Clinical prognostic factors in pleural mesothelioma: best supportive care and anti-tumor treatments in a real-life setting.

BACKGROUND: This study aims to investigate patient- and disease characteristics associated with survival in malignant pleural mesothelioma (MPM) patients with anti-tumor treatment or with best supportive care (BSC). MATERIALS AND METHODS: Consecutive MPM cases diagnosed in North Denmark Region from 1972 to 2015 were reevaluated and verified by two pathologists using modern immunohistochemical techniques. Danish registries and hospital records were used to gather patient-, asbestos exposure-, and disease information. RESULTS: Of the 279 patients, anti-tumor treatment was administered to 184 patients (66.0%). All of those received chemotherapy alone or as part of a multimodal treatment, where pemetrexed was given to 126 (68.5%) patients. Asbestos exposure was documented in 92.5% of all patients. In the treated group, mean age was lower (66 years versus 74 years, p < 0.01), rate of occupational asbestos exposure was higher (74.5 versus 54.7%, p < 0.01), more patients had better performance score (98.4 versus 60%, p < 0.01) and stage was lower (81 versus 63.2%, p < 0.01) compared to the BSC group. Multivariate analysis showed that epithelioid subtype was the only common prognostic factor for OS in both groups. In BSC patients, good PS and female gender was associated with improved OS. Median overall survival (OS) was 17 versus 4 months (p < 0.01), and independently of the histopathological subtype, the median and 2-year survival was higher in the treated versus the BSC group (p < 0.02). CONCLUSIONS: This retrospective study showed that epithelioid subtype is the only independent positive prognostic factor of survival in treated patients with MPM. For BSC patients, the epithelioid subtype, good PS, and female gender were positive prognostic factors, while age and comorbidities were not significant. This study with long-term follow-up of treated and BSC MPM patients can contribute to the clinical stratification of patients. Further validation is appropriate to verify these findings.

Asbestos exposure and haematological malignancies: a Danish cohort study.

Environmental asbestos exposure and occupational asbestos exposure increase the risk of several types of cancer, but the role of such exposures for haematological malignancies remains controversial. We aimed to examine the risk of haematological malignancies: first, in subjects exposed early in life, independently of any occupational exposure occurring later; second, in subjects exposed occupationally. We established an environmentally exposed cohort from four schools located near the only former asbestos cement production plant in Denmark. We identified nearly all pupils in the seventh grade and created an age and sex-matched 1:9 reference cohort from the Danish Central Population Register. Participants were born 1940-1970 and followed up in national registers until the end of 2015. Occupational asbestos exposure was assessed for all participants using two different job exposure matrices. The school cohort included 12,111 participants (49.7% girls) and the reference cohort 108,987 participants. Eight subgroups of haematological malignancy were identified in the Danish Cancer Registry. These cases were analysed for combined overall haematological malignancy, a combined subgroup of lymphomas and a combined subgroup of leukaemias. The data were analysed using Cox regression (hazard ratios (HR)) including other cancers and death as competing risks. Haematological malignancy was identified in 1125 participants. The median follow-up was 49.3 years (0.1-63.4). Early environmental asbestos exposure was not associated with an increased risk of haematological malignancy. Long-term occupational asbestos exposure was associated with overall haematological malignancy (HR 1.69, 95% CI 1.04-2.73); in particular for the leukaemia subgroup (HR 2.14, 95% CI 1.19-3.84). This large follow-up study suggests that long-term occupational asbestos exposure is associated with increased leukaemia risk. However, further studies are needed to confirm these observations.

Inherited Genetic Mutations and Polymorphisms in Malignant Mesothelioma: A Comprehensive Review.

Malignant mesothelioma (MM) is mainly caused by air-born asbestos but genetic susceptibility is also suspected to be a risk factor. Recent studies suggest an increasing number of candidate genes that may predispose to MM besides the well-characterized BRCA1-associated protein-1 gene. The aim of this review is to summarize the most important studies on germline mutations for MM. A total of 860 publications were retrieved from Scopus, PubMed and Web of Science, of which 81 met the inclusion criteria and were consider for this review. More than 50% of the genes that are reported to predispose to MM are involved in DNA repair mechanisms, and the majority of them have a role in the homologous recombination pathway. Genetic alterations in tumor suppressor genes involved in chromatin, transcription and hypoxia regulation have also been described. Furthermore, we identified several single nucleotide polymorphisms (SNPs) that may promote MM tumorigenesis as a result of an asbestos-gene interaction, including SNPs in DNA repair, carcinogen detoxification and other genes previously associated with other malignancies. The identification of inherited mutations for MM and an understanding of the underlying pathways may allow early detection and prevention of malignancies in high-risk individuals and pave the way for targeted therapies.

Epigenetic predictive biomarkers for response or outcome to platinum-based chemotherapy in non-small cell lung cancer, current state-of-art.

Platinum-based chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC). However, its efficacy is limited and no molecular biomarkers that predict response are available. In this review, we summarize current knowledge concerning potential epigenetic predictive markers for platinum-based chemotherapy response in NSCLC. A systematic search of PubMed and ClinicalTrials.gov using keywords "non-small cell lung cancer" combined with "chemotherapy predictive biomarkers", "chemotherapy epigenetics biomarkers", "chemotherapy microRNA biomarkers", "chemotherapy DNA methylation" and "chemotherapy miRNA biomarkers" revealed 1740 articles from PubMed and 36 clinical trials. Finally, 22 papers and no trials fulfilled the review criteria. Among miRNA, combination of miR-1290, miR-196b and miR-135a in tumor tissue, and miR-21, miR-25, miR27b, and miR-326 in plasma were predictive for response to platinum-based chemotherapy in advanced NSCLC. RASSF1A methylation measured in tumor or blood was predictive for response to neoadjuvant chemotherapy. These biomarkers remain experimental and none have been tested in a prospective trial.

Environmental asbestos exposure in childhood and risk of mesothelioma later in life: a long-term follow-up register-based cohort study.

OBJECTIVE: To examine the risk of malignant mesothelioma (MM) in former pupils who attended primary school near an asbestos cement plant. METHODS: A cohort of 12 111 former pupils, born 1940-1970, was established from individual historical records from four primary schools located at a distance of 100-750 m in the prevailing wind direction from an asbestos cement plant operating from 1928 to 1984 in Aalborg, Denmark. The school cohort and a comparison cohort consisting of 108 987 gender and 5-year frequency-matched subjects were followed up (2015) for MM in the Danish Cancer Registry. Using Cox regression, HRs were estimated for the incidence of MM. Adjustments for occupational and familial asbestos exposure were made with a job exposure matrix. An SIR analysis including latency periods testing the cancer incidence rate was performed with the comparison cohort as the reference rate. RESULTS: The median person-years of follow-up were 62.5 years in the school cohort and 62.2 years in the comparison cohort. There were 32 males and 6 females of the former pupils who developed MM during the follow-up: HRmale 7.01 (95% CI 4.24 to 11.57), HRfemale 7.43 (95% CI 2.50 to 22.13). Those who attended school 250 m north of the plant had the highest HR for MM, 10.65 (95% Cl 5.82 to 19.48). No significant trend between school distance and risk of MM was established (p=0.35). CONCLUSION: Our results suggest that boys and girls who attended schools and lived in the neighbourhood of an asbestos cement plant later in life have a significantly increased risk of MM.

Preoperative serum receptor activator of nuclear factor-κB ligand/osteoprotegerin predict stabilization of spontaneously restored sinus rhythm in persistent atrial fibrillation patients after mitral valve surgery.

OBJECTIVE: The osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL) axis may play an important role in the stabilization of restored sinus rhythm (SR) after mitral valve (MV) surgery by stimulating atrial fibrillation (AF)-related atrial remodeling in AF patients. Herein, we investigated the association between preoperative serum soluble RANKL (sRANKL)/OPG and the stabilization of restored SR after MV surgery. METHODS: Persistent AF patients who had spontaneously restored SR after MV replacement were enrolled (n = 203). Comparison was made between patients without AF recurrence (n = 71) and patients experiencing recurrence (n = 132). RESULTS: Patients experiencing recurrence had higher serum levels of sRANKL, OPG and sRANKL/OPG ratio than patients without recurrence. Multivariate survival regression analysis showed that clinical factors such as duration of AF, left atrial diameter and left atrial thrombosis, as well as serum sRANKL level and the sRANKL/OPG ratio, were independent predictors of AF recurrence. Receiver operating characteristic curve analysis showed that the best diagnostic values of the serum sRANKL level and the sRANKL/OPG ratio for predicting recurrence were 3.44 pmol/l and 0.53, respectively. CONCLUSIONS: Patients who had a low preoperative serum sRANKL level and sRANKL/OPG ratio are likely to have a stable spontaneously restored SR postoperatively. Thus, we suggest that patients at high risk of early AF recurrence should be considered for concomitant surgical cardioversion during MV surgery.

CHIP functions as a novel suppressor of tumour angiogenesis with prognostic significance in human gastric cancer.

OBJECTIVE: CHIP (carboxy terminus of Hsc70 interacting protein) is an E3 ubiquitin ligase that can induce ubiquitination and degradation of several tumour related proteins, and acts as a suppressor of tumour metastasis. This study explored the biological function and clinical significance of CHIP in gastric cancer (GC). METHODS: The prognostic value of CHIP expression was evaluated using tissue microarray and immunohistochemical staining in two independent human GC cohorts. The role of CHIP on tumorigenicity and angiogenesis was determined in vitro and in vivo. RESULTS: CHIP expression was significantly decreased in GC lesions compared with paired non-cancerous tissues. Low tumoral CHIP expression significantly correlated with clinicopathological characteristics in patients, as well as with shorter overall survival in both cohorts. Multivariate Cox regression analysis revealed that CHIP expression was an independent prognostic factor for human GC patients. Moreover, CHIP overexpression impeded the formation of anchorage independent colonies in soft agar, suppressed the growth of xenografts in nude mice and inhibited endothelial cell growth and tube formation by suppressing nuclear factor κB (NF-κB) mediated interleukin 8 (IL-8) expression in vitro. In vivo studies also confirmed that CHIP inhibited blood vessel formation and recruitment of CD31 positive cells in matrigel plugs. Also, CHIP interacted with NF-κB/p65 and promoted its ubiquitination and degradation by proteasome, terminating NF-κB activity and inhibiting IL-8-induced angiogenesis, which correlated with subsequent tumour metastasis. CONCLUSIONS: Decreased CHIP expression in GC resulted in increased angiogenesis and contributed to GC progression and poor prognosis. CHIP expression is a GC candidate clinical prognostic marker and a putative treatment target.

Improving Lung Cancer Screening Selection: The HUNT Lung Cancer Risk Model for Ever-Smokers Versus the NELSON and 2021 United States Preventive Services Task Force Criteria in the Cohort of Norway: A Population-Based Prospective Study.

Background: Improving the method for selecting participants for lung cancer (LC) screening is an urgent need. Here, we compared the performance of the Helseundersøkelsen i Nord-Trøndelag (HUNT) Lung Cancer Model (HUNT LCM) versus the Dutch-Belgian lung cancer screening trial (Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON)) and 2021 United States Preventive Services Task Force (USPSTF) criteria regarding LC risk prediction and efficiency. Methods: We used linked data from 10 Norwegian prospective population-based cohorts, Cohort of Norway. The study included 44,831 ever-smokers, of which 686 (1.5%) patients developed LC; the median follow-up time was 11.6 years (0.01-20.8 years). Results: Within 6 years, 222 (0.5%) individuals developed LC. The NELSON and 2021 USPSTF criteria predicted 37.4% and 59.5% of the LC cases, respectively. By considering the same number of individuals as the NELSON and 2021 USPSTF criteria selected, the HUNT LCM increased the LC prediction rate by 41.0% and 12.1%, respectively. The HUNT LCM significantly increased sensitivity (p < 0.001 and p = 0.028), and reduced the number needed to predict one LC case (29 versus 40, p < 0.001 and 36 versus 40, p = 0.02), respectively. Applying the HUNT LCM 6-year 0.98% risk score as a cutoff (14.0% of ever-smokers) predicted 70.7% of all LC, increasing LC prediction rate with 89.2% and 18.9% versus the NELSON and 2021 USPSTF, respectively (both p < 0.001). Conclusions: The HUNT LCM was significantly more efficient than the NELSON and 2021 USPSTF criteria, improving the prediction of LC diagnosis, and may be used as a validated clinical tool for screening selection.

BAP1, Wilms' tumor 1, and calretinin in predicting survival and response to first-line chemotherapy in patients with pleural mesothelioma.

PURPOSE: There are currently no methods to predict response to chemotherapy in pleural mesothelioma (PM). The aim of this study is to investigate the predictive and prognostic role of BAP1, WT1 and calretinin expression and their combinations in pre-treatment tumor samples by immunohistochemical (IHC) staining. METHODS: The study included consecutive PM patients treated with chemotherapy alone at a University hospital between 2009 and 2020. BAP1 analyses were performed on formalin-fixed, paraffin-embedded tumor tissue samples of the patients, while WT1 and calretinin information were obtained from the histopathological diagnosis records. RESULTS: Of the total 107 patients included, 64% had loss of BAP1 expression, whereas 77% had WT1 and 86% had calretinin expression. Patients with the presence of BAP1 expression, one or both of the other two markers, or loss of expression of all three markers (unfavorable status) were more likely to not respond to chemotherapy than those with the presence of all three markers or loss of BAP1 expression and expression of one or two other markers (favorable status) (p = 0.001). Median survival time of patients with favorable and unfavorable status was 15 ± 1.7 and 8.0 ± 2.4 months, respectively (p = 0.027). After adjustment for histopathology and stage, loss of BAP1 (HR = 0.54, 95%CI 0.35-0.83), WT1 (1.75, 1.06-2.90), calretinin (2.09, 1.14-3.84) expression and favourable panel (0.50, 0.27-0.92) was associated with prognosis. CONCLUSIONS: The IHC biomarkers BAP1, WT1, and calretinin, used in the routine diagnosis of PM and their combinations, are the first biomarkers associated with response to chemotherapy and may be a useful tool to select patients for first-line platinum pemetrexed treatment in PM patients. Validation in a large cohort is ongoing.

The HUNT lung-SNP model: genetic variants plus clinical variables improve lung cancer risk assessment over clinical models.

PURPOSE: The HUNT Lung Cancer Model (HUNT LCM) predicts individualized 6-year lung cancer (LC) risk among individuals who ever smoked cigarettes with high precision based on eight clinical variables. Can the performance be improved by adding genetic information? METHODS: A polygenic model was developed in the prospective Norwegian HUNT2 study with clinical and genotype data of individuals who ever smoked cigarettes (n = 30749, median follow up 15.26 years) where 160 LC were diagnosed within six years. It included the variables of the original HUNT LCM plus 22 single nucleotide polymorphisms (SNPs) highly associated with LC. External validation was performed in the prospective Norwegian Tromsø Study (n = 2663). RESULTS: The novel HUNT Lung-SNP model significantly improved risk ranking of individuals over the HUNT LCM in both HUNT2 (p < 0.001) and Tromsø (p < 0.05) cohorts. Furthermore, detection rate (number of participants selected to detect one LC case) was significantly better for the HUNT Lung-SNP vs. HUNT LCM in both cohorts (42 vs. 48, p = 0.003 and 11 vs. 14, p = 0.025, respectively) as well as versus the NLST, NELSON and 2021 USPSTF criteria. The area under the receiver operating characteristic curve (AUC) was higher for the HUNT Lung-SNP in both cohorts, but significant only in HUNT2 (AUC 0.875 vs. 0.844, p < 0.001). However, the integrated discrimination improvement index (IDI) indicates a significant improvement of LC risk stratification by the HUNT Lung-SNP in both cohorts (IDI 0.019, p < 0.001 (HUNT2) and 0.013, p < 0.001 (Tromsø)). CONCLUSION: The HUNT Lung-SNP model could have a clinical impact on LC screening and has the potential to replace the HUNT LCM as well as the NLST, NELSON and 2021 USPSTF criteria in a screening setting. However, the model should be further validated in other populations and evaluated in a prospective trial setting.

Promising microRNAs in pre-diagnostic serum associated with lung cancer up to eight years before diagnosis: a HUNT study.

INTRODUCTION: Blood biomarkers for early detection of lung cancer (LC) are in demand. There are few studies of the full microRNome in serum of asymptomatic subjects that later develop LC. Here we searched for novel microRNA biomarkers in blood from non-cancer, ever-smokers populations up to eight years before diagnosis. METHODS: Serum samples from 98,737 subjects from two prospective population studies, HUNT2 and HUNT3, were considered initially. Inclusion criteria for cases were: ever-smokers; no known cancer at study entrance; 0-8 years from blood sampling to LC diagnosis. Each future LC case had one control matched to sex, age at study entrance, pack-years, smoking cessation time, and similar HUNT Lung Cancer Model risk score. A total of 240 and 72 serum samples were included in the discovery (HUNT2) and validation (HUNT3) datasets, respectively, and analysed by next-generation sequencing. The validated serum microRNAs were also tested in two pre-diagnostic plasma datasets from the prospective population studies NOWAC (n = 266) and NSHDS (n = 258). A new model adding clinical variables was also developed and validated. RESULTS: Fifteen unique microRNAs were discovered and validated in the pre-diagnostic serum datasets when all cases were contrasted against all controls, all with AUC > 0.60. In combination as a 15-microRNAs signature, the AUC reached 0.708 (discovery) and 0.703 (validation). A non-small cell lung cancer signature of six microRNAs showed AUC 0.777 (discovery) and 0.806 (validation). Combined with clinical variables of the HUNT Lung Cancer Model (age, gender, pack-years, daily cough parts of the year, hours of indoor smoke exposure, quit time in years, number of cigarettes daily, body mass index (BMI)) the AUC reached 0.790 (discovery) and 0.833 (validation). These results could not be validated in the plasma samples. CONCLUSION: There were a few significantly differential expressed microRNAs in serum up to eight years before diagnosis. These promising microRNAs alone, in concert, or combined with clinical variables have the potential to serve as early diagnostic LC biomarkers. Plasma is not suitable for this analysis. Further validation in larger prospective serum datasets is needed.

MDM2 is a useful prognostic biomarker for resectable gastric cancer.

Expression of MDM2 protein appears to be increased in malignancy and correlated to prognosis of tumors, but its role in gastric cancer remains controversial. Our recent investigations indicated that JWA was a novel candidate biomarker for gastric cancer. To evaluate the impact of MDM2 protein expression alone, and in combination with JWA, on the prognostic and predictive of patients with resectable gastric cancer, expression of MDM2 and JWA were examined by immunohistochemistry in three large cohorts (total n = 1131) of patient with gastric cancer. We found that MDM2 protein levels were significantly upregulated in gastric cancer (70.4%, 57 of 81) compared with adjacent non-cancerous tissues. High tumoral MDM2 expression significantly correlated with clinicopathologic characteristics, as well as with shorter overall survival (OS; P < 0.001 for all cohorts) in patients without adjuvant treatment. The effect of adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) in improving OS compared with surgery alone was evident only in the high MDM2 group (hazard ratio = 0.57; 95% confidence interval, 0.37-0.89; P = 0.013). Furthermore, knockdown of MDM2 and overexpression of JWA had a synergistic effect on suppression of gastric cancer cell proliferation and migration. Patients with low MDM2 and high JWA expression had a better outcome of survival compared with the other groups (P < 0.001 for all cohorts). For the first time, our data suggest that MDM2 is a potent prognostic and predictive factor for benefit from adjuvant fluorouracil-leucovorin-oxaliplatin chemotherapy in resectable gastric cancer. The combination of MDM2 expression and JWA could serve as a more effective candidate prognostic biomarker for gastric cancer.

OPG/RANK/RANKL axis in stabilization of spontaneously restored sinus rhythm in permanent atrial fibrillation patients after mitral valve surgery.

OBJECTIVE: To investigate the expression of the osteoprotegerin (OPG)/receptor activator of nuclear factor-ĸB (RANK)/RANK ligand (RANKL) axis in the stabilization of spontaneously restored sinus rhythm (SR) in permanent atrial fibrillation (AF) patients after mitral valve (MV) surgery and study its clinical significance. METHODS: Clinical data, biopsies of right atrial appendages were collected from 135 permanent AF patients who spontaneously restored SR after conventional isolated MV replacement. A comparison was made between patients who had recurrence of AF within 7 days and patients with persistent SR for more than 7 days. RESULTS: AF patients had an increased expression of RANK, RANKL, and the RANKL/OPG ratio compared to SR patients, and the degree of fibrosis was lower in SR compared to AF in the atria. Moreover, the expressions of RANK, RANKL, and the RANKL/OPG ratio were positively correlated with the degree of fibrosis. CONCLUSION: These findings suggest that the OPG/RANK/RANKL axis plays important roles in the stabilization of restored SR after MV surgery by stimulating AF-related atrial remodeling in AF patients.

Increased levels of microRNA-320 in blood serum and plasma is associated with imminent and advanced lung cancer.

Lung cancer (LC) incidence is increasing globally and altered levels of microRNAs (miRNAs) in blood may contribute to identification of individuals with LC. We identified miRNAs differentially expressed in peripheral blood at LC diagnosis and evaluated, in pre-diagnostic blood specimens, how long before diagnosis expression changes in such candidate miRNAs could be detected. We identified upregulated candidate miRNAs in plasma specimens from a hospital-based study sample of 128 patients with confirmed LC and 62 individuals with suspected but confirmed negative LC (FalsePos). We then evaluated the expression of candidate miRNAs in pre-diagnostic plasma or serum specimens of 360 future LC cases and 375 matched controls. There were 1663 miRNAs detected in diagnostic specimens, nine of which met our criteria for candidate miRNAs. Higher expression of three candidates, miR-320b, 320c, and 320d, was associated with poor survival, independent of LC stage and subtype. Moreover, miR-320c and miR-320d expression was higher in pre-diagnostic specimens collected within 2 years of LC diagnosis. Our results indicated that elevated levels of miR-320c and miR-320d may be early indications of imminent and advanced LC.

Diagnostic capacity of BAP1 and MTAP in cytology from effusions and biopsy in mesothelioma.

INTRODUCTION: Serous effusion is often the first sign of mesothelioma. Diagnosis based on cytologic material from the effusions remains controversial and complementary biopsy is usually required. However, obtaining representative tissue sample may be challenging, while obtaining cytologic material is a minimally invasive procedure, providing potential for an earlier diagnosis. Loss of BRCA1-associated protein (BAP1), combined with loss of methylthionadenosine phosphorylase (MTAP) detected by immunohistochemistry, have shown to be reliable markers in the diagnosis of mesothelioma on histologic sections. Here we evaluate the value of these biomarkers in cytologic specimens. MATERIALS AND METHODS: The BAP1 and MTAP expression in specimens of 162 mesothelioma patients (156 pleural, 6 peritoneal)-71 cytologic, 91 histologic (44 epithelioid, 31 biphasic, 16 sarcomatoid)-and 20 patients with reactive mesothelial proliferations were investigated. RESULTS: The loss of BAP1 and/or MTAP was highly sensitive and specific in differentiating mesothelioma from reactive mesothelial proliferations, with no significant difference between pleural effusions and biopsies, specificity of 100% in both and a sensitivity of 78.9% and 80.2%, respectively (P = 0.3). There was a 100% concordance of the expression of BAP1 and MTAP in cytologic and corresponding histopathologic samples. Loss of BAP1 and/or MTAP in histologic sections discriminated sarcomatoid, biphasic, and epithelioid mesothelioma from reactive mesothelial proliferations with a sensitivity of 81.2%, 83.9%, and 77.3% respectively. CONCLUSION: Loss of expression of BAP1 and/or MTAP differentiated mesothelioma from reactive mesothelial proliferations with excellent specificity and high sensitivity in cytologic samples, comparable to histopathologic sections.

A Cohort Study on Cancer Incidence among Women Exposed to Environmental Asbestos in Childhood with a Focus on Female Cancers, including Breast Cancer.

OBJECTIVES: To examine the risk of cancer in former school children exposed to environmental asbestos in childhood with a focus on female cancers, including breast cancer. METHODS: We retrieved a cohort of females (n = 6024) attending four schools located in the neighborhood of a large asbestos cement plant in Denmark. A reference cohort was frequency-matched 1:9 (n = 54,200) in sex and five-year age intervals. Using Danish registries, we linked information on historical employments, relatives' employments, cancer, and vital status. We calculated standardized incidence rates (SIRs) for all and specific cancers, comparing these rates with the reference cohort. Hazard ratios were calculated for selected cancers adjusted for occupational and familial asbestos exposure. RESULTS: For cancer of the corpus uteri (SIR 1.29, 95% CI 1.01-1.66) and malignant mesothelioma (SIR 7.26, 95% CI 3.26-16.15), we observed significantly increased incidences. Occupationally, asbestos exposure had a significantly increased hazard ratio for cancer in the cervix, however, a significantly lower risk of ovarian cancer. The overall cancer incidence was similar to that of the reference cohort (SIR 1.02, 95% CI 0.96-1.07). The risk of cancer of the lung was increased for those exposed to occupational asbestos, those with family members occupationally exposed to asbestos and for tobacco smokers. CONCLUSIONS: In our study, environmental asbestos exposure in childhood is associated with an increased risk of cancer of the corpus uteri and malignant mesothelioma in women.

A nomogram to predict survival probability of gastric cancer patients undergoing radical surgery and adjuvant chemotherapy.

Gastric cancer (GC) is the third-leading cause of cancer mortality worldwide. The aim of this study was to develop a nomogram that estimates 1-year, 3-year, and 5-year survival probability of GC patients after D2 gastrectomy combined with adjuvant chemotherapy. The results showed that median age is 58 (range: 18-85) years in the training cohort and 59 (range: 32-85) years in the validation cohort. On multivariate analysis, four factors were found to be significantly associated with worse overall survival (OS): late TNM stage, positive resection margin, preoperative carcinoembryonic antigen (CEA) level, and single chemotherapy regimens compared with multiple chemotherapy regimens. All of these findings were validated in the validation cohort. Furthermore, the four factors were included in the final nomogram for the prediction of 1-year, 3-year, and 5-year survival probability, with accurate calibration and reasonable discrimination (C-index = 0.676 for training cohort, and C-index = 0.664 for validation cohort). The AUC values analyzed by the ROC analysis demonstrated a good predictive accuracy of the nomogram for OS (1-year, 3-year, and 5-year OS were 94.43%, 77.42%, and 73.03% in the training cohort, respectively; 96.95%, 81.54%, and 73.41% in the validation cohort, respectively). In conclusion, the proposed nomogram may be used to objectively and accurately predict survival probability of GC patients in a multi-institutional clinical setting.

BAP1 Loss by Immunohistochemistry Predicts Improved Survival to First-Line Platinum and Pemetrexed Chemotherapy for Patients With Pleural Mesothelioma: A Validation Study.

INTRODUCTION: Pleural mesothelioma (PM) is an aggressive malignancy with no identified predictive biomarkers. We assessed whether tumor BAP1 status is a predictive biomarker for survival in patients receiving first-line combination platinum and pemetrexed therapy. METHODS: PM cases (n = 114) from Aalborg, Denmark, were stained for BAP1 on tissue microarrays. Demographic, clinical, and survival data were extracted from registries and medical records. Surgical cases were excluded. BAP1 status was associated with overall survival (OS) by Cox regression and Kaplan-Meier methods. Results were validated in an independent cohort from Perth, Australia (n = 234). RESULTS: BAP1 loss was found in 62% and 60.3% of all Danish and Australian samples, respectively. BAP1 loss was an independent predictor of OS in multivariate analyses corrected for histological subtype, performance status, age, sex, and treatment (hazard ratio = 2.49, p < 0.001, and 1.48, p = 0.01, respectively). First-line platinum and pemetrexed-treated patients with BAP1 loss had significantly longer median survival than those with retained BAP1 in both the Danish (20.1 versus 7.3 mo, p < 0.001) and Australian cohorts (19.6 versus 11.1 mo, p < 0.01). Survival in patients with BAP1 retained and treated with platinum and pemetrexed was similar as in those with best supportive care. There was a higher OS in patients with best supportive care with BAP1 loss, but it was significant only in the Australian cohort (16.8 versus 8.3 mo, p < 0.01). CONCLUSIONS: BAP1 is a predictive biomarker for survival after first-line combination platinum and pemetrexed chemotherapy and a potential prognostic marker in PM. BAP1 in tumor is a promising clinical tool for treatment stratification.

Dysregulated atrial gene expression of osteoprotegerin/receptor activator of nuclear factor-κB (RANK)/RANK ligand axis in the development and progression of atrial fibrillation.

BACKGROUND: Atrial structural remodeling is increasingly emphasized in initiation and perpetuation of atrial fibrillation (AF). Osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL) axis, a key regulatory system in bone homeostasis, was recently linked to some cardiovascular disorders for its regulatory functions to myocardial remodeling. It was hypothesized that OPG/RANK/RANKL axis is involved in the development and progression of AF by regulating atrial structural remodeling. METHODS AND RESULTS: Clinical data, and biopsies of right atrial appendage were collected from sex- and age-matched subjects: 24 persistent AF patients, 24 paroxysmal AF patients, 24 sinus rhythm patients undergoing isolated mitral valve surgery and 24 healthy heart donors. AF groups had higher atrial gene expression of OPG/RANK/RANKL axis and RANKL/OPG ratio, particularly in paroxysmal AF. This upregulated expression and activity were positively correlated with higher regulatory indicators of atrial structural remodeling as reflected by higher transcripts of tumor necrosis factor (TNF)-related apoptosis-inducing ligand, matrix metalloproteinase (MMP)-2 and MMP-9, pro-inflammatory factors TNF-α and interleukin-6, and higher ratios of MMP-9/tissue inhibitor of metalloproteinase (TIMP)-1 and MMP-2/TIMP-2 in AF. CONCLUSIONS: The present findings suggest a potential role for known mediators of bone metabolism in the development and progression of AF and possibly represent new targets for therapeutic intervention in this disorder.

Cancer Incidence and Risk of Multiple Cancers after Environmental Asbestos Exposure in Childhood-A Long-Term Register-Based Cohort Study.

OBJECTIVES: To examine the asbestos-associated cancer incidence and the risk of multiple cancers in former school children exposed to environmental asbestos in childhood. METHODS: A cohort of 12,111 former school children, born 1940-1970, was established using 7th grade school records from four schools located at a distance of 100-750 m in the prevailing wind direction from a large asbestos-cement plant that operated from 1928 to 1984 in Aalborg, Denmark. Using the unique Danish personal identification number, we linked information on employments, relatives' employments, date of cancer diagnosis, and type of cancer and vital status to data on cohortees extracted from the Supplementary Pension Fund Register (employment history), the Danish Cancer Registry, and the Danish Civil Registration System. We calculated standardized incidence rates (SIRs) for asbestos-associated cancers, all cancers, and multiple cancers using rates for a gender and five-year frequency-matched reference cohort. RESULTS: The overall incidence of cancer was modestly increased for the school cohort (SIR 1.07, 95% confidence interval (CI) 1.02-1.12) compared with the reference cohort. This excess was driven primarily by a significantly increased SIR for malignant mesothelioma (SIR 8.77, 95% CI 6.38-12.05). Former school children who had combined childhood environmental and subsequent occupational exposure to asbestos had a significantly increased risk of lung cancer. Within this group, those with additional household exposure by a relative had a significantly increased SIR for cancer of the pharynx (SIR 4.24, 95% CI 1.59-11.29). We found no significant difference in the number of subjects diagnosed with multiple cancers between the two cohorts. CONCLUSIONS: Our study confirms the strong association between environmental asbestos exposure and malignant mesothelioma and suggests that environmental asbestos exposure in childhood may increase the overall cancer risk later in life.