-
Journal of the National Comprehensive... Sep 2023Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN...
Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term "malignant" is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.
Topics: Humans; Medical Oncology; Mesothelioma; Mesothelioma, Malignant; Peritoneum
PubMed: 37673108
DOI: 10.6004/jnccn.2023.0045 -
Zentralblatt Fur Chirurgie Jun 2024Malignant pleural effusion is a common diagnosis in metastasized cancers. It is always of palliative character. Main symptoms are dyspnoea and reduced quality of life.... (Review)
Review
Malignant pleural effusion is a common diagnosis in metastasized cancers. It is always of palliative character. Main symptoms are dyspnoea and reduced quality of life. Diagnosis is made by ultrasound-guided puncture of the pleural effusion (cytology) and often video-assisted thoracic surgery with biopsy of the pleural surface (histology). The goal of treatment is a fast, sustainable, minimally invasive, patient-centred therapy that increases quality of life. Besides systemic therapy and best supportive care the patient can be treated with local therapy including either pleurodesis (via drainage or VATS) or an indwelling-pleural catheter (IPC). Decision for one of these procedures is made upon performance index (ECOG), expandability of the lung, prognosis and the patient's wish. For the first technique, the lung must be expandable. The latter one (IPC) can be implanted both with expandable and trapped lung. Both are similarly effective in symptom control.
Topics: Pleural Effusion, Malignant; Humans; Thoracic Surgery, Video-Assisted; Pleurodesis; Palliative Care; Drainage; Catheters, Indwelling; Quality of Life; Prognosis; Ultrasonography, Interventional
PubMed: 38838699
DOI: 10.1055/a-1990-5057 -
Molecular Cancer Therapeutics Jan 2024The Hippo pathway and its downstream effectors, the YAP and TAZ transcriptional coactivators, are deregulated in multiple different types of human cancer and are...
The Hippo pathway and its downstream effectors, the YAP and TAZ transcriptional coactivators, are deregulated in multiple different types of human cancer and are required for cancer cell phenotypes in vitro and in vivo, while largely dispensable for tissue homeostasis in adult mice. YAP/TAZ and their main partner transcription factors, the TEAD1-4 factors, are therefore promising anticancer targets. Because of frequent YAP/TAZ hyperactivation caused by mutations in the Hippo pathway components NF2 and LATS2, mesothelioma is one of the prime cancer types predicted to be responsive to YAP/TAZ-TEAD inhibitor treatment. Mesothelioma is a devastating disease for which currently no effective treatment options exist. Here, we describe a novel covalent YAP/TAZ-TEAD inhibitor, SWTX-143, that binds to the palmitoylation pocket of all four TEAD isoforms. SWTX-143 caused irreversible and specific inhibition of the transcriptional activity of YAP/TAZ-TEAD in Hippo-mutant tumor cell lines. More importantly, YAP/TAZ-TEAD inhibitor treatment caused strong mesothelioma regression in subcutaneous xenograft models with human cells and in an orthotopic mesothelioma mouse model. Finally, SWTX-143 also selectively impaired the growth of NF2-mutant kidney cancer cell lines, suggesting that the sensitivity of mesothelioma models to these YAP/TAZ-TEAD inhibitors can be extended to other tumor types with aberrations in Hippo signaling. In brief, we describe a novel and specific YAP/TAZ-TEAD inhibitor that has potential to treat multiple Hippo-mutant solid tumor types.
Topics: Adult; Humans; Animals; Mice; Hippo Signaling Pathway; YAP-Signaling Proteins; Transcription Factors; Mesothelioma; Mesothelioma, Malignant; Protein Serine-Threonine Kinases; Tumor Suppressor Proteins
PubMed: 37748190
DOI: 10.1158/1535-7163.MCT-22-0681 -
Current Oncology Reports Dec 2023In this article, we provide a comprehensive analysis of recent progress in the genetic characterisation of pleural mesothelioma, and the translation of these findings to... (Review)
Review
PURPOSE OF REVIEW
In this article, we provide a comprehensive analysis of recent progress in the genetic characterisation of pleural mesothelioma, and the translation of these findings to clinical practice.
RECENT FINDINGS
Advancements in sequencing technology have allowed the identification of driver mutations and improved our understanding of how these mutations may shape the mesothelioma tumour microenvironment. However, the identification of frequently mutated regions including CDKN2A, BAP1 and NF2 have, to date, not yet yielded targeted therapy options that outperform standard chemo- and immunotherapies. Similarly, the association between mutational profile and the immune microenvironment or immunotherapy response is not well characterised. Further research into the link between tumour mutational profile and response to therapy is critical for identifying targetable vulnerabilities and stratifying patients for therapy.
Topics: Humans; Lung Neoplasms; Mesothelioma, Malignant; Mesothelioma; Pleural Neoplasms; Genomics; Tumor Microenvironment
PubMed: 38015374
DOI: 10.1007/s11912-023-01479-1 -
Chinese Clinical Oncology Dec 2023Tumor treating fields (TTFields) therapy have emerged as a potentially effective treatment for various malignancies by delivering low-intensity, intermediate-frequency... (Review)
Review
BACKGROUND AND OBJECTIVE
Tumor treating fields (TTFields) therapy have emerged as a potentially effective treatment for various malignancies by delivering low-intensity, intermediate-frequency electrical fields that disrupt many processes inside cells, resulting in the interruption of cell division in cancer cells. Additionally, TTFields therapy has been found to be synergistic with existing therapeutic approaches. In this review, we provide an introduction and background to the primary mechanisms of TTFields and discuss the emerging preclinical and clinical outcomes of this novel cancer treatment technology.
METHODS
We performed a literature search on PubMed, ClinicalTrials.Gov, and Google Scholar using the terms 'TTFields' and 'cancer'. We included studies, review articles, and editorials published in English from 1st January 2000 to 1st October 2023. All obtained publications were reviewed and their key references are cross-checked to ensure a balanced and high-quality review.
KEY CONTENT AND FINDINGS
Clinical studies reported to date have demonstrated the survival advantage of TTFields therapy in newly diagnosed glioblastoma (GBM), non-small cell lung cancer (NSCLC), and meaningful clinical activity in recurrent GBM (rGBM) and malignant pleural mesothelioma. Moreover, TTFields therapy has exhibited promising safety profiles across a diverse range of cancers including pancreatic cancer, hepatocellular carcinoma (HCC), ovarian cancer, NSCLC, and gastric cancer, when combined with cytotoxic chemotherapy and/or immunotherapy regimens, suggesting broad applicability as an added treatment modality.
CONCLUSIONS
Based on preclinical and clinical studies, TTFields therapy show promise as a potential treatment option for patients with a number of different malignancies, offering a favorable safety profile and the potential for significant clinical benefit. Further research is warranted to establish the optimal treatment parameters and identify specific patient subgroups that may derive the greatest advantage from this treatment modality.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Carcinoma, Hepatocellular; Lung Neoplasms; Neoplasm Recurrence, Local; Liver Neoplasms; Glioblastoma; Combined Modality Therapy; Brain Neoplasms
PubMed: 37953242
DOI: 10.21037/cco-23-82 -
Modern Pathology : An Official Journal... Sep 2023Primary pericardial mesotheliomas are extremely rare, accounting for <1% of all mesotheliomas, and their molecular genetic features and predisposing factors remain to be...
Primary pericardial mesotheliomas are extremely rare, accounting for <1% of all mesotheliomas, and their molecular genetic features and predisposing factors remain to be determined. Here, we report the clinicopathologic, immunohistochemical, and molecular genetic findings of 3 pericardial mesotheliomas without pleural involvement. Three cases diagnosed between 2004 and 2022 were included in the study and analyzed by immunohistochemistry and targeted next-generation sequencing (NGS); corresponding nonneoplastic tissue was sequenced in all cases. Two patients were female and 1 was male, aged between 66 and 75 years. Two patients each had prior asbestos exposure and were smokers. Histologic subtypes were epithelioid in 2 cases and biphasic in 1 case. Immunohistochemical staining identified expression of cytokeratin AE1/AE3 and calretinin in all cases, D2-40 in 2 cases, and WT1 in 1 case. Staining for tumor suppressors revealed loss of p16, MTAP, and Merlin (NF2) expression in 2 cases and loss of BAP1 and p53 in 1 case. Abnormal cytoplasmic BAP1 expression was observed in an additional case. Protein expression abnormalities correlated with NGS results, which showed concurrent complete genomic inactivation of CDKN2A/p16, CDKN2B, MTAP, and NF2 in 2 mesotheliomas and of BAP1 and TP53 in 1 mesothelioma each, respectively. In addition, 1 patient harbored a pathogenic BRCA1 germline mutation, which resulted in biallelic inactivation in the mesothelioma. All mesotheliomas were mismatch repair proficient and showed several chromosomal gains and losses. All patients died from disease. Our study demonstrates that pericardial mesotheliomas share common morphologic, immunohistochemical, and molecular genetic features with pleural mesothelioma, including recurrent genomic inactivation of canonical tumor suppressors. Our study adds new insights into the genetic landscape of primary pericardial mesothelioma and highlights BRCA1 loss as a potential contributing factor in a subset of cases, thereby contributing to refined precision diagnostics for this rare cancer.
Topics: Humans; Male; Female; Aged; Lung Neoplasms; Neoplasm Recurrence, Local; Mesothelioma, Malignant; Mesothelioma; Pleural Neoplasms; Heart Neoplasms; Thymus Neoplasms; Ubiquitin Thiolesterase; Biomarkers, Tumor
PubMed: 37295554
DOI: 10.1016/j.modpat.2023.100237 -
Journal For Immunotherapy of Cancer Sep 2023ONCOS-102, an oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor, can alter the tumor microenvironment to an immunostimulatory state.... (Randomized Controlled Trial)
Randomized Controlled Trial
ONCOS-102 plus pemetrexed and platinum chemotherapy in malignant pleural mesothelioma: a randomized phase 2 study investigating clinical outcomes and the tumor microenvironment.
BACKGROUND
ONCOS-102, an oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor, can alter the tumor microenvironment to an immunostimulatory state. Combining ONCOS-102 with standard-of-care chemotherapy for malignant pleural mesothelioma (MPM) may improve treatment outcomes.
METHODS
In this open-label, randomized study, patients with unresectable MPM received intratumoral ONCOS-102 (3×10 virus particles on days 1, 4, 8, 36, 78, and 120) and pemetrexed plus cisplatin/carboplatin (from day 22), or pemetrexed plus cisplatin/carboplatin alone. The primary endpoint was safety. Overall survival (OS), progression-free survival, objective response rate, and tumor immunologic activation (baseline and day 36 biopsies) were also assessed.
RESULTS
In total, 31 patients (safety lead-in: n=6, randomized: n=25) were enrolled. Anemia (15.0% and 27.3%) and neutropenia (40.0% and 45.5%) were the most frequent grade ≥3 adverse events (AEs) in the ONCOS-102 (n=20) and chemotherapy-alone (n=11) cohorts. No patients discontinued ONCOS-102 due to AEs. No statistically significant difference in efficacy endpoints was observed. There was a numerical improvement in OS (30-month OS rate 34.1% vs 0; median OS 20.3 vs 13.5 months) with ONCOS-102 versus chemotherapy alone in chemotherapy-naïve patients (n=17). By day 36, ONCOS-102 was associated with increased T-cell infiltration and immune-related gene expression that was not observed in the control cohort. Substantial immune activation in the tumor microenvironment was associated with survival at month 18 in the ONCOS-102 cohort.
CONCLUSIONS
ONCOS-102 plus pemetrexed and cisplatin/carboplatin was well tolerated by patients with MPM. In injected tumors, ONCOS-102 promoted a proinflammatory environment, including T-cell infiltration, which showed association with survival at month 18.
Topics: Humans; Pemetrexed; Platinum; Mesothelioma, Malignant; Cisplatin; Tumor Microenvironment; Carboplatin
PubMed: 37661097
DOI: 10.1136/jitc-2023-007552 -
JAMA Network Open Aug 2023Patients with mesothelioma often have next-generation sequencing (NGS) of their tumor performed; tumor-only NGS may incidentally identify germline pathogenic or likely...
IMPORTANCE
Patients with mesothelioma often have next-generation sequencing (NGS) of their tumor performed; tumor-only NGS may incidentally identify germline pathogenic or likely pathogenic (P/LP) variants despite not being designed for this purpose. It is unknown how frequently patients with mesothelioma have germline P/LP variants incidentally detected via tumor-only NGS.
OBJECTIVE
To determine the prevalence of incidental germline P/LP variants detected via tumor-only NGS of mesothelioma.
DESIGN, SETTING, AND PARTICIPANTS
A series of 161 unrelated patients with mesothelioma from a high-volume mesothelioma program had tumor-only and germline NGS performed during April 2016 to October 2021. Follow-up ranged from 18 months to 7 years. Tumor and germline assays were compared to determine which P/LP variants identified via tumor-only NGS were of germline origin. Data were analyzed from January to March 2023.
MAIN OUTCOMES AND MEASURES
The proportion of patients with mesothelioma who had P/LP germline variants incidentally detected via tumor-only NGS.
RESULTS
Of 161 patients with mesothelioma, 105 were male (65%), the mean (SD) age was 64.7 (11.2) years, and 156 patients (97%) self-identified as non-Hispanic White. Most (126 patients [78%]) had at least 1 potentially incidental P/LP germline variant. The positive predictive value of a potentially incidental germline P/LP variant on tumor-only NGS was 20%. Overall, 26 patients (16%) carried a P/LP germline variant. Germline P/LP variants were identified in ATM, ATR, BAP1, CHEK2, DDX41, FANCM, HAX1, MRE11A, MSH6, MUTYH, NF1, SAMD9L, and TMEM127.
CONCLUSIONS AND RELEVANCE
In this case series of 161 patients with mesothelioma, 16% had confirmed germline P/LP variants. Given the implications of a hereditary cancer syndrome diagnosis for preventive care and familial counseling, clinical approaches for addressing incidental P/LP germline variants in tumor-only NGS are needed. Tumor-only sequencing should not replace dedicated germline testing. Universal germline testing is likely needed for patients with mesothelioma.
Topics: Humans; Male; Middle Aged; Female; Genetic Predisposition to Disease; Mesothelioma; Mesothelioma, Malignant; High-Throughput Nucleotide Sequencing; Genomics; Adaptor Proteins, Signal Transducing; DNA Helicases
PubMed: 37556141
DOI: 10.1001/jamanetworkopen.2023.27351 -
Radiographics : a Review Publication of... Apr 2024The pleura is a thin, smooth, soft-tissue structure that lines the pleural cavity and separates the lungs from the chest wall, consisting of the visceral and parietal... (Review)
Review
The pleura is a thin, smooth, soft-tissue structure that lines the pleural cavity and separates the lungs from the chest wall, consisting of the visceral and parietal pleurae and physiologic pleural fluid. There is a broad spectrum of normal variations and abnormalities in the pleura, including pneumothorax, pleural effusion, and pleural thickening. Pneumothorax is associated with pulmonary diseases and is caused by iatrogenic or traumatic factors. Chest radiography and US help detect pneumothorax with various signs, and CT can also help assess the causes. Pleural effusion occurs in a wide spectrum of diseases, such as heart failure, cirrhosis, asbestos-related diseases, infections, chylothorax, and malignancies. Chest US allows detection of a small pleural effusion and evaluation of echogenicity or septa in pleural effusion. Pleural thickening may manifest as unilateral or bilateral and as focal, multifocal, or diffuse. Various diseases can demonstrate pleural thickening, such as asbestos-related diseases, neoplasms, and systemic diseases. CT, MRI, and fluorodeoxyglucose (FDG) PET/CT can help differentiate between benign and malignant lesions. Knowledge of these features can aid radiologists in suggesting diagnoses and recommending further examinations with other imaging modalities. The authors provide a comprehensive review of the clinical and multimodality imaging findings of pleural diseases and their differential diagnoses. RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.
Topics: Humans; Diagnosis, Differential; Pneumothorax; Positron Emission Tomography Computed Tomography; Pleural Diseases; Pleural Effusion; Asbestos; Pleural Neoplasms
PubMed: 38547031
DOI: 10.1148/rg.230079 -
The Lancet. Respiratory Medicine Jun 2024Most patients with pleural mesothelioma (PM) present with symptomatic pleural effusion. In some patients, PM is only detectable on the pleural surfaces, providing a... (Review)
Review
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.
Topics: Humans; Pleural Neoplasms; Mesothelioma; Pleura; Mesothelioma, Malignant; Antineoplastic Agents; Pleural Effusion, Malignant
PubMed: 38740045
DOI: 10.1016/S2213-2600(24)00111-5