Malignant pleural mesothelioma:The disdained member of thoracic oncology!

Pleural mesothelioma is a very aggressive malignancy that arises from the pleural mesothelial cell lining and is linked strongly to prior asbestos exposure.The ban on asbestos has helped to lower the incidence,but in developing countries like India,it is expected to rise.It has an extended latency period usually progressing over decades and presents with nonspecific symptoms.It has a median survival ranging between 10-22 months.The diagnosis of malignant pleural mesothelioma is challenging and is done using computed tomography(CT),magnetic resonance imaging,or positron emission tomography-CT,with the last two predicting the resectability of the tumor better than CT alone.A pleural biopsy along with an array of immunohistochemical markers,such as p16,BRCA1 associated protein 1,and claudin-4,are required for a definitive diagnosis.Several genetic alterations have prognostic significance as well.The current histological subtype identification is indispensable for decision making because of the new therapeutic avenues being explored.The combination of nivolumab and ipilimumab-based immunotherapy outperformed platinum and pemetrexed-based chemotherapy in terms of survival benefit and improved quality of life especially for non-epithelioid subtypes.However,the latter continues to be a robust treatment option for patients with the epithelioid subtype.Surgery is recommended for resectable cases with radiotherapy being indicated in neoadjuvant,adjuvant,and palliative settings along with systemic treatment.This review article provides an overview of epidemiology,etiology,clinical manifestations,diagnostic approaches(including immunohistochemical and genetic markers),staging,and multidisciplinary approaches to current treatment for malignant pleural mesothelioma using surgery,chemotherapy,immunotherapy,and radiotherapy.It also sheds light on some recent studies(EMPHACIS,CALGB30901,Checkmate-743,etc.)that have led to significant developments in recent years with clinically meaningful results.

Malignant pleural mesothelioma mimics thoracic empyema: A case report

BACKGROUND Thoracic empyema and malignant pleural mesothelioma(MPM)are distinct medical conditions with similar symptoms,including cough,chest pain,and breathing difficulty.We present a rare MPM case mimicking thoracic empyema.Physicians must consider MPM risks for patients exposed to building material who exhibit lobulated pleural effusions,indicating thoracic empyema.CASE SUMMARY A 68-year-old retired male construction worker suffered from shortness of breath and chest tightness over 10 d,particularly during physical activity.A poor appetite and 4 kg weight loss over the past 3 wk were also reported.Chest images and laboratory data concluded a tentative impression of empyema thoracis(right).Video-assisted thoracic surgery with decortication and delobulation(right)was conducted.The pathological report yielded an MPM diagnosis.Refractory pleural bilateral effusions and respiratory failure developed postoperatively,and the patient died three weeks after the operation.CONCLUSION Thoracic empyema and MPM are distinct medical conditions that can present similar symptoms,and video-assisted thoracic surgery facilitates an accurate diagnosis.Empyema-mimicking presentations and postoperative refractory pleural effusion may indicate a poor MPM outcome.

GOECP/SEOR clinical guidelines on radiotherapy for malignant pleural mesothelioma

Malignant pleural mesothelioma(MPM)is a rare tumor with poor prognosis and rising incidence.Palliative care is common in MPM as radical treatment with curative intent is often not possible due to metastasis or extensive locoregional involvement.Numerous therapeutic advances have been made in recent years,including the use of less aggressive surgical techniques associated with lower morbidity and mortality(e.g.,pleurectomy/decortication),technological advancements in the field of radiotherapy(intensity-modulated radiotherapy,image-guided radiotherapy,stereotactic body radiotherapy,proton therapy),and developments in systemic therapies(chemotherapy and immunotherapy).These improvements have had as yet only a modest effect on local control and survival.Advances in the management of MPM and standardization of care are hampered by the evidence to date,limited by high heterogeneity among studies and small sample sizes.In this clinical guideline prepared by the oncological group for the study of lung cancer of the Spanish Society of Radiation Oncology,we review clinical,histologic,and therapeutic aspects of MPM,with a particular focus on all aspects relating to radiotherapy,including the current evidence base,associations with chemotherapy and surgery,treatment volumes and planning,technological advances,and reradiation.

Multiple bowel intussusceptions from metastatic localized malignant pleural mesothelioma:A case report

Localized malignant pleural mesothelioma (LMPM) is a rare occurrence, and gastrointestinal intra-luminal metastases have not previously been reported. Herein, we report a patient with LMPM who presented with a local recurrence 10 mo after initial en bloc surgical resection. Abdominal computed tomography was performed for intractable, vague abdominal pain with episodic vomiting, which showed a "target sign" over the left lower quadrant. Laparotomy revealed several intra-luminal metastatic tumors in the small intestine and colon and a segmental resection of metastatic lesions was performed. Unfortunately, the patient died of sepsis despite successful surgical intervention. Though local recurrence is more frequent in LMPM, the possibility of distant metastasis should not be ignored in patients with non-specifi c abdominal pain.

Results of flexible 3D-conformal radiotherapy for patients with diffuse malignant pleural mesothelioma and comparative study of this technique with conventional radiotherapy

Objective： To observe the effects of the new technique of flexible 3D-conformal radiotherapy with combination of photon and electron （3DCRT） in the treatment of the patients with diffuse malignant pleural mesothelioma （MPM）, and carry out the comparative study between flexible 3DCRT and hemithoracic conventional radiotherapy （CRT）. Methods： From January 2004 to October 2007, 8 patients with MPM were treated with flexible 3DCRT. 5 patients had received cycles of chemotherapy before radiation. New technique of flexible 3DCRT with combination of photon and electron was used in our study, and DT 32.2-64 Gy with conventional split were delivered. CRT technique was mimicked to compare with 3DCRT technique to predict the possibility of lung damage in two methods. Results： One patient reached CR and other 7 patients got PR after radiation. Two patients died during the follow-up. The median survival time （MST） was 15.4 months and it was 18.8 months for sequential chemotherapy and radiotherapy group and 9.7 months for radiotherapy alone group. The V20, V30, and ipsilateral and contralateral median lung dosage （MLD） were 20.5%, 15.6%, 18.8 Gy and 2.2 Gy respectively when the flexible 3DCRT technique was used, whereas they were 36.8%, 27.9%, 31.1 Gy and 1.2 Gy respectively when the CRT technique was used. They were statistically different for the lung V20, V30 and ipsilateral MLD between the two techniques （P 〈 0.01）, whereas there was no different for the contralateral MLD （P = 0.08）. All patients received radiation were found to have lung fibrosis and classified as grades 1-2 radiation pneumonitis. The quality of life was increased from score 2.83 to 3.76 and it was significantly different （P 〈 0.01）. Conclusion： MPM is moderately sensitive to radiation. The flexible 3DCRT technique is feasible in the treatment of MPM and lung damage is reduced apparently comparing with the CRT technique. The quality of life of patients with MPM is improved after irradiation.

Complex Target Volume Delineation and Treatment Planning in Radiotherapy for Malignant Pleural Mesothelioma (MPM)

Introduction: Radiotherapy alone or combined with surgery and/or chemotherapy is being investigated in the treatment of malignant pleural mesothelioma (MPM). This study aimed to simulate a Volumetric Modulated Arc Therapy (VMAT) treatment of a patient with MPM. Materials and Methods: CT images from a patient with intact lungs were imported via DICOM into the Pinnacle3 treatment planning (TP) system (TPS) and used as a model for MPM to delineate organs at risk (OAR) and both clinical and planning target volumes (CTV and PTV) with a margin of 5 mm. Elekta Synergy with 6 MV photons and 80 leafs MLCi2 was employed. VMAT plans were generated using two coplanar arcs with gantry rotation angles of 178° - 182°, the collimator angles of each arc were set to 90°, Octavius® 4D 729 was employed for quality assurance while the calculated and measured doses were compared using VeriSoft. Results: A TP was achieved. The Gamma volume analysis with criteria of 3 mm distance to agreement and 3% dose difference yielded the gamma passing rate = 99.9%. The reference isodose was 42.75 Gy with the coverage constraints for the PTV D95 and V95 = 95.0% of 45 Gy. The remaining dosimetric parameters met the recommendations from the clinically acceptable guidelines for the radiotherapy of MPM. Conclusion: Using well-defined TV and VMAT, a consistent TP compared to similar ones from publications was achieved. We obtained a high agreement between the 3D dose reconstructed and the dose calculated.

Intrathoracic latissimus dorsi muscle transposition: a reliable technique for prevention of bronchopleural fistula developing after extrapleural pneumonectomy and external beam radiotherapy in malignant pleural mesothelioma

Objective: Bronchopleural fistula (BPF) is a life threatening complication after pneumonectomy. Extra thoracic skeletal muscle transposition especially latissimus dorsi muscle flap (LDMF) had been used to prevent this complication. The aim of this study was to assess the effectiveness of LDMF in preventing BPF developing after extrapleural pneumonectomy (EPP) and external radiation therapy in malignant pleural mesothelioma (MPM). Methods: Between May 1999 and Dec. 2008, 37 patients with MPM were operated upon by EPP using LDMF prophylactically to reinforce the bronchial stump, and then received external radiation therapy with or without postoperative chemotherapy. Results: The mean age of all patients was 46.7 (range 26-57) years. Twenty five patients were males and 12 patients were females. Twenty three patients had MPM of the right side and 14 patients had MPM of the left side. The peri-operative mortality was 2.7% and only few flap related postoperative morbidity were reported in the form of minor seroma and subcutaneous surgical emphysema. The median follow up was 17 (range 9-43) months. All cases completed their postoperative external radiation therapy with no reported cases of early or late BPF. Conclusion: Intrathoracic pedicled LDMF transposition is proved to be effective in prevention of BPF developing after EPP and external radiation therapy in MPM and it is advised to be a routine step in EPP in these cases and to use more sophisticated technique of postoperative external beam radiotherapy (3D conformal or IMRT) to minimize this complication.

Extra-pleural pneumonectomy in the setting of tri-modality therapy for patients with malignant pleural mesothelioma

Although declining in the US due to restrictions of asbestos exposure, malignant pleura/mesothelioma （MPP） remains a very serious thoracic malignancy that is rising in incidence worldwide （1）. Trirnodality therapy with chemotherapy and radiotherapy combined with extrapleural pneumonectomy （EPP） has gained acceptance given the acceptable mortality rate （〈5%） and long term survival reported in patients with epithelial histology, negative margins, and no extrapleural lymph node involvement after trimodalitv treatment （2）.

mprovement of Malignant Pleural Mesothelioma Prognosis： Early Diagnosis and Multimodality Treatment

Malignant pleural mesothelioma （MPM） is the most common primary malignancy of the pleura. The occurrence of malignant mesothelioma is typically related to exposure to mineral fibers such as asbestos and erionite.Reports suggest that genetic factors may also play a role in MPM.141 Moreover, latency periods that are the period of time between the first exposure to asbestos and a disease diagnosis range from 20 to 50 years. The mortality burden from asbestos-related diseases （ARD） is heavy andARD accounts for 92,250 deaths per year globally. To improve survival of MPM patients, effective strategy of early diagnosis and effective treatment strategies are highly needed.

Cancer-directed surgery in malignant pleural mesothelioma: extrapleural pneumonectomy and pleurectomy/decortication

Malignant pleural mesothelioma(MPM)is a primary solid malignancy related to inhalational asbestos exposure.Despite advances in therapy,MPM remains challenging to treat with a post-treatment survival of only 15%at 5-year.In recent years,extra-pleural pneumonectomy has decreased in popularity due to a high morbidity rate and mortality compared to pleurectomy/decortication and other therapeutic alternatives.In this review,we will discuss both procedures,outcomes,ongoing studies,and the roles of surgery in the future treatment of this disease.

Tumour suppressor microRNAs contribute to drug resistance in malignant pleural mesothelioma by targeting anti-apoptotic pathways

Aim:Aberrant microRNA expression is a common event in cancer drug resistance,however its involvement in malignant pleural mesothelioma(MPM)drug resistance is largely unexplored.We aimed to investigate the contribution of microRNAs to the resistance to drugs commonly used in the treatment of MPM.Methods:Drug resistant MPM cell lines were generated by treatment with cisplatin,gemcitabine or vinorelbine.Expression of microRNAs was quantified using RT-qPCR.Apoptosis and drug sensitivity assays were carried out following transfection with microRNA mimics or BCL2 siRNAs combined with drugs.Results:Expression of miR-15a,miR-16 and miR-34a was downregulated in MPM cells with acquired drug resistance.Transfection with miR-15a or miR-16 mimics reversed the resistance to cisplatin,gemcitabine or vinorelbine,whereas miR-34a reversed cisplatin and vinorelbine resistance only.Similarly,in parental cell lines,miR-15a or miR-16 mimics sensitised cells to all drugs,whereas miR-34a increased response to cisplatin and vinorelbine.Increased microRNA expression increased drug-induced apoptosis and caused BCL2 mRNA and protein reduction.RNAi-mediated knockdown of BCL2 partly recapitulated the increase in drug sensitivity in cisplatin and vinorelbine treated cells.Conclusion:Drug-resistant MPM cell lines exhibited reduced expression of tumour suppressor microRNAs.Increasing tumour suppressor of microRNA expression sensitised both drug resistant and parental cell lines to chemotherapeutic agents,in part through targeting of BCL2.Taken together,these data suggest that miR-15a,miR-16 and miR-34a are involved in the acquired and intrinsic drug resistance phenotype of MPM cells.

Sarcomatoid malignant pleural mesothelioma confirmed by full-thickness biopsy

Diffuse malignant pleural mesothelioma （DMPM） is a rare thoracic malignancy, but its incidence isdramatically increasing worldwide as a result ot widespread use of asbestos. The World Health Organization classifies DMPM into three types： epithelioid, sarcomatoid, and biphasic types. DMPM remains suffering poor prognosis and the diagnosis should always be based on adequate, representative tissue samples. There still remains a considerable number of patients with DMPM who are misdiagnosed after a complete investigation including thoracoscopic biopsies.

Promising therapeutic potential of tumor suppressor microRNAs for malignant pleural mesothelioma

Malignant pleural mesothelioma(MPM)is an aggressive and recalcitrant surface neoplasm that defies current multimodality treatments.MicroRNAs(miRNAs)are small noncoding RNAs that epigenetically regulate multiple gene networks and cellular processes.In cancer,miRNA dysregulation is associated with tumorigenesis,with tumor suppressor miRNAs underexpressed or lost,while oncogenic miRNAs are overexpressed.Consequently,miRNAs have emerged as potential therapeutic candidates.Because loss of tumor suppressors predominates the pathophysiology of MPM,re-expressing tumor suppressor miRNAs could be an effective therapeutic strategy.This review highlights the most promising MPM-specific tumor suppressor miRNAs that could be developed into novel therapeutics,the supporting data,and what is known about their molecular mechanism(s).

Immunotherapy in malignant pleural mesothelioma:a long story ended in success

Malignant pleural mesothelioma(MPM)is an aggressive and rare disease,mainly due to asbestos exposure,characterized by a poor prognosis.For almost two decades,platinum-based chemotherapy has been the only approved therapeutic regimen for first-line MPM,with an overall survival of 12 months.In the last years,the therapeutic scenario of different tumor types,including MPM,has dramatically changed due to immune checkpoint inhibition.The promising results of this approach have promoted new efforts into clinical research,and many trials investigating novel therapeutic combinations are currently ongoing.The aim of the present review is to provide a comprehensive overview of the most promising immunotherapeutic-based strategies currently under investigation for advanced MPM.

Integrative decomposition procedure and Kappa statistics set up ATF2 ion binding module in malignant pleural mesothelioma(MPM)

Activating transcription factor 2(ATF2)is a member of the ATF/cyclic AMP-responsive element bind-ing protein family of transcription factors.However,the information concerning ATF2 ion-mediated DNA binding module and function of ATF2 in malignant pleural mesothelioma(MPM)has never been addressed.In this study,by using GRNInfer and GVedit based on linear pro-gramming and a decomposition procedure,with integrated analysis of the function cluster using Kappa statistics and fuzzy heuristic clustering in MPM,we identified one ATF2 ion-mediated DNA binding module involved in invasive function including ATF2 inhibition to target genes FALZ,C20orf31,NME2,PLOD2,RNF10,and RNASEH1,upstream RNF10 and PLOD2 activation to ATF2,upstream RNASEH1 and FALZ inhibition to ATF2 from 40 MPM tumors and 5 normal pleural tissues.Remarkably,our results showed that the predominant effect of ATF2 occupancy is to suppress the activation of target genes on MPM.Importantly,the ATF2 ion-mediated DNA binding module reflects‘mutual’positive and negative feedback regulation mechanism of ATF2 with up-and down-stream genes.It may be useful for developing novel prognostic markers and therapeutic targets in MPM.

Treatment of unresectable malignant pleural mesothelioma in 2021: emerging standards in immunotherapy

Patients with unresectable malignant pleural mesothelioma(MPM)have historically poor outcomes and treatment,and their treatments have been limited to palliative chemotherapy.Recent efforts to improve prognosis for these patients by adding angiogenesis inhibitors to chemotherapy led to significant benefits.However,the emergence of immunotherapy combinations for the front-line treatment has upended the standard of care and has led to the first new FDA approvals for the treatment of MPM in nearly two decades.This review aims to cover the main clinical trials in unresectable MPM with VEGF inhibitors and immunotherapy which have led to paradigm shifts in current practice.Ongoing clinical trials exploring the combination of chemo and immunotherapies show a great deal of promise,and continued support for ambitious,large-scale well-designed trials remain vital for defining the future outcomes of patients diagnosed with MPM.

Tsunami of immunotherapy reaches mesothelioma

Malignant pleural mesothelioma(MPM) is the most common type of malignant mesothelioma. It is a rare tumor linked to asbestos exposure and is associated with a poor prognosis. Until very recently, patients with advanced or unresectable disease had limited treatment options, primarily based on doublet chemotherapy with cisplatin and pemetrexed. In 2020 and 2021, after more than a decade with no major advances or new drugs, two phase Ⅲ clinical trials published results positioning immunotherapy as a promising option for the first-and second-line treatment of MPM. Immunotherapy has revolutionized the treatment of many cancers and is also showing encouraging results in malignant mesothelioma. Both immune checkpoint inhibition and dual cytotoxic T-lymphocyte–associated antigen 4 and programmed death-ligand 1 pathway blockade resulted in significantly improved overall survival in randomized phase Ⅲ trials. In the Check Mate 743 trial, first-line therapy with nivolumab plus ipilimumab outperformed standard chemotherapy, while in the CONFIRM trial, nivolumab outperformed placebo in patients previously treated with chemotherapy. These two trials represent a major milestone in the treatment of MPM and are set to position immunotherapy as a viable alternative for treatment-naive patients and patients with progressive disease after chemotherapy.

Does delaying surgery following induction chemotherapy compromise survival in patients with mesothelioma?

Objective:The ideal time interval between induction chemotherapy and surgery and the impact on cancer mortality in patients with mesothelioma remains unclear.Methods:We queried the National Cancer Database(2004-2017)for patients with favorable prognostic factors considered for surgery.Immediate surgery was performed within 3 months following the start of induction chemotherapy,while delayed surgery was defined as surgery performed later than 3 months.We compared both groups to those who did not have an operation despite being surgical candidates,as well as to those who were treated with surgery only.Overall mortality was assessed using Cox proportional hazard models adjusting for covariates.Results:A total of 4,294 patients were included,with the majority of patients undergoing induction chemotherapy followed by no surgery(3,370,78%).The proportion of patients undergoing both immediate and delayed surgery increased over the last decade,but delayed surgery continued to be more common.There were no significant differences in baseline characteristics between the immediate and delayed surgery groups.Higher comorbidity scores were significantly associated with an increased risk of death on multivariable analysis,but the timing of surgery was not.This held true with a sensitivity analysis using 6 months as the definition of delayed surgery.Conclusions:This study shows that delaying surgery following induction chemotherapy does not compromise overall survival in patients with mesothelioma.