MET exon 14 skipping analogs: Rare but potentially clinically actionable.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3141-3141 ◽  
Author(s):  
Rebecca Feldman ◽  
Michelle Ellis ◽  
Jeffrey Swensen ◽  
Wolfgang Michael Korn ◽  
Zoran Gatalica
Keyword(s):  
Receptor Gene ◽  
Negative Regulation ◽  
Clinicopathological Features ◽  
Smoking History ◽  
Protein Overexpression ◽  
Juxtamembrane Domain ◽  
Oncogenic Signaling ◽  
Small Indels ◽  
Nsclc Patients ◽  
The Impact

3141 Background: The DpY motif within the exon 14 juxtamembrane domain of the MET receptor gene is critical for Cbl-mediated negative regulation. Splicing alterations that delete this residue, known as exon 14 skipping mutations (ex14sk mt), lead to prolonged MET protein stability and oncogenic signaling. Specific mt at the Y1021 (aka 1003) residue are thought to lead to similar effects as ex14sk, but due to their rarity, their role in NSCLC is unknown. We sought to identify and characterize non-ex14sk mt that include/surround Y1021. Methods: Retrospective review of molecular profiles for non-ex14sk mt that include/surround the DpY motif (Y1021) in MET. Two NGS platforms were included: MiSeq (2014-2017; n=2865) and NextSeq (2017-2019; n=6084). Immunohistochemistry (IHC) of cMET (SP44) and co-occurring alterations (EGFR, KRAS, ALK, ROS) were also reviewed. Results: Of 8,949 NSCLC patients with successful NGS of MET gene by either platform, 13 cases or 0.2% were identified to have an alteration within the amino acids of interest. Eleven cases included substitutions at Y1021 (5 phenylalanine, 4 histidine and 3 arginine) and the remaining two cases included small insertion-deletions p.E1017_Y1021delinsH and p.D1020_Y1021delinsV, the latter was later excluded as it co-harbored an ex14sk mt. Conclusions: Similar to patients with ex14sk mt, substitutions and small indels at Y1021 exhibit Clinicopathological features such as previous smoking history and older age, mutual exclusivity with oncogene drivers and MET protein overexpression. The rarity of these analogous ex14sk mt suggests deletions of exon 14 provide cellular advantages beyond Cbl-mediated ubiquitinylation of MET. Although rare, the impact of these mt on efficacy of Met-directed therapy deserves further exploration.[Table: see text]

457 The Impact of PAP Therapy on Hematocrit in OSA and Polycythemia: A Pilot Study

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A180-A181
Author(s):  
Mustafa Jafri ◽  
Gabrielle Rosa-Acosta ◽  
Jose Flores Martinez ◽  
Elizabeth Schofield ◽  
Cy Wilkins ◽  
...  
Keyword(s):  
Intervention Group ◽  
Smoking History ◽  
Event Analysis ◽  
Control Groups ◽  
Testosterone Therapy ◽  
Obstructive Sleep ◽  
Significant Difference ◽  
Testosterone Administration ◽  
And Control ◽  
The Impact

Abstract Introduction Untreated polycythemia leads to complications including thrombosis. Obstructive sleep apnea (OSA) is commonly associated with secondary erythrocytosis, which testosterone therapy can perpetuate. Effects of positive airway pressure (PAP) on elevated hematocrit (HCT) is unknown. We hypothesize PAP adherence can reduce HCT in men with OSA and polycythemia. Methods Retrospective chart review of male outpatients with newly diagnosed OSA and HCT≥45% at or 3 months before polysomnography (PSG) was conducted. Intervention group consisted of patients initiating PAP for OSA. HCT within 6 months of PAP initiation and PSG were recorded for intervention and control groups, respectively. Primary endpoint was time-to-HCT reduction of HCT<50% plus 3% decrease. Cox proportional-hazards analysis was used to assess time-to-HCT response. Demographics, smoking history, testosterone administration, STOP-Bang score, AHI, and PAP compliance data were obtained. Patients excluded if PAP not indicated, or if PSG, PAP compliance, or repeat HCT were unavailable. Results 41 men with OSA had HCT≥45%, of which 16 had HCT≥50%. Median age was 60 years and median BMI was 32 kg/m2. 28 started PAP. 21 met definition for PAP compliance within 6 months. Median AHI of intervention and control groups were 23 and 19 events/hr, respectively. Mean baseline HCT of both groups were 49 and 50, respectively. No significant difference in age, BMI, smoking history, testosterone therapy, and baseline HCT between both groups noted. 39% of intervention group exhibited HCT response at 1 or more longitudinal assessments, versus 38% of control. Intervention group had higher mean STOP-Bang than control (mean 5.9 vs. 4.6, p=0.01) and trended towards higher mean baseline AHI (27.4 vs. 19.0, p= 0.06). Time-to-event analysis controlling for STOP-Bang and AHI demonstrated PAP was not associated with time-to-HCT response (HR = 1.3, 95% CI = 0.4–4.4). In moderate-severe OSA patients, 40% of intervention group had HCT response compared to 14% of control, though difference was not significant (HR = 2.5, 95% CI = 0.3–20.0). Conclusion Moderate-severe OSA patients trended towards reduction in HCT with PAP, although not statistically significant. Testosterone administration did not affect HCT response to PAP in this cohort. Larger studies are required to determine HCT response to PAP in these patients. Support (if any):

scholarly journals Clinical impact of subclonal EGFR T790M mutations in advanced-stage EGFR-mutant non-small-cell lung cancers

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tereza Vaclova ◽  
Ursula Grazini ◽  
Lewis Ward ◽  
Daniel O’Neill ◽  
Aleksandra Markovets ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Small Cell ◽  
Phase Iii ◽  
Advanced Stage ◽  
Small Cell Lung ◽  
Nsclc Patients ◽  
The Impact ◽  
Egfr T790m

AbstractAdvanced non-small-cell lung cancer (NSCLC) patients with EGFR T790M-positive tumours benefit from osimertinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). Here we show that the size of the EGFR T790M-positive clone impacts response to osimertinib. T790M subclonality, as assessed by a retrospective NGS analysis of 289 baseline plasma ctDNA samples from T790M‐positive advanced NSCLC patients from the AURA3 phase III trial, is associated with shorter progression-free survival (PFS), both in the osimertinib and the chemotherapy-treated patients. Both baseline and longitudinal ctDNA profiling indicate that the T790M subclonal tumours are enriched for PIK3CA alterations, which we demonstrate to confer resistance to osimertinib in vitro that can be partially reversed by PI3K pathway inhibitors. Overall, our results elucidate the impact of tumour heterogeneity on response to osimertinib in advanced stage NSCLC patients and could help define appropriate combination therapies in these patients.

scholarly journals Dopamine D4 receptor gene polymorphism (DRD4 VNTR) moderates real-world behavioural response to the food retail environment in children

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Catherine Paquet ◽  
Andre Krumel Portella ◽  
Spencer Moore ◽  
Yu Ma ◽  
Alain Dagher ◽  
...  
Keyword(s):  
Energy Density ◽  
Food Environment ◽  
Local Food ◽  
Receptor Gene ◽  
Environment Interaction ◽  
Dopamine D4 Receptor ◽  
Vntr Polymorphism ◽  
Food Retailers ◽  
D4 Receptor ◽  
The Impact

Abstract Background Evidence for the impact of the food retailing environment on food-related and obesity outcomes remains equivocal, but only a few studies have attempted to identify sub-populations for whom this relationship might be stronger than others. Genetic polymorphisms related to dopamine signalling have been associated with differences in responses to rewards such as food and may be candidate markers to identify such sub-populations. This study sought to investigate whether genetic variation of the dopamine D4 receptor gene (DRD4 exon III 48 bp VNTR polymorphism) moderated the association between local exposure to food retailers on BMI and diet in a sample of 4 to12-year-old children. Methods Data collected from a birth cohort and a community cross-sectional study conducted in Montreal, Canada, were combined to provide DRD4 VNTR polymorphism data in terms of presence of the 7-repeat allele (DRD4-7R) for 322 children aged between 4 and 12 (M (SD): 6.8(2.8) y). Outcomes were Body Mass Index (BMI) for age and energy density derived from a Food Frequency Questionnaire. Food environment was expressed as the proportion of local food retailers classified as healthful within 3 km of participants’ residence. Linear regression models adjusted for age, sex, income, cohort, and geographic clustering were used to test gene*environment interactions. Results A significant gene*food environment interaction was found for energy density with results indicating that DRD4-7R carriers had more energy dense diets than non-carriers, with this effect being more pronounced in children living in areas with proportionally more unhealthy food retailers. No evidence of main or interactive effects of DRD4 VNTR and food environment was found for BMI. Conclusions Results of the present study suggest that a genetic marker related to dopamine pathways can identify children with potentially greater responsiveness to unhealthy local food environment. Future studies should investigate additional elements of the food environment and test whether results hold across different populations.

Successful treatment of pulmonary lymphangitic carcinomatosis by anlotinib in 14 Chinese patients with advanced non-small cell lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21064-e21064
Author(s):  
Shencun Fang ◽  
Wanwan Cheng ◽  
Yingming Zhang ◽  
Haitao Zhang ◽  
Si Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Lymphatic Metastasis ◽  
Small Cell ◽  
Smoking History ◽  
Wild Type ◽  
Small Cell Lung ◽  
The Impact ◽  
Lymphangitic Carcinomatosis

e21064 Background: Pulmonary lymphangitic carcinomatosis (PLC) occurs in 6%-8% of intrathoracic metastases among malignant tumor. The median survival was only 2.0 months from time of pulmonary symptoms to death in cases during 2000-2018, which is a poor prognosis. Effective interventions were needed besides standard chemotherapy and symptomatic support. Anlotinib showed a critical effect on lymphangiogenesis, and lymphatic metastasis in mouse models of lung adenocarcinoma, it might be a therapeutic option for tumor lymphatic metastasis. In this study, we retrospectively analyzed the efficacy and safety of anlotinib for PLC in patients with Non-small Cell Lung Cancer (NSCLC). Methods: We retrospectively investigated NSCLC patients with PLC at our hospital between May 2018 and November 2020, who received anlotinib monotherapy or combined therapy for PLC. Data were analyzed for progression-free survival (PFS), overall survival (OS), objective response rate(ORR), disease control rate(DCR) and adverse events (AE). The impact of clinical and genomic factors on PFS and OS were also assessed. Results: A total of 14 patients were enrolled with a median age of 64 years. 10(71.4%) were male, 4(28.6%) has smoking history, 10(71.4%) of patients had a performance status of 2-3. 9, 3, 2 patients had TP53 mutation, EGFR mutation, ALK fusion respectively. 9(64.3%) patients received anlotinib monotherapy. Of 14 patients, 8 achieved partial response (PR), 5 presented stable disease (SD), 1 had progressed disease. The ORR and DCR were 57.1% and 92.9% respectively. The median PFS was 3.1 months (95% CI: 2.0-4.2), the median OS for 1, 2, ≥3 line were 13 months, 7.2 months, 5.2 months, respectively. Median PFS and OS (≥3 line) were significantly longer for patients with TP53-mutant tumors compared with those with TP53–wild-type tumors (median PFS: 7 vs. 1.1 months, median OS (≥3 line): 6.8 vs. 1.9 months). No difference of PFS and OS (≥3 line) was found between EGFR or ALK alteration and the corresponding wild type patients. The most frequently reported AEs were high blood pressure (11, 78.6%), hand foot syndrome (6, 42.9%), diarrhea (5, 35.7%), fatigue (4, 28.6%), hoarseness (3, 21.4%), proteinuria (2, 14.3%) and stomatitis (2, 14.3%). Conclusions: Anlotinib presented favorable efficacy in patients with pulmonary lymphangitic carcinomatosis and conferred considerable survival benefit compared with previous studies, especially in patients harboring TP53 mutations. The AEs were manageable. These indicated that anlotinib can be a promising therapeutic treatment of PLC. More clinical data is needed to validate this finding.

Association of statins and nivolumab activity in patients with metastatic renal cell carcinoma (mRCC): Results from the phase II nivoren—GETUG AFU 26 trial.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 359-359
Author(s):  
Emeline Colomba ◽  
Ronan Flippot ◽  
Cécile Dalban ◽  
Sylvie Negrier ◽  
Christine Chevreau ◽  
...  
Keyword(s):  
Phase Ii ◽  
Immune Modulation ◽  
Performance Status ◽  
Objective Response ◽  
Progression Free Survival ◽  
Population Based ◽  
Metabolic Reprogramming ◽  
Oncogenic Signaling ◽  
Grade 3 ◽  
The Impact

359 Background: Statins are HMG-CoA inhibitors that regulate several mechanisms involved in tumor growth, including mitochondrial metabolism, activation of oncogenic signaling pathways, and immune modulation. Population-based studies showed that statin intake may be negatively associated with RCC onset. The impact of statins on response to immunotherapy in mRCC is unknown. Herein we study the association between statin administration and outcomes in patients with mRCC treated with nivolumab in the NIVOREN-GETUG AFU 26 phase II trial (NCT03013335). Methods: Patients with mRCC who failed previous VEGFR inhibitors were included. We assessed nivolumab activity, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) according to statin intake at baseline. Toxicity was assessed using CTCAE v4.0. Results: Overall,133 patients were treated with statins at baseline among 702 evaluable for concomitant therapies (19%). Among them, median age was 68 (49-90), 84% were male, 85% had a performance status ≥ 80%, 42% were overweight and 20% obese. Patients treated with statins had mostly good (23%) or intermediate (58%) IMDC risk, 64% had grade 3 or 4 tumors, and nivolumab was given in a third line setting or more in 55%. Median follow-up was 23.9 months (95%CI 23.0-24.5) in the overall cohort. The ORR was 26% in patients treated with statins, PFS 5.0 months (CI95% 3.0 – 5.5), OS 27.9 months (CI95% 19.4-30.3). Outcomes of patients with or without statins did not differ significantly. Similar rates of grade 3-5 TRAE were reported in patients with (20%) or without (18%) statin intake. Conclusions: This is the first study to evaluate statin intake and outcomes with nivolumab in patients with mRCC. Despite numerically higher ORR, statins were not significantly associated with improved outcomes. These data require other analyzes considering other factors such as BMI and other comorbidities. Further studies may help better understand the interplay between immunity and metabolic reprogramming in RCC.

scholarly journals Clinical Significance of SERPINA1 Gene and Its Encoded Alpha1-antitrypsin Protein in NSCLC

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1306 ◽  
Author(s):  
Ercetin ◽  
Richtmann ◽  
Delgado ◽  
Gomez-Mariano ◽  
Wrenger ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Survival Rates ◽  
Active Role ◽  
Serum Levels ◽  
Serum Samples ◽  
Serpina1 Gene ◽  
Alpha1 Antitrypsin ◽  
Nsclc Patients ◽  
The Impact

Abstract: High expression of SERPINA1 gene encoding acute phase protein, alpha1-antitrypsin (AAT), is associated with various tumors. We sought to examine the significance of SERPINA1 and AAT protein in non-small-cell lung cancer (NSCLC) patients and NSCLC cell lines. Tumor and adjacent non-tumor lung tissues and serum samples from 351 NSCLC patients were analyzed for SERPINA1 expression and AAT protein levels. We also studied the impact of SERPINA1 expression and AAT protein on H1975 and H661 cell behavior, in vitro. Lower SERPINA1 expression in tumor but higher in adjacent non-tumor lung tissues (n = 351, p = 0.016) as well as higher serum levels of AAT protein (n = 170, p = 0.033) were associated with worse survival rates. Specifically, in NSCLC stage III patients, higher blood AAT levels (>2.66 mg/mL) correlated with a poor survival (p = 0.002). Intriguingly, levels of serum AAT do not correlate with levels of C-reactive protein, neutrophils-to-leukocyte ratio, and do not correlate with SERPINA1 expression or AAT staining in the tumor tissue. Additional experiments in vitro revealed that external AAT and/or overexpressed SERPINA1 gene significantly improve cancer cell migration, colony formation and resistance to apoptosis. SERPINA1 gene and AAT protein play an active role in the pathogenesis of lung cancer and not just reflect inflammatory reaction related to cancer development.

scholarly journals PD-L1 is a Prognostic Biomarker in Resected NSCLC Patients with Moderate/high Smoking History and Elevated Serum SCCA Level

2017 ◽  
Vol 8 (16) ◽  
pp. 3251-3260 ◽  
Author(s):  
Lianjing Cao ◽  
Xinyue Wang ◽  
Shouying Li ◽  
Qiongjie Zhi ◽  
Yuqian Wang ◽  
...  
Keyword(s):  
Prognostic Biomarker ◽  
Elevated Serum ◽  
Smoking History ◽  
Resected Nsclc ◽  
Nsclc Patients

scholarly journals How Can E-Cigarette Fear Appeals Improve the Perceived Threat, Fear, Anger, and Protection Motivation of Young People

2021 ◽  
Vol 12 ◽  
Author(s):  
Chengzhi Sun ◽  
Fangfei Wang ◽  
Mengmeng Jiang
Keyword(s):  
Young People ◽  
Process Model ◽  
Good Control ◽  
Fear Appeals ◽  
Smoking History ◽  
Protection Motivation ◽  
Fear Appeal ◽  
People’S Perception ◽  
Young Smokers ◽  
The Impact

The lack of awareness regarding the risks of e-cigarettes and the misleading business propaganda caused an increase in the popularity of e-cigarettes among young people. The effective communication of the risks associated with e-cigarettes is an important part of current work to control their usage, and the use of fear appeals is an effective method to achieve good control. Based on the Extended Parallel Process Model (EPPM) and Appraisal-Tendency Framework (ATF), this article presents a 2 × 2 control experiment to test the impact of fear appeals on the perception of risk, emotions, and behavioral motivation of young people aged 35 and less. A total of 333 valid samples of adolescents and young adults were included to investigate the different response paths to fear appeals among young people of different age, sex and smoking history. The results show that high-threat, high-efficacy fear appeals are able to: (1) significantly increase young people’s perception of the e-cigarette-associated threats, (2) trigger fear and anger amongst young people, and (3) stimulate their self-protection motivation. Fear appeals do not have an impact on young people’s perception of efficacy, regardless of their level of threat and efficacy. High fear appeals can also increase young people’s perception of threat, which in turn enhances their anger and protection motivation. Furthermore, while this type of fear appeal can enhance young women’s perception of efficacy, it cannot enhance the perception of e-cigarette risks in adolescents, young men and young smokers, regardless of their level of threat and efficacy. Young non-smokers have a higher perception of the risks involved in the use of e-cigarettes compared with young smokers.

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