Efficacy of EGFR-TKIs with or without upfront brain radiotherapy for EGFR-mutant NSCLC patients with central nervous system metastases.

BACKGROUND: Although the clinical efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) patients has been demonstrated, their efficacy in EGFR-mutant NSCLCs with central nervous system (CNS) metastases and the role of radiotherapy remain unclear. This study aimed to determine if it is preferable to add upfront cranial radiotherapy to EGFR-TKIs in patients with EGFR-mutant NSCLC with newly diagnosed brain metastases. METHODS: We retrospectively analyzed the data of EGFR-mutant NSCLC patients with CNS metastases who received EGFR-TKIs as a first-line therapy. RESULTS: A total of 104 patients were enrolled and 39 patients received upfront brain radiotherapy, while 65 patients received first and second generation EGFR-TKIs first. The median time to treatment failure (TTF) was 7.8 months (95% confidence interval [CI]: 6.3-9.4). The median survival time (MST) was 24.0 months (95% CI: 20.1-30.1). The overall response rate of the CNS was 37%. The median CNS progression-free survival (PFS) was 13.2 months (95% CI: 10.0-16.2). Brain radiotherapy prior to EGFR-TKI prolonged TTF (11.2 vs. 6.8 months, P = 0.038) and tended to prolong CNS-PFS (15.6 vs. 11.1 months, P = 0.096) but was not significantly associated with overall survival (MST 26.1 vs. 24.0 months, P = 0.525). Univariate and multivariate analyses indicated that poor performance status and the presence of extracranial metastases were poor prognostic factors related to overall survival. CONCLUSION: EGFR-TKI showed a favorable effect for EGFR-mutant NSCLC patients with CNS metastases. Prolonged TTF and CNS-PFS were observed with upfront brain radiotherapy.

A Phase II Study of Irinotecan for Patients with Previously Treated Small-Cell Lung Cancer.

OBJECTIVE: Chemotherapy with irinotecan plus cisplatin has shown promise in chemo-naïve small-cell lung cancer (SCLC) patients. However, irinotecan treatment for relapsed or refractory SCLC has not been adequately evaluated. This phase II study evaluated the appropriate treatment schedule of irinotecan as a single agent. This study was designed to determine the antitumor activity, toxicity, and survival in previously treated SCLC patients. METHODS: Previously treated SCLC patients with at least one platinum-based regimen received irinotecan (100 mg/m2) on days 1 and 8, every 3 weeks, until disease progression. The assessment of the response rate was the primary endpoint. RESULTS: Thirty patients were enrolled, with an objective response rate of 41.3% (95% confidence interval [CI] 25.5-59.3), and a disease control rate of 69%. Median progression-free and overall survival was 4.1 months (95% CI, 2.2-5.4) and 10.4 months (95% CI, 8.1-14), respectively. The grade 3/4 hematological toxicities were neutropenia (36.7%), thrombocytopenia (3.3%), anemia (13.3%), and febrile neutropenia (6.6%). There were no grade 4 nonhematological toxicities. Frequent grade 3 nonhematological toxicities included diarrhea (10%), anorexia (6.6%), and hyponatremia (6.6%). CONCLUSIONS: This phase II study showed a high objective response rate and long survival. Irinotecan monotherapy schedule used was well tolerated, and could be an active treatment option for these patients.

Histological Transformation to Large Cell Neuroendocrine Carcinoma from Lung Adenocarcinoma Harboring an EGFR Mutation: An Autopsy Case Report.

We herein report a 58-year-old Japanese woman who survived 14 years after surgery for lung adenocarcinoma harboring an epidermal growth factor receptor (EGFR) exon 19 deletion. She developed recurrence, for which she underwent multimodal therapy, including EGFR-tyrosine kinase inhibitor (TKI) administration. She ultimately died from a rapidly progressive right lung tumor that was resistant to EGFR-TKI. According to the autopsy findings, she had combined large-cell neuroendocrine carcinoma (LCNEC) and adenocarcinoma in the right lung, which retained an EGFR exon 19 deletion in both components. Therefore, the histological transformation to LCNEC can be a mechanism of acquired EGFR-TKI resistance.

Sequential Granulocyte-Macrophage Colony-Stimulating Factor Inhalation after Whole-Lung Lavage for Pulmonary Alveolar Proteinosis. A Report of Five Intractable Cases.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by the excessive accumulation of surfactant proteins within the alveolar spaces and by higher titers of autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in the serum and bronchoalveolar lavage fluid. The antibodies inhibit the maturation and phagocytosis of alveolar macrophages. Although the standard therapy for aPAP has been whole-lung lavage (WLL), this procedure is invasive and needs to be repeated for several years. GM-CSF inhalation therapy is a new procedure for treating aPAP and can induce remission with less invasiveness, although it is generally less effective in severe cases. We evaluated five cases with remarkable improvement by using sequential GM-CSF inhalation therapy after WLL; however, the treatment failed when this therapy preceded WLL. Therefore, sequential GM-CSF inhalation after WLL may reinforce the efficiency of WLL in patients with severe aPAP.

Nationwide surveillance of antimicrobial susceptibility patterns of pathogens isolated from surgical site infections (SSI) in Japan.

To investigate the trends of antimicrobial resistance in pathogens isolated from surgical site infections (SSI), a Japanese surveillance committee conducted the first nationwide survey. Seven main organisms were collected from SSI at 27 medical centers in 2010 and were shipped to a central laboratory for antimicrobial susceptibility testing. A total of 702 isolates from 586 patients with SSI were included. Staphylococcus aureus (20.4 %) and Enterococcus faecalis (19.5 %) were the most common isolates, followed by Pseudomonas aeruginosa (15.4 %) and Bacteroides fragilis group (15.4 %). Methicillin-resistant S. aureus among S. aureus was 72.0 %. Vancomycin MIC 2 µg/ml strains accounted for 9.7 %. In Escherichia coli, 11 of 95 strains produced extended-spectrum ß-lactamase (Klebsiella pneumoniae, 0/53 strains). Of E. coli strains, 8.4 % were resistant to ceftazidime (CAZ) and 26.3 % to ciprofloxacin (CPFX). No P. aeruginosa strains produced metallo-ß-lactamase. In P. aeruginosa, the resistance rates were 7.4 % to tazobactam/piperacillin (TAZ/PIPC), 10.2 % to imipenem (IPM), 2.8 % to meropenem, cefepime, and CPFX, and 0 % to gentamicin. In the B. fragilis group, the rates were 28.6 % to clindamycin, 5.7 % to cefmetazole, 2.9 % to TAZ/PIPC and IPM, and 0 % to metronidazole (Bacteroides thetaiotaomicron; 59.1, 36.4, 0, 0, 0 %). MIC90 of P. aeruginosa isolated 15 days or later after surgery rose in TAZ/PIPC, CAZ, IPM, and CPFX. In patients with American Society of Anesthesiologists (ASA) score ≥3, the resistance rates of P. aeruginosa to TAZ/PIPC and CAZ were higher than in patients with ASA ≤2. The data obtained in this study revealed the trend of the spread of resistance among common species that cause SSI. Timing of isolation from surgery and the patient's physical status affected the selection of resistant organisms.

Main bronchial diverticula in the subcarinal region: their relation to airflow limitations.

BACKGROUND: To date, bronchial diverticula have generally been treated as a pathological condition associated with chronic obstructive pulmonary disease (COPD), although only a limited amount of published information is available on the relationship between bronchial diverticula as depicted by multidetector computed tomography (MDCT) and airflow limitations. PURPOSE: To evaluate the relationship between airflow limitations and main bronchial diverticula in the subcarinal region using spirometry and thin-section MDCT. MATERIAL AND METHODS: A total of 189 consecutive adult patients were retrospectively evaluated based on spirometry and thin-section MDCT of the chest. All examinations were performed at our institution between June and October 2008. The study group included 70 women and 119 men with a mean age of 65 years (range 19-86 years). The relationship between the FEV(1)% and bronchial diverticula in the subcarinal region was analyzed (Student's t-test). RESULTS: The indications for conducting the examinations were pulmonary diseases (82 patients), cardiovascular diseases (22), extrapulmonary malignancies (74), and other conditions (11). A total of 84/189 (44.4%) patients showed bronchial diverticula, and the FEV(1)% of 70/84 (83.3%) patients was above 70. The FEV(1)% of patients with lesions ranged from 26.0 to 97.8 (mean 76.8), whereas the range was 28.1-94.4 (mean 73.7) in those without lesions. There was no significant association between the FEV(1)% and the presence of subcarinal bronchial diverticula (P > 0.05). CONCLUSION: Our data demonstrate that thin-section chest CT commonly demonstrates main bronchial diverticula in the subcarinal region in patients without airflow limitations. We propose that the presence of a small number of tiny bronchial diverticula under the carina may not be a criterion for the diagnosis of COPD.

[A patient with HIV encephalopathy presenting with parkinsonism during HAART therapy].

We report the case of a 32-year-old man presenting symptoms of parkinsonism. Neurological examination revealed parkinsonism symptoms such as akinesia and postural instability, dementia and frontal lobe signs. He was diagnosed as having human immunodeficiency virus (HIV) encephalopathy. Brain MRI, 99mTc ECD-SPECT and 1H-MR spectroscopy demonstrated symmetrical cerebral white matter lesions, predominantly in the bilateral frontal lobes. Frontal lobe dysfunction could be responsible for his parkinsonism associated with HIV encephalopathy. His neurological symptoms improved transiently after the initiation of HAART but fluctuated when antiretroviral drugs were changed because of their side effects. Although HAART effectively decreased plasma HIV-RNA load and increased peripheral blood CD4 cell count, his parkinsonism and dementia eventually exacerbated. Our results suggest that a combination of antiretroviral drugs affects the therapeutic efficacy against HIV encephalopathy, and that CNS symptoms could be aggravated during HAART, even when plasma HIV-RNA load and CD4 cell count are maintained under favorable conditions.

Analysis of the effect of surgical lung biopsy on serum KL-6 Levels in patients with interstitial pneumonia: surgical lung biopsy does not elevate serum KL-6 levels.

OBJECTIVE: It is well known that the serum level of KL-6 can be an indicator of disease activity in patients with interstitial pneumonia (IP). However, surgical lung biopsy is often required for the diagnosis of IP, although this can result in IP exacerbation. METHODS: The effect of surgical lung biopsy on the serum level of KL-6 in patients with IP was analyzed. Thirty-two cases of IP were examined in this study. There were no cases showing exacerbation of IP. RESULTS: The serum level of KL-6 demonstrated 1067+/-550 U/ml (mean+/-SD) before lung biopsy, 991+/-471 U/ml a day, 824+/-377 U/ml 4 days and 826+/-384 U/ml 7 days after lung biopsy. The serum KL-6 levels on the 1st, 4th, 7th day after the lung biopsy were significantly lower than that before the lung biopsy (P<0.05, P<0.01 and P<0.01, respectively). The percent decrease of the serum KL-6 levels on the 4th day (the lowest level) was dependent on the urine volume, and the analysis of the urinary levels of KL-6 showed a transient increase in urinary KL-6 excretion, suggesting that the decrease in serum KL-6 levels associated with surgical lung biopsy may be caused by this increase in urinary KL-6 excretion. CONCLUSION: Surgical lung biopsy of patients with IP has little effect on the increase in serum KL-6 levels. An elevation of serum KL-6 after surgical lung biopsy may indicate exacerbation of IP.

Matrix metalloproteinase-1 activation via plasmin generated on alveolar epithelial cell surfaces.

Plasmin is a potent protease related to tissue repair/remodeling not by fibrinolysis alone but also by activation of cytokines such as transforming growth factor and hepatocyte growth factor and by activation of matrix metalloproteases. We examined whether matrix matalloproteinase-1 was activated via plasminogen activation on surfaces of cultured alveolar epithelial cells (A-549). Cells were cultured overnight with plasminogen, pro-matrix metalloproteinase-1, and type I collagen as a substrate. Sodium dodecil sulfate-polyacrylamide gel electrophoresis was used to detect type I collagen degradation in culture supernatant. Collagen degradation corresponded to cell surface plasmin generation. No such finding was seen in the absence of cells or plasminogen. Alveolar epithelial plasminogen activation is important in matrix metalloproteinase-1 activation and thus presumably in tissue remodeling in pulmonary fibrosing pulmonary diseases such as idiopathic pulmonary fibrosis.

Inhibitory effect of antimicrobial agents and anisodamine on the staphylococcal superantigenic toxin-induced overproduction of proinflammatory cytokines by human peripheral blood mononuclear cells.

Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), produces superantigenictoxins, such as toxic shock syndrome toxin-1 (TSST-1). TSST-1 abnormally activates T cells to overproduce inflammatory cytokines (such as tumor necrosis factor-alpha, interleukin-2, and interferon-gamma) leading to shock. In this study, we investigated the inhibitory effect of antimicrobial agents and anisodamine (a Chinese herbal extract) on TSST-1-induced cytokine production. Among the macrolides and related agents examined, azithromycin and rokitamycin showed the greatest inhibitory activity against the TSST-1-induced cytokine production. This inhibitory effect was similar to that of anisodamine, which, however, had no inhibitory activity against bacterial growth. Vancomycin, teicoplanin, arbekacin, and linezolid (anti-MRSA and related agents) had no significant inhibitory effect on cytokine production. The inhibitory effect of the drugs on cell proliferation was not significant. These data indicate that some antimicrobial agents, e.g., azithromycin and rokitamycin, manifest anti-superantigenic toxin activity through the inhibition of cytokine production, just like anisodamine.

[Pneumocystis carinii pneumonia complicating brain tumor].

Brain tumors are frequently treated with steroids due to the presence of peritumoral edema. However, in Japan it is not widely recognized that primary brain tumor patients who are receiving steroid therapy become susceptible to Pneumocystis carinii pneumonia (PCP). We reviewed the clinical features and risk factors for PCP in brain tumor patients treated at our institution between 1994 and 2002. The treated cases consisted of 6 men and 6 women ranging in age from 47 to 78 yr (mean age 65.3). Underlying diseases included malignant glioma in 9 patients, malignant lymphoma in 2 patients and meningioma in one patient. All were diagnosed by respiratory disease specialists using bronchial washings and bronchoalveolar lavage or chest X ray/CT image. Radiation therapies were administered with 20 to 60 Gy (mean 52.9 Gy) except in one patient. Chemotherapy was performed with ranimustine in 4 malignant glioma patients and with methotrexate in 2 malignant lymphoma patients. Prednisone, begun perioperatively, was reduced gradually from a mean initial dosage of 38.3 mg/day orally. The duration of steroid treatment at the onset of PCP in these patients ranged from 41 to 79 days (mean 61.4 days). Six patients (50%) died of PCP despite appropriate antibiotic therapy and 2 patients needed intensive therapy with a respirator. For early diagnosis of PCP, periodic serological (e.g.; the level of lactate dehydrogenase and beta-D-glucan) and radiological examination (e.g.; chest X ray and CT image) is indicated in patients with brain tumors, and prophylaxis against PCP might be needed for patients with intracranial neoplasms and who are also receiving high-dose and long-term steroid treatment.

Interference of (1 --> 3)-beta-D-glucan administration in the measurement of plasma (1 --> 3)-beta-D-glucan.

OBJECTIVE: Blood (1 --> 3)-beta-D-glucan (betaG) measurement is widely used as an effective sero-diagnostic method for deep-seated mycosis. Antitumor betaG (lentinan, schizophyllan) administration is known as one of the false-positive factors of blood betaG measurement. To understand the influence of administered betaG preparation to betaG measurement in blood, we compared the interfering effect of betaG administration in different betaG measuring methods. METHODS: betaG concentration in plasma was measured by three different methods. MATERIALS: betaG concentration was measured in plasma of 18 samples of 7 cases with betaG administration and 86 samples without betaG administration. The period after last betaG administration was three days to three years. RESULTS: In the cases for which betaG was administered, blood betaG level drastically increased using the method which employs alkaline pretreatment. Even in the cases for which betaG was administered three years previously; betaG value measured by alkaline pretreatment was significantly high. Thus, interference of betaG administration in blood betaG measurement continued for years after the last administration. CONCLUSION: Disparity in betaG values measured by different methods for betaG administered cases is due to differences among sample pretreatment methods. Conformation of administered betaG seemed to be transformed into a sensitive form to factor G by alkaline pretreatment. Especially in the case of the alkaline pretreatment method, betaG administration disturbance was much stronger than for dilution-heating pretreatment. Therefore, in suspected cases, it is important to pay attention to betaG administration during the previous few years.

Adult onset anaphylactoid purpura with severe gastrointestinal involvement.

We treated a case of adult-onset severe-form anaphylactoid purpura. This case had been diagnosed as anaphylactoid purpura pathologically by skin biopsy. However, his clinical manifestations were atypical in view of complicated massive gastrointestinal hemorrhage. Intensive therapy including corticosteroid and cyclophosphamide transiently improved his condition. Nevertheless, the beta-D-glucan value in peripheral blood was gradually elevated. Prophylactic use of fluconazole failed to prevent contraction of invasive mycosis. Finally, he suddenly suffered from diffuse cerebral hemorrhage. Postmortem examination revealed systemic invasive aspergillosis as the cause of death.