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INTRODUCTION: Pirfenidone was the first anti-fibrotic drug approved in Europe in 2011 for the treatment of mild-to-moderate idiopathic pulmonary fibrosis. OBJECTIVES: To investigate the clinical course of mild-to-moderate idiopathic pulmonary fibrosis in pirfenidone-treated patients in a real-world setting. METHODS: The non-interventional study was conducted at 18 sites in Germany from 6/2014-12/2016. Adult patients with mild-to-moderate idiopathic pulmonary fibrosis were treated with pirfenidone (escalated from 3×1 to 3×3 capsules of 267 mg/day within 3 weeks) for 12 months. The observation period comprised 4 follow-up visits at months 3, 6, 9 and 12. Disease progression was defined as decrease of ≥10% in vital capacity or ≥15% in diffusing capacity of the lung for carbon monoxide (DLCO) and/or ≥50m in 6-minute walking distance vs. baseline, or "lack of response/progression" as reason for therapy discontinuation. RESULTS: A total of 51 patients (80.4% male, mean age 70.6 years) were included in the full analysis set. Disease progression at any visit was reported for 23 (67.6%) of 34 patients with available data. Over the course of the study, lung function parameters, physical resilience, impact of cough severity on quality of life, and the mean Gender, Age and Physiology Index (stage II) remained stable. In total, 29 patients (56.9%) experienced at least one adverse drug reaction (11 patients discontinued due to adverse drug reactions); serious adverse reactions were reported in 12 patients (23.5%). CONCLUSIONS: The results of this study are in line with the established benefit-risk profile of pirfenidone. Therefore, pirfenidone can be considered a valuable treatment option to slow disease progression in mild-to-moderate idiopathic pulmonary fibrosis. NCT02622477.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Fibrose Pulmonar Idiopática , Piridonas , Adulto , Humanos , Masculino , Idoso , Feminino , Qualidade de Vida , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Tosse , Progressão da DoençaRESUMO
BACKGROUND: In 2022, an update of the German lung cancer guideline, first published in 2010 and revised in 2018, was released. This article aims to show the process of updating, developing, and implementing guideline-based quality indicators (QI) into the certification system for lung cancer centers (LCC). METHODS: A multidisciplinary and interprofessional working group revised the guideline QIs from 2018 using the strong recommendations of the guideline update, a systematic review for QIs, and the results of the implemented QIs from LCC. RESULTS: For 4 out of 8 indicators from the 2018 guideline, the LCC showed an improved implementation of the requirements in the last 3 years (2018-2020). For 3 indicators, the median of the results was constant at a very high level (≥96% or 100%). Only the "adjuvant cisplatin-based chemotherapy" indicator showed declining values between 2018 and 2020. The target values and plausibility limits were well achieved by LCC. After updating the guideline, one QI from 2018 was not included in the new QI set due to the small denominator population. Based on the new strong recommendations, 8 new QIs were defined. From the QI set of the guideline update, 13 of 15 indicators (7 since 2018 and 6 from 2022 on) were adopted into the certification program. CONCLUSIONS: The guideline recommendations are implemented by LCC at a high level. The process presented confirms the successful implementation of the so-called quality cycle in oncology. The QIs developed by the German Guideline Program in Oncology (GGPO) are adopted by the certification program. The implementation of the QI is measured in LCC, evaluated by the German Cancer Society (DKG), and reflected back to the GGPO. The "real world" data have led to the deletion of one QI and show a high implementation of most QIs in LCC.
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Neoplasias Pulmonares , Indicadores de Qualidade em Assistência à Saúde , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapiaRESUMO
A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60-87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45-64)) and the study group arms (53% (95%CI: 47-60) and 59% (95%CI: 58-63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7-14.0) in the CSA, 7.6% (95%CI: 4.5-12.8) in study group A and 11.1% (95%CI: 9.0-13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0-26.9), 17.0% (95%CI: 2.0-23.9), and 19.5% (95%CI: 16.7-22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.
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Leucemia Mieloide Aguda , Mitoxantrona , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Daunorrubicina/efeitos adversos , Intervalo Livre de Doença , Leucemia Mieloide Aguda/tratamento farmacológico , Mitoxantrona/efeitos adversos , Prognóstico , Indução de RemissãoRESUMO
BACKGROUND: The introduction of monoclonal antibodies (biologics) has revolutionized the therapy of severe asthma. Even though there is a response in the majority of patients, the degree of response varies. To date criteria for assessment of response to biologics are not consistently defined. AIM: To define criteria for evaluation of response to biologics that are precise, simple and suitable for daily use in order to guide decision-making regarding continuation, switching or stopping of biological therapy. METHODS: 8 physicians with large experience in this indication, supported by a data-scientist, developed a consensus on criteria to evaluate response to biologics in patients with severe asthma. RESULT: We developed a combined score based on current literature, own experience and practicability. It uses the main criteria exacerbations, oral corticosteroid (OCS) therapy and asthma control (asthma control test, ACT). We defined thresholds for "good response", "response" and "insufficient response" rated with a score of "2", "1" and "0" respectively: annual exacerbations ("0 or reduction ≥â75â%", "reduction 50-74â%", "reductio <â50â%"), daily OCS dose ("stopping or reduction ≥â75â%", "reduction 50-74â%", "reduction <â50â%"), asthma control ("ACT increase ≥â6 or ≥â3 with result ≥â20", "ACT increase 3-5 with result <â20", "ACT increase <â3"). Additional individual criteria like lung function and comorbidities may be important for evaluation of response. We propose 3, 6 and 12 months timepoint for assessment of tolerability and response. Using the combined score, we developed a scheme to guide the decision whether switching the biologic should be considered. CONCLUSION: The Biologic Asthma Response Score (BARS) serves as objective and simple tool to evaluate response to biologic therapy using the three main criteria exacerbations, OCS use and asthma control. A validation of the score was initiated.
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BACKGROUND: The introduction of monoclonal antibodies (biologics) has revolutionized the therapy of severe asthma. Even though there is a response in the majority of patients, the degree of response varies. To date criteria for assessment of response to biologics are not consistently defined. AIM: To define criteria for evaluation of response to biologics that are precise, simple and suitable for daily use in order to guide decision-making regarding continuation, switching or stopping of biological therapy. METHODS: 8 physicians with large experience in this indication, supported by a data-scientist, developed a consensus on criteria to evaluate response to biologics in patients with severe asthma. RESULT: We developed a combined score based on current literature, own experience and practicability. It uses the main criteria exacerbations, oral corticosteroid (OCS) therapy and asthma control (asthma control test, ACT). We defined thresholds for "good response", "response" and "insufficient response" rated with a score of "2", "1" and "0" respectively: annual exacerbations ("0 or reduction ≥â75â%", reduction 50-74â%", "reductio â<â50â%"), daily OCS dose ("stopping or reduction ≥â75â%", "reduction 50-74â%", "reduction <â50â%"), asthma control (ACT increase ≥â6 or ≥â3 with result ≥â20", "ACT increase 3-5 with result <â20", "ACT increase <â3"). Additional individual criteria like lung function and comorbidities may be important for evaluation of response. We propose 3, 6 and 12 months timepoint for assessment of tolerability and response. Using the combined score, we developed a scheme to guide the decision whether switching the biologic should be considered. CONCLUSION: The Biologic Asthma Response Score (BARS) serves as objective and simple tool to evaluate response to biologic therapy using the three main criteria exacerbations, OCS use and asthma control. A validation of the score was initiated.
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Antiasmáticos , Asma , Produtos Biológicos , Humanos , Antiasmáticos/uso terapêutico , Asma/diagnóstico , Asma/tratamento farmacológico , Produtos Biológicos/uso terapêutico , CorticosteroidesRESUMO
The current S3 Lung Cancer Guidelines are edited with fundamental changes to the previous edition based on the dynamic influx of information to this field:The recommendations include de novo a mandatory case presentation for all patients with lung cancer in a multidisciplinary tumor board before initiation of treatment, furthermore CT-Screening for asymptomatic patients at risk (after federal approval), recommendations for incidental lung nodule management , molecular testing of all NSCLC independent of subtypes, EGFR-mutations in resectable early stage lung cancer in relapsed or recurrent disease, adjuvant TKI-therapy in the presence of common EGFR-mutations, adjuvant consolidation treatment with checkpoint inhibitors in resected lung cancer with PD-L1 ≥â50%, obligatory evaluation of PD-L1-status, consolidation treatment with checkpoint inhibition after radiochemotherapy in patients with PD-L1-pos. tumor, adjuvant consolidation treatment with checkpoint inhibition in patients withPD-L1 ≥â50% stage IIIA and treatment options in PD-L1 ≥â50% tumors independent of PD-L1status and targeted therapy and treatment option immune chemotherapy in first line SCLC patients.Based on the current dynamic status of information in this field and the turnaround time required to implement new options, a transformation to a "living guideline" was proposed.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/prevenção & controle , Antígeno B7-H1/genética , Antígeno B7-H1/uso terapêutico , Seguimentos , Receptores ErbB/genética , Carcinoma Pulmonar de Células não Pequenas/patologiaRESUMO
Pulmonary metastasectomy is a well-established contribution to the cure of oligometastatic cancers, but its exact effectiveness is poorly understood. Here we report the outcomes of repeat pulmonary metastasectomy from a multicenter trial. This retrospective study included patients who underwent re-do metastasectomies between January 2010 and December 2014. The exclusion criterion was metastasectomy without curative intent. We reviewed medical files of 621 consecutive patients who underwent initial pulmonary metastasectomy. Of those, 64 patients underwent repeat metastasectomies, and these patients were included in the analysis. All the 64 patients underwent a second metastasectomy, later 35 of them underwent a third metastasectomy, 12 underwent a fourth metastasectomy, and 6 underwent a fifth metastasectomy. The total number of re-do metastasectomies was 181. The median overall survival among the patients undergoing re-do metastasectomy was 66.0 ± 3.8 months. Three and 5-year survival rates were 82.3% and 63.3%, respectively. The 5-year survival rates were 63.3% after the first, 50.9% after the second, 74.4% after the third, 83.3% after the fourth, and 60.0% after the fifth metastasectomy. We conclude that at the current stage of knowledge, there is an indication for repeat re-do metastasectomy with curative intent.
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Neoplasias Colorretais , Neoplasias Pulmonares , Metastasectomia , Sarcoma , Humanos , Neoplasias Pulmonares/cirurgia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Bronchial Thermoplasty (BT) is indicated in patients suffering from severe and symptomatic bronchial asthma despite maximal medical therapy. However, treatment of the right middle lobe (RML) bronchus is currently not recommended. The aim of this study was to investigate the safety and efficacy of BT if the RML bronchus is included. METHODS: BT was performed in 17 consecutive patients, quality of life and pulmonary function were characterized before and 90 days after BT completion. Furthermore, we performed a clean-up bronchoscopy following every BT. This study was approved by the IRB of the University of Essen (No. 17-7356 BO) and registered as a retrospective observational study at the German Clinical Trials Registry (No. DRKS 00011550). RESULTS: The median baseline values of FEV1 and Asthma Questionnaire of Life Quality (AQLQ) were 1.33 l (0.91; 1.73) and 3.01 (2.76; 3.61), respectively, and significantly improved 90 days after treatment with FEV 1 at 1.75 l (p-value 0.002) and AQLQ 3.8 (p-value < 0.05). Also the amount of oral corticosteroid necessity decreased significantly. No severe adverse events occurred due to the procedure. Clean-up bronchoscopies-when performed-revealed significant fibrinous exudation after every BT procedure. CONCLUSION: BT including the RML bronchus is feasible. Functionally limited patients with severe asthma could potentially profit. Due to the relevant fibrinous exudation, BT should be followed by clean-up bronchoscopy, not only after RML treatment.
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Asma/cirurgia , Brônquios/cirurgia , Termoplastia Brônquica , Broncoconstrição , Qualidade de Vida , Corticosteroides/administração & dosagem , Adulto , Asma/diagnóstico , Asma/tratamento farmacológico , Asma/fisiopatologia , Brônquios/efeitos dos fármacos , Brônquios/fisiopatologia , Termoplastia Brônquica/efeitos adversos , Broncoconstrição/efeitos dos fármacos , Broncoscopia , Feminino , Volume Expiratório Forçado , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVES: Solitary fibrous tumours of the pleura (SFTP) are historically considered to be benign soft tissue neoplasms. However, a clinical relevant number of these neoplasms have malignant histological features. The objective of this study was to evaluate the percentage of SFTP presenting unfavourable clinical behaviour in order to predict negative long-term outcome. METHODS: A retrospective review of 74 patients treated at 4 hospitals between 1990 and 2013 was performed. The median follow-up was 10 years (range: 1-20 years). Risk of tumour recurrence and metastases (unfavourable clinical behaviour) with regard to histology using the Kaplan-Meier and Cox proportional hazards methods. RESULTS: The mean age was 61 years (SD 12.75 years). There were 31 male patients (58%) and 43 female patients (42%). Tumour size ranged from 1 to 30 cm (mean 9.09 cm; SD 6.22 cm). Complete resection (R0) was achieved by minimally invasive thoracoscopic resection in 29% and thoracotomy in 57%; 25% of SFTPs showed histological evidence of malignancy, according to England criteria. Recurrence occurred in 21% and 10% of patients had metastases; 83% of patients with metastases and 39% of patients with recurrence died within 5 years. The median recurrence-free survival for histologically benign SFTP was not reached, compared to 8 years for malignant SFTP. The five-year overall survival rate was 84%. Mitotic rate ≥1/10 HPF, high cellularity, nuclear atypia, Ki-67 level >5% and poorly circumscribed (sessile) growth pattern were associated with poor long-term outcome. CONCLUSIONS: Pathological differentiation of SFTP morphology into pedunculated, well circumscribed and poorly circumscribed (sessile) growth pattern is recommended. Due to the misleading classification into histologically benign and malignant, all unpedunculated SFTP should be classified as potentially aggressive. Lifelong follow-up is mandatory.
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Neoplasias Pleurais , Tumor Fibroso Solitário Pleural , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Pleura/patologia , Tumor Fibroso Solitário Pleural/cirurgia , Tumor Fibroso Solitário Pleural/patologia , Neoplasias Pleurais/cirurgia , Estudos Retrospectivos , Toracotomia/métodosRESUMO
Lung carcinoma is still one of the most common forms of cancer in both sexes in Germany and the most common cause of cancer-related death. However, we are in the midst of a revolution in the treatment of lung cancer. Above all, the new immune and target therapies as well as the possible combinations of the individual therapy components have expanded the spectrum of drug therapy for lung cancer in recent years.Great progress has also been made in other fields. Be it in the context of early detection, where low-dose CT screening will soon be established for patients at risk, or in the context of molecular diagnostics with the identification of a large number of targets that can be specifically treated with tyrosine kinase inhibitors.Lung carcinoma therapy is moving on the direction of personalized tumor therapy that is specially tailored to each individual patient. Many studies on new drugs or new markers are ongoing. It is all the more important to keep track of the large number of newly approved substances and possibilities. Every patient should therefore, if possible, be treated in a lung cancer center with a therapy decision made in an interdisciplinary tumor board.The updated S3 guideline "Prevention, diagnostics, therapy and aftercare of lung cancer" was published in November 2022 as part of the guideline program oncology of the Working Group of Scientific Medical Societies, the German Cancer Society and the German Cancer Aid, financed by the German Cancer Aid. The full guideline is available at https://www.leitlinienprogramm-onkologie.de/leitlinien/lungenkrebs/ or in the guideline program app.There are already new treatment options that have not yet been taken into account in the recommendations. In order to take account of the dynamics of medical progress, the S3 guideline is going to be continued as a living guideline with annually updates.
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Carcinoma , Neoplasias Pulmonares , Humanos , Detecção Precoce de Câncer , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Oncologia , PulmãoRESUMO
An important challenge remains in identifying the baseline characteristics of cancer patients who will mostly benefit from immune checkpoint inhibitor (ICI) therapies. Furthermore, biomarkers could help in the choice of an optimal therapy duration after a primary therapy response. In this pilot study, the time courses of four different immune cell parameters were followed in 12 patients with advanced non-small-cell lung cancer (NSCLC) undergoing ICI therapy combined with chemotherapy and surviving at least 12 months. Blood was collected at the time point of the first and third antibody administration, as well as after 12 months of patients' survival. Using multi-color flow cytometry, two suppressive markers (neutrophil/lymphocyte ratio (NLR) and the frequency of circulating HLA-DRlow monocytes), as well as two markers of an ongoing immune response (6-Sulfo LacNAc (slan)+ non-classical monocytes and dendritic cell (DC) subtypes), were determined. In most of those who survived > 12 months, a low NLR and a low number of HLA-DRlow monocytes combined with clearly detectable numbers of slan+ non-classical monocytes and of DC subtypes were seen. Two of the patients had an increase in the suppressive markers paired with a decrease in slan+ non-classical monocytes and in DC subtypes, which, in at least one patient, was the correlate of an ongoing clinical progression. Our results implicate that the NLR, specific subtypes of monocytes, and the number of blood DCs might be useful predictive biomarkers for cancer patients during long-term treatment with ICI/chemotherapy.
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In this exploratory prospective observational study on 40 small cell lung cancer (SCLC) patients treated with a combination of chemotherapy and immune checkpoint inhibitors, blood immune cells were characterized by multi-color flow cytometry at the baseline and at the third therapy cycle. The numbers of neutrophils and of T-, B-, and NK cells, as well as the frequency of HLA-DRlow monocytes, 6-SulfoLacNAc (slan)+ non-classical monocytes and circulating dendritic cell (DC) subtypes were determined. The prognostic value of the parameters was evaluated by the patient's survival analysis with overall survival (OS) as the primary endpoint. In addition, blood cell parameters from SCLC patients were compared to those from non-SCLC (NSCLC). The global median OS of patients was 10.4 ± 1.1 months. Disease progression (15% of patients) correlated with a higher baseline neutrophil/lymphocyte ratio (NLR), more HLA-DRlow monocytes, and lower NK cell and DC numbers. The risk factors for poor OS were the presence of brain/liver metastases, a baseline NLR ≥ 6.1, HLA-DRlow monocytes ≥ 21% of monocytes, slan+ non-classical monocytes < 0.12%, and/or CD1c+ myeloid DC < 0.05% of leukocytes. Lymphocytic subpopulations did not correlate with OS. When comparing biomarkers in SCLC versus NSCLC, SCLC had a higher frequency of brain/liver metastases, a higher NLR, the lowest DC frequencies, and lower NK cell numbers. Brain/liver metastases had a substantial impact on the survival of SCLC patients. At the baseline, 45% of SCLC patients, but only 24% of NSCLC patients, had between three and five risk factors. A high basal NLR, a high frequency of HLA-DRlow monocytes, and low levels of slan+ non-classical monocytes were associated with poor survival in all lung cancer histotypes. Thus, the blood immune cell signature might contribute to a better prediction of SCLC patient outcomes and may uncover the pathophysiological peculiarities of this tumor entity.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Hepáticas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Antígenos HLA-DR , Células Matadoras Naturais , Neutrófilos , Neoplasias Hepáticas/tratamento farmacológicoRESUMO
Although immune checkpoint inhibitor (ICI) therapies have improved the treatment of patients with advanced non-small cell lung cancer (NSCLC), several patients do not achieve durable clinical responses. Biomarkers for the prediction of therapy responses are urgently needed. To identify blood cell parameters correlating with patients' survival, immune cells from 90 patients with NSCLC undergoing a combination of ICI and chemotherapy were prospectively monitored. At the time point of the first and third antibody administration, complete leukocyte blood count, the percentage of HLA-DRlow monocytes, the percentage of 6-Sulfo LacNAc (slan)+CD16+ non-classical monocytes, and the number of circulating dendritic cell (DC) subtypes, as well as T-, B-, and NK cells were determined by multi-color flow cytometry in peripheral blood. The prognostic value of the immune cell parameters investigated was evaluated by patients' survival analysis, with progression-free survival (PFS) as the main criterion. A total of 67 patients (74.4%) showed a partial remission or a stable disease, and 35% of patients even survived 12 months and longer. Patients with a neutrophil-to-lymphocyte ratio (NLR) ≥6.1, a frequency of HLA-DRlow monocytes ≥22%, of slan+ non-classical monocytes <0.25% of leukocytes, and/or a sum of myeloid DC (MDC) and plasmacytoid DC (PDC) ≤0.14% of leukocytes had a poorer prognosis. The hazard ratio for PFS was 2.097 (1.208−3.640) for the NLR, 1.964 (1.046−3.688) for HLA-DRlow monocytes, 3.202 (1.712−5.99) for slan+ non-classical monocytes, and 2.596 (1.478−4.56) for the MDC/PDC sum. Patients without any of the four risk factors showed the best PFS. Furthermore, low NK cell counts correlated with shorter PFS (cutoff 200 cells/µL). Female patients had lower baseline NK cell counts and a shorter PFS. Our study confirms the usefulness of blood immune cells as biomarkers for clinical response and survival in NSCLC patients undergoing a combined ICI/chemotherapy.
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Nivolumab was the first immune checkpoint inhibitor approved for use in advanced non-small cell lung cancer (NSCLC). This noninterventional, prospective cohort study investigates real-world effectiveness of nivolumab in pretreated NSCLC patients in Germany (Enlarge-Lung/CA209-580). Patients with squamous (SQ) or nonsquamous (NSQ) NSCLC previously treated for locally advanced or metastatic (stage IIIB/IV) disease received nivolumab according to the current Summary of Product Characteristics. Overall survival (OS) was the primary endpoint. Of 907 patients enrolled, 660 patients who were followed for at least 12 months across 79 study centers in Germany, were analyzed. Median OS was 11.2 months [95% confidence interval (CI), 9.1-12.9]; outcomes for the 418 patients with NSQ histology [13.1 mo (95% CI, 10.6-15.6)] were more favorable than outcomes for the 242 patients with SQ histology [8.9 mo (95% CI, 6.4-11.3)]. Patients' age, presence of distant or brain metastases, or line of therapy did not affect outcomes; however, patients with poor performance status (ECOG-PS ≥2, n=80) had shorter median OS [4.7 mo (95% CI, 3.1-5.4)]. This study represents one of the largest real-world cohorts providing outcomes of nivolumab in pretreated NSCLC. The results match well with the published evidence from pivotal clinical trials and demonstrate clinical effectiveness of nivolumab in advanced NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/efeitos adversos , Estudos ProspectivosRESUMO
Sarcoidosis can evolve into a chronic disease with persistent granulomas accompanied by progressive fibrosis. While an unlimited inflammatory response suggests an impaired immune control in sarcoid lesions, it stands in contrast to the massive infiltration with CD4(+)CD25(high)FoxP3(+) regulatory T cells. We here revealed that those Treg cells in affected lung lesions were mainly derived from activated natural Treg cells with GARP (LRRC32)-positive phenotype but exhibited reduced repressor capacities despite high IL-10 and TGF-beta 1 levels. The repressive capacity of blood Treg cells, in contrast, was not impaired compared to age-matched healthy donors. Treg derived cells in granuloma lesions have undergone extensive rounds of amplifications indicated by shortened telomeres compared to blood Treg cells of the same patient. Lesional Treg derived cells moreover secreted pro-inflammatory cytokines including IL-4 which sustains granuloma formation through fibroblast amplification and the activation of mast cells, the latter indicated by the expression of membrane-bound oncostatin M.
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Granuloma/imunologia , Sarcoidose Pulmonar/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Proliferação de Células , Separação Celular , Feminino , Citometria de Fluxo , Imunofluorescência , Humanos , Imuno-Histoquímica , Memória Imunológica/imunologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
OBJECTIVES: After decades of unsuccessful efforts in inhibiting KRAS, promising clinical data targeting the mutation subtype G12C emerge. Since little is known about outcome with standard treatment of patients with G12C mutated non-small cell lung cancer (NSCLC), we analyzed a large, representative, real-world cohort from Germany. PATIENTS AND METHODS: A total of 1039 patients with advanced KRAS-mutant or -wildtype NSCLC without druggable alterations have been recruited in the prospective, observational registry CRISP from 12/2015 to 06/2019 by 98 centers in Germany. Details on treatment, best response, and outcome were analyzed for patients with KRAS wildtype, G12C, and non-G12C mutations. RESULTS: Within the study population, 160 (15.4 %) patients presented with KRAS G12C, 251 (24.2 %) with non-G12C mutations, 628 (60.4 %) with KRAS wildtype. High PD-L1 expression (Tumor Proportion Score, TPSâ¯>â¯50 %) was documented for 28.0 %, 43.5 %, and 28.9 % (wildtype, G12C, non-G12C) of the tested patients; 68.8 %, 89.3 %, and 87.7 % of the patients received first-line treatment combined with an immune checkpoint-inhibitor in 2019. TPSâ¯>â¯50 % vs. TPSâ¯<â¯1 % was associated with a significantly decreased risk of mortality in a multivariate Cox model (HR 0.39, 95 % CI 0.26-0.60, p=<0.001). There were no differences in clinical outcome between KRAS wildtype, G12C or non-G12C mutations and KRAS mutational status was not prognostic in the model. CONCLUSION: Here we describe the so far largest prospectively recruited cohort of patients with advanced NSCLC and KRAS mutations, with special focus on the G12C mutation. These data constitute an extremely valuable historical control for upcoming clinical studies that employ KRAS inhibitors.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Alemanha , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras)/genética , Sistema de RegistrosRESUMO
Many different approaches for improving the prognosis of patients with advanced non-small-cell lung cancer (NSCLC) are currently being investigated. This article discusses the significance of maintenance therapy after primary chemotherapy and reviews study data on second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), inhibitors of insulin-like growth factor receptors (IGFR), vascular-disrupting agents (VDAs) and multi-TKIs of vascular endothelial growth factor receptors (VEGFR). The article also looks at the future prospects of using genetic markers in the field of NSCLC.
Assuntos
Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Drogas em Investigação/administração & dosagem , Receptores ErbB/análise , Neoplasias Pulmonares/tratamento farmacológico , Assistência ao Convalescente , Quinase do Linfoma Anaplásico , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Carcinoma Pulmonar de Células não Pequenas/genética , Análise Mutacional de DNA , Drogas em Investigação/efeitos adversos , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Marcadores Genéticos/genética , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Neoplasias Pulmonares/genética , Estadiamento de Neoplasias , Proteínas de Fusão Oncogênica/genética , Prognóstico , Proteínas Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases , Receptores de Somatomedina/antagonistas & inibidores , Receptores de Somatomedina/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
The aim of this study was to investigate the expression of the coinhibitory molecule PD-L1/CD274 in monocytes and dendritic cells (DC) in the blood of lung cancer patients undergoing PD1 inhibitor therapy and to correlate data with patient's outcome. PD-L1/CD274 expression of monocytes, CD1c+ myeloid DC (mDC) and CD303+ plasmacytoid DC (pDC) was determined by flow cytometry in peripheral blood at immunotherapy onset. The predictive value of the PD-L1/CD274-expression data was determined by patients' survival analysis. Patients with a high PD-L1/CD274 expression of monocytes and blood DC subpopulations rarely responded to PD1 inhibitor therapy. Low PD-L1/CD274 expression of monocytes and DC correlated with prolonged progression-free survival (PFS) as well as overall survival (OS). The highest PD-L1/CD274 expression was found in CD14+HLA-DR++CD16+ intermediate monocytes. Whereas the PD-L1/CD274 expression of monocytes and DC showed a strong positive correlation, only the PD-L1/CD274 expression of DC inversely correlated with DC amounts and lymphocyte counts in peripheral blood. Our results implicate that a high PD-L1/CD274 expression of blood monocytes and DC subtypes is a risk factor for therapy response and for the survival of lung cancer patients undergoing PD1 inhibitor therapy.
RESUMO
Characterization of host immune cell parameters before and during immunotherapy is expected to identify predictive biomarkers for clinical outcome. We prospectively monitored blood immune cells from 35 patients with advanced non-small cell lung cancer undergoing checkpoint inhibitor monotherapy. The aim was to identify parameters correlating with better/worse outcome. Peripheral blood was serially collected before each infusion at the onset and at cycle 3 and 5 of immunotherapy. A complete leukocyte blood count, the lymphocytic subpopulations and the percentages of both HLA-DR monocytes and dendritic cells (DC) were monitored. Disease control was defined as partial/complete response and stable disease on computed tomography scan according to RECIST 1.1. The predictive value of the immune cell parameters investigated was evaluated by patients' survival analysis. Forty percent of patients showed a clinical response, and the global median overall survival was 7.0 months (95% confidence interval: 3.5-10.5). Patients with an initial neutrophil-to-lymphocyte ratio (NLR) ≥5.2, and/or an amount of HLA-DR monocytes ≥11% and/or a total DC level ≤0.4% of leukocytes did rarely respond to PD-1 inhibitor therapy. Otherwise, the immunotherapy-induced decrease of the neutrophil-to-lymphocyte ratio and/or HLA-DR monocytes and the increase of total DC frequencies were correlated with improved therapy response and prolonged overall survival. Blood values in the third cycle of immunotherapy did already reflect the effects observed. On the basis of the 3 immune cell parameters identified we created 3 different variants of scores that enable to stratify patients into groups of risk/therapy response. Our results warrant further investigation in larger prospective clinical trials for validation.