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PURPOSE: Little is known about the use of psychosocial services in lung cancer survivors and patients who have survived the diagnosis for at least one year. We investigated the frequency of use, stratified by radiation therapy received, its associated factors, and the reasons for non-use of those services. METHODS: We performed a multicenter (nâ¯= 6 hospitals) cross-sectional study using data from medical records, patient reported questionnaires, and computer-assisted telephone interviews. Odds ratios (OR) for factors potentially associated with the use of any type of psychosocial services were calculated using multivariable logistic regression. RESULTS: We included 604 lung cancer patients/survivors. Of them, 60% (69% of those who had received radiotherapy) had used some kind of psychological and/or social service in the past (47% psychological, 42% social); 39% had used inpatient care, 24% outpatient care (cancer counselling center, general counselling center, psychological counselling by family doctor, psychotherapy, patient support group, pastoral work). Of those who visited a rehabilitation clinic, 66% received psychosocial care there. Factors associated with using psychosocial services in general were female gender (OR 1.96, 95% CI 1.32-2.93), poor emotional functioning (per unit decrease: OR 0.99, 95% CI 0.98-0.996), and younger age (per year decrease: OR 0.95, 95% CI 0.93-0.97). CONCLUSIONS/IMPLICATIONS: The high proportion of psychosocial care users among lung cancer survivors in Germany indicates that patients are interested in using it and that an unmet need exists. The creation of a broad spectrum of easily accessible services with high quality is important to enable and facilitate use.
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Sobreviventes de Câncer/psicologia , Neoplasias Pulmonares/psicologia , Sistemas de Apoio Psicossocial , Adulto , Fatores Etários , Idoso , Sobreviventes de Câncer/estatística & dados numéricos , Ajustamento Emocional , Feminino , Alemanha , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Equipe de Assistência ao Paciente , Fatores SexuaisRESUMO
BACKGROUND: Different work flows have been proposed to use miRNAs as blood-borne biomarkers. In particular, the method used for collecting blood from patients can considerably influence the diagnostic results. METHODS: We explored whether dried blood spots (DBSs) facilitate stable miRNA measurements and compared its technical stability with biological variability. First, we tested the stability of DBS samples by generating from 1 person 18 whole-genome-wide miRNA profiles of DBS samples that were exposed to different temperature and humidity conditions. Second, we investigated technical reproducibility by performing 7 replicates of DBS again from 1 person. Third, we investigated DBS samples from 53 patients with lung cancer undergoing different therapies. Across these 3 stages, 108 genome-wide miRNA profiles from DBS were generated and evaluated biostatistically. RESULTS: In the stability analysis, we observed that temperature and humidity had an overall limited influence on the miRNomes (average correlation between the different conditions of 0.993). Usage of a silica gel slightly diminished DBS' technical reproducibility. The 7 technical replicates had an average correlation of 0.996. The correlation with whole-blood PAXGene miRNomes of the same individual was remarkable (correlation of 0.88). Finally, evaluation of the samples from the 53 patients with lung cancer exposed to different therapies showed that the biological variations exceeded the technical variability significantly (P < 0.0001), yielding 51 dysregulated miRNAs. CONCLUSIONS: We present a stable work flow for profiling of whole miRNomes on the basis of samples collected from DBS. Biological variations exceeded technical variations significantly. DBS-based miRNA profiles will potentially further the translational character of miRNA biomarker studies.
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Teste em Amostras de Sangue Seco/normas , Neoplasias Pulmonares/diagnóstico , MicroRNAs/análise , Estabilidade de RNA , Biologia Computacional , Humanos , MicroRNAs/química , Reprodutibilidade dos TestesRESUMO
Cylindromatosis (CYLD) is a ubiquitously expressed deubiquitinating enzyme which removes activating ubiquitin residues from important signaling molecules of the NF-κB pathway. In CYLDex7/8 transgenic mice, a naturally occurring short isoform (sCYLD) is overexpressed in the absence of full length CYLD, leading to excessive NF-κB activity. Herein, we investigated the impact of the CYLDex7/8 mutation selectively in T cells on the development of experimental allergic airway disease induced by sensitization and challenge with ovalbumin. Compared with their wildtype littermates, mice bearing the T cell-specific mutation (CD4+CYLDex7/8) display stronger eosinophilia and mucus production in the lungs and higher IgE serum levels. The reason for these observations is excessive production of T cell-derived IL-9, a cytokine to whom allergy-promoting properties were ascribed. Consequently, blockade of IL-9 in CD4+CYLDex7/8 mice alleviates the development of disease symptoms. Thus, by polarization of the T cell cytokine response, sCYLD can favor the development of allergic airway disease.
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Asma/genética , Linfócitos T CD4-Positivos/fisiologia , Eosinófilos/fisiologia , Hipersensibilidade/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Cutâneas/genética , Proteínas Supressoras de Tumor/metabolismo , Animais , Enzima Desubiquitinante CYLD , Humanos , Interleucina-9/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Muco/metabolismo , Mutação/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
BACKGROUND: Radical treatment for oligometastatic non-small-cell lung cancer (NSCLC) has a curative potential for selected patients. The present retrospective study was designed to examine the relevance of synchronous vs. metachronous manifestations as a potential prognostic factor when ablative treatments are performed in oligometastatic disease. METHODS: Seventy-five patients with radically treated oligometastatic NSCLC were identified, of whom 39 presented with synchronous and 36 with metachronous metastatic manifestations. For patients with synchronous metastases, an additional therapy of the thoracic locoregional disease with a curative intent (either surgery or radiochemotherapy) was required. All patients with metachronous metastases had a documented remission of the primary tumor. Ablative treatment of the complete extent of oligometastatic disease consisted (as a minimum requirement) of either complete surgical resection or definitive ablative stereotactic radiotherapy. A comparative survival analysis of two groups of patients with oligometastatic NSCLC (synchronous vs. metachronous) and a complementary analysis of prognostic factors for the whole group of patients (by means of Cox regression analysis) was performed. Endpoints were median overall and progression-free survival (OS, PFS, respectively). RESULTS: Of the 75 patients, 57 presented with a solitary metastasis, in only 7 patients metastastatic lesions were present in ≥2 organs and 66 patients had a Karnofsky performance score (KPS) of 80 % or 90 %. The median follow-up was 54.0 months (95 % CI 28-81), the median OS 21.8 months (16.1-27.6) and the median PFS 13.7 months (9.7-17.6). In univariable Cox regression analysis, no single clinical factor was significantly associated with OS. For PFS both 'metastatic involvement of ≥2 organs vs. 1 organ' (hazard ratio (HR) 0.43, 0.23-0.83, p = 0.012) and a 'KPS of 90 % vs. 70-80 %' (HR 4.32, 1.73-10.89, p = 0.02) were significant prognostic factors as calculated by multivariable analysis. Comparing the cohorts with synchronous (n = 39) vs. metachronous oligometastases (n = 36), no differences in median OS and PFS were found. Both cohorts were well-balanced except for the KPS, which was significantly superior in patients with synchronous oligometastases. CONCLUSIONS: Radical treatment of oligometastatic NSCLC was associated with acceptable long-term survival rates in patients with good KPS and it was equally effective for synchronous and metachronous manifestations.
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Neoplasias Encefálicas/terapia , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Neoplasias Primárias Múltiplas/terapia , Segunda Neoplasia Primária/terapia , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Avaliação de Estado de Karnofsky , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/mortalidade , Neoplasias Primárias Múltiplas/secundário , Segunda Neoplasia Primária/mortalidade , Segunda Neoplasia Primária/secundário , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do TratamentoRESUMO
LY2603618 is an inhibitor of checkpoint kinase 1 (CHK1), an important regulator of the DNA damage checkpoints. Preclinical experiments analyzed NCI-H2122 and NCI-H441 NSCLC cell lines and in vitro/in vivo models treated with pemetrexed and LY2603618 to provide rationale for evaluating this combination in a clinical setting. Combination treatment of LY2603618 with pemetrexed arrested DNA synthesis following initiation of S-phase in cells. Experiments with tumor-bearing mice administered the combination of LY2603618 and pemetrexed demonstrated a significant increase of growth inhibition of NCI-H2122 (H2122) and NCI-H441 (H441) xenograft tumors. These data informed the clinical assessment of LY2603618 in a seamless phase I/II study, which administered pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) and escalating doses of LY2603618: 130-275 mg. Patients were assessed for safety, toxicity, and pharmacokinetics. In phase I, 14 patients were enrolled, and the most frequently reported adverse events included fatigue, nausea, pyrexia, neutropenia, and vomiting. No DLTs were reported at the tested doses. The systemic exposure of LY2603618 increased in a dose-dependent manner. Pharmacokinetic parameters that correlate with the maximal pharmacodynamic effect in nonclinical xenograft models were achieved at doses ≥240 mg. The pharmacokinetics of LY2603618, pemetrexed, and cisplatin were not altered when used in combination. Two patients achieved a confirmed partial response (both non-small cell lung cancer), and 8 patients had stable disease. LY2603618 administered in combination with pemetrexed and cisplatin demonstrated an acceptable safety profile. The recommended phase II dose of LY2603618 was 275 mg.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cisplatino/sangue , Cisplatino/farmacocinética , DNA/metabolismo , Feminino , Glutamatos/administração & dosagem , Glutamatos/efeitos adversos , Glutamatos/sangue , Glutamatos/farmacocinética , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/análogos & derivados , Guanina/sangue , Guanina/farmacocinética , Humanos , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/patologia , Pemetrexede , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/sangue , Compostos de Fenilureia/farmacocinética , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Pirazinas/sangue , Pirazinas/farmacocinética , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Advanced non-small cell lung cancer (NSCLC) represents a significant unmet medical need. Despite advances with targeted therapies in a small subset of patients, fewer than 20% of patients survive for more than two years after diagnosis. Cancer vaccines are a promising therapeutic approach that offers the potential for durable responses through the engagement of the patient's own immune system. CV9202 is a self-adjuvanting mRNA vaccine that targets six antigens commonly expressed in NSCLC (NY-ESO-1, MAGEC1, MAGEC2, 5 T4, survivin, and MUC1). METHODS/DESIGN: The trial will assess the safety and tolerability of CV9202 vaccination combined with local radiation designed to enhance immune responses and will include patients with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an EGFR tyrosine kinase inhibitor. Three histological and molecular subtypes of NSCLC will be investigated (squamous and non-squamous cell with/without EGFR mutations). All patients will receive two initial vaccinations with CV9202 prior to local radiotherapy (5 GY per day for four successive days) followed by further vaccinations until disease progression. The primary endpoint of the study is the number of patients experiencing Grade >3 treatment-related adverse events. Pharmacodynamic analyses include the assessment of immune responses to the antigens encoded by CV9202 and others not included in the panel (antigen spreading) and standard efficacy assessments. DISCUSSION: RNActive self-adjuvanted mRNA vaccines offer the potential for simultaneously inducing immune responses to a wide panel of antigens commonly expressed in tumors. This trial will assess the feasibility of this approach in combination with local radiotherapy in NSCLC patients. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01915524/EudraCT No.: 2012-004230-41.
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Vacinas Anticâncer/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , RNA Mensageiro/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimioterapia Adjuvante , Terapia Combinada , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , RNA Mensageiro/efeitos adversos , RNA Mensageiro/uso terapêutico , Doses de Radiação , Radioterapia , Resultado do TratamentoRESUMO
BACKGROUND/AIMS: Congestion is prognostically relevant in cardiac transthyretin amyloidosis (ATTR-CA), but whether congestion has an incremental prognostic value beyond the well-established, congestion-sensitive NT-proBNP is unknown. Therefore, we aimed to comparatively evaluate the prognostic utility of several congestion surrogates over NT-proBNP. METHODS: We estimated hazard ratios by Cox proportional hazards regressions with time-varying covariates from a panel data set of the local amyloidosis cohort study AmyKoS. Different models were compared by using chi(χ)2-statistics measuring overall model significance. RESULTS/CONCLUSION: 131 ATTR-CA patients (wild-type 84.0%, hereditary 6.9%, without genetic testing 9.2%; median age 78.7 (quartiles 73.3, 82.1) years; 85.5% male) with 566 observations across a median follow-up of 38.2 (30.6; 48.2) months were analyzed. 83.2% received disease-modifying treatment; 20.6% participated concurrently in placebo-controlled gene silencer trials. Information on congestion improved biomarker-driven risk stratification and identified patients at the highest risk. Echocardiographic congestion markers performed better than clinical findings and daily diuretic use/dosage. Relevant adjusters were daily diuretic dosage, disease-modifying treatment, eGFR, and right atrial volume. NT-proBNP and the tricuspid regurgitation peak velocity (tr-vmax) provided an easy-to-use stratification with overall model performance similar to NAC and Mayo staging systems. Further analyses are necessary for validation and to identify the optimal cut points of the congestion markers.
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PURPOSE: Phase 3 studies of intravenous amivantamab demonstrated efficacy across EGFR-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy. PATIENTS AND METHODS: Patients with EGFR-mutated advanced NSCLC who progressed following osimertinib and platinum-based chemotherapy were randomized 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Co-primary pharmacokinetic noninferiority endpoints were trough concentrations (Ctrough; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUCD1-D15). Key secondary endpoints were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory endpoint. RESULTS: Overall, 418 patients underwent randomization (subcutaneous group, n=206; intravenous group, n=212). Geometric mean ratios of Ctrough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04-1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27-1.61) at cycle-4-day-1; the cycle-2 AUCD1-D15 was 1.03 (90% CI, 0.98-1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42-0.92; nominal P=0.02). Fewer patients in the subcutaneous group experienced infusion-related reactions (13% versus 66%) and venous thromboembolism (9% versus 14%) versus the intravenous group. Median administration time for first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab from 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; end-of-treatment rates were 85% and 35%, respectively. CONCLUSION: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced infusion-related reactions, increased convenience, and prolonged survival.
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Sobreviventes de Câncer/psicologia , Nível de Saúde , Neoplasias Pulmonares/psicologia , Estresse Psicológico/psicologia , Adulto , Idoso , Ansiedade/psicologia , Estudos Transversais , Depressão/psicologia , Feminino , Alemanha , Humanos , Neoplasias Pulmonares/complicações , Masculino , Pessoa de Meia-Idade , Estresse Psicológico/etiologia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: We initiated this preclinical study in order to analyze the impact of sorafenib single treatment versus combination treatment in human colorectal cancer. METHODS: The effect of increasing sorafenib doses on proliferation, apoptosis, migration, and activation of signal cascades was analyzed in vitro. The effect of sorafenib single treatment versus 5-fluorouracil (5-FU) single treatment and combination therapy on in vivo proliferation and target cytokine receptor/ligand expression was analyzed in a human colon cancer xenograft mouse model using HT29 tumor cells. RESULTS: In vitro, SW480 and HT29 cell lines were sensitive to sorafenib, as compared to Caco2 and SW620 cell lines, independent of the mutation status of K-ras, Raf, PTEN, or PI3K. The effect on migration was marginal, but distinct differences in caspases activation were seen. Combination strategies were beneficial in some settings (sorafenib + 5-FU; irinotecan) and disadvantageous in others (sorafenib + oxaliplatin), depending on the chemotherapeutic drug and cell line chosen. Sensitive cell lines revealed a downregulation of AKT and had a weak expression level of GADD45ß. In resistant cell lines, pp53 and GADD45ß levels decreased upon sorafenib exposure. In vivo, the combination treatment of sorafenib and 5-FU was equally effective as the respective monotherapy concerning tumor proliferation. Interestingly, treatment with either sorafenib or 5-FU resulted in a significant decrease of VEGFR1 and PDGFRß expression intensity. CONCLUSIONS: In colorectal cancer, a sensitivity towards sorafenib exists, which seems similarly effective as a 5-FU monotherapy. A combination therapy, in contrast, does not show any additional effect.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Caspases/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/enzimologia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Fluoruracila/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Antígeno Ki-67/metabolismo , Camundongos , Camundongos SCID , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Compostos de Fenilureia/farmacologia , Transdução de Sinais/efeitos dos fármacos , SorafenibeRESUMO
PURPOSE: We aimed at exploring the quality of life (QOL) of lung cancer survivors with proven tyrosine-kinase receptor (RTK) genetic alterations and targeted tyrosine-kinase inhibitors (TKI) therapy, compared to lung cancer survivors with no-RTK alterations and no-TKI therapy. METHODS: Data were collected in a cross-sectional multi-centre study. Primary lung cancer survivors were asked about their socio-demographic and clinical information, QOL, symptom burden, and distress. QOL and symptom burden were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), and distress with the Patient Health Questionnaire-4 (PHQ-4). Demographic and clinical characteristics were reported in absolute and relative frequencies, QOL, and symptom burden using mean scores. Differences in mean scores with relative 95% confidence intervals were used for comparison. RESULTS: Three groups of survivors were defined: group A with proven RTK alterations, TKI therapy at any time during therapy, and stage IV lung cancer at diagnosis (n = 49); group B: non-TKI therapy and stage IV lung cancer (n = 121); group C: non-TKI therapy and stage I-III lung cancer (n = 495). Survivors in group A reported lower QOL (mean score difference = -11.7 vs. group B) and symptom burden for dyspnoea (difference = -11.5 vs. group C), and higher symptom burden for appetite loss (difference = + 11.4 vs. group C), diarrhoea and rash (differences = + 25.6, + 19.6 and + 13.2, + 13.0, respectively, vs. both groups). CONCLUSIONS: Our results suggest that the specific side effects of TKI therapy can impair QOL among lung cancer survivors. Therefore, specific focus towards the optimal management of these side effects should be considered.
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Sobreviventes de Câncer , Neoplasias Pulmonares , Estudos Transversais , Humanos , Pulmão , Neoplasias Pulmonares/tratamento farmacológico , Qualidade de Vida , Inquéritos e Questionários , Sobreviventes , TirosinaRESUMO
Background: Immune checkpoint inhibitors (ICIs) with or without chemotherapy represent first-line standard of care for patients with advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. The most appropriate second-line therapy after failing immunochemotherapy remains an open question. Nintedanib, an oral triple angiokinase inhibitor that targets the vascular endothelial growth factor receptor, fibroblast growth factor receptor, and, platelet-derived growth factor receptor, in combination with docetaxel, is approved for treatment of advanced NSCLC (adenocarcinoma histology) following progression on first-line chemotherapy. Methods: VARGADO (NCT02392455) is an ongoing, prospective, non-interventional study investigating the efficacy and safety of nintedanib plus docetaxel following first-line chemotherapy with or without ICIs in patients with locally advanced, metastatic, or locally recurrent NSCLC of adenocarcinoma histology. This analysis focuses on Cohort C, which enrolled patients who had received prior first line chemotherapy with ICIs. Patients received second-line docetaxel (75 mg/m2) by intravenous infusion on Day 1, plus oral nintedanib (200 mg twice daily) on Days 2-21 of each 21-day cycle during routine clinical care. The primary endpoint is overall survival (OS) rate 1 year after the start of treatment with nintedanib plus docetaxel. Secondary endpoints include progression-free survival (PFS), OS, and disease control rate (DCR). Safety was also assessed. Results: Among 137 patients treated, the median age was 63 years (range, 37-84); 57 patients (41.6%) were female, most patients had Eastern Cooperative Oncology Group performance status of 0 (28.5%) or 1 (43.1%); 118 (86.1%) had stage IV NSCLC and 27 (19.7%) had brain metastases. Most (n=120, 87.6%) patients had received pembrolizumab/pemetrexed/platinum-based chemotherapy as first-line treatment. In 80 patients with available response data, the DCR was 72.5% (complete response: 1.3%; partial response: 36.3%; stable disease: 35.0%). Median progression-free survival was 4.8 months (95% confidence interval: 3.7-6.6). OS data were immature. Grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs leading to treatment discontinuation were reported in 62 (45.3%), 50 (36.5%), and 40 patients (29.2%), respectively. Conclusions: This analysis indicates that nintedanib plus docetaxel represents an effective second-line treatment option in patients with advanced adenocarcinoma NSCLC following progression on first-line immunochemotherapy. The safety profile was manageable with no unexpected signals.
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Background: Most non-small cell lung cancers occur in elderly and frequently comorbid patients. Therefore, it is necessary to evaluate the efficacy of biomodulatory active therapy regimen, concertedly interfering with tumor-associated homeostatic pathways to achieve tumor control paralleled by modest toxicity profiles. Patients and Methods: The ModuLung trial is a national, multicentre, prospective, open-label, randomized phase II trial in patients with histologically confirmed stage IIIB/IV squamous (n = 11) and non-squamous non-small cell (n = 26) lung cancer who failed first-line platinum-based chemotherapy. Patients were randomly assigned on a 1:1 ratio to the biomodulatory or control group, treated with nivolumab. Patients randomized to the biomodulatory group received an all-oral therapy consisting of treosulfan 250 mg twice daily, pioglitazone 45 mg once daily, clarithromycin 250 mg twice daily, until disease progression or unacceptable toxicity. Results: The study had to be closed pre-maturely due to approval of immune checkpoint inhibitors (ICi) in first-line treatment. Thirty-seven patients, available for analysis, were treated in second to forth-line. Progression-free survival (PFS) was significantly inferior for biomodulation (N = 20) vs. nivolumab (N = 17) with a median PFS (95% confidence interval) of 1.4 (1.2-2.0) months vs. 1.6 (1.4-6.2), respectively; with a hazard ratio (95% confidence interval) of 1.908 [0.962; 3.788]; p = 0.0483. Objective response rate was 11.8% with nivolumab vs. 5% with biomodulation, median follow-up 8.25 months. The frequency of grade 3-5 treatment related adverse events was 29% with nivolumab and 10% with biomodulation. Overall survival (OS), the secondary endpoint, was comparable in both treatment arms; biomodulation with a median OS (95% confidence interval) of 9.4 (6.0-33.0) months vs. nivolumab 6.9 (4.6-24.0), respectively; hazard ratio (95% confidence interval) of 0.733 [0.334; 1.610]; p = 0.4368. Seventy-five percent of patients in the biomodulation arm received rescue therapy with checkpoint inhibitors. Conclusions: This trial shows that the biomodulatory therapy was inferior to nivolumab on PFS. However, the fact that OS was similar between groups gives rise to the hypothesis that the well-tolerable biomodulatory therapy may prime tumor tissues for efficacious checkpoint inhibitor therapy, even in very advanced treatment lines where poor response to ICi might be expected with increasing line of therapy.
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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.
Assuntos
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
PURPOSE: Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) demonstrated survival benefit versus bevacizumab, carboplatin, and paclitaxel (BCP) in chemotherapy-naïve nonsquamous non-small-cell lung cancer (NSCLC). We present safety and patient-reported outcomes (PROs) to provide additional information on the relative impact of adding atezolizumab to chemotherapy with and without bevacizumab in nonsquamous NSCLC. METHODS: Patients were randomly assigned to receive atezolizumab, carboplatin, and paclitaxel (ACP), ABCP, or BCP. Coprimary end points were overall survival and investigator-assessed progression-free survival. The incidence, nature, and severity of adverse events (AEs) were assessed. PROs, a secondary end point, were evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-Core 30 and EORTC QLQ-Lung Cancer 13. RESULTS: Overall, 400 (ACP), 393 (ABCP), and 394 (BCP) patients were safety evaluable (ie, intention-to-treat population that received one or more doses of any study treatment). More patients had grade 3/4 treatment-related AEs during the induction versus maintenance phase (ACP, 40.5% v 8.2%; ABCP, 48.6% v 21.2%; BCP, 44.7% v 11.1%). During induction, the incidence of serious AEs (SAEs) was 28.3%, 28.5%, and 26.4% in the ACP, ABCP, and BCP arms, respectively. During maintenance, SAE incidences were 20.0%, 26.3%, and 13.0%, respectively. Completion rates of the PRO questionnaires were > 88% at baseline and remained ≥ 70% throughout most study visits. Across arms, patients on average reported no clinically meaningful worsening of global health status or physical functioning scores through cycle 13. Patients across arms rated common symptoms with chemotherapy and immunotherapy similarly. CONCLUSION: ABCP seems tolerable and manageable versus ACP and BCP in first-line nonsquamous NSCLC. Treatment tolerability differed between induction and maintenance phases across treatment arms. PROs reflect a minimal treatment burden (eg, health-related quality of life, symptoms) with each regimen.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab/administração & dosagem , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Doxorubicin represents the standard first-line treatment for metastatic soft-tissue sarcoma. We assessed the efficacy and safety of trofosfamide in elderly patients. In this controlled phase II trial, we randomly (1:2) assigned 120 previously untreated patients with soft-tissue sarcoma, older than 60 years, with an Eastern Cooperative Oncology Group score of 0-2, to receive either doxorubicin for 6 cycles (arm A) or oral trofosfamide (arm B). The primary end-point was a 6-month progression-free rate (PFR) in the experimental arm (clinical trial information: NCT00204568). Between August 2004 and October 2012, forty and 80 patients were randomly assigned to arm A and arm B, respectively, in 16 centres. The median age was 70 years (range, 60-89). The primary study end-point (6-month PFR) was exceeded, with 27.6% in arm B (95% confidence interval [CI], 18.0-39.1) and 35.9% in arm A: (95% CI, 21.2-52.8). Survival data in terms of progression-free survival were 4.3 months (95% CI, 2.2-6.3) and 2.8 months (95% CI, 1.7-3.6) and in terms of overall survival were 9.8 months (95% CI, 6.7-11.6) and 12.3 months (95% CI, 9.6-16.2), respectively. The number of serious adverse event (SAE) was 59% in arm A and 30.3% in arm B (p = 0.005). Trofosfamide caused more often dyspnoea and low-grade fatigue, whereas with doxorubicin, more often leukocytopenia, neutropenia and mucositis were seen. Discontinuation rates for reasons other than disease progression were 15.4% (arm A) vs. 7.9% (arm B). In an elderly population of patients, oral trofosfamide achieved the estimated primary end-point 6-month PFR and was associated with a favourable toxicity profile compared with doxorubicin.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/análogos & derivados , Doxorrubicina/uso terapêutico , Sarcoma/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Doxorrubicina/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase NeoplásicaRESUMO
OBJECTIVE: Current in vitro techniques for isolating leukemia-reactive cytotoxic T lymphocytes (CTLs) from healthy donors are of relatively low efficiency and yield responder populations with unknown biological significance. This study aimed at the development of a more reliable approach, allowing generation and expansion of acute myeloid leukemia (AML)-reactive CTLs using primary in vitro stimulation. MATERIALS AND METHODS: We established allogeneic mini-mixed lymphocyte-leukemia cultures (mini-MLLCs) by stimulating donor CD8(+) T cells with human leukocyte antigen (HLA) class I-matched AML blasts in microtiter plates. Before culture, CD8(+) T cells were separated into CD62L((high)+) and CD62L((low)+/neg) subsets enriched for naive/central memory and effector memory cells, respectively. RESULTS: In eight different related and unrelated donor/AML pairs, numerous CTL populations were isolated that specifically lysed myeloid leukemias in association with various HLA-A, -B, or -C alleles. These CTLs expressed T-cell receptors of single Vbeta-chain families, indicating their clonal origin. The majority of CTL clones were obtained from mini-MLLCs initiated with CD62L((high)+) cells. Using antigen-specific stimulation, multiple CTL populations were amplified to 10(8)-10(10) cells within 6 to 8 weeks. Three of four representative CTL clones were capable of completely preventing engraftment of human primary AML blasts in nonobese diabetic/severe combined immune deficient IL2Rgamma(null) mice. CONCLUSION: The mini-MLLC approach allows the efficient in vitro expansion of AML-reactive CTL clones from CD8(+)CD62L((high)+) precursors of healthy donors. These CTLs can inhibit leukemia engraftment in immunodeficient mice, suggesting their potential biological relevance.
Assuntos
Linfócitos T CD8-Positivos/citologia , Subunidade gama Comum de Receptores de Interleucina/genética , Selectina L/biossíntese , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/prevenção & controle , Linfócitos T Citotóxicos/transplante , Alelos , Animais , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Células Clonais , Testes Imunológicos de Citotoxicidade , Genes MHC Classe I , Humanos , Leucemia Mieloide Aguda/sangue , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Transplante de Neoplasias , Padrões de Referência , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologiaRESUMO
Golgi α-mannosidase II (GMII) is a glycoside hydrolase playing a crucial role in the N-glycosylation pathway. In various tumour cell lines, the distribution of N-linked sugars on the cell surface is modified and correlates with the progression of tumour metastasis. GMII therefore is a possible molecular target for anticancer agents. Here, we describe the identification of a non-competitive GMII inhibitor using computer-aided drug design methods including identification of a possible allosteric binding site, pharmacophore search and virtual screening.
Assuntos
Desenho de Fármacos , Complexo de Golgi/enzimologia , alfa-Manosidase/ultraestrutura , Sítio Alostérico , Animais , Sítios de Ligação , Clonagem Molecular , Drosophila melanogaster/enzimologia , Simulação de Acoplamento Molecular , Estrutura Quaternária de Proteína , Proteínas RecombinantesRESUMO
INTRODUCTION: The objective was to assess quality of life (QoL) in lung cancer survivors, compare it to the general population, and identify factors associated with global QoL, physical functioning, emotional functioning, fatigue, pain, and dyspnea. METHODS: Data from NSCLC patients who had survived 1 year or longer after diagnosis were collected cross-sectionally in a multicenter study. QoL was assessed with the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and the lung cancer module QLQ-LC13 across different clinical subgroups and compared to age- and sex-standardized general population reference values. Multivariable linear regression analyses were performed to test the associations of patient-, tumor-, and treatment-related factors with the six primary QoL scales. RESULTS: Six hundred fifty-seven NSCLC patients participated in the study with a median time since diagnosis of 3.7 years (range, 1.0-21.2 years). Compared to the age- and sex-standardized general population, clinically meaningful differences in the QoL detriment were found on almost all domains: lung cancer survivors had clinically relevant poorer global QoL (10 points, p < 0.001). Whereas in 12 months or longer treatment-free patients this detriment was small (8.3), it was higher in patients currently in treatment (16.0). Regarding functioning and symptom scales, respective detriments were largest for dyspnea (41 points), role function (33 points), fatigue (27 points), social function (27 points), physical function (24 points), and insomnia (21 points) observed across all subgroups. The main factor associated with poorer QoL in all primary QoL scales was mental distress (ß |19-31|, all p < 0.001). Detriments in QoL across multiple primary QoL scales were also observed with current treatment (ß |8-12|, p < 0.01), respiratory comorbidity (ß |4-5|, p < 0.01), and living on a disability pension (ß |10-11|, p < 0.01). The main factor associated with better QoL in almost all primary QoL scales was higher physical activity (ß |10-20|, p < 0.001). Better QoL was also observed in patients with high income (ß |10-14|, p < 0.01). CONCLUSIONS: Lung cancer survivors experience both functional restrictions and symptoms that persist long term after active treatment ends. This substantiates the importance of providing long-term supportive care.