Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma.

Rare biallelic BLM gene mutations cause Bloom syndrome. Whether BLM heterozygous germline mutations (BLM+/-) cause human cancer remains unclear. We sequenced the germline DNA of 155 mesothelioma patients (33 familial and 122 sporadic). We found 2 deleterious germline BLM+/- mutations within 2 of 33 families with multiple cases of mesothelioma, one from Turkey (c.569_570del; p.R191Kfs*4) and one from the United States (c.968A>G; p.K323R). Some of the relatives who inherited these mutations developed mesothelioma, while none with nonmutated BLM were affected. Furthermore, among 122 patients with sporadic mesothelioma treated at the US National Cancer Institute, 5 carried pathogenic germline BLM+/- mutations. Therefore, 7 of 155 apparently unrelated mesothelioma patients carried BLM+/- mutations, significantly higher (P = 6.7E-10) than the expected frequency in a general, unrelated population from the gnomAD database, and 2 of 7 carried the same missense pathogenic mutation c.968A>G (P = 0.0017 given a 0.00039 allele frequency). Experiments in primary mesothelial cells from Blm+/- mice and in primary human mesothelial cells in which we silenced BLM revealed that reduced BLM levels promote genomic instability while protecting from cell death and promoted TNF-α release. Blm+/- mice injected intraperitoneally with asbestos had higher levels of proinflammatory M1 macrophages and of TNF-α, IL-1ß, IL-3, IL-10, and IL-12 in the peritoneal lavage, findings linked to asbestos carcinogenesis. Blm+/- mice exposed to asbestos had a significantly shorter survival and higher incidence of mesothelioma compared to controls. We propose that germline BLM+/- mutations increase the susceptibility to asbestos carcinogenesis, enhancing the risk of developing mesothelioma.

What has changed in malignant mesothelioma between 1990 and 2019? A time- series analyses in Turkey.

OBJECTIVES: To investigate the changes in epidemiological and survival characteristics of malignant mesothelioma (MM) cases diagnosed in a 30-year period between 1990 and 2019. METHODS: Data were analyzed considering three time periods (1990-1999, 2000-2009, 2010-2019) when treatment practices changed. The Join point Regression Program was used to analyze the change in clinical and epidemiological characteristics of the cases. Kaplan-Meier analysis was used to calculate the overall survival of the patients. Cox regression analysis was used to determine the effect of variables on survival. RESULTS: The study group consisted of 928 MM patients. During the study period, the mean age of the patients and the percentage of epithelioid subtype increased, while the percentage of female and histopathologically unidentified cases decreased. The median survival (95%CI) of patients according to the study periods was 9.0 (7.2-10.9), 9.0 (7.6-10.4) and 12.0 (10.5-13.5) months, respectively. A significant increase in overall survival was observed in the time trend (p = 0.013). There was no significant change in overall survival in patients receiving best supportive care over the 30-year period (p = 0.060), but an improvement of 1.4 (95%CI 0.2 to 2.7) months (p = 0.027) was observed in patient receiving chemotherapy. An improvement in overall survival of 4.8 (1.2 to 8.4) months was also observed in patients receiving multimodality treatment during 2000-2019 (p = 0.014). MM patients who were younger, female, diagnosed after 2000, epithelioid subtype, early stage, and received chemotherapy or multimodal treatment had longer survival. CONCLUSIONS: It was found that histopathological diagnosis and treatment success in MM have improved over the years.

Evaluation of Exudative Pleural Effusions: A Multicenter, Prospective, Observational Study.

PURPOSE: The aim of this study is to determine the diagnostic performances of pleural procedures in undiagnosed exudative pleural effusions and to evaluate factors suggestive of benign or malignant pleural effusions in tertiary care centers. METHODS: This was a multicenter prospective observational study conducted between January 1 and December 31, 2018. A total of 777 patients with undiagnosed exudative pleural effusion after the initial work-up were evaluated. The results of diagnostic procedures and the patients' diagnoses were prospectively recorded. Sensitivity, specificity, and accuracy estimates with 95% confidence intervals were used to examine the performance of pleural procedures to detect malignancy. RESULTS: The mean age ± SD of the 777 patients was 62.0 ± 16.0 years, and 68.3% of them were male. The most common cause was malignancy (38.3%). Lung cancer was the leading cause of malignant pleural effusions (20.2%). The diagnostic sensitivity and accuracy of cytology were 59.5% and 84.3%, respectively. The diagnostic sensitivity of image-guided pleural biopsy was 86.4%. The addition of image-guided pleural biopsy to cytology increased diagnostic sensitivity to more than 90%. Thoracoscopic biopsy provided the highest diagnostic sensitivity (94.3%). The highest diagnostic sensitivity of cytology was determined in metastatic pleural effusion from breast cancer (86.7%). CONCLUSION: The diagnostic performance increases considerably when cytology is combined with image-guided pleural biopsy in malignant pleural effusions. However, to avoid unnecessary interventions and complications, the development of criteria to distinguish patients with benign pleural effusions is as important as the identification of patients with malignant pleural effusions.

Evaluation of the contribution of fine-needle non-aspiration cytology to diagnosis in cases with pulmonary malignant lesions.

BACKGROUND: Fine-needle non-aspiration cytology (FNNAC) is an easy-to-apply, minimally invasive diagnostic method that contributes to the diagnosis and staging of lung cancer. FNNAC can be performed from peripheral lymph nodes as well as in peripheral lung lesions. This study aimed to evaluate the contribution of FNNAC performed from peripheral lesions or lymph nodes to diagnosis in patients with pulmonary malignant lesions. METHODS: FNNAC was applied from a peripherally located mass in the lung, chest wall lesion, or peripheral lymph node using a needle without an injector or active suction. The collected material was evaluated using the cytoblock method. The FNNAC accuracy was obtained by dividing the true positivity value by a number of needle biopsies performed. The 95% confidence interval of the obtained rate was also calculated. RESULTS: The mean age of 56 patients, two female (3.6%) and 54 male (96.4%), was 63.9 ± 9.1 (38-80) years. FNNAC was performed from the peripheral lymph node in 48 patients, the peripheral pulmonary lesion in four, and the accompanying chest wall lesion in four. While true positivity was present in 42 patients, two patients had true negativity, and 12 had false negativity. In five of the 12 cases reported as false negative, the collected material was evaluated as insufficient, while the malignant diagnoses of the remaining seven cases were confirmed by other diagnostic methods. The diagnostic success of FNNAC was determined as 78.57% (95% CI: 65.56-88.41). FNNAC was more successful in diagnosis when performed from the peripheral lymph node compared to the peripheral pulmonary lesion (p=0.033).

The relationship between nutritional status and prognosis in patients with locally advanced and advanced stage lung cancer.

PURPOSE: The study aimed to determine the poor nutritional status, related factors, and its effect on the prognosis of patients with locally advanced and advanced stage lung cancer. METHODS: The study consisted of 539 patients, 412 (76.4%) of whom were non-small cell lung cancer (NSCLC), and 127 (23.6%) were small cell lung cancer (SCLC). The nutritional status of the patients was evaluated by the Controlling Nutritional Status (CONUT) and Prognostic Nutritional Index (PNI). Poor nutritional status was diagnosed with the CONUT score of ≥ 2 and PNI of ≥the median value. The factors related to nutritional status were determined using a multivariate logistic regression model. The effect of poor nutritional status on survival was calculated by Cox regression analysis. RESULTS: The median age was 64 years (29-87). Poor nutritional status was found in 56.4% (57.8% for NSCLC and 52.0% for SCLC) and 49.2% (51.5% for NSCLC and 41.7% for SCLC) of patients according to CONUT and PNI, respectively. The factors associated with poor nutritional status according to CONUT were age, gender, KPS < 80, and BMI < 18.5 for NSCLC and KPS for SCLC. According to PNI, only KPS < 80 was associated with poor nutritional status by the multivariate logistic regression model. The median overall survival significantly decreased with poor nutritional status according to CONUT and PNI in NSCLC (p < 0.001 and p < 0.001, respectively) and in SCLC (p = 0.05 and p = 0.007, respectively). CONCLUSION: Poor nutritional status is a common factor associated with poor prognosis in patients with locally advanced and advanced stage lung cancer. Patients should be screened for nutritional status and supported.

Midkine is a potential novel marker for malignant mesothelioma with different prognostic and diagnostic values from mesothelin.

BACKGROUND: We evaluated possible diagnostic and prognostic values of serum midkine in malignant pleural mesothelioma in comparison with those of serum mesothelin, a well-established diagnostic biomarker. METHODS: Serum mesothelin and midkine levels were determined with an enzyme-linked immunosorbent assay. We examined specimens from 95 Turkish cases with malignant pleural mesothelioma, 56 metastatic cancers to pleura, 27 other types of benign pleural diseases and 20 benign asbestos pleurisy. The cut-off values were 1.5 nmol/L for mesothelin and 421 pg/mL for midkine. RESULTS: Sensitivity and specificity of mesothelin were 51.6 and 71.4%, 51.6 and 85.2%, and 51.6 and 85% for differentiating mesothelioma from metastatic cancers to pleura, other benign pleural diseases and benign asbestos pleurisy, respectively. Sensitivity and specificity of midkine were 61.1 and 41.1%, 61.1 and 48.1%, and 61.1 and 75% to distinguish mesothelioma from metastatic cancers to pleura, other benign pleural diseases and benign asbestos pleurisy, respectively. Combination of both biomarkers did not improve the differential diagnostic efficacy. Mesothelin levels were elevated in the epitheloid type and in the advanced cases, but were not related to the prognosis. In contrast, elevated baseline levels of midkine were independently associated with a poor prognosis of mesothelioma patients after adjusting for the stage, the histological subtypes and treatment schedules (HR = 1.84; 95% CI: 1.09-3.09) (p = 0.022). CONCLUSIONS: Serum mesothelin showed moderate sensitivity and high specificity to differentiate malignant pleural mesothelioma from metastatic malignancy to pleura and from benign pleural diseases. In contrast, midkine was a useful marker for predicting prognosis of mesothelioma patients.

Proteome screening of pleural effusions identifies galectin 1 as a diagnostic biomarker and highlights several prognostic biomarkers for malignant mesothelioma.

Malignant mesothelioma is an aggressive asbestos-induced cancer, and affected patients have a median survival of approximately one year after diagnosis. It is often difficult to reach a conclusive diagnosis, and ancillary measurements of soluble biomarkers could increase diagnostic accuracy. Unfortunately, few soluble mesothelioma biomarkers are suitable for clinical application. Here we screened the effusion proteomes of mesothelioma and lung adenocarcinoma patients to identify novel soluble mesothelioma biomarkers. We performed quantitative mass-spectrometry-based proteomics using isobaric tags for quantification and used narrow-range immobilized pH gradient/high-resolution isoelectric focusing (pH 4-4.25) prior to analysis by means of nano liquid chromatography coupled to MS/MS. More than 1,300 proteins were identified in pleural effusions from patients with malignant mesothelioma (n = 6), lung adenocarcinoma (n = 6), or benign mesotheliosis (n = 7). Data are available via ProteomeXchange with identifier PXD000531. The identified proteins included a set of known mesothelioma markers and proteins that regulate hallmarks of cancer such as invasion, angiogenesis, and immune evasion, plus several new candidate proteins. Seven candidates (aldo-keto reductase 1B10, apolipoprotein C-I, galectin 1, myosin-VIIb, superoxide dismutase 2, tenascin C, and thrombospondin 1) were validated by enzyme-linked immunosorbent assays in a larger group of patients with mesothelioma (n = 37) or metastatic carcinomas (n = 25) and in effusions from patients with benign, reactive conditions (n = 16). Galectin 1 was identified as overexpressed in effusions from lung adenocarcinoma relative to mesothelioma and was validated as an excellent predictor for metastatic carcinomas against malignant mesothelioma. Galectin 1, aldo-keto reductase 1B10, and apolipoprotein C-I were all identified as potential prognostic biomarkers for malignant mesothelioma. This analysis of the effusion proteome furthers our understanding of malignant mesothelioma, identified galectin 1 as a potential diagnostic biomarker, and highlighted several possible prognostic biomarkers of this disease.

CT Scan-Guided Abrams' Needle Pleural Biopsy versus Ultrasound-Assisted Cutting Needle Pleural Biopsy for Diagnosis in Patients with Pleural Effusion: A Randomized, Controlled Trial.

BACKGROUND: Image-guided pleural biopsies, both using ultrasound (US) or computed tomography (CT), are important in the diagnosis of pleural disease. However, no consensus exists regarding which biopsy needles are appropriate for specific procedures. OBJECTIVES: In this randomized, prospective study, we aimed to compare CT scan-guided pleural biopsy using an Abrams' needle (CT-ANPB) with US-assisted pleural biopsy using a cutting needle (US-CNPB) with respect to both diagnostic yield and safety. METHODS: Between February 2009 and April 2013, 150 patients with exudative pleural effusion who could not be diagnosed by cytological analysis were included in the study. The patients were randomized into either the US-CNPB group or the CT-ANPB group. The two groups were compared in terms of diagnostic sensitivity and complications. RESULTS: Of the 150 patients enrolled in this study, 45 were diagnosed with malignant mesothelioma, 46 were diagnosed with metastatic pleural disease, 18 were diagnosed with pleural tuberculosis, 34 were diagnosed with benign pleural disease, and 7 were lost to follow-up. In the US-CNPB group, the diagnostic sensitivity was 66.7%, compared with 82.4% in the CT-ANPB group; the difference between the two groups was statistically significant (p = 0.029). The sensitivity of CT-ANPB increased to 93.7% for patients with a pleural thickness ≥1 cm. The complication rates were low and acceptable. CONCLUSIONS: The first diagnostic intervention that should be preferred in patients with pleural effusion and associated pleural thickening on a CT scan is CT-ANPB. US-CNPB should be used primarily in cases for which only pleural thickening but no pleural effusion is noted.

[Drug carrier nanosystems in malignant pleural mesothelioma]. / Malign plevral mezotelyomada ilaç tasiyici nanosistemler.

Malignant pleural mesothelioma (MPM), the incidence increased with each passing day, is an important lethal disease due to the limited survive with available treatment methods and with the lack of a standard treatment. Response and survive rates of cytotoxic agents which is used in MPM treatment are not good enough. Therefore, treatment studies of MPM seem to quite important and urgent. In cancer therapy, convensional chemotherapeutic agent applications, due to the lack of selectivity, lead to systemic toxicity. Besides the limited solubility of the agent used, the distribution between the cells is weak. It is very difficult to the pass through cellular barriers, particularly, drug resistance may develop to the treatment. All of these reasons lead to failure in the treatment process. Because of the fact that cytotoxic drugs either kill the rapidly growing and dividing cells or make them disfunctional by showing toxic effect on them, to avoid the side effects and to make an inherent effect for cytotoxic drug of active ingredient given for treatment on tumor, different studies have been under investigation. At the present time, nanocarriers as one of these solutions seem to have an important place. Nanocarriers are promising for the development of therapeutic effectiveness and safety. It seems that use of the nanocarrier in the treatment of mesothelioma has a potential, as effective alternative a method, with improve of the drug efficacy and reduce of toxicity in normal tissues.

The effectiveness and safety of platinum-based pemetrexed and platinum-based gemcitabine treatment in patients with malignant pleural mesothelioma.

BACKGROUND: We aimed to evaluate the efficiency and safety of cis/carboplatin plus gemcitabine, which was previously used for mesothelioma but with no recorded proof of its efficiency, compared with cis/carboplatin plus pemetrexed, which is known to be effective in mesothelioma, in comparable historical groups of malignant pleural mesothelioma. METHODS: One hundred and sixteen patients received cis/carboplatin plus pemetrexed (group 1), while 30 patients received cis/carboplatin plus gemcitabine (group 2) between June 1999 and June 2012. The two groups were compared in terms of median survival and adverse events to chemotherapy. RESULTS: The mean ages of groups 1 and 2 were 60.7 and 60.8 years, respectively. Most of the patients (78.1%) had epithelial type tumors, and 47% of the patients had stage IV disease. There was no difference between the two groups in terms of age, gender, asbestos exposure, histology, stage, Karnofsky performance status, presence of pleurodesis, prophylactic radiotherapy, second-line chemotherapy and median hemoglobin and serum albumin levels. The median survival time from diagnosis to death or the last day of follow up with a 95% confidence interval was 12 ± 0.95 months (95% CI: 10.15-13.85) for group 1 and 11.0 ± 1.09 months (95% CI: 8.85-13.15) for group 2 (Log-Rank: 0.142; p = 0.706). The median survival time from treatment to death or the last day of follow-up with a 95% confidence interval was 11.0 ± 0.99 months (95% CI: 9.06-12.94) for group 1 and 11.0 ± 1.52 months (95% CI: 8.02-13.97) for group 2 (Log-Rank: 0.584; p = 0.445). The stage and Karnofsky performance status were found to be significant variables on median survival time by univariate analysis. After adjusting for the stage and Karnofsky performance status, the chemotherapy schema was not impressive on median survival time (OR: 0.837; 95% CI: 0.548-1.277; p = 0.409). The progression free survival was 7.0 ± 0.61 months for group I and 6.0 ± 1.56 months for group II (Log-Rank: 0.522; p = 0.470). The treatment was generally well tolerated, and the side effects were similar in both groups. CONCLUSIONS: The study indicates that platinum-based gemcitabine is effective and a safe schema in malignant pleural mesothelioma. Further research should include large randomized phase III trials comparing these agents.