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Introduction Symptoms of cancer‐related fatigue (CRF) can have a significant impact on patients' quality of life and treatment adherence. We aimed to investigate the relationship between CRF and multiple psychosocial and somatic indicators within a large mixed cancer sample. Methods In this cross‐sectional study, N = 1787 outpatients with cancer were assessed for CRF, pain, anxiety, and depression using validated screening instruments. We further obtained clinical parameters (Hb, CRP, creatinine, leukocytes, ASAT, and ALAT), sociodemographic data (age, gender, income, education level, marital status, parenthood, and living area), and lifestyle factors. Multivariate linear regression models were applied to estimate the impact of each indicator on CRF. Results Overall, 90.6% of patients experienced some CRF, with 14.8% experiencing severe CRF. No gender difference was found in the prevalence of CRF. Patients with higher levels of pain, depressive symptoms, and lower Hb levels had significantly higher levels of CRF (ps <0.001). Lower levels of CRF were observed in patients who had children (p = 0.03), had less education (p < 0.001), and were physically active for more than 2 h per week before their oncological diagnosis (p = 0.014). The latter was only a significant indicator in the male subsample. Conclusion The present results demonstrate a high prevalence of CRF and highlight that not only somatic and psychosocial factors, but also lifestyle factors prior to diagnosis appear to be associated with the etiology and persistence of CRF. To effectively treat CRF, a biopsychosocial, personalized approach is recommended.

ABSTRACT Background Few malignancies provoke as many controversies about treatment as pleural mesothelioma. There is limited experience with novel radiotherapy techniques worldwide in adjuvant and particularly in neoadjuvant settings within multimodality treatment. The objective of the current study was to investigate the long‐term outcome of neoadjuvant and adjuvant pleural intensity‐modulated radiotherapy (IMRT) combined with macroscopic complete resection with or without chemotherapy. Methods We retrospectively analyzed a consecutive cohort of 59 patients who were diagnosed with pleural mesothelioma and underwent multimodality treatment including macroscopic complete resection and neoadjuvant or adjuvant IMRT between 2005 and 2019 at the Department of Thoracic Surgery, Medical University of Vienna, Austria. Results In total, 59 patients (median age 59 years; IQR 54–66, male, n = 48; 81%) were included. Forty‐seven patients underwent trimodality treatment consisting of induction chemotherapy, extrapleural pneumonectomy, and adjuvant IMRT. Novel neoadjuvant IMRT with (n = 9) or without (n = 3) chemotherapy followed by extrapleural pneumonectomy was performed in 12 patients. Median overall survival (OS) of all patients was 23.2 months (95% CI; 18.1–28.2) and 3‐ and 5‐year survival rates were 33% and 28%, respectively. Survival was comparable between therapies including neoadjuvant versus adjuvant IMRT (median OS 17.5 vs. 24.0 months, p = 0.39). Conclusions Neoadjuvant pleural IMRT has been investigated as a novel treatment option for highly selected cases in pleural mesothelioma. Neoadjuvant IMRT was effective and safe in patients treated in a high‐volume institution but showed no relevant survival benefit compared to adjuvant IMRT within multimodality treatment.

TSLC1 (tumor suppressor in lung cancer-1, IGSF4 ) encodes a member of the immunoglobulin superfamily molecules, which is involved in cell–cell adhesion. TSLC1 is connected to the actin cytoskeleton by DAL-1 (differentially expressed in adenocarcinoma of the lung-1, EPB41L3 ) and it directly associates with MPP3 , one of the human homologues of a Drosophila tumor suppressor gene, Discs large . Recent data suggest that aberrant promoter methylation is important for TSLC1 inactivation in lung carcinomas. However, little is known about the other two genes in this cascade, DAL-1 and MPP3 . Thus, we investigated the expression and methylation patterns of these genes in lung cancer cell lines, primary lung carcinomas and nonmalignant lung tissue samples. By reverse transcription–polymerase chain reaction, loss of TSLC1 expression was observed in seven of 16 (44%) non-small-cell lung cancer (NSCLC) cell lines and in one of 11 (9%) small-cell lung cancer (SCLC) cell lines, while loss of DAL-1 expression was seen in 14 of 16 (87%) NSCLC cell lines and in four of 11 (36%) SCLC cell lines. By contrast, MPP3 expression was found in all tumor cell lines analysed. Similar results were obtained by microarray analysis. TSLC1 methylation was seen in 13 of 39 (33%) NSCLC cell lines, in one of 11 (9%) SCLC cell lines and in 100 of 268 (37%) primary NSCLCs. DAL-1 methylation was observed in 17 of 39 (44%) NSCLC cell lines, in three of 11 (27%) SCLC cell lines and in 147 of 268 (55%) primary NSCLCs. In tumors of NSCLC patients with stage II–III disease, DAL-1 methylation was seen at a statistically significant higher frequency compared to tumors of patients with stage I disease. A significant correlation between loss of expression and methylation of the genes in lung cancer cell lines was found. Overall, 65% of primary NSCLCs had either TSLC1 or DAL-1 methylated. Methylation of one of these genes was detected in 59% of NSCLC cell lines; however, in SCLC cell lines, methylation was much less frequently observed. The majority of nonmalignant lung tissue samples was not TSLC1 or DAL-1 methylated. Re-expression of TSLC1 and DAL-1 was seen after treatment of lung cancer cell lines with 5-aza-2′-deoxycytidine. Our results suggest that methylation of TSLC1 and/or DAL-1 , leading to loss of their expression, is an important event in the pathogenesis of NSCLC.

Background Malignant mesothelioma is an aggressive cancer and has a poor prognosis. Here, we analyzed the feasibility, molecular and gender aspects of targeted therapy recommendations for malignant mesothelioma based on the individual molecular tumor profile. Methods In this single‐center, real‐world retrospective analysis of our platform for precision medicine, we evaluated the molecular profiling of malignant mesothelioma in 14 patients, including nine men and five women. Tumor samples of the patients were examined with a 50 gene next‐generation sequencing (NGS) panel, immunohistochemistry, and fluorescence in situ hybridization, to detect possible molecular aberrations which may be targeted by off‐label therapy custom‐tailored to the individual patient. Results In total, we identified 11 mutations in six of the 14 patients, including BAP1, FANCA, NF1, NF2, PD‐L1, RAD52D, SETD2, SRC, and TP53. No mutation was detected in eight of the 14 patients. Targeted therapy was recommended for 11 out of the 14 patients. All recommendations were mainly based on the molecular characteristics determined by immunohistochemistry. Targeted therapy recommendations were significantly more often for men than women due to gender‐specific differences in PDGFRα expression. Eventually, four patients received the targeted therapy, of whom one patient subsequently achieved stable disease. Conclusions Our observations suggest that a molecular‐guided treatment approach is feasible for the management of advanced malignant mesothelioma. Our analysis revealed gender specific differences in PDGFRα expression that should be further evaluated in clinical trials.

Metabolic reprogramming and cell cycle deregulation are hallmarks of cancer cells. The cell cycle kinase CDK6 has recently been implicated in a wide range of hematopoietic malignancies. We here investigate the role of CDK6 in the regulation of cellular metabolism in BCR::ABL1+ leukemic cells. Our study, using gene expression data and ChIP-Seq analysis, highlights the contribution of CDK6 kinase activity in the regulation of oxidative phosphorylation. Our findings imply a competition for promoter interaction of CDK6 with the master regulator of mitochondrial respiration, NRF-1. In line, cells lacking kinase active CDK6 display altered mitochondria morphology with a defective electron transport chain. The enhanced cytoplasm/mitochondria ATP ratio paralleled by high pyruvate and lactate levels indicate a metabolic switch to glycolysis. Accordingly, combinatorial treatment of leukemic cells including imatinib resistant cells with the CDK4/6 inhibitor palbociclib and the glycolysis inhibitor 2-deoxyglucose (2-DG) enhanced apoptosis, while blocking cell proliferation in leukemic cells. These data may open a new therapeutic avenue for hematologic malignancies with high CDK6 expression by exploiting metabolic vulnerabilities unmasked by blocking CDK6 kinase activity that might even be able to overcome imatinib resistance.

Many distinct regions of 3p show frequent allelic losses in a wide range of tumour types. Previously, the BLU candidate tumour suppressor gene (TSG) encoded by a gene-rich critical deleted region in 3p21.3 was found to be inactivated rarely in lung cancer, although expression was downregulated in a subset of lung tumour cell lines. To elucidate the role of BLU in tumorigenesis, we analysed BLU promoter methylation status in tumour cell lines and detected promoter region hypermethylation in 39% lung, 42% breast, 50% kidney, 86% neuroblastoma and 80% nasopharyngeal (NPC) tumour cell lines. Methylation of the BLU promoter region correlated with the downregulation of BLU transcript expression in tumour cell lines. Expression was recovered in tumour cell lines treated with 5-aza 2-deoxycytidine. Exogenous expression of BLU in neuroblastoma (SK-N-SH) and NSCLC (NCI-H1299) resulted in reduced colony formation efficiency, in vitro . Furthermore, methylation of the BLU promoter region was detected in primary sporadic SCLC (14%), NSCLC (19%) and neuroblastoma (41%). As frequent methylation of the RASSF1A 3p21.3 TSG has also been reported in these tumour types, we investigated whether BLU and RASSF1A methylation were independent or related events. No correlation was found between hypermethylation of RASSF1A and BLU promoter region CpG islands in SCLC or neuroblastoma. However, there was association between RASSF1A and BLU methylation in NSCLC ( P =0.0031). Our data suggest that in SCLC and neuroblastoma, RASSF1A and BLU methylations are unrelated events and not a manifestation of a regional alteration in epigenetic status, while in NSCLC there may be a regional methylation effect. Together, these data suggest a significant role for epigenetic inactivation of BLU in the pathogenesis of common human cancers and that methylation inactivation of BLU occurs independent of RASSF1A in SCLC and neuroblastoma tumours.

IntroductionThe predictive value of the pre-radiosurgery Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Lymphocyte-to-Monocyte Ratio (LMR) and the modified Glasgow Prognostic Score (mGPS) was assessed for the first time in a homogenous group of NSCLC brain metastaes (BM) patients.MethodsWe retrospectively evaluated 185 NSCLC-BM patients, who were treated with Gamma Knife Radiosurgery (GKRS). Patients with immunotherapy or targeted therapy were excluded. Routine laboratory parameters were reviewed within 14 days before GKRS1.ResultsMedian survival after GKRS1 was significantly longer in patients with NLR < 5 (p < 0.001), PLR < 180 (p = 0.003) and LMR ≥ 4 (p = 0.023). The Cox regression model for the continuous metric values revealed that each increase in the NLR of 1 equaled an increase of 4.3% in risk of death (HR: 1.043; 95%CI = 1.020–1.067, p < 0.001); each increase in the PLR of 10 caused an increase of 1.3% in risk of death (HR: 1.013; 95%CI = 1.004–1.021; p = 0.003) and each increase in the LMR of 1 equaled a decrease of 20.5% in risk of death (HR: 0.795; 95%CI = 0.697–0.907; p = 0.001). Moreover, the mGPS group was a highly significant predictor for survival after GKRS1 (p < 0.001) with a HR of 2.501 (95%CI = 1.582–3.954; p < 0.001). NLR, PLR, LMR values and mGPS groups were validated as independent prognostic factors for risk of death after adjusting for sex, KPS, age and presence of extracranial metastases.ConclusionNLR, PLR, LMR and mGPS represent effective and simple tools to predict survival in NSCLC patients prior to radiosurgery for brain metastases.

ObjectivePatients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer.MethodsWe prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint.ResultsDuring a median follow-up of 25 (IQR 16–31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP.ConclusionsCirculating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression.

Background/Objectives: Malignant pleural mesothelioma (MPM) remains challenging to treat, with a poor prognosis. As controversy about clinical management continues, predictive biomarkers for patient selection to indicate the benefit of treatment modalities are urgently needed. Methods: In a retrospective analysis of 195 patients between 1994 and 2020 at the Department of Thoracic Surgery, Medical University of Vienna, Austria, the Mesothelioma Systemic Inflammation Score (MSIS)—consisting of pretreatment neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), C-reactive protein (CRP), and fibrinogen—was tested for its prognostic and predictive significance. The prognostic impact of MSIS was subsequently validated in an independent cohort of 80 patients treated at the Department of Thoracic Surgery, Karl Landsteiner Institute for Clinical and Translational Thoracic Surgery Research, Clinic Floridsdorf, Vienna, Austria. Results: Median overall survival (OS) was 14 months for the entire cohort (95% CI: 11.4–16.6). Patients undergoing multimodality treatment including macroscopic complete resection had a longer OS (22.3 months, 95% CI: 18.6–26.0; p < 0.001). In multivariable analysis, MSIS (p < 0.001), disease stage (p = 0.001), and the type of treatment (p = 0.004) were confirmed as independent predictors for OS. Higher MSIS was associated with shorter OS (p < 0.001). Significant survival benefit of multimodality regimens including surgery was limited to patients with low MSIS. Among patients with low (≤ 2) MSIS, multimodality therapy was associated with significantly prolonged OS when compared with chemo- and/or radiotherapy alone (25.8 months [95% CI: 16.4–35.3] vs. 14.4 months [95% CI: 10.4–18.4], p < 0.001). In contrast, among patients with elevated MSIS, no survival benefit was achieved by surgery over conservative treatment (11.8 months [95% CI: 8.3–15.3] vs. 8.2 months [95% CI: 5.2–11.3], p = 0.233). The ability of MSIS to predict survival was equivalent between the baseline and the independent validation cohort (p < 0.001). Conclusions: The Mesothelioma Systemic Inflammation Score was found to be an independent prognostic score in pleural mesothelioma, predicting benefit from macroscopic complete resection as part of multimodality treatment in distinct patients.

TSLC1 and DAL-1 are tumor suppressor genes involved in cell adhesion. In this study, we examined the expression and methylation pattern of these genes in breast cancer cell lines and primary breast carcinomas. TSLC1 expression was lost in 5 of 8 (63%) and DAL-1 expression was lost in 6 of 8 (75%) breast cancer cell lines, respectively. Downregulation of TSLC1 expression was observed in 43 of 50 (86%) and of DAL-1 expression in 26 of 55 (47%) primary breast carcinomas. TSLC1 methylation was found in 4 of 8 (50%) and DAL-1 methylation was observed in 6 of 8 (75%) breast cancer cell lines, respectively. Of 95 primary breast carcinomas 46 (48%) were TSLC1 methylated and 26 (27%) were DAL-1 methylated. Twenty of 43 (47%) and 10 of 26 (38%) primary breast cancer samples which showed downregulation of TSLC1 and DAL-1 expression were unmethylated for these genes. Re-expression of TSLC1 and DAL-1 was observed after treatment of BT-20 cells with 5-aza-2'-deoxycytidine and TSA. Samples from patients with grade 3 tumors were more frequently TSLC1 and TSLC1 and/or DAL-1 methylated than samples from patients with grade 1 and 2 tumors (P = 0.032, P = 0.023). Moreover, TSLC1 methylation correlated with loss of both ER and PgR staining (P = 0.011, P = 0.02). Our findings suggest that TSLC1 and DAL-1 are involved in the pathogenesis of breast cancer and are frequently inactivated by methylation.