Background
A few studies have reported the incidence and clinical implications of complications after pleurectomy/decortication (P/D).
Objective
The aim of this study was to assess the details of ...complications and predictive factors of particularly durable air leak with P/D.
Methods
Data 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.
Results
Of 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.
Conclusions
Recent 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.
Malignant pleural mesothelioma (MPM) is strongly associated with occupational or environmental asbestos exposure and arises from neoplastic transformation of mesothelial cells in the pleural cavity. ...The only standard initial treatment for unresectable MPM is combination chemotherapy with cisplatin (CDDP) and pemetrexed (PEM). Further, CDDP/PEM is the only approved regimen with evidence of prolonged overall survival (OS), although the median OS for patients treated with this regimen is only 12 months after diagnosis. Thus, the development of new therapeutic strategies has been investigated for approximately 20 years. In contrast to recent advances in personalized lung cancer therapies, diagnostic and prognostic biomarker research has just started in mesothelioma. Epigenetic alterations include DNA methylation, histone modifications, and other chromatin-remodeling events. These processes are involved in numerous cellular processes including differentiation, development, and tumorigenesis. Epigenetic modifications play an important role in gene expression and regulation related to malignant MPM phenotypes and histological subtypes. An immune checkpoint PD-1 inhibitor, nivolumab, was approved as second-line therapy for patients who had failed initial chemotherapy, based on the results of the MERIT study. Various clinical immunotherapy trials are ongoing in patients with advanced MPM. In this review, we describe recent knowledge on epigenetic alterations, which might identify candidate therapeutic targets and immunotherapeutic regimens under development for MPM.
Purpose: To investigate the diagnostic performance of circulating tumor cells (CTC) in discrimination between primary lung cancer
and nonmalignant diseases as well as in prediction of distant ...metastasis.
Patients and Methods: We prospectively evaluated CTCs in 7.5-mL samples of peripheral blood sampled from patients with a suspicion or a diagnosis
of primary lung cancer. A semiautomated system was used to capture CTCs with an antibody against epithelial cell adhesion
molecule.
Results: Of 150 eligible patients, 25 were finally diagnosed as having nonmalignant disease, and 125 were diagnosed as having primary
lung cancer with ( n = 31) or without ( n = 94) distant metastasis. CTCs were detected in 30.6% of lung cancer patients and in 12.0% of nonmalignant patients. CTC
count was significantly higher in lung cancer patients than in nonmalignant patients, but a receiver operating characteristic
(ROC) curve analysis showed an insufficient capability of the CTC test in discrimination between lung cancer and nonmalignant
diseases with an area under ROC curve of 0.598 (95% confidence interval, 0.488-0.708; P = 0.122). Among lung cancer patients, CTC count significantly increased along with tumor progression, especially with development
of distant metastasis. The area under ROC curve for CTC count in prediction of distant metastasis was 0.783 (95% confidence
interval, 0.679-0.886; P < 0.001). When patients with one or more CTCs were judged as having metastatic disease, sensitivity and specificity of the
CTC test were 71.0% and 83.0%, respectively.
Conclusions: CTC is a useful surrogate marker of distant metastasis in primary lung cancer. (Clin Cancer Res 2009;15(22):6980–6)
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.
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.
Limited options exist for treating post-recurrence patients with malignant pleural mesothelioma (MPM). This study aimed to evaluate the efficacy and feasibility of nivolumab in patients with ...post-operative recurrence of MPM in a real-world setting.
This study included 35 patients with post-operative recurrence of MPM. Treatment consisted of 240-mg intravenous nivolumab administration every 2 weeks until progressive disease (PD) or serious adverse events (AEs). Additional post-treatment data were evaluated, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), post-treatment survival and AEs. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors. Survival analysis was performed using the Kaplan-Meier method. The feasibility analysis including AEs was performed with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Of the 35 patients who received nivolumab, median follow-up was 6 months. The median treatment duration was 3 months (range: 1-14 months), and median of 8 cycles (range: 2-32 cycles) was administered. Best overall responses were follows: 1 patient had complete response, 6 had partial response, 18 had stable disease and 8 had PD. The ORR was 20.0%, and the DCR was 77.1%. The median overall survival and PFS were 13.1 and 4.4 months, respectively. There were grade-3 AEs in four patients (11.4%). No grade-4 or -5 AEs were observed.
Nivolumab treatment in patients with post-operative recurrence of MPM seems safe and clinical efficacy.
Small-cell lung cancer (SCLC) is characterized by one of neuroendocrine tumors, and is a clinically aggressive cancer due to its rapid growth, early dissemination, and rapid acquisition of multidrug ...resistance to chemotherapy. Moreover, the standard chemotherapeutic regimen in SCLC has not changed for three decades despite of the dramatic therapeutic improvement in non-SCLC. The development of a novel therapeutic strategy for SCLC has become a pressing issue. We found that expression of Eph receptor A2 (EphA2) is upregulated in three of 13 SCLC cell lines and five of 76 SCLC tumor samples. Genetic inhibition using siRNA of EphA2 significantly suppressed the cellular proliferation via induction of cell cycle arrest in SBC-5 cells. Furthermore, small molecule inhibitors of EphA2 (ALW–II–41-27 and dasatinib) also exclusively inhibited proliferation of EphA2-positive SCLC cells by the same mechanism. Collectively, EphA2 could be a promising candidate as a therapeutic target for SCLC.
•Prognosis of SCLC remains poor over 30 years and targetable oncogenes are yet to be discovered.•EphA2 is a unique RTK which transactivates other growth factor receptors as a ‘hub’ receptor.•EphA2 is overexpressed in a subset of SCLC cell lines and clinical samples.•EphA2 inhibition shows antitumor effects on EphA2-positive SCLC via induction of cell cycle arrest.•EphA2-targeting is promising as a novel molecular targeted therapy in SCLC.
Background
Treatment 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.
Methods
Treatment 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.
Results
Forty-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.
Conclusion
Nivolumab with ipilimumab treatment in patients with recurrent MPM after primary surgical treatment may be clinically efficacious, although serious AEs may be frequently observed.
Background/Aims: Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor and an effective therapy has been little provided as yet. The present study investigated the possibility for the ...adenosine deaminase (ADA) inhibitor EHNA as a target of MPM treatment. Methods: MTT assay, TUNEL staining, monitoring of intracellular adenosine concentrations, and Western blotting were carried out in cultured human MPM cell lines without and with knocking-down ADA. The in vivo effect of EHNA was assessed in mice inoculated with NCI-H2052 MPM cells. Results: EHNA induced apoptosis of human MPM cell lines in a concentration (0.01-1 mM)- and treatment time (24-48 h)-dependent manner, but such effect was not obtained with another ADA inhibitor pentostatin. EHNA increased intracellular adenosine concentrations in a treatment time (3-9 h)-dependent manner. EHNA-induced apoptosis of MPM cells was mimicked by knocking-down ADA, and the effect was neutralized by the adenosine kinase inhibitor ABT-702. EHNA clearly suppressed tumor growth in mice inoculated with NCI-H2052 MPM cells. Conclusion: The results of the present study show that EHNA induces apoptosis of MPM cells by increasing intracellular adenosine concentrations, to convert to AMP, and effectively prevents MPM cell proliferation. This suggests that EHNA may be useful for treatment of the tragic neoplasm MPM.
To compare three FDG-PET criteria (EORTC, PERCIST, imPERCIST) with CT criteria (combined modified RECIST and RECIST 1.1) for response evaluation and prognosis prediction in patients with recurrent ...MPM treated with ICI monotherapy.
Thirty MPM patients underwent FDG-PET/CT and contrast-enhanced CT at the baseline and during nivolumab therapy (median 10 cycles). Therapeutic response was evaluated according to EORTC, PERCIST, imPERCIST, and CT criteria. PFS and OS were examined using log-rank and Cox methods.
CMR/PMR/SMD/PMD numbered 5/3/4/18 for EORTC, 5/1/7/17 for PERCIST, and 5/3/9/13 for imPERCIST. With CT, CR/PR/SD/PD numbered 0/6/10/14. There was high concordance between EORTC and PERCIST (κ = 0.911), and PERCIST and imPERCIST (κ = 0.826), while that between EORTC and imPERCIST (κ = 0.746) was substantial, and between CT and the three PET criteria moderate (κ = 0.516-0.544). After median 14.9 months, 26 patients showed progression and nine died. According to both PET and CT findings, patients with no progression (CMR/PMR/SMD or CR/PR/SD) showed significantly longer PFS and somewhat longer OS than PMD and PD patients (EORTC
= 0.0004 and
= 0.055, respectively; PERCIST
= 0.0003 and
= 0.052; imPERCIST
< 0.0001 and
= 0.089; CT criteria
= 0.0015 and
= 0.056).
Both FDG-PET and CT criteria are accurate for response evaluation of ICI therapy and prediction of MPM prognosis. In comparison with CT, all three FDG-PET/CT criteria judged a greater percentage of patients (16.7%) as CMR, while two (EORTC, PERCIST) judged a greater percentage (10-13.3%) as PMD. For predicting PFS, the three FDG-PET criteria were superior to the CT criteria, and imPERCIST demonstrated the highest rate of accurate prediction.
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