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In August 2018, Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) became the first in the world to approve immune checkpoint inhibitor (ICI) monotherapy with nivolumab for previously treated, unresectable, advanced, or recurrent pleural mesothelioma (PM), setting a global precedent. Subsequently, in October 2020, the U.S. Food and Drug Administration (FDA) approved the combination of nivolumab and ipilimumab (CheckMate 743 trial) as the first-line treatment for unresectable PM. This marked the first update to standard first-line therapy in approximately 15 years since the approval of cisplatin (CDDP) plus pemetrexed (PEM) based on the EMPHACIS trial in 2004. Most recently, in September 2024, the FDA approved pembrolizumab plus platinum and PEM (KEYNOTE-483 trial) as another first-line option for advanced or metastatic PM. These developments underscore the rapid evolution of systemic therapy for PM. However, several urgent clinical questions have emerged in real-world practice. This article aims to address these issues based on the latest evidence and expert insights.

Introduction Taxane-based cytotoxic anticancer drugs are a cornerstone of advanced lung cancer chemotherapy; however, they often result in chemotherapy-induced peripheral neuropathy (CIPN). Along with prolonged recovery, CIPN may cause irreversible damage. Consequently, dose reduction or discontinuation is justified, potentially impacting therapeutic efficacy. With no established treatment for CIPN, low-dose duloxetine is generally used as a supportive drug. However, studies have shown the potential effect of mirogabalin on CIPN. Therefore, at our hospital, patients with advanced lung cancer experiencing CIPN during taxane-based first-line therapy received low-dose duloxetine, and were subsequently treated with mirogabalin. Methods In this study, we conducted a retrospective observational cohort study of the impact of mirogabalin administration on 14 advanced lung cancer patients when duloxetine alone was deemed insufficient. The median age was 71 years (52-89 years), with 9 male and 5 female patients. The Numerical Rating Scale (NRS) was utilized to evaluate outcomes, and Wilcoxon’s signed rank-sum test was used in statistical analysis. Results The median Numerical Rating Scale (NRS) score decreased from 5.5 (interquartile range [IQR]: 4.5-7.0) before to 4.0 (IQR: 3.0-5.0) after mirogabalin administration (P = 0.041), indicating significant pain reduction. Conclusion The addition of mirogabalin to duloxetine shows promise in alleviating CIPN in advanced lung cancer patients treated with taxane anticancer agents. These findings warrant further investigation and consideration for their integration into clinical practice for managing CIPN.

Pleural mesothelioma (PM) is an inflammatory cancer linked with asbestos exposure and has a poor prognosis. We report results of the phase 1b KEYNOTE‐A17 study (NCT04153565) of first‐line pembrolizumab plus chemotherapy in Japanese participants with advanced PM. Participants aged ≥ 20 years with previously untreated, histologically confirmed advanced or unresectable PM received pembrolizumab 200 mg every 3 weeks (Q3W) for ≤ 35 cycles with cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 Q3W for 4–6 cycles. Primary endpoints were the rate of dose‐limiting toxicities (DLTs), adverse events (AEs), and treatment discontinuations due to AEs. DLTs were assessed during cycle 1 in 18 participants, and having ≤ 8 participants with DLTs was considered tolerable. AEs were graded per NCI CTCAE 5.0. Tumor response was evaluated per modified RECIST for PM by the investigator. Among 19 participants enrolled, the median study follow‐up was 30.8 (range, 27.8–33.3) months (data cutoff September 21, 2022). Of 18 participants evaluated for DLTs, 2 (11%) experienced 4 DLTs (hypoalbuminemia, malaise, pyrexia in 1 participant; uveitis in 1 participant). 18/19 participants (95%) experienced treatment‐related AEs; 14 (74%) had grade 3–4 events (no grade 5). Treatment‐related AEs led to discontinuation of any drug in 5 participants (26%). The objective response rate was 74% (partial response, n = 14), and the median (range) duration of response was 16.8 (3.0–26.3+) months. First‐line pembrolizumab plus chemotherapy was tolerable based on the low incidence of DLTs and showed acceptable safety and preliminary antitumor activity in Japanese participants with advanced PM. Trial Registration: NCT04153565 In the phase 1b KEYNOTE‐A17 study of first‐line pembrolizumab plus chemotherapy in Japanese participants with advanced pleural mesothelioma (PM), 2 of 18 participants (11%) evaluated experienced dose‐limiting toxicities. The objective response rate among all 19 participants in the study was 74%, with 14 participants achieving a partial response and a median (range) duration of response of 16.8 (3.0–26.3+) months. Based on these results, first‐line pembrolizumab plus chemotherapy demonstrated acceptable safety and preliminary antitumor activity in Japanese participants with advanced PM.

Surgical resection is the standard therapy for solitary primary or metastatic liver tumors. However, liver tumors are often unresectable at diagnosis and hepatectomy is invasive. Local therapies, such as radiofrequency ablation, are used instead, which can be challenging. Recent advances in modern radiotherapy, including stereotactic body radiation therapy (SBRT), have increased the use of radiotherapy as a curative modality. SBRT delivers ablative high doses of irradiation in small volumes. SBRT for liver tumors provided local control with potential survival benefits in patients with inoperable status. However, the following issues remain: primary vs. metastatic liver cancers; SBRT-related toxicity and prevention; pathological features of liver cancers; and potential SBRT strategies. We summarized a literature review to summarize the effectiveness of SBRT and patient tolerance and present the current status and future perspective of SBRT for liver tumors. SBRT is a potential game changer for multimodal therapy.

Malignant pleural mesothelioma (MPM) is an asbestos‐related aggressive malignant neoplasm. Due to the difficulty of achieving curative surgical resection in most patients with MPM, a combination chemotherapy of cisplatin and pemetrexed has been the only approved regimen proven to improve the prognosis of MPM. However, the median overall survival time is at most 12 mo even with this regimen. There has been therefore a pressing need to develop a novel chemotherapeutic strategy to bring about a better outcome for MPM. We found that expression of interleukin‐1 receptor (IL‐1R) was upregulated in MPM cells compared with normal mesothelial cells. We also investigated the biological significance of the interaction between pro‐inflammatory cytokine IL‐1β and the IL‐1R in MPM cells. Stimulation by IL‐1β promoted MPM cells to form spheroids along with upregulating a cancer stem cell marker CD26. We also identified tumor‐associated macrophages (TAMs) as the major source of IL‐1β in the MPM microenvironment. Both high mobility group box 1 derived from MPM cells and the asbestos‐activated inflammasome in TAMs induced the production of IL‐1β, which resulted in enhancement of the malignant potential of MPM. We further performed immunohistochemical analysis using clinical MPM samples obtained from patients who were treated with the combination of platinum plus pemetrexed, and found that the overexpression of IL‐1R tended to correlate with poor overall survival. In conclusion, the interaction between MPM cells and TAMs through a IL‐1β/IL‐1R signal could be a promising candidate as the target for novel treatment of MPM (Hyogo College of Medicine clinical trial registration number: 2973). In the present study, we clarified the role of tumor‐associated macrophages (TAMs) in the reinforcement of malignant potential of malignant pleural mesothelioma (MPM) cells. High mobility group box 1 (HMGB1) released from MPM cells (signal 1) induces pro‐interleukin (IL)‐1β production through interactions with Toll‐like receptor 4 (TLR4) in TAMs. In TAMs, phagocytosed asbestos constitutively activates the inflammasome (signal 2), which causes maturation and secretion of IL‐1β. Secreted IL‐1β interacts with the IL‐1 receptor on MPM cells via a paracrine mechanism. Finally, MPM cells acquire a cancer stem cell (CSC)‐like phenotype.

BackgroundA few studies have reported the incidence and clinical implications of complications after pleurectomy/decortication (P/D).ObjectiveThe aim of this study was to assess the details of complications and predictive factors of particularly durable air leak with P/D.MethodsData on 163 consecutive patients who underwent neoadjuvant chemotherapy (NAC) followed by P/D for malignant pleural mesothelioma between September 2012 and May 2020 at our institution were retrospectively analyzed. Postoperative complications and the significance of various preoperative risk factors for air leak > 10 days (AL10) to identify the group having a higher risk for particularly durable air leak were investigated. Risk factors for AL10 were sought using univariate and multivariate analyses.ResultsOf 163 patients, 30- and 90-day mortality was 0.6% and 2.5%, respectively. Eighty-four (51.4%) patients experienced grade III or worse postoperative complications according to the Clavien–Dindo classification. The median duration of air leak was 7 postoperative days. AL10 occurred in 53 (32.5%) patients. Fifty-eight patients (35.6%) underwent pleurodesis and five patients (3.1%) underwent reoperation to control the air leak. On univariate analysis, performance status (PS; p = 0.003), prognostic nutritional index (p = 0.01), and pleural effusion (p = 0.04) were statistically significant risk factors for AL10, while on multivariate analysis, PS (odds ratio 4.0, 95% confidence interval 1.3–12.7; p = 0.02) remained the only variable predicted for AL10.ConclusionsRecent postoperative mortality rates in NAC followed by P/D are quite acceptable. Approximately one in every three patients experienced AL10, and PS may be a risk factor associated with AL10.

ObjectivesTo assess whether fluticasone furoate (FF) use, compared with budesonide (BUD), is associated with fewer clinically detected COVID-19 events among inhaled corticosteroids (ICS) users, and to explore virus-specificity using influenza as a comparator outcome. We hypothesised that FF may provide strong local anti-inflammatory effects with limited systemic immunosuppression.DesignRetrospective cohort with outpatient follow-up over 4 years.SettingSingle Japanese medical centre.Participants334 adults (102 ICS users; 232 non-ICS) followed from July 2020 to July 2024.Main outcome measuresClinically detected COVID-19 (primary) and influenza (secondary). The primary exposure comparison was FF versus BUD among ICS users; ICS versus non-ICS was analysed secondarily (exploratory). Cox proportional hazards and logistic regression are adjusted for demographics, comorbidities, vaccination and systemic corticosteroids.ResultsSeventy-nine COVID-19 and 14 influenza events occurred. Among ICS users, FF was associated with fewer clinically detected COVID-19 events than BUD (adjusted HR 0.12, 95% CI 0.02 to 0.73; crude 6.5% vs 32.3%; Fisher’s exact p=0.0047). Under symptom-based testing, ICS users also had fewer clinically detected COVID-19 events than non-ICS users (adjusted HR 0.46, 95% CI 0.22 to 0.94), although this comparison is limited by baseline imbalance and should be interpreted as exploratory and non-causal.ConclusionsUnder symptom-triggered testing, FF was associated with fewer clinically detected COVID-19 events than BUD in the head-to-head comparison among ICS users. The ICS versus non-ICS comparison is exploratory due to confounding by indication and structural imbalance. These findings are hypothesis-generating and warrant prospective studies with systematic testing and stronger designs.

Background/Aim: To evaluate the incidence and grade of radiation pneumonitis after volumetric modulated arc therapy (VMAT) performed for the treatment of non-small cell cancer (NSCLC). Patients and Methods: Fifty consecutive non-surgical candidates with NSCLC underwent VMAT. Thirty-five patients had stage-III tumors and 15 had recurrent tumors. The prescribed radiation dose for the gross tumor and the elective nodal area was 69 Gy in 30 fractions and 51 Gy in 30 fractions, respectively. Results: Radiation pneumonitis developed in 38 patients (76%, 38/50), and grade ≥2 radiation pneumonitis developed in 11 patients (22%, 11/50). The percentage of lung volume that received a dose in excess of 5 Gy (V5), V10, V20, V30, and the mean lung dose (MLD) in the bilateral and ipsilateral lung were significantly associated with the development of grade ≥2 radiation pneumonitis. Conclusion: The incidence and degree of radiation pneumonitis are acceptable following treatment of NSCLC with VMAT.

BackgroundTreatment of recurrent malignant pleural mesothelioma (MPM) remains challenging. Our study examined the efficacy, tolerability, and safety of nivolumab with ipilimumab treatment for recurrent MPM after primary curative-intent surgery.MethodsTreatment comprised 360 mg nivolumab every 3 weeks and 1 mg/kg of ipilimumab every 6 weeks, both administered intravenously. Both were discontinued for progressive disease or serious adverse events (AEs). Additional post-treatment data were evaluated, including objective response rate (ORR), disease control rate (DCR), post-treatment survival, progression-free survival (PFS), and AEs. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Survival analysis was estimated using a Kaplan–Meier plot. Feasibility analysis was performed using the National Cancer Institute Common Terminology Criteria for AEs version 5.0.ResultsForty-one patients received nivolumab with ipilimumab for recurrent MPM after primary curative-intent surgery (median follow-up, 10.4 months; median treatment, 5.1 months). Overall, 18 patients exhibited partial response, 13 exhibited stable disease, and 10 had documented progressive disease. ORR and DCR were 43.9 and 75.6%, respectively. The 12-month post-treatment survival rate and PFS rate were 74.2 and 40.0%, respectively (median survival, not calculated; median PFS, 7.3 months). Further, 47 AEs were reported in 29 patients (70.7%), including grade 3–4 AEs in 14 patients (34.1%). Grade 4 hepatobiliary disorders were observed in 2 patients and grade 4 neutropenia was observed in 1.ConclusionNivolumab with ipilimumab treatment in patients with recurrent MPM after primary surgical treatment may be clinically efficacious, although serious AEs may be frequently observed.

Background/Objectives: Pleural mesothelioma (PM) frequently recurs despite multimodal therapy. Here, we aimed to retrospectively evaluate the safety and potential clinical benefit of radiofrequency ablation (RFA) for recurrent PM. Methods: Fourteen consecutive patients underwent CT-guided RFA between July 2019 and June 2025. The cohort comprised 13 men and 1 woman, with a median age of 69 (range, 54–77) years. All patients had previously received systemic therapy, and 12 had undergone surgery. Seven patients (50%) presented with multiple lesions, and 25 tumors (median diameter 1.8 cm; range, 0.5–7.0 cm) were treated in 23 sessions. Outcomes assessed were local tumor control, complications, and survival. Local progression and overall survival were estimated using Kaplan–Meier analysis. Adverse events were classified according to the Society of Interventional Radiology guidelines. Results: Technical success was achieved in all sessions. Two tumors showed local recurrence, corresponding to 1- and 2-year local progression rates of 10.6%. Seven patients showed distant metastases, most of whom subsequently received systemic therapy. Three patients died, two from disease progression and one from treatment-related gastrointestinal perforation during therapy for an unrelated cancer. The overall survival rates were 100%, 100%, and 60% at 1, 3, and 5 years, respectively. Major and minor complications occurred in one case each (4.3%): a refractory skin ulcer and retroperitoneal hematoma, respectively. Conclusions: RFA was technically feasible and generally well tolerated and helped achieve encouraging local control and survival in patients with recurrent PM, warranting further evaluation of RFA as a complementary approach in multimodal treatment strategies.