磯谷 澄都

Lymphocyte profiles in mediastinal lymph nodes may reflect the immune status of patients with sarcoidosis. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is useful for the diagnosis of diseases with mediastinal lymphadenopathy including sarcoidosis. The purpose of this study was to determine lymphocyte profiles of lymph nodes in sarcoidosis by analyzing EBUS-TBNA samples. We prepared single cell suspensions from EBUS-TBNA samples of mediastinal lymph nodes from patients with sarcoidosis or lung cancer and analyzed surface markers (CD3, CD4, CD8, CD19, CD25) and FoxP3 expression in the resultant lymphocytes using flow cytometry. We studied 26 patients with sarcoidosis and 16 with lung cancer with mediastinal lymph node metastases. In sarcoidosis, the CD4/CD8 ratio was significantly more elevated in lymph nodes than in bronchoalveolar lavage fluid (P<0.001), although both were strongly correlated. The CD4/CD8 ratio was significantly higher in stage I than in stage II both in the BAL fluid and lymph nodes. When compared with lung cancer lymph node metastasis, the CD4/CD8 ratio was significantly higher in sarcoidosis, whereas the CD3/CD19 ratio was significantly higher in lung cancer. The proportion of regulatory T cells (CD4+, CD25+, FoxP3 high) did not differ between sarcoidosis and lung cancer samples. Lymphocyte profiles in mediastinal lymphadenopathy can be analyzed by flow cytometry of EBUS-TBNA samples. These findings might help elucidate the immunopathology of sarcoidosis.

BACKGROUND: When epidermal growth factor receptor (EGFR) gene mutation-positive non-small cell lung cancer (NSCLC) acquires resistance to the initial tyrosine kinase inhibitor (TKI) treatment, reassessing the tumor DNA by re-biopsy is essential for further treatment selection. However, the process of TKI-sensitive tumor re-progression and whether re-biopsy is possible in all cases of acquired resistance to EGFR-TKI remain unclear. METHODS: We retrospectively analyzed data from 69 consecutive patients with EGFR gene mutation-positive advanced NSCLC who had been treated with EGFR-TKI and exhibited disease relapse after initial disease remission. The relapsing lesions were identified at the time of RECIST-progressive disease (PD) and clinical-PD (when the attending physician judged the patient as clinically relapsing and stopped EGFR-TKI therapy). We determined the potential re-biopsy methods for each relapsing lesion and evaluated their feasibility according to difficulty and invasiveness criteria as follows: category A, accessible by conventional biopsy techniques; category B, difficult (but possible) to biopsy and accessible with invasive methods; and category C, extremely difficult to biopsy or inaccessible without using highly invasive methods, including surgical biopsy. RESULTS: The total feasibility rate of re-biopsy (category A or B) was 68% at RECIST-PD and 84% at clinical-PD, and the most common accessible relapsing lesions were primary tumors at RECIST-PD and pleural effusion at clinical-PD. All relapsing lesions at primary sites (categories A and B) were assessed as having the potential for re-biopsy. However, re-biopsy for metastasis was assessed as difficult in a substantial proportion of the study population (42 and 20% category C at RECIST-PD and clinical-PD, respectively). CONCLUSIONS: Re-biopsy of relapsing disease is feasible in many cases, although it may present difficulties in cases with, e.g., metastatic relapsing lesions. To facilitate treatment strategies in NSCLC patients with relapse after EGFR-TKI therapy, re-biopsy should be standardized with the use of simpler and more reliable methods.

PURPOSE: The purpose of this study was to evaluate renal function in lung cancer patients who were administered cisplatin with continuous higher-volume hydration (CH) or a short hydration (SH) regimen. METHODS: We retrospectively evaluated patients with lung cancer who were treated with chemotherapy regimens including >50 mg/m2 of cisplatin between August 2007 and March 2015. Between August 2007 and December 2012, patients received a continuous higher-volume hydration regimen without magnesium (Mg) supplementation (CH group), and after May 2013, patients received a short hydration regimen with Mg supplementation (SH group). To evaluate the factors influencing serum creatinine (SCr) increase during the first course of cisplatin chemotherapy, univariate and multivariate logistic regression analyses were conducted. RESULTS: A total of 122 patients were evaluated, 62 patients in the CH group and 60 patients in the SH group. Grade 1 (National Cancer Institute Common Toxicity Criteria for Adverse Events; version 4.0) or higher SCr increases were more frequently observed in the CH group than in the SH group after the first cycle (P = 0.01, Fisher's exact test) and for all cycles (P = 0.03). Multivariate analysis revealed that short hydration (odds ratio (OR), 0.30; 95% confidence internal (CI) (0.11-0.75), P = 0.01) and estimated creatinine clearance (eCcr) of ≥70 mL/min (OR, 0.25; 95% CI (0.088-0.69), P = 0.008) were associated with a significantly reduced risk for cisplatin-induced grade 1 or higher SCr increase. CONCLUSION: Our study suggested that a short hydration method with Mg supplementation and eCcr of ≥70 mL/min reduced the risk of cisplatin-induced nephrotoxicity.

BACKGROUND: Recent advances in bronchoscopy, such as transbronchial biopsy (TBB) using endobronchial ultrasonography with a guide sheath (EBUS-GS), have improved the diagnostic yield of small-sized peripheral lung lesions. In some cases, however, it is difficult to obtain adequate biopsy samples for pathological diagnosis. Adequate prediction of the diagnostic accuracy of TBB with EBUS-GS is important before deciding whether bronchoscopy should be performed. METHODS: We retrospectively reviewed 149 consecutive patients who underwent TBB with EBUS-GS for small-sized peripheral lung lesions (≤30 mm in diameter) from April 2012 to March 2013. We conducted an exploratory analysis to identify clinical factors that can predict an accurate diagnosis by TBB with EBUS-GS. All patients underwent thin-section chest computed tomography (CT) scans (0.5-mm slices), and the CT bronchus sign was evaluated before bronchoscopy in a group discussion. The final diagnoses were pathologically or clinically confirmed in all studied patients (malignant lesions, 110 patients; benign lesions, 39 patients). RESULTS: The total diagnostic yield in this study was 72.5% (95% confidence interval: 64.8-79.0%). Lesion size, lesion visibility on chest X-ray, and classification of the CT bronchus sign were factors significantly associated with the definitive biopsy result in the univariate analysis. In the multivariate analysis, only the CT bronchus sign remained as a significant predictive factor for successful bronchoscopic diagnosis. The CT bronchus sign was also significantly associated with the EBUS findings of the lesions. CONCLUSION: Our results suggest that the CT bronchus sign is a powerful predictive factor for successful TBB with EBUS-GS.

A 72-year-old man undergoing continuous ambulatory peritoneal dialysis (CAPD) for chronic renal failure and who had undergone right upper lobectomy for lung adenocarcinoma (pT2aN0M0) 2 years ago was admitted for recurrence of lung cancer presenting as multiple brain metastases. An epidermal growth factor receptor mutation analysis of his lung cancer revealed a deletion of 15 nucleotides (E746-A750) in exon 19. After whole-brain radiotherapy, we started daily administration of 250 mg gefitinib under the continuation of CAPD and performed a pharmacokinetic analysis. We speculated that the plasma concentration of gefitinib reached the steady state at least by day 16 after the start of gefitinib (626.6 ng/ml at trough level). On day 46, the plasma concentration was 538.4 ng/ml at trough level and the concentration in the peritoneal dialysis fluid was 34.6 ng/ml, suggesting that CAPD appeared to have little effect on the pharmacokinetics of gefitinib. During gefitinib therapy, there were no significant adverse events except for grade 2 diarrhea. Gefitinib could be safely administered to a patient undergoing CAPD.

BACKGROUND: Cisplatin plus pemetrexed is considered the standard of care for the first-line treatment of patients with advanced non-squamous non-small-cell lung cancer (NSCLC). However, little is known about the efficacy and safety of this regimen in Japanese patients in a daily clinical setting. METHODS: We retrospectively analyzed 40 patients who received cisplatin (75 mg/m/(2)) and pemetrexed (500 mg/m(2)) as a first-line treatment for advanced non-squamous NSCLC. RESULTS: Recorded Grade 3 or 4 hematological toxicities included neutropenia in 7 cases (17.5%), leukopenia in 5 cases (12.5%), anemia in 1 case (2.5%), thrombocytopenia in 1 case (2.5%), and febrile neutropenia in 1 case (2.5%). Grade 3 or 4 nonhematological toxicities included anorexia in 3 cases (7.5%), infection in 1 case (2.5%), rash in 1 case (2.5%), and increased transaminase expression in 1 case (2.5%). Therefore, the adverse events were mostly mild. There were no treatment related deaths. The overall response rate was 37.5%, median progression free survival was 5.6 months, and median overall survival (OS) was 18.8 months. In an epidermal growth factor receptor (EGFR) mutation status subgroup analysis, the median OS of patients with wild-type EGFR or unknown status (n=28)was 16.8 months. CONCLUSION: Cisplatin plus pemetrexed was well tolerated as a first-line treatment and effective in Japanese patients with advanced non-squamous NSCLC.

Recent analysis indicated that afatinib could be effective in treating non-small cell lung cancer harboring uncommon EGFR mutations. A 59-year-old man undergoing hemodialysis for chronic renal failure was diagnosed with adenocarcinoma of the lung (cT4N3M1b). EGFR mutation analysis of his cancer revealed G719A point mutation in exon 18, and we started daily administration of 30. mg afatinib with hemodialysis (three times a week). As the feasibility of afatinib in patients with chronic renal failure undergoing hemodialysis has not been established, we analyzed the pharmacokinetics of afatinib in this patient. The trough level of afatinib in his plasma was almost similar to that of patients with normal renal function. Two months later there was marked tumor shrinkage, indicating a partial response. Our results suggest that afatinib could be safely administered and may exhibit good tumor response in a patient who has advanced lung adenocarcinoma with uncommon mutations undergoing hemodialysis.

BACKGROUND: Although a challenge test using non-steroidal anti-inflammatory drugs (NSAIDs) is crucial for diagnosis of aspirin-induced asthma (AIA), it also has drawbacks in terms of possible side effects. Therefore, alternative in-vitro diagnostic methods for AIA are awaited. METHODS: Nineteen stable non-AIA patients (9 males and 10 females; mean age, 49.4 ± 4.8 years), and 20 AIA patients (9 males and 11 females; mean age, 51.1 ± 4.8 years) were enrolled in this study. CD11b and CD16 expressions on the peripheral-blood granulocytes after administration of aspirin and different concentrations of PGE2 in vitro were examined using flowcytometry. RESULTS: Aspirin induced a significant increase in CD11b expression on eosinophils (CD16 negative granulocytes) in 19 AIA patients and one non-AIA patient. Increase in CD11b expression on eosinophils by aspirin administration was suppressed by PGE2 in a dose-dependent manner. CONCLUSIONS: The measurement of CD11b expression on peripheral-blood eosinophils showed very high sensitivity and specificity of (-95%) in diagnosing AIA. Although this method requires laboratory facilities for flowcytometry, it may be very useful in diagnosis of AIA without side effects. In addition, PGE2 may be involved in regulation of CD11b expression on eosinophils by aspirin administration.

A 64-year old man first visited our clinic approximately 10 years ago because of diabetic nephropathy that had developed into chronic renal failure. He was hospitalized to examine a left S10 tumor shadow. Based on the results of these examinations, a primary left S10 T2N0M1, ED small cell lung cancer, was diagnosed. During his outpatient visits nephropathy was found. Following admission, he began dialysis (HD). During the detailed examinations, chemotherapy with amrubicin (AMR)was performed and the blood concentration of the drug was measured. The results showed no significant variations in blood concentration before and after the dialysis. While PR was achieved in this patient, a reduction in grade 4 eosinophils was observed as an adverse reaction.

OBJECTIVE AND METHODS: To assess the clinical significance of CA19-9 in patients with interstitial pneumonia showing pathological nonspecific interstitial pneumonia (NSIP) pattern (IP/NSIP groups), we measured the levels of serum (n = 14) and bronchoalveolar lavage fluid (BALF, n = 10) CA19-9 in IP/NSIP groups. RESULT: The serum levels of CA19-9 did not correlate with the serum levels of LDH, of KL-6, or of SP-D or with the intensity of chest Ga-67 scintigraphy. There were no significant differences between the serum CA19-9 levels before therapy and those after therapy in improving patients. The levels of CA19-9 in fibrotic NSIP groups (serum:n = 7, 138.3 + /- 79.6 U/ml BALF: n = 5, 845.8 + /- 334.2 U/ml) were significantly higher than those in cellular NSIP groups (serum: n = 7, 12.8 +/-2.1 U/ml, BALF: n = 5, 40.8 +/- 16.2 U/ml). Immunohistochemical stains of CA19-9 showed the strong positivity in the bronchiolar epitheliums located in severe fibrotic lesions and the mucus within the lumens of microscopic honeycomb. The serum levels of CA19-9 were increased in both worsening patients. CONCLUSION: We speculated that the serum levels of CA19-9 may reflect the progression of lung fibrosis but not the disease activity in IP-NSIP groups.