Citations

Background: The AFFINITY trial (NCT05890872) is a prospective, non-randomized, open-label, single-arm study evaluating the safety, immunological impact, and preliminary efficacy of Aliya pulsed electric field ablation in patients with solid tumors. Thirty-one patients were enrolled; thirty received lung lesion ablation prior to continuation on standard-of-care treatment. This manuscript reports six-month local control outcomes and immunological response characteristics. Radiological outcomes were assessed using a modified RECIST 1.1, and immunological impact was evaluated via changes in peripheral blood immunocyte populations and detection of immunoglobulins (Ig) to tumor-associated antigens in serum post-ablation. Methods: Twenty-eight patients underwent radiological assessment of ablated lesions at approximately 1-, 3-, and 6-month post-ablation to evaluate local control. Peripheral blood was collected for immune monitoring using flow cytometry and to detect IgG responses to biopsy-specific and tumor-associated antigens. Results: At 6 months, two cohorts emerged: 12 received ablation only, and 16 received ablation plus systemic and/or focal therapies (radiotherapy or second ablation). In the ablation-only group, imaging showed local control in all ablated lesions (8/12 SD, 4/12 PR), suggesting local efficacy without systemic therapy in those patients. Immunophenotyping showed dynamic changes in circulating immune cells, including T and B cell activation. A subset also exhibited modulation of tumor antigen-specific IgG, indicating a systemic humoral response. Conclusions: This analysis provides preliminary evidence that this form of ablation may promote local tumor control and modulate systemic immune function. These findings support the immunogenic potential of this specialized energy and warrant further investigation. Extended 12-month data for the full cohort will be reported in a future manuscript.

Abstract Understanding tumor cell dynamics can improve prognosis and treatment but remains limited for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA sequencing data from 684 NS-LUAD cases and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histologic data further characterized the subtypes. “Steady,” marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver gene alterations, is linked to prolonged survival and low immune evasion. “Proliferative” shows high proliferation markers, TP53 mutations, and gene fusions. “Chaotic,” with high epithelial-to-mesenchymal transition markers, has the worst prognosis, even within stage I tumors. Lacking known molecular or histologic characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the classification and predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving early-stage NS-LUAD prognostication in clinical settings. Significance: The transcriptome of 684 NS-LUAD identifies three subtypes with different cellular dynamics and genomic and morphologic features. A 60-gene signature accurately stratifies subjects for mortality risk, even in stage I, offering a potential clinically applicable tool for treatment decision-making in patients with NS-LUAD. See related commentary by Azizi et al., p. 423

Background: Biobanks often lack standard mechanisms to keep donors connected to their biospecimens, reflecting a broken feedback loop that compromises trust, engagement, and scientific progress. Decentralized biobanking empowers patients to track their donations throughout the research journey, supporting personalized feedback and research collaboration via a privacy-preserving blockchain network. This case study explores operational feasibility of implementing decentralized biobanking for a large breast cancer biobank at a US academic medical center. Methods: A mixed-methods case study of the groundwork, implementation, and stakeholder feedback for a real-world decentralized biobanking app pilot was conducted. Biobank members were recruited from February to April 2023. Operational feasibility was assessed via analysis of institutional stakeholder perspectives, pilot engagement, and de-bi app activity. Findings: Physicians and other biobank stakeholders surfaced challenges surrounding managing expectations, balancing empowerment with clinical and research workflows, and navigating power dynamics between patients, physicians, scientists, and leadership. A total of 1080 participants enrolled over 10 weeks, including nearly 10% of the biobank with about 4000 biospecimens. During the pilot, biobank enrollment increased 65% versus the prior year, and there were no biobank withdrawals during or within 1 year following the pilot ( p < 0.001 for both). The app, which facilitated biospecimen tracking and research engagement, was downloaded by 405 users. A total of 140 users tested the blockchain component, with 89% successfully claiming a nonfungible token representing their unique, immutable connection and access to donated biospecimens. Feedback was solicited to inform potential process improvements and risk assessments related to public relations, systems infrastructure, and ethical governance, illuminating next steps. Conclusions: We established operational feasibility for the first step toward decentralized biobanking, informed by requirements to manage expectations, workflows, and power dynamics. Our technical solution demonstrated robust participant engagement and compatibility with established biobanks, suggesting potential to build trust and align incentives and identifying next steps for communications, sustainability, and governance.

Abstract Purpose: Mouse models demonstrate a role for RANK and its ligand, RANKL, in osteosarcoma. The primary objective of this single-arm, open-label phase 2 trial was to determine whether denosumab, a RANKL mAb, improved disease control in recurrent osteosarcoma relative to benchmarks derived from historic Children’s Oncology Group clinical trial data. Patients and Methods: Skeletally mature patients ages 11 to 49 years old with measurable disease were eligible for cohort 1, and those with complete surgical resection of all sites of disease were eligible for cohort 2. Patients received denosumab 120 mg subcutaneously every 4 weeks with calcium and vitamin D supplementation. The primary endpoints were RECIST response and remaining event-free for 4 months for cohort 1 and remaining event-free for 12 months for cohort 2. Toxicity, pharmacokinetics, and pharmacodynamic effects were additional endpoints. Results: Fifteen patients in cohort 1 and 38 in cohort 2 were eligible and evaluable for the primary endpoint. One of 15 cohort 1 patients remained event-free at 4 months. There were no objective responses. Ten of 38 cohort 2 patients were event-free at 12 months. The predefined efficacy criteria were not met in either cohort. The most common ≥ grade 3 adverse events were hypocalcemia and hypophosphatemia (8% and 11%, respectively). At steady state, mean serum denosumab trough concentrations were 23.7 to 31 μg/mL in cycles 2 to 7. Serum c-telopeptide and urine n-telopeptide decreased on treatment. Conclusions: Denosumab was well-tolerated with anticipated side effects and pharmacokinetic and pharmacodynamic parameters but had insufficient activity for further development in osteosarcoma.

Abstract Introduction Obesity, defined as an elevated Body Mass Index (BMI) &gt;30, is a prevalent public health concern with far-reaching implications for various medical procedures and outcomes. In the context of inflatable penile prosthesis placement (IPP), where patient well-being and surgical success are of paramount importance, the impact of obesity on postoperative and intraoperative complications warrants thorough investigation. Objective Our study aimed to investigate the impact of BMI on both postoperative and intraoperative complications in an international, multi-institutional cohort of patients who underwent IPP placement. Methods We performed a retrospective chart review of 4398 cases. These cases were divided into two distinct groups based on BMI: less than 30 (n = 2260) and greater than or equal to 30 (n = 2138). The study assessed various surgical factors as well as complications, including overall complications, corporal scarring, incontinence, intraoperative complications, proximal perforation, distal perforation, proximal crossover, distal crossover, and urethral injury. Results Our analysis revealed that there were no statistically significant differences in intraoperative or postoperative complications between the two BMI categories. Notably, proximal corporal measurement was significantly higher for &gt;30 BMI group (9.55 +/−2.18) compared to &lt;30 BMI group (9.14 +/−2.19), (p = &lt; 0.001). The incidence rates for overall complications (30.2% vs. 28.7%; p = 0.164), corporal scarring (18.2% vs. 16.7%; p = 0.36), incontinence (3.53% vs. 3.13%; p = 0.076), intraoperative complications (1.94% vs. 1.68%; p = 0.253), and specific complications all exhibited no significant differences. Similarly, post-operative complications, including both non- infectious (6.99% vs. 6.22%; p = 0.215) and infectious (2.61% vs. 1.87%; p = 0.165) complications, did not significantly vary between BMI categories. Conclusions Our findings indicate that BMI does not exert a statistically significant influence on postoperative and intraoperative complications in the context of high-volume prosthetic urology. In the absence of any other differences between patients of differing BMIs, surgeons may need to be mindful of pump tubing length concerns in obese patients. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Coloplast, Clarus Therapeutics, Antares Pharma, Acerus.

OBJECTIVE Cervical dystonia (or spasmodic torticollis) is a neurological condition that results in abnormal movements and head posture, for which initial surgical intervention typically involves selective denervation of the sternocleidomastoid (SCM) and paraspinal muscles. However, muscle reactivation of the distal SCM stump can result in recurrent symptoms. In this study, the authors present their preliminary experience with distal SCM stump resection following selective denervation, with the aim of evaluating the effectiveness of the procedure and identifying patients who may benefit from this technique. METHODS This is a retrospective single-center cohort study of patients who underwent SCM stump resection as revision surgery for cervical dystonia. RESULTS A total of 18 patients (10 males [56%]) were included with a median (range) age of 54 (40–70) years. All patients received selective denervation of the SCM at the authors’ institution prior to SCM stump resection at a median (range) time of 12 (3–198) months between surgical procedures. At preoperative baseline, 13 patients (72%) possessed a rotational torticollis component to their head deviation, 12 (67%) possessed a laterocollis component, and 2 (11%) possessed a retrocollis component. At the most recent follow-up (median [range] 16 [4–119] months), 6 patients had complete resolution of their cervical dystonia (33%), while 10 had residual deviation (56%) and 2 had recurrent deviation (11%). However, compared to their post–selective denervation head position, 12 patients experienced improvement in their head position (67%), 4 patients had no change in their head position (22%), and 2 had worsening of their cervical dystonia (11%) following SCM stump resection. Importantly, 12 patients experienced improvement in their pain following SCM stump resection (67%). Patients who had a history of other movement/spasmodic disorders were more likely to have improvement in head position and improvement in pain after SCM stump resection, though neither of these results achieved statistical significance (p = 0.054). Additionally, patients who experienced full resolution of their cervical dystonia had shorter time between initial selective denervation surgery and SCM stump resection, though this result also did not achieve statistical significance (p = 0.068). CONCLUSIONS Distal SCM stump resection following selective denervation is a simple, safe, and effective option for many patients in treating refractory cervical dystonia. Patients with more severe preoperative presentations may experience greater benefit from SCM stump resection, though additional investigations are needed.

Case: We present 3 cases of brachial plexus injuries (BPI) secondary to compressive hematomas during extracorporeal membrane oxygenation (ECMO), with follow-up ranging from 18 months to 12 years. Patients exhibited profound upper extremity deficits and underwent variable interventions, including surgical decompression. All demonstrated meaningful neurologic recovery. Conclusion: BPI is a rare but serious complication of ECMO. These cases highlight the importance of early recognition and hematoma evacuation, emphasizing the need for clinical vigilance to optimize neurologic outcomes following hematoma-induced nerve injury.

ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.