[A new one in the lung and pleura neoplasms classification (WHO, 2021, 5th edition)]. / Novoe v Klassifikatsii novoobrazovanii legkikh i plevry (VOZ, 2021 g., 5-e izdanie).

The article contains an overview of the new WHO classification of thoracic tumors (2021). As in the previous edition of 2015, considerable attention is paid to neoplasms of the lungs and pleura. The article presents current data on molecular genetic features and morphological manifestations of a number of new lung tumors, with a detailed histological and immunohistochemical data. Thoracis undifferentiated tumor with SMARCA4 deficiency and bronchiolar adenoma are described. Emphasis is placed on the algorithms of morphological diagnostics, including a complete description of the tumor and facilitating the study in the practice of a pathologist. The main morphological criteria of mesothelial tumors of the pleura are given; describes in detail the procedure for assessing the degree of malignancy of diffuse epithelioid pleural mesothelioma and non-mucinous lung adenocarcinomas.

Deep-learning based classification distinguishes sarcomatoid malignant mesotheliomas from benign spindle cell mesothelial proliferations.

Sarcomatoid mesothelioma is an aggressive malignancy that can be challenging to distinguish from benign spindle cell mesothelial proliferations based on biopsy, and this distinction is crucial to patient treatment and prognosis. A novel deep learning based classifier may be able to aid pathologists in making this critical diagnostic distinction. SpindleMesoNET was trained on cases of malignant sarcomatoid mesothelioma and benign spindle cell mesothelial proliferations. Performance was assessed through cross-validation on the training set, on an independent set of challenging cases referred for expert opinion ('referral' test set), and on an externally stained set from outside institutions ('externally stained' test set). SpindleMesoNET predicted the benign or malignant status of cases with AUC's of 0.932, 0.925, and 0.989 on the cross-validation, referral and external test sets, respectively. The accuracy of SpindleMesoNET on the referral set cases (92.5%) was comparable to the average accuracy of 3 experienced pathologists on the same slide set (91.7%). We conclude that SpindleMesoNET can accurately distinguish sarcomatoid mesothelioma from benign spindle cell mesothelial proliferations. A deep learning system of this type holds potential for future use as an ancillary test in diagnostic pathology.

Modification of existing patient-reported outcome measures: qualitative development of the MD Anderson Symptom Inventory for malignant pleural mesothelioma (MDASI-MPM).

PURPOSE: Malignant pleural mesothelioma (MPM) is an aggressive cancer of the lung pleura. The MD Anderson Symptom Inventory (MDASI) is a patient-reported outcome (PRO) measure of symptom burden, the combined impact of disease-related and treatment-related symptoms on functioning. Validated PRO measures may require modification for use in specific study populations. We sought to modify the MDASI for patients with MPM and create a fit-for-purpose symptom-burden measure for use in a clinical trial, according to US Food and Drug Administration guidance on PRO utilization to support labeling claims. METHODS: A literature review for MPM symptoms was conducted. Patients with MPM were qualitatively interviewed about experiences of disease and treatment. Descriptive analysis identified symptoms and interference with functioning to define MPM-related symptom burden. An expert panel rated the relevance of identified symptoms to patients with MPM. Patients who received the investigational drug in a previous Phase I study were interviewed for drug-specific symptoms. RESULTS: Literature review and interviews of 20 patients identified 31 MPM-related symptoms. A conceptual model of MPM-related symptom burden was developed. After expert-panel relevance review, five MPM-specific items and the 13 core MDASI symptoms met criteria for inclusion in a provisional MDASI-MPM for psychometric testing. Interviews with six patients identified six drug-specific symptoms; three were mentioned by multiple patients. Of these three, one was not in the core MDASI. CONCLUSIONS: The MDASI-MPM has established content validity and, with the addition of one symptom item, is ready for psychometric testing as fit-for-purpose for a clinical trial of an investigational agent.

Pathology analysis for mesothelioma study in the United Kingdom: Current practice and historical development.

Following up on the largest case-control study of malignant mesothelioma yet performed, investigators at the London School of Hygiene and Tropical Medicine assessed 1732 male and 670 female cases as of May 2013. Epidemiological findings of a subset of these were published previously, excluding patients who died or who refused to be interviewed. Pathology reports were collected for subjects, including those both eligible and ineligible for epidemiology study based on vital status. The current investigation examined 860 cases having pathology reports available. Sixty-one cases were diagnosed using cytology only, often with equivocal diagnoses, while 799 reported at least a biopsy of the tumor. Of these, 748 had pathology sufficiently detailed for evaluation. These reports were examined for basis of diagnosis, differences between study cases and ineligible cases, pathology characteristics, and immunohistochemical and other tests used. The most prominent subtype was epithelioid (64% of study cases but only 49% of ineligible cases). Biphasic subtype was present in 10% of study cases and 16% of those ineligible. Sarcomatoid subtype was present in 7% of study cases and 19% of ineligible cases, most of whom died. Twelve percent of study cases displayed no specified subtype, versus 7% of ineligible cases. Of recorded immunohistochemical stains specific for mesothelial cell origin, calretinin (95%) and CK 5/6 or CK5 alone (84%) were by far the most common. Calretinin and CK 5/6 or CK 5 alone were also most sensitive and positive in 92% of cases presenting with surgical pathology report. Ninety percent of cases had at least one immunohistochemical marker for possible lung carcinoma applied, with BER-Ep4 and TTF-1 the most frequent at 68% and CEA at 58%. TTF-1 and CEA were positive in 1% or less of cases. Patterns of use and positive and negative results for each of these as well as other immunohistochemical stains are presented and discussed, along with a brief historical description of their development and use. Possible effects of the pathologic analysis on the results of previously published and future epidemiological studies are discussed.

Detection of malignant mesothelioma using nuclear structure of mesothelial cells in effusion cytology specimens.

Mesothelioma is a form of cancer generally caused from previous exposure to asbestos. Although it was considered a rare neoplasm in the past, its incidence is increasing worldwide due to extensive use of asbestos. In the current practice of medicine, the gold standard for diagnosing mesothelioma is through a pleural biopsy with subsequent histologic examination of the tissue. The diagnostic tissue should demonstrate the invasion by the tumor and is obtained through thoracoscopy or open thoracotomy, both being highly invasive surgical operations. On the other hand, thoracocentesis, which is removal of effusion fluid from the pleural space, is a far less invasive procedure that can provide material for cytological examination. In this study, we aim at detecting and classifying malignant mesothelioma based on the nuclear chromatin distribution from digital images of mesothelial cells in effusion cytology specimens. Accordingly, a computerized method is developed to determine whether a set of nuclei belonging to a patient is benign or malignant. The quantification of chromatin distribution is performed by using the optimal transport-based linear embedding for segmented nuclei in combination with the modified Fisher discriminant analysis. Classification is then performed through a k-nearest neighborhood approach and a basic voting strategy. Our experiments on 34 different human cases result in 100% accurate predictions computed with blind cross validation. Experimental comparisons also show that the new method can significantly outperform standard numerical feature-type methods in terms of agreement with the clinical diagnosis gold standard. According to our results, we conclude that nuclear structure of mesothelial cells alone may contain enough information to separate malignant mesothelioma from benign mesothelial proliferations.

[Comparing the results of pathologic diagnosis of mesothelioma between Chinese and Japanese experts].

OBJECTIVE: To compare the results of pathological diagnosis of 41 patients with malignant mesothelioma between Chinese and Japanese experts, and to provide a basis for the standard for diagnosis of mesothelioma. METHODS: The medical information and tissue samples of 41 patients with malignant mesothelioma were collected in a hospital in Zhejiang Province from 2003 to 2010. The expression levels of calretinin, Wilms' tumor suppressor gene (WT1), podoplanin (D2-40), cytokeratins (CK5/6, AE1/AE3, and CAM5.2), epithelial membrane antigen, carcinoembryonic antigen, BerEP4, MOC31, thyroid transcription factor-1, estrogen receptor, and progesterone receptor in tumor tissues were measured using immunohistochemical staining by Japanese experts, and the pathological classification and diagnosis were made. The results of diagnosis, pathological classification, immunohistochemical marker selection, and slide review were compared between Chinese and Japanese experts. RESULTS: Twenty-nine (70.7%) cases were diagnosed as mesothelioma by Japanese experts, among whom 12 (41.4%) cases were pleura mesothelioma, and 17 (58.6%) cases were peritoneal mesothelioma. Ten (24.4%) cases were confirmed without mesothelioma, and 2 (4.9%) cases were not confirmed due to insufficient information. Thirty-two (78.0%) cases were diagnosed as mesothelioma by Chinese experts, among whom 8 (25.0%) cases were pleura mesothelioma, and 24 (75.0%) cases were peritoneal mesothelioma. One (2.4%) case was confirmed without mesothelioma, and 8 (19.5%) cases were not confirmed. There were significant differences in the results of diagnosis between Chinese and Japanese experts. However, their pathological classifications of mesothelioma were similar. Significant differences in immunohistochemical marker selection and slide review were also found between Chinese and Japanese experts. CONCLUSION: The diagnostic skills of those pathological experts in this hospital remain to be further improved for mesothelioma diagnosis. A panel of immunohistochemical markers including at least 2 mesothelioma-positive and 2 mesothelioma-negative markers are recommended for the diagnosis of malignant mesothelioma.

[Pleural mesothelioma. Cytology and molecular diagnostics]. / Pleuramesotheliom. Zytologie und molekulare Diagnostik.

The definitive diagnosis of malignant mesothelioma (MM) in effusion cytology is often avoided or reluctantly made by cytology alone. The most probable reason for this skepticism is the lack of expertise in cytology among many pathologists and clinicians. When an effusion specimen is composed of cells with unequivocal cytological features of malignancy that have the morphology and immunophenotype of mesothelial cells, the cytological diagnosis of MM is straightforward. However, in the daily routine difficult cases of atypical mesothelial cells are often encountered and additional methods are required to establish an accurate diagnosis. In contrast to reactive mesothelial cells cells of MMs often harbor chromosomal aberrations, most frequently a polysomy in combination with a 9p21 deletion. These chromosomal aberrations can easily be detected by multitarget fluorescence in situ hybridization (FISH); therefore, FISH allows a reliable distinction between reactive mesothelial cells and MM cells. In order to be able to discriminate between MM and adenocarcinoma, an immunocytochemical panel consisting of different mesothelial and epithelial markers is very helpful. In most inconclusive cases of atypical mesothelial cells the combination of morphology, immunocytochemistry and FISH allows a better distinction between reactive mesothelial cells and MM in effusion cytology.

[Morphological diagnostics of malignant pleural mesothelioma]. / Morphologische Diagnostik maligner Pleuramesotheliome.

The World Health Organization (WHO) classification differentiates between pleural tumors of mesothelial and mesenchymal origin as well as lymphoproliferative disorders, with malignant mesotheliomas forming the most common pleural primary tumor. Histologically, epithelioid (40-60 %), sarcomatoid (20-40 %), and biphasic mesotheliomas (20-40 %) are distinguished. The certain morphological diagnosis of a malignant pleural mesothelioma requires the establishment of mesothelial differentiation by means of an appropriate panel of antibodies to exclude pleural dissemination of a pulmonary or extrapulmonary epithelial malignancy and also requires the establishment of at least focal invasive growth to distinguish from reactive mesothelial proliferation. The exclusion of a malignant pleural mesothelioma may induce further differential diagnostic considerations, e. g. concerning the assignment to a certain primary tumor after the establishment of carcinomatous pleuritis.

Malignant Pleural Mesothelioma : Rationale for a New TNM Classification.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy with a poor prognosis. In this regard, a well-defined staging system is of utmost importance in order to correctly diagnose and assign an appropriate treatment to the patient. METHODS: The current TNM-staging system (7th edition) enables to either clinically or pathologically stage the severity of the disease according to extension of the tumor (T), number of nodes (N) and presence of metastases (M). Patients with stage I-III are considered for surgery, while palliative treatment is indicated for stage IV patients according to the current classification. RESULTS: Despite its widespread use, the validity of this staging system is questioned due to the low prevalence, histological variety and retrospective nature of the previous study design. In addition, the role of specific treatment modalities including surgery, has yet to be determined, especially for treatment of early-stage disease. In this regard, the International Association for the Study of Lung Cancer (IASLC) initiated the multi-centre, prospective "Mesothelioma Staging Project" in order to address limitations of the 7th edition and to optimize the staging system in accordance to current needs. CONCLUSIONS: An improved staging system will contribute to the design of prospective multi-institutional clinical trials investigating novel treatment strategies for mesothelioma. In this way comparison of outcome between different medical centres also becomes feasible.

Classification and Detection of Mesothelioma Cancer Using Feature Selection-Enabled Machine Learning Technique.

Cancer of the mesothelium, sometimes referred to as malignant mesothelioma (MM), is an extremely uncommon form of the illness that almost always results in death. Chemotherapy, surgery, radiation therapy, and immunotherapy are all potential treatments for multiple myeloma; however, the majority of patients are identified with the disease at an advanced stage, at which time it is resistant to these therapies. After obtaining a diagnosis of advanced multiple myeloma, the average length of time that a person lives is one year after hearing this news. There is a substantial link between asbestos exposure and mesothelioma (MM). Using an approach that enables feature selection and machine learning, this article proposes a classification and detection method for mesothelioma cancer. The CFS correlation-based feature selection approach is first used in the feature selection process. It acts as a filter, selecting just the traits that are relevant to the categorization. The accuracy of the categorization model is improved as a direct consequence of this. After that, classification is carried out with the help of naive Bayes, fuzzy SVM, and the ID3 algorithm. Various metrics have been utilized during the process of measuring the effectiveness of machine learning strategies. It has been discovered that the choice of features has a substantial influence on the accuracy of the categorization.

Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma.

In humans, mesothelioma has been linked to asbestos exposure, especially crocidolite and amosite asbestos, which contain high amounts of iron. Previously, we established a rat model of iron-induced peritoneal mesothelioma with repeated intraperitoneal injections of iron saccharate and an iron chelator, nitrilotriacetate. Here, we analyze these mesotheliomas using array-based comparative genomic hybridization (aCGH) and gene expression profiling by microarray. Mesotheliomas were classified into two distinct types after pathologic evaluation by immunohistochemistry. The major type, epithelioid mesothelioma (EM), originated in the vicinity of tunica vaginalis testis, expanded into the upper peritoneal cavity and exhibited papillary growth and intense podoplanin immunopositivity. The minor type, sarcomatoid mesothelioma (SM), originated from intraperitoneal organs and exhibited prominent invasiveness and lethality. Both mesothelioma types showed male preponderance. SMs revealed massive genomic alterations after aCGH analysis, including homozygous deletion of CDKN2A/2B and amplification of ERBB2 containing region, whereas EMs showed less genomic alterations. Uromodulin was highly expressed in most of the cases. After 4-week treatment, iron deposition in the mesothelia was observed with 8-hydroxy-2'-deoxyguanosine formation. These results not only show two distinct molecular pathways for iron-induced peritoneal mesothelioma, but also support the hypothesis that oxidative stress by iron overload is a major cause of CDKN2A/2B homozygous deletion.

Diffusion-weighted MRI of malignant pleural mesothelioma: preliminary assessment of apparent diffusion coefficient in histologic subtypes.

OBJECTIVE: The purpose of this study was to prospectively assess, in the evaluation of patients with suspected malignant pleural mesothelioma (MPM), apparent diffusion coefficient (ADC) values derived from diffusion-weighted images obtained with a free-breathing single-shot spin-echo echo-planar imaging sequence and to correlate the ADC values with the three histologic subtypes of MPM. SUBJECTS AND METHODS: Sixty-two patients with a known pleural abnormality and clinical findings suggestive of MPM underwent diffusion-weighted 3-T MRI and ADC calculation. The pathologic diagnosis was confirmed by surgical procedure. ADC values were correlated with the histologic subtypes of MPM. Statistical analysis was performed with analysis of variance and the Student's t test. RESULTS: Fifty-seven patients had MPM. Forty of the tumors were epithelioid, 11 were biphasic, and six were sarcomatoid. The other five patients had pleural thickening (two patients), metastatic adenocarcinoma (one patient), chronic inflammation (one patient), and malignant lymphoma (one patient). Because of image distortion, the diffusion-weighted images and ADC maps were not satisfactory for assessment in seven cases. The ADC values of MPM were 1.31 +/- 0.15 x 10(-3) mm(2)/s for the epithelioid, 1.01 +/- 0.11 x 10(-3) mm(2)/s for the biphasic, and 0.99 +/- 0.07 x 10(-3) mm(2)/s for the sarcomatoid subtypes of MPM. The ADC of the epithelioid subtype was statistically significantly higher than that of the sarcomatoid subtype (p < 0.05). The ADC in the two cases of benign plaque was 0.85 +/- 0.17 x 10(-3) mm(2)/s. CONCLUSION: The ADC values of epithelioid mesothelioma are higher than those of sarcomatoid mesothelioma. There is no significant difference between the ACD values of biphasic and those of sarcomatoid MPM.

Asbestosis and mesothelioma among British asbestos workers (1971-2005).

BACKGROUND: Ascertainment of asbestosis and mesothelioma from underlying cause of death underestimates the burden of these diseases. The aims of this study were to estimate the true frequency of asbestosis and mesothelioma among asbestos workers in Great Britain (GB), and to identify factors associated with the risk of death with these diseases. METHODS: The GB Asbestos Survey was established in 1971 to monitor long-term health outcomes among workers covered by regulations to control asbestos at work. Asbestosis and mesothelioma cases were defined by multiple cause of death, and were ascertained by identifying asbestos workers on the GB Asbestosis and Mesothelioma Registers. Standardized mortality ratios (SMRs) were calculated; the risks of asbestosis and mesothelioma were modeled with Poisson regression analysis. Deaths to the end of 2005 were included. RESULTS: There were 15,557 deaths between 1971 and 2005 among the 98,912 workers. Altogether 477 asbestosis and 649 mesothelioma cases were identified. The SMR for all causes was 1.42, for asbestosis 51.3, and for mesothelioma 13.5. In multiply adjusted analysis, age, sex, job, and birth cohort were significantly associated with asbestosis and mesothelioma. For asbestosis year of first exposure, and for mesothelioma latency, were also statistically significant. CONCLUSIONS: The asbestos workers experienced high mortality from all causes, asbestosis, and mesothelioma. There was some evidence that the risk of asbestosis and mesothelioma was lower in later birth cohorts and among those first occupationally exposed to asbestos more recently. Due to the long latency of both diseases, further follow-up is required to confirm these trends.

Clinical study on mesothelioma in Japan: Relevance to occupational asbestos exposure.

BACKGROUND: In 2003, the number of deaths due to malignant mesothelioma in Japan was 878; however, only 85 cases of mesothelioma due to asbestos exposure were authorized for compensation. The reasons for this discrepancy require evaluation. METHOD: We examined medical records, X-rays, and pathology results to evaluate mesothelioma cases in Japan between 2003 and 2005; used a questionnaire to identify occupational and environmental histories, and determined the concentration of asbestos fibers in pathology specimens. RESULTS: We identified 442 definite cases of malignant mesothelioma with a median age of 68 years. There were 316 malignant mesothelioma cases with occupational asbestos exposure, 12 cases with neighborhood exposure and 5 cases with likely domestic exposure. Most (78%) of the 87 cases exceeded 1,000 asbestos particles per gram of dry lung tissue. CONCLUSION: We conclude that 79.2% of cases of mesothelioma in Japan in recent years were caused by asbestos exposure.

Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial.

BACKGROUND: Malignant pleural mesothelioma is almost always fatal, and few treatment options are available. Although active symptom control (ASC) has been recommended for the management of this disease, no consensus exists for the role of chemotherapy. We investigated whether the addition of chemotherapy to ASC improved survival and quality of life. METHODS: 409 patients with malignant pleural mesothelioma, from 76 centres in the UK and two in Australia, were randomly assigned to ASC alone (treatment could include steroids, analgesic drugs, bronchodilators, palliative radiotherapy [n=136]); to ASC plus MVP (four cycles of mitomycin 6 mg/m2, vinblastine 6 mg/m2, and cisplatin 50 mg/m2 every 3 weeks [n=137]); or to ASC plus vinorelbine (one injection of vinorelbine 30 mg/m2 every week for 12 weeks [n=136]). Randomisation was done by minimisation, with stratification for WHO performance status, histology, and centre. Follow-up was every 3 weeks to 21 weeks after randomisation, and every 8 weeks thereafter. Because of slow accrual, the two chemotherapy groups were combined and compared with ASC alone for the primary outcome of overall survival. Analysis was by intention to treat. This study is registered, number ISRCTN54469112. FINDINGS: At the time of analysis, 393 (96%) patients had died (ASC 132 [97%], ASC plus MVP 132 [96%], ASC plus vinorelbine 129 [95%]). Compared with ASC alone, we noted a small, non-significant survival benefit for ASC plus chemotherapy (hazard ratio [HR] 0.89 [95% CI 0.72-1.10]; p=0.29). Median survival was 7.6 months in the ASC alone group and 8.5 months in the ASC plus chemotherapy group. Exploratory analyses suggested a survival advantage for ASC plus vinorelbine compared with ASC alone (HR 0.80 [0.63-1.02]; p=0.08), with a median survival of 9.5 months. There was no evidence of a survival benefit with ASC plus MVP (HR 0.99 [0.78-1.27]; p=0.95). We observed no between-group differences in four predefined quality-of-life subscales (physical functioning, pain, dyspnoea, and global health status) at any of the assessments in the first 6 months. INTERPRETATION: The addition of chemotherapy to ASC offers no significant benefits in terms of overall survival or quality of life. However, exploratory analyses suggested that vinorelbine merits further investigation.

Deep learning-based classification of mesothelioma improves prediction of patient outcome.

Malignant mesothelioma (MM) is an aggressive cancer primarily diagnosed on the basis of histological criteria1. The 2015 World Health Organization classification subdivides mesothelioma tumors into three histological types: epithelioid, biphasic and sarcomatoid MM. MM is a highly complex and heterogeneous disease, rendering its diagnosis and histological typing difficult and leading to suboptimal patient care and decisions regarding treatment modalities2. Here we have developed a new approach-based on deep convolutional neural networks-called MesoNet to accurately predict the overall survival of mesothelioma patients from whole-slide digitized images, without any pathologist-provided locally annotated regions. We validated MesoNet on both an internal validation cohort from the French MESOBANK and an independent cohort from The Cancer Genome Atlas (TCGA). We also demonstrated that the model was more accurate in predicting patient survival than using current pathology practices. Furthermore, unlike classical black-box deep learning methods, MesoNet identified regions contributing to patient outcome prediction. Strikingly, we found that these regions are mainly located in the stroma and are histological features associated with inflammation, cellular diversity and vacuolization. These findings suggest that deep learning models can identify new features predictive of patient survival and potentially lead to new biomarker discoveries.

Pathologic Considerations and Standardization in Mesothelioma Clinical Trials.

The accurate diagnosis of mesothelioma is critical for the appropriate clinical management of this cancer. Many issues complicate making the diagnosis of mesothelioma including the presence of reactive mesothelial cells in benign pleural effusions, the heterogeneity of mesothelioma histopathology, the relatively high incidence of other epithelial malignancies that metastasize to the pleura, and primary sarcomas that arise within the pleura. Given the rapidly evolving field of molecular profiling and the need for translational correlates in mesothelioma clinical trials, the National Cancer Institute (NCI)-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Clinical Trials Planning Meeting was convened in March 2017 to develop a consensus on standard pathology guidelines for future NCI-sponsored clinical trials in mesothelioma. This consensus statement covers recommendations for specimen handling, pathologic classification and diagnosis, biobanking, and tissue correlative studies.

BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma.

BACKGROUND: Malignant peritoneal mesothelioma (PeM) is a rare and fatal cancer that originates from the peritoneal lining of the abdomen. Standard treatment of PeM is limited to cytoreductive surgery and/or chemotherapy, and no effective targeted therapies for PeM exist. Some immune checkpoint inhibitor studies of mesothelioma have found positivity to be associated with a worse prognosis. METHODS: To search for novel therapeutic targets for PeM, we performed a comprehensive integrative multi-omics analysis of the genome, transcriptome, and proteome of 19 treatment-naïve PeM, and in particular, we examined BAP1 mutation and copy number status and its relationship to immune checkpoint inhibitor activation. RESULTS: We found that PeM could be divided into tumors with an inflammatory tumor microenvironment and those without and that this distinction correlated with haploinsufficiency of BAP1. To further investigate the role of BAP1, we used our recently developed cancer driver gene prioritization algorithm, HIT'nDRIVE, and observed that PeM with BAP1 haploinsufficiency form a distinct molecular subtype characterized by distinct gene expression patterns of chromatin remodeling, DNA repair pathways, and immune checkpoint receptor activation. We demonstrate that this subtype is correlated with an inflammatory tumor microenvironment and thus is a candidate for immune checkpoint blockade therapies. CONCLUSIONS: Our findings reveal BAP1 to be a potential, easily trackable prognostic and predictive biomarker for PeM immunotherapy that refines PeM disease classification. BAP1 stratification may improve drug response rates in ongoing phases I and II clinical trials exploring the use of immune checkpoint blockade therapies in PeM in which BAP1 status is not considered. This integrated molecular characterization provides a comprehensive foundation for improved management of a subset of PeM patients.

Peritoneal mesotheliomas: clinicopathologic features, CT findings, and differential diagnosis.

OBJECTIVE: The objective of our study was to illustrate various CT findings of peritoneal mesotheliomas, to review their clinicopathologic features, and to discuss the differential diagnoses. CONCLUSION: The clinicopathologic features of peritoneal mesotheliomas vary among the subtypes such as malignant mesotheliomas, cystic mesotheliomas, and well-differentiated papillary mesotheliomas, and accordingly, there is a spectrum of CT appearances.

Establishment of a human malignant fibrous mesothelioma cell line and the biological characteristics compared with malignant epithelial mesothelioma cell line.

Two human malignant mesothelioma cell lines, which we designated "epithelial mesothelioma cells" and "fibrous mesothelioma cells", were established from the pleural fluid containing malignant mesothelial cells of a 72-year-old Japanese man. These cell lines were separated by the colonial techniques from the initiation of the primary cultures and grew well without interruption for 12 years. They were characterized as producing hyaluronic acid. These cell lines displayed different biological characteristics, including morphology, heterotransplantability and genetics using with BAC array CGH. The epithelial mesothelioma cells were epithelial in shape and transplantable into the subcutis of nude mice, while the cells of the fibrous mesothelioma line were fibroblast-like and transplantable into the submucosa of Hamster's cheek pouches but not into the subcutis of nude mice. The mesotheliomas are classified into three types: epithelial mesothelioma, fibrous mesothelioma and mixed type. The gene copy number losses observed on 9p21.3, 9p21.2, 9p21.1, among others may be a major mechanism of malignant mesothelioma carcinogenesis. We considered and supported the combination theory for the histogenesis of malignant mesothelioma.