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OBJECTIVES: Gamma-aminobutyric acid (GABA) abnormalities have been implicated in bipolar disorder. However, due to discrepant studies measuring postmortem, cerebrospinal fluid, plasma, and in vivo brain levels of GABA, the nature of these abnormalities is unclear. Using proton magnetic resonance spectroscopy, we investigated tissue levels of GABA in the anterior cingulate cortex and parieto-occipital cortex of participants with bipolar disorder and healthy controls. METHODS: Fourteen stably medicated euthymic outpatients with bipolar disorder type I (mean age 32.6 years, eight male) and 14 healthy control participants (mean age 36.9 years, 10 male) completed a proton magnetic resonance spectroscopy scan at 4-Tesla after providing informed consent. We collected data from two 16.7-mL voxels using MEGAPRESS, and they were analyzed using LCModel. RESULTS: GABA/creatine ratios were elevated in bipolar disorder participants compared to healthy controls [F(1,21) = 4.4, p = 0.048] in the anterior cingulate cortex (25.1% elevation) and the parieto-occipital cortex (14.6% elevation). Bipolar disorder participants not taking GABA-modulating medications demonstrated greater GABA/creatine elevations than patients taking GABA-modulating medications. CONCLUSIONS: We found higher GABA/creatine levels in euthymic bipolar disorder outpatients compared to healthy controls, and the extent of this elevation may be affected by the use of GABA-modulating medications. Our findings suggest that elevated brain GABA levels in bipolar disorder may be associated with GABAergic dysfunction and that GABA-modulating medications reduce GABA levels in this condition.
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Transtorno Bipolar , Giro do Cíngulo , Lobo Parietal , Ácido gama-Aminobutírico/metabolismo , Adulto , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/metabolismo , Transtorno Bipolar/patologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Giro do Cíngulo/metabolismo , Giro do Cíngulo/patologia , Humanos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neuropsiquiatria , Lobo Parietal/metabolismo , Lobo Parietal/patologia , Escalas de Graduação PsiquiátricaRESUMO
Patients diagnosed with generalized anxiety disorder (GAD) exhibit differential responses to standard antidepressant pharmacotherapy. Mounting evidence demonstrates that genetic differences may be implicated in treatment response in disorders like GAD. In this study, we examined whether the OPRM1 gene, which has been implicated in antidepressant treatment response in major depressive disorder, also has an effect in GAD. In our study, 156 patients diagnosed with GAD received venlafaxine XR treatment as part of an 18-month relapse prevention study. Genotypes were obtained for the OPRM1 functional variant A118G for the entire sample (n = 151); however, only the European American population was considered (n = 108) for pharmacogenetic analysis. We found no significant association between A118G and antidepressant treatment response in our GAD population. Future studies that include different single nucleotide polymorphisms of the OPRM1 gene as well as larger populations will need to be conducted to further elucidate the pharmacogenetic role of the endogenous opioid system in anxiety disorders.
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Transtornos de Ansiedade/tratamento farmacológico , Cicloexanóis/uso terapêutico , Receptores Opioides mu/genética , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos de Ansiedade/genética , Cicloexanóis/administração & dosagem , Preparações de Ação Retardada , Método Duplo-Cego , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo de Nucleotídeo Único , Prevenção Secundária , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Cloridrato de Venlafaxina , População Branca/genética , Adulto JovemRESUMO
SUMMARY: The landscape of neoadjuvant immune-checkpoint blockade for resectable non-small cell lung cancer has become an exciting area of clinical and translational exploration. Cascone and colleagues present a platform study of one cycle of novel immunomodulatory agents prior to surgical resection, offering a unique opportunity to perform translational biomarker studies, though many questions remain regarding the ultimate application to a broader patient population. See related article by Cascone et al., p. 2394 (1).
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Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Terapia Neoadjuvante , Antineoplásicos Imunológicos/uso terapêutico , Estadiamento de NeoplasiasRESUMO
Although lung cancer treatment has been transformed by the advent of checkpoint inhibitor immunotherapies, there remains a high unmet need for new effective therapies for patients with progressive disease. Novel treatment strategies include combination therapies with currently available programmed death ligand 1 inhibitors, targeting alternative immune checkpoints, and the use of novel immunomodulatory therapies. In addition, antibody-drug conjugates offer great promise as potent management options. As these agents are further tested in clinical trials, we anticipate that more effective therapies for patients with lung cancer are integrated into regular clinical practice.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/terapia , Imunoterapia , Terapia CombinadaRESUMO
Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured â¼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. SIGNIFICANCE: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Mutação , Fator 2 Relacionado a NF-E2/metabolismo , DNA Helicases/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fatores de Transcrição/genéticaRESUMO
The discoveries of EGFR mutations and ALK rearrangements as actionable oncogenic drivers in non-small-cell lung cancer (NSCLC) has propelled a biomarker-directed treatment paradigm for patients with advanced-stage disease. Numerous EGFR and ALK tyrosine kinase inhibitors (TKIs) with demonstrated efficacy in patients with EGFR-mutant and ALK-rearranged NSCLCs have been developed, culminating in the availability of the highly effective third-generation TKIs osimertinib and lorlatinib, respectively. Despite their marked efficacy, resistance to these agents remains an unsolved fundamental challenge. Both 'on-target' mechanisms (largely mediated by acquired resistance mutations in the kinase domains of EGFR or ALK) and 'off-target' mechanisms of resistance (mediated by non-target kinase alterations such as bypass signalling activation or phenotypic transformation) have been identified in patients with disease progression on osimertinib or lorlatinib. A growing understanding of the biology and spectrum of these mechanisms of resistance has already begun to inform the development of more effective therapeutic strategies. In this Review, we discuss the development of third-generation EGFR and ALK inhibitors, predominant mechanisms of resistance, and approaches to tackling resistance in the clinic, ranging from novel fourth-generation TKIs to combination regimens and other investigational therapies.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Identification of targetable fusions as oncogenic drivers in non-small cell lung cancer has transformed its diagnostic and therapeutic paradigm. In a recent article in Nature, Izumi et al. report the discovery of CLIP1-LTK fusion as a novel oncogenic driver in lung cancer, targetable using the ALK tyrosine kinase inhibitor lorlatinib.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Fusão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores Proteína Tirosina Quinases/genéticaRESUMO
Introduction: Co-occurring mutations in KRAS-mutant NSCLC are associated with discrete biological properties and modulate therapeutic susceptibilities. As G12D-specific inhibitors are expected to enter the clinic, we sought to investigate the characteristics and outcomes of patients with KRAS G12D-mutant NSCLC. Methods: This was a retrospective single-institution study. Patients with NSCLC and KRAS G12D mutations detected by the Massachusetts General Hospital SNaPshot next-generation sequencing assay were identified. Clinical and pathologic characteristics were collected by chart review. Results: A total of 107 patients with KRAS G12D-mutant NSCLC were identified. Most patients were former smokers (80, 74.8%) and had tumors with adenocarcinoma pathologic subtype (93, 86.9%). Among 56 patients evaluated for programmed death-ligand 1 expression, tumor proportion score was less than 50% in 43 (76.8%). Concomitant mutations were identified in STK11 (17 of 107, 15.9%), KEAP1 (10 of 58, 17.2%), TP53 (36 of 107, 33.6%), and SMARCA4 (11 of 107, 10.3%). Among 57 patients treated with first-line therapy, patients with STK11 co-mutations had shorter progression-free survival (1.2 mo, 95% confidence interval [CI]: 0.6-2.9 versus 4.1 mo, 95% CI: 2.5-6.0, p = 0.0235) and overall survival (4.3 mo, 95% CI: 1.2-10.6 versus 17.9 mo, 95% CI: 8.6-31.1, p = 0.0018) compared with wild type. Patients with KEAP1 co-mutations had shorter overall survival (4.6 mo, 95% CI: 1.2-10.6 versus 17.9 mo, 95% CI: 7.1-30.1, p = 0.0125) than those without. TP53 co-mutations exerted no influence on survival. Conclusions: Co-occurring mutations were common in patients with KRAS G12D-mutant NSCLC. STK11 and KEAP1 co-mutations were associated with worse clinical outcomes, whereas co-occurring TP53 did not affect survival.
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Rationale: There have been advances in both cancer and sepsis treatment over the past several decades, yet little is known about trends in sepsis-associated mortality in patients with versus without cancer.Objectives: To assess trends in sepsis-associated mortality in hospitalized patients with and without cancer using objective clinical criteria to identify sepsis and detailed clinical data to adjust for severity of illness.Methods: This was a retrospective cohort study at a tertiary referral hospital and cancer center. Adult in-patients with clinical indicators of sepsis (U.S. Centers for Disease Control and Prevention Adult Sepsis Event criteria) were identified between 2003 and 2014. Patients with cancer were identified using diagnosis codes from their hospitalization or the preceding 90 days. Sepsis-associated in-hospital mortality rates were assessed in 3-year intervals. Multivariable logistic regression models were used to adjust for case mix and severity of illness and to test for subgroup interactions in trends.Results: The cohort included 20,975 patients with sepsis, of whom 7,489 (35.7%) had cancer (61.7% solid and 38.3% hematologic). Sepsis-associated mortality rates in patients with cancer decreased from 31.3% in 2003-2005 to 26.0% in 2012-2014 (absolute decrease, 5.2% [95% confidence interval (CI), 2.3-8.2%]). This mortality reduction persisted after risk adjustment (adjusted odds ratio, 0.53 [95% CI, 0.45-0.63] in 2012-2014 relative to 2003-2005). In contrast, sepsis-associated mortality rates increased in patients without cancer from 20.9% in 2003-2005 to 23.9% in 2012-2014 (absolute increase, 2.1% [95% CI, 0.1-4.1%]), but were stable after risk-adjustment (adjusted odds ratio, 0.90 [95% CI, 0.79-1.03]) (P < 0.001 for comparison of trends between patients with vs. without cancer on both crude and adjusted analysis). Among patients with cancer, declines in risk-adjusted sepsis-associated mortality were observed in both solid and hematologic cancer subgroups, with both community-onset and hospital-onset sepsis, in patients receiving active cancer treatments, and in patients requiring mechanical ventilation at sepsis onset.Conclusions: Sepsis-associated mortality rates declined significantly over a 12-year period in patients with cancer, but not in patients without cancer. Potential explanations include advances in the management of cancer and/or better sepsis treatments specifically in patients with cancer. Further research is needed to elucidate the reasons for our findings and to assess their generalizability to other hospitals.
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Mortalidade Hospitalar/tendências , Hospitalização/estatística & dados numéricos , Neoplasias/complicações , Sepse/mortalidade , Idoso , Feminino , Humanos , Modelos Logísticos , Masculino , Massachusetts/epidemiologia , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Risco Ajustado , Índice de Gravidade de Doença , Centros de Atenção TerciáriaRESUMO
PURPOSE: We pursued genomic analysis of an exceptional responder with non-small cell lung cancer (NSCLC) through a multi-platform effort to discover novel oncogenic targets. EXPERIMENTAL DESIGN: In this open-label, single-arm phase II study (NCT01829217), an enriched cohort of patients with advanced NSCLC was treated with the multi-kinase inhibitor sunitinib. The primary endpoint was objective response rate. Tissue was collected for multi-platform genomic analysis of responders, and a candidate oncogene was validated using in vitro models edited by CRISPR-Cas9. RESULTS: Of 13 patients enrolled, 1 patient (8%), a never smoker, had a partial response lasting 33 months. Genomic analysis of the responder identified no oncogenic variant using multi-platform DNA analysis including hotspot allelotyping, massively parallel hybrid-capture next-generation sequencing, and whole-exome sequencing. However, bulk RNA-sequencing (RNA-seq) revealed a novel fusion, TMEM87A-RASGRF1, with high overexpression of the fusion partners. RASGRF1 encodes a guanine exchange factor which activates RAS from GDP-RAS to GTP-RAS. Oncogenicity was demonstrated in NIH/3T3 models with intrinsic TMEM87A-RASGRF1 fusion. In addition, activation of MAPK was shown in PC9 models edited to express this fusion, although sensitivity to MAPK inhibition was seen without apparent sensitivity to sunitinib. CONCLUSIONS: Sunitinib exhibited limited activity in this enriched cohort of patients with advanced NSCLC. Nonetheless, we find that RNA-seq of exceptional responders represents a potentially underutilized opportunity to identify novel oncogenic targets including oncogenic activation of RASGRF1.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Membrana/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Sunitinibe/farmacologia , ras-GRF1/metabolismo , Idoso , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , RNA-Seq , Sunitinibe/uso terapêutico , Proteínas ras/genética , ras-GRF1/genéticaAssuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Receptor ErbB-2RESUMO
IMPORTANCE: Abnormalities in neural activity and cerebral bioenergetics have been observed in schizophrenia (SZ). Further defining energy metabolism anomalies would provide crucial information about molecular mechanisms underlying SZ and may be valuable for developing novel treatment strategies. OBJECTIVE: To investigate cerebral bioenergetics in SZ via measurement of creatine kinase activity using in vivo 31P magnetization transfer spectroscopy. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional case-control study in the setting of clinical services and a brain imaging center of an academic psychiatric hospital. Twenty-six participants with chronic SZ (including a subgroup diagnosed as having schizoaffective disorder) and 26 age-matched and sex-matched healthy control subjects (25 usable magnetic resonance spectroscopy data sets from the latter). INTERVENTION: 31P magnetization transfer spectroscopy. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the forward rate constant (k(f)) of the creatine kinase enzyme in the frontal lobe. We also collected independent measures of brain intracellular pH and steady-state metabolite ratios of high-energy phosphate-containing compounds (phosphocreatine and adenosine triphosphate [ATP]), inorganic phosphate, and the 2 membrane phospholipids phosphodiester and phosphomonoester. RESULTS: A substantial (22%) and statistically significant (P = .003) reduction in creatine kinase kf was observed in SZ. In addition, intracellular pH was significantly reduced (7.00 in the SZ group vs 7.03 in the control group, P = .007) in this condition. The phosphocreatine to ATP ratio, inorganic phosphate to ATP ratio, and phosphomonoester to ATP ratio were not substantially altered in SZ, but a significant (P = .02) reduction was found in the phosphodiester to ATP ratio. The abnormalities were similar between SZ and schizoaffective disorder. CONCLUSIONS AND RELEVANCE: Using a novel 31P magnetization transfer magnetic resonance spectroscopy approach, we provide direct and compelling evidence for a specific bioenergetic abnormality in SZ. Reduced kf of the creatine kinase enzyme is consistent with an abnormality in storage and use of brain energy. The intracellular pH reduction suggests a relative increase in the contribution of glycolysis to ATP synthesis, providing convergent evidence for bioenergetic abnormalities in SZ. The similar phosphocreatine to ATP ratios in SZ and healthy controls suggest that the underlying bioenergetics abnormality is not associated with change in this metabolite ratio.
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Encéfalo/metabolismo , Metabolismo Energético/fisiologia , Espectroscopia de Ressonância Magnética , Esquizofrenia/metabolismo , Trifosfato de Adenosina/análise , Adulto , Encéfalo/fisiopatologia , Química Encefálica , Estudos de Casos e Controles , Creatina Quinase/metabolismo , Estudos Transversais , Feminino , Lobo Frontal/metabolismo , Lobo Frontal/fisiopatologia , Humanos , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética/métodos , Masculino , Fosfocreatina/análise , Isótopos de Fósforo/metabolismo , Esquizofrenia/fisiopatologiaRESUMO
The pituitary adenylate cyclase-activating peptide (PACAP) and its receptor (PAC1) are involved in stress response and anxiety. Genotypes for PACAP/PAC1 were examined for effects on treatment response to venlafaxine XR in generalized anxiety disorder. The Asp54Gly (rs2856966) variant in the PACAP gene was associated with better treatment outcome.
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Transtornos de Ansiedade/tratamento farmacológico , Cicloexanóis/uso terapêutico , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Polimorfismo Genético , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Adulto , Antidepressivos de Segunda Geração/uso terapêutico , Transtornos de Ansiedade/psicologia , Esquema de Medicação , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Neuropeptídeos/genética , Farmacogenética , Resultado do Tratamento , Cloridrato de VenlafaxinaRESUMO
BACKGROUND: In schizophrenia (SZ), disturbances in integration of activity among brain regions seem to be as important as abnormal activity of any single region. Brain regions are connected through white matter (WM) tracts, and diffusion tensor imaging has provided compelling evidence for WM abnormalities in SZ. However, diffusion tensor imaging alone cannot currently pinpoint the biological basis of these abnormalities. METHODS: In this study, we combined a myelin-specific and an axon-specific magnetic resonance imaging approach to examine potentially distinct abnormalities of WM components in SZ. Magnetization transfer ratio (MTR) provides information on myelin content, whereas diffusion tensor spectroscopy provides information on metabolite diffusion within axons. We collected data from a 1 × 3 × 3 cm voxel within the right prefrontal cortex WM at 4 Tesla and studied 23 patients with SZ and 22 age- and sex-matched healthy control participants. RESULTS: The MTR was significantly reduced in SZ, suggesting reduced myelin content. By contrast, the apparent diffusion coefficient of N-acetylaspartate (NAA) was significantly elevated, suggesting intra-axonal abnormalities. Greater abnormality of both MTR and the apparent diffusion coefficient of NAA correlated with more adverse outcomes in the patient group. CONCLUSIONS: The results suggest that WM abnormalities in SZ include both abnormal myelination and abnormal NAA diffusion within axons. These processes might be associated with abnormal signal transduction and abnormal information processing in SZ.