cortex, was thought to be at high risk for postoperative hemorrhage from normal perfusion pressure breakthrough. We therefore decided to proceed with staged presurgical embolization to gradually normalize the perilesional hemodynamics, and therefore possibly reduce the risk of postoperative morbidity. The patient underwent 3 embolization sessions at 6-wk intervals. An MRI after the last embolization showed near-complete resolution of the fluid-attenuated inversion-recovery (FLAIR) signal around the AVM. Microsurgical resection was performed on the day after the last embolization. The patient tolerated the procedure well and was discharged at her neurological baseline with mild contralateral hemiparesis, which has continued to improve at follow-up. Postoperative angiography showed complete resection of the AVM. The patient consented to the procedure as shown in this operative video and gave informed written consent for use of her images in publication.

Abstract Context Guidelines for the dosage of vitamin D supplementation vary widely globally. Objective To investigate the impact of 2 vitamin D doses, bracketed between the IOM recommended dietary allowance (RDA) and the upper tolerable limit, on vitamin D nutritional status in elderly individuals. Methods This post hoc analysis of data collected from a 12-month, double-blind, randomized control trial included 221 ambulatory participants (≥ 65 years) with a mean BMI of 30.2 kg/m2 and a mean baseline serum 25-hydroxyvitamin D [25(OH)D] level of 20.4 ± 7.4 ng/mL, who were recruited from 3 outpatient centers in Lebanon. All participants received 1000 mg of elemental calcium daily from calcium citrate plus the daily equivalent of either 600 IU or 3750 IU of vitamin D3. Results Mean 25(OH)D level at 12 months was 26.0 ng/mL with low dose and 36.0 ng/mL with high dose vitamin D3. The proportion of participants reaching a value ≥ 20 ng/mL was 86% in the low dose, and 99% in the high dose arms, with no gender differences. The increment of 25(OH)D per 100 IU/day was 1 ng/mL with the low dose, and 0.41 ng/mL with the high dose. Serum 25(OH)D levels at 1 year were highly variable in both treatment arms. Baseline 25(OH)D level and vitamin D dose—but not age, BMI, gender, or season—were significant predictors of serum 25(OH)D level post-intervention. Conclusion The IOM Recommended Dietary Allowance (RDA) of 600 IU/day does not bring 97.5% of ambulatory elderly individuals above the desirable threshold of 20 ng/mL. Country-specific RDAs are best derived taking into account the observed variability and predictors of achieved 25(OH)D levels.

Abstract Background: Hypercalcemia of malignancy is the second most common cause of hypercalcemia and is associated with significant morbidity and mortality. Several treatment options are available including pharmacological therapy with bisphosphonates, denosumab, glucocorticoids, and calcimimetics, as well as conventional therapy with hydration and possibly calcitonin. While guidelines have previously considered treatment effects, no guideline has yet considered a range of contextual factors impacting recommendations for the management. Objective: The aim of this study is to summarize the available evidence on important decisional factors for the development of guidelines for the treatment of hypercalcemia of malignancy. These include patient’s values and preferences, cost, acceptability, feasibility, and equity. Methods/Design: This is a systematic review of observational studies, case series, trials, reviews and qualitative studies involving treatment of adult patients with hypercalcemia of malignancy. We developed and executed two independent search strategies using five databases: Pubmed, Medline (OVID), Embase.com, CINAHL (EBSCO) and Cochrane, and reviewed their combined output. Two reviewers screened titles and abstracts and full texts and will implement data abstraction from relevant studies independently and in duplicate. The outcomes of interest are the decisional factors that influence drug selection, with possible subgroup analyses by drug class or etiology of hypercalcemia of malignancy. We will present the data collected in a narrative and thematic approach. Discussion: This systematic review will identify important treatment decisional factors, and will assist guidelines panels, physicians and patients to decide on therapeutic options based on the current evidence.