Immunocheckpoint Blockade in Malignant Pleural Mesothelioma

Targeting immunocheckpoint with immunomodulatory monoclonal antibodies has proven to be an effective antitumor strategy across a variety of cancers. The immunosuppressive tumor microenvironment in malignant pleural mesothelioma (MPM) has suggested that MPM might benefit from this kind of immunotherapy. In recent years, immunocheckpoint inhibitors (ICIs) have shown encouraging results for patients with MPM. Antibodies against programmed death 1 (PD-1) and PD-ligand 1 (PD-L1) have demonstrated favorable response, progression-free survival, and overall survival. The toxicity profiles were similar to those observed with ICIs in other malignancies, like melanoma and non-small cell lung cancer, and they appeared to be manageable. Nivolumab, an anti-PD-1 antibody, was approved in Japan for advanced or metastatic MPM patients resistant or intolerant to other chemotherapies. Important future issues include developing a combination therapy, where ICIs are combined with other agents (including other ICIs), and developing biomarkers for determining which patients might respond well and which might experience unacceptable toxicities

Immunotherapy in Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is an extremely aggressive plural malignancy mainly caused by asbestos exposure. Basic research about the immune suppressive tumor microenvironment in MPM has suggested that MPM might be a good candidate for immune therapy. Immunocheckpoint inhibitors have shown some promising results. A phase Ib trial with pembrolizumab, an antibody specific for the programmed cell death 1 protein (anti-PD-1), showed efficacy in patients with programmed death-ligand 1 (PD-L1)-positive MPM. Among 25 patients tested, 5 patients (20%) achieved a partial response. A Japanese group evaluated the efficacy and safety of nivolumab, an anti-PD-L1 antibody, for patients with advanced MPM in a phase II study. Ten (29%) patients showed an objective response. Based on those results, nivolumab was approved in Japan for unresectable recurrent MPM. A phase III randomized study was conducted to compare nivolumab plus ipilimumab to platinum doublet chemotherapy as a first-line therapy in unresectable MPM. The primary endpoint, overall survival (OS), was significantly improved in the nivolumab plus ipilimumab group. Cellular therapies and cancer vaccines are limited by many challenges; therefore, improvements to overcome these difficulties are urgently warranted. Further research is needed, including large-scale clinical trials, to clarify the utility and safety of immunotherapy in MPM

Recent Advances in Systemic Therapy for Malignant Pleural Mesothelioma: Focus on Anti-Angiogenic Inhibitors and Immune Checkpoint Inhibitors

Malignant pleural mesothelioma (MPM) is a neoplasm strongly associated with past exposure to asbestos. In general, the prognosis of patients with MPM is poor; however, in recent years, some encouraging results have been reported for systemic therapies for MPM. In a randomized phase III study, the combination of nivolumab and ipilimumab improved overall survival, compared to the standard platinum-based chemotherapy. An important clinical issue is whether the outcome of patients with MPM might be further improved by combining immunotherapies with cytotoxic chemotherapy and/or angiogenesis inhibitors. This chapter covers recent findings on systemic therapies, including cytotoxic chemotherapy, anti-angiogenic inhibitors, and/or immune checkpoint inhibitors

Triplet Chemotherapy with Cisplatin, Docetaxel, and Irinotecan for Patients with Recurrent or Refractory Non-small Cell Lung Cancer

We examined the feasibility of triplet chemotherapy using cisplatin, docetaxel, and irinotecan for patients with recurrent or refractory non-small cell lung cancer (NSCLC), retrospectively. Twenty-five patients (21 men and 4 women) with NSCLC and good performance status who were &#60;70 years old were analyzed. The median age was 58 years. Most patients had performance status 1 (16/25), stage IV disease (18/25) and adenocarcinoma-histology (16/25). Cisplatin and docetaxel were given on day 1 and irinotecan on day 2;the cycle was repeated every 3 weeks. The objective response rate was 39.1% (95% confidence interval:18.7-59.5%). The median survival time and actual 2-, 3-, and 5-year survival rates were 14.3 months, 32%, 20%, and 8%, respectively. Of note, only 6 patients were treated with gefitinib at the recurrence after triplet chemotherapy;of these, 4 (67%) achieved a partial response, which might result in favorable survival. Grade 3/4 toxicities consisted of neutropenia (100%), neutropenic fever (56%), nausea/vomiting (40%), and diarrhea (16%);no cases of treatment-related death occurred. Triplet chemotherapy showed impressive survival data in our clinical trial, but proved too toxic for use in treating patients with NSCLC in the clinical practice.</p

Pylorus preserving pancreatoduodenectomy in a 6-year-old girl with recurrent pancreatitis due to an annular pancreas

AbstractThe pancreatitis caused by an annular pancreas rarely needs a surgical management in children. Here, we report a case of a 6-year old girl in whom pylorus-preserving pancreatoduodenectomy (PPPD) was performed for the pancreatitis caused by an annular pancreas. As she had previous operations for duodenal atresia and pancreaticobiliary maljunction, PPPD was chosen as a definitive surgical treatment of annular pancreas. She has been free from symptoms for 2 years after the operation

Pilot Analysis of Asbestos-induced Diffuse Pleural Thickening with Respiratory Compromise

We investigated the clinical features of asbestos-induced diffuse pleural thickening (DPT) with severe respiratory compromise. We conducted a retrospective study of consecutive subjects with asbestos-induced DPT. Medical data such as initial symptoms, radiological findings, respiratory function test results, and clinical course were collected and analyzed. There were 24 patients between 2003 and 2012. All were men, and the median age at the development of DPT was 74 years. The top occupational category associated with asbestos exposure was dockyard workers. The median duration of asbestos exposure was 35.0 years, and the median latency from first exposure to the onset of DPT was 49.0 years. There were no significant differences in respiratory function test results between the higher and lower Brinkman index groups or between unilateral and bilateral DPT. Thirteen patients had a history of benign asbestos pleural effusion (BAPE), and the median duration from pleural fluid accumulation to DPT with severe respiratory compromise was 28.4 months. DPT with severe respiratory compromise can develop after a long latency following occupational asbestos exposure and a history of BAPE

Novel prospective umbrella-type lung cancer registry study for clarifying clinical practice patterns: CS-Lung-003 study protocol

Introduction Conventional cancer registries are suitable for simple surveillance of cancer patients, including disease frequency and distribution, demographics, and prognosis; however, the collected data are inadequate to clarify comprehensively diverse clinical questions in daily practice. Methods We constructed an umbrella‐type lung cancer patient registry (CS‐Lung‐003) integrating multiple related prospective observational studies (linked studies) that reflect clinical questions about lung cancer treatment. The primary endpoint of this registry is to clarify daily clinical practice patterns in lung cancer treatment; a key inclusion criterion is pathologically diagnosed lung cancer. Under this registry, indispensable clinical items are detected in advance across all active linked studies and gathered prospectively and systematically to avoid excessive or insufficient data collection. Researchers are to input information mutually, irrespective of the relevance to each researcher's own study. Linked studies under the umbrella of the CS‐Lung‐003 registry will be updated annually with newly raised clinical questions; some linked studies will be newly created, while others will be deleted after the completion of the analysis. Enrollment began in July 2017. Discussion We successfully launched the umbrella‐type CS‐Lung‐003 registry. Under this single registry, researchers collaborate on patient registration and data provision for their own and other studies. Thus, the registry will produce results for multiple domains of study, providing answers to questions about lung cancer treatment raised by other researchers. Through such analysis of each linked study, this registry will contribute to the comprehensive elucidation of actual daily practice patterns in lung cancer treatment. Key points CS‐Lung‐003 registry directly integrates multiple linked studies created under the umbrella of this cancer registry to solve various clinical questions regarding daily practice patterns of lung cancer treatment

Transcriptional Profiling of Non-Small Cell Lung Cancer Cells with Activating EGFR Somatic Mutations

Activating somatic mutations in epidermal growth factor receptor (EGFR) confer unique biologic features to non-small cell lung cancer (NSCLC) cells, but the transcriptional mediators of EGFR in this subgroup of NSCLC have not been fully elucidated.Here we used genetic and pharmacologic approaches to elucidate the transcriptomes of NSCLC cell lines. We transcriptionally profiled a panel of EGFR-mutant and -wild-type NSCLC cell lines cultured in the presence or absence of an EGFR tyrosine kinase inhibitor. Hierarchical analysis revealed that the cell lines segregated on the basis of EGFR mutational status (mutant versus wild-type), and expression signatures were identified by supervised analysis that distinguished the cell lines based on mutational status (wild-type versus mutant) and type of mutation (L858R versus Delta746-750). Using an EGFR mutation-specific expression signature as a probe, we mined the gene expression profiles of two independent cohorts of NSCLC patients and found the signature in a subset. EGFR tyrosine kinase inhibitor treatment regulated the expression of multiple genes, and pharmacologic inhibition of the protein products of two of them (PTGS2 and EphA2) inhibited anchorage-independent growth in EGFR-mutant NSCLC cells.We have elucidated genes not previously associated with EGFR-mutant NSCLC, two of which enhanced the clonogenicity of these cells, distinguishing these mediators from others previously shown to maintain cell survival. These findings have potential clinical relevance given the availability of pharmacologic tools to inhibit the protein products of these genes

Development of split-force-controlled body weight support (SF-BWS) robot for gait rehabilitation

This study introduces a body-weight-support (BWS) robot actuated by two pneumatic artificial muscles (PAMs). Conventional BWS devices typically use springs or a single actuator, whereas our robot has a split force-controlled BWS (SF-BWS), in which two force-controlled actuators independently support the left and right sides of the user’s body. To reduce the experience of weight, vertical unweighting support forces are transferred directly to the user’s left and right hips through a newly designed harness with an open space around the shoulder and upper chest area to allow freedom of movement. A motion capture evaluation with three healthy participants confirmed that the proposed harness does not impede upper-body motion during laterally identical force-controlled partial BWS walking, which is quantitatively similar to natural walking. To evaluate our SF-BWS robot, we performed a force-tracking and split-force control task using different simulated load weight setups (40, 50, and 60 kg masses). The split-force control task, providing independent force references to each PAM and conducted with a 60 kg mass and a test bench, demonstrates that our SF-BWS robot is capable of shifting human body weight in the mediolateral direction. The SF-BWS robot successfully controlled the two PAMs to generate the desired vertical support forces

The degree of microRNA-34b/c methylation in serum-circulating DNA is associated with malignant pleural mesothelioma

Objectives: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis. microRNA-34b/c (miR-34b/c), which plays an important role in the pathogenesis of MPM, is frequently downregulated by DNA methylation in approximately 90% of MPM cases. In this study, we estimated the degree of miR-34b/c methylation in serum-circulating DNA using a digital methylation specific PCR assay (MSP). Materials and methods: A real-time MSP assay was performed using the SYBR Green method. The melting temperature (Tm) of each PCR product was examined using a melting curve analysis. For a digital MSP assay, 40 wells were analyzed per sample. A total of 110 serum samples from 48 MPM cases, 21 benign asbestos pleurisy (BAP) cases, and 41 healthy volunteers (HVs) were examined. Results: Positive range of Tm value for miR-34b/c methylation was defined as 77.71-78.79 degrees C which was the mean 3 standard deviations of 40 wells of a positive control. The number of miR-34b/c methylated wells was counted per sample according to this criterion. The number of miR-34b/c methylated wells in MPM cases was significantly higher than that in BAP cases (P = 0.03) or HVs (P < 0.001). Advanced MPM cases tended to have higher number of miR-34b/c methylated wells than early MPM cases. Receiver-operating characteristic (ROC) curve analysis revealed that three number of miR-34b/c methylated wells per sample was the best cut-off of positivity of MPM with a 67% of sensitivity and a 77% specificity for prediction. The area under the ROC curve was 0.77. Conclusions: Our digital MSP assay can quantify miR-34b/c methylation in serum-circulating DNA. The degree of miR-34b/c methylation in serum-circulating DNA is associated with MPM, suggesting that this approach might be useful for the establishment of a new detection system for MPM