Effectiveness and Safety of Immune Checkpoint Inhibitors Alone or in Combination With Chemotherapy in Pulmonary Sarcomatoid Carcinoma.

Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer associated with poor prognosis and resistance to conventional chemotherapy. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, were found to have clinical benefits in PSC in recent studies. Nevertheless, because these studies included a small number of patients owing to disease rarity, larger studies are needed to evaluate the effectiveness and safety of ICI-based therapy for PSC. Methods: This multicenter retrospective study evaluated patients with ICI-naive advanced or metastatic PSC who were treated with ICI-based therapy at 25 hospitals in Japan. Results: A total of 124 patients were evaluated. The overall response rate, median progression-free survival (PFS), and median overall survival (OS) were 59.0%, 10.5 months, and 32.8 months, respectively. The PFS and OS rates at 24 months were 35.3% and 51.5%, respectively. Programmed death-ligand 1 expression, concomitant chemotherapy, and the treatment line were not significantly associated with PFS or OS. Immune-related adverse events (irAEs) were observed in 70 patients (56.5%), including 30 (24.2%) with grade 3 to 5 events. Patients with mild irAEs (grades 1-2) had longer PFS and OS than did those with severe (grades 3-5) or no irAEs. In a multivariate analysis, any-grade irAEs and the absence of liver metastases were independently associated with PFS, whereas any-grade irAEs and Eastern Cooperative Oncology Group performance status less than or equal to 1 were independently associated with OS. Conclusions: ICI-based therapy was found to have promising effectiveness in patients with advanced or metastatic PSC, regardless of programmed death-ligand 1 expression, concomitant chemotherapy, or treatment line.

Real-world outcomes of nivolumab plus ipilimumab and pembrolizumab with platinum-based chemotherapy in advanced non-small cell lung cancer: a multicenter retrospective comparative study.

INTRODUCTION: Nivolumab plus ipilimumab with chemotherapy (NICT) and pembrolizumab with chemotherapy (PCT) are commonly used in patients with advanced non-small cell lung cancer (NSCLC). Compared with immune checkpoint inhibitor (ICI) monotherapy, ICI combination therapy can increase immune-related toxicity instead of prolonging survival. This study aimed to compare the efficacy and safety of NICT and PCT to decide on the favorable treatment. METHODS: We conducted a multi-center retrospective cohort study on patients who underwent NICT or PCT between December 2018 and May 2022. Propensity score matching (PSM) was performed with the variables age, sex, smoking status, performance status, stage, histology, and programmed cell death ligand-1 (PD-L1). The Kaplan-Meier method was used to compare survival for the matched patients. RESULTS: Six hundred consecutive patients were included. After PSM, 81 and 162 patients were enrolled in the NICT and PCT groups, respectively. The baseline characteristics were well-balanced. The median progression-free survival was equivalent (11.6 vs. 7.4 months; P = 0.582); however, the median overall survival (OS) was significantly longer in the NICT group than in the PCT group (26.0 vs. 16.8 months; P = 0.005). Furthermore, OS was better in PD-L1-negative patients who underwent NICT than in those who underwent PCT (26.0 vs. 16.8 months; P = 0.045). Safety profiles did not differ significantly in terms of severe adverse event and treatment-related death rates (P = 0.560, and 0.722, respectively). CONCLUSIONS: Real-world data suggests that NICT could be a favorable treatment option compared with PCT for patients with advanced NSCLC. Further follow-up is needed to determine the long-term prognostic benefit.

Nivolumab Versus Gemcitabine or Pegylated Liposomal Doxorubicin for Patients With Platinum-Resistant Ovarian Cancer: Open-Label, Randomized Trial in Japan (NINJA).

PURPOSE: This phase III, multicenter, randomized, open-label study investigated the efficacy and safety of nivolumab versus chemotherapy (gemcitabine [GEM] or pegylated liposomal doxorubicin [PLD]) in patients with platinum-resistant ovarian cancer. MATERIALS AND METHODS: Eligible patients had platinum-resistant epithelial ovarian cancer, received ≤ 1 regimen after diagnosis of resistance, and had an Eastern Cooperative Oncology Group performance score of ≤ 1. Patients were randomly assigned 1:1 to nivolumab (240 mg once every 2 weeks [as one cycle]) or chemotherapy (GEM 1000 mg/m2 for 30 minutes [once on days 1, 8, and 15] followed by a week's rest [as one cycle], or PLD 50 mg/m2 once every 4 weeks [as one cycle]). The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), overall response rate, duration of response, and safety. RESULTS: Patients (n = 316) were randomly assigned to nivolumab (n = 157) or GEM or PLD (n = 159) between October 2015 and December 2017. Median OS was 10.1 (95% CI, 8.3 to 14.1) and 12.1 (95% CI, 9.3 to 15.3) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.0; 95% CI, 0.8 to 1.3; P = .808). Median PFS was 2.0 (95% CI, 1.9 to 2.2) and 3.8 (95% CI, 3.6 to 4.2) months with nivolumab and GEM or PLD, respectively (hazard ratio, 1.5; 95% CI, 1.2 to 1.9; P = .002). There was no statistical difference in overall response rate between groups (7.6% v 13.2%; odds ratio, 0.6; 95% CI, 0.2 to 1.3; P = .191). Median duration of response was numerically longer with nivolumab than GEM or PLD (18.7 v 7.4 months). Fewer treatment-related adverse events were observed with nivolumab versus GEM or PLD (61.5% v 98.1%), with no additional or new safety risks. CONCLUSION: Although well-tolerated, nivolumab did not improve OS and showed worse PFS compared with GEM or PLD in patients with platinum-resistant ovarian cancer.

Final analysis of a phase II study of nivolumab in combination with ipilimumab for unresectable chemotherapy-naive advanced melanoma.

Nivolumab plus ipilimumab combination is currently one of the preferred regimens for advanced melanoma in recently updated clinical practice guidelines. However, the evidence on the efficacy of the combination for acral or mucosal subtypes remains less robust. This is the final analysis of a multicenter, open-label, uncontrolled phase II study that investigated the long-term efficacy and safety in treatment-naive Japanese patients with advanced melanoma, including acral or mucosal subtypes, and subsequent therapy after discontinuation of the investigational agents. Patients received four doses of nivolumab (1 mg/kg i.v.) in combination with ipilimumab (3 mg/kg i.v.) at 3-week intervals, followed by doses of nivolumab (3 mg/kg i.v.) at 2-week intervals. The median follow-up period was 20.8 months (range, 5.2-35.0). The centrally and locally assessed objective response rates were both 43.3% (13/30; 95% confidence interval [CI], 25.5-62.6). Median progression-free survival was not reached (95% CI, 3.02-not reached), and median overall survival was also not reached (95% CI, 19.52-not reached). The 30-month progression-free survival and overall survival rates were 50.3% and 54.2%, respectively. No new safety concerns were detected. After discontinuation of the investigational agents, 83.3% of patients received some form of subsequent therapy including 43.3% of patients who received nivolumab monotherapy and 26.7% of patients who received radiotherapy. Of the four patients who discontinued the investigational agents because of immune-related adverse events, two received subsequent therapy (nivolumab and ipilimumab, respectively) and the other two showed long-term treatment-free survival (659 and 590 days, respectively). Long-term survival with nivolumab plus ipilimumab was observed in Japanese patients with melanoma including acral and mucosal subtypes, which is consistent with the CheckMate 067 study. Many patients continued to receive some form of treatment safely after stopping treatment with nivolumab plus ipilimumab.

Clinical Efficacy and Safety of Nivolumab: Results of a Multicenter, Open-label, Single-arm, Japanese Phase II study in Malignant Pleural Mesothelioma (MERIT).

PURPOSE: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with poor prognosis. Patients with MPM who do not respond to standard first-line chemotherapy have limited treatment options. We evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, for the treatment of advanced or metastatic MPM. PATIENTS AND METHODS: Japanese patients with unresectable, advanced, or metastatic MPM resistant or intolerant to ≤2 regimens of chemotherapy and ≥1 measurable lesion(s) were enrolled. Patients received nivolumab 240 mg intravenously every 2 weeks until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate by central assessment according to the Modified Response Evaluation Criteria in Solid Tumors. Adverse events (AEs) and treatment-related AEs (TRAEs) were evaluated. RESULTS: Thirty-four patients were enrolled between July 2016 and October 2016. Median follow-up was 16.8 (range: 1.8-20.2) months. Ten (29%, 95% confidence interval, 16.8-46.2) patients showed a centrally assessed objective response. The objective response rates were 26% (7/27), 67% (2/3), and 25% (1/4) patients for epithelioid, sarcomatoid, and biphasic histologic subtypes, respectively. Median duration of response was 11.1 months with a 68% disease control rate. Median overall survival and progression-free survival were 17.3 and 6.1 months, respectively. The objective response rate was 40% with programmed death-ligand 1 expression ≥1% and 8% with <1%. Thirty-two patients (94%) experienced AEs and 26 (76%) experienced TRAEs. CONCLUSIONS: Nivolumab met the primary endpoint as second- or third-line treatment for patients with MPM and showed promising efficacy with manageable toxicity.See related commentary by Mansfield and Zauderer, p. 5438.

Nivolumab alone or in combination with cisplatin plus gemcitabine in Japanese patients with unresectable or recurrent biliary tract cancer: a non-randomised, multicentre, open-label, phase 1 study.

BACKGROUND: This study aimed to assess the safety and tolerability of the immune checkpoint inhibitor nivolumab, as monotherapy or combined with chemotherapy, in Japanese patients with biliary tract cancer. METHODS: This multicentre, open-label, phase 1 trial was done at four cancer centres in Japan. Eligible patients were aged 20-79 years, had biliary tract adenocarcinoma (intrahepatic bile duct cancer, extrahepatic bile duct cancer, gallbladder cancer, or ampullary cancer), Eastern Cooperative Oncology Group performance status 0 or 1, adequate hepatic, renal, and haematological function, and tumour tissue samples for PD-L1 expression analysis. Patients with unresectable or recurrent biliary tract cancer that was refractory or intolerant to gemcitabine-based treatment regimens received nivolumab monotherapy (240 mg every 2 weeks [monotherapy cohort]). Chemotherapy-naive patients with unresectable or recurrent biliary tract cancer received nivolumab (240 mg every 2 weeks) and cisplatin (25 mg/m2) plus gemcitabine (1000 mg/m2) chemotherapy (combined therapy cohort). The primary objective was to assess tolerability and safety. The primary objective was assessed in the safety population of all patients who had received at least one dose of nivolumab. This study is registered with www.clinicaltrials.jp, number JapicCTI-153098, and follow-up is ongoing. FINDINGS: 30 patients were enrolled into each cohort between Jan 13, 2016, and April 19, 2017. Data cutoff was Aug 31, 2017. In the monotherapy cohort, the most frequently reported treatment-related adverse events were decreased appetite (five [17%]), malaise (four [13%]), and pruritus (four [13%]). Grade 3-4 treatment-related adverse events were reported by three (10%) patients (rash, maculopapular rash, and amylase increase) and treatment-related serious adverse events were reported by one (3%) patient (pleurisy). In the combined therapy cohort, the most frequently reported treatment-related adverse events were neutrophil count decrease (any grade 25 [83%]; grade 3-4 in 23 [77%] patients) and platelet count decrease (any grade 25 [83%] of 30; grade 3-4 in 15 [50%] patients). Six (20%) patients reported 11 treatment-related serious adverse events (platelet count decrease [three patients], febrile neutropenia [two patients], neutrophil count decrease, anaemia, anaphylactic reaction, decreased appetite, pyrexia, and myocarditis [one patient each]). In the monotherapy cohort, median overall survival was 5·2 months (90% CI 4·5-8·7), median progression-free survival was 1·4 months (90% CI 1·4-1·4), and one of 30 patients had an objective response. In the combined therapy cohort, median overall survival was 15·4 months (90% CI 11·8-not estimable), median progression-free survival was 4·2 months (90% CI 2·8-5·6), and 11 of 30 patients had an objective response. INTERPRETATION: Nivolumab had a manageable safety profile and signs of clinical activity in patients with unresectable or recurrent biliary tract cancer. This initial assessment of nivolumab for the treatment of advanced biliary tract cancer provides supportive evidence for future larger randomised studies of nivolumab in this difficult to treat cancer. FUNDING: Ono Pharmaceutical Co Ltd and Bristol-Myers Squibb Inc.

Efficacy and safety of nivolumab in combination with ipilimumab in Japanese patients with advanced melanoma: An open-label, single-arm, multicentre phase II study.

AIM: The aim of the study was to evaluate the efficacy and safety of nivolumab combined with ipilimumab in treatment-naïve Japanese patients with advanced melanoma. METHODS: In this multicentre, single-arm study, treatment-naïve Japanese patients with unresectable stage III/IV or recurrent melanoma received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for four doses, followed by biweekly doses of nivolumab (3 mg/kg). The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included overall survival (OS), progression-free survival (PFS), disease control rate and safety. RESULTS: The subtypes of the thirty patients enrolled were: 12, mucosal; eight, non-acral cutaneous; seven, acral; two, uveal and one, unknown primary melanoma. The ORR was 43.3% (95% confidence interval [CI]: 25.5, 62.6) with central and local assessment. The centrally and locally assessed disease control rate (95% CI) were 73.3% (54.1, 87.7) and 86.7% (69.3, 96.2), respectively. At the median follow-up period of 14.1 months (range 5.2-27.7), median OS and centrally assessed PFS were not reached. OS (95% CI) at 6, 12, 18 and 24 months was 93.3% (75.9, 98.3), 83.3% (64.5, 92.7), 72.9% (50.0, 86.5) and 65.6% (40.4, 82.2), respectively. Treatment-related adverse events (AEs) occurred in all patients. Grade III-IV and serious AEs occurred, mostly during the combination phase, in 23 (76.7%) and 20 (66.7%) patients, respectively. No treatment-related deaths occurred. CONCLUSIONS: This study confirmed the efficacy and safety of nivolumab plus ipilimumab in treatment-naïve Japanese patients with advanced melanoma including rare subtypes. Incidence rates for grade III-IV AEs were high but manageable with appropriate medical attention and treatment. TRIAL REGISTRATION: JapicCTI-152869.

A randomized, open-label, Phase III clinical trial of nivolumab vs. therapy of investigator's choice in recurrent squamous cell carcinoma of the head and neck: A subanalysis of Asian patients versus the global population in checkmate 141.

OBJECTIVES: To assess efficacy and safety of nivolumab versus investigator's choice of therapy (IC) in Asian patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: Thirty-four patients from Japan, Taiwan, Hong Kong, and Korea received nivolumab 3mg/kg (n=23) every 2weeks or IC (n=11), as part of a global trial (n=361), until intolerable toxicity or disease progression. The primary endpoint was overall survival (OS). RESULTS: Median OS was 9.5months (95% confidence interval [CI] 9.1-NR) with nivolumab and 6.2months (95% CI 2.6-NR) with IC. Seven (30.4%) patients receiving nivolumab and six (54.5%) receiving IC died. The hazard ratio (HR) for risk of death (nivolumab vs. IC) was 0.50 (95% CI 0.17-1.48). Median progression-free survival was 1.9months (95% CI 1.6-7.5) with nivolumab and 1.8months (95% CI 0.4-6.1) with IC (HR 0.57 [95% CI 0.25-1.33]). Objective response rates (complete+partial responses) were 26.1% (6/23 patients; 95% CI 10.2-48.4) for nivolumab and 0% (0/11 patients; 95% CI 0.0-28.5) for IC. Sixteen (69.6%) nivolumab-treated patients and 10 (90.9%) patients receiving IC had a treatment-related adverse event, most commonly decreased appetite (21.7%), pruritus, rash, and fatigue (17.4% each) with nivolumab, and nausea, stomatitis, and decreased appetite (27.3% each) with IC. CONCLUSION: Nivolumab demonstrated a survival advantage compared with conventional treatments in Asian patients with platinum-refractory recurrent or metastatic SCCHN, and was well tolerated. Clinical trial registration NCT02105636.

Nivolumab-induced interstitial lung disease analysis of two phase II studies patients with recurrent or advanced non-small-cell lung cancer.

OBJECTIVES: Drug-induced interstitial lung disease (ILD) is often associated with high mortality; however it is difficult to predict and manage. we examined the clinical findings and imaging characteristics of nivolumab induced ILD reported in the two phase II studies patients with recurrent or advanced non-small-cell lung cancer. MATERIALS AND METHODS: We examined the clinical findings and imaging characteristics of all cases of ILD reported in two phase II trials of nivolumab, an anti-programmed death-1 antibody, in Japanese patients with recurrent or advanced non-small-cell lung cancer. These studies are registered with the Japan Pharmaceutical Information Center, numbers JapicCTI-132072, JapicCTI-132073. RESULTS: Eight (7.2%; two with squamous cell carcinoma, six with non-squamous cell carcinoma) of the 111 patients included in these two studies experienced ILD, and a causal relationship with nivolumab could not be ruled out in any of them. ILD of ≥grade 3 severity was found in four patients (3.6%), and ILD was considered a serious treatment-related adverse event in seven patients (6.3%). All of the patients who experienced ILD were male and had a history of smoking, with a median age of 65 years (range 52-78 years). In seven of the eight patients who experienced ILD, their events were rapidly resolving or resolved spontaneously or with steroid therapy; one patient died of respiratory failure without resolution of ILD, after docetaxel treatment was initiated following nivolumab discontinuation. Chest computed tomography images for the seven patients with resolving or resolution of ILD showed a pattern of organizing pneumonia or nonspecific interstitial pneumonia without traction bronchiectasis, while the patient who died had traction bronchiectasis. CONCLUSION: Although the risk factors for nivolumab-induced ILD were not identified, careful monitoring including imaging examinations is important in preventing the worsening of ILD in patients receiving nivolumab.

Retrospective efficacy and safety analyses of erlotinib, pemetrexed, and docetaxel in EGFR-mutation-negative patients with previously treated advanced non-squamous non-small-cell lung cancer.

OBJECTIVE: Several guidelines recommend erlotinib, pemetrexed, or docetaxel for second-line chemotherapy in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). The aim of this study was to retrospectively evaluate the efficacy of erlotinib, pemetrexed, and docetaxel in epidermal growth factor receptor (EGFR) mutation-negative patients with previously treated advanced non-squamous NSCLC. MATERIALS AND METHODS: We analyzed the efficacy of these agents in patients with previously treated advanced non-squamous NSCLC who had EGFR wild-type tumors, performance status (PS) of 0, 1, or 2 and received erlotinib, pemetrexed, or docetaxel between December 2007 and September 2011. Variability among patient backgrounds was evaluated using propensity scores to assess comparability. The efficacy of these agents was evaluated in patient subgroups with low variability. RESULTS: The propensity scores showed that the backgrounds of the groups that received second-line therapy with each agent had low variability and were adequate for comparison. Patients were divided into the PS0/1 and PS2 groups for analysis. The median progression-free survival (PFS) in patients treated with erlotinib was 2.8 months in the PS0/1 group, as compared with 1.0 month in the PS0/1/2 group and 0.90 months in the PS2 group. PFS in PS0/1 patients who received erlotinib was comparable to that in PS0/1 patients who received pemetrexed (2.5 months) or docetaxel (1.9 months). Overall survival (OS) in erlotinib-, pemetrexed-, and docetaxel-treated PS0/1 patients was 16.1, 7.4 and 10.0 months, respectively. The study had limited power to detect differences in PFS and OS because of the small sample size. CONCLUSIONS: Erlotinib appears to be a useful second-line option in PS0/1 patients with EGFR mutation-negative advanced non-squamous NSCLC given its mild adverse effects. The results should be carefully interpreted because of the small sample size, limited power, and retrospective nature of the study.

Polymorphisms of CYP2D6 gene and gefitinib-induced hepatotoxicity.

INTRODUCTION: Gefitinib induces severe hepatotoxicity in approximately a quarter of Japanese patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Gefitinib is metabolized by cytochrome P450 (CYP) enzymes--including CYP3A4/5, CYP1A1, and CYP2D6--in the liver. We hypothesized that polymorphisms of the CYP2D6 gene may account for gefitinib-induced hepatotoxicity. PATIENTS AND METHODS: Polymorphisms of the CYP2D6 gene were analyzed in 55 patients with NSCLC who experienced grade ≥ 2 transaminase elevation from gefitinib. The distribution of the CYP2D6 genotype was compared with that of the healthy Japanese population. The correlations between the nonfunctional allele *5 or the reduced-function allele *10 and hepatotoxicity-related clinical factors were also examined. RESULTS: The distribution of the CYP2D6 genotype in the study participants was not different from that of the general Japanese population, reported previously. Existence of allele *5 or *10 did not correlate with clinical factors such as onset of hepatotoxicity within 2 months, grade ≥ 3 serum transaminase elevation, and tolerability to dose reduction or rechallenge of gefitinib. However, in 7 patients taking CYP3A4-inhibitory drugs, rechallenge of gefitinib again caused hepatotoxicity in 4 patients with allele *5 or *10 but not in 3 patients with normal alleles (P = .029). Moreover, switching to erlotinib did not cause hepatotoxicity in any of 17 patients with allele *5 or *10 but did in 3 of 8 patients without these alleles (P = .024). CONCLUSION: Reduced function of CYP2D6 may partly account for gefitinib-induced hepatotoxicity when CYP3A4 is inhibited. Erlotinib could be safely used in patients with decreased CYP2D6 activity even after they experienced gefitinib-induced hepatotoxicity.

Randomized Phase II trial of paclitaxel and carboplatin followed by gemcitabine switch-maintenance therapy versus gemcitabine and carboplatin followed by gemcitabine continuation-maintenance therapy in previously untreated advanced non-small cell lung cancer.

BACKGROUND: In recent years, maintenance chemotherapy is increasingly being recognized as a new treatment strategy to improve the outcome of advanced non-small cell lung cancer (NSCLC). However, the optimal maintenance strategy is still controversial. Gemcitabine is a promising candidate for single-agent maintenance therapy because of little toxicity and good tolerability. We have conducted a randomized phase II study to evaluate the validity of single-agent maintenance chemotherapy of gemcitabine and to compare continuation- and switch-maintenance. METHODS: Chemonaïve patients with stage IIIB/IV NSCLC were randomly assigned 1:1 to either arm A or B. Patients received paclitaxel (200 mg/m2, day 1) plus carboplatin (AUC 6 mg/mL/min, day 1) every 3 weeks in arm A, or gemcitabine (1000 mg/m2, days 1 and 8) plus carboplatin (AUC 5 mg/mL/min, day1) every 3 weeks in arm B. Non-progressive patients following 3 cycles of induction chemotherapy received maintenance gemcitabine (1000 mg/m2, days 1 and 8) every 3 weeks. ( TRIAL REGISTRATION: UMIN000008252) RESULTS: The study was stopped because of delayed accrual at interim analysis. Of the randomly assigned 50 patients, 49 except for one in arm B were evaluable. Median progression-free survival (PFS) was 4.6 months for arm A vs. 3.5 months for arm B (HR = 1.03; 95% CI, 0.45-2.27; p = 0.95) and median overall survival (OS) was 15.0 months for arm A vs. 14.8 months for arm B (HR = 0.79; 95% CI, 0.40-1.51; p = 0.60), showing no difference between the two arms. The response rate, disease control rate, and the transit rate to maintenance phase were 36.0% (9/25), 64.0% (16/25), and 48% (12/25) for arm A vs. 16.7% (4/24), 50.0% (12/24), and 33% (8/24) for arm B, which were also statistically similar between the two arms (p = 0.13, p = 0.32, and p = 0.30, respectively). Both induction regimens were tolerable, except that more patients experienced peripheral neuropathy in arm A. Toxicities during the maintenance phase were also minimal. CONCLUSION: Survival and overall response were not significantly different between the two arms. Gemcitabine may be well-tolerable and feasible for maintenance therapy.

Pulmonary disease caused by rapidly growing mycobacteria: a retrospective study of 44 cases in Japan.

BACKGROUND: The features of pulmonary disease caused by rapidly growing mycobacteria (RGM) have not been sufficiently documented. OBJECTIVES: To establish these features, we retrospectively evaluated 44 patients. METHODS: We screened respiratory isolates at the National Toneyama Hospital (Osaka, Japan) between 2003 and 2007. Diagnosis was based on the latest guidelines of the American Thoracic Society. The patients were classified into 3 types according to their radiographic findings: fibrocavitary, nodular bronchiectatic and unclassified variant. RESULTS: We obtained 1,348 nontuberculous mycobacteria respiratory isolates from 1,187 patients, including 119 RGM isolates from 100 patients. Forty-four of these 100 patients were definitively diagnosed with respiratory disease due to RGM. The most common pathogen was Mycobacterium abscessus, which accounted for 65.9% of cases, followed by Mycobacterium fortuitum at 20.5%. There was a statistically significant difference in smoking history between patients infected with these 4 RGM species (excluding those with an unknown smoking history; p = 0.039). The overall evaluation of radiographic findings revealed 18.2% as fibrocavitary, 43.2% as nodular bronchiectatic and 38.6% as unclassified variants in these 44 patients. There was a significant difference in radiographic findings between the 4 RGM species (p = 0.002). There was also a significant difference in radiographic findings between M. abscessus and M. fortuitum infected patients (p = 0.022). CONCLUSIONS: Patients with M. abscessus seem to have less of a smoking history and more frequent nodular bronchiectatic radiographic patterns than patients with M. fortuitum. In contrast, fibrocavitary patterns might be more frequent with M. fortuitum infection.

CXCL12 as a biological marker for the diagnosis of tuberculous pleurisy.

Although a chemokine CXCL12 is implicated in some infectious diseases, especially those in which T cell-mediated immunity plays critical roles, the relevance of CXCL12 to tuberculosis has never been elucidated. To determine the clinical efficacy of CXCL12 as a diagnostic marker for tuberculous (TB) pleurisy, we measured CXCL12 concentration in pleural fluid and serum from patients with various etiologies. Of 60 patients with pleural fluid, the median age of TB patients was 52 which was significantly lower than 71 of non-TB patients (P < 0.01). CXCL12 level in TB effusion (4456 ± 1013 pg/mL, n = 15) was significantly higher than non-TB effusion (2851 ± 1229 pg/mL, n = 45) (P < 0.01). On the other hand, serum CXCL12 level showed no significant differences among TB pleurisy, non-TB pleurisy, and normal healthy subjects. The sensitivity and specificity of CXCL12 in pleural fluid for the diagnosis of TB pleurisy was 60.0% and 93.2% (cut-off value = 4600 pg/mL), respectively. Area under the receiver operating characteristic (ROC) curve (AUC) for CXCL12 was 0.84. As the source of CXCL12, pleural mesothelium, endothelium of pulmonary vessels, bronchial epithelium, multinucleated giant epithelioid cells, and macrophages were positive for CXCL12 staining. Increased CXCL12 level in pleural fluid could be an informative diagnostic marker for differentiating TB pleurisy from other etiologies.

Treatment of Non-Small-Cell Lung Cancer with Erlotinib following Gefitinib-Induced Hepatotoxicity: Review of 8 Clinical Cases.

Objective. Gefitinib often induces liver damage. A few reports have described that the subsequent administration of erlotinib was associated with less hepatotoxicity, but the safety and efficacy of this treatment are still not fully investigated. Therefore, we evaluated retrospectively the patients with erlotinib following gefitinib-induced hepatotoxicity. Methods and Patients. We retrospectively reviewed the medical records between December 2007 and March 2010. The patients were evaluated including the following information: age, gender, histology of lung cancer, performance status, smoking status, epidermal growth factor receptor (EGFR) mutation status, liver metastasis, viral hepatitis, alcoholic liver injury, clinical response, and hepatotoxicity due to EGFR tyrosine kinase inhibitors. Results. We identified 8 patients with erlotinib following gefitinib-induced hepatotoxicity. All achieved disease control by gefitinib. Hepatotoxicity was grades 2 and 3 in 3 and 5 patients, respectively. The median duration of treatment with gefitinib was 112.5 days and the median time to gefitinib-induced hepatotoxicity was 51.5 days. The median duration of treatment with erlotinib was 171.5 days. Grade 1 and 2 erlotinib-induced hepatotoxicity was observed in 2 and 1 patient, respectively. Conclusions. Erlotinib administration with careful monitoring is thought to be a good alternative strategy for patients who respond well to gefitinib treatment but experience hepatotoxicity.

[A case of sarcomatoid carcinoma of the lung successfully treated with carboplatin, paclitaxel and bevacizumab].

A 63-year-old male smoker with left chest pain was admitted for examination of an abnormal chest shadow. A chest computed tomography (CT) scan revealed a tumor in S6 of the left lung, and left pleural effusion. Histological examination by CT-guided needle biopsy revealed a proliferation of spindle-shaped tumor cells with sarcomatous features. Immunohistochemical staining confirmed the tumor cells to be of epidermal origin, indicating a diagnosis of sarcomatoid carcinoma of the lung. No distant metastases were found, and his disease was judged to be clinical stage IV (T3N2M1a). He received 5 courses of systemic chemotherapy consisting of carboplatin, paclitaxel and bevacizumab, and the tumor shrank. Systemic chemotherapy is generally ineffective for sarcomatoid carcinoma of the lung. However, in the present case this chemotherapy was effective with the addition of bevacizumab.

A case of acute and severe thrombocytopenia due to readministration of rifampicin.

A 49-year-old-woman was diagnosed with tuberculosis of the left humerus. She had received treatment, including rifampicin, for tuberculosis 17 years previously. Treatment was begun with isoniazid, rifampicin, ethambutol, and pyrazinamide, but these were discontinued because of mild neutropenia and thrombocytopenia 2 weeks posttreatment. Rifampicin and ethambutol were readministered after a 4-day interruption; however, generalized purpura appeared several hours later. By the next day, her platelet count was reduced from 160 × 10(3) to 3 × 10(3)/µl. The patient improved rapidly after platelet transfusion and steroid treatment. Readministration of drugs other than rifampicin did not induce thrombocytopenia; therefore, thrombocytopenia was likely due to rifampicin.

Inflammatory pseudotumor of the lung with rapid growth.

A 58-year-old man presented with a nodule in the right lung. Initially, the chest CT showed a ground-glass shadow. However, the shadow had become a solid nodule one month later. Histological examination revealed it was an inflammatory pseudotumor of the lung and subsequent surgery showed it to be an organizing pneumonia type. This disease is rare and in most cases is considered to be slow growing. Chest CT findings in the early stages have not been reported previously. Therefore, the present case is noteworthy in that we could confirm the CT findings in the early stages of this disease with rapid growth.

[Case of bilateral pneumothorax observed during the administration of gefitinib for lung adenocarcinoma with multiple pulmonary metastases].

A 61-year-old woman who had never smoked was given a diagnosis of adenocarcinoma of the lung with multiple pulmonary metastases. Systemic chemotherapy consisting of carboplatin and paclitaxel was not effective, thereafter daily oral administration of gefitinib was initiated. Six days later, bilateral pneumothorax was found. The extent of the pneumothorax was slight and she recovered without drainage within about one month although treatment of gefitinib was restarted. Gefitinib was effective for lung cancer in this case. Bilateral pneumothorax is a rare complication of chemotherapy for lung cancer. Only 3 such cases under treatment with gefitinib were reported in Japan.

[A case of lung adenocarcinoma effectively treated with sivelestat and corcicosteroid for drug-induced lung disease due to gefitinib].

A 70-year-old Japanese man was re-admitted because of relapse of adenocarcinoma of the lung. He received daily administration of gefitinib as second-line chemotherapy. He was given a diagnosis of drug-induced lung disease due to gefitinib on day 6 because of hypoxemia and ground glass opacities in the bilateral lung fields. There was no response to corticosteroid pulse therapy. Continuous administration of sivelestat was intravenously added from day 9. Although mechanical ventilation was required for 10 days, lung infiltrates and hypoxia gradually improved. Sivelestat and corcicosteroid was apparently effective in this case and may be useful treatment for drug-induced lung disease due to gefitinib.