bluuebunny/crossref_metadata_2025 huggingface dataset:
The causal relationship between anti-diabetic drugs and gastrointestinal disorders: a drug-targeted mendelian randomization study
Authors: Ju Mingyan , Deng Tingting , Jia Xuemin , Gong Menglin , Li Yuying , Liu Fanjie , Yin Ying
Published: June 2024

Background

The incidence of diabetic gastrointestinal diseases is increasing year by year. This study aimed to investigate the causal relationship between antidiabetic medications and gastrointestinal disorders, with the goal of reducing the incidence of diabetes-related gastrointestinal diseases and exploring the potential repurposing of antidiabetic drugs.

Methods

We employed a two-sample Mendelian randomization (TSMR) design to investigate the causal association between antidiabetic medications and gastrointestinal disorders, including gastroesophageal reflux disease (GERD), gastric ulcer (GU), chronic gastritis, acute gastritis, Helicobacter pylori infection, gastric cancer (GC), functional dyspepsia (FD), irritable bowel syndrome (IBS), ulcerative colitis (UC), Crohn’s disease (CD), diverticulosis, and colorectal cancer (CRC). To identify potential inhibitors of antidiabetic drug targets, we collected single-nucleotide polymorphisms (SNPs) associated with metformin, GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, insulin, and its analogs, thiazolidinediones, sulfonylureas, and alpha-glucosidase inhibitors from published genome-wide association study statistics. We then conducted a drug-target Mendelian randomization (MR) analysis using inverse variance weighting (IVW) as the primary analytical method to assess the impact of these inhibitors on gastrointestinal disorders. Additionally, diabetes was selected as a positive control.

Results

Sulfonylureas were found to significantly reduce the risk of CD (IVW: OR [95% CI] = 0.986 [0.978, 0.995], p = 1.99 × 10− 3), GERD (IVW: OR [95% CI] = 0.649 [0.452, 0.932], p = 1.90 × 10− 2), and chronic gastritis (IVW: OR [95% CI] = 0.991 [0.982, 0.999], p = 4.50 × 10− 2). However, they were associated with an increased risk of GU development (IVW: OR [95%CI] = 2 0.761 [1.259, 6.057], p = 1 0.12 × 10− 2).

Conclusions

The results indicated that sulfonylureas had a positive effect on the prevention of CD, GERD, and chronic gastritis but a negative effect on the development of gastric ulcers. However, our research found no causal evidence for the impact of metformin, GLP-1 agonists, SGLT2 inhibitors, DPP 4 inhibitors, insulin and its analogs, thiazolidinediones, or alpha-glucosidase inhibitors on gastrointestinal diseases.

Graphical abstract
The longitudinal trajectory of CSF sTREM2: the alzheimer’s disease neuroimaging initiative
Authors: Wang Yu , Ye Meijie , Ji Qianqian , Liu Qi , Xu Xiaowei , Zhan Yiqiang
Published: June 2024

Background

The soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) is considered a biomarker of microglia activity. The objective of this study was to investigate the trajectory of CSF sTREM2 levels over time and examine its association with sex.

Methods

A total of 1,017 participants from the Alzheimer’s Disease Neuroimaging Initiative Study (ADNI) with at least one CSF sTREM2 record were included. The trajectory of CSF sTREM2 was analyzed using a growth curve model. The association between CSF sTREM2 levels and sex was assessed using linear mixed-effect models.

Results

CSF sTREM2 levels were increased with age over time (P < 0.0001). No significant sex difference was observed in sTREM2 levels across the entire sample; however, among the APOE ε4 allele carriers, women exhibited significantly higher sTREM2 levels than men (β = 0.146, P = 0.002).

Conclusion

Our findings highlight the association between CSF sTREM2 levels and age-related increments, underscoring the potential influence of aging on sTREM2 dynamics. Furthermore, our observations indicate a noteworthy association between sex and CSF sTREM2 levels, particularly in individuals carrying the APOE ε4 allele.
Multiparametric MRI-based radiomic model for predicting lymph node metastasis after neoadjuvant chemoradiotherapy in locally advanced rectal cancer
Authors: Wei Qiurong , Chen Ling , Hou Xiaoyan , Lin Yunying , Xie Renlong , Yu Xiayu , Zhang Hanliang , Wen Zhibo , Wu Yuankui , Liu Xian , Chen Weicui
Published: June 2024

Objectives

To construct and validate multiparametric MR-based radiomic models based on primary tumors for predicting lymph node metastasis (LNM) following neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC) patients.

Methods

A total of 150 LARC patients from two independent centers were enrolled. The training cohort comprised 100 patients from center A. Fifty patients from center B were included in the external validation cohort. Radiomic features were extracted from the manually segmented volume of interests of the primary tumor before and after nCRT. Feature selection was performed using multivariate logistic regression analysis. The clinical risk factors were selected via the least absolute shrinkage and selection operator method. The radiologist’s assessment of LNM was performed. Eight models were constructed using random forest classifiers, including four single-sequence models, three combined-sequence models, and a clinical model. The models’ discriminative performance was assessed via receiver operating characteristic curve analysis quantified by the area under the curve (AUC).

Results

The AUCs of the radiologist’s assessment, the clinical model, and the single-sequence models ranged from 0.556 to 0.756 in the external validation cohort. Among the single-sequence models, modelpost_DWI exhibited superior predictive power, with an AUC of 0.756 in the external validation set. In combined-sequence models, modelpre_T2_DWI_post had the best diagnostic performance in predicting LNM after nCRT, with a significantly higher AUC (0.831) than those of the clinical model, modelpre_T2_DWI, and the single-sequence models (all p < 0.05).

Conclusions

A multiparametric model that incorporates MR radiomic features before and after nCRT is optimal for predicting LNM after nCRT in LARC.

Critical relevance statement

This study enrolled 150 LARC patients from two independent centers and constructed multiparametric MR-based radiomic models based on primary tumors for predicting LNM following nCRT, which aims to guide therapeutic decisions and predict prognosis for LARC patients.

Key Points

The biological characteristics of primary tumors and metastatic LNs are similar in rectal cancer.

Radiomics features and clinical data before and after nCRT provide complementary tumor information.

Preoperative prediction of LN status after nCRT contributes to clinical decision-making.

Graphical Abstract
Health behavior and psychological treatment utilization in adults with avoidant/restrictive food intake disorder symptoms
Authors: Engelkamp Julia Enya , Hartmann Andrea Sabrina , Petrowski Katja , Herhaus Benedict , Fegert Jörg Michael , Sachser Cedric , Kropp Peter , Müller Britta , Brähler Elmar , Hilbert Anja
Published: June 2024

Background

Avoidant/restrictive food intake disorder (ARFID), an eating disorder not associated with weight and shape concerns, results in nutrient or energy deficiencies related with further health consequences and a pronounced need for specialized treatment. These interventions need to be tailored to individual health behavior. However, research about health behavior and treatment utilization in ARFID is scarce, particularly in adults, as ARFID is more common in children despite occurring across the lifespan. One important aspect of health behavior is the individual’s health regulatory focus (i.e., health prevention and health promotion). Additionally, symptoms of eating disorders have generally been associated with various health risk behaviors, such as smoking, drinking, or unhealthy physical (in)activity. Therefore, the present study aimed to investigate health behavior and psychological treatment utilization in adults with symptoms of ARFID.

Methods

A representative adult population sample (N = 2415) completed several self-report questionnaires assessing symptoms of eating disorders and health behavior. Differences between groups (symptoms of ARFID vs. no symptoms of ARFID) were tested with analysis of variance, Mann-Whitney-U-tests, and binary logistic regression.

Results

Individuals with symptoms of ARFID (n = 20) did not differ in their health regulatory focus, smoking status, physical activity or psychological treatment utilization from individuals without symptoms of ARFID (n = 2395). However, they reported higher alcohol misuse than individuals without symptoms of ARFID.

Conclusion

The findings suggest a relevance of further exploration of the relationship between alcohol misuse and ARFID, given the preliminary nature of these results. This exploration could inform treatment strategies for addressing potential comorbid substance misuse. Furthermore, the low psychological treatment utilization in adults with symptoms of ARFID suggest a need for more specialized psychological treatment services, public education about ARFID being an indication for psychological treatment, and further research about treatment barriers.
Detectability of low-viscosity zone along lithosphere–asthenosphere boundary beneath the Nankai Trough, Japan, based on high-fidelity viscoelastic simulation
Authors: Murakami Sota , Hashima Akinori , Iinuma Takeshi , Fujita Kohei , Ichimura Tsuyoshi , Hori Takane
Published: June 2024

After the 2011 Tohoku-oki earthquake, a seafloor observation system observed rapid landward deformation. These seafloor observation data are potentially explicable via modeling of a low-viscosity zone under the subducting plate, called the lithosphere–asthenosphere boundary (LAB). However, the effect of a low-viscosity LAB has not been empirically examined in past earthquakes because of the absence of seafloor observation data, which are expected to have high sensitivity in the detection of a low-viscosity LAB. The Nankai Trough, southwest Japan, is one location where seafloor geodetic stations are in operation that could detect a low-viscosity LAB after a future earthquake. Therefore, we quantitatively model how the low-viscosity of the LAB is expected to affect postseismic crustal deformation following an anticipated future large earthquake under the Nankai Trough. Calculating viscoelastic deformation using a model that takes into account the realistic crustal structure in the southwestern Japanese Archipelago, we examine the effects of LAB viscosity on surface deformation patterns. The results show for very low LAB viscosities ($$2.5 \times 10^{17}$$

2.5
×

10
17

 Pa s), rapid landward displacement as large as 38 cm/yr occurs in the offshore area, with uplift and subsidence patterns highly dependent on the viscosity structure. Especially in the first year after the earthquake, the difference in deformation between the cases with and without a low-viscosity LAB was much larger than the observational error level of the current seafloor observation system. For such low LAB viscosities, the probability of detection is therefore high. On the other hand, for moderately low LAB viscosities ($$2.5 \times 10^{18}$$

2.5
×

10
18

 Pa s), the deformation patterns in the cases with and without a low-viscosity LAB are similar. Indeed, the difference in displacement lies within the observational error level of the current observational network, so detection is expected to be difficult for a LAB of only moderately low-viscosity. However, such a LAB may be detected by improving observational accuracy in the Global Navigation Satellite System–acoustic observation technique by performing more frequent measurements. Additional detection potential lies in expected future accuracy improvements in vertical displacement estimates at the DONET stations.

Graphical Abstract
Case report of QT interval prolongation induced by anamorelin in an obese patient with non-small cell lung cancer
Authors: Yokota Hayato , Asahi Ruriko , Akamine Yumiko , Kobayashi Mizuki , Wakabayashi Hiyu , Sakamoto Sho , Okuda Yuji , Sato Kazuhiro , Nakayama Katsutoshi , Kikuchi Masafumi
Published: June 2024

Background

Anamorelin, a drug to treat cancer cachexia, binds to ghrelin receptors and improves body weight and appetite. In clinical trials in Japan, patients experienced a 10.7% frequency of stimulant conduction system depression as a severe side effect. Although rare, anamorelin sometimes causes fatal arrhythmias. Because patients with cancer cachexia are often underweight, data on the safety of anamorelin in obese patients are lacking. We report a case of QT interval prolongation after anamorelin administration to an obese patient with non-small cell lung cancer.

Case presentation

A female patient with a body mass index of 30 kg/m2 underwent immunotherapy for lung adenocarcinoma. She presented with severe weight loss, anorexia, and fatigue. She had no history of heart disease. On day 12, after administration of anamorelin 100 mg once daily, the patient developed nausea, diarrhea, and anorexia, which were considered cancer immunotherapy-induced immune-related adverse events, and she was admitted to the hospital. An electrocardiogram (ECG) on admission showed a QTc interval of 502 ms. On admission, her hepatic function was Child–Pugh class B, and anamorelin was discontinued the next day. On day 3 after anamorelin discontinuation, the QTc interval was prolonged by up to 557 ms, then decreased to 490 ms on day 6, and improved to 450 ms on day 16. Re-administration of anamorelin was avoided.

Conclusions

When administering anamorelin to obese patients, we should be aware of the potential for stimulatory conduction system depression, as in underweight patients. Therefore, we should monitor patients by ECG from the early stages of anamorelin administration. Anamorelin is lipophilic, and its volume of distribution is increased in obese patients. Consequently, obese patients may continue to have QT interval prolongation after discontinuation of anamorelin, requiring long-term side-effect monitoring.
Association between waist circumference and lung function in American middle-aged and older adults: findings from NHANES 2007–2012
Authors: Xu Zichen , Zhuang Lingdan , Li Lei , Jiang Luqing , Huang Jianjun , Liu Daoqin , Wu Qiwen
Published: June 2024

Purpose

There is a major epidemic of obesity, and many obese patients suffer from respiratory symptoms and disease. However, limited research explores the associations between abdominal obesity and lung function indices, yielding mixed results. This study aims to analyze the association between waist circumference (WC), an easily measurable marker of abdominal obesity, and lung function parameters in middle-aged and older adults using the National Health and Nutrition Examination Survey (NHANES).

Methods

This study utilized data obtained from the National Health and Nutrition Examination Survey (NHANES) spanning 2007 to 2012, with a total sample size of 6089 individuals. A weighted multiple regression analysis was conducted to assess the relationship between WC and three pulmonary function parameters. Additionally, a weighted generalized additive model and smooth curve fitting were applied to capture any potential nonlinear relationship within this association.

Results

After considering all confounding variables, it was observed that for each unit increase in WC, in males, Forced Vital Capacity (FVC) increased by 23.687 ml, Forced Expiratory Volume in one second (FEV1) increased by 12.029 ml, and the FEV1/FVC ratio decreased by 0.140%. In females, an increase in waist circumference by one unit resulted in an FVC increase of 6.583 ml and an FEV1 increase of 4.453 ml. In the overall population, each unit increase in waist circumference led to a FVC increase of 12.014 ml, an FEV1 increase of 6.557 ml, and a decrease in the FEV1/FVC ratio by 0.076%. By constructing a smooth curve, we identified a positive correlation between waist circumference and FVC and FEV1. Conversely, there was a negative correlation between waist circumference and the FEV1/FVC ratio.

Conclusions

Our findings indicate that in the fully adjusted model, waist circumference, independent of BMI, positively correlates with FVC and FEV1 while exhibiting a negative correlation with FEV1/FVC among middle-aged and older adults in the United States. These results underscore the importance of considering abdominal obesity as a potential factor influencing lung function in American middle-aged and older adults.
Comprehensive testing technology for new energy vehicle power batteries based on improved particle swarm optimization
Authors: Liu Hongxing , Liang Yi
Published: June 2024

As the new energy industry continues to progress, the health management of power batteries has become the key to ensuring the performance and safety of automobiles. Therefore, accurately predicting battery capacity decline is particularly important. A battery capacity degradation prediction model combining unscented particle filtering, particle swarm optimization, and SVR is constructed. It optimizes regression parameters through the introduced optimization strategy. Unscented particle filtering is used to improve particle swarm optimization and battery detection model. The study tested four various models of lithium-ion batteries. The model predicted a mean square error of 0.0011 for battery 5, 0.0007 for battery 6, 0.0022 for battery 7, and 0.0013 for battery 18. In the prediction of different battery types, the mean square error of the NIMH battery was reduced by 0.0008 compared with the particle swarm optimization-support vector regression algorithm, and by 0.0005 compared with the unscented particle filtering-regression vector regression algorithm. The mean square error of lithium-iron phosphate battery was reduced by 0.0008 and 0.0004 respectively compared with comparison models. The mean square error value of lithium titanate battery was reduced by 0.0007 and 0.0003 respectively in the research model compared with comparison models. It improves the prediction accuracy in lithium-ion batteries. Its application in battery health management can provide important technical support for improving battery performance and extending service cycles. The proposed method can be used for battery monitoring and management of power grid energy storage system. By accurately predicting the capacity decline of battery, the operation strategy of energy storage system can be optimized to ensure the efficient operation and long life of the system. The battery management system can be used for drones and aviation equipment to predict battery health and capacity decline in real time, ensuring the safety and reliability of flight missions.
Promise and Perils of Precision Oncology for Patients With Pediatric and Young Adult Sarcomas
Authors: Church Alanna J. , Wakefield Claire E. , Hetherington Kate , Shern Jack F.
Published: June 2024

The completion of multiple national pediatric precision oncology platform trials and the incorporation of standardized molecular profiling into the diagnostic care of pediatric and young adult patients with sarcomas have proven the feasibility and potential of the approach. In this work, we explore the current state of the art of precision oncology for pediatric and young adults with sarcoma. We highlight important lessons learned and the challenges that should be addressed in the next generation of trials. The chapter outlines current efforts to improve standardization of molecular assays, harmonization of data collection, and novel molecular tools such as cell-free DNA analyses. Finally, we discuss the impacts and psychosocial outcomes experienced by patients and communication strategies for providers.
Taiwan national lung cancer early detection program for heavy smokers and non-smokers with family history of lung cancer.
Authors: Yang Pan-Chyr , Chen Tony Hsiu-Hsi , Huang Kuo-Ping , Lin Li-Ju , Wu Chao-Chun
Published: June 2024

8009

Background: Lung cancer incidence in Taiwan has been rising with the epidemiological profiles distinct from Western country. Notably, nonsmoking lung cancers accounts for more than 60% and half of lung cancers were diagnosed in advanced stages. For early detection, a national program is therefore initiated to offer biennial low-dose computed tomography (LDCT) screening for heavy smokers and subjects with lung cancer family history (LCFH). Here, we report basic screening findings, analyze relevant effectiveness in reducing advanced lung cancer, and project the potential benefit of mortality reduction. Methods: Taiwan National Lung Cancer Early Detection Program was launched on July 1, 2022 to offer heavy smokers (30 pack-years) and nonsmokers (including light smokers) with a LCFH aged 45-74 years for female and aged 50-74 years for male. This is a continuous screening program using before and after study design for evaluation. We provided the overall first-year basic screening findings until Dec 31, 2023 and did per protocol analysis of stage II+ cancer reduction in comparison with tumor stage distribution in the year preceding the introduction of the national program. The corresponding findings were presented for subjects with LCFH and heavy smokers. The result for heavy smoker was compared with those per-protocol findings from previous randomized controlled trials. The potential mortality reduction was further projected. Results: A total of 78,000 individuals participated in this program, male 44,381 (56.9%) female 33,619 (43.1%); 31,111 participants (39.9%) were heavy smokers, 43,853 (56.2%) nonsmokers but with a LCFH, and 3,036 (3.9%) had both risk factors. Lung cancer confirmed in 956 subjects by surgery or biopsy, 85.0% were stage 0-1. The lung cancer detection rate was 1.2%. Subjects with a LCFH exhibited a higher detection rate (overall: 1.6%, nonsmokers: 1.7% and light smokers 0.9%) compared to heavy smokers (0.7%) and both (1.1%). Early detection of LDCT led to a statistically significant 77% (51%-89%) of reducing advanced stage of lung cancer, 53% (-3%-78%) reduction for heavy smokers, consistent with the corresponding 36%-64% reduction derived from the NLST trial and the Nelson trial, and 85% (67%-93%) reduction for nonsmokers with a LCFH. The benefit of reducing stage II or severe in conjunction with five-year stage-specific survival rate further projected 55% (10%-78%) of mortality reduction from lung cancer. Conclusions: This is the first large-scale LC screening service enrolling 40% heavy smokers and 60% non-smoker with a LCFH. The potential effectiveness of early detection was demonstrated for both targets. As the results based on per-protocol analysis for heavy smoker were consistent with those of previous evidence-based studies the similar and significant intention-to-treat results as before while waiting for the subsequent follow-up would be expected.
The impact of HIV and CD4 count stratification on all cause mortality for adenocarcinoma and squamous cell lung cancers in the antiretroviral therapy era: Analysis of National Veterans Affairs and Kaiser Permanente Northern cohorts.
Authors: Chiao Elizabeth Y. , Malgave Devesh , Hartman Christine , Kramer Jennifer , Hechter Rulin , Sakoda Lori C. , Leyden Wendy , Pak Katherine , Lea Alexandra , Zafeiropoulou Efthalia , Rivera Ado , Richardson Peter , Dong Yongquan , White Donna L. , Lin Lilie L. , Boyer Matthew J , Silverberg Michael
Published: June 2024

8070

Background: Since the widespread introduction of antiretroviral therapy (ART), people living with HIV (PWH) have experienced substantially decreased morbidity and mortality. However, PWH are at higher risk for lung cancer and have decreased cancer survival rates compared to people without HIV (PWoH). Few studies have evaluated histology-specific lung cancer survival by stage and HIV immune control. Methods: A retrospective cohort study was conducted with newly diagnosed non-small cell lung cancer (NSCLC), including PWH with PWoH, identified between 2008 and 2020 from the US Department of Veterans Affairs and Kaiser Permanente, California. Adjusted hazard ratios for 5-year survival by CD4 count (≥ 500 cells/mm3, <500 cells/mm3, ref: PwOH) were estimated using Cox models stratified by subtype (adenocarcinoma, squamous) and TNM (I, II/III, IV) stage. Results: This cohort consisted of 562 PWH (53% adenocarcinoma, 33% squamous cell) and 91,370 PWoH (52% adenocarcinoma, 33% squamous cell, 15% not specified). The PWH cohort tended to be younger (62 vs. 69 years), male (97% vs. 83%), and non-Hispanic Black race (48% vs. 14%), compared to PWoH. Among PWH, 41% had CD4 ≥500 cells/mm3, 59% had CD4 <500 cells/mm3 . The median survival in years for PWoH, PWH CD4 count ≥500 cell/mm3and <500 cells/mm3 were: 2.4 ±0.10, 2.3 ± 0.17, 2.0±0.17, respectively for adenocarcinoma, and 2.1±0.01, 2.3±0.21, 1.6±0.17 respectively for squamous cell carcinoma. The table shows the adjusted HR for all-cause mortality for Adenocarcinoma and Squamous Cell Carcinoma comparing PWH ≥500 and PWH<500 to PWoH (as reference) stratified by stage. Conclusions: Although it is well known that low CD counts (<200) are associated with poor cancer outcomes, higher CD4 counts (CD<500) at the time of lung cancer diagnosis may still play a role in the treatment outcomes of NSCLC. PWH who have CD4 counts ≥500 appear to have similar survival compared to PWoH, but CD4<500, those with (vs. without) HIV have higher rates of mortality for both adenocarcinoma and squamous cell histologies. Adjusted hazard ratios (HR)* with 95% confidence intervals (CI) for 5-year all-cause-mortality associated with HIV by CD4 count (reference: PWoH), across Adenocarcinoma and Squamous Cell Cancer histology and baseline cancer stage. [Table: see text]
An interpretable AI-derived radiology signature to identify patients at risk of progression on the PACIFIC regimen for unresectable non-small cell lung cancer.
Authors: Haji Maghsoudi Omid , Chung Liam IL Young , Lee Seyoung , Lee Jeeyeon , Kim Haseok , Hiremath Amogh , Zhang Kai , Cantor Diego , Yadav Monica , Kim Hye Sung , Yu Jisang , Kim Yuchan , Hong Ilene , Kang Grace , Cho Amy , Velichko Yury , Velcheti Vamsidhar , Madabhushi Anant , Braman Nathaniel , Chae Young Kwang
Published: June 2024

8079

Background: Advances in the treatment of unresectable NSCLC have emerged through the combination of chemotherapy, radiotherapy, and immune checkpoint inhibitors (ICI), also known as the PACIFIC regimen. Despite this protocol’s benefits, it lacks predictive biomarkers and many patients will ultimately fail to respond. Artificial intelligence (AI) has shown promise in identifying patients responsive to ICI, but its ability to identify patients who may not benefit from such combination regimens remains underexplored. We introduce an AI-enabled approach leveraging interpretable imaging biomarkers, such as tumor heterogeneity and twistedness of the tumor-associated vasculature, to identify patients who will fail to benefit from chemo-radio-immunotherapy (CRIT) using pretreatment scans. Methods: We analyzed CT data from 148 NSCLC patients with predominantly stage III (91%) disease from two institutions. Target lesions were delineated by a trained radiologist. The Picture Health Px platform was utilized to segment the lungs and pulmonary vessels. Subsequently, a number of interpretable imaging features from the tumor and surrounding tissues were extracted. A Cox proportional hazards model of feature clusters was developed on the training set (n = 101) to stratify patients into benefit groups associated with progression-free survival (PFS). A cohort of 47 patients receiving CRIT were held out for testing. Results: The imaging-derived high-risk group defined by the model was associated with decreased PFS in the test set, with a hazard ratio (HR) of 4.99 (95% CI: 2.04-12.18; p < 0.005) and concordance index (C-index) of 0.66. The risk groups identified by the model outperformed PD-L1 negative status in identifying likely progressors (C-index = 0.52; HR = 1.49 [0.51-4.54], p = 0.47), and were additionally independently prognostic of PD-L1 status when compared in a multivariable analysis (p < 0.001). The primary features driving the model were measurements of the radius and tortuosity of the tumor-associated vasculature, as well as heterogeneity metrics of the tumor. Conclusions: An AI imaging tool that stratifies patients by risk after CRIT from baseline radiology was developed. The tool was able to strongly identify a subset of patients at very high risk of progression if treated with CRIT. These risk groups outperformed PD-L1 and thus may address biomarker gaps in the CRIT setting. With further clinical validation, radiology-based risk stratification could be used to identify a subset of unresectable NSCLC patients for whom alternatives to the standard of care should be explored.
Outcome of chemo-immunotherapy for extensive-stage small-cell lung cancer according to potential clinical trial eligibility: 3-year outcomes from prospective cohort study.
Authors: Tamiya Motohiro , Fujimoto Daichi , Hata Akito , Matsumoto Hirotaka , Sugisaka Jun , Yokoyama Toshihide , Taniguchi Yoshihiko , Uchida Junji , Hara Satoshi , Saito Go , Miura Satoru , Suzuki Hidekazu , Ikeda Satoshi , Hiraoka Ryota , Yanai Masaaki , Yamamoto Nobuyuki , Akamatsu Hiroaki
Published: June 2024

8087

Background: Chemo-immunotherapy is the standard 1st-line therapy for patients with extensive-stage small-cell lung cancer (ES-SCLC). Our large previous real-world prospective analysis showed outcomes of chemo-immunotherapy for these patients according to potential clinical trial eligibility with a minimum follow-up period of 1 year. However, long-term outcomes have not been studied in the real-world setting. Methods: We conducted a 32-hospital prospective cohort study of consecutive patients with ES-SCLC who received carboplatin and etoposide with atezolizumab as 1st-line therapy between September 2019 and September 2020. Patients who met eligibility criteria for pivotal phase 3 clinical trials were considered “trial-eligible.” We present 3-year outcomes from this study. Results: In total, 207 patients with ES-SCLC were analyzed. The median (range) time from the start of treatment to data cutoff (September 30, 2023) was 42.2 (35.8.-48.2) months. The median age was 72 years, and 64 patients (31%) were elderly (≥75 years). Most patients (89%) had a performance status (PS) of 0 or 1. As a result, 132 (64%) were categorized as trial-eligible patients. The 3-year PFS and OS probability of all patients was 6.1 % (95%CI:3.5-10.4%) and 20.9 % (95%CI:15.6-27.3%), respectively. Patients achieving 3-year OS included significantly higher proportions of trial-eligible patients (30 out of 132 versus 5 out of 75, respectively; p = 0.002). Kaplan-Meier estimates of the 3-year OS rate were 26.7% for the trial-eligible group and 9.5 % for the trial-ineligible group. Conclusions: This is the first real-world study to show the long-term efficacy of chemo-immunotherapy for ES-SCLC by using the largest prospective cohort of its kind. Additionally, this study demonstrated that trial eligibility was associated with long-term efficacy. Our study suggests that long-term clinical outcomes among trial-eligible patients may not translate to ineligible patients.
Efficacy and safety of lurbinectedin (LUR) with irinotecan (IRI) in patients (Pts) with relapsed small cell lung cancer (SCLC): Results from a phase 2 expansion cohort.
Authors: Paz-Ares Luis G. , Falcon Gonzalez Alejandro , Navarro Alejandro , Sanchez-Gastaldo Amparo , Cote Gregory Michael , Bockorny Bruno , Molina-Cerrillo Javier , Artal Angel , Baena Javier , Gil Ana , Ponce Aix Santiago , Bote de Cabo Helena , Martinez Sara , Martinez Julia Martinez , Lopez-Vilariño Jose Antonio , Kahatt Carmen Maria , Zeaiter Ali Hassan , Gomez Javier , Zugazagoitia Jon
Published: June 2024

8094

Background: LUR has been approved in the US and elsewhere for treatment of adult pts with metastatic SCLC and disease progression on or after platinum-based chemotherapy. Preclinical studies found synergy for LUR with IRI (Galmarini C. Cancer Res 2013; 73: Abst 5499). The phase 1b/2 study PM1183-A-014-15 (NCT02611024) evaluated the LUR/IRI combination in pretreated pts with advanced solid tumors. The phase 1b part defined the recommended dose at LUR 2.0 mg/m2 on Day (D)1 + IRI 75 mg/m2 on D1,D8 every three weeks with primary G-CSF prophylaxis, and found promising results for the combination in SCLC pts after first-line therapy (Ponce Aix S. Ann Oncol 2019; 30: Abst 471P). Methods: Eligibility criteria for this cohort of the phase 2 part of this study included: confirmed SCLC, progression after one platinum-containing regimen, controlled brain metastases and ECOG PS ≤ 1. The primary endpoint was overall response rate (ORR). Results: 101 evaluable pts were enrolled. Baseline characteristics included: median age 63 (range, 45-77 y), 60.4% males, 76.2% ECOG PS 1, 28.7% CNS involvement, 39.6% bulky disease and 41.6% pretreated with immunotherapy. Chemotherapy-free interval (CTFI) was <90 d in 51.4% of pts (26.7% had CTFI<30 d. Median CTFI was 85 d (range, 0-323 d). Median number of cycles per pt was 6 (range, 1-34); 25.7% received >10 cycles. Efficacy results by independent review committee are summarized in the table. Treatment-related adverse events (AEs) were observed in 99.0% of pts (grade ≥3 in 69.3%). Most relevant grade ≥3 events/abnormalities were neutropenia (52.5%), anemia (27.7%), diarrhea (19.8%), fatigue (18.8%), and febrile neutropenia (9.9%). Treatment-related SAEs occurred in 25.0% of pts and 5.0% discontinued due to treatment-related AEs. No treatment-related deaths occurred. Conclusions: The LUR/IRI combination showed promising antitumor activity and a manageable safety profile in these pts with poor prognosis, particularly those with CTFI>30 d. These encouraging results reinforce the rationale for including this combination as an experimental arm in the ongoing pivotal phase 3 LAGOON trial (NCT05153239) in relapsed SCLC with CTFI>30 d. Clinical trial information: NCT02611024 . [Table: see text]
Repotrectinib in tyrosine kinase inhibitor (TKI)-naïve patients (pts) with advanced ROS1 fusion-positive (ROS1+) NSCLC in the phase 1/2 TRIDENT-1 trial: Clinical update, treatment beyond progression and subsequent therapies.
Authors: Drilon Alexander E. , Dziadziuszko Rafal , Camidge David Ross , Lin Jessica Jiyeong , Besse Benjamin , Kim Sang-We , Lee Ki Hyeong , Solomon Benjamin J. , Nagasaka Misako , Goto Koichi , Wolf Juergen , De Langen Adrianus Johannes , Cheema Parneet Kaur , Yang Nong , Velcheti Vamsidhar , Elamin Yasir Y , Xu Yuanfang , Calvet Christophe , Ades Felipe , Cho Byoung Chul
Published: June 2024

8522

Background: Repotrectinib, a next-generation ROS1 TKI, has demonstrated durable clinical activity in the pivotal phase 1/2 TRIDENT-1 trial (NCT03093116). We report updated efficacy with a median follow-up of 33.9 months (mo) [~10 mo of additional follow-up], the first analyses of progression patterns, treatment beyond progression, and an update on subsequent anticancer therapies. Methods: Recommended phase 2 dose was 160 mg QD for 14 days, then 160 mg BID. Phase 2 primary endpoint was confirmed objective response rate (cORR) by blinded independent central review (BICR) per RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), intracranial ORR (icORR), and safety. Treatment beyond BICR-assessed progression and sites of progression (per investigator) were also assessed. Safety assessments included all treated pts. Results: As of 15 Oct 2023, median follow-up in the TKI-naïve cohort (n = 71) was 33.9 (range, 24.0–76.5) months (mo). cORR was 79% (95% CI, 68–88); median DOR was 34.1 (95% CI, 27.4–not estimable [NE]) mo and 70% (95% CI, 57–83) of responders maintained a response of ≥ 24 mo. Median PFS was 35.7 (95% CI, 24.6–NE) mo and 63% (95% CI, 51–75) of pts were progression-free at 24 mo. Of 9 pts with measurable baseline brain metastases, icORR was 89% (95% CI, 52–100). Results for pts who received repotrectinib beyond progression are shown in the table. Of pts with disease progression per investigator (n = 37), the most common sites were lung (49%) and lymph nodes (35%). Of 42 (59%) pts who discontinued repotrectinib for any reason, 11 (26%) received single-agent TKI as the first subsequent anticancer therapy, 10 (24%) received chemo with/without immunotherapy (IO), and 2 (5%) received IO alone. Among all pts who received ≥ 1 dose of repotrectinib (n = 565), grade ≥ 3 treatment-emergent adverse events occurred in 323 (57%) pts and treatment-related adverse events in 162 (29%) pts. Treatment-emergent dizziness occurred in 63% of pts and was mostly grade 1-2. Conclusions: With a median follow-up of ~3 years in TRIDENT-1, repotrectinib continued to demonstrate durable clinical activity in ROS1 TKI-naïve pts. Progression patterns and treatment beyond progression were described for the first time. Clinical trial information: NCT03093116 . [Table: see text]
Unraveling CASTOR1's tumor suppressive role: Genetic ablation of CASTOR1 and KRAS-driven mouse model of non-small cell lung cancer.
Authors: Wang Xian , Sun Shenyu , Loo Suet Kee , Chen Luping , Ding Ling , Li Tingting , Wang Man-Tzu , Burns Timothy F. , Stabile Laura P. , Gao Shou-Jiang
Published: June 2024

8528

Background: Cytosolic Arginine Sensor for mTORC1 Subunit 1 (CASTOR1) has emerged as a potent suppressor of mTORC1 activity, playing a pivotal role in various cancer contexts. Previously implicated as a tumor suppressor in multiple cancers, CASTOR1 is tightly regulated in cancer, including inhibition by viral miRNAs in KSHV-induced cancer and degradation via AKT-phosphorylation and RNF167-mediated ubiquitination. Notably, CASTOR1's role extends beyond normal cellular contexts, as evidenced by its tumor-suppressive function in breast cancer xenograft models and its prognostic value in lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). This study aims to elucidate CASTOR1’s role in a transgenic Kras-driven LUAD mouse model, shedding light on its tumor-suppressive potential. Methods: Utilizing a novel CASTOR1 knockout (KO) mouse model crossed with the Kras (LSL-KrasG12D/+) NSCLC model, we established a new mouse model with simultaneous Kras activation and homozygous CASTOR1 ablation. Tumor incidence and growth were monitored in Kras mice harboring wild-type (WT) and KO CASTOR1. Further investigations examined the proliferative dynamics and activation status of various oncogenic pathways, and assessed mTORC1 inhibitor sensitivities in human LUAD cell lines with altered CASTOR1 expression levels. Results: CASTOR1 deficiency markedly heightened lung tumor incidence and size, concomitant with an elevated proliferative index. Intriguingly, a novel antibody identified robust pCASTOR1 levels in CASTOR1 WT mouse LUAD tumors, positively correlated with tumor stage and inversely related to total CASTOR1 abundance, hinting at an active degradation mechanism promoting tumor progression. Elevated mTORC1 signaling, evidenced by increased levels of p4EBP and pS6, underscored the pathway's activation consequent to CASTOR1 loss, likely driving tumor development. Furthermore, heightened pERK levels in CASTOR1 KO tumors unveiled a novel feedback loop intertwining CASTOR1/mTORC1 and the Kras/ERK pathway. Notably, treatment with mTORC1 inhibitors sensitized organoids of Kras tumors with mTORC1 hyperactivation to Kras G12D inhibitor. Conclusions: Our findings elucidate CASTOR1's tumor-suppressive role in Kras-dependent mouse LUAD tumors, suggesting the potential efficacy of combined Kras and mTORC1 inhibition in LUAD subsets characterized by hyperactivated Kras and diminished CASTOR1 levels or mTORC1 hyperactivity.
Association of combination tumor texture and vessel tortuosity with progression free survival across PD-L1 subgroups in durvalumab treated non-small cell lung cancer (NSCLC): Blinded validation results from CP1108.
Authors: Khorrami Mohammadhadi , Mutha Pushkar , Viswanathan Vidya Sankar , Gupta Amit , Velcheti Vamsidhar , Madabhushi Anant
Published: June 2024

8600

Background: Immunotherapy (IO) has shown a durable response with minimal toxicity in the treatment of metastatic NSCLC. However, only 30-50% of these patients (pts) actually respond. Despite initial optimism surrounding PD-L1 expression as a potential biomarker, IO provides benefit across PD-L1 low (<25%) and high (≥25%) status. This highlights a critical need for more effective biomarkers to guide treatment decisions. Here, we present blinded validation results of a CT-based biomarker of change in quantitative vessel tortuosity (1) (Δ-QVT) and texture radiomics (2) (Δ-Rad) between baseline (B) and 6 weeks post-treatment (TP1) for predicting response, overall survival (OS) and progression free survival (PFS) in CP1108 (NCT01693562). Methods: CT scans at B and TP1 were retrospectively analyzed from two studies (a) a multi-center training set (Str, N=110) of metastatic NSCLC pts treated with first line IO and (b) a blinded NSCLC cohort of N = 151 pts treated with Durvalumab in CP1108 study (Sv). In Sv, N=75 pts were PD-L1 high (Sv+) whereas N=65 pts were PD-L1 low (Sv-). An in-house MATLAB based algorithm was used to extract intra-tumoral, peri-tumoral texture and QVT features from up to two largest measurable tumors in each CT. A classifier (MCombo) was trained on Str to predict best overall response defined as per the RECIST v1.1 criteria using combination of Δ-QVT and Δ-Rad features. Area under the receiver operating characteristic (AUC) was used to evaluate MCombo against RECIST response whereas univariable and multivariable Cox regression models with log-rank test, hazard ratio (HR) with confidence interval (CI) and concordance index (C-index) were used to study the association of MCombo with OS and PFS in Sv, Sv+, and Sv-. Results: MCombo predicted objective response with an AUC of 0.78 in Sv and was statistically significantly associated with PFS (Table) in Sv, Sv+, and Sv-. MCombo was associated with OS in Sv, Sv+, but not in Sv-. Multivariable analysis with PD-L1 status, histological subtype, ECOG status, liver metastasis, line of therapy and sex showed independent association of MCombo across OS and PFS. Conclusions: Our results indicate that combination of radiomics and vessel tortuosity biomarker from CT is independently prognostic of response and PFS across PD-L1 levels. Prospective validation of this biomarker is needed. 1. Alilou et al. Sci Adv 2022. 2. Khorrami et al. Cancer Immunol Res 2020. [Table: see text]
Characterization of DNA damage repair (DDR) alterations and the tumor immune microenvironment (TIME) in advanced non-small cell lung cancer (NSCLC).
Authors: Sankar Kamya , Mercer Jacob , Jaeger Ellen B. , Godden Jen , Berkman Jonathan David , Williams Edward , Thompson Michael A. , Patel Shetal Arvind , Reckamp Karen L. , Weinberg Frank
Published: June 2024

8603

Background: Exploiting the DDR pathway with synthetic lethality agents such as PARP inhibitors has been clinically validated in several cancers. In NSCLC, novel agents leveraging defects in the DDR pathway are being studied alone and in combination with checkpoint inhibitors. To expand on combination approaches and inform biomarker selected strategies, we analyzed DDR alteration prevalence and impact on the TIME in metastatic NSCLC. Methods: We retrospectively analyzed de-identified next-generation sequencing data from patients (pts) with metastatic NSCLC in the Tempus Database. Tumors were sequenced with the Tempus xT DNA and xR RNA assays. DDR pathway genes were defined as previously described (PMID 29617664). Pts were stratified based on the presence (DDRmt) or absence (DDRwt) of a pathogenic somatic alteration or copy number deletion in a DDR pathway gene. The associations of DDR alteration with immune cell infiltration predicted from gene expression patterns, PD-L1 from IHC, TMB (TMB-H, >10 mut/Mb), and microsatellite instability (MSI) were examined. Wilcoxon rank-sum and Pearson’s Chi-squared/Fisher's exact tests were used to assess statistical significance (p<0.05, q<0.05 for false discovery rate correction for multiple testing). Results: Across 14,127 samples, 5,255 (37%) were DDRmt and 8,872 (63%) were DDRwt. The median age at diagnosis was 67 (IQR 60-74). Current/former smokers (83%; n=10,445) had a higher prevalence of DDRmt (86% vs. 82%; p<0.001). The most prevalent DDRmt was SMARCA4 (18%), followed by PTEN (13%), BRCA2 (11%), ATM (9.0%), ERCC3 (6.6%), PMS2 (6.0%), and MUTYH (5.1%). TMB-H was more common (18% [n=931] vs. 11% [n=1001]; p<0.001) and median TMB was higher (5.4 vs. 4.6; p<0.001) in DDRmt pts compared to DDRwt. MSI-H was more prevalent in the DDRmt group (1.1% [n=57] vs. <0.1% [n=7]; p<0.001), while PD-L1 positivity was similar in DDRmt and DDRwt pts (55% [n=1918] vs. 58% [n=3314]; p=0.071). Compared to DDRwt, pts with DDRmt exhibited modest changes in immune cell infiltration patterns (Table). Conclusions: In this large, real-world cohort of pts with metastatic NSCLC, DDRmt was associated with distinct TIME patterns including high TMB, MSI-H, and modest changes in immune cell infiltrates. These findings warrant further studies to understand how DDR pathway alterations mediate changes in the TIME to inform novel combinatorial immunotherapeutic approaches in NSCLC.[Table: see text]
Amivantamab plus chemotherapy vs chemotherapy as first-line treatment among patients with EGFR exon 20 insertion–mutated advanced non-small cell lung cancer (NSCLC): PAPILLON Chinese subgroup analysis.
Authors: Tang Ke-Jing , Liu Baogang , Yao Yu , Zhao Yanqiu , Zhou Jianying , Sun Ping , Wang Donglin , Lv Dongqing , Wang Huijie , Hu Yi , Li Qiang , Song Yujiao , Gao Grace , Wang Liyun , Agrawal Trishala , Bhattacharya Archan , Baig Mahadi , Lorenzini Patricia A , Wortman-Vayn Honeylet , Zhou Caicun
Published: June 2024

8606

Background: Amivantamab (Ami) is a bispecific antibody targeting EGFR and MET tyrosine kinase receptors with immune cell-directing activity. The phase 3 PAPILLON study (NCT04538664) investigated the combination of Ami and carboplatin/pemetrexed (ACP) vs. carboplatin/pemetrexed (CP) as first-line treatment in patients (pts) with advanced EGFR Exon20ins-mutated NSCLC. ACP improved progression free survival (PFS) in both the overall population and Asian subgroup. Methods: Pts were randomized 1:1 to ACP or CP. The primary endpoint was PFS by blinded independent central review (BICR) and key secondary endpoints included objective response rate (ORR), PFS after first subsequent therapy (PFS2), overall survival (OS), and safety. Crossover to Ami monotherapy was allowed for pts in CP arm following disease progression. Results: Among the 308 pts enrolled, 87 were Chinese, with 39 receiving ACP and 48 receiving CP. Median age was 57/57 years, 46%/63% were female, and 15%/25% history of brain metastases for pts in ACP/CP arms. Baseline characteristics were generally balanced between arms. After a median follow-up of 16.4 months (mo), median PFS was 12.3 mo (95% CI: 7.00, NE) in ACP arm compared with 6.7 mo (95% CI: 4.21, 8.57) in CP arm (hazard ratio [HR], 0.47; 95% CI, 0.26-0.85; P = 0.011) (Table). ORR was 71.8% (95% CI, 55.1%-85.0%) for ACP, and 48.9% (95% CI, 34.1%–63.9%) for CP (odds ratio, 2.46; 95% CI, 1.01-5.98; P = 0.048). Median PFS2 was not estimable (NE) for ACP vs 18.8 mo for CP (HR, 0.32; 95% CI, 0.11-0.88; P = 0.021). Interim OS showed a favorable trend for ACP vs CP (HR, 0.58; 95% CI: 0.17-2.02; P = 0.387) despite crossover among CP-randomized pts (n = 24, 50%) who had progressed. Most common AEs (all grades) ( > 50%) in ACP arm were rash, paronychia, hypoalbuminemia, neutropenia, anemia, leukopenia and thrombocytopenia which were consistent with the known safety profile of the individual agents. Notably, no pts had discontinuation of Ami due to an AE. Conclusions: ACP demonstrated superior PFS compared to CP in Chinese pts. The safety profile was manageable and tolerable. These findings in Chinese subgroup were consistent with those of overall population and Asian subgroup. Clinical trial information: NCT04538664 . [Table: see text]