Clinical Outcomes of Second-Line Chemotherapy in Patients with Previously Treated Advanced Thymic Carcinoma: A Retrospective Analysis of 191 Patients from the NEJ023 Study.

BACKGROUND: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. MATERIAL AND METHODS: We performed a multi-institutional, retrospective study named NEJ023 for patients with advanced thymic carcinoma. Patients without indications for curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions in the North East Japan Study Group. Demographic and clinicopathologic characteristics, data on treatment methods, and outcomes of second-line chemotherapy were obtained from medical records. RESULTS: In total, 191 patients were enrolled in this study. Second-line chemotherapy included platinum-based doublets in 57.6% of patients, other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide) in 13.6%, and monotherapy in 28.8%. The median follow-up time was 50.5 months, and the median overall survival (OS) from the start of second-line chemotherapy was 22.4 (95% confidence interval, 17.5-26.7) months. The average response rate (RR) was 20.0% overall; it was 21.6% for patients treated with platinum-based doublet chemotherapy, 13.6% for those treated with other multidrug chemotherapy, and 19.6% for those treated with single agent chemotherapy. There was no significant difference in OS between platinum-based doublet chemotherapy, other multidrug chemotherapy, and monotherapy (the median OS was 22.4, 25.7, and 21.4 months, respectively). CONCLUSION: The median OS was 22.4 months in patients with advanced thymic carcinoma treated with second-line chemotherapy. There were no significant differences in RR and OS between monotherapy and multidrug chemotherapy in this study. IMPLICATIONS FOR PRACTICE: Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. This is the largest data for those patients treated with second-line chemotherapy. This study suggests there is no significant difference in efficacy between monotherapy and multidrug chemotherapy for previously treated advanced thymic carcinoma. This result can support the adequacy to select monotherapy as treatment of those patients.

A Case of Long-Term Survival after Checkpoint Inhibitor Pneumonitis in a Patient with Squamous Cell Lung Cancer.

The management of grade 1 checkpoint inhibitor pneumonitis (CIP) is to withhold immune checkpoint inhibitors; however, the natural history of this condition is unknown. We herein report the case of a woman with squamous cell lung cancer who was a long-term survivor after CIP. After 4 rounds of treatment with nivolumab, a chest CT revealed a reticular pattern and ground-glass attenuation with shrinkage of the primary nodule. Nivolumab treatment was withheld without the administration of steroids. Although she remained asymptomatic, subsequent images revealed an increasing interstitial shadow until 2 months after the stop of nivolumab treatment. Thereafter, the interstitial shadow began to improve spontaneously without steroid treatment. Moreover, although the patient has not received additional therapy, disease control of lung cancer has been obtained within a follow-up period of more than 3 years. Although the exacerbation of CIP may appear on images for several months, asymptomatic cases can be followed without the administration of steroids. If the tumor had already responded prior to the onset of CIP, a favorable long-term prognosis can be expected.

Ceritinib Treatment for Carcinomatous Meningitis with a Secondary Mutation at I1171T in Anaplastic Lymphoma Kinase.

The mechanisms underlying anaplastic lymphoma kinase (ALK) resistance have not been well investigated in clinical practice. We herein report the case of a lung cancer patient with carcinomatous meningitis who had an ALK I1171T resistance mutation revealed by direct DNA sequencing of the cerebrospinal fluid after treatment with cytotoxic chemotherapy, crizotinib, and alectinib. I1171T is considered to be sensitive to ceritinib. Although ceritinib was not effective initially, we chose ceritinib again after whole-brain radiotherapy and ventriculoperitoneal shunting. Although the response duration was short, spinal magnetic resonance imaging revealed a marked response. The identification of an acquired ALK resistance mutation will aid in choosing the optimum sequence therapy.

Retrospective analysis of lung cancer patients treated with supportive care alone.

BACKGROUND: It is not uncommon for patients with lung cancer to receive supportive care alone. However, the clinical characteristics of these patients have not been fully studied. We conducted a retrospective study to identify the clinical characteristics of definitive lung cancer patients treated with supportive care alone. METHODS: We retrospectively analyzed the percentage of and reasons for definitive lung cancer patients treated with supportive care alone at a regional cancer center. We also investigated the histological diagnostic approaches, palliative therapy types, primary treatment locations after hospital consultation, and places of death. RESULTS: A total of 1,223 patients were histologically diagnosed as having lung cancer between 2011 and 2014. Of these, 160 (13%) patients were treated with supportive care alone. The primary reason for treatment with supportive care alone was a poor performance status (PS) in almost half of the patients. Overall, 40% of the patients received supportive care at home, and 17% were admitted to a palliative care unit (PCU). Death occurred at home for 17% of the patients and in the PCU for 42% of the patients. CONCLUSION: This study revealed that 13% of histologically proven lung cancer patients were treated with supportive care alone, mostly because of a poor PS. Only 40% of these patients received home care, suggesting the need for a more accessible home care system for patients and their families.

Successful Diagnosis of a Thymoma by Endobronchial Ultrasound-guided Transbronchial Needle Aspiration: A Report of Two Cases.

We herein report two cases of thymomas diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). In both cases, the tumor was adjacent to the central airway. Therefore, we attempted to perform EBUS-TBNA in order to obtain specimens for a histopathological examination, which resulted in a diagnosis of thymoma. In one case, surgical resection was conducted and the histological evaluation of the resected specimen confirmed thymoma type AB, consistent with the histology from the EBUS-TBNA specimen. As a safe and minimally invasive procedure, EBUS-TBNA may be considered for the diagnosis of mediastinal tumors, including thymoma.

[Targeted therapy for solid tumors in the elderly].

The majority of cancer incidences and deaths occur in the elderly. Elderly patients are a heterogeneous population in terms of physical reserve, comorbidity, polypharmacy, and other geriatric conditions. The elderly has been under-represented in clinical trials of cancer therapy, even in the era of targeted therapy. It is widely believed that targeted therapy, which interferes with specific pathways required for tumor development and growth, is more effective and less toxic than cytotoxic chemotherapy. However, some toxicities are concerned in the elderly such as arterial thromboembolism associated with the use of bevacizumab and cardiotoxicity with trastuzumab. This article reviews the available evidence on the efficiency and toxicity of targeted therapy for solid tumors in the elderly.

Endobronchial ultrasound-guided transbronchial needle aspiration in a patient with pericardial mesothelioma.

Pericardial mesothelioma is a very rare pericardial tumor. Diagnosing pericardial disease can be challenging, and obtaining an antemortem diagnosis of pericardial mesothelioma is particularly difficult. We herein report the case of a 60-year-old man with pericardial mesothelioma diagnosed on endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Chest computed tomography showed a mass surrounding the pericardium, and EBUS-TBNA of the right inferior paratracheal and subcarinal stations was consequently performed. No uptake was noted on (18)F-fluorodeoxy glucose positron emission tomography, other than in the pericardial mass. The results of histological and immunohistochemical examinations indicated the features of malignant mesothelioma. We therefore diagnosed the patient with pericardial mesothelioma, which was subsequently confirmed at autopsy.

Frequency of brain metastases in non-small-cell lung cancer, and their association with epidermal growth factor receptor mutations.

BACKGROUND: The brain is a frequent site of metastases from non-small-cell lung cancer (NSCLC). We analyzed the frequency of brain metastases (BMs) from NSCLC in the era of magnetic resonance images, and evaluated the correlation between epidermal growth factor receptor (EGFR) mutations and BMs among East Asian patients. METHODS: Frequency, number, and size of BMs, and survival of 1,127 NSCLC patients were retrospectively reviewed. Mutation status of EGFR was evaluated in all cases, and its association with BMs was statistically evaluated. RESULTS: EGFR mutations were found for 331 cases (29.4 %). BM was the cause of primary symptoms for 52 patients (4.6 %), and found before initiation of treatment for 102 other patients (9.1 %); In addition to these 154 patients, 107 patients (9.5 %) developed BMs, giving a total of 261 patients (23.2 %) who developed BMs from 1,127 with NSCLC. BM frequency was higher among EGFR-mutated cases (31.4 %) than EGFR-wild cases (19.7 %; odds ratio: 1.86; 95 % confidence interval (CI) 1.39-2.49; P < 0.001). BMs from EGFR-mutated NSCLC were small, but often became disseminated. EGFR mutations accounted for 39.9 % of BMs, but patient survival after BMs was significantly longer for EGFR-mutated cases than for EGFR-wild cases (hazard ratio: 2.23; 95 % CI 1.62-3.10; P < 0.001). CONCLUSIONS: Patients with EGFR-mutated NSCLC were more likely to develop BMs, but apparently also survived longer after BMs.

Endobronchial ultrasonography for positron emission tomography and computed tomography-negative lymph node staging in non-small cell lung cancer.

BACKGROUND: Integrated positron emission tomography (PET) with computed tomography (CT) is a useful modality to investigate lymph node metastases for non-small cell lung cancer, but is less sensitive for normal-sized lymph nodes. We sometimes encounter cases with radiologically normal lymph nodes and unsuspected mediastinal metastases detected by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). However, few studies have investigated staging in patients with radiologically normal mediastina, and the accuracy of EBUS-TBNA staging for radiologically normal mediastina and hila is unclear. METHODS: This study was a retrospective, single-institution review of a prospectively maintained database at Chiba Cancer Center between May 1, 2008, and September 1, 2013. We analyzed 113 non-small cell lung cancer patients with both CT-negative and PET/CT-negative lymph nodes (N0) in preoperative nodal staging performed by EBUS-TBNA. After preoperative staging was performed, patients with either N0 or N1 clinical staging underwent surgery. Final N factors were determined by mediastinal lymphadenectomy. RESULTS: In our study, the overall rate of N2 disease was 17.6% (20 of 113). For nodal staging by EBUS-TBNA, the sensitivity, specificity, negative predictive value, and diagnostic accuracy were 35.0% (7 of 20), 100% (93 of 93), 87.7% (93 of 106), and 88.4% (100 of 113), respectively. There were no severe complications from EBUS-TBNA staging. CONCLUSIONS: The overall rate of unsuspected N2 was not low. EBUS-TBNA was accurate and feasible for preoperative mediastinal nodal staging of non-small cell lung cancer with both CT-negative and PET/CT-negative lymph nodes. The sensitivity of EBUS-TBNA for radiologically normal mediastina and hila was low. Further investigations are required.

Effect of metformin on residual cells after chemotherapy in a human lung adenocarcinoma cell line.

Cancer chemotherapy, including molecular targeted therapy, has major limitations because it does not kill all the cancer cells; the residual cells survive until they acquire chemoresistance. In the present study, the combined effects of metformin and gefitinib were examined in vivo in a mouse xenograft model, inoculated with a human lung adenocarcinoma cell line that possesses an activating epidermal growth factor receptor mutation. The mechanism of the interaction was further elucidated in vitro. Metformin did not suppress the growth of already established tumors, nor did metformin augment tumor shrinkage by gefitinib. However, metformin significantly suppressed the regrowth of the tumor after effective treatment with gefitinib, suggesting the specific effect of metformin on the residual cells. Cytotoxicity of metformin was characterized by the absence of apoptosis induction and unremarkable cell cycle shift in vitro. The residual cell population after treatment with gefitinib was characterized by enriched cells with high expression of CD133 and CD24. Metformin was still effective on this specific cell population. Targeting residual cells after chemotherapy may represent an effective novel strategy for the treatment of cancer. Elucidating the mechanism of metformin cytotoxicity provides insights into future development of anticancer therapeutics.

Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines.

Although cisplatin and pemetrexed are key drugs in the treatment of malignant pleural mesothelioma, their drug-drug interactions, cross-resistance and resistance mechanisms in malignant pleural mesothelioma are not well understood. In the present study, the interaction of these 2 agents was determined by clonogenic assays followed by isobologram analysis of 4 human malignant pleural mesothelioma cell lines. The cell lines were exposed to the agents using a stepwise dose-escalation method to establish drug-resistant sublines. Thymidylate synthase mRNA expression was evaluated in the drug-resistant sublines. As a consequence, cisplatin and pemetrexed had synergistic effects in 3 cell lines and an additive effect in the fourth cell line. The former 3 cell lines showed similar pemetrexed sensitivity in the parental cells and their cisplatin-resistant sublines, whereas the fourth cell line exhibited cross-resistance. In contrast, cisplatin had diverse effects on pemetrexed-resistant sublines. High thymidylate synthase expression did not correlate with natural pemetrexed resistance. Elevated thymidylate synthase expression correlated with acquired pemetrexed resistance in 2 sublines. In conclusion, cisplatin and pemetrexed showed synergistic activity and no cross-resistance in 3 of the 4 malignant pleural mesothelioma cell lines, suggesting the clinical relevance of their combination in chemotherapy. Thymidylate synthase expression did not necessarily correlate with pemetrexed resistance. The information together with the experimental model presented here would be useful for further investigating therapeutic targets of malignant mesothelioma.

Antiproliferative action of metformin in human lung cancer cell lines.

The oral antidiabetic agent metformin has anticancer properties, probably via adenosine monophosphate-activated protein kinase activation. In the present study, growth inhibition was assessed by a clonogenic and by a cell survival assay, apoptosis induction was assessed by Hoechst staining and caspase activities and cell cycle alteration after exposure to metformin, and the interaction of metformin with cisplatin in vitro were elucidated in four human lung cancer cell lines representing squamous, adeno-, large cell and small cell carcinoma. Clonogenicity and cell proliferation were inhibited by metformin in all the cell lines examined. This inhibitory effect was not specific to cancer cells because it was also observed in a non-transformed human mesothelial cell line and in mouse fibroblast cell lines. Inhibition of clonogenicity was observed only when the cells were exposed to metformin for a long period, (10 days) and the surviving fraction, obtained after inhibiting proliferation by increasing the dose, reached a plateau at approximately 0.1-0.3, indicating the cytostatic characteristics of metformin. Metformin induced significant apoptosis only in the small cell carcinoma cell line. A tendency of cell cycle accumulation at the G0/G1 phase was observed in all four cell lines. Cisplatin, in a dose-dependent manner, severely antagonized the growth inhibitory effect of metformin, and even reversed the effect in three cell lines but not in the adenocarcinoma cell line. The present data obtained using various histological types of human lung cancer cell lines in vitro illustrate the cytostatic nature of metformin and its cytoprotective properties against cisplatin.

[A case of small-cell lung carcinoma accompanied by the syndrome of inappropriate secretion of antidiuretic hormone and Lambert-Eaton myasthenic syndrome].

Although the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and Lambert-Eaton myasthenic syndrome (LEMS) are often individually accompanied by small-cell lung carcinoma, simultaneous occurrence of the 2 syndromes is rare. A 61-year-old man was admitted to our hospital because of fatigue and myasthenia in the extremities, and small-cell lung carcinoma with pulmonary metastasis was diagnosed, together with SIADH and LEMS. These syndromes markedly ameliorated following tumor shrinkage, with 4 cycles of chemotherapy consisting of carboplatin and etoposide. On progression of the tumor thereafter, neither syndrome recurred. A literature review disclosed that these syndromes frequently resolve with tumor shrinkage.

[A case of multicentric Castleman's disease with metachronous pulmonary and nephric (renal) involvement].

A 52-year-old woman was referred to our hospital due to cough and sputum in January, 1996. Chest CT scans showed multiple hilar and mediastinal lymphadenopathy and laboratory tests revealed anemia, strong inflammatory reaction, polyclonal hyperimmunoglobulinemia, and an elevated interleukin-6 level. Video-assisted thoracoscopic lung biopsy revealed lymphocytic and plasmacytic infiltration around the bronchovascular band, suggesting a diagnosis of Castleman's disease, and so we began to administer steroids. Although her pulmonary symptoms improved, anemia and hyperimmunoglobulinemia continued. In 2001, her feeling of malaise worsened and gallium scintigraphy revealed new accumulation in her kidneys. Renal biopsy revealed lymphocytic and plasmacytic infiltration mimicking her prior pulmonary involvement. We therefore diagnosed multicentric Castleman's disease with renal involvement. Case in which lymphocytes and plasmacytes infiltrated both the lungs and kidneys metachronously are unusual. We discuss it in relation to the pertinent literature.