BACKGROUND: Programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) immune-checkpoint blockade is a promising new therapeutic strategy in cancer. However, expression patterns and prognostic significance of PD-L1 and PD-1 are still controversial in human malignant pleural mesothelioma (MPM). METHODS: Formalin-fixed paraffin-embedded (FFPE) tumor samples from 203 MPM patients receiving standard treatment without immunotherapy were collected from 5 European centers. PD-L1 and PD-1 expression of tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemistry and correlated with clinical parameters and long-term outcome. RESULTS: High (>10%) PD-L1 TC and PD-1 TILs expressions were found in 18 (8%) and 39 (24%) patients, respectively. PD-L1 was rarely expressed by TILs [≥1%, n=13 (8%); >10%, n=1]. No significant associations were found between the PD-L1 or PD-1 expression of TCs or TILs and clinicopathological parameters such as stage or histological subtype. Notably, patients with high (>10%) TC-specific PD-L1 expression exhibited significantly worse median overall survival (OS) (6.3 vs. 15.1 months of those with low TC PD-L1 expression; HR: 2.51, P<0.001). In multivariate cox regression analysis adjusted for clinical parameters, high TC PD-L1 expression (>10%) proved to be an independent negative prognostic factor for OS (HR: 2.486, P=0.005). There was no significant correlation between PD-L1 or PD-1 expression of TILs and OS. CONCLUSIONS: In this multicenter cohort study, we demonstrate that high (>10%) PD-L1 expression of TCs independently predicts worse OS in MPM. Further studies are warranted to investigate the value of PD-L1/PD-1 expression as a marker for treatment response in MPM patients receiving immunotherapy.

• Klíčová slova
• Malignant pleural mesothelioma (MPM), prognosis, programmed cell death 1 (PD-1), programmed death ligand 1 (PD-L1),
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Spitzoid melanocytic lesions represent a heterogeneous group of proliferations with ambiguous and overlapping terminology. The exact distinction of a Spitz nevus from a Spitzoid melanoma can be very difficult or, in some cases, impossible. Among the Spitzoid lesions, there is a lesion termed an atypical Spitz tumour (AST) that has intermediate histopathologic features between those of a Spitz nevus and a Spitzoid melanoma and thus uncertain malignant potential. There are several rare cases of patients with a Spitzoid melanoma initially misdiagnosed as a Spitz nevus or an AST with fatal consequences. It is, therefore, advised to perform a molecular characterization in cases where uncertain skin lesions are presented, as it may provide extended set of information with a possible impact on the treatment options. Furthermore, preventive measures, such as regular physical and skin examinations, as well as thorough scheduling of individual follow-up visits, are essential in patients with potentially malignant skin nevi. CASE REPORT: We report a case of a young adult female with a history of AST excision with a negative sentinel lymph node biopsy (SLNB) and insufficient follow-up. Four years after the primary dermatological diagnosis, she presented with a giant tumour in the right hemithorax. Radical en bloc resection of the tumour with right pneumonectomy and resection of the pericardium with reconstruction of the pericardium using mesh was performed. A definitive histopathological examination revealed a metastatic melanoma. The association of the previously diagnosed AST and subsequent appearance of melanoma metastases led to a retrospective re-evaluation of the initial lesion. The suspected diagnosis of Spitzoid melanoma, however, was not confirmed. Moreover, the molecular examination revealed a major discordance between the initial lesion and the lung tumour, which most likely excluded the possible association of the lung metastasis with the initial skin lesion. The initial skin lesion was a BRAF-mutant melanoma with Spitzoid features and termed as AST, while the giant lung metastasis was NRAS-mutant melanoma. The subsequent postoperative course was complicated by the appearance of brain metastases that were stereotactically irradiated. Nevertheless, despite complex specialised medical care, the patient's clinical condition rapidly deteriorated. By this time, no active oncological treatment was possible. The patient was delegated to local hospice for palliative care six months after the surgery and died three weeks later. CONCLUSIONS: Our patient was surgically treated at the age of 20 for AST and died four years later of metastatic NRAS-mutant melanoma most likely of different occult origin. Molecular characterization, as well as the close clinical follow-up should be always precisely performed in patients with uncertain skin lesions, such as AST.

• Klíčová slova
• Atypical spitz tumour, Case report, Conventional melanoma, Metastasis, Molecular analysis, Spitz nevus, Spitzoid melanoma,
• MeSH
• epiteloidní a vřetenobuněčný névus genetika   patologie   MeSH
• GTP-fosfohydrolasy genetika   MeSH
• lidé MeSH
• maligní melanom kůže MeSH
• melanom genetika   sekundární   MeSH
• membránové proteiny genetika   MeSH
• mladý dospělý MeSH
• mnohočetné primární nádory genetika   patologie   MeSH
• mutace MeSH
• nádory kůže genetika   patologie   sekundární   MeSH
• nádory plic sekundární   MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• Check Tag
• lidé MeSH
• mladý dospělý MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• BRAF protein, human MeSH Prohlížeč
• GTP-fosfohydrolasy MeSH
• membránové proteiny MeSH
• NRAS protein, human MeSH Prohlížeč
• protoonkogenní proteiny B-Raf MeSH

BACKGROUND: Activating BRAF mutations result in constitutive activation of the MAP kinase signaling cascade, stimulating cell proliferation. BRAF mutations are typical for malignant melanoma, but occur less frequently in other tumors, including in 1-2% cases of non-small cell lung cancer (NSCLC) [1,2]. CASE: We present two case reports of BRAF+ NSCLC patients, treated with 3rd line dabrafenib monotherapy on our department, and also brief review of available information about dabrafenib and its use in monotherapy of BRAF+ NSCLC. CONCLUSION: Monotherapy with BRAF inhibitors presents a viable alternative for BRAF+ NSCLC patients, incapable of combined therapy with trametinib. The lack of proper indication and reimbursement for NSCLC cases remains a problem, and individual treatment approval is required.

• Klíčová slova
• dabrafenib – BRAF – lung cancer – non-small cell – NSCLC – monotherapy,
• MeSH
• antitumorózní látky terapeutické užití   MeSH
• imidazoly terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• nádory plic farmakoterapie   genetika   MeSH
• nemalobuněčný karcinom plic farmakoterapie   genetika   MeSH
• oximy terapeutické užití   MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• antitumorózní látky MeSH
• dabrafenib MeSH Prohlížeč
• imidazoly MeSH
• inhibitory proteinkinas MeSH
• oximy MeSH
• protoonkogenní proteiny B-Raf MeSH

OBJECTIVES: DNA repair proteins have emerged as potential predictors for immunotherapy response alongside PD-L1 expression, tumor-infiltrating lymphocytes (TILs) and tumor mutational burden. We analyzed expression of PD-L1, TILs count and expression of the homologous recombination (HR) protein RAD51, as potential prognostic factors in patients with resected non-small-cell lung carcinoma (NSCLC). MATERIALS AND METHODS: Discovery set included 96 NSCLC patients from the University Hospital Olomouc (Czech Republic) and a replication set included 1109 NSCLC patients from University Hospital Zurich (Switzerland). Tissue microarrays (TMAs) were stained using the automated staining platform Ventana Benchmark Ultra with antibodies against RAD51,CD3, CD8, CD68 and PD-L1. RESULTS: Loss of nuclear RAD51 protein was associated with high TILs (r=-0.25, p = 0.01) and PD-L1 status (10.6 vs. 2.4 %, p = 0.012) in patients receiving neoadjuvant chemo-/radiotherapy (CT/RT). In silico analysis from the TCGA data set showed a negative relationship between RAD51 mRNA expression and CD45 (r = ‒0.422, p < 0.0001), CD68 (r = ‒0.326, p < 0.001), CD3 (r = ‒0.266, p < 0.001) and CD8 (r = ‒0.102, p < 0.001). RAD51 low/PD-L1 high patients were clustered as separate entity in the replication set and in TCGA dataset. High TILs status was significantly associated with improved OS in the replication set (unadjusted HR = 0.57, 95 % CI 0.42-0.76, p < 0.001). Similar results have been seen for CD3, CD8 and CD68. CONCLUSIONS: In conclusion, RAD51 nuclear loss is weakly associated with increased TILs and high PD-L1 at the time of surgery in curatively resected NSCLC and after prior exposure to neoadjuvant chemo- or radiotherapy. Both high TILs and RAD51 nuclear loss were confirmed as independent prognostic factors in curatively resected NSCLC.

• Klíčová slova
• Neoadjuvant, PD-L1, Prognostic, RAD51, Tumor infiltrating lymphocytes,
• MeSH
• antigeny CD274 genetika   MeSH
• lidé MeSH
• nádory plic * genetika   terapie   MeSH
• nemalobuněčný karcinom plic * genetika   terapie   MeSH
• oprava DNA MeSH
• prognóza MeSH
• rekombinasa Rad51 genetika   MeSH
• tumor infiltrující lymfocyty MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Švýcarsko MeSH
• Názvy látek
• antigeny CD274 MeSH
• CD274 protein, human MeSH Prohlížeč
• RAD51 protein, human MeSH Prohlížeč
• rekombinasa Rad51 MeSH

Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. We present a GWAS of a Japanese cohort (700 sarcoidosis cases and 886 controls) with replication in independent samples from Japan (931 cases and 1,042 controls) and the Czech Republic (265 cases and 264 controls). We identified three loci outside the HLA complex, CCL24, STYXL1-SRRM3, and C1orf141-IL23R, which showed genome-wide significant associations (P < 5.0 × 10-8) with sarcoidosis; CCL24 and STYXL1-SRRM3 were novel. The disease-risk alleles in CCL24 and IL23R were associated with reduced CCL24 and IL23R expression, respectively. The disease-risk allele in STYXL1-SRRM3 was associated with elevated POR expression. These results suggest that genetic control of CCL24, POR, and IL23R expression contribute to the pathogenesis of sarcoidosis. We speculate that the CCL24 risk allele might be involved in a polarized Th1 response in sarcoidosis, and that POR and IL23R risk alleles may lead to diminished host defense against sarcoidosis pathogens.

• MeSH
• alely MeSH
• celogenomová asociační studie MeSH
• chemokin CCL24 genetika   metabolismus   MeSH
• genetická predispozice k nemoci * MeSH
• genetické asociační studie MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• lokus kvantitativního znaku MeSH
• odds ratio MeSH
• receptory interleukinů genetika   metabolismus   MeSH
• sarkoidóza diagnóza   etiologie   metabolismus   MeSH
• systém (enzymů) cytochromů P-450 genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Japonsko MeSH
• Názvy látek
• CCL24 protein, human MeSH Prohlížeč
• chemokin CCL24 MeSH
• IL23R protein, human MeSH Prohlížeč
• POR protein, human MeSH Prohlížeč
• receptory interleukinů MeSH
• systém (enzymů) cytochromů P-450 MeSH

We present the clinical case of the patient with nitrofurantoin (FUR) lung toxicity. Diagnosis was made from detailed history of the patient and by studying CT images before the start of FUR treatment. An extensive interstitial changes were evident on HRCT scan at the presentation at our clinic. The definitive diagnosis was supported by negative microbiology and autoantibody screening and almost complete regression of changes after FUR treatment withdrawal. There was no need for corticosteroid treatment or immunosuppressive medication.

• Klíčová slova
• drug induced lung toxicity, nitrofurantoin, treatment,
• MeSH
• antiinfekční látky močové * škodlivé účinky   MeSH
• autoprotilátky MeSH
• lidé MeSH
• nitrofurantoin * škodlivé účinky   MeSH
• plíce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• antiinfekční látky močové * MeSH
• autoprotilátky MeSH
• nitrofurantoin * MeSH

AIM: To compare survival outcomes in patients with non-small cell lung cancer (NSCLC) treated with modern-era drugs (antifolates, antiangiogenics, tyrosine kinase and anaplastic lymphoma kinase inhibitors, immunotherapy) with treatment initiation in 2011-12 and 2015-16, respectively. PATIENTS AND METHODS: Prospective data from Czech TULUNG Registry (960 patients from 2011-12 and 512 patients from 2015-16) were analyzed. Kaplan-Meier analysis was used to estimate overall survival (OS) and progression-free survival (PFS); Cox proportional hazards model to assess factors associated with 2-year survival. RESULTS: Survival at 2 years was more frequent in cohort 2015-16 compared to cohort 2011-12 (43.2% vs. 24% for adenocarcinoma; p<0.001 and 28.7% vs. 11.8% for squamous-cell lung carcinoma; p=0.002). Assignment to cohort 2015-16 and treatment multilinearity (two or more lines in sequence) were associated with higher probability of 2-year survival (hazard ratio=0.666 and hazard ratio=0.597; p<0.001). Comparison of 2-year survivors from both cohorts showed no differences. CONCLUSION: Survival at 2 years probability in stage IIIB-IV NSCLC doubled between 2011-12 and 2015-16; advanced-stage NSCLC may be considered a chronic disease in a large proportion of patients.

• Klíčová slova
• 2-year survival, Non-small cell lung cancer, chronic disease, modern-era treatment, personalized treatment,
• MeSH
• adenokarcinom plic epidemiologie   mortalita   patologie   terapie   MeSH
• chronická nemoc MeSH
• dospělí MeSH
• kohortové studie MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• nádory plic epidemiologie   mortalita   patologie   terapie   MeSH
• následné studie MeSH
• nemalobuněčný karcinom plic epidemiologie   mortalita   patologie   terapie   MeSH
• prognóza MeSH
• registrace statistika a číselné údaje   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• spinocelulární karcinom epidemiologie   mortalita   patologie   terapie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH

BACKGROUND: Iatrogenic pneumothorax is a common complication of various diagnostic and therapeutic procedures such as transbronchial lung biopsies. The classical mode of treatment is chest tube insertion. Pneumothorax devices are now available on the market but there is a dearth of data on their efficacy to treat iatrogenic pneumothorax. It is important to provide such data as the pathophysiology of iatrogenic pneumothorax is different in comparison with spontaneous pneumothorax for which some data is available. METHODS: This is a randomized, non-blinded, actively controlled trial of effectivity of iatrogenic pneumothorax treatment using the Pleuralvent™ device and chest tube insertion (16F). The secondary aim is to compare the overall pain level and the need for analgesic treatment in both treatment arms. We are planning to enrol 126 patients (63 in each treatment arm). DISCUSSION: Preliminary results showed similar effectivity of the Pleuralvent™ system compared to large bore chest tube insertion. This randomized clinical trial should confirm these results and prove that the Pleuralvent™ system is an effective way of treatment of patients with iatrogenic pneumothorax. If Pleuralvent™ proves to have the same level of efficacy, it may become the standard of care of patients with iatrogenic pneumothorax. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03700554.

• Klíčová slova
• Pleuralvent™, chest tube, iatrogenic pneumothorax,
• MeSH
• analgetika terapeutické užití   MeSH
• bolesti na hrudi farmakoterapie   etiologie   MeSH
• hrudní trubice * MeSH
• iatrogenní nemoci * MeSH
• lidé MeSH
• pneumotorax terapie   MeSH
• randomizované kontrolované studie jako téma MeSH
• thorakocentéza škodlivé účinky   přístrojové vybavení   metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• protokol klinické studie MeSH
• Názvy látek
• analgetika MeSH

BACKGROUND: Cardiopulmonary exercise testing (CPET) is a standard part of preoperative evaluation in patients before lung surgical resection. According to current guidelines the risk of such a procedure is estimated according to maximum oxygen consumption (VO2max). Chronotropic incompetence (CI) is a prevalent condition which could possibly influence cardiopulmonary fitness. The aim of this study was to assess the prevalence of CI in patients before surgical lung resections and its influence on CPET results. METHODS: This study enrolled 154 patients (97 men) of average age 66.4±8.3 with newly diagnosed lung cancer indicated for surgical lung resections. All patients underwent CPET (cycle ergometry). Age predicted maximal HR was calculated using the traditional equation (220 - age). Three levels of CI were defined as, 85% HRpred, 80% HRpred and 70% HRpred. The influence of CI on CPET results was evaluated. RESULTS: CI was present in the following ratios: 85% HRpred-48.7%; 80% HRpred-39.6% and 70% HRpred-16.9%. A significant negative correlation was also found between VO2max, maximal heart rate (HR) and maximal work load among all CI groups (P<0.0001). The presence of CI significantly correlated with beta-blocker treatment (P<0.0001). CONCLUSIONS: CI significantly decreases VO2max in patients before lung cancer surgery. It is strongly associated with beta-blocker treatment which could negatively influence risk assessment. It is thus a matter for future discussion, as to whether the evaluation of CI should be part of preoperative care guidelines.

• Klíčová slova
• Chronotropic incompetence (CI), lung cancer surgery, preoperative examination,
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC. METHODS: In this double-blind study, patients with relapsed or refractory SCLC were stratified by relapse type (sensitive versus resistant or refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo plus paclitaxel (henceforth referred to as placebo/paclitaxel) in 28-day cycles. The primary end point was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated. RESULTS: A total of 178 patients were enrolled (89 in each arm). The median PFS was 3.32 months with alisertib/paclitaxel versus 2.17 months with placebo/paclitaxel (hazard ratio [HR] = 0.77, 95% confidence limit [CI]: 0.557-1.067, p = 0.113 in the intent-to-treat population versus HR = 0.71, 95% CI: 0.509-0.985, p = 0.038 with corrected analysis applied). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (cyclin-dependent kinase 6 gene [CDK6], retinoblastoma-like 1 gene [RBL1], retinoblastoma-like 2 gene [RBL2], and retinoblastoma 1 gene [RB1]) had significantly improved PFS with alisertib/paclitaxel versus with placebo/paclitaxel (3.68 versus 1.80 months, respectively [HR = 0.395, 95% CI: 0.239-0.654, p = 0.0003]), and overall survival (7.20 versus 4.47 months, respectively [HR = 0.427, 95% CI: 0.259-0.704, p = 0.00085]). A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. The incidence of grade 3 or higher drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve patients (14%) versus 11 (12%) died on study, including four versus zero treatment-related deaths. CONCLUSIONS: Efficacy signals were seen with alisertib/paclitaxel in relapsed or refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted.

• Klíčová slova
• Alisertib, Aurora A kinase, Paclitaxel, Phase II, SCLC,
• MeSH
• azepiny MeSH
• biologické markery MeSH
• dvojitá slepá metoda MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• nádory plic * farmakoterapie   MeSH
• paclitaxel * MeSH
• přežití po terapii bez příznaků nemoci MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• pyrimidiny MeSH
• retrospektivní studie MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• azepiny MeSH
• biologické markery MeSH
• MLN 8237 MeSH Prohlížeč
• paclitaxel * MeSH
• pyrimidiny MeSH