RESUMO
Lung cancer is one of the most aggressive tumour types. Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small-cell lung cancer (NSCLC)1. However, such oncogenic drivers are not found in 25-40% of cases of lung adenocarcinoma, the most common histological subtype of NSCLC2. Here we identify a novel fusion transcript of CLIP1 and LTK using whole-transcriptome sequencing in a multi-institutional genome screening platform (LC-SCRUM-Asia, UMIN000036871). The CLIP1-LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive with other known oncogenic drivers. We show that kinase activity of the CLIP1-LTK fusion protein is constitutively activated and has transformation potential. Treatment of Ba/F3 cells expressing CLIP1-LTK with lorlatinib, an ALK inhibitor, inhibited CLIP1-LTK kinase activity, suppressed proliferation and induced apoptosis. One patient with NSCLC harbouring the CLIP1-LTK fusion showed a good clinical response to lorlatinib treatment. To our knowledge, this is the first description of LTK alterations with oncogenic activity in cancers. These results identify the CLIP1-LTK fusion as a target in NSCLC that could be treated with lorlatinib.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Transformação Celular Neoplásica/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Receptores Proteína Tirosina Quinases/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 15/genética , Humanos , Lactamas/farmacologia , Lactamas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Camundongos Nus , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Teleost oocytes are surrounded by a structure called chorion or egg envelopes, which is composed of zona pellucida (ZP) proteins. As a result of the gene duplication in teleost, the expression site of the zp genes, coding the major component protein of egg envelopes, changed from the ovary to the maternal liver. In Euteleostei, there are three liver-expressed zp genes, named choriogenin (chg) h, chg hm, and chg l, and the composition of the egg envelope is mostly made up of these Chgs. In addition, ovary-expressed zp genes are also conserved in the medaka genomes, and their proteins have also been found to be minor components of the egg envelopes. However, the specific role of liver-expressed versus ovary-expressed zp genes was unclear. In the present study, we showed that ovary-synthesized ZP proteins first form the base layer of the egg envelope and then Chgs polymerize inwardly to thicken the egg envelope. To analyze the effects of dysfunction of the chg gene, we generated some chg knockout medaka. All knockout females failed to produce normally fertilized eggs by the natural spawning. The egg envelopes lacking Chgs were significantly thinner, but layers formed by ZP proteins synthesized in the ovary were found in the thin egg envelope of knockout as well as wildtype eggs. These results suggest that the ovary-expressed zp gene is well conserved in all teleosts, including those species in which liver-derived ZP proteins are the major component, because it is essential for the initiation of egg envelope formation.
Assuntos
Proteínas de Peixes , Fígado , Oryzias , Ovário , Glicoproteínas da Zona Pelúcida , Animais , Feminino , Sequência de Aminoácidos , Fígado/metabolismo , Oryzias/genética , Oryzias/metabolismo , Ovário/anatomia & histologia , Ovário/metabolismo , Zona Pelúcida/química , Zona Pelúcida/metabolismo , Glicoproteínas da Zona Pelúcida/genética , Glicoproteínas da Zona Pelúcida/metabolismo , Técnicas de Inativação de Genes , Expressão Gênica , Óvulo/citologia , Óvulo/metabolismoRESUMO
For the evaluation of novel therapeutic agents for diabetic kidney disease (DKD), it is desirable to examine their efficacy in animal models by using the glomerular filtration rate (GFR) as an index. For this purpose, animal models that demonstrate a short-term GFR decline because of disease progression are required. Therefore, we aimed to develop such an animal model of DKD by using obese type 2 diabetic spontaneously diabetic Torii (SDT) fatty rats treated with salt loading by drinking water containing sodium chloride with or without unilateral nephrectomy. As a result, we have found that 0.3% salt loading with unilateral nephrectomy or 0.8% salt loading alone caused a rapid GFR decline, hypertension and rapid development of tubulointerstitial fibrosis. Moreover, the addition of losartan to a mixed diet suppressed the GFR decline in SDT fatty rats treated with 0.3% salt loading with unilateral nephrectomy. These results suggest that the model of SDT fatty rats treated with 0.3% salt loading and unilateral nephrectomy could be used as a hypertensive DKD model for evaluating therapeutic agents based on suppression of GFR decline.
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Hipertensão , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/cirurgia , Nefropatias Diabéticas/etiologia , Modelos Animais de Doenças , Feminino , Taxa de Filtração Glomerular , Humanos , Hipertensão/complicações , Hipertensão/cirurgia , Masculino , Nefrectomia/efeitos adversos , Obesidade/complicações , Obesidade/cirurgia , Ratos , Cloreto de Sódio , Cloreto de Sódio na DietaRESUMO
BACKGROUND: Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown. METHODS: Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2-4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety. RESULTS: Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3-5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations. CONCLUSION: Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
BACKGROUND: A subset analysis of the CA031 trial showed significant improvement in the overall response rate after administration of carboplatin plus weekly albumin-bound paclitaxel compared to carboplatin plus paclitaxel for squamous cell carcinoma of the lung (SQ). We conducted this phase II study to compare carboplatin plus weekly albumin-bound paclitaxel (CnP) to cisplatin plus gemcitabine (CG), a standard regimen for SQ. METHODS: Chemotherapy-naïve patients with SQ were randomly assigned to receive cisplatin (80 mg/m2) on day 1 plus gemcitabine (1000 mg/m2) on days 1 and 8 every 3 weeks or carboplatin (area under the curve: 6 mg/mL/min) on day 1 plus nab-paclitaxel (75 mg/m2) on days 1, 8, and 15 every 3 weeks. The primary endpoint was overall response rate. The secondary endpoints were progression-free survival, overall survival, disease control rate, and toxicity. RESULTS: Between June 2013 and October 2018, 71 patients were enrolled and assigned to either the CG arm (n = 35) or the CnP arm (n = 36) of the study. The overall response rate was 43% [95% confidence interval (CI) 27.3-58.5] in the CG arm and 47% (95% CI 31.7-62.7) in the CnP arm. Although drug combination efficacies did not differ, there were differences in toxicity: hematologic toxicities (leukopenia, neutropenia, and thrombocytopenia) were found mostly in the CG arm, whereas anemia and sensory neuropathy were more common in the CnP arm. CONCLUSIONS: CnP had similar response as CG despite being a carboplatin-based regimen and toxicities differed between arms. Regarding ORR, CnP was comparable to CG for SQ.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Pulmonares , Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/efeitos adversos , Desoxicitidina/análogos & derivados , Humanos , Japão , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/efeitos adversos , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: Resistance to first-generation or second-generation EGFR tyrosine kinase inhibitor (TKI) monotherapy develops in almost half of patients with EGFR-positive non-small-cell lung cancer (NSCLC) after 1 year of treatment. The JO25567 phase 2 trial comparing erlotinib plus bevacizumab combination therapy with erlotinib monotherapy established the activity and manageable toxicity of erlotinib plus bevacizumab in patients with NSCLC. We did a phase 3 trial to validate the results of the JO25567 study and report here the results from the preplanned interim analysis. METHODS: In this prespecified interim analysis of the randomised, open-label, phase 3 NEJ026 trial, we recruited patients with stage IIIB-IV disease or recurrent, cytologically or histologically confirmed non-squamous NSCLC with activating EGFR genomic aberrations from 69 centres across Japan. Eligible patients were at least 20 years old, and had an Eastern Cooperative Oncology Group performance status of 2 or lower, no previous chemotherapy for advanced disease, and one or more measurable lesions based on Response Evaluation Criteria in Solid Tumours (1.1). Patients were randomly assigned (1:1) to receive oral erlotinib 150 mg per day plus intravenous bevacizumab 15 mg/kg once every 21 days, or erlotinib 150 mg per day monotherapy. Randomisation was done by minimisation, stratified by sex, smoking status, clinical stage, and EGFR mutation subtype. The primary endpoint was progression-free survival. This study is ongoing; the data cutoff for this prespecified interim analysis was Sept 21, 2017. Efficacy was analysed in the modified intention-to-treat population, which included all randomly assigned patients who received at least one dose of treatment and had at least one response evaluation. Safety was analysed in all patients who received at least one dose of study drug. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000017069. FINDINGS: Between June 3, 2015, and Aug 31, 2016, 228 patients were randomly assigned to receive erlotinib plus bevacizumab (n=114) or erlotinib alone (n=114). 112 patients in each group were evaluable for efficacy, and safety was evaluated in 112 patients in the combination therapy group and 114 in the monotherapy group. Median follow-up was 12·4 months (IQR 7·0-15·7). At the time of interim analysis, median progression-free survival for patients in the erlotinib plus bevacizumab group was 16·9 months (95% CI 14·2-21·0) compared with 13·3 months (11·1-15·3) for patients in the erlotinib group (hazard ratio 0·605, 95% CI 0·417-0·877; p=0·016). 98 (88%) of 112 patients in the erlotinib plus bevacizumab group and 53 (46%) of 114 patients in the erlotinib alone group had grade 3 or worse adverse events. The most common grade 3-4 adverse event was rash (23 [21%] of 112 patients in the erlotinib plus bevacizumab group vs 24 [21%] of 114 patients in the erlotinib alone group). Nine (8%) of 112 patients in the erlotinib plus bevacizumab group and five (4%) of 114 patients in the erlotinib alone group had serious adverse events. The most common serious adverse events were grade 4 neutropenia (two [2%] of 112 patients in the erlotinib plus bevacizumab group) and grade 4 hepatic dysfunction (one [1%] of 112 patients in the erlotinib plus bevacizumab group and one [1%] of 114 patients in the erlotinib alone group). No treatment-related deaths occurred. INTERPRETATION: The results of this interim analysis showed that bevacizumab plus erlotinib combination therapy improves progression-free survival compared with erlotinib alone in patients with EGFR-positive NSCLC. Future studies with longer follow-up, and overall survival and quality-of-life data will be required to further assess the efficacy of this combination in this setting. FUNDING: Chugai Pharmaceutical.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/efeitos adversos , Feminino , Humanos , Japão , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Transdução de Sinais , Fatores de TempoRESUMO
Proper attachment of microtubules to kinetochores is essential for accurate chromosome segregation. Here, we report a novel protein involved in kinetochore-microtubule attachment, chromosome alignment-maintaining phosphoprotein (CAMP) (C13orf8, ZNF828). CAMP is a zinc-finger protein containing three characteristic repeat motifs termed the WK, SPE, and FPE motifs. CAMP localizes to chromosomes and the spindle including kinetochores, and undergoes CDK1-dependent phosphorylation at multiple sites during mitosis. CAMP-depleted cells showed severe chromosome misalignment, which was associated with the poor resistance of K-fibres to the tension exerted upon establishment of sister kinetochore bi-orientation. We found that the FPE region, which is responsible for spindle and kinetochore localization, is essential for proper chromosome alignment. The C-terminal region containing the zinc-finger domains negatively regulates chromosome alignment, and phosphorylation in the FPE region counteracts this regulation. Kinetochore localization of CENP-E and CENP-F was affected by CAMP depletion, and by expressing CAMP mutants that cannot functionally rescue CAMP depletion, placing CENP-E and CENP-F as downstream effectors of CAMP. These data suggest that CAMP is required for maintaining kinetochore-microtubule attachment during bi-orientation.
Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Cinetocoros/metabolismo , Microtúbulos/metabolismo , Fosfoproteínas/metabolismo , Proteínas Cromossômicas não Histona/análise , Proteínas Cromossômicas não Histona/genética , Cromossomos Humanos , Células HeLa , Humanos , Cinetocoros/ultraestrutura , Proteínas Mad2 , Microtúbulos/ultraestrutura , Mitose , Fosfoproteínas/análise , Fosfoproteínas/genética , Proteínas/metabolismo , Interferência de RNA , Fuso Acromático/ultraestruturaRESUMO
BACKGROUND: Standard first-line chemotherapy for elderly non-small cell lung cancer (NSCLC) patients has been monotherapy with vinorelbine or gemcitabine. Docetaxel has also been considered as an alternative option for the elderly population in Japan. We have previously demonstrated the high efficacy of carboplatin plus weekly paclitaxel for elderly NSCLC patients. Consequently, we conducted a randomized phase II study to select the proper regimen for a future phase III trial. METHODS: Eligible patients were aged 70 years or older with newly diagnosed advanced NSCLC. Patients were randomly assigned either to a combination of carboplatin (area under the curve: 6 mg/mL per minute) with weekly paclitaxel (70 mg/m²) (CP regimen) or to single-agent docetaxel (60 mg/m²). The primary endpoint of this study was objective response rate. Secondary endpoints were progression-free survival, overall survival, and toxicity profile. RESULTS: Among 83 eligible patients (41 to CP, 42 to docetaxel), the objective response rates were 54% (95% confidence interval: 39%-69%) and 24% (95% confidence interval: 11%-37%) and median progression-free survival was 6.6 months and 3.5 months in the CP arm and the docetaxel arm, respectively. Severe neutropenia, febrile neutropenia, and nausea were significantly frequent in the docetaxel arm, whereas toxicities in the CP arm were generally moderate. One treatment-related death was observed in the docetaxel arm. CONCLUSION: The CP regimen achieved higher activity with less toxicity than single-agent docetaxel. Considering the results of this phase II trial and the IFCT-0501 trial, we have selected the CP regimen for a future phase III trial in elderly patients with advanced NSCLC.
Assuntos
Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/uso terapêutico , Taxoides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Docetaxel , Esquema de Medicação , Humanos , Japão , Neoplasias Pulmonares/mortalidade , Paclitaxel/efeitos adversos , Taxoides/efeitos adversos , Resultado do TratamentoRESUMO
Introduction: Immune checkpoint inhibitor (ICI)-based treatment has become standard treatment for patients with advanced NSCLC. We aimed to determine the survival benefit of upfront radiotherapy for brain metastases (BMs) in patients with NSCLC who received ICI alone (ICI-alone) or with chemotherapy (ICI-chemo). Methods: This study included consecutive patients with NSCLC having BMs who received ICI alone or ICI-chemo at 50 institutes between February 2017 and September 2021. The presence of BMs was confirmed by imaging before treatment. Treatment outcomes were compared between patients who did and did not receive upfront radiotherapy for BMs. Potential confounding factors were adjusted between the groups through inverse probability treatment weighting (IPTW) analysis and overlap weighting (OW) analysis with propensity scores. Results: Patients were grouped as ICI-alone cohort, 224 patients (upfront-radiotherapy group, 135 patients; no-radiotherapy group, 89 patients) and ICI-chemo cohort, 367 patients (upfront-radiotherapy group, 212 patients; no-radiotherapy group, 155 patients). In the ICI-alone cohort, the overall survival of the upfront-radiotherapy group was significantly longer than that of the no-radiotherapy group (IPTW-adjusted hazards ratio [HR] = 0.45 [95% confidence interval [CI]: 0.29-0.72], OW-adjusted HR = 0.52 [95% CI: 0.35-0.77]). In contrast, in the ICI-chemo cohort, the OS of the upfront-radiotherapy group was not significantly different from that of the no-radiotherapy group (IPTW-adjusted HR = 1.02 [95% CI: 0.70-1.48], OW-adjusted HR = 0.93 [95% CI: 0.65-1.33]). Conclusions: Upfront radiotherapy for BMs was associated with longer overall survival in patients with NSCLC who received ICI alone; however, it did not exhibit survival benefits in the patients who received ICI-chemo.
RESUMO
BACKGROUND: The risk and survival of patients with non-small cell lung cancer (NSCLC) with pre-existing autoimmune disorders (AIDs) receiving immune checkpoint blockade (ICB) therapy have not been clearly established. PATIENTS AND METHODS: This multi-institutional, retrospective cohort study was conducted in collaboration with 20 centers in Japan. RESULTS: In total, 229 patients with advanced or recurrent NSCLC and pre-existing AID, with or without ICB treatment from January 2010-February 2020, were included and analyzed. Among 69 patients who received ICB, 2 received two lines of ICBs with a total of 71 ICB treatments; 57 (80.3 %) and 14 (19.7 %) patients received ICB monotherapy and combination therapy, respectively. AID flares were observed in 18 patients (25.4 %, 95 % confidence interval [CI], 15.8-37.1 %) receiving ICB. AID exacerbations were more likely when NSCLC was diagnosed less than 1 year after the AID diagnosis (odds ratio 5.26 [95 % CI, 1.40-21.61]; P = 0.016). Immune-related adverse events were observed in 32 patients (45.1 %, 95 % CI, 33.2-57.3 %); 17 had grade 3 or higher. The safety profile of combination immunotherapy was not significantly different from that of the monotherapy. After inverse probability weighting, the use of ICB prolonged survival (hazard ratio 0.43 [95 % CI, 0.26-0.70]; P = 0.0006). CONCLUSIONS: These findings revealed a novel risk factor for AID flares following ICB treatment, that is the diagnosis of NSCLC within 1 year of AID diagnosis, and showed that ICBs may improve survival in this population. These results support the utilization of ICB in patients with NSCLC and pre-existing AID.
Assuntos
Doenças Autoimunes , Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Estudos Retrospectivos , Feminino , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Idoso , Doenças Autoimunes/mortalidade , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/complicações , Pessoa de Meia-Idade , Análise de Sobrevida , Japão/epidemiologia , Idoso de 80 Anos ou mais , Taxa de Sobrevida , AdultoRESUMO
Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain.
Assuntos
Fármacos Antiobesidade/química , Benzimidazóis/química , Receptores de Neuropeptídeo Y/agonistas , Sulfonas/química , Administração Oral , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/uso terapêutico , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Meia-Vida , Camundongos , Obesidade/tratamento farmacológico , Ratos , Receptores de Neuropeptídeo Y/metabolismo , Relação Estrutura-Atividade , Sulfonas/farmacologia , Sulfonas/uso terapêutico , Aumento de Peso/efeitos dos fármacosRESUMO
OBJECTIVE: Cochlear implantation (CI) for the treatment of single-sided deafness (SSD) is a relatively new treatment modality. Although comparing the effectiveness of CI and contralateral routing of signal (CROS) hearing aids (HAs) is important, very few reports on this topic exist. In this study, objective assessments and subjective assessments were conducted to determine which SSD individuals would prefer CI or CROS HAs. MATERIALS AND METHODS: Objective assessments (speech perception and sound localization) and subjective assessments (Hearing Handicap Inventory for Adults (HHIA), Abbreviated Profile of Hearing Aid Benefit (APHAB), MOS Short-Form 36-Item Health Survey version 2 (SF-36v2)) were performed on 87 SSD patients. Of the 87 SSD patients, 33 patients hoped for CROS HAs, and 17 patients hoped for CI. The CI group underwent subjective and objective assessments at 6 and 12 months postoperatively. The CROS HAs group underwent objective assessments at 1 month after wearing CROS HAs. RESULTS: After the intervention, the localization ability was significantly improved in the CI group (p < 0.05) with no significant improvement in that of the CROS HAs group (p = 0.48). No significant improvement in speech perception in noise was observed in the CROS (Signal-to-Noise ratio + 10, p = 0.08; SN + 0, p = 0.17); however, a significant improvement in the CI group was observed at 12 months postoperatively. The APHAB subscale "background noise" and SF-36v2 health concepts of role-physical, general health, vitality, role-emotional, and mental health were significantly higher in the CI group. CONCLUSION: CI was superior to CROS HAs in speech perception in terms of noise and sound localization. Patients with postlingual acute-onset hearing loss and more handicaps and a more positive view of their hearing loss possibly tend to choose CI.
Assuntos
Implante Coclear , Implantes Cocleares , Surdez , Auxiliares de Audição , Perda Auditiva Unilateral , Perda Auditiva , Localização de Som , Percepção da Fala , Adulto , Humanos , Estudos Prospectivos , Surdez/cirurgia , Surdez/reabilitação , Perda Auditiva Unilateral/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Osimertinib was first approved for the treatment of non-small cell lung cancer (NSCLC) in patients who have developed the epidermal growth factor receptor (EGFR) T790M mutation after treatment with EGFR tyrosine kinase inhibitors (TKIs). We routinely evaluated the plasma of NSCLC patients with the T790M mutation to more rapidly detect an increase in disease activity and resistance to treatment. METHODS: Eligible patients received osimertinib after resistance to the first- or second-generation of EGFR-TKIs in NSCLC harboring T790M mutation detectable in tumor tissue or plasma. Plasma samples were collected every 8 weeks during osimertinib treatment. The plasma analysis was performed using an improved PNA-LNA PCR clamp method. We tested samples for a resistance mechanism, including EGFR-activating, T790M, and C797S mutations, and assessed the association between the mutations and osimertinib treatment. RESULTS: Of the 60 patients enrolled in the study, 58 were eligible for this analysis. In plasma collected before osimertinib treatment, activating mutations were detected in 47 of 58 patients (81.0%) and T790M was detected in 44 patients (75.9%). Activating mutations were cleared in 60.9% (28/46) and T790M was cleared in 93.0% (40/43). Of these, 71.4% (20/28) of activating mutations and 87.5% (35/40) of T790M mutation were cleared within 8 weeks of treatment. The total response rate (RR) was 53.4% (31/58). The median duration of treatment was 259 days, with a trend toward longer treatment duration in patients who experienced the clearance of activating mutations with osimertinib. At the time of disease progression during osimertinib treatment, C797S was detected in 3 of 37 patients (8.1%). CONCLUSION: Plasma EGFR mutation analysis was effective in predicting the effect of osimertinib treatment.
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BACKGROUND/AIM: Osimertinib is currently used as a first-line treatment for EGFR-mutated non-small cell lung cancer, and the emergence of drug resistance poses a substantial challenge. Liquid biopsy with a multi-gene panel can examine both the molecular mechanisms and possibility of early resistance diagnosis. PATIENTS AND METHODS: We used a molecular barcode library construction kit (Archer® LiquidPlex™) that allowed the analysis of multiple cancer-related genes using cell-free DNA from the plasma samples of patients. We collected plasma from 17 consecutive patients with lung adenocarcinoma at our hospital at various time points and cell-free DNA was extracted and subjected to LiquidPlex analysis. RESULTS: Plasma DNA concentration was not associated with the presence or absence of resistance to osimertinib. The pathological mutations detected using next-generation sequencing in the resistant specimens were in MAP2K1, PIK3CA, TP53, BRAF, and EGFR. Among the recurrent cases, EGFR mutations identified at the initial diagnosis were detected within 6 months before relapse confirmation in four cases (average 88 days). Many of the recurrent cases without detection of known EGFR mutations in the liquid biopsy showed a longer interval between the detection of relapse and the last blood draw for the liquid biopsy (average 255 days). CONCLUSION: Frequent liquid biopsies are useful for identifying known EGFR mutations as markers for early detection of relapse. Several cancer driver mutations were observed, suggesting a variety of mechanisms of resistance in first-line osimertinib-treated lung adenocarcinoma.
Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Ácidos Nucleicos Livres , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Recidiva Local de Neoplasia , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Biópsia Líquida , Recidiva , Receptores ErbB/genéticaRESUMO
Osimertinib is a standard treatment for patients with EGFR-mutated non-small cell lung carcinoma (NSCLC). We evaluated the relationship between plasma osimertinib concentrations and treatment outcome in patients with NSCLC for this cohort study. The plasma levels of osimertinib and its metabolite AZ5104 were measured a week after the start of treatment (P1). The primary endpoint was to evaluate the correlation between plasma concentration and adverse events (AEs). The correlation with treatment efficacy was one of the secondary endpoints. In patients with CNS metastases, the concentration in the cerebrospinal fluid was also measured. Forty-one patients were enrolled. The frequency of AEs was highest for rash, followed by anorexia and thrombocytopenia. Thirty-eight cases provided measurements for P1. The median plasma concentration of osimertinib was 227 ng/mL, and that of AZ5104 was 16.5 ng/mL. The mean CNS penetration rate of two cases was 3.8%. The P1 in the group with anorexia was significantly higher than that in the group without anorexia (385.0 ng/mL vs. 231.5 ng/mL, p = 0.009). Divided into quartiles by P1 trough level, Q2 + Q3 (164-338 ng/mL) had longer PFS, while Q1 and Q4 had shorter PFS. An appropriate plasma level of osimertinib may avoid some adverse events and induce long PFS. Further large-scale trials are warranted.
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Introduction: Necitumumab plus gemcitabine and cisplatin (GCN) is a standard therapy for patients with advanced lung squamous cell carcinoma (LSqCC). However, the efficacy and tolerability of GCN in second-line or later treatment for patients previously treated with immune checkpoint inhibitors (ICIs) remain unknown. Methods: This multicenter, retrospective, cohort study assessed the efficacy and tolerability of GCN initiated between November 1, 2019 and March 31, 2022 as second-line to fourth-line treatment in patients with advanced LSqCC who had been pretreated with ICIs. The primary end point was progression-free survival (PFS). Results: A total of 93 patients from 35 institutions in Japan were enrolled. The median PFS, median overall survival (OS), and objective response rate were 4.4 months (95% confidence interval [CI]: 3.8-5.3), 13.3 months (95% CI: 9.6-16.5), and 27.3% (95% CI: 18.3-37.8), respectively. The median PFS, median OS, and objective response rate for second-line, third-line, and fourth-line treatment groups were 4.8 months, 3.8 months, and 4.3 months (p = 0.24); 15.7 months, 11.6 months, and 10.1 months (p = 0.06); and 31.0%, 13.6%, and 37.5% (p = 0.22), respectively. The severity of GCN-related skin disorders was associated with longer PFS (p < 0.05) and OS (p < 0.05). The frequencies of grade ≥3 skin disorders, hypomagnesemia, pneumonitis, and febrile neutropenia were 16.1%, 7.5%, 1.1%, and 4.3%, respectively. There were no treatment-related deaths. Conclusions: GCN for ICI-pretreated patients with LSqCC seems tolerable and offers promising efficacy regardless of treatment line, and ICI pretreatment might enhance GCN efficacy.
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Optimization of lead compound 2 is described, mainly focusing on modification at the C-2 position of the benzimidazole core. Replacement of the phenyl linker of 2 with saturated rings resulted in identification of compound 8b which combines high Y5 receptor binding affinity with a good ADME profile leading to in vivo efficacy.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Administração Oral , Animais , Desenho de Fármacos , Estabilidade de Medicamentos , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Obesos , Ligação Proteica/efeitos dos fármacos , Solubilidade , Relação Estrutura-AtividadeRESUMO
Optimization of our HTS hit 1, mainly focused on modification at the C-2 position of the benzimidazole core, is described. Elimination of the flexible and metabolically labile -S-CH(2)- part and utilization of less lipophilic pyridone substructure led to identification of novel NPY Y5 receptor antagonists 6, which have low to sub-nanomolar Y5 receptor binding affinity with improved CYP450 inhibition profiles, good solubilities and high metabolic stabilities.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Piridonas/química , Piridonas/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Benzimidazóis/síntese química , Benzimidazóis/metabolismo , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Desenho de Fármacos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Obesidade/tratamento farmacológico , Piridonas/síntese química , Piridonas/metabolismo , Ratos , Receptores de Neuropeptídeo Y/metabolismoRESUMO
We report a hit to lead study on a novel benzoxazole NPY Y5 antagonist. Starting from HTS hit 1, structure-activity relationships were developed. Compound 12 showed reduction of food intake and a tendency to suppress body weight gain over the 21-day experimental period.