Citations

The translation of AI-generated brain metastases (BM) segmentation into clinical practice relies heavily on diverse, high-quality annotated medical imaging datasets. The BraTS-METS 2023 challenge has gained momentum for testing and benchmarking algorithms using rigorously annotated internationally compiled real-world datasets. This study presents the results of the segmentation challenge and characterizes the challenging cases that impacted the performance of the winning algorithms. Untreated brain metastases on standard anatomic MRI sequences (T1, T2, FLAIR, T1PG) from eight contributed international datasets were annotated in stepwise method: published UNET algorithms, student, neuroradiologist, final approver neuroradiologist. Segmentations were ranked based on lesion-wise Dice and Hausdorff distance (HD95) scores. False positives (FP) and false negatives (FN) were rigorously penalized, receiving a score of 0 for Dice and a fixed penalty of 374 for HD95. The mean scores for the teams were calculated. Eight datasets comprising 1303 studies were annotated, with 402 studies (3076 lesions) released on Synapse as publicly available datasets to challenge competitors. Additionally, 31 studies (139 lesions) were held out for validation, and 59 studies (218 lesions) were used for testing. Segmentation accuracy was measured as rank across subjects, with the winning team achieving a LesionWise mean score of 7.9. The Dice score for the winning team was 0.65 ± 0.25. Common errors among the leading teams included false negatives for small lesions and misregistration of masks in space. The Dice scores and lesion detection rates of all algorithms diminished with decreasing tumor size, particularly for tumors smaller than 100 mm3. In conclusion, algorithms for BM segmentation require further refinement to balance high sensitivity in lesion detection with the minimization of false positives and negatives. The BraTS-METS 2023 challenge successfully curated well- annotated, diverse datasets and identified common errors, facilitating the translation of BM segmentation across varied environments and providing the tools for future development of personalized volumetric reports to patients undergoing BM treatment.

Cancer cachexia is a multifactorial syndrome involving muscle and fat wasting, inflammation, and metabolic dysfunction. Across cancer subtypes, pancreatic cancer has one of the highest cachexia incidence rates at ∼80%. Given the advanced age of most pancreatic cancer patients, we sought to query cancer-associated muscle wasting using an age-matched murine model. We found that histamine and histamine decarboxylase (HDC) activity were specifically elevated in the muscles of aged tumor-bearing mice. We further found that (1) wasting stimuli induced histamine production and enhanced HDC activity; (2) exogenous histamine was sufficient to induce atrophy-associated gene expression; (3) inhibition of HDC activity by α-fluoromethylhistidine (FMH) protected against atrophy; (4) treatment of tumor-bearing mice with FMH rescued muscle wasting; and (5) a calcineurin inhibitor was able to rescue histamine-associated increases in calcium/atrogene signaling. In summary, we present a novel metabolic pathway that has significant implications for the treatment of cachectic cancer patients.

PURPOSE To report the results of the multicenter, open-label IRAKLIA trial (ClinicalTrials.gov identifier: NCT05405166 ) of isatuximab subcutaneous (SC) versus intravenous (IV), plus pomalidomide and dexamethasone, in relapsed/refractory multiple myeloma (MM), to our knowledge, the first phase III MM trial using an on-body injector (OBI). METHODS Patients with ≥1 prior line of therapy were randomly assigned 1:1 to Isa OBI (1,400 mg) or IV (10 mg/kg) once weekly in cycle (C)1 and then every 2 weeks, plus pomalidomide (4 mg once daily, day [D]1-21) and dexamethasone (40 mg once weekly [age ≥75: 20 mg]) and treated until progression, unacceptable toxicity, or patient request. Coprimary end points were overall response rate (ORR; noninferiority margin, 0.839) and Isa C trough (C6D1 predose; noninferiority margin, 0.8). Noninferiority of OBI versus IV was demonstrated if both coprimary end points achieved noninferiority. RESULTS IRAKLIA randomly assigned 531 patients (OBI, n=263; IV, n=268). After 12-month median follow-up, the ORR was 71.1% (OBI) and 70.5% (IV; relative risk, 1.008 [95% CI, 0.903 to 1.126]; lower CI exceeded noninferiority margin). The mean (standard deviation) C6D1 C trough was 499 (259) μg/mL (OBI) and 340 (169) μg/mL (IV). The C trough geometric mean ratio (90% CI) was 1.532 (1.316 to 1.784); lower CI exceeded noninferiority margin. Grade ≥3 treatment-emergent adverse event incidences were 81.7% (OBI) and 76.1% (IV); infusion reaction incidences were 1.5% and 25.0%. Injection site reactions occurred in 0.4% of OBI injections (all grade 1-2); 99.9% of injections completed without interruption. CONCLUSION IRAKLIA demonstrated efficacy and pharmacokinetic noninferiority between Isa OBI and IV. No unexpected safety signal was observed, with excellent local tolerability of Isa OBI. Efficacy and safety were comparable with Isa IV in ICARIA-MM, except the lower OBI infusion reaction rate. These results support potential use of the OBI, designed to improve practice efficiency.

Study Design Retrospective Cohort Study. Objectives To determine if 3D printed porous titanium (Ti) cages compared to non-porous polyetheretherketone (PEEK) cages predicted improved fusion rate or clinical outcomes after transforaminal lumbar interbody fusion (TLIF). Methods All adult patients who underwent one- and two-level TLIF for degenerative conditions by a single surgeon at an academic center between 2017-2021 were retrospectively identified. Patients were dichotomized into porous Ti and non-porous PEEK interbody cage groups. Fusion status was assessed by at 6-months and 1-year postoperatively by CT Bridwell scale and flexion/extension X-Rays. Postoperative complications (CT-based subsidence, adjacent segment disease, reoperation rates) and interval changes in lumbar radiographic alignment at short- and long-term follow-up were determined. Univariate and multivariate analysis compared patient and surgical factors, fusion rates, alignment, and complications across interbody groups. Results A total of 136 patients with 169 unique fusion levels (125 Ti cages, 44 PEEK cages) met the inclusion/exclusion criteria. Ti relative to PEEK interbodies had significantly decreased surface area and increased height and lordosis. Ti cage use was associated with greater subsidence ( P < 0.001) but did not independently predict maximum subsidence on regression ( P = 0.109). In the overall cohort, there were no significant differences in fusion rates or lumbopelvic alignment between interbody groups. Reoperation (Ti: 10.9% vs PEEK: 28.6%, P = 0.026) and reoperation for pseudoarthrosis (Ti: 2.0% vs PEEK: 11.4%, P = 0.038) was significantly more likely in the PEEK relative to the Ti group. Conclusions Use of 3D printed porous Ti cages relative to non-porous PEEK cages may mitigate pseudoarthrosis related reoperation after TLIF.

BACKGROUND AND OBJECTIVES: There has been limited assessment between anterior cervical diskectomy and fusion (ACDF) and anterior cervical corpectomy and fusion (ACCF) on patient-reported outcome measures (PROMs) in the treatment of cervical spondylotic myelopathy. We sought to compare PROMs from two-level ACDF with single-level ACCF procedures. We evaluate these results in the context of minimum clinically important difference (MCID) thresholds, which have not been performed previously. METHODS: This retrospective analysis of prospectively collected data from the Quality Outcomes Database Spine Collaborative Research Study Group compared two-level ACDF and single-level ACCF at 3-, 12-, and 24 months postoperatively. PROMs included arm pain Numeric Rating Scale, neck pain Numeric Rating Scale, Neck Disability Index, and North American Spine Society Patient Satisfaction Index. Multivariate logistic regression was used to determine differences in perioperative outcomes, as well as the impact of two-level ACDF vs one-level ACCF on PROMs. MCID thresholds were based off previously established limits. RESULTS: Three hundred and thirty patients were included (236 ACDF, 94 ACCF), and the follow-up rate was 82% at 2 years. There was a significantly higher baseline age, American Society of Anesthesiologists grade, proportion of diabetes, osteoarthritis, ambulation dependence, and myelopathy severity in the ACCF cohort. On multivariable analysis, the ACCF group had greater average length of stay and estimated blood loss. There were no significant differences between reoperation rates or nonroutine discharge. There were similar rates of MCID achievement for PROMs at all time points. CONCLUSION: This study suggests that both ACDF and ACCF procedures for cervical spondylotic myelopathy are able to achieve similar, clinically meaningful improvements in PROMs by 2 years. Patients undergoing single-level ACCF have more estimated blood loss and longer length of stay, as well as worse baseline myelopathy. Both procedures have efficacious, durable outcomes. It is reasonable that other factors, such as radiographic characteristics and patient symptoms, may influence patient selection for ACDF vs ACCF.

Abstract Background:Chronic obstructive pulmonary disease (COPD) is a major global health burden, with genome-wide association studies explaining only a fraction of its heritability. Recent advancements, including large-scale, multi-ancestry whole-genome sequencing and a focus on severe, early-onset cases, offer promising avenues to identify additional COPD-related variants. Furthermore, recent studies show that adjusting for polygenic risk scores (PRS) enhances statistical power to detect rare variants, advancing efforts to understand COPD's genetic basis. Methods:We performed a whole genome sequencing association study of severe, early-onset COPD (FEV1 &lt; 50%, age ≤ 55), FEV1 and FEV1/FVC in eight population-based studies (ARIC, CARDIA, CFS, CHS, FHS, HCHS/SOL, JHS, MESA) and seven COPD-enriched studies (COPDGene, ECLIPSE, Boston Early-Onset COPD Study, LTRC, TCGS (Poland), ICGN, SPIROMICS). We performed single-variant analyses using regenie software, applying a genome-wide significance threshold of P &lt; 5.0 x 10-8. For rare variant set (MAF &lt;1%) analysis, we annotated variants with loss of function or deleterious missense using WGS Annotator and prediction tools LOFTEE, SIFT, and PolyPhen2, then analyzed these variants with SKATO-ACAT method in regenie, adjusting for covariates including sex, sequencing center, and principal components of ancestry. We additionally evaluated adjusting the analyses for PRSs for lung function traits. Results: We analyzed 53,028 participants including 34,751 European, 12,508 African, 1,088 Latino American, and 674 East Asian ancestry. Across cohorts, we analyzed 5,063 severe (FEV1 &lt; 50%) COPD cases, among whom 1,103 were early-onset (age ≤ 55). Excluding variants within 1 Mbp of known variants, single-variant analysis identified 68 novel associations (MAC ≥ 30), with 8 common associations (MAF ≥ 1%) in 6 genomic regions. Our most significant novel association for severe early-onset COPD was rs74297390 (intergenic to POM121L12, MAF = 9.6%, Beta = 0.41, P = 3.5 x 10-8). For FEV1 and FEV1/FVC ratio, variants near DKK2 and AKR1E2 were significantly associated and were replicated in an independent dataset (Shrine et al., 2019). DKK2 is an antagonist in the Wnt pathway. In a preliminary variant set analysis, CHRM3-AS1 was associated with severe early-onset COPD, GPAT with FEV1, and COL8A1I and HMCN1 with FEV1/FVC. With PRS adjustment, ST6GALNAC5 was associated with FEV1/FVC. Conclusions: In a whole genome sequencing study of lung function and severe early-onset COPD, we identified new loci for COPD-related phenotypes, including two novel loci that replicated in an independent dataset. Ongoing work involves variant set-based analyses with additional covariate adjustments, as well as PRS adjustments for binary traits.

We here present evidence-based guidelines for the pharmacological treatment of migraine. These guidelines, created by the Italian Society for the Study of Headache and the International Headache Society, aim to offer clear, actionable recommendations to healthcare professionals. They incorporate evidence-based recommendations from randomized controlled trials and expert-based opinions. The guidelines follow the GRADE approach for assessing the quality of evidence. The guideline development involved a systematic review of literature across multiple databases, adherence to Cochrane review methods, and a structured framework for data extraction and interpretation. Although the guidelines provide a robust foundation for migraine treatment, they also highlight gaps in current research, such as the paucity of head-to-head drug comparisons and the need for long-term outcome studies. These guidelines serve as a resource to standardize migraine treatment and promote high-quality care across different healthcare settings.

We here present evidence-based guidelines for the pharmacological treatment of migraine. These guidelines, created by the Italian Society for the Study of Headache and the International Headache Society, aim to offer clear, actionable recommendations to healthcare professionals. They incorporate evidence-based recommendations from randomized controlled trials and expert-based opinions. The guidelines follow the Grading of Recommendations, Assessment, Development and Evaluation approach for assessing the quality of evidence. The guideline development involved a systematic review of literature across multiple databases, adherence to Cochrane review methods, and a structured framework for data extraction and interpretation. Although the guidelines provide a robust foundation for migraine treatment, they also highlight gaps in current research, such as the paucity of head-to-head drug comparisons and the need for long-term outcome studies. These guidelines serve as a resource to standardize migraine treatment and promote high-quality care across different healthcare settings.

Abstract Background: Leukocyte immunoglobulin-like receptor B2 (LILRB2) suppresses immune cell activation, particularly within myeloid cells in the tumor microenvironment (TME), while the PD-1/PD-L1 axis serves as a key immune checkpoint that inhibits T-cell function. SPX-303 is a novel bispecific antibody designed to simultaneously block LILRB2 and PD-L1, thereby revitalizing antitumor immune responses. Here, we present initial findings from the ongoing first-in-human Phase 1 trial of SPX-303 in patients with advanced solid tumors, including safety, pharmacokinetics (PK), and receptor occupancy (RO). Methods: This is an open-label, multicenter Phase 1 study for patients with advanced solid malignancies with 3+3 dose-escalation design, followed by an expansion cohort at the recommended Phase 2 dose (RP2D). SPX-303 is administered intravenously every three weeks and safety is assessed through CTCAE v5.0 criteria. Primary Objectives of this study are to determine the safety, tolerability, and RP2D of SPX-303. Secondary endpoints include antitumor activity as well as characterization of the PK and PD of SPX-303. This study is currently open and enrolling in escalation cohorts. Citation Format: Justin Moser, Hao Xie, Yujie Zhao, Yousef Zakharia, Dongdong Li, Brandon William, Dinh-Duc Nguyen, Jack Hovey, Tiffany Li, Robert Cai, Jichun Ma, Jingdong Qin, Martin Siekierzycki, Anthony Haight, Hua Jin, Weiwei Mao, Kevin Bin Li, Gui-Dong Zhu. A first-in-human phase 1 study on the safety, PK, receptor occupancy, and pharmacodynamic markers of SPX-303, a first-in-class LILRB2×PD-L1 bispecific antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT116.

Abstract Recent studies have described the tumor microenvironment and the key transcription factors in untreated small cell lung cancer (SCLC), but less is known about the salient features in recurrent SCLC (rSCLC). This information could provide valuable insight about the effectiveness of second and later line therapies. In this study, we compared transcriptome profiles (by RNA-seq) of rSCLC against untreated primaries (pSCLC). rSCLC samples (n=23) were obtained from frozen biopsies in patients enrolled in our MC1923 (NCT04607954) phase 2 clinical trial whose disease progressed after chemoimmunotherapy. The pSCLC group (n=73) included publicly available data from fresh frozen primary tumors after surgical resections. Normalized expression data were used in immune deconvolution and gene set enrichment analysis (GSEA) in molecular signature database. Additional GSEA included gene sets describing ASCL1 (A), NEUROD1 (N), ASCL1 and NEUROD1 (AN), and POU2F3 (P) transcription factor activities which are used for subtyping of SCLC. Immune deconvolutions by multiple software algorithms suggested depletion of immune infiltrates in rSCLC compared with pSCLC including dendritic cells, B cells, CD8+ T cells, and M1 macrophages. Furthermore, we found decreased chemotaxis and increased apoptosis of dendritic cells, reduced TNF signaling, and reduced lymphocyte co-stimulation in rSCLC by GSEA. Additionally, in comparisons with pSCLC, rSCLC tumors had significantly lower enrichment scores for POU2F3 activity, representing the SCLC-P subtype (p &lt; 0.007). Importantly, the SCLC-P was recently reported to be more immune inflamed than the other A, N, and AN subtypes. Altogether, our analyses provide strong evidence that the tumor microenvironment of rSCLC is significantly more immunosuppressed and with reduced immune cell infiltrates compared to pSCLC. Developing therapeutic strategies aimed at “warming” the tumor microenvironment and enhancing anti-tumor immune activity in ongoing multimodal therapies of recurrent SCLC will likely provide significant benefits to patients. Citation Format: Farhad Kosari, Mohamed Ali, Sarah H. Johnson, Alex Adjei, Julian R. Molina, Aaron S. Mansfield, Anastasios Dimou, Kaushal Parikh, Mohamed Shanshal, Katherine E. Smith, Ailsa G. Luce, Anna J. Schwecke, Janet Lensing, Ying-Chun Lo, John C. Cheville, George Vasmatzis, Konstantinos Leventakos. Small cell lung cancer (SCLC) at recurrence has a “colder” tumor microenvironment than primary SCLC according to gene expression profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6614.