tbuckley/cabot-search huggingface dataset:
Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): Expanded efficacy analysis from CheckMate 8HW.
Authors: Heinz-Josef Lenz, Sara Lonardi, Elena Elez, Eric Van Cutsem, Lars Henrik Jensen, Jaafar Bennouna, Guillermo Mendez, Michael Schenker, Christelle De La Fouchardiere, Maria Luisa Limon, Takayuki Yoshino, Jin Li, Jose Luis Manzano, Giampaolo Tortora, Rocio Garcia-Carbonero, Rohit Joshi, Elvis Cela, Tian Chen, Lixian Jin, Thierry Andre
Journal: Journal of Clinical Oncology (2024)

3503 Background: NIVO + IPI demonstrated superior progression-free survival (PFS) vs chemo in patients (pts) with previously untreated MSI-H/dMMR mCRC in the randomized phase 3 CheckMate 8HW study (NCT04008030). We report expanded efficacy analysis from the prespecified interim analysis of NIVO + IPI vs chemo in the 1L setting. Methods: Pts with unresectable or mCRC and MSI-H/dMMR status by local testing were enrolled across different lines of therapy and randomized 2:2:1 to NIVO (240 mg) + IPI (1 mg/kg) Q3W (4 doses, then NIVO 480 mg Q4W), NIVO (240 mg) Q2W (6 doses, then NIVO 480 mg Q4W), or chemo ± targeted therapies; treatments continued until disease progression or unacceptable toxicity (all arms) or for up to 2 years (NIVO ± IPI arms). In pts with blinded independent central review (BICR)–documented progression with chemo, crossover to NIVO + IPI was permitted. Dual primary endpoints were PFS by BICR per RECIST v1.1 for NIVO + IPI vs chemo (1L) and NIVO + IPI vs NIVO (all lines) in pts with centrally confirmed MSI-H/dMMR mCRC. PFS2 (time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death) was a key exploratory endpoint. Results: Among 303 pts randomized to NIVO + IPI (n = 202) or chemo (n = 101), 171 pts in the NIVO + IPI arm and 84 pts in the chemo arm had centrally confirmed MSI-H/dMMR. At 31.5-months (mo) median follow-up (range 6.1–48.4), NIVO + IPI demonstrated superior PFS vs chemo (HR 0.21; 97.91% CI 0.13–0.35; P &lt; 0.0001). Subsequent systemic therapy was received by 20 (12%) and 57 (68%) pts in the NIVO + IPI and chemo arms, respectively. In the chemo arm, 56 (67%) pts received subsequent immunotherapy (39 [46%] crossed over to NIVO + IPI on study; 17 [20%] received non-study immunotherapy). Median PFS2 was not reached (NR) with NIVO + IPI and 29.9 mo with chemo (HR 0.27; 95% CI 0.17–0.44; Table). Any grade and grade 3/4 treatment-related adverse events (TRAEs) are presented (Table). Treatment-related deaths were reported for 2 pts in the NIVO + IPI arm. Conclusions: Clinical benefit with 1L NIVO + IPI vs chemo was maintained after subsequent therapy, as shown by improved PFS2 in pts with centrally confirmed MSI-H/dMMR mCRC. No new safety concerns were identified with NIVO + IPI. These results further support NIVO + IPI as a standard-of-care 1L treatment option for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . [Table: see text]
KEYNOTE-158: Final analysis of pembrolizumab in patients of Chinese descent with microsatellite instability-high/mismatch repair deficient advanced solid tumors.
Authors: Jianming Xu, Yimin Mao, Nong Xu, Yuxian Bai, Dong Wang, Xiaojun Chen, Xianli Yin, Yanhong Deng, Jianwei Yang, Jieqing Zhang, Jie Tang, Yi Huang, Jiayi Li, Suxia Luo, Miaomiao Xu, Nan Li, Yixiang Mao, Alexander Gozman, Xiaohua Wu
Journal: Journal of Clinical Oncology (2024)

e15137 Background: The multicohort non-randomized, phase 2 KEYNOTE-158 (NCT02628067) trial supported the FDA approval of pembrolizumab for unresectable or metastatic microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) solid tumors. Incidence of advanced MSI-H/dMMR tumors in patients (pts) of Chinese descent is similar to that in Western populations. In KEYNOTE-158 cohort L, we evaluated the antitumor activity of pembrolizumab in pts of Chinese descent with MSI-H/dMMR solid tumors. We previously reported an ORR of 70% in 20 pts from cohort L. Here we present results of the final analysis for 30 pts with 18 months (mo) of follow up. Methods: Eligible pts of Chinese descent from China aged ≥18 years were enrolled. Pts had to have confirmed unresectable or metastatic MSI-H/dMMR tumors, and ≥1 prior lines of therapy. Pts received 200 mg pembrolizumab Q3W for up to 35 cycles, until progression, unacceptable toxicity, or pt/investigator withdrawal. MSI-H/dMMR status was assessed centrally by PCR and IHC. The primary endpoint was ORR per RECIST 1.1 by central review. Secondary endpoints were DOR, PFS, OS and safety. The database cut-off date was May 5, 2023. Results: A total of 30 pts were enrolled; 7 (23%) were aged ≥65 years, and 20 (67%) were female. At data cut-off, 14 (47%) pts discontinued treatment; 12 (40%) due to progressive disease, 1 (3%) due to adverse events (AE), and 1 (3%) due to physician decision. The median follow-up (range) was 18.0 mo (6.4 – 32.7). The ORR was 66.7% (6 CR; 14 PR [95% CI: 47.2%- 82.7%]). The median DOR was not reached (NR) (range, 1.8+ - 29.5+) with a 12-mo DOR rate of 85.9%. Median PFS was NR (95% CI: 8.1-NR) with an 18-mo PFS rate of 63.0%. The median OS was NR (95% CI: 19.1, NR) with an 18-mo OS rate of 78.8%. Treatment-related AEs were reported in 22 (73%) pts. Grade 3-4 treatment-related AEs occurred in 7 (23%) pts. There were no grade 5 AEs. Immune-mediated AEs occurred in 11 pts (37%); 2 (7%) had grade 3 AEs (myositis or rash in 1 pt each). No grade 4-5 immune-mediated AEs occurred. Conclusions: Pembrolizumab continues to provide clinically meaningful antitumor activity and durable responses with a manageable safety profile in pts of Chinese descent with MSI-H/dMMR tumors. No new safety signals were identified. These results are consistent with those reported in the global population and further support the use of pembrolizumab in pts of Chinese descent with MSI-H/dMMR tumors. Clinical trial information: NCT02628067 .
Phase I clinical study of FC084CSA, a high selective AXL kinase inhibitor that ameliorates tumor microenvironment and augments the effectivity of immunotherapy.
Authors: Wei Li, Lei Wang, Jing Wang, Zhengbo Song, Qingyuan Zhang, Caicun Zhou
Journal: Journal of Clinical Oncology (2024)

e15116 Background: NSCLC patients with STK11 gene mutations could not benefit from immunotherapy, according to the data of multiple clinical trials. This is associated with immunosuppressive tumor microenvironment (TME) due to elevated AXL expression, and deficiency in pro-inflammatory cytokines and effector T cells. AXL inhibitor bemcentinib (formerly BGB324) has been found to improve the effectiveness of immunotherapy of immune checkpoint inhibitors. FC084CSA is a high selective AXL inhibitor. Methods: This is an ongoing first-in-human, phase I study of FC084CSA in patients with advanced solid tumors. The primary objective is to evaluate the safety and tolerability of FC084CSA. The secondary objectives include preliminary efficacy and pharmacokinetics. Results: As of January 10th, 2024, 9 patients with a median age of 60 years (44-73) were enrolled in 4 different dose levels: 100mg QD, 200mg QD, 400mg QD and 600mg QD. All patients had ≥ 2 prior lines of prior therapy. No dosing-limiting toxicities were observed. 8 (88.9%) patients experienced treatment-related adverse events (TRAEs). Most TRAEs were grade 1 or 2 and only one grade 3 TRAE was observed. The most common TRAEs (≥20%) included increased blood lactate dehydrogenase (44.4%), elevated gamma-glutamyl transferase (33.3%), proteinuria (33.3%), anemia (33.3%), increased aspartate aminotransferase (22.2%), weight loss (22.2%), increased blood creatinine (22.2%) and vomiting (22.2%). A total of 8 patients had at least 1 post-baseline tumor assessment. Objective response rate (ORR) was 0% and disease control rate (DCR) was 62.5% (5/8). Conclusions: FC084CSA was well tolerated in patients with previously heavily treated solid tumors. Clinical trial information: NCT06231550 .
First-in-human phase 1 study of SPH4336, a novel cyclin-dependent kinase 4/6 inhibitor, in patients with advanced solid tumors.
Authors: Yong-Sheng Wang, Yu Jiang, Meili Sun, Xu Liang, Huiping Li
Journal: Journal of Clinical Oncology (2024)

e15107 Background: The inhibition of cyclin-dependent kinases (CDKs) is a highly promising and attractive strategy for the development of anticancer drugs. SPH4336, a novel oral inhibitor with high selectivity and improved inhibition for CDK4/6, has demonstrated promising anti-tumor activity in preclinical studies. This was a first-in-human, multicenter, phase 1 dose-escalation and -expansion study to assess the safety, pharmacokinetics (PK) and preliminary efficacy of SPH4336 in patients with advanced solid tumors. Methods: Patients aged 18-70 years with histologically or cytologically confirmed advanced solid tumors that were refractory or intolerant to standard treatment or for which no standard treatment exists were included. Dose escalation of SPH4336 was conducted at doses of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg and 600 mg once a day. Primary endpoint was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of SPH4336. Secondary endpoints included assessment of adverse events (AEs) and efficacy. Descriptive statistics summarized safety, efficacy and PK parameters. Kaplan-Meier method was used to analyze time-to-event variables. Results: A total of 29 patients were enrolled with a median age of 55.0 years (23–66) and 72% being females. The most common tumor types were breast cancer (n=14, 48.3%) and sarcoma (n=8, 27.6%). No DLT was observed within 50 to 600 mg and MTD was not determined. Treatment-related adverse events (TRAEs) were reported in 29 (100%) patients, the most common TRAEs were white blood cell count decreased (n=21, 72.4%), diarrhea (n=20, 69.0%), neutrophil count decreased (n=19, 65.5%) and anemia (n=18, 62.1%). No grade 4 TRAEs were observed and death occurred in 1 patient (200 mg cohort) due to disease progression. Of the 27 evaluable patients, 1 patient achieved partial response lasting 169 days, and disease control rate was 59.3% (95% CI: 38.8%-77.6%). Regression of target lesion was observed in 100, 400 and 600 mg cohorts from baseline. PK assessments showed that the exposure of SPH4336 increased in a dose-dependent manner except with 600 mg dose. SPH4336 reached a steady state at 2 weeks of continuous dosing administration at 400 mg. Conclusions: This study demonstrated that SPH4336 was well tolerated at doses ranging from 50 to 600 mg dose levels. A dose of 400 mg could be considered for further clinical trials. Clinical trial information: NCT05905614 .
Prediction models of locally advanced rectal cancer prognosis incorporating perioperative longitudinal clinical data: A retrospective longitudinal cohort study.
Authors: Jeng You WU, Chia-Yu Su
Journal: Journal of Clinical Oncology (2024)

e15624 Background: For locally advanced rectal cancer, neoadjuvant chemoradiation(CCRT) followed by surgery is a standard treatment. Clinical T/N stage, whether pathological complete remission (pCR) after neoadjuvant CCRT or not are well recognized tumor features that predict disease prognosis. Although the parameters that determine pathologic stage are the strongest predictors of postoperative outcome, other clinical, molecular, and histologic features may influence prognosis independent of stage. The aim is to compare the predictive efficiency, between different models for overall survival in rectal cancer patients. Methods: This retrospective study is approved by TMU-JIRB(Protocol Number: N201809032).This is also a single institute study. 175 newly-diagnosed patients with locally advanced rectal cancer were retrospectively enrolled between Jan.2011 and Dec.2016. Basic information include sex, age, body weight, body height, previous medical history were recorded. CEA level, chemotherapy regimen, type of surgery, and distance between tumor and anal verge were also collected. Chemotherapy regimen of CCRT including 5FU+LV, capecitabine (Xeloda), FOLFOX, and FOLFIRI are recorded. Surgical resection was then followed 4-8 weeks after completion of CCRT. The 2010 AJCC tumor response grading (TRG) system was used to report treatment response of proctectomy samples. The progression free survival (PFS) and overall survival (OS) are then calculated. PFS is defined as survival without any recurrence or distant metastasis before Dec 31st, 2023. A comprehensive evaluation was conducted by incorporating all these machine learning models together. The aim was to compare their predictive efficiency, with models such as Random Forest, Naïve Bayes, KNeighbor, SVM, Decision Tree, Logistic Regression, XGBoost, and LightGBM. Results: 175 patients (104 men and 71 women) were enrolled in this study. The median follow up time was 7.1 yrs. The BMI was 24.05 ± 0.03 for men and 24.20 ± 0.07 for women. 32 (17.3%) patients achieved pCR, TRG 0. Clinical staging cT3 (78.8%) and nodal positive (78.8%) are the most common tumor feature in this study group. The median age of male and female patient is 58.6 and 56.1 respectively. Upon applying various machine learning models, different predictive accuracies emerged. The Random Forest, KNeighbor, and SVM models all achieved an accuracy of 0.9250. Naïve Bayes had an accuracy of 0.8620, while the SVC model registered at 0.9310, and XGBoost was slightly behind at 0.9286. SVC model is marking the best-performing model in this evaluation. Conclusions: This multicenter retrospective data-driven deep learning prediction model informed that SVC model yielded the best predictive results. Further prospective clinical trials and external validation of this prediction model are needed to further reinforce our findings.
Efficacy of chemotherapy followed by chemoradiation versus initial chemoradiation as part of the total neoadjuvant therapy for patients with locally advanced rectal cancer: An NCDB analysis.
Authors: Amina Dhahri, Yanal Mufeed Alnimer, Insija Ilyas Selene, Reema Anil Patel, Zhonglin Hao
Journal: Journal of Clinical Oncology (2024)

e15629 Background: Results from multiple trials lead to modern management for locally advanced rectal cancer, with total neoadjuvant therapy (TNT) followed by surgery. However, the best sequence of different treatment modalities is unclear. Methods: We used the National Cancer Database (NCDB) to identify patients with locally advanced rectal adenocarcinoma. We divided patients into different categories based on the timing of chemo and radiation therapy relative to surgery. We used chi-square and Wilcoxon rank test for unadjusted comparison. To compare treatment efficacy with initial chemotherapy to concurrent chemoradiation in downstaging (clinical to pathological stage), we used a linear mixed effect model (LME) with adjustments on age, sex, race, facility type, and year of diagnosis. Also, we evaluated the probability of having positive lymph nodes in the pathological specimen (N+) in the multivariable logistic regression model with adjustment on the clinical stage in addition to the previously mentioned variables. All analyses were done using R 4.6.2. Results: A total of 100509 patients were identified. Only 695 patients received six cycles of neoadjuvant chemotherapy before concurrent chemoradiation (TNT chemotherapy), and 8677 patients received upfront radiation therapy with neoadjuvant chemotherapy administered within 12 weeks of neoadjuvant radiation therapy (TNT radiation). Patients whose start date of chemotherapy or radiation after surgery were excluded. The median age of participants was 63 (IQR = 54-63), and 83% were white. Patients who had TNT chemotherapy were younger (56.4 VS 59.5, P-value &lt; 0.01), had clinically and pathologically advanced stage (IIIB, IIIC) compared to TNT radiation (64%VS 37% and 33%VS 29%, P-value &lt; 0.01). Patients who received TNT radiation had an upgrade in their pathological stage compared to their clinical stage by 0.67 points in the LME (P value &lt; 0.01). In multivariable logistic regression. TNT chemotherapy had a 17% lower risk of (N+) with an OR of 0.83 (0.95 CI 0.59-1.16). However, it was not statistically significant. The two groups had no difference in OS, with a median OS of 137 months (0.95 CI 110 -NR) and 143 (0.95 CI 137-151), respectively. Conclusions: Upfront chemotherapy before starting chemoradiation could be associated with more significant downstaging. Future trials to validate our finding is warranted. [Table: see text] [Table: see text]
Cardiac function, haemodynamics, and valve competence with exercise in patients with heart failure with preserved ejection fraction and mild to moderate secondary mitral regurgitation
Authors: Tomonari Harada, Jwan A. Naser, Atsushi Tada, Shunichi Doi, Tatsuro Ibe, Sorin V. Pislaru, Mackram F. Eleid, Hidemi Sorimachi, Masaru Obokata, Yogesh N.V. Reddy, Barry A. Borlaug
Journal: European Journal of Heart Failure (2024)
Colchicine in acute heart failure: Rationale and design of a randomized double‐blind placebo‐controlled trial (<scp>COLICA</scp>)
Authors: Domingo Pascual‐Figal, Julio Núñez Villota, Maria Teresa Pérez‐Martínez, José Ramón González‐Juanatey, Mikel Taibo‐Urquía, Pau Llàcer Iborra, Javier González‐Martín, Sandra Villar, Meritxel Soler, Sonia Mirabet, Alberto Aimo, Alejandro Riquelme‐Pérez, Manuel Anguita Sánchez, Manuel Martínez‐Sellés, Pedro L. Sánchez, Borja Ibáñez, Antoni Bayés‐Genís
Journal: European Journal of Heart Failure (2024)

Abstract Aims Heart failure (HF) elicits a pro‐inflammatory state, which is associated with impaired clinical outcomes, but no anti‐inflammatory therapies have demonstrated a clinical benefit yet. Inflammatory pathways related with the interleukin‐1 axis are overactivated during episodes of acute HF. Colchicine, an anti‐inflammatory drug with proven benefits in acute pericarditis and ischaemic heart disease, may target this inflammatory response. This study aims to assess the efficacy of colchicine in acute HF patients. Methods COLICA is a multicentre, randomized, double‐blind, placebo‐controlled trial enrolling 278 patients across 12 sites. Patients presenting with acute HF, clinical evidence of congestion requiring ≥40 mg of intravenous furosemide and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) &gt;900 pg/ml, are eligible for participation. Patients are enrolled irrespective of left ventricular ejection fraction, HF type (new‐onset or not) and setting (hospital or outpatient clinic). Patients are randomized 1:1 within the first 24 h of presentation to either placebo or colchicine, with an initial loading dose of 2 mg followed by 0.5 mg every 12 h for 8 weeks (reduced dose if &lt;70 kg, &gt;75 years old, or glomerular filtration rate &lt;50 ml/min/1.73 m 2 ). The primary efficacy endpoint is the time‐averaged proportional change in NT‐proBNP concentrations from baseline to week 8. Key secondary and exploratory outcomes include symptoms, diuretic use, worsening HF episodes, related biomarkers of cardiac stress and inflammation, total and cardiovascular readmissions, mortality and safety events. Conclusion COLICA will be the first randomized trial testing the efficacy and safety of colchicine for acute HF.
Cell-class-specific electric field entrainment of neural activity
Authors: Soo Yeun Lee, Konstantinos Kozalakis, Fahimeh Baftizadeh, Luke Campagnola, Tim Jarsky, Christof Koch, Costas A. Anastassiou
Journal: Neuron (2024)

Electric fields affect the activity of neurons and brain circuits, yet how this happens at the cellular level remains enigmatic. Lack of understanding of how to stimulate the brain to promote or suppress specific activity significantly limits basic research and clinical applications. Here, we study how electric fields impact subthreshold and spiking properties of major cortical neuronal classes. We find that neurons in the rodent and human cortex exhibit strong, cell-class-dependent entrainment that depends on stimulation frequency. Excitatory pyramidal neurons, with their slower spike rate, entrain to both slow and fast electric fields, while inhibitory classes like Pvalb and Sst (with their fast spiking) predominantly phase-lock to fast fields. We show that this spike-field entrainment is the result of two effects: non-specific membrane polarization occurring across classes and class-specific excitability properties. Importantly, these properties are present across cortical areas and species. These findings allow for the design of selective and class-specific neuromodulation.
Myocardial infarction accelerates the progression of MASH by triggering immunoinflammatory response and induction of periosti
Authors: Wei Xie, Jing Gan, Xiaodong Zhou, Huiying Tian, Xingchao Pan, Wenyue Liu, Xiaokun Li, Jie Du, Aimin Xu, Minghua Zheng, Fan Wu, Yulin Li, Zhuofeng Lin
Journal: Cell Metabolism (2024)
Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency
Authors: Isaac Marin-Valencia, Arif Kocabas, Carlos Rodriguez-Navas, Vesselin Z. Miloushev, Manuel González-Rodríguez, Hannah Lees, Kelly E. Henry, Jake Vaynshteyn, Valerie Longo, Kofi Deh, Roozbeh Eskandari, Arsen Mamakhanyan, Marjan Berishaj, Kayvan R. Keshari
Journal: Cell Metabolism (2024)
The role of complement in kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference
Authors: Marina Vivarelli, Jonathan Barratt, Laurence H. Beck, Fadi Fakhouri, Daniel P. Gale, Elena Goicoechea de Jorge, Marta Mosca, Marina Noris, Matthew C. Pickering, Katalin Susztak, Joshua M. Thurman, Michael Cheung, Jennifer M. King, Michel Jadoul, Wolfgang C. Winkelmayer, Richard J.H. Smith, Federico Alberici, Luca Antonucci, Tadej Avcin, Arvind Bagga, Ingeborg M. Bajema, Miquel Blasco, Sophie Chauvet, H. Terence Cook, Paolo Cravedi, Marie-Agnès Dragon-Durey, Lauren Fischer, Agnes B. Fogo, Ashley Frazer-Abel, Véronique Frémeaux-Bacchi, Nina Görlich, Mark Haas, Alister Humphreys, Vivekanand Jha, Arenn Jauhal, David Kavanagh, Andreas Kronbichler, Richard A. Lafayette, Lynne D. Lanning, Mathieu Lemaire, Moglie Le Quintrec, Christoph Licht, Adrian Liew, Steve McAdoo, Nicholas R. Medjeral-Thomas, Pier Luigi Meroni, Johann Morelle, Carla M. Nester, Manuel Praga, Raja Ramachandran, Heather N. Reich, Giuseppe Remuzzi, Santiago Rodríguez de Córdoba, Gary Robinson, Pierre Ronco, Peter Rossing, David J. Salant, Sanjeev Sethi, Marianne Silkjaer, Wen-chao Song, Fabrizio Spoleti, Ronald P. Taylor, Nicole C.A.J. van de Kar, Cees van Kooten, Len Woodward, Yuzhou Zhang, Peter F. Zipfel, Marco Zuccato
Journal: Kidney International (2024)

Uncontrolled complement activation can cause or contribute to glomerular injury in multiple kidney diseases. While complement activation plays a causal role in atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G), over the past decade a rapidly accumulating body of evidence has shown a role for complement activation in multiple other kidney diseases, including diabetic nephropathy and several glomerulonephritides. The number of available complement inhibitor therapies has also increased during the same period. In 2022 KDIGO convened a Controversies Conference, The Role of Complement in Kidney Disease, to address the expanding role of complement dysregulation in the pathophysiology, diagnosis, and management of various glomerular diseases, diabetic nephropathy, and other forms of HUS. Conference participants reviewed the evidence for complement playing a primary causal or secondary role in progression for several disease states and considered how evidence of complement involvement might inform management. Participating patients with various complement-mediated diseases and caregivers described concerns related to life planning, implications surrounding genetic testing, and the need for inclusive implementation of effective novel therapies into clinical practice. The value of biomarkers in monitoring disease course and the role of the glomerular microenvironment in complement response were examined, and key gaps in knowledge and research priorities were identified.