Irinotecan and Gemcitabine as Second-Line Treatment in Patients with Malignant Pleural Mesothelioma following Platinum plus Pemetrexed Chemotherapy: A Retrospective Study.

BACKGROUND: Cisplatin-pemetrexed combination chemotherapy is the current standard primary treatment for malignant pleural mesothelioma (MPM). It was first approved for untreated and unresectable MPM in the 2003 National Comprehensive Cancer Network (NCCN) guidelines. However, to date, standard treatments for patients with MPM who previously underwent chemotherapy, as recommended by the NCCN Malignant Pleural Mesothelioma guidelines, have been inadequate. To explore treatment options for such patients, we performed this retrospective study of patients who received irinotecan plus gemcitabine as second-line therapy for MPM. METHODS: We investigated 62 patients diagnosed with unresectable MPM between January 2008 and October 2017 who experienced recurrence following cisplatin treatment (or carboplatin) plus pemetrexed or pemetrexed monotherapy as first-line treatment, and who underwent irinotecan plus gemcitabine combination therapy as second-line treatment. Irinotecan (60 mg/m2) and gemcitabine (800 mg/m2) were administered on days 1 and 8 every 3 weeks, including a 1-week washout period. Our endpoints were efficacy, survival period, and toxicity. RESULTS: patients' median age was 65 years (range 50-79), and the histological MPM types were epithelioid (n = 48), sarcomatoid (n = 6), biphasic (n = 6), and desmoplastic (n = 2). One patient experienced a partial response, 40 had stable disease, and 21 had progressive disease. The disease control rate was 66.1% and the response rate 2.1%. Additionally, the median progression-free and overall survival time were 5.7 and 11.3 months, respectively. The most common adverse events were neutropenia (32.2%), loss of appetite (16.1%), nausea/diarrhea (11.3%), and thrombocytopenia/phlebitis (9.7%). Grade 3 adverse events included neutropenia (12.9%) and thrombocytopenia/phlebitis (2.1%); however, all adverse events were managed with symptomatic therapy. CONCLUSIONS: Despite the fact that second-line irinotecan plus gemcitabine combination therapy did not produce marked tumor shrinkage, it achieved a relatively high disease control rate of >65% with an acceptable toxicity profile. Hence, the combination of irinotecan plus gemcitabine may be considered for MPM treatment, with consideration of combination with immune checkpoint inhibitors as a potential next step.

Tumor-associated macrophage-derived inflammatory cytokine enhances malignant potential of malignant pleural mesothelioma.

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-1ß and the IL-1R in MPM cells. Stimulation by IL-1ß 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-1ß 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-1ß, 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-1ß/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).

Adenosine Deaminase in Pleural Effusion and Its Relationship with Clinical Parameters in Patients with Malignant Pleural Mesothelioma.

Pleural effusion adenosine deaminase (ADA) levels are elevated in various diseases. We investigated whether pleural effusion ADA levels differ among patients with malignant pleural mesothelioma (MPM), lung cancer (LC), and benign diseases, including tuberculous pleurisy. We examined 329 patients from February 2002 to July 2013. There were 131 MPM cases with ADA levels of 32.29 IU/L; 117 LC cases with ADA levels of 21.12 IU/L; 54 benign disease cases with ADA levels of 20.98 IU/L. A significant difference existed in pleural effusion ADA levels between MPM and benign disease patients. Pleural effusion ADA levels were significantly higher in MPM patients.

EphA2 inhibition suppresses proliferation of small-cell lung cancer cells through inducing cell cycle arrest.

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.

Primary Squamous Cell Lung Cancer With Frequent Episodes of Sustained Ventricular Tachycardia due to Myocardial Metastasis.

Myocardial metastasis from lung cancer rarely occurs. We encountered a patient with squamous cell lung cancer who was diagnosed with myocardial metastasis before death and sustained ventricular tachycardia during the course of the disease. The patient was a 56-year-old woman. A tumor was noted in the apex area of the left lung and was diagnosed as stage IVA of squamous cell lung cancer after a detailed examination. She underwent concurrent chemoradiotherapy with weekly treatment of carboplatin + paclitaxel. A 12-lead electrocardiogram performed upon admission for additional chemotherapy showed negative T waves in leads III, aVF, and V1-4. Transthoracic echocardiography and computed tomography showed a tumor lesion in the right ventricular wall, which was diagnosed as myocardial metastasis from lung cancer. During the course of the disease, the patient had frequent episodes of sustained ventricular tachycardia, which were refractory to treatment with antiarrhythmic drugs. However, the sinus rhythm was restored with cardioversion. Subsequently, the patient received palliative treatment and eventually died 4 months after the diagnosis of cardiac metastasis and 3 weeks after the diagnosis of ventricular tachycardia. Myocardial metastasis might reflect poor prognosis due to serious arrhythmia or some other complications. Therefore, the early diagnosis and appropriate treatment of cardiac metastasis by chemotherapy, cardiac radiotherapy, or surgery, are necessary prior to the development of symptoms in tolerant cases.

A superior vena cava aneurysm discovered by chance at regular physical examination.

A superior vena cava (SVC) aneurysm is a rare disease that can be confused with upper mediastinal tumor. A 57-year-old female visited our hospital regarding an abnormal shadow in her mediastinum on a chest X-ray. Upon closer examinations, which included three-dimensional computed tomography, we diagnosed it as a SVC aneurysm. Since her SVC aneurysm was regarded as fusiform type at low risk of rupture and thrombosis, she has been managed conservatively and is free from any complications to date. Thus, it is important to keep SVC aneurysms in mind during routine examinations.

Correlation between renal function and common risk factors for chronic kidney disease in a healthy middle-aged population: a prospective observational 2-year study.

BACKGROUND/AIMS: Age, proteinuria, metabolic syndrome, and hyperuricemia are the reported risk factors for chronic kidney disease (CKD) and cardiovascular disease (CVD). However, the best predictor of changes in renal function in the early stages of renal disease in a healthy middle-aged population is still unknown. Our study evaluated the correlation between changes in renal function and common risk factors to determine such a predictor. METHODS: In total, 2,853 healthy persons aged ≤50 years participated in the study. They had no proteinuria and were not on medications for hypertension, diabetes mellitus, hyperlipidemia, or hyperuricemia. Over 2 years, participants underwent annual health screening. The relationship between changes in estimated glomerular filtration rate (eGFR) and changes in risk factors for CKD was evaluated using univariate and multivariate linear regression analyses. RESULTS: Over 2 years, eGFR showed a significant decrease. Univariate regression analysis revealed that changes in fasting plasma glucose (FPG), total cholesterol, LDL-cholesterol, serum uric acid levels, and hemoglobin showed a significant negative correlation with changes in eGFR. Multiple regression analysis confirmed that changes in FPG, serum uric acid levels, in particular, and hemoglobin had a significant negative correlation with changes in eGFR. CONCLUSION: The changes in eGFR and other variables over 2 years were small and could be within expected biologic variation. A longer observational study is needed to elucidate whether FPG, serum uric acid and hemoglobin represent the earliest markers of eGFR decline.