bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term survival adjusted for treatment crossover in patients (pts) with myelofibrosis (MF) treated with momelotinib (MMB) vs danazol (DAN) in the MOMENTUM trial.
Authors: Gupta Vikas , Gerds Aaron Thomas , Vannucchi Alessandro , Kiladjian Jean-Jacques , Harrison Claire , Urbano Alisa , Huang Jireh , Ellis Catherine Elizabeth , Mesa Ruben A. 
Published: June 2024

6571 Background: Anemia and transfusion dependence affect nearly all pts with MF and are associated with poor prognosis.The phase 3 MOMENTUM trial (NCT04173494) evaluatedMMB—a JAK1, JAK2, and ACVR1 inhibitor—vs DAN (2:1 randomization) in JAK inhibitor (JAKi)–experienced pts with MF and anemia who had symptoms and splenomegaly. While MMB showed spleen, symptom, and anemia benefits vs DAN at wk 24, comparative estimates of long-term overall and leukemia-free survival (OS and LFS) are confounded and may underestimate the MMB effect, as all pts in the DAN arm who entered the open-label phase of the trial crossed over to receive MMB at wk 24. We used a rank-preserving structural failure time (RPSFT) model to estimate the OS and LFS that might have been observed without crossover. Methods: This exploratory analysis evaluated survival over the entire MOMENTUM trial period; most pts entered an extended access study (NCT03441113) after wk 48. The RPSFT model assumes that treatment slows the speed of disease progression and death proportionally regardless of time of crossover. Analyses were conducted with and without recensoring, and CIs were constructed to appropriately account for additional model fitting uncertainty. Results: As of December 29, 2022, 38 (29%) and 20 (31%) deaths had occurred in the MMB and DAN arms, respectively. Risk of death was reduced with MMB vs DAN by 11% (HR, 0.89) with no crossover adjustment, and by 22% (HR, 0.78) and 13% (HR, 0.87) using the RPSFT model with and without recensoring, respectively. Similarly, 40 (31%) and 22 (34%) LFS events had occurred at data cutoff in the MMB and DAN arms, respectively. Risk of an LFS event was reduced with MMB vs DAN by 20% (HR, 0.80) with no crossover adjustment, and by 36% (HR, 0.64) and 23% (HR, 0.77) using the RPSFT model with and without recensoring, respectively (Table). Conclusions: Consistent with the original unadjusted survival analysis, RPSFT models adjusting for the effects of treatment crossover showed prolonged OS and LFS in pts initially randomized to MMB vs those initially randomized to DAN; HRs in favor of MMB were lower after crossover adjustment. While these RPSFT analyses maintain the significance level of the original unadjusted analysis ( P>.05), these results support the trend of long-term survival benefits with MMB vs DAN in JAKi–experienced pts with MF and anemia. Clinical trial information: NCT04173494 . Clinical trial information: NCT03441113 .[Table: see text]
Efficacy and safety of ibrutinib plus venetoclax in patients with mantle cell lymphoma (MCL) and TP53 mutations in the SYMPATICO study.
Authors: Wang Michael , Jurczak Wojciech , Trneny Marek , Belada David , Wrobel Tomasz , Ghosh Nilanjan , Keating Mary-Margaret , van Meerten Tom , Fernández-Álvarez Rubén , von Keudell Gottfried , Thieblemont Catherine , Peyrade Frederic , Andre Marc , Hoffmann Marc , Naganuma Maoko , Szafer-Glusman Edith , Lin Jennifer , Dean James P. , Neuenburg Jutta Katrin , Tam Constantine S. 
Published: June 2024

7007 Background: TP53 mutations confer high risk of early progressive disease (PD) and poor outcomes with standard chemoimmunotherapy in patients (pts) with MCL. To date, data on novel treatment options for these pts are limited to small single-arm analyses. The phase 3 SYMPATICO study is evaluating ibrutinib (Ibr) + venetoclax (Ven) in 3 cohorts of pts with MCL. Primary analysis of the randomized phase showed superior PFS with Ibr+Ven vs Ibr+placebo (Pbo) in pts with relapsed/refractory (R/R) MCL (Wang M et al, ASH 2023) with similar hazard ratios for pts with and without TP53mutations (0.57 [95% CI, 0.33–0.97] and 0.52 [95% CI, 0.32–0.82], respectively). Here, we report efficacy and safety of Ibr+Ven in pts with TP53 mutations across cohorts. Methods: The SYMPATICO cohorts are: open-label safety run-in phase to evaluate concurrent initiation of Ibr+Ven in R/R MCL (n=21); randomized phase to evaluate Ibr+Ven (n=134) vs Ibr+Pbo (n=133) in R/R MCL; and open-label cohort to evaluate first-line (1L) Ibr+Ven (n=78). Data were pooled across cohorts for pts with TP53mutations treated with oral Ibr 560 mg once daily and Ven (5-wk ramp-up to 400 mg once daily) for 2 y, then single-agent Ibr 560 mg until PD or unacceptable toxicity. Response was assessed by investigators per Lugano criteria. Results: In total, 74 pts with TP53 mutations received Ibr+Ven in the safety run-in phase (n=5), the randomized phase (n=40), and the 1L cohort (n=29). At baseline, median age was 67 y, 96% of pts had ECOG PS of 0–1, 43% had high-risk simplified MIPI score, 36% had bulky disease ≥5 cm, 64% had bone marrow involvement, and 39% had splenomegaly. With a median time on study of 40.1 mo (range, 0.6+ to 60.7), median PFS was 20.9 mo vs not reached (NR) in pts without TP53 mutations. ORR was 84%, and the CR rate was 57%. Median OS was 47.1 mo. Outcomes were generally comparable in 1L and R/R MCL (Table). Median duration of treatment was 15.9 mo (range, 0.3–58.9); at data cutoff, treatment was ongoing with Ibr in 24% of pts and with Ven in 4%. The most frequent grade ≥3 AEs (in ≥10% of pts) were neutropenia (32%), anemia (15%), and thrombocytopenia (15%). Conclusions: Ibr+Ven demonstrated promising efficacy with high CR rates and durable remissions in high-risk pts with MCL and TP53mutations in SYMPATICO (n=74; 29 1L and 45 R/R), the largest single-study cohort of such pts reported to date. Clinical trial information: NCT03112174 . [Table: see text]
Efficacy and safety of immunotherapy plus chemotherapy for lung cancer neoadjuvant treatment: A network meta-analysis based on randomized controlled trials.
Authors: Li Shen , Yang Jiaqing , Xu Chenhao , Ma Xuelei 
Published: June 2024

8026 Background: With immunotherapy's swift progress in lung cancer treatment, combining immunotherapy with chemotherapy (CT) for neoadjuvant use has attracted significant interest, though direct comparisons of its efficacy and safety are still scarce. This study aims to comprehensively evaluate the efficacy and safety of immunotherapy combined with chemotherapy versus chemotherapy alone in the neoadjuvant treatment of lung cancer. Methods: We searched databases, including PubMed and EMBASE, for phase II and III randomized global trials that assessed neoadjuvant lung cancer treatment with immunotherapy combined with chemotherapy. We performed a Bayesian random-effects network meta-analysis to evaluate efficacy, presenting Hazard Ratios (HRs) and 95% Confidence Intervals (95%CI). Bias risk was determined using the Cochrane risk of bias tool, and evidence quality was appraised via the CINeMA framework. Results: Our analysis included eight randomized controlled trials, comprising a total of 3,316 patients. The results indicated that, compared to neoadjuvant chemotherapy alone, the Event-Free Survival (EFS) was highest for the durvalumab+CT group, ranking first with an HR of 2 (95% CI: 1.0 to 3.7). The pembrolizumab+CT group ranked second with an HR of 1.8 (95% CI: 0.76 to 4.2), followed by the nivolumab+CT group in third place with an HR of 1.7 (95% CI: 0.95 to 3.1). Both the nivolumab and ipilimumab+CT and toripalimab+CT groups tied for fourth place with HRs of 1.4 (95% CI: 0.58 to 3.5) and 1.5 (95% CI: 0.70 to 3.2), respectively. The camrelizumab+CT group had the lowest EFS ranking, with an HR of 1.7 (95% CI: 0.74 to 3.8). The combination of nivolumab+ipilimumab+CT showed the most favorable outcomes in terms of Pathologic Complete Response (PCR) and R0 resection rates among the six treatments, with lnOR values of 3.17 and 1.48, respectively. This combination also had the lowest occurrence of treatment-related adverse events greater than grade 3, with an lnOR value of -1.38. Conclusions: This network meta-analysis indicates that durvalumab, when combined with chemotherapy, offers the best EFS among the immunotherapy options evaluated, demonstrating good safety and efficacy. Concurrent use of nivolumab and ipilimumab resulted in the highest pCR and R0 resection rates. Moreover, for patients with lung cancer, the preliminary evidence supports the value of combining immunotherapy with chemotherapy as a neoadjuvant treatment strategy over chemotherapy alone. [Table: see text]
Investigation of the role of personalized molecular residual disease in the assessment of high-risk non-small cell lung cancer (NSCLC) post-operation.
Authors: Zhou Yu-Heng , Lin Yaobin , Rao Bing-Yu , Feng Shoucheng , Teng Jiaman , Cheng Shaochen , Zhong Jiasheng , Long Hao 
Published: June 2024

8027 Background: Radical surgical resection is preferred treatment for early-stage Non-Small Cell Lung Cancer (NSCLC) patients. Despite this, recurrence and metastasis significantly impact patient survival. High-risk factors like Tumor Thrombus (TT) and Spread Through Air Spaces (STAS) are known to exacerbnate the recurrence and metastasis rates, yet there is lacking research exploring the association between these riskes and treatment outcomes. The study aims to evaluate the utility of circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) in assessing and monitoring high-risk NSCLC post-operatively. Methods: NSCLC patients underwent curative surgery (R0) were recruited in this study and their tissue samples were collected after surgical resection. Whole exome sequencing (WES) was performed to identify somatic mutation information across individual, from which bespke molecular residual disease (MRD) detection panel was designed and used in later detection. Plasma samples were collected 3-4 weeks post-surgery and analyzed for MRD status through using next-generation sequencing (NGS) at 100,000x sequencing depths. Results: The study enrolled 124 NSCLC patients with a median age of 60 years (ranged 29-86)., The cohort comprised 63 male (77.3%) and 61 females (22.7%). Pathologically, 92 patients were classified in stage I, 5 as stage II, 17 as stage III, and 10 as stage IV. A total of 10,260 somatic mutationwere identified across 6,315 genes, including 639 insertions/deletions (InDels), 9613 single nucleotide variants (SNVs), and 8 gene fusions. The most prevalent mutations were EGFR (58.87%), followed by TTN (45.97%), TP53 (40.32%), CEP192 (20.97%), XIRP2 (19.35%), ZFHX4 (19.35%), and TOPAZ1 (16.94%). The MRD positivity was observed in 29.0% (36/124) of patients, with a higher incidence in males (34.9%, 22/63) than females (22.9%, 14/61). By stage, MRD positivity was 16.3% (16/92) in stage I, 40.0% (2/5) in stage II, 47.0% (8/17) in stage III, and 100% (10/10) in stage IV patients. Among patients with risk factors, 31.6% (12/38) with STAS, , 60.0% (6/10) with TT, and 53.8% (7/13) with pleural invasion were MRD positive, which indicating a higher postoperative MRD positivity in high-risk groups. Conclusions: NSCLC patients with high-risk factors, such as STAS and TT, , exhibit a high rate postoperative MRD positivity, even after R0 resection. Current research reports indicate that the MRD post-operation is an indicator of recurrence, metastasis, and poor prognosis. The findings imply that NSCLC patients harboring these high-risk factors are more susceptible to recurrence and metastasis, possibly necessitating postoperative adjuvant therapy for effective management.
Lymph node metastasis prediction with non-small cell lung cancer histopathology imaging.
Authors: Lee Victor , King Amber Loren Ong , Sritharan Durga , Moore Nicholas Simms , Chadha Saahil , Maresca Ryan , Hager Tommy , Aneja Sanjay 
Published: June 2024

8063 Background: Lymph nodal metastasis (LNM) plays a critical role in the prognosis and treatment strategy formulation for non-small cell lung cancer (NSCLC). Initial diagnosis typically involves a CT scan, but its sensitivity for detecting mediastinal LNM is limited, sometimes as low as 51%. To improve detection, PET-CT, mediastinoscopy, and Endobronchial ultrasound-guided transbronchial needle aspiration are employed, with sensitivities of 74%, 78%, and 90%, respectively. The ability to anticipate nodal metastasis from primary tumor data could significantly influence clinical decisions, particularly for patients at risk from invasive procedures like EBUS. By leveraging the pathology data from the National Lung Screening Trial (NLST), this study aims to harness machine learning algorithms, with the goal of refining the staging process and individualizing patient care, thus enhancing the therapeutic outcome and potentially sparing patients from the morbidity associated with more invasive diagnostic techniques. Methods: This research used digital hematoxylin and eosin (H&E) stained histopathology slide images of NSCLC from the NLST provided by The Cancer Imaging Archive. It excluded cases with undefined nodal or distant metastasis status (Nx or Mx), as well as those with confirmed distant metastasis (M1). Cases were categorized as node positive if they had N1, N2, or N3 disease, and node negative if they had N0 disease. The analysis of pathology slide images was performed using the CLAM analysis pipeline, which operates by creating patches, extracting features via a ResNet-50 model pre-trained on ImageNet, and training models with attention modules that assign scores to each patch. The study was performed using Python 3.7 and the CLAM library. Results: 636 whole slide images were analyzed, comprising 453 cases without lymph node metastasis (node negative) and 183 cases with lymph node metastasis (node positive). The study revealed that the CLAM model could predict LNM with an average area under the curve (AUC) of 0.78 over a series of 10 folds. The median sensitivity of the model at the threshold values of 0.3, 0.5, and 0.7 was 0.78, 0.48, and 0.24, respectively. Correspondingly, the median specificity at these same cutoffs was 0.49, 0.91, and 1.00, respectively. Conclusions: The study provided a proof of concept that nodal metastasis can be predicted from H&E slide images of primary resections using solely deep learning methods. The integration of deep learning models into the diagnostic process could fundamentally transform how clinicians evaluate the risk of LNM, tailor treatment plans, and ultimately enhance survival rates and quality of life for patients with NSCLC.
Efficacy and safety of MCLA-129, an anti-EGFR/c-MET bispecific antibody, in non-small-cell lung cancer (NSCLC) with c-METexon 14 skipping mutations (METex14).
Authors: Brandao Mariana da Rocha Almeida , Zugazagoitia Jon , Dingemans Anne-Marie C. , Duruisseaux Michaël , Parent Pauline , Juan-Vidal Oscar , Spira Alexander I. , Vicier Cecile , Zalcman Gerard , Barasa Ben , Yan Chris , Doze Petra , Joe Andrew K. , Laus Gianluca , Felip Enriqueta 
Published: June 2024

8583 Background: Epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-MET) are dysregulated in many tumors, including NSCLC. In particular, splice-site alterations resulting in the loss of transcription of exon 14 in the oncogenic driver c-MET ( METex14 skipping mutations) occur in ~3% of NSCLC and lead to oncogenic MET activation. MCLA-129 is a bispecific antibody that targets EGFR and c-MET with multiple mechanisms of action, including inhibition of EGFR and c-MET signaling, antibody-dependent cellular phagocytosis and enhanced antibody-dependent cellular cytotoxicity. In the dose escalation part of a phase 1/2 trial (NCT04868877), the initial recommended phase 2 dose of MCLA-129 monotherapy was determined to be 1500 mg every 2 weeks (Q2W) with 28-day cycles. Significant tumor shrinkage was observed in one patient with METex14 NSCLC previously treated with multiple chemotherapy agents and the c-MET tyrosine kinase inhibitor (TKI) capmatinib. Preliminary data are presented of patients (pts) with advanced or metastatic METex14 NSCLC treated with MCLA-129 in the dose expansion phase of the trial. Methods: Pts with advanced/metastatic METex14 NSCLC Pts received MCLA-129 1500 mg IV Q2W, until disease progression or unacceptable toxicity. Tumor imaging was conducted every 8 weeks. Primary endpoint: investigator-assessed ORR (RECIST v1.1), in pts with measurable disease, ≥2 MCLA-129 cycles, and ≥1 post-baseline scan. Secondary endpoints: DCR and safety. Biomarker analyses of EGFR/c-MET expression and ctDNA mutation status are planned. Results: As of December 1, 2023, 15 pts were dosed. The median age was 72 years (range 61-83), 40% were male, and 13%/87% of pts had ECOG performance status 0/1 respectively. The trial is ongoing; further analysis of safety and efficacy is planned with a later data cutoff date and will be presented at the meeting. Conclusions: MCLA-129 is being evaluated as monotherapy for the treatment of patients with locally advanced/metastatic c-MET exon 14 skipping NSCLC. Clinical trial information: NCT04868877 .
Clinical Predictors of Overall Survival in Very Elderly Patients With Glioblastoma: A National Cancer Database Multivariable Analysis
Authors: Gendreau Julian , Mehkri Yusuf , Kuo Cathleen , Chakravarti Sachiv , Jimenez Miguel Angel , Shalom Moshe , Kazemi Foad , Mukherjee Debraj 
Published: June 2024

BACKGROUND AND OBJECTIVES:
Surgery for the very elderly is a progressively important paradigm as life expectancy continues to rise. Patients with glioblastoma multiforme often undergo surgery, radiotherapy (RT), and chemotherapy (CT) to prolong overall survival (OS). However, the efficacy of these treatment modalities in patients aged 80 years and older has yet to be fully assessed in the literature.

METHODS:
The National Cancer Database was used to retrospectively identify patients aged 65 years and older with glioblastoma multiforme (1989-2016). All available patient demographic characteristics, disease characteristics, and clinical outcomes were collected. To study OS, bivariable survival models were created using Kaplan-Meier estimates. A Cox proportional-hazards model was used for final adjusted analyses.

RESULTS:
A total of 578 very elderly patients (aged 80 years and older) and 2836 elderly patients (aged 65-79 years) were identified. Compared with elderly patients, very elderly patients were more likely to have Medicare (odds ratio [OR] 1.899 [95% CI: 1.417-2.544], P < .001) while less likely to have private insurance status (OR 0.544 [95% CI: 0.401-0.739], P < .001). In addition, very elderly patients were more likely to travel the least distance for treatment and have multiple tumors (P < .001). When controlling for demographic and disease characteristics, very elderly patients were less likely to receive gross total resection (GTR) (OR 0.822 [95% CI: 0.681-0.991], P < .041), RT (OR 0.385 [95% CI: 0.319-0.466], P < .001), or postoperative CT (OR 0.298 [95% CI: 0.219-0.359], P < .001) relative to elderly counterparts. Within very elderly patients, GTR, RT, and CT all independently and significantly predicted improved OS (P < .001 for all). These predictive models were deployed in an online calculator (https://spine.shinyapps.io/GBM_elderly).

CONCLUSION:
Very elderly patients are less likely to receive GTR, RT, or CT when compared with elderly counterparts despite use of these therapies conferring improved OS. Selected very elderly patients may benefit from more aggressive attempts at surgical and adjuvant treatment.
An Appraisal of the Quality of Development and Reporting of Predictive Models in Neurosurgery: A Systematic Review
Authors: Khalid Syed I. , Massaad Elie , Roy Joanna Mary , Thomson Kyle , Mirpuri Pranav , Kiapour Ali , Shin John H. 
Published: June 2024

BACKGROUND AND OBJECTIVES:
Significant evidence has indicated that the reporting quality of novel predictive models is poor because of confounding by small data sets, inappropriate statistical analyses, and a lack of validation and reproducibility. The Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD) statement was developed to increase the generalizability of predictive models. This study evaluated the quality of predictive models reported in neurosurgical literature through their compliance with the TRIPOD guidelines.

METHODS:
Articles reporting prediction models published in the top 5 neurosurgery journals by SCImago Journal Rank-2 (Neurosurgery, Journal of Neurosurgery, Journal of Neurosurgery: Spine, Journal of NeuroInterventional Surgery, and Journal of Neurology, Neurosurgery, and Psychiatry) between January 1st, 2018, and January 1st, 2023, were identified through a PubMed search strategy that combined terms related to machine learning and prediction modeling. These original research articles were analyzed against the TRIPOD criteria.

RESULTS:
A total of 110 articles were assessed with the TRIPOD checklist. The median compliance was 57.4% (IQR: 50.0%-66.7%). Models using machine learning-based models exhibited lower compliance on average compared with conventional learning-based models (57.1%, 50.0%-66.7% vs 68.1%, 50.2%-68.1%, P = .472). Among the TRIPOD criteria, the lowest compliance was observed in blinding the assessment of predictors and outcomes (n = 7, 12.7% and n = 10, 16.9%, respectively), including an informative title (n = 17, 15.6%) and reporting model performance measures such as confidence intervals (n = 27, 24.8%). Few studies provided sufficient information to allow for the external validation of results (n = 26, 25.7%).

CONCLUSION:
Published predictive models in neurosurgery commonly fall short of meeting the established guidelines laid out by TRIPOD for optimal development, validation, and reporting. This lack of compliance may represent the minor extent to which these models have been subjected to external validation or adopted into routine clinical practice in neurosurgery.