A 73-year-old man was admitted to another hospital with left irregular pleural thickening (PT) and pleural effusion (PE). A surgical pleural biopsy was performed in that hospital. Histopathological findings showed atypical spindle cells distributed with inflammatory cells in a fibrous organization that was rich in collagen fibers, which invaded the striated muscle and adipose tissue (Fig. 1A). The patient was diagnosed with desmoplastic MPM. The patient was referred to Kyoto University Hospital for consideration of the multidisciplinary treatment since surgical treatment could not be performed at the referring hospital. However, the referring hospital is undisclosed in this report because this hospital is not affiliated with any of this study authors. After reviewing the case, we decided to treat the patient with systemic drug therapy. One cycle of systemic chemotherapy with carboplatin [area under the concentration-time curve (AUC)=5] and pemetrexed (400 mg/m²) (Carbo/Pem) was administered; however, the PT did not improve, and liver metastasis was confirmed. We deemed the Carbo/Pem treatment ineffective and initiated nivolumab as a second-line treatment. After five cycles of nivolumab, positron emission tomography (PET)/computed tomography (CT) using ¹⁸F-fluorodeoxyglucose (FDG) showed a reduction in liver metastases and a decrease in FDG uptake in the same area (Fig. 1B and C). Nivolumab treatment was judged to have achieved a partial response (PR) and was continued; however, new bone metastases appeared, and liver metastases reappeared after 12 cycles (Fig. 1D). Consequently, nivolumab treatment was judged to have resulted in progressive disease (PD) and discontinued. The patient was then treated with chemotherapy, but the disease worsened, and he died 4 months after completing nivolumab treatment. During the course of treatment, there were no side effects that could be attributed to nivolumab.

A 66-year-old man was referred to our hospital with a large left-sided PE. PET/CT showed an irregular mass extending to the left pleura with increased FDG uptake. The patient was diagnosed with sarcomatoid or desmoplastic MPM by ultrasound-guided pleural biopsy. As the first-line treatment, Carbo (AUC=5)/Pem (400 mg/m²) was administered; however, after one cycle, the left PT worsened. Carbo/Pem was determined to be ineffective, and nivolumab was administered as the second-line treatment. After three cycles of nivolumab, PET-CT revealed a decrease in the left PT and PE, with a decrease in FDG uptake (Fig. 2A). In this case, the patient developed complicated eosinophilia and eosinophilic PE, which improved over time after nivolumab treatment. Further details on the progress of this case were previously reported (5). Then, we determined that nivolumab produced a good PR and continued the treatment; however, after nine cycles, the left pleural lesion thickening re-occurred with increased FDG uptake (Fig. 2B). We considered that the nivolumab treatment had resulted in PD and therefore discontinued it. Two months after treatment completion, the patient developed acute kidney injury and nephrotic syndrome due to immune-related adverse events (Fig. 3, baseline data as Table SI). Steroid therapy was started with dialysis, and although the patient showed signs of recovery, he later developed gastrointestinal bleeding and died. The autopsy revealed that the bleeding was due to metastasis to the small intestine. Here, we have reported Case 2 again to additionally describe the occurrence of side effects after the previous publication (5) and to make conclusions on the treatment choice as part of a case series that included the other two cases.

An 82-year-old man was admitted to our hospital with right PT and PE. Surgical pleural biopsy was performed. Histopathological findings showed atypical cells with large oval or spindle nuclei multiplying into a seat form with necrosis. These tumor cells were immunoreactive to calretinin but not to TTF-1 or p40 (Fig. 4). Based on these findings, the patient was diagnosed with sMPM. He was also diagnosed with neoplastic fever before biopsy. The patient was started on Carbo (AUC=4.5)/Pem (375 mg/m²), but the fever persisted along with high levels of C-reactive protein, and his performance status declined. After one cycle, no improvement was observed on the chest radiograph. Carbo/Pem was determined to be ineffective, and nivolumab was administered as the second-line treatment. After two cycles of nivolumab, the fever resolved and PET/CT showed a decrease in the right PT and PE, as well as a decrease in FDG uptake (Fig. 5A and B). However, before the start of the third cycle, the patient developed liver dysfunction due to immune-related adverse events (Fig. 6, baseline data as Table SII). Although the liver damage improved with steroid treatment, nivolumab treatment was discontinued because of the adverse event. Thereafter, the patient was placed on a treatment-free follow-up, and the tumor remained stable for 6 months. The patient died of aspiration pneumonia 1 month after the tumor began to re-grow (Fig. 5C).

The clinical characteristics of the three patients are summarized in Table I. Fig. 7 shows the progress of the patients after starting nivolumab therapy. The three patients had varied histories of smoking, and two of them had a history of known asbestos exposure. Notably, the time to disease progression for the three cases following nivolumab treatment was 223, 211, and 202 days, respectively, which is similar to the median progression-free survival reported in the two previous trials (3,4), despite the difference in the number of cycles of nivolumab administration among the three patients, with 12, 9, and 2 cycles, respectively. We tested the expression of programmed death ligand 1 (PD-L1) in tumor cells, using DAKO 22C3 tumor proportion scoring method (Fig. 8). The results were positive in all the three cases, with Case 3 having more than 50% PD-L1 positivity (Cases 1 and 2 were 1–24% positive).