Immunotherapy for advanced and recurrent malignant pleural mesothelioma.

OBJECTIVES: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects of immune checkpoint inhibitors (single-agent or combination therapy) in people with advanced malignant pleural mesothelioma in a first-line or salvage setting.

Postoperative early laboratory changes and follow-up process of patients underwent hyperthermic intrathoracic chemotherapy.

BACKGROUND: The aim of combining hyperthermic intrathoracic chemotherapy (HITHOC) with surgery is to achieve local control in patients with pleural malignancies. Liver and kidney dysfunction resulting from this procedure have been reported in the literature. The objective of the study is to examine whether the laboratory abnormalities observed during the initial period persist until day 30. METHODS: The study conducted a retrospective analysis of the blood glucose levels, renal function markers, and hepatic function markers of 30 patients who underwent pleurectomy-decortication and HITHOC for pleural mesothelioma from January 2010 to April 2022. The measurements were taken in the postoperative period on the first four and 30th days. The study analyzed the initial and final laboratory results caused by the procedure. RESULTS: Out of the total of 30 patients, 29, 28, 14, and 12 patients had elevated glucose levels on the first four days after the surgery, respectively. There was no association between glucose abnormalities and preoperative-postoperative diabetes mellitus. A minority of patients experienced atypical alterations in kidney and liver functions during the initial postoperative period. There was no apparent relationship between the renal and hepatic functions in the early and late periods after the surgery. CONCLUSION: Although there were fluctuations in glucose levels and renal and hepatic functions in the early period after surgery, there were no persistent alterations in these parameters by day 30. Elevated glucose levels during the early period were not associated with the development of newly diagnosed diabetes mellitus after surgery. The findings of our study provide evidence that HITHOC is a favorable and well-tolerated treatment option for mesothelioma.

Diagnosis of Pleural Mesothelioma: Is Everything Solved at the Present Time?

Ranked high in worldwide growing health issues, pleural diseases affect approximately one million people globally per year and are often correlated with a poor prognosis. Among these pleural diseases, malignant pleural mesothelioma (PM), a neoplastic disease mainly due to asbestos exposure, still remains a diagnostic challenge. Timely diagnosis is imperative to define the most suitable therapeutic approach for the patient, but the choice of diagnostic modalities depends on operator experience and local facilities while bearing in mind the yield of each diagnostic procedure. Since the analysis of pleural fluid cytology is not sufficient in differentiating historical features in PM, histopathological and morphological features obtained via tissue biopsies are fundamental. The quality of biopsy samples is crucial and often requires highly qualified expertise. Since adequate tissue biopsy is essential, medical or video-assisted thoracoscopy (MT or VATS) is proposed as the most suitable approach, with the former being a physician-led procedure. Indeed, MT is the diagnostic gold standard for malignant pleural pathologies. Moreover, this medical or surgical approach can allow diagnostic and therapeutic procedures: it provides the possibility of video-assisted biopsies, the drainage of high volumes of pleural fluid and the administration of sterile calibrated talcum powder under visual control in order to achieve pleurodesis, placement of indwelling pleural catheters if required and in a near future potential intrapleural therapy. In this context, dedicated diagnostic pathways remain a crucial need, especially to quickly and properly diagnose PM. Lastly, the interdisciplinary approach and multidisciplinary collaboration should always be implemented in order to direct the patient to the best customised diagnostic and therapeutic pathway. At the present time, the diagnosis of PM remains an unsolved problem despite MDT (multidisciplinary team) meetings, mainly because of the lack of standardised diagnostic work-up. This review aims to provide an overview of diagnostic procedures in order to propose a clear strategy.

Clinical Characteristics and Outcomes of Patients with Well-Differentiated Papillary Peritoneal Mesothelial Tumors.

PURPOSE: Well-differentiated papillary peritoneal mesothelial tumors (WDPMTs) are understudied and discrete from peritoneal mesotheliomas (PMs). We report clinicopathologic characteristics and outcomes of a large prospective WDPMT cohort. METHODS: Patients with WDPMT identified between August 2007 and December 2020 were followed through January 2023. Clinical characteristics and outcomes were annotated. Overall survival (OS) was assessed from pathologic diagnosis. Germline variants were analyzed, and targeted next-generation sequencing (NGS; MSK-IMPACT) data were compared to PMs and diffuse pleural mesotheliomas (DPMs). RESULTS: Among 54 patients, median age at diagnosis was 55 (range 20-76), 50% were female (n = 27), and 46% were smokers (n = 25; median 8 pack/years). Most (94%, n = 51) WDPMTs were found during surgical explorations for other indications, primarily other malignancies. Two patients underwent surgical resection for WDPMT; none received systemic therapy for WDPMT. Median OS was not reached (19/54; median follow up 4.5 years). Somatic NGS was available for 35% (19/54) of patients. TRAF7 alterations were enriched in WDPMT (89%; 17/19) compared with PM (0%; 0/50; p < 0.0001) and DPM (0%; 0/74; p < 0.0001). In WDPMT compared with PM and DPM, there were less BAP1 (0% [0/0] vs. 4% [8/50] vs. 46% [34/74]; p = 0.001 and p < 0.0001, respectively) and NF2 (0% [0/0] vs. 24% [12/50] vs. 31% [23/74]; p = 0.03 and p = 0.001 respectively) alterations. Pathogenic germline variants were present in 23% (4/17) of WDPMTs. CONCLUSIONS: Well-differentiated papillary peritoneal mesothelial tumors were primarily incidental findings. There was no WDPMT-related mortality, so there was no distinct role for routine cytoreductive surgery or systemic therapy. Genomic profiles can help to differentiate WDPMT from DPM and PM.

[Malignant mesothelioma of the vaginal testis: diagnostic and therapeutic considerations]. / Le mésothéliome malin de la vaginale testiculaire : aspects diagnostiques et thérapeutiques.

Mesothelioma of the testicular vagina is a rare malignant tumour, most often discovered by chance. The rarity of this type of tumour has not led to the development of specific guidelines. Median survival is estimated at 30 months. The lack of data and official recommendations makes surgical and medical management and follow-up difficult. Men who have not undergone radical orchiectomy die very rapidly after diagnosis. The remission rate at 1 year post-orchidectomy is 47 %, the recurrence rate at 1 year is 53 % and 92 % of relapses occur within 5 years post-operatively. The treatment option of hemiscrotectomy in the first instance has rarely been used; a second-look resection with negative margins may be proposed. The usefulness of adjuvant chemotherapy and/or radiotherapy has not been clearly demonstrated. Local recurrence is accompanied by metastasis in 85 % of cases. In the case of metastatic cancer (15 %), the retro-peritoneal, inguinal and iliac lymph nodes may be invaded. Follow-up by injected thoraco-abdomino-pelvic CT scan is recommended every 3 months for 2 years, then once a year for 3 years, for a total of 5 years of close follow-up. The long-term recurrence rate is 3 %.

Le mésothéliome de la vaginale testiculaire est une tumeur maligne rare et souvent de découverte fortuite. Sa rareté d'apparition n'a pas permis de développer des recommandations spécifiques. La survie médiane est estimée à 30 mois. Le manque de recommandations officielles rend sa prise en charge chirurgicale, médicale et son suivi difficiles. Les hommes n'ayant pas bénéficié d'orchidectomie radicale décèdent très rapidement après le diagnostic. Le taux de rémission à 1 an post-orchidectomie est de 47 %, le taux de récurrence à 1 an est de 53 % et 92 % des rechutes se font endéans les 5 ans post-opératoires. L'option thérapeutique par hémi-scrotectomie en première intention a rarement été pratiquée, une résection de «second look¼ en marges saines peut être proposée. L'utilité d'une chimiothérapie et/ou d'une radiothérapie adjuvante n'a pas été clairement démontrée. Une rechute locale est accompagnée de métastases dans 85 % des cas. En cas de cancer d'emblée métastatique (15 %), les relais ganglionnaires rétro-péritonéaux, inguinaux et iliaques peuvent être envahis. Un suivi par scanner thoraco-abdomino-pelvien injecté est recommandé tous les 3 mois pendant 2 ans, puis 1 fois par an pendant 3 ans pour un total de 5 ans. Le taux de récidive au long cours est de 3 %.

Integration of the PD-L1 inhibitor atezolizumab and WT1/DC vaccination into standard-of-care first-line treatment for patients with epithelioid malignant pleural mesothelioma-Protocol of the Immuno-MESODEC study.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with a very poor prognosis. Recently, immune checkpoint inhibition (ICI) has taken center stage in the currently ongoing revolution that is changing standard-of-care treatment for several malignancies, including MPM. As multiple arguments and accumulating lines of evidence are in support of the existence of a therapeutic synergism between chemotherapy and immunotherapy, as well as between different classes of immunotherapeutics, we designed a multicenter, single-arm, phase I/II trial in which both programmed-death-ligand 1 (PD-L1) inhibition and dendritic cell (DC) vaccination are integrated in the first-line conventional platinum/pemetrexed-based treatment scheme for epithelioid MPM patients (Immuno-MESODEC, ClinicalTrials.gov identifier NCT05765084). Fifteen treatment-naïve patients with unresectable epithelioid subtype MPM will be treated with four 3-weekly (±3 days) chemo-immunotherapy cycles. Standard-of-care chemotherapy consisting of cisplatinum (75mg/m2) and pemetrexed (500mg/m2) will be supplemented with the anti-PD-L1 antibody atezolizumab (1200 mg) and autologous Wilms' tumor 1 mRNA-electroporated dendritic cell (WT1/DC) vaccination (8-10 x 106 cells/vaccination). Additional atezolizumab (1680 mg) doses and/or WT1/DC vaccinations (8-10 x 106 cells/vaccination) can be administered optionally following completion of the chemo-immunotherapy scheme. Follow-up of patients will last for up to 90 days after final atezolizumab administration and/or WT1/DC vaccination or 24 months after diagnosis, whichever occurs later. The trial's primary endpoints are safety and feasibility, secondary endpoints are clinical efficacy and immunogenicity. This phase I/II trial will evaluate whether addition of atezolizumab and WT1/DC vaccination to frontline standard-of-care chemotherapy for the treatment of epithelioid MPM is feasible and safe. If so, this novel combination strategy should be further investigated as a promising advanced treatment option for this hard-to-treat cancer.

Living with mesothelioma: a systematic review of mental health and well-being impacts and interventions for patients and their informal carers.

OBJECTIVES: Mesothelioma is an aggressive cancer predominantly affecting the lung and abdominal linings. It can have a unique impact on mental health and well-being (MHWB) due to its incurability, poor prognosis and asbestos-exposure causation. This review's aims were to identify/synthesise international evidence on mesothelioma's MHWB impacts; explore MHWB interventions used by patients and carers; and identify evidence of their effectiveness. DESIGN: Systematic review. DATA SOURCES: Databases, searched March 2022 and March 2024, were MEDLINE; CINAHL; PsycINFO; Cochrane Library; ASSIA. ELIGIBILITY CRITERIA: We included study designs focusing on psychological impacts of living with mesothelioma and MHWB interventions used by patients and informal carers, published in English since January 2002. DATA EXTRACTION AND SYNTHESIS: A team of reviewers screened included studies using standardised methods. Quality was assessed using validated tools: Mixed-Methods Appraisal tool for primary research and Joanna Briggs Institute Critical Appraisal Checklist for Systematic Reviews. RESULTS: Forty-eight studies met the inclusion criteria: 20 qualitative, 16 quantitative, nine reviews, two mixed-methods, one combined systematic review/qualitative study. UK studies predominated. Many MHWB impacts were reported, including traumatic stress, depression, anxiety and guilt. These were influenced by mesothelioma's causation, communication issues and carer-patient relational interactions. Participants used wide-ranging MHWB interventions, including religious/spiritual practice; talking to mental-health professionals; meaning-making. Some strategies were presented as unhelpful, for example, denial. Participants reported lack of access to support. CONCLUSIONS: Most qualitative studies were rated high quality. The quality of the quantitative studies and reviews varied. The sparse literature regarding MHWB in mesothelioma means more research is needed into impacts on patients and carers, including trauma. To enable access to evidence-based support, research is recommended concerning MHWB interventions' effectiveness in mesothelioma. PROSPERO REGISTRATION NUMBER: CRD42022302187.

Dendritic cells loaded with allogeneic tumour cell lysate plus best supportive care versus best supportive care alone in patients with pleural mesothelioma as maintenance therapy after chemotherapy (DENIM): a multicentre, open-label, randomised, phase 2/3 study.

BACKGROUND: Dendritic cell immunotherapy has proven to be safe and induces an immune response in humans. We aimed to establish the efficacy of dendritic cells loaded with allogeneic tumour cell lysate (MesoPher, Amphera BV, 's-Hertogenbosch, Netherlands) as maintenance therapy in patients with pleural mesothelioma. METHODS: In this open-label, randomised, phase 2/3 study, patients with histologically confirmed unresectable pleural mesothelioma, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status score of 0-1, and non-progressing disease after four to six cycles of standard chemotherapy (with pemetrexed 500 mg/m2 plus platinum [cisplatin 75 mg/m2 or carboplatin area under the curve of 5]) were recruited from four centres in Belgium, France, and The Netherlands. Participants were randomly assigned (1:1), using block randomisation (block size of 4), stratified by centre and histology (epithelioid vs other), to MesoPher treatment plus best supportive care or best supportive care alone. Patients received up to a maximum of five MesoPher infusions, with treatment administered on days 1, 15, and 29, and weeks 18 and 30. At each timepoint, participants received an injection of 25 × 106 dendritic cells (two-thirds of the dendritic cells were administered intravenously and a third were injected intradermally). Best supportive care was per local institutional standards. The primary endpoint was overall survival, assessed in all participants randomly assigned to treatment (full analysis set) and safety assessed in all randomly assigned participants, and who underwent leukapheresis if they were in the MesoPher group. This study is registered with ClinicalTrials.gov, NCT03610360, and is closed for accrual. FINDINGS: Between June 21, 2018, and June 10, 2021, 176 patients were screened and randomly assigned to the MesoPher group (n=88) or best supportive care alone group (n=88). One participant in the MesoPher group did not undergo leukapheresis. Mean age was 68 years (SD 8), 149 (85%) of 176 were male, 27 (15%) were female, 173 (98%) were White, two were Asian (1%), and one (1%) was other race. As of data cutoff (June 24, 2023), after a median follow up of 15·1 months (IQR 9·5-22·4), median overall survival was 16·8 months (95% CI 12·4-20·3; 61 [69%] of 88 died) in the MesoPher group and 18·3 months (14·3-21·9; 59 [67%] of 88 died) in the best supportive care group (hazard ratio 1·10 [95% CI 0·77-1·57]; log-rank p=0·62). The most common grade 3-4 treatment-emergent adverse events were chest pain (three [3%] of 87 in the MesoPher group vs two [2%] of 88 in the best supportive care group), dyspnoea (none vs two [2%]), anaemia (two [2%] vs none), nausea (none vs two [2%]), and pneumonia (none vs two [2%]). No deaths due to treatment-emergent adverse events were recorded. Treatment-related adverse events consisted of infusion-related reactions (fever, chills, and fatigue), which occurred in 64 (74%) of 87 patients in the MesoPher group, and injection-site reactions (itch, erythema, and induration), which occurred in 73 (84%) patients, and all were grade 1-2 in severity. No deaths were determined to be treatment related. INTERPRETATION: MesoPher did not show improvement in overall survival in patients with pleural mesothelioma. Immune checkpoint therapy is now standard of care in pleural mesothelioma. Further randomised studies are needed of combinations of MesoPher and immune checkpoint therapy, which might increase efficacy without adding major toxicities. FUNDING: Amphera BV and EU HORIZON.

Rethinking continuity in primary care for people with mesothelioma.

BACKGROUND: Mesothelioma is a terminal disease that is linked to asbestos exposure. Continuity is difficult for GPs, and other healthcare professionals (HCPs), to provide within the current NHS primary care system, but is highly valued by people with mesothelioma. AIM: To understand the experiences of continuity in primary care among people with mesothelioma, their close persons, and their HCPs; how they achieve this (or not); and how it affects their healthcare service use. METHOD: Realist case studies of patient journeys through the healthcare system (involving longitudinal interviews with people with mesothelioma, their close persons, and HCPs; and exploration of the organisational context). Data analysis allowed understanding of hidden mechanisms (resources and reasoning), triggered in certain contexts, leading to specific outcomes. RESULTS: Forty-eight interviews (involving 9 patients, 8 close persons, and 12 HCPs) were undertaken (totalling 30.8 hours/1848 minutes). Context-Mechanism-Outcome configurations related to: challenges unique to mesothelioma; capacity of patients/close persons/HCPs to facilitate continuity; multidisciplinary (MDT) approach differs from the family doctor model; and 'the NHS primary care system is broken'. CONCLUSION: Patients perceive their continuity needs to be unmet by the inflexible primary care system, which needs to adapt to a society in which people receive increasingly novel treatments and live longer with complex healthcare needs. A societal perspective shift is required to understand that an MDT now shares responsibility for care, rather than an individual family doctor. Policy documents continue to focus on access, and still do not advocate strongly enough for continuity, despite unequivocal evidence demonstrating its worth.

[Advances in Targeted Therapy for Malignant Pleural Mesothelioma].

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 (ADP-ribose) 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.
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Strategies to address recruitment to a randomised trial of surgical and non-surgical treatment for cancer: results from a complex recruitment intervention within the Mesothelioma and Radical Surgery 2 (MARS 2) study.

OBJECTIVES: Recruiting to randomised trials is often challenging particularly when the intervention arms are markedly different. The Mesothelioma and Radical Surgery 2 randomised controlled trial (RCT) compared standard chemotherapy with or without (extended) pleurectomy decortication surgery for malignant pleural mesothelioma. Anticipating recruitment difficulties, a QuinteT Recruitment Intervention was embedded in the main trial phase to unearth and address barriers. The trial achieved recruitment to target with a 4-month COVID-19 pandemic-related extension. This paper presents the key recruitment challenges, and the strategies delivered to optimise recruitment and informed consent. DESIGN: A multifaceted, flexible, mixed-method approach to investigate recruitment obstacles drawing on data from staff/patient interviews, audio recorded study recruitment consultations and screening logs. Key findings were translated into strategies targeting identified issues. Data collection, analysis, feedback and strategy implementation continued cyclically throughout the recruitment period. SETTING: Secondary thoracic cancer care. RESULTS: Respiratory physicians, oncologists, surgeons and nursing specialists supported the trial, but recruitment challenges were evident. The study had to fit within a framework of a thoracic cancer service considered overstretched where patients encountered multiple healthcare professionals and treatment views, all of which challenged recruitment. Clinician treatment biases, shaped in part by the wider clinical and research context alongside experience, adversely impacted several aspects of the recruitment process by restricting referrals for study consideration, impacting eligibility decisions, affecting the neutrality in which the study and treatment was presented and shaping patient treatment expectations and preferences. Individual and group recruiter feedback and training raised awareness of key equipoise issues, offered support and shared good practice to safeguard informed consent and optimise recruitment. CONCLUSIONS: With bespoke support to overcome identified issues, recruitment to a challenging RCT of surgery versus no surgery in a thoracic cancer setting with a complex recruitment pathway and multiple health professional involvement is possible. TRIAL REGISTRATION NUMBER: ISRCTN ISRCTN44351742, Clinical Trials.gov NCT02040272.

Malignant pleural mesothelioma: Description of pleural decortication and hyperthermic chemotherapy technique in multimodal therapy.

The current treatment for mesothelioma, in selected cases, consists of extended pleurodecortication and intrathoracic hyperthermic chemotherapy. This technique is laborious and detailed and must be followed step by step to achieve good results. We present the case of a patient with epithelioid mesothelioma meeting surgical criteria who underwent the mentioned technique, experiencing an adequate postoperative period and an early discharge. This experience demonstrates that the technique is safe when performed in centres with experience and the means to address this complex pathology.

Leveraging the pleural space for anticancer therapies in pleural mesothelioma.

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.