tbuckley/cabot-search huggingface dataset:
Efficacy and safety of ruxolitinib in patients with lower risk myelofibrosis: A single-arm, exploratory and prospective study.
Authors: Shiwei Hu, Xiudi Yang, Hongyan Tong, Jie Jin, Jian Huang
Journal: Journal of Clinical Oncology (2024)

6573 Background: The COMFORT studies assessed the efficacy and safety of ruxolitinib in patients with intermediate-2 and high risk myelofibrosis (MF), and JUMP study has broadened the investigation including patients with intermediate-1 MF in the classification of DIPSS. However, there have been limited prospective studies evaluating the efficacy and safety of patients with low risk MF in the classification of more comprehensive scoring system. Here we present a single-arm, exploratory and prospective study to assess the efficacy and safety of ruxolitinib in patients with lower risk MF in China. Methods: Lower risk was defined as MIPSS-70 ≤ 3, MIPSS+V2.0 ≤ 3, DIPSS-Plus ≤ 1, DIPSS ≤ 2 or MYSEC-PM &lt; 14 according to the expert guidelines. Patients aged ≥ 18 with overt primary myelofibrosis (overt-PMF), prefibrotic primary myelofibrosis (pre-PMF), post-polycythemia vera myelofibrosis (post-PV MF) or post-essential thrombocythemia myelofibrosis (post-ET MF), classified as lower risk were enrolled. The primary endpoint was the proportion of patients with a spleen length reduction of ≥ 50% from baseline at week 48. Secondary endpoints included the best spleen response, the proportion of patients with a ≥ 50% reduction in Total Symptom Score (TSS50) and safety. Results: A total of 40 patients were enrolled in the lower risk group, including 7 pre-PMF, 17 overt-PMF, 8 PPV-MF, and 8 PET-MF patients. The median age was 62.0 years. 32 (80%) were JAK2V617F positive. 16 patients had next generation sequencing (NGS), the most frequent non-driver mutation was in TET2 (43.8%), followed by BCOR (12.5%). By week 48, 26 (65.0%) patients achieved a ≥ 50% decrease in palpable spleen length. 32 (80.0%) patients achieved a ≥ 50% reduction from baseline at any time. The median time to a spleen response was 4.3 weeks. The TSS50 rates at week 48 was 25%. No patients required red blood cell transfusion at baseline. And only 1 patient had a baseline hemoglobin (HB) &lt;100 g/L, which remained stable during the follow-up process. The most common grade ≥ 3 hematological treatment emergent adverse events (TEAEs) were anemia (10.0%) and thrombocytopenia (2.5%). 6 (15.0%) and 15 (37.5%) patients experienced grade 1 or 2 anemia and thrombocytopenia, respectively. The mostly common non-hematological TEAEs was infection (12.5), including upper respiratory tract infection (7.5%), urinary infection (2.5%), fever (2.5%), predominantly of grade 1 or 2. Of note, 1 patient developed staphylococcal sepsis and 1 patient experienced acute renal failure. No one discontinued ruxolitinib treatment due to TEAEs. Conclusions: Ruxolitinib is an effective treatment for patients with intermediate-1 and low risk MF, resulting in improved spleen and symptom responses, along with fewer hematological and non-hematological TEAEs. This trial was registered as ChiCTR2200064250 at ClinicalTrials.gov . Clinical trial information: ChiCTR2200064250.
Impact of <i>EGFR</i> mutation and types of treatment on the longitudinal recurrence risk in patients with completely resected non-small cell lung cancer: A combined analysis of two phase III studies (JIPANG and IMPACT).
Authors: Hiroaki Akamatsu, Tomomi Nishikawa, Toshihiro Misumi, Tadashi Aoki, Hiroyasu Shoda, Motohiro Yamashita, Noriaki Sakakura, Haruko Daga, Shunichi Sugawara, Kyoichi Okishio, Hirotsugu Kenmotsu, Nobuyuki Yamamoto, Hirohito Tada, Masahiro Tsuboi, Tetsuya Mitsudomi
Journal: Journal of Clinical Oncology (2024)

8023 Background: In completely resected non-small cell lung cancer patients who received adjuvant treatment, the impact of EGFR mutation and types of treatment on the longitudinal recurrence risk has not been elucidated. Methods: The individual data was obtained from two adjuvant phase III trials conducted almost the same period in Japan (JIPANG [CDDP + PEM versus CDDP + VNR] and IMPACT [gefitinib versus CDDP+VNR]). According to EGFR mutation status and types of adjuvant treatment, 626 patients were categorized into three groups (arm A [ EGFR wild-type, chemo: n = 299], arm B [ EGFR mutant, chemo: n = 211], and arm C [ EGFR mutant, gefitinib: n = 116]). Disease-free survival (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier method, and sites of recurrence were compared. Additionally, the longitudinal recurrence risk was analyzed by estimating hazard function among the arms. The impact of EGFR mutation and the types of adjuvant treatment on the recurrence site (central nervous system vs others) and death was also analyzed using the multi-state model. Results: Median follow-up time was 69.3 months (range, 0.0 to 113.4 months). DFS was not different between the arms (median DFS: 42.2 months in arm A, 30.3 months in arm B, and 35.9 months in arm C, respectively), however, the DFS rate at 8 years was numerically different (arm A: 40.4%, arm B: 33.9%, and arm C: 22.3%, respectively: Table). Median OS was not reached in each arm, and OS rates at 8 years were 61.3%, 67.7%, and 59.8%, respectively. In the longitudinal recurrence risk analysis, arms A and B had a higher hazard function level than arm C for the first two years and the curves crossed thereafter. Risks in arms A and B gradually decreased and reached a plateau at a lower level, whereas arm C sustained a recurrence risk and finally it was higher than arms A and B. Regarding sites of recurrence, arm C showed a slightly higher distant relapse (51.7%) than arm A (47.2%) or arm B (45.5%), of those, CNS was the most frequent site (33.8%). Among EGFR mutant cases, gefitinib likely to have higher risk of CNS relapse (HR 1.46, 95% confidence interval: 0.62-3.45) than chemotherapy. When treated with chemotherapy, EGFR mutation status did not affect any types of recurrence. Conclusions: In patients with completely resected NSCLC, chemotherapy led to cure regardless of EGFRmutation status, whereas gefitinib showed a sustained recurrence risk even after completion. Clinical trial information: UMIN000006252 and UMIN000006737. [Table: see text]
Neoadjuvant hypofractionated radiotherapy combined with pembrolizumab plus chemotherapy for potentially resectable non-small cell lung cancer: A phase Ib study.
Authors: Naixin Ding, Lijun Zhao, Shuai Zhang, Ninglei Qiu, Xue Song, Cheng Kong, Ning Jiang, Yang Zhao, Jianfeng Huang, Feng Jiang, Ming Jiang, Zihao Zhu, Rong Yin, Binhui Ren, Xiangzhi Zhu, Ming Li
Journal: Journal of Clinical Oncology (2024)

8054 Background: Neoadjuvant PD-1 inhibitor plus chemotherapy in resectable non-small cell lung cancer (NSCLC) has become a standard of care. hypofractioned radiotherapy (HFRT) served as an immunomodulator and enhanced the effect of preoperative immunotherapy. In this phase Ib study, we evaluated the safety and feasibility of neoadjuvant HFRT with pembrolizumab plus chemotherapy in patients with potentially resectable stage III NSCLC. Methods: Patients with potentially resectable stage III NSCLC with EGFR/ALK wild-type were recruited to receive HFRT to the primary tumor followed by two cycles of pembrolizumab (100 mg/body) plus platinum-based doublet chemotherapy (Q3W). HFRT was delivered using 3 daily fractions, with a dose of 24 Gy for peripheral lesions and 12 Gy for central lesions. Central lesion is defined as a 2 cm area around the pulmonary artery and main bronchus. The decision for surgery was made through multidisciplinary team (MDT) discussion within a 4–6-week period after the completion of neoadjuvant treatment. Patients underwent surgery followed by adjuvant pembrolizumab for 2 years. Primary endpoint was safety. Secondary endpoints were efficacy, such as pathological complete response (pCR), progression-free survival (PFS), and overall survival (OS). Results: Between April 2021 and November 2023, 17 patients were enrolled with a median age of 66 years (range 54-74) and 15 (88.2%) having squamous cell lung cancer. 12 (70.6%) patients had stage IIIB disease, and 10 (58.8%) had central primary lesion. PD-L1 was ≥1% in 9 patients (52.9%). All patients received HFRT and at least one cycle of immunochemotherapy. No grade 3 or high adverse events were observed during neoadjuvant therapy. Only one patient had grade 1 nephrotoxicity, and another patient had grade 2 pneumonitis. A partial response was achieved in 16 out of 17 patients (94.1%), while one patient had stable disease after neoadjuvant therapy. Following MDT discussion, 11 patients (64.7%) met the surgical standards, while the remaining 6 patients were transitioned to definitive chemoradiotherapy. Among the 11 patients who underwent surgery, 8 (72.7%) achieved R0 resection, and 6 patients (54.5%) attained pCR. Only one patient died from intraoperative bleeding, and the remaining patients were followed up. The median PFS was 21.7 months, median OS were not reached, and the 2-year OS rate was 85.6%. The study was terminated early due to slow recruitment. Conclusions: Neoadjuvant HFRT with immunotherapy for potentially resectable stage III NSCLC is a tolerable treatment with an improved surgical conversion rate and pCR rate. Clinical trial information: ChiCTR2100045361.
The safety and efficacy of induction chemoimmunotherapy in initially unresectable stage III non-small cell lung cancer.
Authors: Min Tang, Zhe Zhao, Ping Zhang, Xin Nie, Xiaonan Wu, Yue Yuan, Lian Liu, Lipin Liu, Peng Jiao, Lin Li
Journal: Journal of Clinical Oncology (2024)

8058 Background: Definitive concurrent chemoradiation followed by consolidation immunotherapy is the standard of care for unresectable stage III non-small cell lung cancer. Several studies demonstrated addition of induction immunotherapy may further improve outcome, and it is necessary to assess the response-adapted strategy based on early tumor retraction to induction therapy. This study evaluated safety and treatment outcomes of induction chemoimmunotherapy followed by surgery or RT in unresectable stage III NSCLC. Methods: Patients with previously untreated, unresectable, pathologically and radiologically confirmed stage III NSCLC, EGFR/ALK-wild-type, with measurable disease were included. Patients received 3 to 4 cycles (Q3W) of chemoimmunotherapy including carboplatin (area under the curve [AUC] 5mg/mL/min), nab-paclitaxel (squamous NSCLC, 260mg/m 2 ) or pemetrexed (non-squamous NSCLC, 500mg/m 2 ), and tislelizumab(200mg). After Multi-Disciplinary Treatment, those operable patients after induction chemoimmunotherapy received radical minimally invasive surgery followed by 14 cycles of tislelizumab. The still unresectable patients received standard thoracic radiotherapy followed by 14 cycles of tislelizumab. Coprimary end points include 24-month progression-free survival (PFS) rate and incidence of grade 3 to 5 pneumonitis. Results: Between May 2020 and November 2023, a total of 59 patients received treatment (54 men [91.5%]; median [range] age, 65 [46-82] years; 34 patients [57.7%] with programmed cell death ligand 1 [PD-L1] tumor proportion score ≥ 1%); 40 patients [67.8%] were squamous cell NSCLC; 33.9%, 45.8%, and 20.3% patients were stage IIIA, IIIB and IIIC. Sixteen patients received radical minimally invasive surgery (9 pCR), 42 patients received thoracic radiotherapy, and 1 patient had brain metastasis after 2 cycles of induction therapy. The median follow-up period was 20.1 (1.9-44.1) months, and median PFS was not reached, the 24-months PFS rate was 77.6% (95%CI, 59.9%-88.2%). The objective response rate was 93.2% (95%CI, 83.5%-98.1%), and DCR was 98.3% (95%CI, 90.9%-100.0%). Grade 3 pneumonitis occurred in 2 of 59 patients (3.4%). Conclusions: The findings of this study indicate encouraging antitumor activity and manageable safety of induction chemoimmunotherapy, and the response-adapted strategy requires further exploration in locally advanced unresctable non-small cell lung cancer. Clinical trial information: ChiCTR2200064104. [Table: see text]
Single-cell genomics details the maturation block in BCP-ALL and identifies therapeutic vulnerabilities in DUX4-r cases
Authors: Hanna Thorsson, Rasmus Henningsson, Noelia Puente-Moncada, Pablo Peña-Martínez, Ludvig Sjöström, Helena Ågerstam, Carl Sandén, Marianne Rissler, Anders Castor, Hanne Vibeke Hansen Marquart, Signe Modvig, Kajsa Paulsson, Cornelis Jan Pronk, Kjeld Schmiegelow, Axel Hyrenius-Wittsten, Christina Orsmark-Pietras, Henrik Lilljebjörn, Thoas Fioretos
Journal: Blood (2024)
Outcome of Hematopoietic Stem Cell Transplantation in 813 Pediatric Patients with Fanconi Anemia
Authors: Su Han Lum, Dirk-Jan Eikema, Brian Piepenbroek, Robert F. Wynn, Sujith Samarasinghe, Arnaud Dalissier, Krysztof Kalwak, Mouhab Ayas, Rose-Marie Hamladji, Akif Yesilipek, Jean-Hugues Dalle, Duygu Uckan-Cetinkaya, Marc Bierings, Alphan Kupesiz, Khalid Halahleh, Elena Skorobogatova, Gülyüz Öztürk, Maura Faraci, Cecile Renard, Pamela Evans, Selim Corbacioglu, Franco Locatelli, Carlo Dufour, Antonio Risitano, Régis Peffault de Latour
Journal: Blood (2024)
Novel MAGIC composite scores using both clinical symptoms and biomarkers best predict treatment outcomes of acute GVHD
Authors: Yu Akahoshi, Nikolaos Spyrou, Daniela Weber, Paibel Aguayo-Hiraldo, Francis Ayuketang Ayuk, Chantiya Chanswangphuwana, Hannah K Choe, Matthias Eder, Aaron M. Etra, Stephan A. Grupp, Elizabeth O. Hexner, William J Hogan, Carrie L. Kitko, Sabrina Kraus, Monzr M. Al Malki, Pietro Merli, Muna Qayed, Ran Reshef, Tal Schechter, Evelyn Ullrich, Ingrid Vasova, Matthias Wölfl, Robert Zeiser, Janna Baez, Rahnuma Beheshti, Gilbert W Eng, Sigrun Gleich, Nikolaos Katsivelos, Steven Kowalyk, George Morales, Rachel Young, Yi-Bin Chen, Ryotaro Nakamura, John E Levine, James L.M. Ferrara
Journal: Blood (2024)
High-dose furmonertinib in patients with <i><i>EGFR</i></i>-mutated non-small cell lung cancer and leptomeningeal metastases: A real-world study.
Authors: Haiyang Chen, Lili Wang, Yingxi Wu, Yufeng Wu, Shuxiang Ma, Sen Yang, Zhen He, Yuqing Mo, Cuicui Zhang, Qiming Wang
Journal: Journal of Clinical Oncology (2024)

8587 Background: Leptomeningeal metastasis (LM) is one of the most severe complications of non-small cell lung cancer (NSCLC) and always accompanied with poor prognosis. Furmonertinib is a pan-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with high brain penetration and wide therapeutic window. This study aimed to evaluate the efficacy and safety of high-dose furmonertinib in patients with EGFR-mutated NSCLC and LM in the real world. Methods: Eligible patients were aged at least 18 years old and had histological or cytological confirmed advanced NSCLC harboring an EGFR mutation. Patients were diagnosed as probable or confirmed LM according to the EANO-ESMO criteria. Patients were treated with furmonertinib 240mg once daily. The primary endpoint was overall survival (OS), time to treatment discontinuation (TTD) and clinical response rate were secondary endpoints. Clinical response rate assessed with improvement of neurologic symptoms or signs and changes in the performance status. Additional efficacy evaluations included changes in brain magnetic resonance imaging (MRI) according to the RANO-LM radiologic criteria. Results: Between May 1, 2021, and December 28, 2023, 48 patients were enrolled at Henan Cancer Hospital. All of the enrolled patients had poor performance status, 13 (27.1%) patients had an ECOG score of 2, 35 (72.9%) patients had an ECOG score of 3. And 35 (72.9%) patients had received other 3rd generation EGFR-TKIs. The median follow-up time was 15 months. 31 OS events occurred at the data cut-off. The primary endpoint of median OS was 8.433 months (95%CI, 5.481 to 11.386 months). The secondary endpoint of median TTD was 8.267 months (95%CI, 5.395 to 11.138 months). The clinical response rate was 75%. The LM objective response rate (ORR) and disease control rate (DCR) assessed by investigator according to RANO-LM radiologic criteria were 47.4% and 92.1%, respectively. The adverse event profiles were consistent with previous reports of furmonertinib. 22 (45.8%) patients had adverse events (AEs) possibly related to furmonertinib. 3 (6.3%) patients had grade 3 elevated aminotransaminase or nausea or leucopenia, respectively, leading to dose reduction to 160mg daily. Conclusions: In the real world, high-dose furmonertinib demonstrated significant clinical efficacy and tolerable safety in patients of EGFR-mutated NSCLC with LM, even in patients who had been treated with other 3rd generation EGFR-TKIs previously. Clinical trial information: ChiCTR2300072092.
Dysregulated KLF4 expression plays a pivotal role in the pathogenesis of pancreatic intraductal papillary mucinous neoplasms
Authors: Xiangsheng Zuo, Liang Wang, Yi Liu, Huamin Wang, Margarete Hafley, Mihai Gagea, Ru Chen, Yun Xiong, Sheng Pan, Imad Shureiqi, Robert S Bresalier, Daoyan Wei
Journal: Gut (2024)
Homoharringtonine Inhibits the NOTCH/MYC Pathway and Exhibits Anti-Tumor Effects in T-Cell Acute Lymphoblastic Leukemia
Authors: Shanshan Suo, Dandan Zhao, Fenglin Li, Yi Zhang, Sonia Rodriguez-Rodriguez, Le Xuan Truong Truong Nguyen, Lucy Y. Ghoda, Nadia Carlesso, Guido Marcucci, Bin Zhang, Jie Jin
Journal: Blood (2024)
A Phase 1 Clinical Trial of NKTR-255 with CD19-22 CAR-T Cell Therapy for Refractory B-cell Acute Lymphoblastic Leukemia
Authors: Hrishikesh Krishna Srinagesh, Clayton Jackson, Parveen Shiraz, Nikeshan Jeyakumar, Mark P Hamilton, Emily Egeler, Sharon Mavroukakis, Adam Kuo, Juancarlos Cancilla, Bita Sahaf, Neha Agarwal, Alyssa M Kanegai, Anne Marijn Kramer, Sally Arai, Sushma Bharadwaj, Saurabh Dahiya, Hitomi Hosoya, Laura J Johnston, Vanessa E Kennedy, Michaela Liedtke, Robert Lowsky, Lekha Mikkilineni, Robert S. Negrin, Andrew R. Rezvani, Surbhi Sidana, Judith A. Shizuru, Melody Smith, Wen-Kai Weng, Steven A Feldman, Matthew J. Frank, Zachary Lee, Mary Tagliaferri, A Mario Q. Marcondes, David B Miklos, Crystal L. Mackall, Lori Muffly
Journal: Blood (2024)

Abstract Although chimeric antigen receptor (CAR) T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed/refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, 9 of whom successfully received CAR19-22 followed by NKTR-255. There were no dose-limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with 8 of 9 patients (89%) achieving measurable residual disease–negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T cells in the blood and 10-fold increases in cerebrospinal fluid CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible, and associated with high rates of durable responses. This trial was registered at www.clinicaltrials.gov as #NCT03233854.
Multi-omics analysis in IgM monoclonal gammopathies reveals epigenetic influence on oncogenesis via DNA methylation
Authors: Karan L. Chohan, Jonas Paludo, Surendra Dasari, Patrizia Mondello, Joseph Novak, Jithma P. Abeykoon, Kerstin Wenzl, Zhi-Zhang Yang, Shahrzad Jalali, Vaishali Bhardwaj, Jordan Edward Krull, Esteban Braggio, Michelle K. Manske, Aneel Paulus, Craig Reeder, Sikander Ailawadhi, Asher Chanan-Kahn, Prashant Kapoor, Robert A Kyle, Morie A Gertz, Anne J. Novak, Stephen M Ansell
Journal: Blood (2024)
Combined Exposures and Mixtures Research: An Enduring NIEHS Priority
Authors: Danielle J. Carlin, Cynthia V. Rider
Journal: Environmental Health Perspectives (2024)

The National Institute of Environmental Health Sciences (NIEHS) continues to prioritize research to better understand the health effects resulting from exposure to mixtures of chemical and nonchemical stressors. Mixtures research activities over the last decade were informed by expert input during the development and deliberations of the 2011 NIEHS Workshop "Advancing Research on Mixtures: New Perspectives and Approaches for Predicting Adverse Human Health Effects." NIEHS mixtures research efforts since then have focused on key themes including
Organophosphate Ester Flame Retardants and Plasticizers in Relation to Fetal Growth in the LIFECODES Fetal Growth Study
Authors: Paige A. Bommarito, Danielle R. Stevens, Barrett M. Welch, Maria Ospina, Antonia M. Calafat, John D. Meeker, David E. Cantonwine, Thomas F. McElrath, Kelly K. Ferguson
Journal: Environmental Health Perspectives (2024)

Organophosphate esters (OPEs), used ubiquitously as flame retardants and plasticizers in consumer products, are suspected of having developmental toxicity.