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Hormonal imbalance during pregnancy is a risk factor for neuropsychiatric impairment in the offspring. It has been suggested that hypothyroidism leads to dysfunction of cortical GABAergic interneurons and inhibitory system development that in turn underlies impairment of the central nervous system. Here we investigated how gestational hypothyroidism affected offspring GABAergic system development as well as redox regulation parameters, because of previous links identified between the two. Experimental Gestational Hypothyroidism (EGH) was induced in CD-1 mice with 0.02% methimazole (MMI) in drinking water from embryonic day 9 (E9) until tissue collection at embryonic day 14 (E14) or E18. We examined GABAergic cell distribution and inhibitory system development gene expression as well as redox relevant gene expression and direct measures across all embryos regardless of sex. Intrauterine restriction of maternal thyroid hormones significantly impacted both of these outcomes in brain, as well as altering redox regulation in the placenta. GAD67+ neuronal migration was reduced, accompanied by a disruption in gene expression influencing GABAergic cell migration and cortical inhibitory neural system development. EGH also altered embryonic brain gene expression of Gpx1, Nfe2l2, Cat levels in the dorsal E14 brains. Additionally, EGH resulted in elevated TBARS, Gpx1 and Nfe2l2 in the ventral E18 brains. Furthermore, EGH downregulated placental Gpx1 gene expression at E14 and increased protein oxidation at E18. These findings support the hypothesis that sufficient maternal thyroid hormone supply to the fetus influences central nervous system development, including processes of GABAergic system development and redox equilibrium.
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Encéfalo , Neurônios GABAérgicos , Glutationa Peroxidase GPX1 , Glutationa Peroxidase , Hipotireoidismo , Estresse Oxidativo , Animais , Feminino , Gravidez , Hipotireoidismo/metabolismo , Camundongos , Encéfalo/metabolismo , Encéfalo/embriologia , Neurônios GABAérgicos/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Peroxidase/genética , Metimazol , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genética , Movimento Celular , Glutamato Descarboxilase/metabolismo , Glutamato Descarboxilase/genética , Masculino , Placenta/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight significant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classification and systemic therapy options.
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Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Humanos , Pleura , Mesotelioma/diagnóstico , Mesotelioma/terapia , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/terapiaRESUMO
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Biomarcadores Tumorais/genética , Terapia de Alvo Molecular/métodos , Estadiamento de NeoplasiasRESUMO
Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term "malignant" is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.
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Mesotelioma Maligno , Mesotelioma , Humanos , Oncologia , Mesotelioma/diagnóstico , Mesotelioma/terapia , PeritônioRESUMO
The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for management of disease in patients with NSCLC. These NCCN Guidelines Insights focus on neoadjuvant and adjuvant (also known as perioperative) systemic therapy options for eligible patients with resectable NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Terapia NeoadjuvanteRESUMO
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Humanos , Imunoterapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Oncologia , Recidiva Local de NeoplasiaRESUMO
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/terapia , Humanos , Imunoterapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapiaRESUMO
BACKGROUND: In patients with critical medical illness, data regarding new-onset atrial fibrillation (NOAF) is relatively sparse. This study examines the incidence, associated risk factors, and associated outcomes of NOAF in patients in the medical intensive care unit (MICU). METHODS: This single-center retrospective observational cohort study included 2234 patients with MICU stays in 2018. An automated extraction process using ICD-10 codes, validated by a 196-patient manual chart review, was used for data collection. Demographics, medications, and risk factors were collected. Multiple risk scores were calculated for each patient, and AF recurrence was also manually extracted. Length of stay, mortality, and new stroke were primary recorded outcomes. RESULTS: Two hundred and forty one patients of the 2234 patient cohort (11.4%) developed NOAF during their MICU stay. NOAF was associated with greater length of stay in the MICU (5.84 vs. 3.52 days, p < .001) and in the hospital (15.7 vs. 10.9 days, p < .001). Patients with NOAF had greater odds of hospital mortality (odds ratio (OR) = 1.92, 95% confidence interval (CI) 1.34-2.71, p < .001) and 1-year mortality (OR = 1.37, 95% CI 1.02-1.82, p = .03). CHARGE-AF scores performed best in predicting NOAF (area under the curve (AUC) 0.691, p < .001). CONCLUSIONS: The incidence of NOAF in this MICU cohort was 11.4%, and NOAF was associated with a significant increase in hospital LOS and mortality. Furthermore, the CHARGE-AF score performed best in predicting NOAF.
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Fibrilação Atrial/epidemiologia , Unidades de Terapia Intensiva , Idoso , Fibrilação Atrial/mortalidade , Estado Terminal , Feminino , Mortalidade Hospitalar , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
Introduction TAS-114 is a potent inhibitor of deoxyuridine triphosphatase, which is a gatekeeper protein preventing uracil and 5-fluorouracil (5-FU) misincorporation into DNA. TAS-114 has been suggested to enhance the antitumor activity of 5-FU. This randomized, phase 2 study investigated TAS-114 plus S-1 (TAS-114/S-1) vs. S-1 in non-small-cell lung cancer (NSCLC) patients. Methods Patients with advanced NSCLC, previously treated with ≥ 2 regimens, were randomized 1:1 to receive TAS-114 (400 mg)/S-1 (30 mg/m2) or S-1 (30 mg/m2). Progression-free survival (PFS, independent central review) was the primary endpoint. Secondary endpoints included disease control rate (DCR), overall survival (OS), overall response rate (ORR), and safety. Results In total, 127 patients received treatment. Median PFS was 3.65 and 4.17 months in the TAS-114/S-1 and S-1 groups, respectively (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.71-1.88; P = 0.2744). DCR was similar between groups (TAS-114/S-1 80.3%, S-1 75.9%) and median OS was 7.92 and 9.82 months for the TAS-114/S-1 and S-1 groups, respectively (HR 1.31, 95% CI 0.80-2.14; P = 0.1431). The ORR was higher in the TAS-114/S-1 group than the S-1 group (19.7% vs. 10.3%), and more patients with tumor shrinkage were observed in the TAS-114/S-1 group. Incidence rates of anemia, skin toxicities, and Grade ≥ 3 treatment-related adverse events were higher in the TAS-114/S-1 group compared with the monotherapy group. Conclusions Although the TAS-114/S-1 combination improved the response rate, this did not translate into improvements in PFS. Clinical Trial Registration No. NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016.
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Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Ácido Oxônico/administração & dosagem , Pirimidinas/administração & dosagem , Pirofosfatases/antagonistas & inibidores , Sulfonamidas/administração & dosagem , Tegafur/administração & dosagem , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Oxônico/efeitos adversos , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Tegafur/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: The United Kingdom Clinical Aptitude Test (UKCAT) is an aptitude test used since 2006 within selection processes of a consortium of UK medical and dental schools. Since 2006, student numbers have increased in medical training and schools now have an increased focus on widening access. A growing evidence base has emerged around medical student selection (Patterson et al., Med Educ 50:36-60, 2016) leading to changes in practice. However, whilst some papers describe local selection processes, there has been no overview of trends in selection processes over time across Universities. This study reports on how the use of the UKCAT in medical student selection has changed and comments on other changes in selection processes. METHODS: Telephone interviews were conducted annually with UKCAT Consortium medical schools. Use of the UKCAT was categorised and data analysed to identify trends over time. RESULTS: The number of schools using the UKCAT to select applicants for interview has risen, with cognitive test results contributing significantly to outcomes at this stage at many universities. Where schools use different weighted criteria (Factor Method), the UKCAT has largely replaced the use of personal statements. Use of the test at offer stage has also increased; the most significant use being to discriminate between applicants at a decision borderline. A growing number of schools are using the UKCAT Situational Judgement Test (SJT) in selection. In 2018, all but seven (out of 26) schools made some adjustment to selection processes for widening access applicants. Multiple Mini Interviews (MMIs) are now used by the majority of schools. Whilst medical student numbers have increased over this time, the ratio of applicants to places has fallen. The probability of applicants being invited to interview or receiving an offer has increased. CONCLUSIONS: More medical schools are using the UKCAT in undergraduate selection processes in an increasing number of ways and with increasing weight compared with 2007. It has replaced the use of personal statements in all but a few Consortium medical schools. An increased focus on academic attainment and the UKCAT across medical schools may be leading to the need for schools to interview and make offers to more applicants.
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Critérios de Admissão Escolar , Estudantes de Medicina , Testes de Aptidão , Humanos , Faculdades de Medicina , Reino UnidoRESUMO
BACKGROUND: NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron oxidoreductase expressed in multiple tumour types. ARQ 761 is a ß-lapachone (ß-lap) analogue that exploits the unique elevation of NQO1 found in solid tumours to cause tumour-specific cell death. METHODS: We performed a 3+3 dose escalation study of 3 schedules (weekly, every other week, 2/3 weeks) of ARQ 761 in patients with refractory advanced solid tumours. Tumour tissue was analysed for NQO1 expression. After 20 patients were analysed, enrolment was restricted to patients with NQO1-high tumours (H-score ≥ 200). RESULTS: A total of 42 patients were treated. Median number of prior lines of therapy was 4. Maximum tolerated dose was 390 mg/m2 as a 2-h infusion every other week. Dose-limiting toxicity was anaemia. The most common treatment-related adverse events were anaemia (79%), fatigue (45%), hypoxia (33%), nausea (17%), and vomiting (17%). Transient grade 3 hypoxia, reflecting possible methemoglobinaemia, occurred in 26% of patients. Among 32 evaluable patients, best response was stable disease (n = 12); 6 patients had tumour shrinkage. There was a trend towards improved efficacy in NQO1-high tumours (P = 0.06). CONCLUSIONS: ARQ 761 has modest single-agent activity, which appears associated with tumour NQO1 expression. Principal toxicities include anaemia and possible methemoglobinaemia.
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Apoptose/efeitos dos fármacos , NAD(P)H Desidrogenase (Quinona)/análise , NAD(P)H Desidrogenase (Quinona)/biossíntese , Naftoquinonas/uso terapêutico , Necrose/induzido quimicamente , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naftoquinonas/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: On elective students may not always be clear about safeguarding themselves and others. It is important that placements are safe, and ethically grounded. A concern for medical schools is equipping their students for exposure to and response to uncomfortable and/or unfamiliar requests in locations away from home, where their comfort and safety, or that of the patient, may be compromised. This can require legal, ethical, and/or moral reasoning on the part of the student. The goal of this article is to establish what students actually encounter on elective, to inform better preparing students for safe and ethical medical placements. We discuss the implications of our findings, which are arguably applicable to other areas of graduate training, e.g. first medical roles post-qualification. METHOD: An anonymised survey exploring clinical and ethical dilemmas on elective was issued across 3 years of returning final year elective medical students. Questions included the prevalence and type of potentially unsafe scenarios encountered, barriers to saying 'no' in unsafe situations, perceived differences between resource poor and developed world settings and the degree to which students refused or consented to participation in events outside of the 'norms' of their own training experience. RESULTS: Three hundred seventy-nine students participated. 45% were asked to do something "not permissible" at home. 27% were asked to do something they felt "uncomfortable" with, often an invasive clinical task. Half asked to do something not usually permissible were "comfortable". 48% felt it more acceptable to bypass guidelines in developing settings. 27% refused an offer outside their experience. CONCLUSION: Of interest are reasons for "going along with" uncomfortable invitations, e.g. "emergency", self-belief in 'capability' and being 'more qualified' than host-personnel. This "best pair of hands available" merits scrutiny. Adverse scenarios were not exclusive to developing settings. We discuss preparing students for decision-making in new contexts, and address whether 'home' processes are too inflexible to prepare students for 'real' medical life? Ethical decision-making and communicating reluctance should be included in elective preparation.
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Segurança do Paciente , Estudantes de Medicina , Competência Clínica , Educação Médica/ética , Educação Médica/métodos , Feminino , Humanos , Masculino , Faculdades de Medicina/ética , Faculdades de Medicina/organização & administração , Estudantes de Medicina/psicologia , Reino UnidoRESUMO
BACKGROUND: Cyclooxygenase 2 (COX-2)-dependent signaling represents a potential mechanism of resistance to therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. This is mediated in part through an EGFR-independent activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) by prostaglandin E2 (PGE2). PGE2 promotes downregulation of E cadherin and epithelial to mesenchymal transition. The current study investigated EGFR and COX-2 inhibition in patients with non-small cell lung cancer (NSCLC) and elevated baseline urinary metabolite of PGE2 (PGEM). METHODS: Patients with stage IIIB/IV (AJCC 6th edition) NSCLC who progressed after at least 1 line of therapy or refused standard chemotherapy were randomized to receive erlotinib and celecoxib versus erlotinib and placebo. The primary endpoint was progression-free survival (PFS) with 80% power to detect a 50% improvement with a 1-sided significance level of .2 in the intent-to-treat and elevated baseline PGEM populations. Secondary endpoints included response rate, overall survival, and evaluation of molecular markers to assess targeting COX-2-related pathways and evaluate EGFR tyrosine kinase inhibitor resistance. RESULTS: A total of 107 patients were enrolled with comparable baseline characteristics. Among the patients treated with celecoxib, those with wild-type EGFR were found to have an increased PFS (3.2 months vs 1.8 months; P = .03). PFS was numerically improved among patients in the intent-to-treat group who received erlotinib and celecoxib compared with those treated with erlotinib and placebo (5.4 months vs 3.5 months; P = .33) and was increased in patients in the erlotinib and celecoxib arm with elevated baseline PGEM (5.4 months vs 2.2 months; P = .15). Adverse events were similar in both treatment arms. CONCLUSIONS: The combination of erlotinib and celecoxib did not appear to improve outcomes in an unselected population, but selection by elevated baseline PGEM led to an increase in PFS with this combination. Patients with EGFR wild-type status may benefit from the combination of erlotinib and celecoxib.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Celecoxib/administração & dosagem , Análise Mutacional de DNA , Dinoprostona/urina , Intervalo Livre de Doença , Método Duplo-Cego , Cloridrato de Erlotinib/administração & dosagem , Feminino , Genes erbB-1 , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: The UK Clinical Aptitude Test (UKCAT) was designed to address issues identified with traditional methods of selection. This study aims to examine the predictive validity of the UKCAT and compare this to traditional selection methods in the senior years of medical school. This was a follow-up study of two cohorts of students from two medical schools who had previously taken part in a study examining the predictive validity of the UKCAT in first year. METHODS: The sample consisted of 4th and 5th Year students who commenced their studies at the University of Aberdeen or University of Dundee medical schools in 2007. Data collected were: demographics (gender and age group), UKCAT scores; Universities and Colleges Admissions Service (UCAS) form scores; admission interview scores; Year 4 and 5 degree examination scores. Pearson's correlations were used to examine the relationships between admissions variables, examination scores, gender and age group, and to select variables for multiple linear regression analysis to predict examination scores. RESULTS: Ninety-nine and 89 students at Aberdeen medical school from Years 4 and 5 respectively, and 51 Year 4 students in Dundee, were included in the analysis. Neither UCAS form nor interview scores were statistically significant predictors of examination performance. Conversely, the UKCAT yielded statistically significant validity coefficients between .24 and .36 in four of five assessments investigated. Multiple regression analysis showed the UKCAT made a statistically significant unique contribution to variance in examination performance in the senior years. CONCLUSIONS: Results suggest the UKCAT appears to predict performance better in the later years of medical school compared to earlier years and provides modest supportive evidence for the UKCAT's role in student selection within these institutions. Further research is needed to assess the predictive validity of the UKCAT against professional and behavioural outcomes as the cohort commences working life.
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Testes de Aptidão , Testes de Aptidão/normas , Testes de Aptidão/estatística & dados numéricos , Competência Clínica/normas , Competência Clínica/estatística & dados numéricos , Feminino , Humanos , Masculino , Estudos Prospectivos , Reprodutibilidade dos Testes , Faculdades de Medicina/normas , Faculdades de Medicina/estatística & dados numéricos , Estudantes de Medicina/estatística & dados numéricos , Reino Unido/epidemiologia , Adulto JovemRESUMO
We report the case of corneal transplant rejection in a 77-year-old male receiving durvalumab as consolidative therapy for stage IIIB non-small cell lung cancer (NSCLC). Following successful chemoradiation and initiation of durvalumab, the patient underwent a right corneal transplant for corneal dystrophy. Six months after an initially stable post-transplant course, he developed progressive visual decline culminating in graft failure 1 year later despite treatment with prednisone eye drops. This case adds to the limited evidence implicating immune checkpoint inhibitors (ICIs) in corneal graft rejection, emphasizing the need for multidisciplinary evaluation and close monitoring of corneal transplant recipients undergoing ICI therapy.
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Introduction: The KRAS G12C inhibitor sotorasib was approved for treating advanced NSCLC in the second line or later on the basis of the CodeBreaK100 trial. Nevertheless, data on the real-world efficacy and safety of sotorasib, and to its optimal dose, remain limited. Methods: Patients treated with sotorasib for NSCLC through the Veterans Health Administration were retrospectively identified from the Corporate Data Warehouse. Survival, response, and toxicity data were obtained from chart review. Results: Among the 128 patients treated with sotorasib through the Veterans Health Administration, objective response rate was 34%, progression-free survival (PFS) six months, and overall survival 12 months. Similar PFS was observed among the 16 patients who received frontline sotorasib without any prior systemic therapy for NSCLC. Toxicity leading to sotorasib interruption or dose reduction occurred in 37% of patients, whereas sotorasib discontinuation for toxicity occurred in 25%. Notably, sotorasib dose reduction was associated with substantially improved PFS and OS. Conclusions: In this real-world study, the observed efficacy of sotorasib was similar to the results of CodeBreaK100. Patients who received frontline sotorasib had similar PFS to our overall cohort, suggesting that first-line sotorasib monotherapy may benefit patients who are not eligible for chemotherapy. Toxicities leading to sotorasib interruption, dose reduction, or discontinuation were common. Sotorasib dose reduction was associated with improved survival, suggesting that sotorasib dose reduction may not compromise efficacy.
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INTRODUCTION: Consolidative durvalumab, an anti-programmed death ligand 1 (PDL1) immune checkpoint inhibitor, administered after concurrent chemoradiation improves outcomes of patients with locally advanced non-small cell lung cancer (NSCLC) without substantially increasing toxicities. We studied a chemotherapy-free regimen of thoracic radiotherapy (RT) with concurrent and consolidative durvalumab. METHODS: This single-arm phase II trial enrolled patients with stage III NSCLC (regardless of tumor PDL1 expression), performance status ECOG 0-1, adequate pulmonary function, and RT fields meeting standard organ constraints. Participants received two cycles of durvalumab (1500 mg every 4 weeks) concurrently with thoracic RT (60 Gy in 30 fractions), followed by up to 13 cycles of consolidative durvalumab. RESULTS: After 10 patients were enrolled, the trial was closed due to poor clinical outcomes. With a median follow-up of 12 months, five patients had disease progression and eight patients died. Six patients experienced 15 treatment-related, grade ≥3 events, including one grade 4 acute kidney injury during consolidation and two fatal pulmonary events. One fatal pulmonary event occurred during the concurrent phase in an active smoker; the other occurred after the first cycle of consolidative durvalumab. The primary endpoint of progression-free survival (PFS) at 12 months was 20% (50% for PDL1≥1% versus 0% for PDL1 unavailable or <1%). Median overall survival (OS) was not reached, 10.5 months, and 7 months, for PDL1 ≥1%, <1%, and unavailable, respectively. CONCLUSIONS: In PDL1 unselected stage III NSCLC, thoracic RT plus concurrent and consolidative durvalumab is associated with high-grade toxicity and early disease progression.
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Background: A useful clinical biomarker requires not only association but also a consistent temporal relationship. For instance, chemotherapy-induced neutropenia and epidermal growth-factor inhibitor-related acneiform rash both occur within weeks of treatment initiation, thereby providing information prior to efficacy assessment. Although immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAE) have been associated with therapeutic benefit, irAE may have delayed and highly variable onset. To determine whether ICI efficacy and irAE could serve as clinically useful biomarkers for predicting each other, we determined the temporal relationship between initial efficacy assessment and irAE onset in a diverse population treated with ICI. Methods: Using two-sided Fisher exact and Cochran-Armitage tests, we determined the relative timing of initial efficacy assessment and irAE occurrence in a cohort of 155 ICI-treated patients (median age 68 years, 40% women). Results: Initial efficacy assessment was performed a median of 50 days [interquartile range (IQR) 39-59 days] after ICI initiation; median time to any irAE was 77 days (IQR 28-145 days) after ICI initiation. Median time to first irAE was 42 days (IQR 20-88 days). Overall, 58% of any irAE and 47% of first irAE occurred after initial efficacy assessment. For clinically significant (grade ≥2) irAE, 60% of any and 53% of first occurred after initial efficacy assessment. The likelihood of any future irAE did not differ according to response (45% for complete or partial response vs. 47% for other cases; P=1). In landmark analyses controlling for clinical and toxicity follow-up, patients demonstrating greater tumor shrinkage at initial efficacy assessment were more likely to develop future grade ≥2 (P=0.05) and multi-organ (P=0.02) irAE. Conclusions: In contrast to that seen with chemotherapy and molecularly targeted therapies, the temporal relationship between ICI efficacy and toxicity is complex and bidirectional. In practice, neither parameter can be routinely relied on as a clinical biomarker to predict the other.
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Biomarcadores , Inibidores de Checkpoint Imunológico , Neoplasias , Humanos , Feminino , Masculino , Idoso , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/terapia , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Resultado do Tratamento , Fatores de TempoRESUMO
The interaction between antigens and antibodies (B cell receptors, BCRs) is the key step underlying the function of the humoral immune system in various biological contexts. The capability to profile the landscape of antigen-binding affinity of a vast number of BCRs will provide a powerful tool to reveal novel insights at unprecedented levels and will yield powerful tools for translational development. However, current experimental approaches for profiling antibody-antigen interactions are costly and time-consuming, and can only achieve low-to-mid throughput. On the other hand, bioinformatics tools in the field of antibody informatics mostly focus on optimization of antibodies given known binding antigens, which is a very different research question and of limited scope. In this work, we developed an innovative Artificial Intelligence tool, Cmai, to address the prediction of the binding between antibodies and antigens that can be scaled to high-throughput sequencing data. Cmai achieved an AUROC of 0.91 in our validation cohort. We devised a biomarker metric based on the output from Cmai applied to high-throughput BCR sequencing data. We found that, during immune-related adverse events (irAEs) caused by immune-checkpoint inhibitor (ICI) treatment, the humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. In contrast, extracellular antigens on malignant tumor cells are inducing B cell infiltrations, and the infiltrating B cells have a greater tendency to co-localize with tumor cells expressing these antigens. We further found that the abundance of tumor antigen-targeting antibodies is predictive of ICI treatment response. Overall, Cmai and our biomarker approach filled in a gap that is not addressed by current antibody optimization works nor works such as AlphaFold3 that predict the structures of complexes of proteins that are known to bind.
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Introduction: Characteristics of long-term survivors in EGFR-mutant (EGFRm) NSCLC are not fully understood. This retrospective analysis evaluated a multi-institution cohort of patients with EGFRm NSCLC treated in the pre-osimertinib era and sought to describe characteristics of long-term survivors. Methods: Clinical characteristics and outcomes were abstracted from the electronic medical records of patients with EGFRm metastatic NSCLC who started first-line therapy before 2015. Demographics and comutations were compared between greater than or equal to 5-year survivors and less than 5-year survivors. Multivariable Cox proportional hazard and logistic regression models were used to evaluate factors associated with survival and the odds of death within 5 years, respectively. Results: Overall, 133 patients were greater than or equal to 5-year survivors; 127 were less than 5-year survivors. Burden of pathogenic comutations including TP53 and PIK3CA was similar between greater than or equal to 5-year survivors and less than 5-year survivors. Receipt of first-line chemotherapy rather than EGFR tyrosine kinase inhibitor was similar between the groups (22% of <5-y versus 31% of ≥5-y). Baseline brain metastasis and history of smoking were associated with higher odds of death within 5 years (odds ratio = 2.16, p = 0.029 and odds ratio = 1.90, p = 0.046, respectively). Among patients without baseline brain metastases, cumulative incidence of brain metastases at 5 years was 42.3%. Both baseline and post-baseline brain metastasis were associated with worse overall survival compared with no brain metastasis (hazard ratio = 3.26, p < 0.001 and hazard ratio = 4.99, p < 0.001, respectively). Conclusions: Within patients treated for EGFRm metastatic NSCLC before 2015, absence of brain metastasis and nonsmoking status were predictive of 5-year survival. Our findings help to define a subset of patients with EGFRm NSCLC with excellent survival outcomes who may not require intensification of initial therapy.