Citations

ABSTRACT Artificial intelligence (AI) is revolutionizing cardiac imaging, including echocardiography. However, AI has scarce penetration in resource‐limited regions. The implementation of AI‐aided echocardiography (AIE) poses unique challenges and opportunities in resource‐limited areas. Some obvious advantages of AIE include aiding image acquisition, interpretation, and triaging patients based on severity. The challenges AIE faces in resource‐limited regions include a lack of data accessibility for model development, physician apprehension, and an outdated regulatory framework. Based on our early experience with AI, we believe AIE in resource‐limited regions will enhance health equity, improve access to the technology, and lead to cost savings. However, significant efforts are needed to realize these objectives.

OBJECTIVE Advances in surgical technology and microneurosurgery have led to increased utilization of so-called minimally invasive approaches, including the supraorbital eyebrow (SE) and minipterional (MPT) approaches for lesions involving the interpeduncular region. This study aimed to describe and compare anatomical landmarks, along with highlighting the advantages and disadvantages of the SE and MPT approaches to the interpeduncular region. METHODS Ten formalin-fixed, latex-injected cadaveric specimens were used to perform bilateral SE and MPT approaches to the interpeduncular region. The operative depth of each approach to key anatomical landmarks was measured. Forty-five axial thin-slice computed tomography studies were reviewed to calculate the operative angles, with consideration of the midline as a reference. A 3D interactive anatomical model generated through the photogrammetry scanning technique was described. RESULTS The depths of the operative corridors of the SE and MPT approaches to the interpeduncular fossa were 83.4 ± 1.8 mm and 67.7 ± 3.2 mm, respectively (p < 0.001). The mean angle of the MPT approach to the interpeduncular fossa was significantly wider than the one provided by the SE approach (39.9° ± 5.1° vs 28.4° ± 3.6°, p < 0.001). The interpeduncular region can consistently be accessed through the carotid-oculomotor triangle with the SE approach, as well as with the MPT approach. Furthermore, the SE route offered adequate access to the interpeduncular fossa through the opticocarotid triangle. The MPT route provided direct access to the upper prepontine cistern and anterior mesencephalic zone (AMZ). CONCLUSIONS The MPT approach provides a wider and shorter operative corridor and can be employed for lesions in the interpeduncular region with extension to the prepontine cistern and ventrolateral midbrain lesions requiring access through the AMZ. The SE approach is better suited for ventromedial midbrain lesions requiring access via the interpeduncular fossa safe entry zone. Additional studies analyzing these approaches in a clinical setting will help to delineate their reliability and efficacy.

Background Intraventricular hemorrhage is a calamitous type of stroke where bleeding into the ventricular system can be defined as: primary, if confined within the ventricles; or secondary, due to intracerebral hemorrhage extending from adjacent parenchyma. Intraventricular blood clot can lead to secondary insult and inflammatory responses that culminates in hydrocephalus as the most common cause of death. Purpose THerein, we report a patient with a high modified Graeb scale and low Glasgow coma scale. She spontaneously recanalized her fourth ventricle, decompressed her reticular activating system with remarkable spontaneous bilateral eye opening, and a consequently experienced a halfway drop in her mGS. Results This is the first reported case of a spontaneous recanalization of 4th ventricle obstruction secondary to IVH without intervention and subsequent dramatic neurological improvement. We believe that the apixaban primarily preserved the liquid state of hemorrhage and her presumed elevated ICP was sufficient to push out the liquified blood in the 4th ventricle into the upper spinal canal , recanalizing the 4th ventricle by continuously creating downward CSF pressure waves. Given the RAS location around the 4th ventricle, we hypothesize spontaneous decompression from the clot lysis triggered the RAS activation with sudden arousal manifested as spontaneous bilateral eyes opening. Hence, we refer to this as the reticular activating system reactivation after ventricular hemorrhage evacuation, or simply the “REVIVE” phenomenon. Conclusion This dramatic improvement from coma to awake state is worthy of recognition for future neurotherapeutic interventions.

Abstract Background The loss-of-function (LOF) classification of most missense variants in tumor suppressor breast cancer genes BRCA1, BRCA2, PALB2 , and RAD51C remains unclassified and confounds clinical actionability. Classifying these variants is challenging due to their rarity, leading clinicians to rely on in silico predictive methods. Protein stability changes are associated with function, making stability predictors valuable. Stability predictions upon missense variant perturbations require high-resolution protein structures. However, the availability of these high-resolution structures is lacking. This study explores using generative AI to predict high-resolution protein structures, which can then be analyzed with in silico protein stability prediction methods to assess LOF activity in ordered regions of the protein. This study also determines the appropriate in silico protein stability and dedicated in silico missense prediction methods in dbNSFP v4.7 database to predict LOF activity in ordered regions of these four genes. Functional classifications from homology recombination DNA repair (HDR) assays and variant classifications from the ClinVar database provide a reliable dataset for evaluating the performance of these in silico prediction methods. Results Complex AlphaFold2 structures of the BRCA1-C terminal (BRCT) domain and the DNA-binding (DB) domain of BRCA2, analyzed using protein stability tool FoldX predicts LOF activity from missense variants significantly better than experimentally-derived structures in ordered regions. The BRCT domain achieved an Area Under the Curve (AUC)= 0.861 (95 % CI:0.858–0.863) and AUC= 0.842 (95 % CI:0.840–0.845), while the DB domain achieved an AUC= 0.836 (95 % CI:0.8322–0.841), compared to AUC= 0.847 (95 % CI:0.844–0.850) and AUC= 0.835 (95 % CI:0.832–0.837) from the BRCT domain, and AUC= 0.830 (95 % CI:0.821–0.8320) from the DB domain from experimentally-derived structures. Protein stability does not predict LOF activity from missense variants better than dedicated in silico missense predictors. Overall, we find that AlphaMissense ranks highly, with an average AUC= 0.890 (95 % CI 0.886–0.895) from ordered regions across these four cancer genes, compared to all other in silico missense predictors present in the dbNSFP database. Conclusions The study reveals that generative AI protein predicted structures can outperform experimentally-derived structures in evaluating LOF activity from predicted protein stability in ordered regions of genes BRCA1, BRCA2, PALB2 and RAD51C. The study also highlights the predictive performance of AlphaMissense as the premier in silico missense prediction method to predict LOF activity from missense variants in these four tumor suppressor breast cancer genes. The code for this study can be downloaded for free on GitHub ( https://github.com/rohandavidg/CarePred )

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology , to patients seen in their own clinical practice.

4591 Background: EV-302 and CheckMate 901 demonstrated significant survival benefit with enfortumab vedotin-pembrolizumab (EVPembro) and gemcitabine-cisplatin-nivolumab (GemCisNivo) as 1L therapy, respectively, in patients (pts) with la/mUC. However, whether these treatments are cost-effective or not remains unclear. Methods: A three-state Markov model (progression-free, progression and death) was developed. State utilities were derived from published literature. State transition probabilities were informed from point-probabilities and hazard ratios for OS and PFS obtained from the latest follow-up of eligible trials. Average sales price (2024 USD) for individual treatments (excluding ancillary charges) were obtained from the center of medicare and medicaid services (US payer’s perspective). Treatment strategies were modeled in accordance with the dose/schedule reported in the eligible trials. Pts who received GemCis or Gem-carboplatin (GemCarbo) and did not progress were modeled to receive Avelumab maintenance. Half-cycle corrected costs and utilities were accrued over a 10-year lifetime horizon and were discounted at 3%. Monte Carlo simulation was used to estimate quality adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). A willingness-to-pay threshold (WTP) of 100,000$ per QALY was used. Results: In cisplatin-eligible pts, GemCisNivo demonstrated a 0.8 QALY gain over GemCis at an ICER of 21,127 ($/QALY). GemCisNivo was also associated with an incremental net monetary benefit (INMB) of 63,099$ relative to GemCis. EVPembro demonstrated a 2.4 QALY gain over GemCis at an ICER of 915,283 and a 1.6 QALY gain over GemCisNivo at an ICER of 1,406,308. In cisplatin-ineligible pts, EVPembro demonstrated a 2.4 QALY gain over Gem-carboplatin (GemCarbo) at an ICER of 934,761. Price threshold analyses demonstrated that EVPembro is likely to be cost-effective at a cost of 12,344$ for cisplatin-eligible and 13,374$ per cycle for cisplatin-ineligible pts (original cost: 35,665.60$ per cycle). Sensitivity analysis using a total of 12 cycles for EVPembro showed cost-effectiveness at an ICER of 69,594 relative to GemCisNivo in cisplatin-eligible pts, and at an ICER of 53,099 relative to GemCarbo in cisplatin-ineligible pts. Conclusions: In terms of US payer’s perspective, GemCisNivo is most likely to be cost-effective in cisplatin-eligible pts at the WTP of 100,000 $/QALY. Limiting the number of cycles for EVPembro may render it as a cost-effective 1L treatment in la/mUC pts regardless of cisplatin-eligibility status.

Abstract Ciltacabtagene autoleucel (cilta-cel) was approved in 2022 for patients with relapsed/refractory multiple myeloma (RRMM). We report outcomes with cilta-cel in the standard-of-care setting. Patients with RRMM who underwent leukapheresis for cilta-cel manufacturing between 1 March 2022 and 31 December 2022 at 16 US academic medical centers were included. Overall, 255 patients underwent leukapheresis and 236 (92.5%) received cilta-cel, of which 54% would not have met CARTITUDE-1 eligibility criteria. In treated patients (N = 236), cytokine release syndrome was seen in 75% (grade ≥3, 5%), immune effector cell–associated neurotoxicity syndrome in 14% (grade ≥3, 4%), and delayed neurotoxicity in 10%. Overall and complete response rates were as follows: all patients who received cilta-cel (N = 236), 89% and 70%; patients receiving conforming cilta-cel (n = 191), 94% and 74%; and conforming cilta-cel with fludarabine/cyclophosphamide lymphodepletion (n = 152), 95% and 76%, respectively. Nonrelapse mortality was 10%, most commonly from infection. After a median follow-up of 13 months from cilta-cel, the median progression-free survival (PFS) was not reached, with 12-month estimate being 68% (95% confidence interval, 62-74). High ferritin levels, high-risk cytogenetics, and extramedullary disease were independently associated with inferior PFS, with a signal for prior B-cell maturation antigen–targeted therapy (P = .08). Second primary malignancies excluding nonmelanoma skin cancers were seen in 5.5% and myeloid malignancies/acute leukemia in 1.7%. We observed a favorable efficacy profile of standard-of-care cilta-cel in RRMM, despite more than half the patients not meeting the CARTITUDE-1 eligibility criteria.

Goals: To determine long-term efficacy and safety of tCS for treatment of EoE. Background: Maintenance therapy with topical corticosteroids (tCS) is recommended for eosinophilic esophagitis (EoE), but data for long-term use are still needed. Study: This retrospective cohort study assessed newly diagnosed patients with EoE who were treated with a tCS and had a follow-up endoscopy with biopsy after at least 5 years. Histologic symptomatic and endoscopic responses were extracted from medical records. Patients who did and did not have long-term tCS treatment were compared at baseline, and outcomes for patients were assessed at their last endoscopy while on tCS. Results: Of 431 patients with EoE treated with tCS, 104 met inclusion criteria for long-term use. For patients with long-term tCS use, the median time (IQR) on tCS was 6.5 years (5.4 to 8.8 y). At the last endoscopy, 54% had histologic response (<15 eos/hpf), but those with excellent adherence had a histologic response of 64%. Endoscopic severity also decreased with improved adherence which was strongly associated with EREFS (1.7 vs. 2.8 vs. 4.0 for excellent, good, and poor adherence; P<0.001). Symptomatic response was 68% overall, but only 40% in those with poor adherence (P=0.07). Complications of taking tCS were uncommon (adrenal insufficiency: 1%; osteopenia: 1%; and esophageal candidiasis: 4% at final endoscopy). Conclusions: Long-term tCS (median 6.5 y) were generally effective, especially with better adherence, and also safe, with only rare serious complications. These data can be used to help patients make clinical decisions about chronic tCS use in EoE.