Yasuto Nakatsumi

Importance of atopic cough, cough variant asthma and sinobronchial syndrome as causes of chronic cough in the Hokuriku area of Japan

Objective:  A prospective multicentre study was conducted to elucidate the causes of chronic cough in Japan.

Comparative analysis of epidermal growth factor receptor mutations and gene amplification as predictors of gefitinib efficacy in Japanese patients with nonsmall cell lung cancer

Because the investigation of epidermal growth factor receptor gene (EGFR) status as a predictor of gefitinib efficacy in Japanese patients has shown promise, the authors evaluated EGFR mutations and gene amplification in biopsy specimens from Japanese patients with nonsmall cell lung cancer (NSCLC) who received treatment with gefitinib to analyze the correlation between EGFR gene status and clinical outcome.

EGFR Mutation of Tumor and Serum in Gefitinib-Treated Patients with Chemotherapy-Naive Non–small Cell Lung Cancer

Background: The authors evaluate the efficacy and safety of gefitinib monotherapy in chemotherapy-naive patients with advanced non–small-cell lung cancer (NSCLC). A secondary endpoint is to evaluate the relationship between clinical manifestations and epidermal growth factor receptor (EGFR) mutation status. Methods: Japanese chemotherapy-naive NSCLC patients were enrolled. They had measurable lesions, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ and bone marrow function. Patients received 250 mg of oral gefitinib daily. EGFR mutations in exon 18, 19, and 21 of DNA extracted from tumor and serum were analyzed by genomic polymerase chain reaction and direct sequence. Results: All 30 patients were eligible for the assessment of efficacy and safety. An objective response and stable disease were observed in 10 patients (33.3%) and nine patients (30.0%), respectively. The median time to progression was 3.3 months and the median overall survival was 10.6 months. The 1-year survival rate was 43.3%. Grade 3 toxicities were observed in seven patients. EGFR mutation was observed in four of 13 (30.8%) tumors, and two of them achieved partial response. In serum samples, three of 10 patients with EGFR mutations in the serum before treatment had a response to gefitinib. EGFR mutation was observed in 10 of 27 and significantly more frequently observed in the posttreatment samples from patients with a partial response or stable disease than in those from patients with progressive disease (p = 0.006). Conclusions: Gefitinib monotherapy in chemotherapy-naive NSCLC patients was active, with acceptable toxicities. These results warrant further evaluation of gefitinib monotherapy as a first-line therapy. The EGFR mutation in serum DNA may be a biomarker for monitoring the response to gefitinib during treatment.

Additive effect of continuous low-dose ofloxacin on erythromycin therapy for sinobronchial syndrome

It has been established that long-term low-dose erythromycin therapy (EM therapy) is very effective for sinobronchial syndrome, a common condition in Japan characterized by chronic upper and lower airway inflammation. The effect does not result from its bacteriocidal activity and the detailed mechanisms are not known. It takes 3-6 months for EM therapy to improve the symptoms. This study was designed to evaluate the additive effect of continuous low dosage or intermittent usual dosage of ofloxacin (OFLX) on EM therapy in patients with sinobronchial syndrome. Patients with sinobronchial syndrome were randomly allocated to receive one of the following four regimens. Patients in Group A received both low-dose OFLX and EM therapy daily for 6 months. Patients in Group B received EM therapy and intermittent treatment of OFLX for 6 months. Patients in Group C underwent EM therapy for 6 months. Patients in Group D received neither OFLX nor EM therapy. All patients were given carbocystein for more than 2 months before starting each treatment and during the study period. In patients receiving OFLX and/or EM therapy, these antimicrobial agents were well-tolerated during the treatment period. Amount of sputum in the morning was significantly less in Group C than in Group D after 3-6 months, and decreased significantly in Group A as compared with Group B after 2 weeks, Group C after 2 weeks to 2 months, and Group D after 2 weeks to 6 months. Other symptoms such as number of expectorations, difficulty of expectoration and severity of cough also improved rapidly in Group A. These findings suggest that it is useful to add low-dose OFLX to EM therapy for sinobronchial syndrome, especially within 1-2 months from starting treatment, and it may be cost-effective as this combination therapy can shorten the treatment period of EM therapy.

Analysis of thrombocytopenia due to carboplatin combined with etoposide in elderly patients with lung cancer

Thrombocytopenia induced by carboplatin combined with etoposide for elderly lung cancer patients was analyzed in relation to the predicted thrombocytopenia by the equations advocated by Egorin et al. and Taguchi et al. The thrombocytopenia actually observed was strongly correlated with and significantly more severe than that predicted if carboplatin had been administered as a single agent. The AUC (area under the curve) of carboplatin predicted by Calverts equation significantly affected the degree of thrombocytopenia. These data suggested that dosing of carboplatin should be determined individually on the basis of renal function, as recommended earlier. The reason for the enhancement of thrombocytopenia is yet to be determined in future trials.

Establishment and characterization of non-small cell lung cancer cell lines resistant to mitomycin C under aerobic conditions

To elucidate the mechanisms of acquired resistance to mitomycin C (MMC) in non‐small cell lung cancer (NSCLC), we established two MMC‐resistant NSCLC sublines by continuous exposure to MMC, using PC‐9 as a parent cell line. The sublines, PC‐9/MC2 and PC‐9/MC4, were 6.4‐ and 10‐fold more resistant to MMC than their parent cell line, respectively, at the IC50 value as determined by MTT assay. They exhibited cross‐resistance to EO9, but were not resistant to cisplatin, vindesine, etoposide, carboquone, or KW‐2149, a novel MMC derivative. They were collaterally sensitive to adriamycin and menadione. Accumulation of the drug was decreased in the resistant sublines to about 60% of that in the parent cells. Cytosolic DT‐diaphorase (DTD) activities were decreased to 13.5±3.2 in PC9/MC2 and 1.3±0.6 in PC‐9/MC4 from 261.5±92.7 nmol/min/mg protein in the parent PC‐9. NADH:cytochrome b5 reductase activities in both of the resistant cell lines were significantly decreased as compared to that in the parent cell line. Addition of dicumarol resulted in a two‐fold increase in IC50 value in PC‐9, whereas the IC50 value showed no change in PC‐9/MC4. Moreover, dicumarol did not affect the sensitivities to KW‐2149 but decreased the sensitivities to EO9 in both the parent and the resistant cell lines. Formation of an alkylating metabolite was significantly decreased in the resistant cells, in parallel to the degree of resistance. We concluded that deficient drug activation due to decreased DTD activity was important as a mechanism of resistance to MMC in PC‐9, a relatively DTD‐rich NSCLC cell line.

Addition of a 2-month low-dose course of levofloxacin to long-term erythromycin therapy in sinobronchial syndrome

Background: We previously reported that a 6‐month low‐dose course of ofloxacin combined with long‐term low‐dose erythromycin therapy (EM therapy) was superior to EM therapy alone for sinobronchial syndrome (SBS), especially during the initial 2 months of treatment. However, there was no data as to whether discontinuation of low‐dose ofloxacin after 2 months results in symptom relapse. This study was designed to clarify this issue.

Additive Effect of Continuous Low Dose Ofloxacin on Erythromycin Therapy for Sinobronchial Syndrome

It has been established that long-term low-dose erythromycin therapy (EM therapy) is very effective for sinobronchial syndrome, a common condition in Japan characterized by chronic upper and lower airway inflammation. The effect does not result from its bacteriocidal activity and the detailed mechanisms are not known. It takes 3-6 months for EM therapy to improve the symptoms. This study was designed to evaluate the additive effect of continuous low dosage or intermittent usual dosage of ofloxacin (OFLX) on EM therapy in patients with sinobronchial syndrome. Patients with sinobronchial syndrome were randomly allocated to receive one of the following four regimens. Patients in Group A received both low-dose OFLX and EM therapy daily for 6 months. Patients in Group B received EM therapy and intermittent treatment of OFLX for 6 months. Patients in Group C underwent EM therapy for 6 months. Patients in Group D received neither OFLX nor EM therapy. All patients were given carbocystein for more than 2 months before starting each treatment and during the study period. In patients receiving OFLX and/or EM therapy, these antimicrobial agents were well-tolerated during the treatment period. Amount of sputum in the morning was significantly less in Group C than in Group D after 3-6 months, and decreased significantly in Group A as compared with Group B after 2 weeks, Group C after 2 weeks to 2 months, and Group D after 2 weeks to 6 months. Other symptoms such as number of expectorations, difficulty of expectoration and severity of cough also improved rapidly in Group A. These findings suggest that it is useful to add low-dose OFLX to EM therapy for sinobronchial syndrome, especially within l-2 months from starting treatment, and it may be cost-effective as this combination therapy can shorten the treatment period of EM therapy.

A Case of Pulmonary Epithelioid Hemangioendothelioma.

症例は37歳, 女性. 血痰を主訴として両側肺野に多発性小粒状陰影を指摘された. 胸腔鏡下肺生検にて結節には空胞をもつ異型類上皮細胞を認め, 免疫染色にて内皮細胞のマ-カ-である第VIII因子関連抗原およびビメンチンの発現を確認し, 類上皮血管内皮腫と診断した. 腹部CTにて肝に占拠性病変を1個認め, 同様の病変が疑われた. 現在無治療にて経過観察中である. 類上皮血管内皮腫は血管内皮細胞由来の稀な腫瘍であり, 単発例では手術的切除が施行されるが, 手術不能例では予後は平均5年程度と不良である.

Effect of Fosfomycin on Cisplatin Nephrotoxicity and its Pharmacokinetics.

Cisplatin (CDDP) の腎障害に対するfosfomycin (FOM) の軽減効果とその時のCDDPの血中動態について検討した.対象はCDDP80mg/m2を投与された肺癌患者13例で, 1・3コース目にFOMを1日4-6g, 5日間静脈内投与した.2コース目はNAGの24時間尿中排泄量がCDDP投与2日目から4日目をピークとして上昇を示し, 3日目で1・3コース目と比べて有意に増加した.総Platinum (Pt) 濃度のarea under the curve (AUC) については2コース目は1コース目より有意に高く, 3コース目は1コース目より高い傾向にあり, 最高血中濃度は2コース目は1コース目より高い傾向にあった.非蛋白結合型Ptの血中濃度はいずれのコースでも明らかな差異は認めなかった.蛋白結合型Ptの最高血中濃度については2コース目は1コース目より有意に高かった.また, 総Ptおよび蛋白結合型PtのAUCは尿中NAGのピークと有意な相関関係を認めた.以上よりFOMはCDDPの腎障害の軽減作用を示した.薬物動態学的検討からはFOMが総Ptおよび蛋白結合型Ptに何らかの影響をもたらすことが示唆されたが, 非蛋白結合型Ptに影響はなく抗腫瘍効果に影響を与えないものと考えられた.