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Advances in Anatomic Pathology Jul 2023A remarkable amount of new information has been generated on peritoneal mesothelioma (PeM), ranging from nomenclature changes, including the removal of "malignant" when...
A remarkable amount of new information has been generated on peritoneal mesothelioma (PeM), ranging from nomenclature changes, including the removal of "malignant" when referring to this neoplasm and the use of the term "tumor" rather than "mesothelioma" to designate the neoplasm formerly known as "well-differentiated papillary mesothelioma", to the acknowledgment that PeMs can be associated with tumor predisposition syndromes or germline mutations. Although the disease is still more frequently seen in caucasian males, PeM is not uncommon in women. In addition, it can represent a diagnostic challenge when it has an uncommon presentation (ie, paraneoplastic syndrome or incidental finding) or when it has confounding histologic features. Ancillary testing, including immunohistochemical stains, in situ hybridization for CDKN2A or NF2 , and molecular studies, in selected cases, allows its correct diagnosis. The molecular landscape of PeM is still a work in progress; however, some findings, such as ALK gene rearrangements and EWSR1/FUS-ATF1 fusions, are specifically seen in PeM of young patients. The biological behavior of PeM is variable; however, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have markedly improved the survival of patients affected by this disease.
Topics: Male; Humans; Female; Mesothelioma, Malignant; Mesothelioma; Peritoneal Neoplasms; Germ-Line Mutation
PubMed: 36729766
DOI: 10.1097/PAP.0000000000000387 -
Lancet (London, England) Dec 2023Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum-pemetrexed is a standard treatment. We hypothesised that the addition... (Randomized Controlled Trial)
Randomized Controlled Trial
Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial.
BACKGROUND
Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum-pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum-pemetrexed would improve overall survival in patients with pleural mesothelioma.
METHODS
We did this open-label, international, randomised phase 3 trial at 51 hospitals in Canada, Italy, and France. Eligible participants were aged 18 years or older, with previously untreated advanced pleural mesothelioma, with an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) to intravenous chemotherapy (cisplatin [75 mg/m] or carboplatin [area under the concentration-time curve 5-6 mg/mL per min] with pemetrexed 500 mg/m, every 3 weeks for up to 6 cycles), with or without intravenous pembrolizumab 200 mg every 3 weeks (up to 2 years). The primary endpoint was overall survival in all randomly assigned patients; safety was assessed in all randomly assigned patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02784171, and is closed to accrual.
FINDINGS
Between Jan 31, 2017, and Sept 4, 2020, 440 patients were enrolled and randomly assigned to chemotherapy alone (n=218) or chemotherapy with pembrolizumab (n=222). 333 (76 %) of patients were male, 347 (79%) were White, and median age was 71 years (IQR 66-75). At final analysis (database lock Dec 15, 2022), with a median follow-up of 16·2 months (IQR 8·3-27·8), overall survival was significantly longer with pembrolizumab (median overall survival 17·3 months [95% CI 14·4-21·3] with pembrolizumab vs 16·1 months [13·1-18·2] with chemotherapy alone, hazard ratio for death 0·79; 95% CI 0·64-0·98, two-sided p=0·0324). 3-year overall survival rate was 25% (95% CI 20-33%) with pembrolizumab and 17% (13-24%) with chemotherapy alone. Adverse events related to study treatment of grade 3 or 4 occurred in 60 (27%) of 222 patients in the pembrolizumab group and 32 (15%) of 211 patients in the chemotherapy alone group. Hospital admissions for serious adverse events related to one or more study drugs were reported in 40 (18%) of 222 patients in the pembrolizumab group and 12 (6%) of 211 patients in the chemotherapy alone group. Grade 5 adverse events related to one or more drugs occurred in two patients on the pembrolizumab group and one patient in the chemotherapy alone group.
INTERPRETATION
In patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum-pemetrexed chemotherapy was tolerable and resulted in a significant improvement in overall survival. This regimen is a new treatment option for previously untreated advanced pleural mesothelioma.
FUNDING
The Canadian Cancer Society and Merck & Co.
Topics: Humans; Male; Aged; Female; Pemetrexed; Platinum; Canada; Mesothelioma, Malignant; Mesothelioma; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37931632
DOI: 10.1016/S0140-6736(23)01613-6 -
Advances in Anatomic Pathology Jul 2023Primary pericardial mesothelioma (PM) is a rare tumor arising from the mesothelial cells of the pericardium. It has an incidence of <0.05% and comprises <2% of all...
Primary pericardial mesothelioma (PM) is a rare tumor arising from the mesothelial cells of the pericardium. It has an incidence of <0.05% and comprises <2% of all mesotheliomas; however, it is the most common primary malignancy of the pericardium. PM should be distinguished from secondary involvement by the spread of pleural mesothelioma or metastases, which are more common. Although data are controversial, the association between asbestos exposure and PM is less documented than that with other mesotheliomas. Late clinical presentation is common. Symptoms may be nonspecific but are usually related to pericardial constriction or cardiac tamponade, and diagnosis can be challenging usually requiring multiple imaging modalities. Echocardiography, computed tomography, and cardiac magnetic resonance demonstrate heterogeneously enhancing thickened pericardium, usually encasing the heart, with findings of constrictive physiology. Tissue sampling is essential for diagnosis. Histologically, similar to mesotheliomas elsewhere in the body, PM is classified as epithelioid, sarcomatoid, or biphasic, with the biphasic type being the most common. Combined with morphologic assessment, the use of immunohistochemistry and other ancillary studies is helpful for distinguishing mesotheliomas from benign proliferative processes and other neoplastic processes. The prognosis of PM is poor with about 22% 1-year survival. Unfortunately, the rarity of PM poses limitations for comprehensive and prospective studies to gain further insight into the pathobiology, diagnosis, and treatment of PM.
Topics: Humans; Prospective Studies; Mesothelioma, Malignant; Mesothelioma; Pleural Neoplasms; Sarcoma; Heart Neoplasms
PubMed: 37104724
DOI: 10.1097/PAP.0000000000000399 -
Journal For Immunotherapy of Cancer Aug 2023Although immune checkpoint blockade (ICB) therapy has shown remarkable benefits in cancers, a subset of patients with cancer exhibits unresponsiveness or develop...
BACKGROUND
Although immune checkpoint blockade (ICB) therapy has shown remarkable benefits in cancers, a subset of patients with cancer exhibits unresponsiveness or develop acquired resistance due to the existence of abundant immunosuppressive cells. Tumor-associated macrophages (TAMs), as the dominant immunosuppressive population, impede the antitumor immune response; however, the underlying mechanisms have not been fully elucidated yet.
METHODS
Single-cell RNA sequencing analysis was performed to portray macrophage landscape and revealed the underlying mechanism of component 1q (C1q) TAMs. Malignant pleural effusion (MPE) of human and mouse was used to explore the phenotypes and functions of C1q TAMs.
RESULTS
C1q TAMs highly expressed multiple inhibitory molecules and their high infiltration was significantly correlated with poor prognosis. C1q TAMs promote MPE immunosuppression through impairing the antitumor effects of CD8 T cells. Mechanistically, C1q TAMs enhance fatty acid binding protein 5 (FABP5)-mediated fatty acid metabolism, which activate transcription factor peroxisome proliferator-activated receptor-gamma, increasing the gene expression of inhibitory molecules. A high-fat diet increases the expression of inhibitory molecules in C1q TAMs and the immunosuppression of MPE microenvironment, whereas a low-fat diet ameliorates these effects. Moreover, FABP5 inhibition represses the expression of inhibitory molecules in TAMs and tumor progression, while enhancing the efficacy of ICB therapy in MPE and lung cancer.
CONCLUSIONS
C1q TAMs impede antitumor effects of CD8 T cells promoting MPE immunosuppression. Targeting C1q TAMs effectively alleviates the immunosuppression and enhances the efficacy of ICB therapy. C1q TAMs subset has great potential to be a therapeutic target for cancer immunotherapy.
Topics: Humans; Animals; Mice; Complement C1q; Pleural Effusion, Malignant; Tumor-Associated Macrophages; CD8-Positive T-Lymphocytes; Immunosuppression Therapy; Immunosuppressive Agents; Tumor Microenvironment; Fatty Acid-Binding Proteins
PubMed: 37604643
DOI: 10.1136/jitc-2023-007441 -
Ugeskrift For Laeger Jan 2024Mesothelioma of the tunica vaginalis testis (MTVT) is a rare tumour and a cause of hydrocele. This case report concerns a 26-year-old male with hydrocele treated with...
Mesothelioma of the tunica vaginalis testis (MTVT) is a rare tumour and a cause of hydrocele. This case report concerns a 26-year-old male with hydrocele treated with left hydrocelectomy. Histopathology revealed MTVT, and left radical orchiectomy was performed followed by chemotherapy. Fluorescence in situ hybridization, DNA and RNA next-generation sequencing showed no mesothelioma-associated tumour suppressor gene mutations, but deletion of CDKN2A and a rare TFG-ADGRG7 fusion both reported in pleural mesotheliomas, were detected. Clinicians should consider malignancy in case of discrepancy between symptoms and objective findings in scrotal conditions.
Topics: Male; Humans; Adult; Testis; In Situ Hybridization, Fluorescence; Testicular Neoplasms; Mesothelioma; Mesothelioma, Malignant; Testicular Hydrocele
PubMed: 38305267
DOI: 10.61409/V07230476 -
Histopathology Jan 2024Mesothelioma is a rare disease with an historically poor prognosis. Over the past decade, a grading system has been developed that is a powerful prognostic tool in... (Review)
Review
Mesothelioma is a rare disease with an historically poor prognosis. Over the past decade, a grading system has been developed that is a powerful prognostic tool in epithelioid mesothelioma. Grading of epithelioid mesothelioma is now required or strongly recommended by expert consensus, the College of American Pathologists, the World Health Organization, and the International Mesothelioma Interest Group. The original nuclear grading system for epithelioid mesothelioma, developed in the United States, split epithelioid mesotheliomas into three prognostic groups with marked differences in survival. Now, this three-tiered nuclear grading system has been combined with the presence or absence of necrosis to form the currently recommended two-tiered grading system of low- and high-grade epithelioid mesothelioma. This review will focus on the development of this grading system in mesothelioma, the grading system's shortcomings, and the application of the grading system to cytology specimens and other extra-pleural sites. Lastly, this review will briefly discuss alternative grading systems and future considerations.
Topics: Humans; Pleural Neoplasms; Lung Neoplasms; Neoplasm Grading; Mesothelioma, Malignant; Mesothelioma; Prognosis; Biomarkers, Tumor
PubMed: 37872123
DOI: 10.1111/his.15065 -
Seminars in Respiratory and Critical... Aug 2023In this review, we provide an update on the status of cancer biomarkers for the clinical management of pleural mesothelioma, an aggressive cancer associated with... (Review)
Review
In this review, we provide an update on the status of cancer biomarkers for the clinical management of pleural mesothelioma, an aggressive cancer associated with asbestos exposure. Mesothelioma can be difficult to diagnose, and response to treatment is transient, even with recently adopted immune checkpoint inhibitor (ICI) combinations. Identification of mesothelioma-specific biomarkers could facilitate early diagnosis and tailor treatment strategies. Mesothelioma is characterized by frequent loss or alteration of the tumor suppressor genes () and () Accumulating data show these genes and/or their related protein products will be valuable tissue-based biomarkers for mesothelioma. Loss of BAP1, CDKN2A, p16, or methylthioadenosine phosphorylase provide pathologists with a reliable means of differentiating between mesothelioma and reactive mesothelial cell proliferations. This can aid diagnosis in difficult cases and is requisite for the identification of the new pathological entity malignant mesothelioma in situ. However, limited progress in identifying clinically useful soluble biomarkers in this cancer type has been made, with mesothelin remaining the benchmark. To date, results from studies to identify predictive biomarkers for ICI response have been disappointing. A recent retrospective study demonstrated BAP1 loss was predictive of improved survival following combination pemetrexed- and platinum-based chemotherapy. Validation of this result could have important clinical implications. Clinical trials aimed at targeting therapy based on biomarker expression are generally in the early phase setting, with overall results being moderate. The identification of biomarkers for mesothelioma remains a key research question due to their potential to improve patient outcomes in this deadly cancer.
Topics: Humans; Mesothelioma, Malignant; Lung Neoplasms; Mesothelioma; Pleural Neoplasms; Biomarkers, Tumor
PubMed: 37253383
DOI: 10.1055/s-0043-1769097 -
Journal of Translational Medicine Nov 2023In recent decades, using circulating tumor cell (CTC), circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), exosomes and etc. as liquid biomarkers has received... (Review)
Review
In recent decades, using circulating tumor cell (CTC), circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), exosomes and etc. as liquid biomarkers has received enormous attention in various tumors, including breast cancer (BC). To date, efforts in the area of liquid biopsy predominantly focus on the analysis of blood-based markers. It is worth noting that the identifications of markers from non-blood sources provide unique advantages beyond the blood and these alternative sources may be of great significance in offering supplementary information in certain settings. Here, we outline the latest advances in the analysis of non-blood biomarkers, predominantly including urine, saliva, cerebrospinal fluid, pleural fluid, stool and etc. The unique advantages of such testings, their current limitations and the appropriate use of non-blood assays and blood assays in different settings are further discussed. Finally, we propose to highlight the challenges of these alternative assays from basic to clinical implementation and explore the areas where more investigations are warranted to elucidate its potential utility.
Topics: Humans; Female; Breast Neoplasms; Biomarkers, Tumor; Liquid Biopsy; DNA, Neoplasm; RNA, Neoplasm; Neoplastic Cells, Circulating
PubMed: 37957623
DOI: 10.1186/s12967-023-04660-z