tbuckley/cabot-search huggingface dataset:
Nivolumab Plus Chemotherapy in Epidermal Growth Factor Receptor–Mutated Metastatic Non–Small-Cell Lung Cancer After Disease Progression on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: Final Results of CheckMate 722
Authors: Tony Mok, Kazuhiko Nakagawa, Keunchil Park, Yuichiro Ohe, Nicolas Girard, Hye Ryun Kim, Yi-Long Wu, Justin Gainor, Se-Hoon Lee, Chao-Hua Chiu, Sang-We Kim, Cheng-Ta Yang, Chien Liang Wu, Lin Wu, Meng-Chih Lin, Jens Samol, Kazuya Ichikado, Mengzhao Wang, Xiaoqing Zhang, Judi Sylvester, Sunney Li, Ann Forslund, James Chih-Hsin Yang
Journal: Journal of Clinical Oncology (2024)

PURPOSE The phase III CheckMate 722 trial (ClinicalTrials.gov identifier: NCT02864251 ) evaluated nivolumab plus chemotherapy versus chemotherapy in patients with epidermal growth factor receptor ( EGFR)–mutated metastatic non–small-cell lung cancer (NSCLC) after disease progression on EGFR tyrosine kinase inhibitors (TKIs). METHODS Patients with disease progression after first- or second-generation EGFR TKI therapy (without EGFR T790M mutation) or osimertinib (with/without T790M mutation) were randomly assigned 1:1 to nivolumab (360 mg once every 3 weeks) plus platinum-doublet chemotherapy (once every 3 weeks) or platinum-doublet chemotherapy alone (once every 3 weeks) for four cycles. Primary end point was progression-free survival (PFS). Secondary end points included 9- and 12-month PFS rates, overall survival (OS), objective response rate (ORR), and duration of response (DOR). RESULTS Overall, 294 patients were randomly assigned. At final analysis (median follow-up, 38.1 months), PFS was not significantly improved with nivolumab plus chemotherapy versus chemotherapy (median, 5.6 v 5.4 months; hazard ratio [HR], 0.75 [95% CI, 0.56 to 1.00]; P = .0528), with 9- and 12-month PFS rates of 25.9% versus 19.8%, and 21.2% versus 15.9%, respectively. Post hoc PFS subgroup analyses showed a trend favoring nivolumab plus chemotherapy in patients with tumors harboring sensitizing EGFR mutations (HR, 0.72 [95% CI, 0.54 to 0.97]), one line of previous EGFR TKI (0.72 [95% CI, 0.54 to 0.97]), or both (0.64 [95% CI, 0.47 to 0.88]). Median OS was 19.4 months with nivolumab plus chemotherapy versus 15.9 months with chemotherapy, while ORR was 31.3% versus 26.7%, and median DOR was 6.7 versus 5.6 months, respectively. Grade 3/4 treatment-related adverse events occurred in 44.7% and 29.4% of patients treated with nivolumab plus chemotherapy and chemotherapy alone, respectively. CONCLUSION Nivolumab plus chemotherapy did not significantly improve PFS versus chemotherapy in patients with EGFR-mutated metastatic NSCLC previously treated with EGFR TKIs. No new safety signals were identified.
Phase II study of the safety and efficacy of discontinuing pegfilgrastim for pancreatic adenocarcinoma treated with FOLFIRINOX.
Authors: Masahiro Yanagi, Takeshi Terashima, Tatsuya Yamashita, Makoto Yamamoto, Hidenori Kido, Hidetoshi Nakagawa, Akihiro Seki, Kouki Nio, Taro Yamashita
Journal: Journal of Clinical Oncology (2024)

663 Background: The original FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) for pancreatic ductal adenocarcinoma (PDAC) is associated with a high risk of febrile neutropenia (FN), and pegfilgrastim has been used to reduce the risk. However, it remains unclear how long pegfilgrastim needs to continue. This study evaluated the safety and efficacy of FOLFIRINOX after discontinuing pegfilgrastim in PDAC patients. Methods: This prospective phase II trial included patients with PDAC who received the first three courses of FOLFIRINOX, with primary pegfilgrastim prophylaxis for FN, and did not experience FN. The patients continued on FOLFIRINOX without pegfilgrastim from the fourth course. The primary endpoint was development of FN. The secondary endpoints included relative dose intensity (RDI), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The threshold and expected development of FN were 20% and 7%, respectively, at a one-sided significance level of 0.10 and statistical power of 80%. Based on this hypothesis, we calculated the number of patients needed to be 33. Results: In total, 34 patients (20 male, median age 66 years) were enrolled from August 2017 to September 2021. Twenty-three patients were unresectable, and 11 were borderline resectable. FN developed in one patient. Grade 4 neutropenia was observed in six patients, grade 3 neutropenia in 10 (29.4%), anemia in four (11.8%), diarrhea in two (5.9%), and malaise, lung infection, peripheral sensory neuropathy, colitis, and biliary tract infection in one (2.9%) each. Twenty-two patients required dose reduction, mainly because of neutropenia. Mean RDIs at the sixth course of oxaliplatin, irinotecan, leucovorin, acute infusion of fluorouracil, and continuous infusion of fluorouracil were 77.0%, 88.2%, 81.8%, 84.4%, and 87.6%, respectively. ORR, median PFS, and median OS were 44.1%, 15.8 months, and 25.8 months, respectively. Conclusions: FOLFIRINOX can be continued safely with a low incidence of FN after discontinuing pegfilgrastim in PDAC patients who did not experience FN during the first three courses of FOLFIRINOX, if the drug dose is reduced appropriately for neutropenia from the fourth course. Clinical trial information: UMIN000028055 .
Retrospective analysis of the real-world demographics, clinical characteristics, and treatment patterns in metastatic CRC among patients treated with encorafenib in combination with cetuximab in the United States.
Authors: Aparna Raj Parikh, Maria Cecilia Vieira, Michelle Silver, Andrew Rava, Reina Rau, Benjamin Li
Journal: Journal of Clinical Oncology (2024)

63 Background: The presence of BRAF V600E mutations (BRAF-m) occurs in approximately 7% of patients with metastatic CRC (mCRC). Encorafenib (enco) plus cetuximab (cetux) were approved in April 2020 as the first targeted therapy for the treatment of adult patients with BRAF-m mCRC. The purpose of this study is to assess the demographics, clinical characteristics, and treatment patterns in BRAF-m mCRC among patients treated with enco, based on a claims database in the US. Methods: This was a retrospective cohort study in the IQVIA PharMetrics Plus claims database. Adults ≥18 years old with ≥1 claim for enco (first claim for enco on/after 4/1/2020) with concurrent cetux, as approved, or with EGFR panitumumab (pani), ≥2 ICD-9/10 codes for malignancy of the colon or rectum ≥30 days apart in the 1 year before index date, and ≥1 day of pharmacy and medical continuous enrollment during the index date were included. Patients were excluded if they had a record of melanoma or non-small cell lung cancer during the year before index date, were enrolled in a clinical trial any time after the CRC diagnosis date or did not have a treatment regimen starting on or after CRC diagnosis date. Index date was the date of first treatment of enco+EGFR during the identification period (4/1/2020-3/31/2022). Patient demographics and disease characteristics were assessed at baseline, and treatment patterns were evaluated during the pre-index and follow-up periods. Results: 125 patients were included. Median (Q1 [1 st quartile], Q3 [3 rd quartile]) age at index was 58 (49, 63) years; 52.0% were female; 47.2% residents in the South, 26.4% in the Midwest, 14.4% in the East and 12.0% in the West. In terms of healthcare coverage, 64.0% were under commercial, 27.2% self-insured and 8.8% under Medicare plans. Most patients (60.8%) at the start of enco had metastases in 3 or more sites, predominantly in the liver (76.8%), lymph nodes (50.4%), and lung (43.2%). The 2011 Modified Quan Charlson Comorbidity Index was 0 for 44.8% of the patients, 1-2 for 39.2%, and 3 or more for 16.0%. Mean (SD [standard deviation]) number of pre-index treatment regimens was 0.87 (0.73). Among the enco patients who had a previous treatment computed in claims, FOLFOX +/- bevacizumab (beva) and FOLFIRI + beva were the most common. Among the ones who had a subsequent treatment computed in claims, FOLFIRI +/- beva was the most common. Conclusions: This study provides current RW demographics, disease characteristics and treatment patterns among BRAF mCRC patients treated with enco in the US.
Predictive machine learning models for survival outcomes in patients with pancreatic cancer.
Authors: Yang-Chen Shen, Po-See Chen, Cheng-Feng Lin, Ping-Yen Liu, Peng-Chan Lin, Chia-Jui Yen, Yan-Shen Shan
Journal: Journal of Clinical Oncology (2024)

625 Background: Identifying prognostic markers is essential for accurately assessing risk levels in pancreatic cancer patients, leading to more personalized treatment approaches. In light of this, our study endeavors to build a survival prediction model for pancreatic cancer patients using various machine learning (ML) techniques, taking into account both clinical and inflammatory factors. Methods: The research included 311 pancreatic cancer patients on a prospective basis. Their data was sourced from the Clinical Data Warehouse of National Cheng Kung University Hospital. For the purpose of predicting 6 and 12-month survival, patients were randomly allocated into training, validation, and test groups in an 8:1:1 ratio. We utilized machine learning techniques and assessed them on the QOCA Aim (Quanta Omni Cloud Care for AI Medical Platform, version 2.0) platform. The model's effectiveness was gauged using the area under the receiver operating characteristic curve (AUC). Results: The cohort exhibited a mean age of 63.5 years with a standard deviation of 11. The median overall survival was documented at 16.8 months (95% confidence interval [CI] = 15.6–18). Analytical evaluation indicated that the optimal model for prognostication of 6-month survival was the balanced bagging classifier, yielding an AUC of 93.7%. Conversely, for the 12-month survival prediction, the k-nearest neighbors (kNN) classifier was superior, demonstrating an AUC of 86.1%. Subsequent variable importance analysis elucidated that salient predictors encompassed C-Reactive protein (CRP), surgical intervention, carbohydrate antigen (CA)19-9, age at diagnosis, and the neutrophil–lymphocyte ratio (NLR). Conclusions: The findings indicated that machine learning can be employed to develop high-efficacy predictive models for survival in pancreatic cancer patients. Such models offer promise for enhanced risk categorization and personalized prognostic assessment in this patient cohort.
Consensus recommendations on the management of toxicity associated with CD3×CD20 bispecific antibody therapy
Authors: Jennifer L. Crombie, Tara Graff, Lorenzo Falchi, Yasmin H. Karimi, Rajat Bannerji, Loretta Nastoupil, Catherine Thieblemont, Renata Ursu, Nancy Bartlett, Victoria Nachar, Jonathan Weiss, Jane Osterson, Krish Patel, Joshua Brody, Jeremy S. Abramson, Matthew Lunning, Nirav N. Shah, Ayed Ayed, Manali Kamdar, Benjamin Parsons, Paolo Caimi, Ian Flinn, Alex Herrera, Jeffrey Sharman, Marshall McKenna, Philippe Armand, Brad Kahl, Sonali Smith, Andrew Zelenetz, Lihua Elizabeth Budde, Martin Hutchings, Tycel Phillips, Michael Dickinson
Journal: Blood (2024)
<i>CALR</i> mutation burden in essential thrombocythemia and disease outcome
Authors: Paola Guglielmelli, Natasha Szuber, Naseema Gangat, Giulio Capecchi, Chiara Maccari, Michaël Harnois, Omer Karrar, Maymona Abdelmagid, Manjola Balliu, Elena Nacca, Alessandro Atanasio, Ilaria Sestini, Audrey Désilets, Giuseppe Gaetano Loscocco, Giada Rotunno, Lambert Busque, Ayalew Tefferi, Alessandro Maria Vannucchi
Journal: Blood (2024)

Abstract Among 281 patients with essential thrombocythemia and calreticulin (CALR) mutation, we found a variant allele frequency of ≥60% to be associated with significantly shortened myelofibrosis-free survival, mostly apparent with CALR type-1 and CALR type-indeterminate mutations.
Survival trends in gastric cancer in Brazil: Real-life data from a large cancer center.
Authors: Angelo Borsarelli Carvalho Brito, Diego Rodrigues Mendonca e Silva, Maria Paula Curado, Lais Corsino Durant, Rodrigo Gomes Taboada, Adriane Graicer Pelosof, Alessandro Landskron Diniz, Felipe José Fernández Coimbra, Tiago Cordeiro Felismino
Journal: Journal of Clinical Oncology (2024)

413 Background: Gastric cancer (GC) is the fourth leading cause of cancer deaths globally. There is a paucity of real-life data on GC in Brazil. Our study aimed to evaluate survival trends in gastric adenocarcinoma (GA) in a large cancer center in Brazil during 2000-2017. Methods: Based on our Hospital Cancer Registry Database, all individuals diagnosed with GA between 2000 and 2017, and treated at A.C. Camargo Cancer Center, were retrospectively included. The primary objectives were to describe the patient demographics, clinicopathological characteristics, treatment modalities, and survival trends during four separate periods of diagnosis (2000-2004; 2005-2009; 2010-2014; and 2015-2017). χ2 test was performed between two specified periods (2000-2004 and 2015-2017) to compare categorical variables. Overall survival (OS) curves were stratified by four separate periods and compared with log-rank tests. Results: The current analysis comprises a retrospective cohort of 1406 patients (552 female and 854 male individuals). Across all periods, most patients were men aged 50 to 69 and presented with Lauren’s intestinal subtype. There were significant differences between staging groups during the study. Specifically, between 2000-2004, stage IV varied from 43.6% to 32.8% in 2015-2017 (P&lt;0.001). The most substantial variation in nonmetastatic cases occurred in stage II, comprising 9.4% of cases from 2000-2004 and rising to 24.8% in 2015-2017 (P&lt;0.001). Concerning treatment modalities, we observed an increased utilization of a combined approach involving chemotherapy and surgery throughout the investigation. Specifically, from 2000-2004, only 12% of patients received a multimodal treatment regimen consisting of chemotherapy and surgery, whereas, between 2015-2017, this proportion increased to 36.3% (P&lt;0.001). Also, patients receiving surgery + radiotherapy + chemotherapy varied from 12.4% of patients in 2000-2004 to 4.5% in 2015-2017 (P&lt;0.001). When the entire cohort was analyzed, the predicted 5-year OS of patients with GA between 2000-2004 was 27.8%, which increased to 53.9% in the period from 2015-2017 (P&lt;0.001). Among females, 5-year OS increased from 31.3% between 2000-2004 to 58.5% between 2015-2017 (P=0.001). Among males, 5-year OS increased from 25.2% to 51.0% in the same comparison (P&lt;0.001). Conclusions: Our hospital-based data shows an upward trend in survival rates across patients with GA. We observed that 5-year OS almost doubled among men and women during the analyzed period. Recent improvements in staging methods and treatment have increased cure rates. Nevertheless, further investigation is essential to determine significant differences in OS between males and females.
Differential burdens: A study of gastric cancer hospitalization and outcomes across race and ethnicities.
Authors: Chun-Wei Pan, Alejandro Nieto Dominguez, Ayobami Gbenga Olafimihan, Muhammad Bilal Ibrahim
Journal: Journal of Clinical Oncology (2024)

256 Background: Despite advances in H. pylori screening and eradication, gastric cancer remains a significant public health issue as the 4th most common cancer globally. Racial and ethnic disparities in disease presentation, surgical intervention, and healthcare burden in United States are not well understood. Methods: We retrospectively analyzed National Inpatient Sample data (2016-2020) for gastric cancer hospitalizations in patients ≥18 years. Primary outcome was in-hospital mortality. Secondary outcomes included disparities in gastrectomy, length of stay (LOS), and total hospital charges. Results: In our study, we analyzed 207,690 hospitalizations related to gastric cancer from 2016- 2019. Over this period, we observed a decrease in gastric cancer-related hospitalizations, from 42,865 to 39,855. However, among Hispanics, there was a significant increase in hospitalizations from 6,309 to 6,930 cases (annual percentage change [APC] of 1.89%, P&lt;0.01). Notably, there was a significant higher in in-hospital mortality odds for African-American (AA) (aOR 1.15, 95CI: 1.03-1.29), Asian (aOR 1.23, 95CI: 1.06-1.42), and all other races (aOR 1.35, 95CI: 1.13-1.60). Surgical interventions differed among racial groups, with AA having lower odds of undergoing total gastrectomy (aOR 0.71, 95CI: 0.60-0.86), and Asians having higher odds of receiving partial gastrectomy (aOR 1.59, 95CI: 1.41-1.78). LOS also differs between ethnicities, AA had the highest LOS 7.9±0.1d days, followed by Native American/Other (NA) at 7.5±0.2 days. The financial impact of also differs, with Asians incurring the highest mean total charges at 101,436.8±3,253.5, followed by NA at 93,102.7±3,954.7. The total hospital charge burden of gastric cancer increased from 3,682.8 million to 3,880.0 million (APC 1.04%). The white population experienced the highest increase in this burden, from 1,879.2 million to 1,990.0 million (APC of 1.10%). Conclusions: Despite an overall decrease in gastric cancer hospitalizations, our study reveals notable disparities across racial and ethnic groups. Hospitalizations increased among Hispanics, and AA, Asians, and NA faced higher mortality odds. AA experienced the longest lengths of stay, while Asians bore the highest mean total charges. These findings highlight the need for targeted interventions to mitigate these disparities.[Table: see text]
Treatment outcomes by stratifying the N-acetyl transferase 2 phenotype in pre-treated patients with advanced refractory biliary tract cancer treated with nanvuranlat, an L-type amino acid transporter inhibitor: An ad-hoc analysis of a randomized, double-blind, placebo-controlled phase 2 study.
Authors: Naohiro Okano, Fumio Nagashima, Mariko Nishioka, Haruki Kusaka, Kouji Yamamoto, Junji Furuse
Journal: Journal of Clinical Oncology (2024)

483 Background: L-type amino acid transporter 1 (LAT1, SLC7A5) is overexpressed in cancer cells, leading to aggressive proliferation and lymphatic metastases. In a placebo-controlled, randomized phase 2 trial involving patients with pre-treated, advanced, refractory biliary tract cancer (BTC), monotherapy with nanvuranlat (JPH203), a selective LAT1 inhibitor, demonstrated a significant improvement in progression free survival (PFS) as the primary endpoint compared to placebo. The safety profile was comparable between nanvuranlat and placebo treated patients, except for a higher rate of cholangitis in the nanvuranlat group. Nanvuranlat is metabolized to its main inactive, off-target metabolite, Nac-JPH203 by N-acetyl transferase 2 ( NAT2). Since the NAT2 unknown patients mislead the benefit and risk ratio of nanvuranlat treatment, an ad-hoc analysis was conducted in enriched NAT2 non-rapid (NR) phenotype patients who slowly produced Nac-JPH203 in plasma. Methods: Among 104 (full analytical set (FAS) - nanvuranlat:69 &amp; placebo:35) enrolled patients, 25 with unknown NAT2 phenotype were enrolled prior to an amendment to only enroll NAT2-NR phenotype. Subsequently, further analysis was conducted to determine the NAT2 phenotypes of these 25 patients. Results: Among the 25 NAT2 unknown patients, 16 and 9 patients were assigned to nanvuranlat or placebo, respectively. NAT2 ad hoc analysis recorded those 9 patients in nanvuranlat and 5 in placebo as NAT2 NR, and 7 patients in nanvuranlat and 4 in placebo were NAT2 rapid (R). As a result, number of NAT2 NR patients was increased from 81 to 94. Efficacy analysis of this enriched population (FAS-NR-nanvuranlat:63 &amp; placebo:31) revealed a significant improvement in PFS. With respect to cholangitis, 8 all-grade (12.7%) and 7 over grade 3 (11.1%) were documented in the FAS-NR population. In the FAS-R population, 2 all grades (28.5%) and 2 over grade 3 (28.5%) were observed (Table). Conclusions: By classifying BTC patients by NAT2 phenotype in this ad hoc analysis, the LAT1 inhibitor nanvuranlat further improved its clinical efficacy and safety in the NAT2 NR population. Therefore, selecting NAT2 NR for nanvuranlat treatment may improve the risk -benefit ratio. Clinical trial information: UMIN000034080 . [Table: see text]
Induced pluripotent stem cell–derived exosomes attenuate vascular remodelling in pulmonary arterial hypertension by targeting HIF-1α and Runx2
Authors: Pei-Ling Chi, Chin-Chang Cheng, Mei-Tzu Wang, Jia-Bin Liao, Shu-Hung Kuo, Kun-Chang Lin, Min-Ci Shen, Wei-Chun Huang
Journal: Cardiovascular Research (2024)

Abstract Aims Pulmonary arterial hypertension (PAH) is characterized by extensive pulmonary arterial remodelling. Although mesenchymal stem cell (MSC)-derived exosomes provide protective effects in PAH, MSCs exhibit limited senescence during in vitro expansion compared with the induced pluripotent stem cells (iPSCs). Moreover, the exact mechanism is not known. Methods and results In this study, we used murine iPSCs generated from mouse embryonic fibroblasts with triple factor (Oct4, Klf4, and Sox2) transduction to determine the efficacy and action mechanism of iPSC-derived exosomes (iPSC-Exo) in attenuating PAH in rats with monocrotaline (MCT)-induced pulmonary hypertension. Both early and late iPSC-Exo treatment effectively prevented the wall thickening and muscularization of pulmonary arterioles, improved the right ventricular systolic pressure, and alleviated the right ventricular hypertrophy in MCT-induced PAH rats. Pulmonary artery smooth muscle cells (PASMC) derived from MCT-treated rats (MCT-PASMC) developed more proliferative and pro-migratory phenotypes, which were attenuated by the iPSC-Exo treatment. Moreover, the proliferation and migration of MCT-PASMC were reduced by iPSC-Exo with suppression of PCNA, cyclin D1, MMP-1, and MMP-10, which are mediated via the HIF-1α and P21-activated kinase 1/AKT/Runx2 pathways. Conclusion IPSC-Exo are effective at reversing pulmonary hypertension by reducing pulmonary vascular remodelling and may provide an iPSC-free therapy for the treatment of PAH.
Depleting inositol pyrophosphate 5-InsP7 protected the heart against ischaemia–reperfusion injury by elevating plasma adiponectin
Authors: Lin Fu, Jimin Du, David Furkert, Megan L Shipton, Xiaoqi Liu, Tim Aguirre, Alfred C Chin, Andrew M Riley, Barry V L Potter, Dorothea Fiedler, Xu Zhang, Yi Zhu, Chenglai Fu
Journal: Cardiovascular Research (2024)

Abstract Aims Adiponectin is an adipocyte-derived circulating protein that exerts cardiovascular and metabolic protection. Due to the futile degradation of endogenous adiponectin and the challenges of exogenous administration, regulatory mechanisms of adiponectin biosynthesis are of significant pharmacological interest. Methods and results Here, we report that 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP7) generated by inositol hexakisphosphate kinase 1 (IP6K1) governed circulating adiponectin levels via thiol-mediated protein quality control in the secretory pathway. IP6K1 bound to adiponectin and DsbA-L and generated 5-InsP7 to stabilize adiponectin/ERp44 and DsbA-L/Ero1-Lα interactions, driving adiponectin intracellular degradation. Depleting 5-InsP7 by either IP6K1 deletion or pharmacological inhibition blocked intracellular adiponectin degradation. Whole-body and adipocyte-specific deletion of IP6K1 boosted plasma adiponectin levels, especially its high molecular weight forms, and activated AMPK-mediated protection against myocardial ischaemia–reperfusion injury. Pharmacological inhibition of 5-InsP7 biosynthesis in wild-type but not adiponectin knockout mice attenuated myocardial ischaemia–reperfusion injury. Conclusion Our findings revealed that 5-InsP7 is a physiological regulator of adiponectin biosynthesis that is amenable to pharmacological intervention for cardioprotection.