Randomized phase II study of zoledronate dosing every four versus eight weeks in patients with bone metastasis from lung cancer (Hanshin Cancer Group0312).

BACKGROUND: Zoledronic acid (ZA) reduces the incidence of skeletal-related events (SREs) in patients with bone metastases from solid tumors. However, the optimal dosing interval of ZA for patients with lung cancer is uncertain. METHODS: We conducted a randomized, open-label, feasibility phase 2 trial at eight Japanese hospitals. Patients with bone metastases from lung cancer were randomly assigned to receive either 4 mg of ZA every four weeks (4wk-ZA) or every eight weeks (8wk-ZA). The primary endpoint was the time to the first SRE and the rate and types of SREs after one year. SREs were defined as pathologic bone fracture, bone radiation therapy or surgery, and spinal cord compression. Secondary endpoints were the SRE incidence at six months, pain assessment, changes in analgesic consumption, serum N-telopeptide, toxicity, and overall survival. RESULTS: Between November 2012 and October 2018, 109 patients were randomly assigned to the 4wk-ZA group (54 patients) and the 8wk-ZA group (55 patients). The number of patients who received chemotherapy or molecular-targeted agents was 30 and 23 and 18 and 16 in the 4wk-ZA and 8wk-ZA groups, respectively. The median time to the first SRE could not be calculated because of a low SRE. The time to the first SRE of all patients did not differ between the groups (P = 0.715, HR = 1.18, 95% CI = 0.48, 2.9). The SRE rate of all patients after 12 months was 17.6% (95% CI = 8.4, 30.9%) in the 4wk-ZA and 23.3% (95% CI = 11.8, 38.6%) in the 8wk-ZA group, without significant differences between the groups. There was no difference in any secondary endpoint between groups, and these endpoints did not differ among treatment modalities. CONCLUSIONS: An eight-week ZA interval does not increase the SRE risk for patients with bone metastasis from lung cancer and could be considered clinically.

Massive digital gene expression analysis reveals different predictive profiles for immune checkpoint inhibitor therapy between adenocarcinoma and squamous cell carcinoma of advanced lung cancer.

BACKGROUND: Immune checkpoint inhibitors prolong the survival of non-small cell lung cancer (NSCLC) patients. Although it has been acknowledged that there is some correlation between the efficacy of anti-programmed cell death-1 (PD-1) antibody therapy and immunohistochemical analysis, this technique is not yet considered foolproof for predicting a favorable outcome of PD-1 antibody therapy. We aimed to predict the efficacy of nivolumab based on a comprehensive analysis of RNA expression at the gene level in advanced NSCLC. METHODS: This was a retrospective study on patients with NSCLC who were administered nivolumab at the Kansai Medical University Hospital. To identify genes associated with response to anti-PD-1 antibodies, we grouped patients into responders (complete and partial response) and non-responders (stable and progressive disease) to nivolumab therapy. Significant genes were then identified for these groups using Welch's t-test. RESULTS: Among 42 analyzed cases (20 adenocarcinomas and 22 squamous cell carcinomas), enhanced expression of MAGE-A4, BBC3, and OTOA genes was observed in responders with adenocarcinoma, and enhanced expression of DAB2, HLA-DPB,1 and CDH2 genes was observed in responders with squamous cell carcinoma. CONCLUSIONS: This study predicted the efficacy of nivolumab based on a comprehensive analysis of mRNA expression at the gene level in advanced NSCLC. We also revealed different gene expression patterns as predictors of the effectiveness of anti PD-1 antibody therapy in adenocarcinoma and squamous cell carcinoma.

A Randomized Phase II Study of Maintenance Bevacizumab, Pemetrexed or Bevacizumab Plus Pemetrexed for Advanced Non-squamous Non-small Cell Lung Cancer.

BACKGROUND/AIM: Continuation maintenance therapy is standard for advanced nonsquamous non-small cell lung cancer; however, the optimal maintenance strategy has yet to be determined. PATIENTS AND METHODS: Patients without disease progression after four cycles of carboplatin (CBDCA)+ pemetrexed (PEM)+ bevacizumab (BEV) were randomized to maintenance therapy with BEV, PEM, or BEV+PEM. The primary endpoint was 1-year progression-free survival (PFS) rate. RESULTS: Of the 90 patients enrolled, 64 were randomly assigned to maintenance therapy. The 1-year PFS rate was 9.1% in the BEV arm, 19.1% in the PEM arm, and 19.1% in the BEV+PEM arm. The median PFS and overall survival (OS) were 4.0 and 43.1 months in the BEV arm, 4.5 and 32.0 months in the PEM arm, and 6.4 and 41.8 months in the BEV+PEM arm. CONCLUSION: The median PFS was numerically better in the BEV+PEM arm, but the median OS was not significantly different among the three arms.

A Phase II Study of Cisplatin Plus Gemcitabine followed by Maintenance Gemcitabine for Advanced Squamous Non-Small-Cell Lung Cancer: Kyoto Thoracic Oncology Research Group 1302.

BACKGROUND: There has been no study so far on gemcitabine continuous maintenance therapy targeting only squamous non-small-cell lung cancer (NSCLC) patients. This study aimed to assess the efficacy and safety of cisplatin plus gemcitabine followed by maintenance gemcitabine for chemotherapy- naïve Japanese patients with advanced squamous NSCLC. METHODS: The patients received 4 cycles of gemcitabine (1,000 mg/m2, days 1 and 8) and cisplatin (80 mg/m2, day 1) every 3 weeks, followed by gemcitabine alone as maintenance therapy every 3 weeks until disease progression or unacceptable toxicity. The primary end point of the study was progression-free survival (PFS) from the date of registration. RESULTS: From May 2013 to October 2018, 26 patients were enrolled, and 25 patients received ≥1 cycle of planned treatment. Eighteen patients (69.2%) received 4 cycles of cisplatin plus gemcitabine, and 16 patients (61.5%) received ≥1 cycle of maintenance gemcitabine. The median PFS from the date of registration was 5.3 months (95% CI 2.9-7.3 months). In 16 patients who received ≥1 cycle of maintenance gemcitabine, the median PFS from the date of maintenance gemcitabine initiation was 3.8 months (95% CI 2.3-5.2 months). Their median overall survival from the date of registration was 11.9 months (95% CI 7.5-26.5 months). During the maintenance therapy, adverse events (AEs) were mostly Common Terminology Criteria for AE grade 1. CONCLUSIONS: While this trial did not meet the primary endpoint, the sufficient efficacy and feasibility of gemcitabine maintenance therapy were suggested.

Pembrolizumab-induced autoimmune encephalitis in a patient with advanced non-small cell lung cancer: A case report.

Immune checkpoint inhibitors have markedly changed lung cancer treatment and improved overall survival. However, immune checkpoint inhibitors may be associated with various adverse events, including encephalitis, although this complication is rare. We herein describe the clinical characteristics of a case of immune checkpoint inhibitor-induced encephalitis and its management. A 51-year-old man with squamous non-small cell lung cancer was receiving pembrolizumab treatment when he suddenly displayed an altered level of consciousness. Cerebrospinal fluid examination revealed elevated lymphocyte count and autoimmune encephalitis was suspected. The patient was promptly started on steroids and his consciousness immediately improved. Pembrolizumab treatment was discontinued; however, stable disease was maintained. In conclusion, encephalitis is a rare but possibly fatal adverse event of immune checkpoint inhibitors, and prompt diagnosis and treatment are mandatory.

Does afatinib plus bevacizumab combination therapy induce positive conversion of T790M in previously-negative patients?

Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are markedly effective for T790M-positive patients. To confer their clinical benefit to more patients, a novel therapy to induce positive conversion in T790M-negative patients may be possible. We retrospectively reviewed medical records of patients who had received rebiopsy after completion of ABC-study: a prospective phase II study of Afatinib plus Bevacizumab Combination (ABC)-therapy after acquired resistance to EGFR-TKI. Between October 2014 and September 2016, 32 eligible patients were enrolled in ABC-study at our institutes. Eighteen patients were T790M-negative and 14 were T790M-positive before ABC-therapy. Rebiopsy was performed on 13 T790M-negative and 5 T790M-positive patients after progression of ABC-therapy. In 8 (62%) of 13 T790M-negative patients, T790M status changed from negative to positive after ABC-therapy. Seven of these 8 patients underwent osimertinib therapy. The response rate and median time to treatment failure were 86% and 12.2 months, respectively. There were no adverse events ≥grade 3, nor any treatment-related deaths. On the other hand, T790M remained positive after ABC-therapy in all 5 previous T790M-positive patients. ABC-therapy could induce positive conversion of T790M even in previously-negative patients. We hypothesize that ABC-therapy could provoke "clonal selection", which purifies T790M-positive cancer cells in heterogeneous tumors. Further studies are warranted to confirm this phenomena.

Afatinib plus bevacizumab combination after acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: Multicenter, single-arm, phase 2 trial (ABC Study).

BACKGROUND: Preclinical studies suggested that the addition of bevacizumab could overcome acquired resistance (AR) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The aim of this study was to evaluate the clinical efficacy and safety of a combination of afatinib and bevacizumab after AR. METHODS: Patients with EGFR-mutant non-small cell lung cancer after AR were enrolled during any line of therapy. Afatinib was prescribed at 30 mg, and 15 mg/kg bevacizumab was administered every 3 weeks until progression. RESULTS: Between October 2014 and May 2017, 32 eligible patients were evaluated. The mutation subtypes were Del-19 (20 [63%]), L858R (11 [34%]), and L861Q (1 [3%]). T790M was detected in 14 patients (44%). The median number of prior regimens was 4 (range, 1-10). Six patients obtained a partial response, and 23 had stable disease; this resulted in an objective response rate (ORR) of 18.8% (95% confidence interval [CI], 7.2%-36.4%) and a disease control rate of 90.7% (95% CI, 75.0%-98.0%). The median progression-free survival (PFS) was 6.3 months (95% CI, 3.9-8.7 months). The ORRs and median PFS times of T790M+ and T790M- patients were 14.3% and 22.2%, respectively, and 6.3 and 7.1 months, respectively; those of Del-19 and L858R patients were 20.0% and 11.1%, respectively, and 6.3 and 5.1 months, respectively. Grade 3 or higher adverse events (incidence ≥ 10%) included paronychia (25%), hypertension (41%), and proteinuria (19%). There were no treatment-related deaths, interstitial lung disease, or bevacizumab-associated severe bleeding. CONCLUSIONS: Afatinib plus bevacizumab demonstrated clinical efficacy and safety after AR to EGFR TKIs and could be a therapeutic salvage option for T790M- populations.

Immune checkpoint inhibitor re-challenge in patients with advanced non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors have dramatically changed lung cancer treatment, demonstrating an overall survival benefit. There are limited data about re-challenge in patients with non-small cell lung cancer. We attempted to address this question for re-challenge of immune checkpoint inhibitor in patients with advanced non-small cell lung cancer. METHODS: We retrospectively analyzed 11 patients with advanced non-small cell lung cancer treated with nivolumab and re-challenged with nivolumab/pemblorizumab at Kansai Medical University Hospital from December 2015 to December 2017. RESULTS: Three patients achieved PR and two patients were in SD. These patients were apt to be good responders to the initial treatment, to develop immune-related adverse events and to be immediately started on re-challenge with immune checkpoint inhibitor. The median PFS was 2.7 (range, 0.5-16.1) months. Five patients (45%) had mild to moderate immune-related adverse events. CONCLUSION: Our study shows the effectiveness of re-challenge of immune checkpoint inhibitors in a subset of non-small cell lung cancer patients. Re-challenge might become one of treatment option for advanced non-small cell lung cancer.

Differential efficacy of cisplatin plus pemetrexed between L858R and Del-19 in advanced EGFR-mutant non-squamous non-small cell lung cancer.

BACKGROUND: LUX-Lung 3 showed afatinib improved progression-free survival (PFS) compared with cisplatin plus pemetrexed in patients with epidermal growth factor receptor (EGFR) mutations. In this study, chemotherapy efficacy tended to differ between patients with Leu858Arg (L858R) point mutation and Exon 19 deletion (Del-19); PFS in L858R patients (8.1 months) was greater than in Del-19 patients (5.6 months). We investigated whether there is any difference in efficacy of cisplatin plus pemetrexed between Del-19 and L858R. METHODS: This study is a multicenter retrospective study. We reviewed medical records of patients who had received cisplatin plus pemetrexed as first line chemotherapy. Efficacies were evaluated between EGFR mutation status: Del-19 and L858R. Wild type cases were reference arm only, and not included in any statistical analysis. RESULTS: Among 304 patients, 78 (25.7%) harbored EGFR mutations: Del-19 (36/78 patients, 46.2%); and L858R (42/78, 53.8%). Median PFS of L858R group (9.4 months, 95% confidence interval [CI]: 7.0-12.6) was significantly longer than Del-19 group (5.5 months, 95% CI, 3.6-8.6) (p = 0.049). Response rate (RR) and OS presented no significant difference between L858R and Del-19. In multivariate analysis, EGFR mutation status (L858R versus Del-19) was the only significant factor for longer PFS (Hazard ratio [HR]: 0.78, 95% CI: 0.62-0.98) (p = 0.033). CONCLUSION: Our study indicated better efficacy of cisplatin plus pemetrexed in L858R than in Del-19 patients. In EGFR-mutant NSCLC, EGFR-TKIs are undoubtedly the premier therapy. However, in second line or later settings, cisplatin plus pemetrexed regimen may confer higher efficacy for L858R patients.

Pemetrexed monotherapy for chemo-naïve elderly (aged ≥80) patients with non-squamous non-small cell lung cancer: results from combined analysis of two single arm phase II studies (HANSHIN002 and 003).

PURPOSE: The aim of this retrospective study was to evaluate via combined analysis the efficacy and safety of pemetrexed monotherapy for chemo-naïve elderly patients aged ≥80 with non-squamous non-small cell lung cancer (NSCLC). METHODS: We conducted a combined analysis from two phase II studies of pemetrexed for chemo-naïve elderly (aged ≥75) (n = 47) and performance status 2 (n = 28) patients with advanced non-squamous NSCLC. Population aged ≥80 (80+ Group) was compared to those aged 70-79 (70's Group). RESULTS: We analyzed a total of 66 patients (37 70s and 29 80+ Groups) after exclusion of 4 ineligible and 5 aged ≤69 patients. Overall response rate, disease control rate, median progression-free survival, and median overall survival of 70s vs. 80+ Groups were 13.5 vs. 13.8% [p = not significant (NS)], 67.6 vs. 58.6% (p = 0.608), 3.7 months vs. 4.2 months (p = 0.5588) and 18.5 vs. 13.5 months (p = 0.2621), respectively. Non-hematological and hematological toxicities ≥grade 3 of 70s vs. 80+ Groups were 24 vs. 35% (p = 0.4192) and 49 vs. 52% (p = NS), respectively. Dose reduction and/or delay due to toxicities of 70s vs. 80+ Groups was 19 vs. 28% (p = 0.7784). Febrile neutropenia and interstitial lung disease were not observed. Treatment-related death (bacterial pneumonia) was confirmed in one (3%) of 29 80+ Group patients. CONCLUSIONS: Pemetrexed monotherapy demonstrated similar efficacy and safety between aged ≥80 and aged 70-79 populations. It could be a therapeutic option in clinical practice for elderly non-squamous NSCLC patients aged ≥80 without indications of carboplatin-based combination regimens or docetaxel monotherapy.

Elemental analysis of occupational granulomatous lung disease by electron probe microanalyzer with wavelength dispersive spectrometer: Two case reports.

The parenchymal lung diseases caused by metal inhalation include interstitial fibrosis, giant cell interstitial pneumonitis, chemical pneumonitis, and granulomatous disease, among others. We reported two cases of granulomatous lung disease with occupational exposure to metal dusts other than beryllium. They had worked in the battery manufacturing industry for 7 years and in an aluminum-processing factory for 6 years, respectively. Chest high-resolution computed tomography showed diffuse micronodules, and histology of video-assisted lung biopsy specimens revealed granulomatous lesions in the pulmonary interstitium. Results of microscopic examination of the tissue with special stains for mycobacteria and fungi were negative. Analysis by an electron probe microanalyzer with a wavelength-dispersive spectrometer (EPMA-WDS) confirmed the presence of silicon, iron, aluminum, and titanium in the granulomas. In particular, aluminum was distributed in a relatively high concentration in the granulomatous lesions. Although chronic beryllium disease is well known as an occupational granulomatous lung disease, much less is known about the other metals that cause granulomatous reactions in humans. Our report pointed out manifestations similar to beryllium disease after other metal dust exposures, in particular aluminum exposure. To our knowledge, this is the first report showing two-dimensional images of elemental mapping in granulomatous lesions associated with metal inhalation using EPMA-WDS.

Effectiveness of Tyrosine Kinase Inhibitors in Japanese Patients with Non-small Cell Lung Cancer Harboring Minor Epidermal Growth Factor Receptor Mutations: Results from a Multicenter Retrospective Study (HANSHIN Oncology Group 0212).

AIM: Non-small cell lung cancer (NSCLC) with minor mutations in the epidermal growth factor receptor (EGFR) gene, except for the common 15 base-pair deletions in exon 19 and the L858R mutation in exon 21, is rare, and only few data exist on this patient population. The aim of the present study was to describe the clinical characteristics and to clarify the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in patients with NSCLC harboring minor mutations of the EGFR gene. PATIENTS AND METHODS: This was a multicenter, retrospective study that analyzed specimens from patients with NSCLC who had minor EGFR gene mutations and were treated with EGFR-TKIs between June 2002 and March 2012. RESULTS: Out of 56 patients with minor mutations of the EGFR gene, 44 were treated with either gefitinib or erlotinib. Mutation sites were G719X in exon 18 (n=35), L861Q in exon 21 (n=11), and G874S in exon 21 (n=1). Three patients had both the G719S and the L861Q mutation. The response rate to TKI treatment was 29.5%, and the disease control rate was 63.6%. The median progression-free survival (PFS) was 6.7 months [95% confidence interval (CI)=2.06-8.66 months]. The median PFS was 7.2 months (95% CI=4.23-12.3 months) in 32 patients who received first- or second-line treatment with EGFR-TKIs, whereas the median PFS was 1.57 months (95% CI=0.73-3.8 months) in 12 patients treated with EGFR-TKIs as a third-line or later treatment. In multivariate Cox analysis, erlotinib therapy was associated with a longer PFS than gefitinib (p=0.025). CONCLUSION: Patients with NSCLC harboring minor mutations of the EGFR gene exhibited a modest response to EGFR-TKI treatment. Treatment with first-generation EGFR-TKIs, in particular erlotinib, may be considered a first- or second-line option for patients with NSCLC with minor EGFR mutations.

A randomized phase II study of bevacizumab in combination with docetaxel or S-1 in patients with non-squamous non-small-cell lung cancer previously treated with platinum based chemotherapy (HANSHIN Oncology Group 0110).

OBJECTIVES: This randomized phase II trial investigated the efficacy and safety of docetaxel plus bevacizumab and S-1 plus bevacizumab in the second-line treatment of non-squamous (non-Sq) non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with non-Sq NSCLC who experienced disease progression after prior platinum-based chemotherapy with or without bevacizumab were randomly assigned to receive docetaxel plus bevacizumab (DB) once every 3 weeks or S-1 orally twice daily on days 1-14 plus bevacizumab (SB) on day 1 every 3 weeks until disease progression. RESULTS: Ninety patients were randomized. The median progression-free survival (PFS) was 3.9 months (95% confidence interval [CI]=3.0-6.5) in DB and 3.5 months (95% CI=2.9-5.9) in SB. The objective response rate was significantly higher in DB than in SB (22.2% vs. 2.2%; P=0.004), whereas the disease control rates of the arms were identical (62.2% vs. 62.2%; P=1.00). Patients receiving DB were more likely to have ≥grade 3 neutropenia (93.4% vs. 4.4%) and febrile neutropenia (33.3% vs. 0%) than SB. In DB, PFS and overall survival (OS) were significantly longer among bevacizumab-naïve patients than among bevacizumab-experienced patients (median PFS: 7.2 vs. 2.9 months; P=0.004; and median OS: 21.3 vs. 14.1 months; P=0.012). CONCLUSION: DB and SB produced modest PFS benefits in the second-line treatment of patients with advanced non-Sq NSCLC. Because of the toxicity of DB and the low response rate of SB, neither regimen warrants further investigation, excluding DB in bevacizumab-naïve patients with advanced non-Sq NSCLC.

A phase II study of pemetrexed monotherapy in chemo-naïve Eastern Cooperative Oncology Group performance status 2 patients with EGFR wild-type or unknown advanced non-squamous non-small cell lung cancer (HANSHIN Oncology Group 002).

PURPOSE: The aim of our study was to investigate the efficacy and safety of pemetrexed monotherapy in chemo-naïve Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 patients with epidermal growth factor receptor (EGFR) wild-type or unknown advanced non-squamous non-small cell lung cancer (NSCLC). METHODS: Pemetrexed was administered at 500 mg/m(2) triweekly until progression with supplementations in chemo-naïve ECOG PS 2 patients with EGFR wild-type or unknown advanced non-squamous NSCLC. RESULTS: Between September 2009 and April 2013, twenty-eight patients were enrolled. Median age was 75 (range 59-89). Nineteen (68 %) of 28 were ever smoker, and 18 (64 %) had pulmonary emphysema. Sixteen (57 %) had comorbidities such as hypertension, heart disease, and/or diabetes. In 26 eligible patients, the overall response rate, disease control rate, median PFS, and median overall survival were 11.5, 53.8 %, 3.0 [95 % confidence interval (CI) 1.9-5.7] months and 9.5 (95 % CI 3.3-12.5) months, respectively. Median administered course number was 3 (range 1-14). Median duration of PS maintenance ≤2 was 4.9 (95 % CI 1.3-9.7) months. Common (≥10 %) grade 3/4 toxicities included 7 (27 %) neutropenia, 7 (27 %) leukopenia, 4 (15 %) fatigue, and 3 (12 %) thrombocytopenia. Febrile neutropenia and interstitial lung disease were not observed. There were no treatment-related deaths. CONCLUSION: Pemetrexed monotherapy demonstrated moderate efficacy and good safety in chemo-naïve PS 2 patients with EGFR wild-type or unknown non-squamous NSCLC. It can be a therapeutic option in "frail" PS 2 non-squamous NSCLC patients without the indication of combination regimens, if the patient is EGFR wild-type.

Possible differential EGFR-TKI efficacy among exon 19 deletional locations in EGFR-mutant non-small cell lung cancer.

BACKGROUND: Exon 19 deletion mutations (Del-19s) and the exon 21 L858R point mutation are the most common epidermal growth factor receptor (EGFR) mutations. In Del-19, several subtypes actually exist, consisting of the deletional location with or without amino acid insertion/substitution. Little evidence has been described whether the Del-19 subtype affects EGFR-tyrosine kinase inhibitor (TKI) efficacy. METHODS: Between December 2005 and July 2012, we investigated 105 patients harboring a Del-19 who had received EGFR-TKIs. Efficacies of EGFR-TKIs such as response rate (RR), progression-free survival (PFS), and overall survival (OS) were retrospectively evaluated among various patient characteristics. RESULTS: Among these 105 patients with Del-19s, 78 (74%) patients had a deletion from E746 (Del-E746), and 27 (26%) exhibited a deletion from L747 (Del-L747). Median PFS of Del-E746 (11.7 months, 95% confidence interval [CI]: 9.3-15.6) was significantly longer than Del-L747 (10.0 months, 95% CI: 6.4-12.7) (p=0.022). Insertions/substitutions were found in 19 patients (18%), and 91 patients (82%) were without insertions/substitutions. Median PFS without insertions/substitutions (11.7 months, 95% CI 9.3-15.2) was significantly longer than with insertions/substitutions (10.0 months, 95% CI: 4.0-10.6) (p=0.024). No relationships were found for RR among all patient characteristics. In multivariate analysis, performance status (PS) (0/1 vs. 2/3) and initial deletion site (Del-E746 vs. Del-L747) were significant factors for longer PFS, whereas PS, gender (male vs female) and histology (adeno vs squamous) for longer OS. CONCLUSIONS: Our data indicated better efficacy of EGFR-TKI in Del-E746 than Del-L747. Deletional locations may affect EGFR-TKI efficacy.

Association of hyperglycemia on admission and during hospitalization with mortality in diabetic patients admitted for pneumonia.

OBJECTIVE: Information available on the clinical features and outcomes of pneumonia in diabetic patients is limited. There are no data on the association between glycemic control during hospitalization and mortality in this population. The objective of this study is to examine whether the presence of hyperglycemia on admission and during hospitalization is associated with mortality in diabetic patients admitted to the hospital for pneumonia. METHODS: This study is a retrospective observational cohort study of diabetic adults hospitalized for the first time for pneumonia between 2005 and 2011 in a 358-bed community hospital. Univariate and multivariate analyses were performed for 30-day all-cause hospital mortality adjusted for sex, age, type of pneumonia (community-acquired pneumonia or nursing and health care-associated pneumonia), severity of pneumonia according to the A-DROP score and various comorbidities in consideration of the serum glucose and hemoglobin A1c levels on admission and the mean plasma glucose level during hospitalization. RESULTS: Of the 1,499 pneumonia patients evaluated, 185 (12.3%) (mean age 75 years) had diabetes mellitus. Fourteen (7.6%) of the 185 diabetic patients died within 30 days after admission. According to the univariate analysis, 30-day mortality was significantly associated with the A-DROP score (p<0.0001), the admission glucose level (p=0.01) and the mean plasma glucose level during hospitalization (p<0.0001). Even after adjusting for factors related to the severity of pneumonia, the mean plasma glucose level during hospitalization remained significantly associated with 30-day mortality (p=0.004). CONCLUSION: Hyperglycemia determined according to the mean plasma glucose level during hospitalization is independently associated with 30-day all-cause hospital mortality in diabetic patients admitted for pneumonia.

AP-VAS 2012 case report: anti-glomerular basement membrane disease with high titer of myeloperoxidase anti-neutrophil cytoplasmic antibody-an autopsy case report.

It has been reported that patients who are positive for both myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) and anti-glomerular basement membrane (GBM) antibody have a poor prognosis. We present an autopsy case of anti-GBM disease with a high titer of MPO-ANCA. The patient was a 77-year-old woman with a medical history of idiopathic interstitial pneumonia. After being treated for bacterial pneumonia, she was referred to our hospital for evaluation of non-nephrotic range proteinuria, hematuria, and a course of rapidly progressive glomerulonephritis. Results of urinalysis were 2+ for protein and 3+ for blood, with many dysmorphic red blood cells observed in the urinary sediment. A sample of a 24-h urine collection contained 0.3 g protein. The serum creatinine concentration was 5.0 mg/dl on admission. The patient tested positive for MPO-ANCA at a titer of >640 EU and for anti-GBM antibody at a titer of 14 EU. Renal biopsy revealed glomerulonephritis with crescent formation, and immunofluorescence studies showed that the glomeruli had a generalized linear fluorescence and anti-immunoglobulin G (IgG) and C3 along the peripheral glomerular capillaries. She was diagnosed with anti-GBM disease. Treatment was started with intravenous prednisolone and oral cyclophosphamide, followed by plasma exchange. Despite improved renal function, she died of pulmonary hemorrhage. Autopsy revealed deposits of IgG and C3 in the basement membranes of lung alveoli.

[Three autopsy cases of chronic necrotizing pulmonary aspergillosis].

Chronic necrotizing pulmonary aspergillosis (CNPA), also called semi-invasive pulmonary aspergillosis, was first described in the early 1980s as a distinct type of pulmonary aspergillosis. CNPA was an indolent, cavitary, infectious process of the lung parenchyma secondary to local invasion by Aspergillus species. Diagnosis is confirmed by pathological evidence of lung tissue invasion by the fungus. Clinical diagnosis by combined clinical, radiological and laboratory findings is needed because histopathological confirmation cannot always be obtained in the clinical setting. CNPA is recognized as a clinical syndrome in Japan, and has been poorly defined histologically. We report three autopsy cases of CNPA evaluated histopathologically. Subjects were middle-aged to older men with a medical history of pulmonary mycobacterial infection who presented with pulmonary or systemic symptoms. Radiologically, progressive upper lobe cavitary infiltrates were seen with mycetomas and infiltration in lower lung fields. Clinically, CNPA was diagnosed based on 2007 Japanese guidelines for the diagnosis and treatment of deep fungal infection. Subjects died of respiratory failure within one month to three years of diagnosis despite antifungal therapy including micafungin, voriconazole, or itraconazole combined with broad spectrum antibiotics. Autopsy findings showed cavities containing the fungus but no fungal invasion of viable lung tissue. The area of progressive infiltration revealed bacterial pneumonia, organizing pneumonia or organizing diffuse alveolar damage without Aspergillus. In conclusion, CNPA is a chronic progressive clinical form of pulmonary aspergillosis with significant morbidity and mortality.

Phase II study of carboplatin and pemetrexed in advanced non-squamous, non-small-cell lung cancer: Kyoto Thoracic Oncology Research Group Trial 0902.

BACKGROUND: Subgroup analyses of randomized studies have consistently shown that pemetrexed is exclusively effective in non-small-cell lung cancer (NSCLC) other than squamous cell carcinoma and the combination of pemetrexed and platinum agents is recommended for first-line chemotherapy in advanced non-squamous NSCLC; however, there have been few prospective studies of a selected population. PATIENTS AND METHODS: This was a single-arm phase II study of carboplatin and pemetrexed in Japanese patients with chemo-naive advanced non-squamous NSCLC. Patients received six cycles of pemetrexed (500 mg/m(2)) combined with carboplatin (area under the curve: AUC 6) every 3 weeks. Maintenance chemotherapy with pemetrexed was permitted in patients whose disease did not progress after combination chemotherapy. The primary endpoint was the response rate, and secondary endpoints were safety and survival. RESULTS: Fifty-one patients were enrolled between November 2009 and March 2011, and 49 patients were evaluable for both safety and efficacy. All but one patient had adenocarcinoma histology. Forty-four (90 %) patients completed four cycles, and 33 (67 %) completed six cycles of chemotherapy. Partial response was achieved in 25 patients (response rate: 51 %) and stable disease in 18 patients (37 %). Median progression-free survival (PFS) and overall survival (OS) were 6.3 months and 24.3 months, respectively. The median PFS and OS were 7.9 months and 24.3 months in patients with epidermal growth factor receptor (EGFR) mutation, and 6.3 months and 21.0 months in patients with EGFR wild type or unknown. There were no statistical differences between EGFR mutants and non-mutants for both PFS (p = 0.09) and OS (p = 0.23). Grade 3/4 neutropenia and thrombocytopenia were observed in 16 (33 %) and 9 (18 %) patients, respectively. Non-hematologic toxicities were generally mild, and there were no treatment-related deaths. CONCLUSIONS: The combination of carboplatin and pemetrexed was safe and effective in advanced non-squamous NSCLC. Although the sample size was small, our results indicate that pemetrexed is a key drug for advanced non-squamous NSCLC, irrespective of the EGFR mutation status (UMIN-CTR number 000002451).