bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of FCN-159, a MEK1/2 inhibitor in pediatric participants with neurofibromatosis type 1: Results from a phase 2 trial.
Authors: Wang JinHu , Li Wenbin , Zeng Kang , Lin Xiaoxi , Li Yanling , Guan Zhonghai , Kang Zhuang , Li Changxing , Hu Xiaojie , Ma Yaohui , Wu Zhuli , Wang Xingli , Han Pu , Lin Hongmei , Zhong Wen 
Published: June 2024

3096 Background: Neurofibromatosis type 1(NF1) is an autosomal dominant tumor predisposition syndrome characterized by NF1 gene variants, resulting in over-activation of the RAS pathway. Plexiform neurofibroma (PN) is benign tumors that arise from nerve tissue and are a hallmark feature of NF1. They typically grow along nerves and cause disfigurement, pain, and other complications depending on their location and size. FCN-159, a highly potent and selective inhibitor of MEK1/2 by targeting inhibition of the RAS pathway, holds promise as a therapeutic agent for treating NF1-related PN. Methods: A multi-center, open-label phase 1/2 clinical trial was conducted to assess the safety and efficacy in pediatric patients(pts) with NF1-related PN. Here, we reported the safety and efficacy outcomes observed during phase 2 in pediatric pts, who received FCN-159 at the 5 mg/m2 dose once daily on a continuous basis in a 28-day cycle. Preliminary findings from the phase 1/2 trial were previously disclosed at ASCO 2023. Results: As of November 24, 2023,46 pts enrolled. The median age is 8.0 years (range 2-17). The most frequent PN related complications were disfigurement (69.6%) and pain (63.0%). Median volume of target neurofibroma were 37.7 cm³ (range 2.2-1144.1). Efficacy outcomes are reported for 43 pts (modified intent-to-treat population). With the median follow-up of 15.1 months (range 14.1-16.4), the investigator and Blinded Independent Review Committee (BIRC) assessed ORR were 48.8% and 30.2%, respectively. The mDoR and median mPFS were not reached. Preliminary efficacy data are presented in the table. Among the 16 pediatric subjects with tumor pain at baseline (overall tumor pain NRS≥1) and at least one post-baseline assessment, pain scores decreased by at least 2 points in 81.3% (13/16) pts, and pain scores reduced to 0 points (indicating no pain sensation) in 81.3% (13/16) pts, signifying clinically meaningful improvement. 43 pts (93.5%) experienced TRAEs with grade ≥3 TRAEs occurred in 8 pts (17.4%), including dermatitis acneiform (4.3%), folliculitis (4.3%), pneumonia (2.2%), upper respiratory tract infection (2.2%), ejection fraction decreased (2.2%), and blood creatine phosphokinase increased (2.2%). 2 pts (4.3%) reported treatment-related serious adverse events (one case of dermatitis acneiform and pneumonia each). No TRAEs resulting in dose reduction, discontinuation or death. Conclusions: FCN-159 demonstrated good tolerability and exhibited notable anti-tumor activity in pediatric pts with NF1-related PN. Clinical trial information: NCT04954001 . [Table: see text]
Real-world first-line serplulimab-based immunochemotherapy for extensive-stage small cell lung cancer: The multicenter ASTRUM-005R study.
Authors: Wu Lin , Hu ChengPing , Su Wenzhong , Yu Yan , Hong Wei , Liu Zhigang , Su Haichuan , Liu Zhentian , Wang Caixia , Pu Qing , Guo Hui , Min Xuhong , Chen Yifei 
Published: June 2024

e20106 Background: In the phase 3 ASTRUM-005 study (NCT04063163), serplulimab, an anti-PD-1 monoclonal antibody, combined with chemotherapy, demonstrated promising antitumor activity as first-line treatment in patients with extensive-stage small cell lung cancer (ES-SCLC). This led to its approval by the NMPA and designation as an orphan drug by the FDA. Here, we present a multicenter cohort study investigating the real-world efficacy and safety of first-line serplulimab-based immunochemotherapy for ES-SCLC in China. Methods: This cohort study enrolled adult patients with ES-SCLC at 12 sites in China from April 2022 to December 2023. These patients received at least two cycles of first-line serplulimab combined with an etoposide-platinum regimen and underwent at least one response assessment. The primary endpoint was real-world progression-free survival (rwPFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety profiles. Results: A total of 420 patients were enrolled and evaluated for both efficacy and safety. The participants had a median age of 63 years (range 30-84), with 361 (85.95%) being male and 310 (73.81%) having a history of smoking. Most patients (386, 91.91%) had an ECOG PS of 0 or 1. Comorbidities, excluding other primary tumors, were present in 40.95% (172 patients). Liver and brain metastases were observed in 32.14% (n = 135) and 21.67% (n = 91), respectively. The median number of immunochemotherapy cycles was 4 (range 2-6), with 45.24% (n = 190) receiving more than 4 cycles. The median rwPFS was 9.1 months (95% CI 8.2-9.7), with a 1-year rwPFS rate of 34.3%, surpassing the 1-year PFS rate of 28.2% reported for the Asian in the ASTRUM-005 study. The median rwPFS was 9.8 months (95% CI 9.1-12.8) in patients without liver metastasis, significantly longer than the 6.7 months (95% CI 6.1-8.7) in patients with liver metastasis ( P < 0.0001). Patients who received radiotherapy also had a significantly longer median rwPFS of 9.8 months (95% CI 8.6-15.1) compared to 8.7 months (95% CI 7.3-9.6) for patients who did not receive radiotherapy ( P = 0.022). Additionally, patients who received > 4 cycles of immunochemotherapy had a median rwPFS of 10.5 months (95% CI 9.3-13.3), which was significantly longer than the 6.6 months (95% CI 5.6-9.1) in patients who received ≤4 cycles ( P < 0.0001). The ORR was 69.71%, and OS was not yet mature. Safety analysis revealed grade ≥3 AEs occurring in 19.05% of the cases. Conclusions: This cohort study reports the real-world survival outcomes of first-line serplulimab-based immunochemotherapy and provides valuable insights in a clinical setting. The study complements the ASTRUM-005 study, offering further evidence in ES-SCLC.
Neuroendocrine features in small cell lung cancer (SCLC) and associations with platinum-sensitivity, metastatic tropism, and overall survival.
Authors: He Weston , Karkash Ahmad , Han Yan , Shi Justin Wang , Marin-Acevedo Julian A. A. , Tran Mya , Shields Misty Dawn 
Published: June 2024

e20113 Background: SCLC heterogeneity can be classified into neuroendocrine (NE) subtypes (ASCL1, NeuroD1, POU2F3, YAP1) with plasticity along its NE spectrum. SCLC harbors conventional NE features on immunohistochemistry (IHC) utilized for diagnosis. In the era of chemoimmunotherapy, insight into the role of conventional SCLC NE IHC with proclivity for metastatic site tropism and therapeutic outcomes, including chemotherapy-free interval (CTFI) and overall survival (OS), has not been studied. Methods: We retrospectively reviewed patients with SCLC who received antineoplastic therapy within the Indiana University (IU) Health System Affiliates from January 2018 to January 2024. Data was stored in an institutional review board approved RedCap. Demographics, treatment, metastases, TTF-1 and NE IHC markers, CTFI, and OS were recorded. IHC expression of Chromogranin A, synaptophysin, and INSM-1 were utilized to classify tumors into NE-low (1-3 negative markers), NE-moderate ( < 3 positive markers), and NE-high (3 positive markers). ANOVA, Kruskal-Wallis, Chi-square, Fisher’s Exact, and log-rank tests were applied. Results: One-hundred and fifty-three patients diagnosed with SCLC were included. Forty-six patients with limited-stage (LS-SCLC, 30.1%) and 107 patients with extensive-stage (ES-SCLC, 69.9%) were identified. Classification by conventional NE IHC included NE-low (n = 41), NE-moderate (n = 18), and NE-high (n = 94), with enrichment for the NE-high category ( P = < 0.0001). No differences were observed in age, sex, smoking history, or stage across NE categories. TTF-1 positivity by IHC independently predicted NE-high ( P = 0.04). The presence of metastases did not significantly differ ( P = 0.93), but trends in enrichment of bone ( P = 0.16) and pancreatic ( P = 0.15) metastases were observed in NE-low. No difference in CTFI was identified between NE cohorts ( P = 0.28) . Median 1-year OS across the NE-low, -moderate, and -high categories was 57.2% (95% CI, 40.4-70.8%), 36.1% (13.7-59.4%), and 53.3% (42.2-63.1%), respectively (log-rank, P = 0.09). Conclusions: Conventional NE IHC fails to predict CTFI in the era of chemoimmunotherapy. SCLC significantly enriches for NE-high. TTF-1 can independently predict NE-high SCLC. Trends in metastatic tropism and shorter 1-year OS in NE-moderate SCLC were identified but limited by sample size. Enrollment expansion is ongoing. Exploration into NE subtypes and multi-omics is in process.
PD-(L)1 inhibitors plus anlotinib: A superior option for second-line treatment of extensive-stage small cell lung cancer.
Authors: Zhang Jian , Sun Yuping , Gao Qin ai 
Published: June 2024

e20117 Background: To evaluate the efficacy of PD-(L)1 inhibitors plus anlotinib as the second-line therapy of extensive-stage small cell lung cancer (ES-SCLC) in the real-world. Methods: EL-SCLC (n = 389) patients who received second-line treatment at 3 cancer centers between January 2008 and January 2023 were retrospectively analyzed. All patients received PD-(L)1 inhibitors in combination with anlotinib and/or chemotherapy(I+A±C), or PD-(L)1 inhibitors in combination with chemotherapy(I+C), or chemotherapy alone (C) as the second-line therapy. The efficacy including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), as well as safety were compared among three groups. Results: The baseline clinical characteristics among 3 groups were largely balanced. Compared with I+C (ORR=17.6%, DCR=68.8%) and C (ORR=18.0%, DCR=53.9%), I+A±C treatment had significantly higher ORR (30.2%) and DCR (82.6%). In addition, treatment with I+A±C generated the longest mPFS (7.2 months) and mOS (33.5 months) compared to that with I+C (mPFS=4.6 months, mOS=19.0 months, both P < 0.001) or C (mPFS=3.4 months, P < 0.01; mOS=18.3 months, P=0.083). However, addition of chemotherapy upon I+A did’t impact PFS (7.2 vs. 7.1 months, P=0.431) and OS (NA vs. 33.5 months, P=0.598). Stratified analysis showed that patients with female gender and oligometastasis (≤ 3 metastasis sites) benefit more from I+A±C treatment compared to male patients and those with polymetastasis, respectively. In addition, the combination of anlotinib with PD-L1 inhibitors generated superior PFS compared to that with PD-1 inhibitors. In patients not receiving PD-(L)1 inhibitors in first-line therapy, I+A±C treatment showed better PFS. The incidence of ≥ grade 3 myelosuppression is much lower in I+A±C group than those in I+C and C groups (3.5% vs 11.2% vs 16.3%, P < 0.01). However, I+A±C treatment generated a higher prevalence of immune-related pneumonia (2.3% vs 0% vs 0%, P < 0.05) and hemoptysis (1.4% vs 0% vs 0.6%, P < 0.05) compared with I+C and C. Conclusions: PD-(L)1 inhibitors plus anlotinib and/or chemotherapy has promising efficacy and manageable toxicity as second-line therpay of ES-SCLC.
Therapeutic stratification for small cell lung cancer with multiplexed proteomic analysis.
Authors: Kim Tae Jung 
Published: June 2024

e20130 Background: Even with standard platinum doublet therapy, most patients with small-cell lung cancer (SCLC) survive less than 1 year. For those with refractory or relapsed disease, second-line, single-agent chemotherapy is recommended. Pre-treated SCLC patients can opt for clinical trials of agents such as temozolomide, fluorouracil (5FU), and antibody-drug conjugates (ADC) targeting the proteins DLL3, CD56, or TROP2. Some of these therapies have produced responses in untreated SCLC. To assess the proportions of patients who would be likely to respond to these therapies, we profiled protein targets in clinical tumor biopsies of SCLC using quantitative mass spectrometry. Methods: Archived tumor samples from 99 SCLC patients were microdissected and solubilized for proteomic quantification of 58 therapeutically relevant biomarkers. In each sample, quantities of tumor protein were compared with pre-defined thresholds based on evidence from clinical studies or quantification limits of proteomic assays. Prevalence and protein expression levels in SCLC were compared with those of other cancer indications analyzed in the same clinical laboratory. Results: 15 of 83 (18%) SCLC tumors had low or absent MGMT protein expression ( < 200 attomoles per microgram [amol/ug]), indicating likely response to temozolomide. 14 of 88 (15%) overexpressed TYMP protein ( > 1335 amol/ug), suggesting a likely response to 5FU. Except for one patient, likely responder to temozolomide or 5FU were mutually exclusive. The prevalence of quantifiable levels of the ADC markers DLL3, TROP2, and CD56 were 43%, 49%, and 97%, respectively. The SCLC tumors expressed a wide range of DLL3 protein (range: 101 – 1201 amol/ug); median expression in SCLC was 2 times higher than in pediatric neurological cancers, while median expression of TROP2 was lower in SCLC than in other indications. CD56 protein levels in SCLC were similar to other indications, but with higher prevalence in SCLC. Conclusions: In patients with SCLC, clinical proteomics identified protein targets of multiple approved and investigational therapies. Multiplexed clinical proteomic testing revealed additional treatment options in SCLC patients, which may be useful in first-line or later-line settings.
Tislelizumab combined with nab-paclitaxel single-agent chemotherapy plus bevacizumab for patients with EGFR-TKIs-resistant advanced NSCLC with ECOG PS 0-2.
Authors: Xie Xiaohong , Zhou MaoLin , Yang YiLin , Lin Xinqing , Xie Zhanhong , Qin Yinyin , Zhang Jiexia , Liu Ming , Li Ru , Zhou ChengZhi 
Published: June 2024

e20138 Background: Treatment options are limited for EGFR-TKIs-resistant advanced NSCLC. A retrospective study from our center showed that ICIs plus platinum-free, single-agent chemotherapy provided progression-free survival, overall response rate benefit, and a low rate of severe AEs in such pts. Meanwhile,there were many NSCLC patients after treatment failure with EGFR-TKIs who ECOG performance status was 2 ,they were excluded from existing prospective studies. This study was designed to further explore the efficacy and safety of Tis plus nab- paclitaxel and Beva foradvancedNSCLCpts with ECOG ps 0-2 failed to EGFR-TKIs. Methods: This is a single-arm, phase II study (NCT04310943). Pts with EGFR mutations who had failed to prior EGFR-TKIs accepted Tis (200mg, d1) ,nab-paclitaxel (100mg/m2, d1,8,15) and Beva (15mg/kg, d1) Q3W for up to 4 cycles, followed by Tis plus Beva (7.5mg/kg) maintenance therapy. Primary endpoints are 6m-PFS% and safety, secondary endpoints include ORR and 1-year OS rate. The planned sample size was 24 with unacceptable control of 25%, an expected value of 55%, a one-sided α of 0.05, and a power of 80%, Simon's two-stage design. Results: The median age was 57 (range: 30-70). Thirteen pts (54.2%) harbored EGFR exon 19del and 9 pts (37.5%) had exon 21 L858R at the initial diagnosis. There were 9 pts (37.5%) with ECOG ps 2 and18 pts (75%) with clinical stage IVB. Twelve pts (50%) had stable brain metastases. Fifteen pts (63.6%) progressed on both 1st/2nd and 3rd EGFR-TKIs. As of Dec30, 2023, The median follow-up time was 22.2 m (95%CI 0-51.1). Among the 21pts in the efficacy analysis set, the median PFS was 6.3 m(95%CI 5.5-7.1), the 6m-PFS % was 61.6%, the 6m-PFS% of pts with ECOG ps 2 was18.1%. The ORR was 61.9%, the median DOR was 4.4 m (95%CI 2.1-6.7), DCR was 100.0%. The median OS was 15.4 (95%CI 10.1-20.7) and 1y-OS% was 59.7%. The safety was manageable: the incidence of ≥grade 3 TRAE was 25%. Conclusions: Tislelizumab combined with nab-paclitaxel plus bevacizumab is effective with a manageable safety profile for EGFR-TKIs resistant NSCLC patients with ECOG ps 0-2. Clinical trial information: NCT04310943 . [Table: see text]
High LDL Particle and APOB Concentrations in Patients With Adrenal Cortical Adenomas
Authors: Sandooja Rashi , Saini Jasmine , Kittithaworn Annop , Gregg-Garcia Raul , Dogra Prerna , Atkinson Elizabeth , Yu Kai , Fell Vanessa , Simha Vinaya , Connelly Margery A , Dullaart Robin P F , Bancos Irina 
Published: June 2024

Abstract

Context
Patients with nonfunctioning adenomas (NFAs), adenomas with mild autonomous cortisol secretion (MACS) and Cushing syndrome (CS) demonstrate an increased cardiovascular risk.

Objective
This work aimed to determine the extent of lipoprotein abnormalities in NFA, MACS, and CS.

Methods
We conducted a single-center, cross-sectional study of patients with NFA (n = 167), MACS (n = 213), CS (n = 142), and referent individuals (n = 202) between January 2015 and July 2022. Triglyceride-rich lipoprotein particles (TRLP), low-density lipoprotein particles (LDLP), high-density lipoprotein particles (HDLP), their subclasses and sizes were measured using nuclear magnetic resonance spectroscopy. Multivariable logistic analyses were adjusted for age, sex, body mass index, smoking, hypertension, diabetes and lipid-lowering drug therapy.

Results
In age- and sex-adjusted analysis, all patients categories demonstrated increased very large TRLP, large TRLP, and greater TRLP size (odds ratio [OR], 1.22-2.08) and total LDLP (OR, 1.22-1.75) and decreased LDL and HDL size compared to referent individuals. In fully adjusted analysis, LDLP concentrations remained elevated in all patient categories (OR, 1.31-1.84). Total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B (ApoB) were also higher in all patient categories in age- and sex-adjusted analysis, with ApoB remaining elevated in all patient categories in fully adjusted analysis. Similar LDLP and ApoB elevations were observed in all patient categories after excluding individuals on lipid-lowering therapy.

Conclusion
Patients with overt, mild, and even absent cortisol excess demonstrate lipoprotein profile abnormalities, in particular, high LDLP and ApoB concentrations, which conceivably contribute to high cardiometabolic risk.
Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients
Authors: Gong Wenfeng , Chen Wenzhe , Dong Jianjun , Liao Lin 
Published: June 2024

Abstract

Aims
Rabson-Mendenhall syndrome (RMS) is a rare autosomal, recessive disorder characterized by severe insulin resistance due to mutations in the insulin receptor (INSR) gene. This study aims to analyze the clinical features and gene mutations in RMS, which have not been extensively studied.

Methods
PubMed, Embase, the China National Knowledge Infrastructure, and Wanfang were searched for “Rabson-Mendenhall syndrome” or “Black acanthosis hirsutism insulin resistance syndrome.”

Results
A total of 42 cases from 33 articles were included. The body mass index ranged from 18.50 to 20.00 kg/m2 with an average of 16.00 kg/m2. There were no overweight (25.00∼29.90 kg/m2) or obese (≥30.00 kg/m2) patients. Acanthosis was present in 29 cases (29/42, 69.05%); growth retardation in 25 cases (25/42, 59.52%); dental anomalies including absence of teeth, crowding, and malocclusion in 23 cases (23/42, 54.76%); and hirsutism in 17 cases (17/42, 40.48%). The average glycosylated hemoglobin was 9.35%, and the average fasting blood-glucose was 8.44 mmol/L; the mean fasting insulin was 349.96 μIU/mL, and the average fasting C-peptide was 6.00 ng/mL. Diabetes was reported in 25 cases (25/33, 75.76%) all of which were diagnosed before 23 years old. All 42 patients had recorded gene mutations, with 22 patients (22/42, 52.38%) having ≥ 2 mutations and 20 cases (20/42, 47.62%) having only 1 mutation. No statistical differences were found in clinical features and laboratory parameters between patients with different mutations.

Conclusion
The study indicates that RMS should be considered in young patients with hyperinsulinemia, hyperglycemia with low weight, acanthosis nigricans, growth retardation, dental anomalies, and hirsutism.
Noxious Nicotine
Authors: Røsstad Hilde Kristin 
Published: June 2024

Abstract
Many horticulturists in the 1950s used nicotine-based products both for personal consumption and for pesticidal application. Growers in postwar Norwegian horticulture were sometimes poisoned by nicotine sulfate, but many also smoked tobacco, and this was widely considered a way to ameliorate the negative effects. This might have made them ambivalent about the risks, even though they knew it could be hazardous in certain dosages. This article explores the ambiguity of the meaning of nicotine in Norwegian horticulture in the 1950s as well as how growers understood the risks tied to chemical components that potentially had other more mundane and culturally endorsed uses.
Altering developmental oxygen exposure influences thermoregulation and flight performance of Manduca sexta
Authors: Wilmsen Sara M. , Dzialowski Edward M. 
Published: June 2024

ABSTRACT
Endothermic, flying insects are capable of some of the highest recorded metabolic rates. This high aerobic demand is made possible by the insect's tracheal system, which supplies the flight muscles with oxygen. Many studies focus on metabolic responses to acute changes in oxygen to test the limits of the insect flight metabolic system, with some flying insects exhibiting oxygen limitation in flight metabolism. These acute studies do not account for possible changes induced by developmental phenotypic plasticity in response to chronic changes in oxygen levels. The endothermic moth Manduca sexta is a model organism that is easy to raise and exhibits a high thorax temperature during flight (∼40°C). In this study, we examined the effects of developmental oxygen exposure during the larval, pupal and adult stages on the adult moth's aerobic performance. We measured flight critical oxygen partial pressure (Pcrit­), thorax temperature and thermoregulating metabolic rate to understand the extent of developmental plasticity as well as effects of developmental oxygen levels on endothermic capacity. We found that developing in hypoxia (10% oxygen) decreased thermoregulating thorax temperature when compared with moths raised in normoxia or hyperoxia (30% oxygen), when moths were warming up in atmospheres with 21–30% oxygen. In addition, moths raised in hypoxia had lower critical oxygen levels when flying. These results suggest that chronic developmental exposure to hypoxia affects the adult metabolic phenotype and potentially has implications for thermoregulatory and flight behavior.