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Pulmonary pathologists often must make a diagnosis based on small specimens derived from aspirated or solid tissue fragments, extracted under radiological guidance, containing limited diagnostic material. This poses a diagnostic challenge. Advances in treatment also demand tissue is analysed for multiple molecular anomalies therefore pathologists must be judicious in their use of ancillary tests such as immunohistochemistry. Whilst the majority of tumours encountered are non-small cell lung carcinomas, the lungs and thorax are a common metastatic site and can display a wide variety of different tumour types. Some tumours can closely mimic the appearances of non-small cell carcinomas and failure to recognise these can result in misdiagnosis and incorrect treatment and management for the patient. In this article we specifically focus on a variety of different tumours that can masquerade as non-small cell carcinomas. This includes both benign and malignant primary lung tumours, sarcomas, melanomas and germ cell tumours. We describe how to approach and recognise these entities, with specific focus on the histological and immunohistochemical appearances, and identify potential pitfalls to avoid in routine practice. [ABSTRACT FROM AUTHOR]

Extended pleurectomy decortication for complete macroscopic resection for pleural mesothelioma has never been evaluated in a randomised trial. The aim of this study was to compare outcomes after extended pleurectomy decortication plus chemotherapy versus chemotherapy alone. MARS 2 was a phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial conducted in the UK. The trial took place across 26 hospitals (21 recruiting only, one surgical only, and four recruiting and surgical). Following two cycles of chemotherapy, eligible participants with pleural mesothelioma were randomly assigned (1:1) to surgery and chemotherapy or chemotherapy alone using a secure web-based system. Individuals aged 16 years or older with resectable pleural mesothelioma and adequate organ and lung function were eligible for inclusion. Participants in the chemotherapy only group received two to four further cycles of chemotherapy, and participants in the surgery and chemotherapy group received pleurectomy decortication or extended pleurectomy decortication, followed by two to four further cycles of chemotherapy. It was not possible to mask allocation because the intervention was a major surgical procedure. The primary outcome was overall survival, defined as time from randomisation to death from any cause. Analyses were done on the intention-to-treat population for all outcomes, unless specified. This study is registered with ClinicalTrials.gov , NCT02040272 , and is closed to new participants. Between June 19, 2015, and Jan 21, 2021, of 1030 assessed for eligibility, 335 participants were randomly assigned (169 to surgery and chemotherapy, and 166 to chemotherapy alone). 291 (87%) participants were men and 44 (13%) women, and 288 (86%) were diagnosed with epithelioid mesothelioma. At a median follow-up of 22·4 months (IQR 11·3–30·8), median survival was shorter in the surgery and chemotherapy group (19·3 months [IQR 10·0–33·7]) than in the chemotherapy alone group (24·8 months [IQR 12·6–37·4]), and the difference in restricted mean survival time at 2 years was –1·9 months (95% CI –3·4 to –0·3, p=0·019). There were 318 serious adverse events (grade ≥3) in the surgery group and 169 in the chemotherapy group (incidence rate ratio 3·6 [95% CI 2·3 to 5·5], p<0·0001), with increased incidence of cardiac (30 vs 12; 3·01 [1·13 to 8·02]) and respiratory (84 vs 34; 2·62 [1·58 to 4·33]) disorders, infection (124 vs 53; 2·13 [1·36 to 3·33]), and additional surgical or medical procedures (15 vs eight; 2·41 [1·04 to 5·57]) in the surgery group. Extended pleurectomy decortication was associated with worse survival to 2 years, and more serious adverse events for individuals with resectable pleural mesothelioma, compared with chemotherapy alone. National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/188/31), Cancer Research UK Feasibility Studies Project Grant (A15895). [ABSTRACT FROM AUTHOR]

Most patients with pleural mesothelioma (PM) present with symptomatic pleural effusion. In some patients, PM is only detectable on the pleural surfaces, providing a strong rationale for intrapleural anticancer therapy. In modern prospective studies involving expert radiological staging and specialist multidisciplinary teams, the population incidence of stage I PM (an approximate surrogate of pleura-only PM) is higher than in historical retrospective series. In this Viewpoint, we advocate for the expansion of intrapleural trials to serve these patients, given the paucity of data supporting licensed systemic therapies in this setting and the uncertainties involved in surgical therapy. We begin by reviewing the unique anatomical and physiological features of the PM-bearing pleural space, before critically appraising the evidence for systemic therapies in stage I PM and previous intrapleural PM trials. We conclude with a summary of key challenges and potential solutions, including optimal trial designs, repurposing of indwelling pleural catheters, and new technologies. [ABSTRACT FROM AUTHOR]

Malignant pleural mesothelioma (MPM) is a rare cancer with high malignancy and aggressiveness on the pleural, caused by the following risk factors including asbestos inhalation, genetic factors, and genetic mutation. The present chemotherapy, antiangiogenic therapy, and immunotherapy methods are ineffective and the survival time of patients is very short. There is an urgent need to find potential therapeutic targets for MPM. At present, it has been found the following types of targets: gene mutation targets such as BRCA associated protein 1 (BAP1) and cyclin-dependent kinase 2A (CDKN2A); epigenetic targets such as lysine (K)-specific demethylase 4A (KDM4A) and lysine-specific demethylase 1 (LSD1), and signal protein targets such as glucose-regulated protein 78 (GRP78) and signal transducer and activator of transcription 3 (STAT3). So far, available clinical trials include phase II clinical trials of histone methyltransferase inhibitor Tazemetostat, poly (ADPribose) polymerase (PARP) inhibitor Rucaparib and cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor Abemaciclib, as well as phase I clinical trials of mesothelin-targeting chimeric antigen receptor T-cell immunotherapy (CAR-T) cell injection in the thoracic cavity and TEA domain family member (TEAD) inhibitor VT3989 and IK-930, and the results of these trials have showed certain clinical efficacy. [ABSTRACT FROM AUTHOR]

Oncolytic viruses (OVs) are biological therapeutic agents that selectively destroy cancer cells while sparing normal healthy cells. Besides direct oncolysis, OV infection induces a proinflammatory shift in the tumor microenvironment and the release of tumor‐associated antigens (TAAs) that might induce an anti‐tumor immunity. Due to their immunostimulatory effect, OVs have been explored for cancer vaccination against specific TAAs. However, this approach usually requires genetic modification of the virus and the production of a new viral vector for each target, which is difficult to implement for low prevalent antigens. In a recent study, Chiaro et al. presented an elegant proof of concept on how to implement the PeptiCRAd vaccination platform to overcome this limitation for the treatment of mesothelioma. Authors showed the feasibility of identifying immunogenic TAAs in human mesothelioma and using them to coat oncolytic adenovirus particles. The result was a customized virus‐based cancer vaccine that circumvents time and resource‐consuming steps incurred from genetically engineering viruses. Although some questions remain to be addressed, this interesting approach suggests novel strategies for personalized cancer medicine using oncolytic virotherapy. [ABSTRACT FROM AUTHOR]

Mesothelioma is a type of late‐onset cancer that develops in cells covering the outer surface of organs. Although it can affect the peritoneum, heart, or testicles, it mainly targets the lining of the lungs, making pleural mesothelioma (PMe) the most common and widely studied mesothelioma type. PMe is caused by exposure to fibres of asbestos, which when inhaled leads to inflammation and scarring of the pleura. Despite the ban on asbestos by most Western countries, the incidence of PMe is on the rise, also facilitated by a lack of specific symptomatology and diagnostic methods. Therapeutic options are also limited to mainly palliative care, making this disease untreatable. Here we present an overview of biological aspects underlying PMe by listing genetic and molecular mechanisms behind its onset, aggressive nature, and fast‐paced progression. To this end, we report on the role of deubiquitinase BRCA1‐associated protein‐1 (BAP1), a tumour suppressor gene with a widely acknowledged role in the corrupted signalling and metabolism of PMe. This review aims to enhance our understanding of this devastating malignancy and propel efforts for its investigation. [ABSTRACT FROM AUTHOR]

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. We evaluated the impact of CDK4/6 inhibition by palbociclib in 28 MPM cell lines including 19 patient‐derived ones, using various approaches including RNA‐sequencing. Palbociclib strongly and durably inhibited the proliferation of 23 cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. When observed, insensitivity to palbociclib was mostly explained by the lack of active T172‐phosphorylated CDK4. This was associated with high p16INK4A (CDKN2A) levels that accompany RB1 defects or inactivation, or (unexpectedly) CCNE1 overexpression in the presence of wild‐type RB1. Prolonged palbociclib treatment irreversibly inhibited proliferation despite re‐induction of cell cycle genes upon drug washout. A senescence‐associated secretory phenotype including various potentially immunogenic components was irreversibly induced. Phosphorylated CDK4 was detected in 80% of 47 MPMs indicating their sensitivity to CDK4/6 inhibitors. Its absence in some highly proliferative MPMs was linked to very high p16 (CDKN2A) expression, which was also observed in public datasets in tumours from short‐survival patients. Our study supports the evaluation of CDK4/6 inhibitors for MPM treatment, in monotherapy or combination therapy. [ABSTRACT FROM AUTHOR]

Mesothelioma is a type of late‐onset cancer that develops in cells covering the outer surface of organs. Although it can affect the peritoneum, heart, or testicles, it mainly targets the lining of the lungs, making pleural mesothelioma (PMe) the most common and widely studied mesothelioma type. PMe is caused by exposure to fibres of asbestos, which when inhaled leads to inflammation and scarring of the pleura. Despite the ban on asbestos by most Western countries, the incidence of PMe is on the rise, also facilitated by a lack of specific symptomatology and diagnostic methods. Therapeutic options are also limited to mainly palliative care, making this disease untreatable. Here we present an overview of biological aspects underlying PMe by listing genetic and molecular mechanisms behind its onset, aggressive nature, and fast‐paced progression. To this end, we report on the role of deubiquitinase BRCA1‐associated protein‐1 (BAP1), a tumour suppressor gene with a widely acknowledged role in the corrupted signalling and metabolism of PMe. This review aims to enhance our understanding of this devastating malignancy and propel efforts for its investigation. [ABSTRACT FROM AUTHOR]

Oncolytic viruses (OVs) are biological therapeutic agents that selectively destroy cancer cells while sparing normal healthy cells. Besides direct oncolysis, OV infection induces a proinflammatory shift in the tumor microenvironment and the release of tumor‐associated antigens (TAAs) that might induce an anti‐tumor immunity. Due to their immunostimulatory effect, OVs have been explored for cancer vaccination against specific TAAs. However, this approach usually requires genetic modification of the virus and the production of a new viral vector for each target, which is difficult to implement for low prevalent antigens. In a recent study, Chiaro et al. presented an elegant proof of concept on how to implement the PeptiCRAd vaccination platform to overcome this limitation for the treatment of mesothelioma. Authors showed the feasibility of identifying immunogenic TAAs in human mesothelioma and using them to coat oncolytic adenovirus particles. The result was a customized virus‐based cancer vaccine that circumvents time and resource‐consuming steps incurred from genetically engineering viruses. Although some questions remain to be addressed, this interesting approach suggests novel strategies for personalized cancer medicine using oncolytic virotherapy. [ABSTRACT FROM AUTHOR]

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. We evaluated the impact of CDK4/6 inhibition by palbociclib in 28 MPM cell lines including 19 patient‐derived ones, using various approaches including RNA‐sequencing. Palbociclib strongly and durably inhibited the proliferation of 23 cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. When observed, insensitivity to palbociclib was mostly explained by the lack of active T172‐phosphorylated CDK4. This was associated with high p16INK4A (CDKN2A) levels that accompany RB1 defects or inactivation, or (unexpectedly) CCNE1 overexpression in the presence of wild‐type RB1. Prolonged palbociclib treatment irreversibly inhibited proliferation despite re‐induction of cell cycle genes upon drug washout. A senescence‐associated secretory phenotype including various potentially immunogenic components was irreversibly induced. Phosphorylated CDK4 was detected in 80% of 47 MPMs indicating their sensitivity to CDK4/6 inhibitors. Its absence in some highly proliferative MPMs was linked to very high p16 (CDKN2A) expression, which was also observed in public datasets in tumours from short‐survival patients. Our study supports the evaluation of CDK4/6 inhibitors for MPM treatment, in monotherapy or combination therapy. [ABSTRACT FROM AUTHOR]

Objective: To review the pathological diagnosis of possible cases and/or hidden cases of malignant mesothelioma (MM) between 2000 and 2012 using the Hospital-Based Cancer Registry database in the state of São Paulo, Brazil. Methods: Possible cases were retrieved by assessing the database. Inclusion criteria were being older than 30 years of age and having ICD-O-3 topography and morphology codes related to MM. A board of expert pathologists reviewed the pathology reports and requested paraffin blocks in cases that demanded revision. After staining with calretinin, D2-40, WT-1 (as positive MM markers) and Ber-EP4 and MOC31 (as negative MM markers), cases were divided and studied independently by a pair of pathologists to confirm or discard the diagnosis of MM. Results: Our sample comprised 482 cases from 25 hospitals, and 130 needed further histological revision. We received 73 paraffin blocks with adequate material. After board analysis, there were 9 cases with a definitive diagnosis of MM, improving the diagnostic rate in 12%. Two cases of previously diagnosed MM were discarded by review. Conclusions: Our results confirm that part of MM underdiagnosis and underreporting in Brazil is due to incomplete or mistaken pathological diagnosis. [ABSTRACT FROM AUTHOR]

Background: Malignant pleural effusion is a common and unfortunately serious condition that is related to life poor quality and mortality. The majority of malignant pleural effusion is metastatic in nature, with the most encountered primary neoplasm in men is the lung cancer while in women is the breast cancer. Ultrasound elastography, with its ability of evaluating tissue stiffness, has been used to differentiate malignant from benign diseases. Shear wave elastography (SWE) has been explored in several organs, like the liver, breast, thyroid, lymph nodes and prostate, with the pleura can now be included among the growing list of SWE applications. Shear wave elastography may help in the differentiation of transudative and exudative types of pleural effusions. Results: In this study, a total of 36 patients were included, 50% revealed malignant pleural effusions (10/18 mesothelioma) and (8/18 metastatic), while the 50% revealed benign pleural effusions (9/18 transudates) and (9/18 exudates). By using sensitivity analysis test of the SWE values with V1 represents the minimum value, V2 the maximum value to calculate the cutoff values that will be used in our final diagnosis in order to differentiate benign and malignant cases. V1 shear wave elastography can significantly predict the malignant pleural effusion with p value 0.001 using a cutoff 48 kPa with calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were as follows 94.4%, 88.9%, 89.5% & 94.4% respectively with diagnostic accuracy of 92%. SWE maximum value (V2) can significantly predict the malignant pleural effusion with p value 0.001 using a cutoff 54.2 kPa, with calculated sensitivity, specificity, PPV and NPV were as follows 94.4%, 94.4%, 94.4% and 94.4% respectively with diagnostic accuracy 94.4%. So, through comparing both cutoff values, we concluded that the cutoff value 2 is better with greater specificity, PPV and NPV in relation to the final diagnosis. Conclusions: Combination of both conventional transthoracic ultrasound and SWE quantitative and qualitative abilities in assessment of both pleural and parenchymal lesions can result in high diagnostic accuracy. Shear wave elastography alone is a sensitive, specific, useful, cost-effective, widely available and noninvasive tool for assessment of tissue stiffness and in matters of high sensitivity. 54.2 kPa can be used as the cutoff value to distinguish MPE from benign pleural disease. [ABSTRACT FROM AUTHOR]

Mesothelioma is a rare malignancy often observed in the pleura of patients exposed to asbestos. Peritoneal mesothelioma is a rare malignancy accounting for less than 20% of all mesothelioma cases. Many older adults might have been exposed to asbestos in the past; therefore, they could still develop mesothelioma later. Due to its rarity and nonspecific presentation, peritoneal mesothelioma is often overlooked. We present the case of a 64-year-old man who had been exposed to asbestos for two year 40 years ago because he lived in an asbestos factory. He visited our emergency room because of acute abdominal pain for one day. Abdominal computed tomography showed many ascites with an irregularly thickened peritoneum, and ascites without portal hypertension were suspected. Esophagogastroduodenoscopy, small-bowel capsule endoscopy, and colonoscopy revealed no organic lesions. Diagnostic laparotomy revealed uniform epithelioid tumor cells with eosinophilic cytoplasm and a predominant tubular pattern infiltrating the peritoneal stroma. Therefore, peritoneal mesothelioma was diagnosed, and the patient received cytoreduction plus hyperthermic intraperitoneal chemotherapy (HIPEC) with a stable condition. [ABSTRACT FROM AUTHOR]

Malignant mesotheliomas with localized growth are extremely rare in dogs. A 9-year-old male dog presented with a localized tumour that originated from the parietal pleura and had polypoid growth in the thoracic cavity. Histological examination revealed that the tumour consisted of tubular formations with scattered cysts and minimal papillary growth pattern. Neoplastic cells were immunopositive for mesothelial markers (calretinin and Wilms' tumour gene 1) and negative for carcinoma markers (thyroid transcription factor 1 and tumour protein 63). The animal was alive with no recurrence or metastasis/dissemination 11 months after surgery. To the best of our knowledge, this is the first report of a localized mesothelioma in a dog without metastasis/dissemination and highlights the value of mesothelial markers for an accurate diagnosis. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The cytological diagnosis of mesothelioma is a controversial issue, and definitive diagnosis often requires ancillary tests. The aim of this study was to investigate the contribution of BRCA1-associated protein (1) (BAP1) loss and p16 (CDKN2A) homozygous deletion (HD) on the early diagnosis of mesothelioma in effusion fluids. MATERIALS AND METHODS: Between 2019-2022, 21 pleural and peritoneal fluid samples diagnosed with atypical mesothelial proliferation in our institution were included in the study. The slides of the cases that underwent BAP1 immunohistochemistry (IHC) were retrieved from the archive and re-examined. Homozygous deletion (HD) of p16 (CDKN2A) was investigated by the fluorescence in situ hybridization (FISH) method in cell blocks of cytology samples. At least 100 atypical mesothelial cells were counted in each case, and the HD threshold value was >10%. RESULTS: The mean age of the cases was 63.47 years (34-90 years), female/male ratio was 3/1. Of the pleural mesothelioma cases, 16 were epithelioid, 2 were biphasic, and 1 were sarcomatoid. Two cases were diagnosed with peritoneal well-differentiated papillary mesothelioma (WDPM). BAP1 loss was observed in 11 (69%) of 16 cases. HD deletion of p16 (CDKN2A) was seen in 11 (58%) patients with FISH. The HD threshold value was 10-20% in 6 of the cases, 30-50% in 3 cases, and above 90% in 2 cases. While HD deletion was observed in p16 (CDKN2A) in all biphasic and sarcomatoid cases (n=3), no deletion was observed in peritoneal WDPM (n=2). Positivity was observed with at least one method in 12 (86%) of 14 pleural mesotheliomas who underwent both BAP1 IHC and p16 (CDKN2A) FISH. Due to technical reasons, the FISH signal could not be obtained in two cell blocks, so no results could be obtained. CONCLUSIONS: Asbestos exposure in areas where mesothelioma is endemic and/or the presence of proliferating mesothelial cells in cytological examination are important clues for diagnosis. In controversial cases, BAP1 IHC should be the first step in an ancillary test. Although the FISH method applied to cell blocks has cytology-specific limitations and difficulties, investigating the p16 (CDKN2A) deletion with FISH in selected cases will contribute to the diagnosis. [ABSTRACT FROM AUTHOR]

Background: The study describes the 466 cases of malignant mesotheliomas (MM) collected by the National Mesothelioma Register (ReNaM) in Italy from 1993-2018 relating to subjects with exclusive asbestos exposure in merchant or military navy. Methods: The cases among maritime workers represent 1.8% of the total patients with defined exposure registered in the ReNaM, of which (45.4%) were among merchant maritime workers and 254 cases (54.5%) among the navy. The distribution by site of mesothelioma showed 453 (97.2%) MM cases of the pleura, 11 (2.3%) of the peritoneum, and 2 (0.4%) of the tunica vaginalis of the testis. With regard to occupational exposure, it was classified as certain in 318 (68.2%) cases, probable in 69 (14.8%) cases, and possible in 79 (16.9%) cases. Results: Among the 23 classified jobs, the highest percentages of certain exposures are among naval engineers, motor mechanics, machine captains, and sailors. Machine crew accounted for 49.3% of the cases, and deck crew for 27.6%. All cases began exposure on board between 1926 and 1988. Seamen were exposed to asbestos while at sea by living onboard ships and from the continual release of asbestos fibers due to the motion of a vessel. Conclusions: Epidemiological surveillance through the ReNaM has allowed us to verify among cases in the maritime, navy, and merchant marine sectors that, in the past, subjects were exposed regardless of the ship’s department where they have provided service; therefore, all these cases must be considered occupational diseases. [ABSTRACT FROM AUTHOR]

A 25-year-old female California sea lion (Zalophus californianus) reared in an aquarium died following a history of anorexia, lethargy, abnormal protrusion of the skin, and oral respiration. At necropsy, multiple yellowish-white nodules with diameters of 0.1-0.5 cm were disseminated in the thoracic cavity and lungs. Histopathologically, the nodules were continuous with normal mesothelium and were characterized by the proliferation of spindle-shaped to polygonal neoplastic cells with prominent atypia. The neoplastic cells exhibited diffuse, strong staining for vimentin and partial, weak to moderate staining for cytokeratin AE1/AE3. Based on these findings, the lesions were diagnosed as pleural mesothelioma. This study reports the first case of pleural mesothelioma in California sea lion. [ABSTRACT FROM AUTHOR]

The association of mesothelioma, a lethal lung disease, with asbestos has led to an absolute ban on asbestos in at least 55 countries worldwide. The purpose of this paper is to review residual exposure to asbestos as well as other emerging causes of mesothelioma outside asbestos. The review provides detailed description of asbestos minerals, their geographical locations, mesothelioma in these areas, as well as contemporary possible sources of asbestos exposure. Second, we examine other emerging causes of mesothelioma including: ionizing radiation as the second most important risk factor after asbestos, particularly relevant to patients undergoing radiotherapy, third, carbon nanotubes which are under investigation and fourth, Simian virus 40. In the case of asbestos per se, the greatest risk is from occupational exposure during mining and subsequent processing. Of the non-occupational exposures, environmental exposure is most serious, followed by exposure from indoor asbestos minerals and secondary familial exposure. Overall, asbestos is still a major risk factor, but alternative causes should not be neglected, especially in young people, in women and those with a history of radiotherapy or living in high-risk locations. [ABSTRACT FROM AUTHOR]

Background: An increased risk of mesothelioma has been reported in various countries for construction workers. The Italian National Mesothelioma Registry, from 1993 to 2018, reported exposure exclusively in the construction sector in 2310 cases. We describe the characteristics of these cases according to the job title. Methods: We converted into 18 groups the original jobs (N=338) as reported by ISTAT codes ('ATECO 91'). The exposure level was attributed to certain, probable, and possible in accordance with the qualitative classification of exposure as reported in the Registry guidelines. Descriptive analysis by jobs highlights the total number of subjects for every single job and certain exposure, in descending order, insulator, plumbing, carpenter, mechanic, bricklayer, electrician, machine operator, plasterer, building contractor, painter, and laborer. Results: The cases grow for plumbing in 1993-2018, while, as expected, it decreased for the insulator. Within each period considered, the most numerous cases are always among bricklayers and laborers; these data confirm the prevalence of non-specialized "interchangeable" jobs in the Italian construction sector in the past. Conclusions: Despite the 1992 ban, the construction sector still presents an occupational health prevention challenge, and circumstances of asbestos exposure may still occur due to incomplete compliance with prevention and protection measures. [ABSTRACT FROM AUTHOR]

Mesothelioma is a nearly uniformly fatal tumor. Multimodality therapy including cytoreductive surgery and chemotherapy is associated with long-term survival in some patients. Cytoreductive surgery for thoracic disease includes a lung-sparing operation called an "extended pleurectomy/decortication" or a lung-sacrificing surgery called an "extrapleural pneumonectomy." The benefit of cytoreductive surgery for bicavitary disease (chest and abdomen) is poorly understood. Our objective was to evaluate the long-term survivals for patients undergoing cytoreductive surgery for bicavitary disease and to determine whether any prognostic factors were associated with outcome. We reviewed our Institutional Review Board–approved, institutional, International Association for the Study of Lung Cancer Mesothelioma Staging Project database. Inclusion criteria were all patients who underwent cytoreductive surgery for bicavitary disease. Overall survival was calculated by Kaplan–Meier methodology. All International Association for the Study of Lung Cancer database elements were evaluated by univariable analysis. From February 2014 to August 2021, 440 patients with mesothelioma were evaluated. Fourteen patients (3%) underwent cytoreductive surgery of both chest and abdomen as a planned 2-stage operation. Most patients (13/14; 93%) underwent chest surgery before abdomen surgery. For the entire cohort, the median overall survival was 33.6 months with a 5-year survival of 20%. Extended pleurectomy/decortication was associated with a better outcome compared with extrapleural pneumonectomy, with median overall survivals of 58.2 versus 13.5 months, respectively. For a highly selected group of patients with bicavitary mesothelioma, long-term survival can be achieved with an aggressive, staged surgical approach. The patients who undergo extended pleurectomy/decortication with preservation of the lung appear to have more favorable outcomes compared with patients undergoing extrapleural pneumonectomy. [ABSTRACT FROM AUTHOR]

Mesothelioma is a rare incurable cancer caused by exposure to asbestos. Patients with mesothelioma have palliative care needs throughout the course of their illness, from diagnosis to the end of life. Mesothelioma clinical nurse specialists (CNSs) are central to providing care for patients with mesothelioma, but little is known about their role in providing palliative care. The aim of this study was to explore the views of mesothelioma patients and CNSs on the role of palliative care in mesothelioma, and explore which aspects of palliative care are provided by CNS's. The cross-sectional study included: (1) Secondary analysis of existing data from 510 mesothelioma patients who completed a 2019 survey of patient experiences and; (2) A survey of 23 Mesothelioma UK CNS's exploring their role in delivering palliative care. Data were analysed using descriptive statistics. Results indicated that 63% of mesothelioma patients did not feel that palliative care was needed at the time of survey completion. Data from the CNS survey showed that over 95% of CNS's felt they had a role in providing palliative care, and all CNSs had received some prior training or education in palliative care. Confidence in delivering palliative care was generally high with the mean score of 26.52 (SD = 2.68) out of a maximum of 30. CNS's are highly skilled at providing palliative care in mesothelioma, providing both specialist and generalist palliative care. However, work is required to encourage patients and their families to engage with palliative care earlier in the disease trajectory. [ABSTRACT FROM AUTHOR]

Mesothelioma is a rare but highly aggressive malignancy with poor prognosis that frequently present with recurrent effusions. Establishing the diagnosis by cytology can lead to early diagnosis and treatment and consequently improve prognosis. This review examines the cytological diagnosis of mesothelioma in the context of its historical and morphologic evolution and provides an update of the current reporting systems. Clues to identify the mesothelial and malignant nature of the sample are detailed as well as the supporting ancillary tests. Cytologically, the samples are overwhelmingly cellular and malignancy is recognized by both architectural and cytological atypia. Numerous variably sized clusters and enlarged cells are easily identified, some with papillary architecture and collagen cores. Recognizing the mesothelial nature of the cells and supportive immunostains are essential to rule out the differential diagnosis of metastatic carcinomas and reactive mesothelium. Current ancillary tests such as homozygous deletion of CDKN2A, loss of BRCA1-associated protein, and methylthioadenosine phosphorylase expression can provide further support of malignancy. At this time with the aid of current ancillary tests and in the hands of cytopathologists with adequate experience with the interpretation of effusions, the diagnosis of mesothelioma can be established with accuracy in most cases. [ABSTRACT FROM AUTHOR]

Background: The outcomes associated with receipt of adjuvant radiation in patients after surgery for MPM are poorly understood. Objective: The objective of this study was to use 2 registries to compare the outcomes of patients receiving adjuvant radiation or no radiation after definitive surgery for pathologic stage I–III MPM. Methods: Patients with resected pathologic stage I–III MPM were identified from the Duke University registry (1996–2016) and National Cancer Database (NCDB) (2004–2015). The primary outcome was overall survival. Propensity score-matched and landmark subgroup analyses were performed. Results: A total of 212 institutional and 1615 NCDB patients met criteria. In both cohorts, patients who underwent radiation were more likely to have margin-negative resection and more advanced pathologic stage. At a landmark time of 4.4 and 4.7 months from surgery, Duke [hazard ratio (HR) 1.14; 95% confidence interval (CI) 0.62–2.11] and NCDB patients (HR 0.97; 95% CI 0.81–1.17) who received adjuvant radiation did not experience improved survival compared to those who did not receive radiation in multivariable analysis. Duke patients who received radiation had similar incidence of recurrence and time to both overall recurrence and ipsilateral recurrence (HR 0.87; 95% CI 0.43–1.77) compared to those who did not. Duke patients experienced 100 grade 1/2, 21 grade 3/4, and one grade 5 toxicity events during radiation. Conclusions: In this dual registry analysis of patients with resected stage I–III MPM, the receipt of adjuvant hemithoracic radiation was not associated with improved survival compared to no radiation. [ABSTRACT FROM AUTHOR]

Malignant peritoneal mesothelioma (MPM) is a rare and aggressive cancer that has a poor prognosis. An earlier population-based study found that the majority of Dutch patients do not receive anti-cancer treatment. In 2015, Dutch Malignant Mesothelioma care was centralized in two expert centers. We reviewed treatment patterns at these centers, to assess the impact of centralization of MPM care in the Netherlands. Data from all patients referred to the Dutch MPM expert centers from 2014 to 2020, were retrospectively collected. Descriptive statistics regarding referrals, patient and tumor characteristics, and treatment patterns were provided. Population-based incidence rates were provided by the Netherlands Cancer Registry. From 2014 to 2020, 78 patients were referred to the Dutch Mesothelioma expert centers, of whom 32 were female (41%). From 2014 to 2017, 27 patients were referred, whereas 51 patients were referred from 2018 to 2020. This represents about 24% and 61% of the estimated population incidence, respectively. Treatment patterns were comparable between both periods. Between 2014 and 2018, 33% of patients underwent surgery, 44% systemic therapy, and 22% received best supportive care (BSC), while this was 29%, 37%, and 33% respectively from 2018 to 2020. Centralization of care for patients with MPM resulted in an increase of annual referrals to the Dutch mesothelioma expert centers. While population-based incidence did not change during the study period, the absolute number of patients receiving treatment at our centers did increase. This might be considered a first important step towards better treatment for patients with this fatal disease. [ABSTRACT FROM AUTHOR]

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We previously observed increased levels of adenosine‐deaminase‐acting‐on‐dsRNA (Adar)‐dependent RNA editing during mesothelioma development in mice exposed to asbestos. The aim of this study was to characterize and assess the role of ADAR‐dependent RNA editing in mesothelioma. We found that tumors and mesothelioma primary cultures have higher ADAR‐mediated RNA editing compared to mesothelial cells. Unsupervised clustering of editing in different genomic regions revealed heterogeneity between tumor samples as well as mesothelioma primary cultures. ADAR2 expression levels are higher in BRCA1‐associated protein 1 wild‐type tumors, with corresponding changes in RNA editing in transcripts and 3'UTR. ADAR2 knockdown and rescue models indicated a role in cell proliferation, altered cell cycle, increased sensitivity to antifolate treatment, and type‐1 interferon signaling upregulation, leading to changes in the microenvironment in vivo. Our data indicate that RNA editing contributes to mesothelioma heterogeneity and highlights an important role of ADAR2 not only in growth regulation in mesothelioma but also in chemotherapy response, in addition to regulating inflammatory response downstream of sensing nucleic acid structures. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Loss of BAP1 and/or MTAP by immunohistochemistry can distinguish malignant mesothelioma cells from reactive mesothelial proliferations in cytology samples comparably to histology sections with excellent specificity and good sensitivity. • However, a negative cytology should not be used to exclude malignant mesothelioma due to a lower sensitivity of both markers and the fact that sarcomatoid subtype rarely sheds cells into pleural or peritoneal effusions and therefore may not be detected. [ABSTRACT FROM AUTHOR]

Malignant pleural mesothelioma (MPM) is an aggressive cancer mainly related to asbestos exposure. Despite recent therapeutic advances, notably immunotherapies, the benefit remains limited and restricted to a small percentage of patients. Thus, a better understanding of the disease is needed to identify new therapeutic strategies. Recently, interleukin 7 receptor (IL-7R) has been described as being expressed by MPM cells and associated with poorer patient survival. Thus, the aim of this work was to study the IL-7R/IL-7 pathway in MPM using patient samples. We found that, although more than 40% of MPM cells expressed IL-7R, IL-7 had no effect on their intracellular signaling. Accordingly, the addition of IL-7 to the culture medium did not affect MPM cell growth. Using The Cancer Genome Atlas (TCGA) database, we showed that high IL7 gene expression in MPM tumors was associated with a higher overall patient survival and an induction of genes involved in the immune response. In pleural effusions (PEs), we found that IL-7 concentration was not a good diagnostic biomarker. However, we observed that high IL-7 levels in PEs were associated with shorter survival of MPM patients, but not of lung cancer patients. The prognostic value of IL-7 was also conserved when only patients with epithelioid mesothelioma, the most common histological type of MPM, were analyzed. Taken together, our study suggests that, although the IL-7R/IL-7 signaling pathway is not functional in MPM cells, IL-7 expression in PEs may have prognostic value in MPM patients. [ABSTRACT FROM AUTHOR]

Background: The aim of this study is to describe the incidence of malignant mesothelioma (MM) and asbestos exposure in an Italian region in the period 1996-June 2021. Methods: The study included cases with microscopic confirmation and those with instrumental confirmation. For each case, information on sex, age, tumour site, morphology and date of diagnosis was collected, along with details of exposure to asbestos. Results: 3,097 cases of MM (2,233 males and 864 females) were registered: 90.8% with microscopic confirmation. A total of 2,840 cases involved the pleura (92%), 230 cases the peritoneum (7%), and a small number of cases the pericardium and testis (9 and 18, respectively). Most cases (78.0%) occurred after 65 years of age, while only 1.5% concerned individuals with age<45 years. The standardized incidence rate for the entire period (adjusted to the 2000 Italian standard population and calculated per 100,000 person-years) was equal to 3.9 in males and 1.4 in females, and the trend showed an increase with age in both sexes. Concerning asbestos exposure, 79.7% of cases were exposed (86.7% males and 60.1% females). In 70.3%, exposure was occupational (83.4% males and 33.2% females), while 20.7% of females and 0.8% of males had familial exposure. Building construction, rolling stock manufacture/repair and metalworking were the most prevalent economic activities associated with occupational exposure. Conclusions: This study offers an overview of MM in an Italian region characterized by high incidence and high exposure due to its particular production activities. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the process of diagnosing patients with malignant pleural mesothelioma (MPM) at a tertiary care hospital. Methods: This was a retrospective study involving patients referred to a tertiary-care cancer center in Brazil between 2009 and 2020. The diagnostic process was divided into four steps: onset of symptoms, referral to a specialist visit, histopathological diagnosis, and beginning of treatment. The intervals between each phase and the factors for delays were evaluated. Data including clinical status, radiological examinations, staging, treatment modalities, and survival outcomes were collected. Results: During the study period, 66 patients (mean age = 64 years) were diagnosed with MPM and underwent treatment. Only 27 (41%) of the patients had knowledge of prior exposure to asbestos. The median number of months (IQR) between the onset of symptoms and the first specialist visit, between the specialist visit and histopathological characterization, and between definite diagnosis and beginning of treatment was, respectively, 6.5 (2.0-11.4), 1.5 (0.6-2.1), and 1.7 (1.2-3.4). The knowledge of prior asbestos exposure was associated with a shorter time to referral to a specialist (median: 214 vs. 120 days; p = 0.04). A substantial number of nondiagnostic procedures and false-negative biopsy results (the majority of which involved the use of Cope needle biopsy) were found to be decisive factors for the length of waiting time. The mean overall survival was 11.9 months. Conclusions: The unfamiliarity of health professionals with MPM and the patient's lack of knowledge of prior asbestos exposure were the major factors to cause a long time interval between the onset of symptoms and beginning of treatment. An overall survival shorter than 1 year is likely to have been due to the aforementioned delays. [ABSTRACT FROM AUTHOR]

The mediastinal serous cavity (MSC)—well documented but seldom recognized in the caudal mediastinum—is embryologically derived from the omental bursa. Mesothelioma arising from the MSC in two dogs is described. Both dogs presented with acute life-threatening hemorrhagic pleural effusion. Contrast computed tomography revealed a large solitary spherical-to-cylindrical tumor in the caudal mediastinum with variably thick, contrast-enhancing walls with lobular to frond-like proliferations that arose circumferentially and projected internally into a single, variably sized, fluid-attenuating lumen. The wall and lumen corresponded to the serous membrane and serous cavity of the MSC. Surgical exploration confirmed that both tumors arose from the mediastinum. Both had similar histologic findings, and special stains were necessary for definitive diagnosis. The tumor was nonresectable in one dog, and it was euthanized intraoperatively. The other survived 7 mo. An MSC mesothelioma should be considered a possible cause of hemothorax in dogs that may be detected on thoracic radiography and computed tomography. Differential diagnoses include esophageal foreign body or neoplasm, paraesophageal diaphragmatic hernia, MCS empyema, and pulmonary adenocarcinoma, with thoracic computed tomography helping to rule out foreign body and diaphragmatic hernia. For confirmed neoplasms, histochemistry and immunohistochemistry should be performed to differentiate between mesothelioma and pulmonary adenocarcinoma. [ABSTRACT FROM AUTHOR]

Mesothelioma is an incurable, asbestos related cancer with a poor prognosis. Little is known about how patients and carers living with the condition manage their mental health and wellbeing needs. This paper reports findings on interventions being used by patients and informal carers living with mesothelioma and those which they find most helpful. In-depth interviews with patients (n = 10) and (informal) carers (n = 11) living with mesothelioma in the UK. We analysed our data inductively using a reflexive thematic analysis approach. Participants described the importance of both smaller and larger actions and strategies which helped with their mental health. This included spending more time with family and friends and going on holidays. Professionals who participants said supported their mental health journey included not only specialist nurses and mental health professionals but also legal and Asbestos Support Group professionals. The latter demonstrates the unique needs and support required for this population. Exposure to asbestos as the cause of mesothelioma, has led to a social justice aspect of the experience of living with this cancer. Participants reported the importance of collective action to their mental health and wellbeing. The data indicate that patients and carers may have distinct mental health and wellbeing requirements and need to manage these in different ways at different times. Findings have implications for nurses and other key professionals working in healthcare, community and legal settings supporting this client group, and for those living with mesothelioma who want to understand ways to enhance their own wellbeing. • Both smaller and larger actions are of importance to mental health and wellbeing. • Patients and carers may have distinct mental health and wellbeing requirements. • Nurses provide direct and signposting support for mental health. • Mental health, Asbestos Support Group and legal professionals also provide support. • Social justice elements are pertinent in a mental health and mesothelioma context. [ABSTRACT FROM AUTHOR]

Mesothelioma is an incurable, asbestos-related cancer with a poor prognosis. There is scant evidence about the mental health and well-being impacts on patients and carers living with the illness. This study aimed to investigate mesothelioma's impact on mental health and well-being and the scale of mental health conditions in patients and informal carers. A mixed-methods design was used: a cross-sectional survey of mesothelioma patients and informal carers plus semi-structured interviews with patients and carers. The survey used validated scales collecting data on mental health aspects of mesothelioma: the EQ5D to assess health-related quality-of-life; the Hospital Anxiety and Depression scale; the PCL-5 to assess Posttraumatic Stress; and the Posttraumatic Growth Inventory. The datasets were integrated during analysis. 96 useable survey responses were received. A clinical level of depression was reported by 29 participants (30.21%), of anxiety by 48 (50%), of posttraumatic distress disorder by 32 (33.33%), and of posttraumatic growth by 34 (35.42%). Carers had worse scores than patients. Three main themes were developed from interviews with 10 patients and 11 carers: 'Prognosis', 'Support from services', and 'Social connections and communication'. Healthcare professionals delivering a mesothelioma diagnosis require regular training in communication skills plus updating in current treatment options, so they provide an appropriate mix of realism and hope. Better signposting to mental health support is needed for patients and carers. Our introduction of posttraumatic growth into the mesothelioma literature is novel. We recommend specialist nurses are trained to recognise, understand, and foster posttraumatic growth. • Anxiety, depression and posttraumatic stress are high in mesothelioma patients. • Informal carers had significantly worse depression and posttraumatic stress. • Informal carers and patients showed significant levels of posttraumatic growth. [ABSTRACT FROM AUTHOR]

Purpose: BAP1 germline mutation can promote risk of uveal melanoma and mesothelioma. In this study, we report a patient with BAP1 germline mutation and uveal melanoma who developed a rare form of mesothelioma in the peritoneum. Method: Case report. Results: A 55-year-old white man noted blurred vision in the left eye. Examination revealed superotemporal episcleral sentinel vessels and a dark brown iris mass suspicious for melanoma, with angle invasion and involvement of the ciliochoroidal region. The tumor measured 14 mm in diameter and 10.3 mm in thickness. A diagnosis of iridociliochoroidal melanoma was rendered and plaque radiotherapy applied. Genetic testing revealed BAP1 germline mutation. At 3.5-year follow-up, tumor control was achieved, but radiation-related complications led to enucleation. At 5.5-year follow-up, incidental findings by laparoscopy revealed multiple peritoneal tumors, histopathologically proven to be malignant peritoneal mesothelioma. Lung evaluation was normal, and there was no melanoma-related or mesothelioma-related metastasis. Likewise, magnetic resonance imaging of the abdomen showed no evidence of hepatic metastasis. Conclusion: BAP1 tumor predisposition syndrome can promote risk of uveal melanoma and malignant peritoneal mesothelioma. Cancer screening for these malignancies is warranted. [ABSTRACT FROM AUTHOR]

Background and objective Malignant pleural mesothelioma (MPM) is a highly aggressive disease arising from pleural mesothelial cells. Advanced pleural mesothelioma has a poor prognosis, with a median survival of no more than 15 months. First line standard chemotherapy regimen recommended is Pemetrexed based chemotherapy regimen, with or without bevacizumab. There is no consensus on whether patients who have received first-line standard chemotherapy can benefit from pemetrexed maintenance chemotherapy. The study aimed to investigate the efficacy and safety of pemetrexed maintenance therapy (PMT) after treatment with a pemetrexed and platinum regimen for patients with MPM. Methods A total of 40 MPM patients were collected from Cancer Hospital Chinese Academy of Medical Sciences from January 2013 to January 2018, eligible patients were unresectable MPM, without disease progression following 4 to 6 cycles of pemetrexed and platinum, including pemetrexed maintenance therapy group (22 cases) and observation group (18 cases). The last follow-up was conducted in January 2020. The primary endpoint were progression free survival (PFS), and the secondary end points were overall survival (OS), the efficacy, adverse reactions of PMT. Results The median PFS in the PMT arm was longer than that in the observation arm (8.5 mon vs 3 mon, P=0.008), but there was no significant difference in median OS (26.4 mon vs 15.7 mon, P=0.177). Objective response rate (ORR) of two group were 22.7% and 0%, respectively. The grade 3-4 toxicity in PMT group included grade 4 neutropenia in 1 patient (4.5%), grade 3 neutropenia in 1 patient (4.5%), grade 4 anemia in 1 patient (4.5%) and grade 3 nausea and anorexia in 1 patient (4.5%). Conclusions Pemetrexed maintenance therapy following initial pemetrexed and platinum chemotherapy improve PFS in patients with MPM, and is well tolerated. [ABSTRACT FROM AUTHOR]

ATM serine/threonine kinase (ATM; previously known as ataxia‐telangiectasia mutated) plays a critical role in maintaining genomic stability and regulates multiple downstream pathways, such as DNA repair, cell cycle arrest, and apoptosis. As a serine/threonine kinase, ATM has an array of downstream phosphorylation substrates, including checkpoint effector checkpoint kinase 2 (CHK2). ATM inhibits cell cycle progression by phosphorylating and activating CHK2, which plays an important role in the formation and development of tumors and participates in DNA repair responses after double‐stranded DNA breaks. In this study, we used a recently developed mammalian functional genetic screening system to explore a series of ATM substrates and their role in DNA damage to enhance our understanding of the DNA damage response. Ubiquilin 4 (UBQLN4), which belongs to the ubiquilin family characterized by its ubiquitin‐like (UBL) and ubiquitin‐associated (UBA) domains, was identified as a new substrate for ATM. UBQLN4 is involved in various intracellular processes, such as autophagosome maturation, p21 regulation, and motor axon morphogenesis. However, the biological function of UBQLN4 remains to be elucidated. In this study, we not only identified UBQLN4 as a substrate for ATM, but also found that UBQLN4 interacts with and stabilizes the anti‐apoptotic proteins Bcl‐2‐related protein A1 (BCL2A1) and Bcl‐2‐like protein 10 (BCL2L10) and prevents mesothelioma cell apoptosis in response to DNA damage. These findings expand our understanding of the role of UBQLN4 in mesothelioma and provide new insights into potential mesothelioma treatments targeting substrates for ATM. [ABSTRACT FROM AUTHOR]

The NIBIT-MESO-1 study demonstrated the efficacy and safety of tremelimumab combined with durvalumab in patient with unresectable mesothelioma followed up for a median of 52 months [IQR 49–53]. Here, we report 4-year survival and outcomes after retreatment, and the role of tumour mutational burden (TMB) in identifying patients who might have a better outcome in response to combined therapy. NIBIT-MESO-1 was an open-label, non-randomised, phase 2 trial of patients with unresectable pleural or peritoneal mesothelioma who received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. In this follow-up study, patients with disease progression following initial clinical benefit—ie, a partial repsonse or stable disease—were eligible for retreatment and with the same doses and schedules for tremelimumab and durvalumab as used in the NIBIT-MESO-1 trial. The primary endpoint, immune-related objective response rate, was evaluated per immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST) or immune-related RECIST 1.1 criteria for patients with pleural or peritoneal malignant mesothelioma, respectively. Key secondary endpoints were overall survival and safety, and TMB was also evaluated post hoc in patients who had tumour tissue available before treatment. The intention-to-treat population was used for analysis of all efficacy endpoints. This study is registered with ClinicalTrials.gov , number NCT02588131. 40 patients were enrolled in the NIBIT-MESO-1 study between Oct 30, 2015, and Oct 12, 2016. At data cut-off, April 30, 2020, five (13%) of 40 patients were alive, and 35 (88%) patients had died of progressive disease. At a median follow-up of 52 months (IQR 49–53), median overall survival was 16·5 months (95% CI 13·7–19·2). Survival was 20% (eight of 40 patients) at 36 months and 15% (six of 40 patients) and 48 months. 17 (43%) of 40 patients met the criteria for enrolment in the retreatment study and were retreated with at least one dose of tremelimumab and durvalumab. No immune-related objective responses were observed in the 17 retreated patients. Seven (41%) of 17 patients achieved immune-related stable disease. From the start of retreatment to a median follow-up of 24 months (22·0–25·0), median overall survival was 12·5 months (95% CI 0·0–25·8), and survival at 12 months was 52·9%, at 18 months was 35·3%, and at 24 months was 23·5%. There were no grade 3–4 immune-related adverse events in the retreatment cohort. In a post-hoc analysis of 28 patients for whom tumour tissue before treatment was available, patients with a TMB higher than the median value of 8·3 mutations per Mb had a higher median overall survival compared with patients with TMB below the median value, but this difference was non-significant. Moreover, when patients were additionally stratified for ICI retreatment (n=13), there was a significant difference in survival between those with a TMB higher than the median of 8·3 mutations per Mb and those with TMB lower than the median in the retreated cohort (41·3 months vs 17·4 months; p=0·02). Tremelimumab combined with durvalumab was associated with long-term survival in patients with mesothelioma. Retreatment was safe and resulted in clinically meaningful outcomes, thus suggesting its potential application in the clinical practice of mesothalioma patients. NIBIT Foundation, Fondazione AIRC, AstraZeneca. [ABSTRACT FROM AUTHOR]

Malignant peritoneal mesothelioma is an aggressive local-regional disease with dissemination to all parts of the abdomen and pelvis at the time of diagnosis. Recently, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been used and improved survival was documented with this local-regional treatment strategy. Concerning CT features were described that were specific for malignant peritoneal mesothelioma. The incidence of concerning radiologic features and their impact on survival was determined. The prognostic assessment of concerning CT features was compared to the peritoneal cancer index (PCI) and the completeness of cytoreduction score (CC score). One hundred patients with a preoperative CT were evaluated by 11 concerning CT features. The incidence of these CT features varied between 5% and 41%. Nine of the 11 CT features statistically significantly predicted a reduced survival in these patients treated in a uniform manner. When concerning radiologic features were grouped as none, a single feature or two or more features, a significant composite analysis was achieved with p < 0.001. The prognostic information from concerning CT features compared favorably with the prognostic implications of PCI and CC score. The availability of the concerning CT features to predict prognosis at the initiation of treatments for malignant peritoneal mesothelioma shows that this radiologic assessment may be of great value to the clinician in planning a treatment strategy for an individual patient. Synopsis: Preoperative CT findings, quantitatively evaluated, showed a statistically significant impact on outcome of treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. This objective prognostic information was available to the multidisciplinary team at the time of the patient's evaluation for an aggressive surgical intervention. [ABSTRACT FROM AUTHOR]

Significant progress in the diagnosis and classification of pleural mesothelioma has been made in the past 5 years. Novel biomarkers are now entering more widespread use following major advances in understanding the genomic landscape of the malignancy. As the diagnosis and management of mesothelioma becomes more multidisciplinary together with the increasing role of histopathology in providing additional prognostic information to guide downstream management, we review herein newly proposed prognostic variables, diagnostic biomarkers, utility of pleural effusion cytology in diagnosis, and mesothelioma surgery. A section on the upcoming WHO classification on malignant pleural mesothelioma is also included. [ABSTRACT FROM AUTHOR]

Mesotheliomas are uncommon neoplasms that arise from mesothelial cells in either the abdominal or thoracic cavities and are rarely diagnosed in cats. A 10-y-old spayed female domestic shorthair cat was presented to the Louisiana State University oncology service for evaluation of a large amount of abdominal effusion. Abdominal ultrasound identified a large mesenteric mass with numerous ill-defined nodules. An abdominocentesis was performed with cytologic and immunocytochemical findings consistent with a neoplastic effusion, with large clusters of epithelioid cells that exhibited strong cytoplasmic expression of pancytokeratin, vimentin, and Wilms tumor 1 antigens. Further testing was declined, and meloxicam was prescribed until the cat died 23 d after initial presentation. Upon postmortem examination, the omentum was contracted into a firm mass adhered to multiple organs and accompanied by numerous small white nodules throughout the abdominal cavity. On histopathology and immunohistochemistry, neoplastic cells were found throughout the abdominal cavity; 60–95% exhibited moderate-to-strong cytoplasmic immunoreactivity for cytokeratin, vimentin, and Wilms tumor 1 protein. The final diagnosis was an epithelioid mesothelioma. Our case illustrates the utility of cytology, immunocytochemistry, and its relation to histology and immunohistochemistry. We also reviewed the reported cases of feline mesothelioma. [ABSTRACT FROM AUTHOR]

Mesothelioma has been reported frequently in large felids. These neoplasms present a diagnostic challenge given their highly variable morphology that mimics carcinomas or sarcomas at different locations. Our goal was to characterize mesotheliomas morphologically and immunohistochemically to determine if a panel of antibodies could be used to more accurately support the diagnosis of these neoplasms in large felids. Mesotheliomas from 6 large felids, including 4 clouded leopards, 1 Bengal tiger, and 1 cheetah, were immunohistochemically labeled for vimentin, E-cadherin, pancytokeratin, Wilms tumor 1 (WT1), MUC-1, and calretinin. The mesotheliomas of the 4 clouded leopards and the tiger were of the epithelial subtype; the mesothelioma from the cheetah was biphasic. All 6 mesotheliomas had strong immunohistochemical labeling for vimentin, E-cadherin, and pancytokeratin. All cases had cytoplasmic labeling for WT1, and 2 also had nuclear labeling. The 3 mesotheliomas with distinct papillary fronds were weakly positive for MUC-1. These and one other epithelial mesothelioma were also positive for calretinin. Our study demonstrates that the morphologic and immunohistochemical phenotypes of mesothelioma that have been identified in humans and domestic species can occur in large felids, and a panel of pancytokeratin, vimentin, WT1, and calretinin can be utilized to support the diagnosis of these neoplasms. [ABSTRACT FROM AUTHOR]

Malignant mesothelioma (MM) is a rare aggressive neoplasm arising from mesothelial lining of body cavities, most commonly pleura and peritoneum. It is characterised by a poor prognosis and limited treatment options. A universally recognised risk factor for the development of MM is exposure to asbestos. However, evidence supporting a genetic susceptibility to the development of MM has been accumulating during the last decades. Intensive research for the identification of MM susceptibility genes has led to the discovery of BAP1 and to the definition of the so-called "BAP1-related tumour predisposition syndrome". Patients carrying germline BAP1 mutations have an increased risk for the early development of tumours, including MMs, uveal melanomas, cutaneous melanocytic lesions, clear cell renal cell carcinomas and basal cell carcinomas. Furthermore, pathogenic variants in tumour suppressor genes with a role in DNA repair have been recently described in families with clustered MM cases. These genetic alterations seem to confer exaggerate sensitivity to asbestos carcinogenic effect and, arguably, increased response to specific chemotherapeutic strategies. While the translational significance of BAP1 alterations is explored in the research field, the identification of families carrying germline BAP1 mutations is mandatory to start appropriate surveillance programs and guarantee the best clinical management to these patients. [ABSTRACT FROM AUTHOR]

Malignant pleural mesothelioma (MPM) is a malignant tumor with strong invasiveness, low survival rate and lack of effective treatment options. As the only first-line treatment plan for the advanced MPM, combination of pemetrexed and cisplatin chemotherapy have been existing since the last 20 years. Immunotherapy has long been considered as a potential treatment plan for MPM, mainly including immune checkpoint inhibitors (ICIs), immunotoxin therapy, anti-cancer vaccine and adoptive T-cell therapy. This review focuses on summarizing the current research status of immune checkpoint inhibitors in MPM, discusses the effect of tumor heterogeneity on ICIs treatment, and describes that the biomarker-oriented immunotherapy is a new vision for the realization of individualized treatment of MPM. [ABSTRACT FROM AUTHOR]

Malignant pleural mesothelioma (MPM) has few treatment options. Pembrolizumab showed preliminary clinical benefit in programmed death ligand 1 (PD-L1)-positive MPM. We evaluated the efficacy and safety of pembrolizumab monotherapy in patients with previously treated MPM irrespective of PD-L1 status in the KEYNOTE-158 study. The ongoing open-label, multicohort, single-arm, phase 2 KEYNOTE-158 study enrolled eligible adults (≥18 years) with MPM who had progression on or intolerance to standard therapy, Eastern Cooperative Oncology Group performance status 0–1, and biomarker-evaluable tumour samples. Individuals were enrolled from 35 academic facilities and community-based institutions across 14 countries in Australia, North America, Europe, and Asia. Participants received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. The primary efficacy endpoint was objective response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, based on radiological imaging every 9 weeks for the first year of the study and every 12 weeks thereafter and assessed by independent central review. Efficacy and safety were analysed in all patients who received at least one dose of pembrolizumab. This trial is registered with ClinicalTrials.gov , NCT02628067. Patients were enrolled in the MPM cohort between Feb 9, 2016, and Aug 16, 2016. As of June 27, 2019, 118 patients had been enrolled and received at least one dose of pembrolizumab. Ten (8% [95% CI 4–15]) patients had an objective response. Median duration of objective response was 14·3 months (range 4·0 to 33·9+), and 60% of objective responses were ongoing at 12 months. Objective responses were observed in six (8%) of 77 patients with PD-L1-positive MPM (median response duration 17·7 months [range 5·8 to 33·9+]) and four (13%) of 31 patients with PD-L1-negative MPM (10·2 months [4·0–16·6]). Median overall survival was 10·0 months (95% CI 7·6–13·4) and median progression-free survival was 2·1 months (2·1–3·9). Treatment-related adverse events occurred in 82 (69%) of 118 patients and serious adverse events that were considered to be treatment-related occurred in 14 (12%) of 118 patients. 19 (16%) patients had grade 3–4 treatment-related events, and most common of these were colitis (three patients), hyponatraemia (three), and pneumonitis (two). One patient died from treatment-related apnoea. By the end of the trial, 113 (96%) patients had discontinued pembrolizumab and progressive disease was the most common reason for discontinuation. Pembrolizumab showed durable antitumour activity and manageable toxicity in patients with advanced MPM, regardless of PD-L1 status. Our data support the programmed death 1 (PD-1) and PD-L1 pathway as a potential therapeutic target in some patients with previously treated mesothelioma but biomarkers that can effectively identify such patients are yet to be elucidated. Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA. [ABSTRACT FROM AUTHOR]

Malignant mesothelioma remains an incurable cancer, with no effective treatments in the setting of relapsed disease. Homologous recombination deficiency predicts sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. In mesothelioma, BRCA1 -associated protein 1 carboxy-terminal hydrolase (BAP1), which regulates DNA repair, is frequently mutated. We aimed to test the hypothesis that BAP1-deficient or BRCA1 -deficient mesotheliomas would be sensitive to PARP inhibition by rucaparib. We did a single-centre, open-label, single-arm, phase 2a trial in Leicester, UK, with prospective molecular stratification (Mesothelioma-Stratified Therapy 1 [MiST1]). Patients aged 18 years or older who had radiologically progressing, histologically confirmed, malignant mesothelioma after at least one course of systemic treatment; with cytoplasmic-BAP1-deficient or BRCA1 -deficient mesothelioma (pleural or peritoneal or other primary localisation), and who met the other inclusion criteria, were deemed eligible. All eligible patients who consented to take part were given rucaparib 600 mg twice a day orally, for six cycles of 28 days, or until disease progression, unacceptable toxicity, withdrawal of consent, or death. Response was measured by CT scan every 6 weeks. The primary outcome was disease control (complete response, partial response, or stable disease) at 12 weeks in all patients who received study drug; secondary outcomes were the safety and toxicity profile, objective response rate (proportion of complete or partial responses), and disease control rate at 24 weeks. Recruitment is now closed. This trial is registered with ClinicalTrials.gov , NCT03654833. Between Feb 9 and June 10, 2019, we enrolled 26 molecularly and clinically eligible patients. Ten (38%) of 26 patients were BAP1 negative and BRCA1 negative, 23 patients (89%) were BAP1 negative, and 13 patients (50%) were BRCA1 negative. Disease control rate at 12 weeks was 58% (95% CI 37–77; 15 of 26 patients), and at 24 weeks was 23% (9–44; six of 26 patients). Rucaparib was well tolerated, with 15 (9%) of 166 adverse events being grade 3 or 4, which were seen in nine (35%) of 26 patients, and there were no deaths. The most common grade 1–2 adverse events were nausea (18 [69%] of 26 patients), fatigue (14 patients [54%]), and decreased appetite (ten patients [38%]). The most common grade 3–4 adverse events were upper respiratory tract infection (three patients [12%]) and anaemia (three patients [12%]). All six cycles of rucaparib were received by eight (31%) of 26 patients. One or more dose reductions occurred in nine patients (35%). Rucaparib in patients with BAP1-negative or BRCA1 -negative mesothelioma met the prespecified criteria for success, showing promising activity with manageable toxicity. Further investigation of homologous recombination deficiency mutations is planned to refine the identification of predictive biomarkers for PARP inhibition in mesothelioma. University of Leicester (Leicester, UK), Asthma UK and British Lung Foundation Partnership, and the Victor Dahdaleh Foundation (Toronto, ON, Canada). [ABSTRACT FROM AUTHOR]

Almost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy, but none has shown a great effect. We aimed to assess the efficacy and safety of switch-maintenance gemcitabine in patients with malignant mesothelioma without disease progression after first-line chemotherapy. We did a randomised, open-label, phase 2 trial in 18 hospitals in the Netherlands (NVALT19). We recruited patients aged older than 18 years with unresectable malignant mesothelioma with no evidence of disease progression after at least four cycles of first-line chemotherapy (with platinum and pemetrexed), who had a WHO performance status of 0–2, adequate organ function, and measurable or evaluable disease. Exclusion criteria were active uncontrolled infection or severe cardiac dysfunction, serious disabling conditions, symptomatic CNS metastases, radiotherapy within 2 weeks before enrolment, and concomitant use of any other drugs under investigation. Patients were randomly assigned (1:1), using the minimisation method, to maintenance intravenous gemcitabine (1250 mg/m2 on days 1 and 8, in cycles of 21 days) plus supportive care, or to best supportive care alone, until disease progression, unacceptable toxicity, serious intercurrent illness, patient request for discontinuation, or need for any other anticancer agent, except for palliative radiotherapy. A CT scan of the thorax or abdomen (or both) and pulmonary function tests were done at baseline and repeated every 6 weeks. The primary outcome was progression-free survival in the intention-to-treat population. Safety was analysed in all participants who received one or more doses of the study drug or had at least one visit for supportive care. Recruitment is now closed; treatment and follow-up are ongoing. This study is registered with the Netherlands Trial Registry, NTR4132/NL3847. Between March 20, 2014, and Feb 27, 2019, 130 patients were enrolled and randomly assigned to gemcitabine plus supportive care (65 patients [50%]) or supportive care alone (65 patients [50%]). No patients were lost to follow-up; median follow-up was 36·5 months (95% CI 34·2 to not reached), and one patient in the supportive care group withdrew consent. Progression-free survival was significantly longer in the gemcitabine group (median 6·2 months [95% CI 4·6–8·7]) than in the supportive care group (3·2 months [2·8–4·1]; hazard ratio [HR] 0·48 [95% CI 0·33–0·71]; p=0·0002). The benefit was confirmed by masked independent central review (HR 0·49 [0·33–0·72]; p=0·0002). Grade 3–4 adverse events occurred in 33 (52%) of 64 patients in the gemcitabine group and in ten (16%) of 62 patients in the supportive care group. The most frequent adverse events were anaemia, neutropenia, fatigue or asthenia, pain, and infection in the gemcitabine group, and pain, infection, and cough or dyspnoea in the supportive care group. One patient (2%) in the gemcitabine group died, due to a treatment-related infection. Switch-maintenance gemcitabine, after first-line chemotherapy, significantly prolonged progression-free survival compared with best supportive care alone, among patients with malignant mesothelioma. This study confirms the activity of gemcitabine in treating malignant mesothelioma. Dutch Cancer Society (Koningin Wilhelmina Fonds voor de Nederlandse Kankerbestrijding) and Stichting NVALT studies. [ABSTRACT FROM AUTHOR]