Mesothelioma In Japan Research Articles

True Benefits of Immune Checkpoint Inhibitors in the Treatment of Malignant Pleural Mesothelioma in Japan.

In February 2004, the Food and Drug Administration (FDA) was the first to approve the combination of cisplatin (CDDP) and pemetrexed (PEM) as standard first-line chemotherapy for untreated, unresectable malignant pleural mesothelioma (MPM). However, after that approval, no progress was made in the standard first-line treatment of MPM for almost 15 years. Positive results from a phase 3 study (Mesothelioma Avastin Cisplatin Pemetrexed Study: MAPS) verifying the effect of bevacizumab, an anti-angiogenesis agent added to CDDP/PEM for unresectable MPM, were published in The Lancet in December 2015; however, this did not lead to approval by national drug regulatory agencies. Furthermore, no second-line treatment was established for cases refractory to CDDP/PEM. In August 2018, the Pharmaceuticals and Medical Devices Agency of Japan was the first in the world to approve monotherapy with nivolumab, an immune checkpoint inhibitor (ICI), for previously unresectable, advanced, or recurrent MPM. Following Japan, in October 2020, the FDA approved the combination of nivolumab and ipilimumab for the treatment of previously untreated, unresectable MPM. In this article, we review the transition of drug treatment for MPM, in light of the historical background, focusing on the benefits of ICIs.

Real-world safety of nivolumab in patients with malignant pleural mesothelioma in Japan: post-marketing surveillance study.

This post-marketing surveillance (PMS) was conducted to evaluate the incidence of adverse events with nivolumab in patients with unresectable, advanced or recurrent malignant pleural mesothelioma (MPM) that had progressed after first-line chemotherapy and to identify factors that potentially affected its safety in real-world clinical practice. Patients who had not received nivolumab previously were registered between November 2018 and February 2021. Nivolumab was given intravenously 240mg every 2weeks or 480mg every 4weeks. Patients were followed up for 6months after treatment initiation. Information on patient characteristics, treatment status, and adverse events was collected. This PMS enrolled 124 patients, involving 48 sites across Japan. At 6months, nivolumab therapy was ongoing in 35.5% of patients (44/124) and had been discontinued in 64.5% (80/124). The overall incidence of treatment-related adverse events (TRAEs) was 40.3%; the incidence of Grade 3 or higher TRAEs was 12.9%. The pattern of TRAEs based on System Organ Class categories was generally consistent with those seen in the Japanese phase II MERIT study. The most common Grade 3 or higher TRAEs were interstitial lung disease (2.4%), lung disorder, and diarrhea (each 1.6%). The incidence of TRAEs was significantly higher in inpatients or patients who had good PS, high bodyweight, high body mass index, or autoimmune diseases than in those without these characteristics. The post-marketing incidence of TRAEs with nivolumab in patients with MPM has been evaluated, and no new safety signals were identified compared to the phase II clinical trial in Japan.

Nationwide prospective registry database of patients with newly diagnosed untreated pleural mesothelioma in Japan.

Due to the scarcity of large-sized prospective databases, the Japanese Joint Committee for Lung Cancer Registry conducted a nationwide prospective registry for newly diagnosed and untreated pleural mesothelioma. All new cases diagnosed pathologically as any subtype of pleural mesothelioma in Japan during the period between April 1, 2017, to March 31, 2019, were included before treatment. Data on survival were collected in April 2021. The eligible 346 patients (285 men [82.3%]; 61 women [17.7%]; median age, 71.0 years [range, 44-88]) were included for analysis. Among these patients, 138 (39.9%) underwent surgery, 164 (47.4%) underwent non-surgical therapy, and the remaining 44 (12.7%) underwent best supportive care. The median overall survival for all 346 patients was 19.0 months. Survival rates at 1, 2, and 3 years for all patients were, 62.8%, 42.3%, and 26.5%, respectively. Median overall survival was significantly different among patients undergoing surgery, non-surgical treatment, and best supportive care (32.2 months vs. 14.0 months vs. 3.8 months, p < 0.001). The median overall survival of patients undergoing pleurectomy/decortication and extrapleural pneumonectomy was 41.8 months and 25.0 months, respectively. Macroscopic complete resection resulted in longer overall survival than R2 resection and partial pleurectomy/exploratory thoracotomy (41.8 months vs. 32.2 months vs. 16.8 months, p < 0.001). Tumor shape, maximum tumor thickness, and sum of three level thickness were significant prognostic factors. The data in the prospective database would serve as a valuable reference for clinical practice and further studies for pleural mesothelioma.

Depression and Complicated Grief, and Associated Factors, of Bereaved Family Members of Patients Who Died of Malignant Pleural Mesothelioma in Japan.

Objectives: we investigated the prevalence and associated factors of depression and complicated grief (CG) among bereaved family members of malignant pleural mesothelioma (MPM) patients in Japan. Methods: Bereaved family members of MPM patients (n = 72) were surveyed. The Japanese version of the Patient Health Questionnaire-9 (PHQ-9) and the Japanese version of the Brief Grief Questionnaire (BGQ) were used to assess depression and complicated grief (CG), respectively. Socio-economic factors, anger toward asbestos, care satisfaction, achievement of good death, and quality of end-of-life care were assessed in relation to depression and CG. Results: In the family members of MPM patients, the frequencies of depression and CG were 19.4% and 15.3%, respectively. The bereaved family members who were not compensated by the asbestos-related health-damage relief system (p = 0.018) and who felt the financial impacts of the patient’s MPM on the family (p = 0.006) had a higher likelihood of depression. The bereaved family members who were not satisfied with the care given when the patient became critical (p = 0.034), who were not compensated by the asbestos-related health-damage relief system (p = 0.020), who felt the financial impact of the patient’s MPM on the family (p = 0.016), and whose deceased relative underwent surgery (p = 0.030) had a higher likelihood of CG. Conclusions: For bereaved family members of MPM patients, routine screening for depression and CG and the provision of grief care are suggested. In addition, for family members of MPM patients, financial support, including the promotion of the asbestos-related health-damage relief system, and improved care for patients who undergo surgery and when patients become critical, are recommended.

Nivo-lution in Mesothelioma.

The MERIT study was a single-arm, phase II clinical trial of nivolumab for the second- or third-line treatment of patients with malignant pleural mesothelioma in Japan. MERIT confirmed that PD-1 inhibition has activity in mesothelioma and led to the regulatory approval of nivolumab for the treatment of mesothelioma in Japan.See related article by Okada et al., p. 5485.

Physician requests by patients with malignant pleural mesothelioma in Japan

BackgroundMalignant pleural mesothelioma (MPM) is a fatal and rare disease that is caused by the inhalation of asbestos. Treatment and care requests made by MPM patients to their physicians were collected and analyzed.MethodsThis cross-sectional survey was part of a larger study (N = 133) regarding the quality of life of MPM patients. Specific responses to two open-ended questions related to patients’ requests regarding treatment and care were quantified, analyzed and divided into categories based on content.ResultsResponses (N = 217) from MPM patients (N = 73) were categorized into 24 subcategories and then abstracted into 6 categories. The majority of requests were related to patient-physician communication. Patients wanted clear and understandable explanations about MPM and wanted their physician to deliver treatment based on the patient’s perspective by accepting and empathizing with their anxiety and pain. Patients expected physicians to be dedicated to their care and establish an improved medical support system for MPM patients.ConclusionPatients with MPM had a variety of unmet needs from their physicians. Physicians who provide care to MPM patients should receive training in both communication skills and stress management. A multidisciplinary care system that includes respiratory and palliative care for MPM patients should be established.

Quality of life of survivors of malignant pleural mesothelioma in Japan: a cross sectional study

BackgroundPrevious studies have indicated that people with malignant pleural mesothelioma (MPM) have a poor quality of life (QOL); however, information about the QOL of people with MPM in Japan is anecdotal. The aims of this study were to investigate the QOL of survivors of MPM in Japan and to determine the factors that correlate with their QOL.MethodsThis was a cross sectional study. The included patients were those diagnosed with MPM in Japan. We created a self-administered questionnaire consisting of 64 questions. The questionnaires were sent to hospitals and patient advocacy groups, distributed to the patients, completed, and sent back to the researchers by postal mail. QOL was assessed with the European Organization for Research and Treatment of Cancer 16 questionnaire (QLQ) and the short version of the core domains of the Comprehensive Quality of Life Outcome questionnaire (CoQoLo).ResultsIn total, 133 questionnaires were collected. The QLQ assessments demonstrated that the survivors of MPM most frequently complained of fatigue, pain, sleep disturbances, and dyspnea. The symptom scales were acceptable, but the functional scales were significantly poorer for the patients with poor performance statuses (PSs). The short CoQoLo assessment was very unfavorable for ‘Being free from physical pain.’ Being a long-term survivor and a survivor with a poor PS were significantly correlated with poor global health status.ConclusionsSurvivors of MPM have impaired function, a variety of symptoms, and lower QOL. Survivors of MPM, even those in good physical condition, need broad support.

1622P - Evaluation of quality of life in survivors with malignant pleural mesothelioma in Japan

1622P - Evaluation of quality of life in survivors with malignant pleural mesothelioma in Japan

Erratum to: Fatal pleural mesothelioma in Japan (2003–2008): evaluation of computed tomography findings

Japanese Ministry of Health, Labor and Welfare. This study was approved by the Japan Health, Labor, and Welfare Organization and the ethical review boards of the principal investigator’s institution (Okayama Rosai Hospital). Patient confidentiality was strictly maintained. Informed consent was obtained from the closest living relatives of each patient. Erratum to: Jpn J Radiol DOI 10.1007/s11604‐016‐0539‐1

Fatal pleural mesothelioma in Japan (2003-2008): evaluation of computed tomography findings.

The purpose of this study was to clarify the characteristic findings of mesothelioma at the time of diagnosis, and determine precautions and guidelines for diagnosing mesothelioma early in imaging studies. Overall, 327 patients with pleural mesothelioma were selected from 6030 patients who died of mesothelioma between 2003 and 2008 in Japan. Their imaging findings were examined retrospectively. Plaques were found in 35% of computed tomography (CT) scans. Asbestosis, diffuse pleural thickening, and rounded atelectasis were found in only seven (2%), five (2%), and two cases (1%), respectively. Pleural thickening findings on CT scans were classified into four stages: no irregularity, mild irregularity, high irregularity, and mass formation. Overall, 18% of cases did not show a clear irregularity. Localized thickening was observed in the mediastinal (77%) and basal (76%) pleura and in the interlobar fissure (49%). Eight percent of cases did not have any thickening in these three areas. Upon examination of the CT scans at diagnosis, 18% of mesothelioma cases did not show a clear irregularity. When diagnosing pleural effusion of unknown etiology, it is necessary to consider the possibility of mesothelioma even when no plaque and pleural irregularity are observed.

Caring for patients with malignant pleural mesothelioma in Japan: evaluation of a Palliative Care Educational Program.

This study evaluated the effect of an Educational PROGRAM on Palliative Care for MPM for Nurses in Japan. The 5-h program consisted of lectures and care planning group work. This study used a pretest-posttest design with a single cohort of nurses and included a Difficulties in Palliative Care for Patients with MPM (DPCMPM) Scale with 15 items. The pre- and posttest scores were compared using a t-test. We included 27 female nurses with a mean of 14.4 years of nursing experience. In 12 of 15 DPCMPM items, the posttest difficulty scores were lower than the pretest scores. Participants highly evaluated the program for validity, clarity, clinical usefulness, and the facilitators. The Palliative Care for MPM Handbook for Nurses was developed as an educational tool for clinical settings. The Educational PROGRAM on Palliative Care for MPM for Nurses was effective in reducing nursing difficulties.

Impact of a nursing education program about caring for patients in Japan with malignant pleural mesothelioma on nurses' knowledge, difficulties and attitude: A randomized control trial

In Japan nursing care lags behind the growing population of patients with malignant pleural mesothelioma. This study evaluated an educational program for nurses about caring for patients with malignant pleural mesothelioma in Japan. In this randomized controlled study relative to care for malignant pleural mesothelioma, Knowledge, Difficulties and Attitude were measured at baseline, at post-test and at follow-up one month later. The two-day program with a half-day follow-up program included lectures, group work, role-playing and group discussion. 188 participants were randomly assigned to the intervention group (program, n=96) and control group (n=92; self-study by a similar content handbook). At baseline the groups showed no statistical differences in Knowledge (p=0.921), Difficulty (p=0.458) and Attitude (p=0.922). Completing the study were 177 participants yielding 88 in the intervention group and 89 in the control group. Human rights and privacy of participants were protected. The Knowledge score was significantly higher in the intervention post-test (t=14.03, p=0.000) and follow-up test (t=8.98, p=0.000). Difficulty score was significantly lower in the intervention at post-test (t=-3.41, p=0.001) and follow-up test (t=-3.70, p=0.000). The Attitude score was significantly higher in the intervention post-test (t=7.11, p=0.000) and follow-up test (t=4.54, p=0.000). The two-way analysis of variance with repeated measures on time showed an interaction between time and group; the subsequent simple main effect test found significant differences (p=0.000-0.001) between groups for after-program and at follow-up and a significant difference (p=0.000) in time only within the intervention group. The educational program was effective in improving the nurses' knowledge and attitude toward malignant pleural mesothelioma care and decreasing the difficulty in MPM care, therefore this program has potential for nurses' in-service education throughout Japan.

Treatment and survival analyses of malignant mesothelioma in Japan

Background. There are few reports concerning treatment strategies and their contributions to survival of patients with malignant mesothelioma (MM) in Japan. Material and methods. We extracted all death cases due to MM between 2003 and 2008. The diagnosis of MM was confirmed in 929 cases. Histological subtypes was determined in 709 cases, including 396 (55.9%) epithelioid, 154 (21.7%) sarcomatoid, 126 (17.8%) biphasic, and 33 (4.7%) other types. Results and conclusion. Median overall survival (OS) of all MM cases was 7.7 months (95% confidence interval, 7.1–8.3). Median OS of patients with epithelioid MM was significantly longer than that of patients with biphasic (p = 0.030) or sarcomatoid (p < 0.001) MM. Surgical resection was performed in 172 patients (18.5%) and 449 (48.3%) received systemic chemotherapy. Survival of patients treated with both surgery and systemic chemotherapy was favorable. Median OS of patients in the late phase of the study period (2006–2008) was significantly longer than that in the early phase (2003–2005) (8.1 vs. 7.5 months, p = 0.008). Independent favorable prognostic factors included age younger than 70 years, female gender, epithelioid subtype, and clinical stage I–III. Multivariate analysis demonstrated that patients who had radical surgery and systemic chemotherapy showed a longer survival, though this could be due to selection bias of patients.

BioKnife, a uPA Activity-dependent Oncolytic Sendai Virus, Eliminates Pleural Spread of Malignant Mesothelioma via Simultaneous Stimulation of uPA Expression

Malignant pleural mesothelioma (MPM) is highly intractable and readily spreads throughout the surface of the pleural cavity, and these cells have been shown to express urokinase-type plasminogen activator receptor (uPAR). We here examined the potential of our new and powerful recombinant Sendai virus (rSeV), which shows uPAR-specific cell-to-cell fusion activity (rSeV/dMFct14 (uPA2), named "BioKnife"), for tumor cell killing in two independent orthotopic xenograft models of human. Multicycle treatment using BioKnife resulted in the efficient rescue of these models, in association with tumor-specific fusion and apoptosis. Such an effect was also seen on both MSTO-211H and H226 cells in vitro; however, we confirmed that the latter expressed uPAR but not uPA. Of interest, infection with BioKnife strongly facilitated the uPA release from H226 cells, and this effect was completely abolished by use of either pyrrolidine dithiocarbamate (PDTC) or BioKnife expressing the C-terminus-deleted dominant negative inhibitor for retinoic acid-inducible gene-I (RIG-IC), indicating that BioKnife-dependent expression of uPA was mediated by the RIG-I/nuclear factor-κB (NF-κB) axis, detecting RNA viral genome replication. Therefore, these results suggest a proof of concept that the tumor cell-killing mechanism via BioKnife may have significant potential to treat patients with MPM that is characterized by frequent uPAR expression in a clinical setting.

Is adenosine deaminase in pleural fluid a useful marker for differentiating tuberculosis from lung cancer or mesothelioma in Japan, a country with intermediate incidence of tuberculosis?

The objective of this study was to evaluate the utility of the determination of adenosine deaminase (ADA) level in pleural fluid for the differential diagnosis between tuberculous pleural effusion (TPE) and malignant pleural effusion (MPE) in Japan, a country with intermediate incidence of tuberculosis (TB). We retrospectively reviewed the clinical records of 435 patients with pleural effusion and investigated their pleural ADA levels as determined by an auto analyzer. ROC analysis was also performed. The study included patients with MPE (n＝188), TPE (n＝124), benign nontuberculous pleural effusion (n＝94), and pleural effusion of unknown etiology (n＝29). The median ADA level in the TPE group was 70.8U/L, which was significantly higher than that in any other groups (p＜0.05). The area under the curve (AUC) in ROC analysis was 0.895. With a cut-off level for ADA of 36U/L, the sensitivity, specificity, positive predictive value, and negative predictive value were 85.5%, 86.5%, 69.7%, and 93.6%, respectively. As many as 9% of patients with lung cancer and 15% of those with mesothelioma were false-positive with this ADA cutoff setting. Although the ADA activity in pleural fluid can help in the diagnosis of TPE, it should be noted that some cases of lung cancer or mesothelioma show high ADA activity in geographical regions with intermediate incidence of TB, in contrast to high prevalence areas.

Clinical study on mesothelioma in Japan: Relevance to occupational asbestos exposure

In 2003, the number of deaths due to malignant mesothelioma in Japan was 878; however, only 85 cases of mesothelioma due to asbestos exposure were authorized for compensation. The reasons for this discrepancy require evaluation. We examined medical records, X-rays, and pathology results to evaluate mesothelioma cases in Japan between 2003 and 2005; used a questionnaire to identify occupational and environmental histories, and determined the concentration of asbestos fibers in pathology specimens. We identified 442 definite cases of malignant mesothelioma with a median age of 68 years. There were 316 malignant mesothelioma cases with occupational asbestos exposure, 12 cases with neighborhood exposure and 5 cases with likely domestic exposure. Most (78%) of the 87 cases exceeded 1,000 asbestos particles per gram of dry lung tissue. We conclude that 79.2% of cases of mesothelioma in Japan in recent years were caused by asbestos exposure.

Clinical investigation of malignant mesothelioma in Japan

The asbestos-related problems caused much social concern; however, no large-scale study was conducted about clinical features of MM in Japan. Patients with MM who have a history of occupational asbestos exposure (AE) are provided worker's compensation in Japan. However, only about 10% of MM cases were actually claimed and compensated. So there is still controversy over the association between MM and AE. The aim of this study is to investigate the clinical features of MM. We also aimed to clarify the association between MM and occupational AE in Japan. We examined the clinical features of MM cases. Clinical information was obtained including gender, age, site of origin, pathological subtype, radiological findings, and treatment outcome. To investigate the association between MM and AE, investigators interviewed all patients regarding work and residential history. Between January 2005 and December 2007, 105 cases (median age: 63years, range 35-80, male/female: 88/17) were diagnosed with MM in the Rosai Hospital group and related facilities. Among them, 94(89.5%) cases originated in the pleura, 7(6.7%) in the peritoneum, 2(1.9%) in the pericardium, and 1(0.9%) in the tunica vaginalis testis. There were 69(65.7%) epithelioid, 19(18.1%) biphasic, 16(15.2%) sarcomatoid, and 1 unclassified pathological subtypes of MM. A favorable survival rate was indicated in the patient group of MPM that underwent surgery compared to others, though it was not statistically significant (P=0.1743). The occupational AE was indicated in 89 cases (84.8%). Three patients had no history of occupational AE, but lived with someone who was in an occupation that handled asbestos. There were two patients in which AE was indicated in their life environment. Altogether, AE was indicated in 93(88.6%) patients. This study stresses the urgent need for physicians to acknowledge the association between MM and AE, and to inquire thoroughly regarding AE to the patients with MM.

Accuracy of pathological diagnosis of mesothelioma cases in Japan: Clinicopathological analysis of 382 cases

Incidences of mesothelioma are on the rise in Japan. However, the accurate frequency of mesothelioma occurrence is still unknown. The aim of this study is to clarify the accuracy of pathological diagnosis of mesothelioma. Among the 2742 mesothelioma death cases extracted from the document “Vital Statistics of Japan” for 2003–2005, pathological materials were obtained for 382 cases. After these materials were reviewed and immunohistochemical analyses were conducted, mesothelioma was diagnosed by discussions based on clinical and radiological information. Sixty-five cases (17.0%) were categorized as “definitely not/unlikely” mesotheliomas, and 273 cases (71.5%) were categorized as “probable/definite” mesotheliomas. The percentage of “probable/definite” pleural and peritoneal mesothelioma cases in males was 74.3% and 87.5%, respectively, and that of pleural cases in females was 59.2%; however, the percentage of “probable/definite” peritoneal cases in females was only 22.2%. These results suggest that the diagnostic accuracy of mesothelioma is relatively low in females and in cases of peritoneal and sarcomatoid subtype mesotheliomas; furthermore, approximately 15% of cases of deaths due to mesothelioma in Japan are diagnostically suspicious.

Malignant mesothelioma of the tunica vaginalis testis related to recent asbestos

We report an extremely rare case of malignant mesothelioma in the tunica vaginalis testis. A 67-year-old man was referred to our hospital complaining of painless swelling in the right scrotum. Ultrasonography and computed tomography demonstrated a mass of approximately 6 cm in the right scrotum. He underwent tumor resection under a diagnosis of right intrascrotal tumor. The histopathological diagnosis was malignant mesothelioma, and he died 26 months later from multiple metastases. Asbestos may be a significant contributor to malignant mesothelioma in Japan. There have been 46 cases reported in urology departments in this country of the related symptoms, but only two of these have been clearly attributable to asbestos, which may be due to the investigations being insufficient to obtain a definitive diagnosis. In addition, this symptom is often diagnosed preoperatively as hydrocele testis; it is therefore important to carry out ultrasonography when a hydrocele testis has been diagnosed.

Asbestos-related malignant mesothelioma in Japan

18182 Large amounts of asbestos use from 1960’s induced the increase of death caused by malignant mesothelioma in Japan. However, a national survey of the relationship between malignant mesothelioma and asbestos exposure, as well as diagnosis and treatment of malignant mesothelioma has not done up to today. One hundred and fifty-three cases of malignant mesothelioma diagnosed and treated in the Rosai Hospitals located all over Japan were studied, and 132 cases (80.4%) proved to be the definite diagnosis of malignant mesothelioma; another 21 cases were diagnosed as lung cancer, etc. As for definite 132 cases, 105 cases are male and other 27 cases are female with the ratio of 3.9:1. Ages ranges from 28 to 92 years old with the mean of 66.2 years old. One hundred and twelve cases originated from pleura, 18 cases from peritoneum, and each one case originated from pericardium and testicular tunica vaginalis. Final diagnosis of 104 cases (78.8%) was done by the tumor tissues. According to IMIG classification, stage I was 29 cases, stage II 6 cases, stage III 28 cases and stage IV was 44 cases. For the treatment, 29 cases were done extrapleurectomy, 58 cases were chemotherapy and other 39 cases were best supportive care. Median survival term of 132 cases were 9.5 months with 9.8 months of pleural origin and 5.6 months of peritoneal origin. By the clinical staging, stage I and II were 17.2 months, stage III 10.4 months and stage IV 5.4 months. By the treatment, extrapleurectomy was 18.1 months, chemotherapy 8.0 months and palliative care was 5.7 months. Seventy six percent cases were induced by occupational asbestos exposure and the mean exposuring time was 27.6 years and the mean latency was 43 years. Occupational histories were mainly shipbuilders, carpenters, electricians and piping workers. Summary: Seventy-six percent of Japanese malignant mesothelioma appeared by the occupational exposure to asbestos. Seventy-eight percent of final diagnosis were done by histological examination of tumor tissue. Extrapleurectomy was effective for the prognosis. [Table: see text] No significant financial relationships to disclose.