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Much evidence has accumulated that the epidermal growth factor receptor (EGFR) and its family members are strongly implicated in the development and progression of lung cancers. Somatic mutations of the EGFR gene were found in about 25–40% of Japanese lung cancer patients. More recently, erbB2 mutations are found in about 4% of European-derived lung cancer patients. We have investigated EGFR and erbB2 mutation status in 95 surgically treated nonsmall cell lung cancer (NSCLC) cases from Nagoya City University Hospital. Seventy-five adenocarcinoma cases were included. The presence or absence of EGFR and ernB2 mutations of kinase domains were analyzed by reverse transcription polymerase chain reaction (RT-PCR) amplifications and direct sequences. We have also investigated erbB2 mutation status in 27 surgically treated NSCLC cases followed by treatment with gefitinib from Kinki-chuo Chest Medical Center. EGFR mutations (CTGfiCGG; L858R) were found from 14 of 95 lung cancer patients. We also detected the deletion 1a-type mutations from 9 patients and deletion 4-type mutations from 6 patients in exon 19. In exon 20, 4 mutations including 2 novel mutations were found. Total EGFR mutations were present in 35 patients (36.8%). These mutation statuses were significantly correlated with gender (women 73.3% vs. men 20%, p < 0.0001), smoking status (never smoker 69.4% vs. smoker 16.9%, p < 0.0001), pathologic subtypes (adenocarcinoma 45.1% vs. nonadenocarcinoma 12.5%, p 5 0.0089) and differentiation status of the lung cancers (well 51% vs. moderately or poorly 18.4%, p 5 0.0021). On the other hand, erbB2 mutation was only found from 1 of 95 patients, at exon 20. This patient was female and a never smoker with adenocarcinoma. This 12 nucleotide insertion mutation (2324–2325 ins ATACGTGATGGC) was located in the exon 20 at kinase domain (775–776 ins YVMA). There was no erbB2 mutation in 27 gefitinib-treated NSCLC patients. In total, we have found only 1 erbB2 mutation from 122 (0.8%) Japanese NSCLC patients. There was a significantly higher erbB2 positive (21/31) ratio in EGFR mutant patients (13/25, 52.0%) compared to EGFR wild-type patients (10/ 62, 16.1%; p 5 0.0247). The NSCLC specimen with erbB2 mutation showed 11 immunoreactivity. The EGFR mutation status might correlate with the clinicopathologic features related to good response to gefitinib, such as gender, smoking history and pathologic subtypes of lung cancers. However, erbB2 mutation is rare from Japanese lung cancer and is of limited value for molecular target therapy. ' 2005 Wiley-Liss, Inc.

Purpose: To evaluate the efficacy and toxicity of a novel combination chemotherapeutic regimen including cisplatin with an oral anticancer agent, S-1 that consisted of tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate, for non–small-cell lung cancer (NSCLC) patients. Experimental Design: In this phase II trial, patients with locally advanced and metastatic NSCLC were treated with the oral administration of S-1 at 40 mg/m2 twice a day for 21 consecutive days while cisplatin (60 mg/m2) was administered intravenously on day 8. This schedule was repeated every 5 weeks. Results: Of 56 patients enrolled in the study, 55 patients were eligible and analyzed. The median number of cycles administered was 3 (range, 1–12 cycles). Among these 55 patients, one complete response and 25 partial responses were observed with an overall response rate of 47% (95% confidence interval, 34–61%). The median survival time was 11 months and the 1-year survival rate was 45%. Hematologic toxicities of grades 3 and 4 included neutropenia (29%) and anemia (22%). No grade 4 nonhematologic toxicity was observed. Grade 3 toxicity included anorexia (13%), vomiting (7%), or diarrhea (7%). Conclusions: S-1 plus cisplatin combination chemotherapy showed a promising effectiveness with acceptable toxicity rates in patients with advanced NSCLC. These results warrant further investigations of this regimen including a randomized controlled trial for its use as a first line treatment for NSCLC.

Background: We conducted an open-label, dose titration study to assess the efficacy and tolerability of controlled-release oxycodone in the therapy of cancer pain management, starting with a newly developed 5 mg tablet every 12 h. Methods: Twenty-two Japanese cancer patients with pain who had not been taking opioid analgesics over the previous 2 weeks were enrolled. The length of time and the dose needed to attain stable and adequate pain control were evaluated in addition to the assessment of analgesic efficacy and safety during the study period. Results:Eighteenpatientsintheefficacypopulation(18outof20,90%)attainedstable,adequate pain control. Two-thirds of the patients attained stable, adequate pain control without any dose titration. The mean length of time was 1.2 days. In these patients, the pain was significantly reduced in intensity, even at 1 h after the initial dose intake. Fifteen patients (68%) reported at least one side effect, but only one patient had to withdraw from the study because of a side effect. Conclusion: The results suggest that controlled-release oxycodone tablets offered stable and adequate pain control within a short period of time in most Japanese cancer patients who have not been taking opioid analgesics, and could be effectively titrated against pain from a starting dose of 5 mg every 12 h. This indicates that a lower strength controlled-release oxycodone formulation may make it possible to start and titrate the dose more appropriately and carefully in patients who are sensitive to opioid analgesics.

目的.非小細胞肺癌における, プラチナを含まない新規抗癌剤3剤による経時的投与法による有効性と毒性の評価. 対象と方法.44施設の共同第II相試験.未治療の切除不能非小細胞肺癌44例. gemcitabine (GEM) 1000mg/m2とvinorelbine (VNR) 25mg/m2, iv, days1, 8, 3週毎, 3サイクルの後にDocetaxe1 (DOC) 60mg/m2, iv, day1, 3週毎, 3サイクルを投与した. RECISTによる奏効率は47.7%, 1年生存率は59%, 生存期間中央値は15.7%であった. 主な毒性は骨髄抑制であったが, GEM/VNRのサイクルではgrade3及び4の好中球減少症は36.6%, grade3～4の貧血は4.5%, grade3の血小板減少症は2.3%と軽微であり, grade3の肺臓炎は2例 (4.5%) に起こった.DOCのサイクルではgrade3～4の好中球減少は39.4%に出現した.33症例がGEM/VNRの3サイクルを完遂し, うち22例はDOCの3サイクルを完了した. 治療関連死はなかった. 結論. この治療法はactiveで毒性も軽度であった. 現在この治療法と標準的治療の一つであるcarboplatin+paclitaxelとの第III相比較試験をJapan.SWOG common arm trialとして実施中である.

We designed a phase II study of weekly irinotecan (CPT-11) and carboplatin for refractory or relapsed small cell lung cancer (SCLC) and assessed the response rate, survival, and toxicity. Twenty-nine patients with refractory or relapsed SCLC were entered onto the trial. The median time off chemotherapy was 3.5 months (range: 0.8-12.9). Patients were treated at 4-week intervals using CPT-11 (50 mg/m(2) intravenously on days 1, 8 and 15) plus carboplatin (AUC = 2 mg/ml min, intravenously on days 1, 8, 15). All patients were assessable for toxicity and survival; 28 patients were assessable for response. There were nine partial responses (PRs). Overall response rate was 31.0% (95% CI: 15.3-50.8%). The median time to progression was 3.5 months. Median survival time was 6.1 months. Major toxicity was myelosuppression. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 52 and 21% of patients, respectively. Grade 3-4 diarrhea was observed in 7%. There was one treatment-related death due to febrile neutropenia and sepsis. This combination of CPT-11 and carboplatin seems to be active second-line regimen with acceptable toxicity against small cell lung cancer.

Background The combination of paclitaxel (225 mg/m(2), 3 h infusion) and carboplatin [area under the curve (AUC) 6 mg/ml x min] is used widely for non-small cell lung cancer in the USA and is one of the standard regimens in the Southwest Oncology Group. In Japan, however, the upper limit of the approved dose for single-use paclitaxel is 210 mg/m(2) and the optimum dose of this agent in combination with carboplatin has not yet been established. This study was designated to determine whether the paclitaxel dose of 225 mg/m(2 ) plus carboplatin (AUC = 6) is tolerable for Japanese patients with untreated advanced non-small cell lung cancer. Methods Ten patients were enrolled between October 1999 and June 2000 and all of these patients were evaluable for toxicity. Chemotherapy consisted of carboplatin (AUC = 6 mg/ml x min) and 225 mg/m(2 )of paclitaxel on day 1 every 3 weeks. Results Neutropenia was the major toxicity and grade 4 neutropenia was observed in seven of the 10 patients (70%), but febrile neutropenia was not observed. Grade 4 anemia as a dose-limiting toxicity was observed in two patients. This was due to gastric ulcer bleeding in both patients. Only one patient experienced grade 3 peripheral neuropathy. No grade 3 or more myalgia or arthralgia was reported. Overall, 44 courses of chemotherapy were administered in 10 patients. Partial responses were observed in six of the 10 patients (60%). Median survival time was 7.7 months. Conclusion Paclitaxel at 225 mg/m(2) in a 3 h infusion and carboplatin AUC = 6 appears to be tolerable in Japanese patients with untreated advanced non-small cell lung cancer.

Irinotecan hydrochloride, a topoisomerase I inhibitor, is effective against small-cell lung cancer. In a phase 2 study of irinotecan plus cisplatin in patients with extensive small-cell lung cancer, there was a high response rate and a promising median survival time.We conducted a multicenter, randomized, phase 3 study in which we compared irinotecan plus cisplatin with etoposide plus cisplatin in patients with extensive (metastatic) small-cell lung cancer.The planned size of the study population was 230 patients, but enrollment was terminated early because an interim analysis found a statistically significant difference in survival between the patients assigned to receive irinotecan and cisplatin and those assigned to receive etoposide and cisplatin; as a result, only 154 patients were enrolled. The median survival was 12.8 months in the irinotecan-plus-cisplatin group and 9.4 months in the etoposide-plus-cisplatin group (P=0.002 by the unadjusted log-rank test). At two years, the proportion of patients surviving was 19.5 percent in the irinotecan-plus-cisplatin group and 5.2 percent in the etoposide-plus-cisplatin group. Severe or life-threatening myelosuppression was more frequent in the etoposide-plus-cisplatin group than in the irinotecan-plus-cisplatin group, and severe or life-threatening diarrhea was more frequent in the irinotecan-plus-cisplatin group than in the etoposide-plus-cisplatin group.Irinotecan plus cisplatin is an effective treatment for metastatic small-cell lung cancer.

Background Usually, total and filtered platinum concentrations in plasma are monitored after cisplatin administration. However, these concentrations represent a mixture of unchanged cisplatin and metabolites. In this work, we studied population pharmacokinetic analysis based on these platinum concentrations. Methods Twenty-seven patients (23 males, four females) were administered cisplatin (60-100 mg/m2) with intravenous constant infusion for 90 min. Blood samples were taken at about three points per patient. The concentrations of cisplatin and platinum in the plasma were determined by high-performance liquid chromatography and atomic absorption spectrometry, respectively. Population pharmacokinetic analysis was performed using the program NONMEM (Version V) with the one- or two-compartment model with zero-order infusion. Results The clearance and volume of distribution for all platinum species studied were significantly related to the body surface area of the patients. Only the clearance of filtered platinum was significantly related to urinary N-acetyl-beta-D-glucosaminidase and the other covariates were not related to these pharmacokinetic parameters with respect to unchanged cisplatin and total platinum concentrations. Conclusion The dosage regimen based on the filtered platinum concentration which is usually monitored may result in possible misinterpretation because the detected covariate is different between unchanged cisplatin and filtered platinum.

The purpose of this study was to evaluate the efficacy and safety of a novel oral anticancer fluoropyrimidine derivative, S-1, in patients receiving initial chemotherapy for unresectable, advanced non-small-cell lung cancer (NSCLC). Between June 1996 and July 1998, 62 patients with NSCLC who had not received previous chemotherapy for advanced disease were enrolled in this study. 59 patients (22 stage IIIB and 37 stage IV) were eligible for the evaluation of efficacy and safety. S-1 was administered orally, twice daily, after meals. 3 dosages of S-1 were prescribed according to body surface area (BSA) so that they would be approximately equivalent to 80 mg m−2day−1: BSA < 1.25 m2, 40 mg b.i.d.; BSA≥1.25 but

Modification of vestibular function by strong vestibular stimuli (SVS) was studied using electro-oculography (EOG) in 12 subjects with congenital nystagmus (CN). Rotation tests using a computerized rotary chair system were repeated five times in the same subjects. In the first and fifth tests, a conventional trapezoid (±6°/s 2 for 10 s) rotation was used. In the second to fourth tests, sudden deceleration (-60°/s 2 for 1 s) was employed for 60 s after the same rotation. Waveforms were classified into three types: jerk to the right (n=5); jerk to the left (n=4); and pendular (n=3). Analysis of the changes in the duration and the frequency of vestibular nystagmus (VN) with decelerative stimuli between the first and fifth tests was conducted. The duration of VN increased in all subjects with jerk to the right and in one of three subjects with pendular nystagmus. The frequency of VN increased in all but one of the subjects with jerk to the right and in one of the four subjects with jerk to the left, but did n...

肺癌臨床試験でのインフォームドコンセント (以下, IC) におけるナースの役割について検討した.進行肺癌に対する臨床試験対象患者30名に対し, ICにおける医師の説明内容の理解度をアンケートで調査し, 理解不足箇所には看護婦による補足説明やパンフレットによる説明を行い, 患者の理解度への影響を検討した.ナースの補助説明により, 12項目のアンケート項目中, 11項目で患者の理解度は改善し, 治療の選択を自己又は家族と相談のうえ, 自分で決めたとする回答が26/30名 (86.7%) であり, 自己決定の割合が多くを占めていた.また, 意志決定の上でナースの補助が手助けになったとの回答は26/30名 (86.7%) の患者に得られた.ナースは被験者のよりよい医療を受ける権利, 人権の擁護などを保障するなどの, 臨床試験のICをより円滑に行う上で, 分かりやすい情報の提供とその実質的な理解にとって重要な役割を持つと考えられる.

Background: To determine the efficacy, toxicity and pharmacokinetics of intrapleural cisplatin (CDDP) and etoposide as a treatment for malignant pleural effusions (MPE) in patients with non-small cell lung cancer (NSCLC). Methods: Seventy patients with MPE associated with NSCLC were enrolled in this study. In 68 patients, a catheter was inserted into the pleural cavity, within 24 h after complete drainage of the pleural effusion, CDDP (80 mg/m2) and etoposide (80 mg/m2) were simultaneously administered successfully via the catheter and the catheter was clamped. Seventy-two hours later, the catheter was unclamped to allow drainage. The catheter was removed when the accumulated intrapleural fluid decreased to 20 ml or less per day. Results: The pharmacokinetic profiles showed high maximum concentrations of CDDP (free form, 88 µg/ml) and etoposide (182.4 µg/ml) in intrapleural fluids. CDDP did not remain for a long period (free form, β-phase half-life = 10.51 h) in the fluids, while etoposide persisted for a long period (β-phase half-life = 62.53 h). The overall response rate was 46.2%, the median survival time 32.3 weeks, the 1-year survival rate 28.7% and the 2-year survival rate 12.8%. The most serious adverse reactions were WHO grade 3 anemia (3 patients), grade 3 nausea and vomiting (17 patients), grade 3 constipation (1 patient), grade 3 pulmonary toxicity (1 patient), grade 4 fever (1 patient), grade 3 infection (1 patient) and grade 3 mental disorder (1 patient). Conclusion: Intrapleural administration of CDDP and etoposide was an effective and acceptable regimen for patients with MPE due to NSCLC.

The present report is on a 67-year-old man with stage IV small cell lung cancer and early-stage centrally located squamous cell cancer of the lung. He was diagnosed as small cell lung cancer with multiple metastasis to the ipsilateral lung and was found to have a central-type early-stage squamous cell cancer by bronchoscope. After obtaining a complete response to the small cell lung cancer with chemotherapy and radiotherapy, photodynamic therapy was applied to the squamous cell carcinoma, resulting in complete disappearance of the tumor. Recurrence of small cell cancer occurred at the ipsilateral lung and this patient died of small cell cancer 8 years after initiation of treatment. Post mortem examination confirmed complete disappearance of squamous cell cancer treated by photodynamic therapy. This is a rare case of long-term survival with stage IV small cell lung cancer and early-stage central-type squamous cell lung cancer successfully treated by photodynamic therapy.

Background: Etoposide is a highly schedule-dependent drug. We investigated combination chemotherapy of oral etoposide and intravenous cisplatin for small cell lung cancer (SCLC). Methods: Fifty-seven patients withSCLCwithextensive disease (ED)or limited disease(LD)with pleural effusion registered in the 21 institutions of the JapanClinical Oncology Groupweretreated with oral etoposide 40 mg/m 2/d for 21 days and cisplatin 80 mg/m 2 on day 1 of every28-period day. The entry period was between February 1992 and August 1995.The actualpercentages of patients treated with etoposide were 93.6, 89.5, 92.3 and 96.9% in the first, second, third and fourth cycles, respectively. Results: Nine patients(15.8%) achieved a complete response resulting in an overall response rateof 82.5%(95%confidence interval, 70.1-91.3%). Leukopenia andthrombocytopenia of grade 3 or 4 were observed in 36 (49.1%) and 8 (14.0%) patients, respectively. Anemia of grade 3 or 4 occurred in 28 (49.1 %) patients. Nausea, vomiting, anorexia and alopecia were common adverse events. One patient died of hemoptysis due to grade 4 thrombocytopenia.The mean survival time was 47.0 weeks. Conclusions: Thisdoseandschedule of administration of etoposide in combination withcisplatin areconsidered to beclinically active. However, prolonged gastrointestinal toxicityof oraletoposide was a problem in comparison withthe standard etoposide platinum regimen givenby intravenous administration.

A phase II trial was conducted to evaluate the efficacy and toxicity of the Egorin's carboplatin dosing formula with 14-day oral etoposide in 38 elderly patients with small-cell lung cancer (SCLC). The overall response rate was 81%. Median survival times were 15.1 months for 16 limited-disease (LD) and 8.6 months for 22 extensive-disease (ED) patients. Myelosuppression was the principal side-effect. This regimen is an active regimen in the treatment of elderly SCLC patients.

The level of hyaluronic acid (HA) was determined in the pleural fluid of 99 patients, including 19 with malignant mesothelioma, 27 with lung cancer, 1 with breast cancer, 1 with mediastinal tumor and 51 with non-malignant diseases. With a cut-off level at 100 micrograms/ml, the pleural fluid concentration of HA was high in 36.8% of patients (7 of 19) with malignant mesothelioma and 1.3% of patients (1 of 80) with lung cancer and other malignant and non-malignant diseases. The mean concentration of pleural fluid HA was significantly higher in patients with mesothelioma than in those with lung cancer and other malignant and non-malignant diseases. The pre-test probability of MM was 5.9% in this series. The LRs foror = 100, 50-99 andor = 49 micrograms/ml are 28.3, 3.3 and 0.5, respectively; these put the post-test probabilities at 64, 17 and 3%, respectively. Indeed, in cases of uncommon disease such as MM, the post-test probability is low even if the cut-off level of HA isor = 100 micrograms/ml. The discrimination between malignant mesothelioma and lung cancer needs special attention. In these two diseases, the LRs of MM for pleural fluid CEA30, 10-30 and10 ng/ml were 0.2, 1.9 and 2.4, respectively. The pre-test probability of MM for HAor = or 100 micrograms/ml is 64%. Furthermore, because the LR for CEA is10 ng/ml, the post-test probability is 81%. When the combination of two markers is considered, the high level of HA and the low level of CEA may be useful for the differential diagnosis of MM from pleuritis carcinomatosa.

Sixty-three patients with extensive-stage small-cell lung cancer were randomized to receive either cyclophosphamide, vincristine, doxorubicin and etoposide (CODE) alone or CODE plus recombinant human granulocyte colony-stimulating factor (rhG-CSF). rhG-CSF administration in support of CODE chemotherapy resulted in increased mean total received dose intensity for all drugs (P = 0.03) with a significant improvement in survival (P = 0.004).

国療肺癌研究会で経験した肺芽腫8例を対象として, その臨床像および病理像を検討した.8例のうち男性6例, 女性2例であった.5例では胸痛および血痰などの自覚症状がみられたが, 残りの3例は無症状であり検診などで発見された.今回検討した8例はすべて手術例であった.術前に肺芽腫と診断されていたものは経皮針生検で診断された1例のみで残りの7例はすべて切除標本で肺芽腫と診断されており, 術前診断は困難であった.切除後の予後をみてみると2例は術後10年5ヵ月および3年2ヵ月の現在生存中であり, 3例は術後9ヵ月, 4ヵ月および3ヵ月で原病死していた.残りの3例は他病死であった.その病理組織像をみてみると生存中の2例は上皮性成分が主体で間葉系成分はわずかであり, 術後1年以内に原病死した3例では逆に間葉系成分が主体となっており, 腫瘍の病理像とその予後は深く関係していることが示唆された.

肺癌を非小細胞癌と小細胞癌に分け,各々の化学療法につき述べた.ユニークな化学構造や作用機序を有する新規抗癌薬が近年出て来ており,これらを併用した治療成績は従来のものより優れているようである.

A previous study showed a survival benefit with maintenance therapy with pemetrexed in patients with advanced non-small cell lung cancer (NSCLC). However, it remains unclear whether continuation maintenance therapy with pemetrexed is beneficial in Japanese patients. Here, we present our phase II study that assessed the efficacy and safety of cisplatin plus pemetrexed as induction chemotherapy, followed by maintenance therapy with pemetrexed in advanced NSCLC patients in Japan.Chemotherapy-naïve patients received 500 mg/m(2) pemetrexed and 75 mg/m(2) cisplatin on day one every three weeks for four cycles. In patients who responded to therapy or achieved stable disease, pemetrexed was continued until disease progression. The primary endpoint of this study was the progression-free survival rate at six months (PFS-6).Of the 35 patients initially enrolled in the study, 18 (51%) received maintenance chemotherapy with pemetrexed. The median PFS was 6.7 months, and the PFS-6 was 60% (95% confidence interval [CI], 42-76%). Median overall survival (OS) was 15.5 months (95% CI, 8.3-22.7 months). The median PFS and OS in patients who received maintenance chemotherapy with pemetrexed were 9.5 months and 25.3 months, respectively. The most frequently noted severe toxicity during induction chemotherapy was neutropenia, which occurred in seven patients. Two patients discontinued maintenance therapy owing to prolonged grade 2 edema in one patient and grade 3 neutropenia in another.Continuation maintenance chemotherapy with pemetrexed is associated with a survival benefit in patients who have completed induction chemotherapy for non-squamous NSCLC.

This paper proposes an interference detection method in MIMO transmission, which utilizes periodical preamble signals in a frequency domain. The signals are mapped in only several subcarriers in short preamble signals of IEEE802.11 based OFDM signals and the signal in a frequency domain is transformed by IFFT at the transmitter. We assume the collision due to multiple short preamble signals. In the propose method, second antenna receives the preamble signals while first antenna transmits the preamble signals. The interference can be detected by subtracting the short preamble signal which is multiplied by the estimated channel response from the received signal after the FFT processing. Moreover, we utilize the dual polarization to reduce the mutual coupling between the transmitter and receiver. By a computer simulation, it is shown that proposed method can successfully detect interference in OFDM signal when the interfering power is greater than the noise power.

Assessment of the efficacy of docetaxel plus carboplatin vs. paclitaxel plus carboplatin in Japanese patients with advanced non-small cell lung cancer (NSCLC).Chemotherapy-naïve patients were randomly assigned at a ratio of 2 to 1 to receive six cycles of either docetaxel (60 mg/m(2)) plus carboplatin [area under the curve (AUC)=6 mg/ml min] or paclitaxel (200 mg/m(2)) plus carboplatin (same dose), on day 1 every 21 days. The primary end-point was progression-free survival (PFS).A total of 90 patients were enrolled. Overall response rate, median PFS and median survival time in the docetaxel-plus-carboplatin group and the paclitaxel-plus-carboplatin group were 23% vs. 33%, 4.8 months vs. 5.1 months, and 17.6 months vs. 15.6 months, respectively. The docetaxel-plus-carboplatin group had a higher incidence of grade 3 or 4 neutropenia (88% vs. 60%).Both regimens were similarly effective in Japanese patients with advanced NSCLC.

Summary Purpose We compared the activity and toxicity of vinorelbine (VRB) and vindesine (VDS) in a randomized crossover study in patients with previously untreated stages IIIB or IV non-small-cell lung cancer (NSCLC). Patients and methods Two hundred four patients were assessable for response and toxicity. VRB was administered at a dose of 25 mg/m2 weekly and VDS at a dose of 3 mg/m2 weekly. Patients who failed to respond after 4 cycles of initial monotherapy were switched to a combination chemotherapy (VRB → VDS + cisplatin (P) or VDS ← VRB + P). Results Objective response was observed in 31.1% of patients in the VRB arm versus 8.9% of those in the VDS arm (P = 0.0002). The median duration of response to VRB was 18.5+ weeks (range, 7.9 to 107.5+ weeks) compared with 11.7+ weeks (range, 6.0 to 35.0+ weeks) for VDS. Of the 69 patients who failed to respond to initial monotherapy, 33 in the VRB group who subsequently received VDS + P did not respond and 13 (26.5%) of 49 initially on VDS who received subsequent VRB + P responded. The rates of grades 3 and 4 leukopenia were similar in the two monotherapy arms (VRB, 55.3% vs. VDS, 48.5%). However, grade 3 anemia was more frequent in the patients on VRB than in those on VDS. The incidence of peripheral neurotoxicity was significantly higher with VDS than with VRB (P = 0.002), but VRB induced a slightly higher rate of local cutaneous reaction than VDS (P = 0.012). With the combination of cisplatin and these vinca alkaloids, peripheral neurotoxicity was less frequent in the VRB group than in the VDS group. Conclusion Our results demonstrate that VRB yields a higher response rate than VDS in stage IIIB or IV NSCLC, with the same extent of toxicity in terms of leukocytopenia. The peripheral neurotoxic effects were also milder with VRB than with VDS. In second-line chemotherapy, there was a notable difference in response between the VRB + P and VDS + P regimens.

Data on 16 potential risk factors for myelosuppression were assessed in 134 patients who received either vindesine and cisplatin (VP) or mitomycin C, vindesine and cisplatin (MVP) for inoperable stage III or IV non-small cell lung cancer in a randomized trial. Determinant factors for myelosuppression were evaluated by using univariate analysis and the logistic regression model. Recursive partitioning and amalgamation (RPA) was also used to define patient subgroups frequently suffering from severe bone marrow toxicity. Overall, 33 (25%) of 134 patients experienced at least one episode of grade 4 leukopenia. In univariate analysis, age, body surface area, serum creatinine, and pretreatment hemoglobin concentration were associated with severe leukopenia. A multivariate analysis using the logistic regression method showed that only raised creatinine level was an independent predictor for grade 4 leukopenia (P = 0.049). The RPA model generated three distinct subgroups based on age, body surface area and regimen. The three subgroups were distinguished by the frequency of severe (grade 4) leukopenia (50%, 25%, and 2.4%, respectively) (P0.001). Grade 4 leukopenia occurred more frequently in patients in class 3 (ageor = 65 years and treatment with MVP). The RPA model was useful in identifying the risk factors for myelosuppression induced by cisplatin-based chemotherapy, and in defining patient subgroups with elevated risk of toxicity.

Twenty-four previously treated patients with refractory or relapsed small cell lung cancer (SCLC) were entered into a prospective, multicenter phase II study. All 24 patients had been pretreated with some form of cisplatin-based chemotherapy. The median time of chemotherapy was 4.2 months (range 1.4-9.4 months). Patients were treated with a dose of 25 mg/m2 of vinorelbine weekly. Twenty-four patients were eligible for response and for toxicity. Partial response was observed in 3 out of 24 eligible patients (12.5%; 95% confidence interval, 2.7-32.4%). All 3 patients who responded had previous chemotherapy including vincristine. The most common toxicity was leukopenia (91.7%, 66.7% in WHO 3-4 grade) and anemia (70.8%, 20.8% in WHO 3 grade). Nonhematological toxicities were moderate and mild. These results support a two-state sequential study design of previously untreated patients for further phase II study in SCLC.

Between May 1987 and March 1994, upper airway and tracheobronchial electrosurgery with snare was performed in 13 patients (10 men and 3 women), ranging in age from 18 to 87 years. Four patients had benign lesions, and nine had malignant tumors. Total eradication has been achieved in the two patients with benign lesions. Electroexcision of the endobronchial portion of the tumor helped to clear the respiratory airways in all cases with malignant tumors. There has been no major side effects such as bleeding due to this method. Electrocautery is an available economical tool, which helps to diagnose and treat obstructing airway mass lesions.

We report 11 cases of endobronchial foreign body. From January 1982 through December 1994, a total of 11 cases were diagnosed roentogenographically and bronchoscopically at our hospital. These patients consisted of 10 men and 1 woman with a mean age of 58.5 years (range 33 to 77 years). Symptoms on presenting were usually cough, sputum, or chest pain. The foreign bodies were inorganic in 10 cases and of organic origin in 1 case. Three patients were not aware that they had aspirated a foreign body. In 9 patients, the endobronchial foreign bodies were successfully removed endoscopically. One patient spontaneously expectorated the foreign body before bronchoscopy. One patient underwent thoracotomy because the foreign body could not be removed bronchoscopically. There were no severe complications during or after the endoscopic removal of the foreign bodies, but in one patient extraction of the foreign body caused pneumonia after bronchoscopy. In conclusion, flexible bronchoscopy is useful for the diagnosis and treatment of endobronchial foreign bodies.

OBJECTIVE The purpose of this study was to evaluate the diagnostic accuracy of bronchoscopy with virtual bronchoscopy (VB) navigation. PATIENTS AND METHODS Forty-two consecutive patients with ≤30-mm diameter peripheral pulmonary shadows or lesions that were difficult or impossible to identify on plain x-rays regardless of size were selected. Before bronchoscopy, multidetector computed tomography was performed, and VB images were created. Then, ultrathin bronchoscopy was carried out with VB navigation followed by conventional 4-mm diameter bronchoscopy. RESULTS Thirty-seven patients were finally enrolled. There were 12 re-examination cases in which earlier conventional bronchoscopy was nondiagnostic. Diagnosis was established in 28 patients (25 malignant and 3 benign lesions), with the diagnostic yield of 75.7% (sensitivity 86.2%, specificity 62.5%, positive predictive value 89.3%, negative predictive value 55.6%, and accuracy 81.1%). The diagnostic yield for lesions of diameter ≤20 mm, 21 to 30 mm, and ≥31 mm were 76.9%, 76.5%, and 71.4%, respectively, for all patients, and 90%, 84.6%, and 83.3%, respectively, for malignant cases. The diagnostic yield in patients who underwent re-examinations was 83.3% for all cases and 88.9% for malignant cases. Three patients had completely invisible shadows on x-ray fluoroscopy and all of these cases were diagnosed on bronchoscopy. No statistically significant difference was observed between the diagnostic yield for the different sizes, pathology, and number of bronchoscopies required. CONCLUSIONS Bronchoscopy with VB navigation yielded high accuracy even for small peripheral pulmonary nodules and shadows that were difficult or impossible to identify on plain x-rays, even for patients in whom earlier conventional bronchoscopy was nondiagnostic.

Background Gefitinib is an effective treatment for patients with non-small cell lung cancer who harbor activating epidermal growth factor receptor (EGFR) mutations. However, no optimal strategy has been established for these patients after gefitinib fails. The aim of this retrospective study was to assess the survival benefit of continued gefitinib treatment in these cases. Patients and methods We analyzed gefitinib responders with activating EGFR mutations who developed progressive disease (PD) during the course of therapy. Prognostic variables were analyzed using a Cox proportional-hazards model. Results A total of 134 patients were retrospectively reviewed. Exon-19 deletion mutations and L858R point mutations were detected in 71 and 63 patients, respectively. Median survival time after PD with gefitinib was 14.3 months (95% confidence interval: 11.7–16.9). The median duration of continued gefitinib therapy beyond PD was 3.2 months. Statistical analysis showed that good performance status (0–1) (hazard ratio [HR]: 0.6), progression of a previously evaluated lesion (HR: 0.6), and at least 3 months of continued treatment (HR: 0.4) were independent prognostic factors. Conclusion Continuation of gefitinib beyond PD is an effective optional treatment in EGFR-mutated patients.

Summary Background It is unknown whether combined chemoradiotherapy improves overall survival in elderly patients with locally advanced non-small-cell lung cancer (NSCLC). The aim of this study was to assess whether radiotherapy plus carboplatin results in longer survival than radiotherapy alone in elderly patients with NSCLC. Methods This was a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Patients older than 70 years with unresectable stage III NSCLC were randomly assigned to chemoradiotherapy (60 Gy plus concurrent low-dose carboplatin [30 mg/m 2 per day, 5 days a week for 20 days]) or radiotherapy alone, using a minimisation method with biased-coin assignment balancing on Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1 vs 2), stage (IIIA vs IIIB), and institution. The primary endpoint was overall survival, which was analysed for the eligible population and stratified by ECOG performance status, stage, and institution. The trial was stopped early as a result of the second planned interim analysis. This study is registered with UMIN Clinical Trials Registry, number C000000060, and ClinicalTrials.gov, number NCT00132665. Findings 200 patients were enrolled from Sept 1, 2003 to May 27, 2010: 100 in the chemoradiotherapy group and 100 in the radiotherapy group. The second planned interim analysis was done 10 months after completion of patient accrual. At this time, median follow-up for censored cases was 19·4 months (IQR 10·3–33·5). In accordance with the prespecified stopping rule, the JCOG data and safety monitoring committee recommended early publication of this trial because the difference in overall survival favoured the chemoradiotherapy group. Median overall survival for the chemoradiotherapy and radiotherapy alone groups were 22·4 months (95% CI 16·5–33·6) and 16·9 months (13·4–20·3), respectively (hazard ratio 0·68, 95·4% CI 0·47–0·98, stratified log-rank test one-sided p value=0·0179). More patients had grade 3–4 haematological toxic effects in the chemoradiotherapy group than in the radiotherapy alone group, including leucopenia (61 [63·5%] vs none), neutropenia (55 [57·3%] vs none), and thrombocytopenia (28 [29·2%] vs two [2·0%]). Grade 3 infection was more common with chemoradiotherapy (12 patients [12·5%]) than with radiotherapy (four patients [4·1%]). Incidences of grade 3–4 pneumonitis and late lung toxicity were similar between groups. There were seven treatment-related deaths: three of 100 patients (3·0%) in the chemoradiotherapy group and four of 100 (4·0%) in the radiotherapy group. Interpretation For a select group of elderly patients with locally advanced NSCLC, combination chemoradiotherapy provides a clinically significant benefit over radiotherapy alone, and should be considered for this population. Funding Ministry of Health, Labour, and Welfare of Japan.

To evaluate the effectiveness of vinorelbine (NVB) in patients with non-small cell lung cancer (NSCLC), a late Phase II study was conducted. A total of 80 patients with Stage III or IV NSCLC who had no previous therapy were entered into the study. Seventy-nine patients were eligible for response and toxicity. NVB was administered weekly by intravenous injection at a dose of 25 mg/m 2 in 20 ml of saline and was generally administered in four cycles or more, unless patients had disease progression. Of the 79 eligible patients, 23 (29.1%) showed a partial response (95% confidence interval, 19.1–40.4%). The median duration of partial responses was 14.7+ weeks. The median survival time for all patients was 40.1+ weeks. The major toxicity was leukopenia. Grade 3 and 4 leukopenia occurred in 48 patients (60.8%). Other toxicities of grade 3 or more included anemia (6.3%), local cutaneous reaction (3.8%), pneumonitis (1.3%), nausea and vomiting (1.3%), mucositis (1.3%) and constipation (1.3%). The absolute dose-intensity of NVB was 22.33 mg/m 2 /week. A weekly schedule of intravenous administration of 25 mg/m 2 /week of NVB was reasonable for maintenance of activity, and acceptable for toxicity in the chemotherapy of advanced NSCLC.

The decomposition of PAN in the presence of nitric oxide and propene in the air was investigated at 30 °C under dark conditions. The number of nitric oxide molecules oxidized per each PAN molecule decomposed varied from 3.7 to above 5 with increase of the ratio of initial concentration of propene to that of nitric oxide.

Purpose: To determine the maximum tolerated dose of amrubicin (AMR) with a fixed dose of irinotecan (CPT-11). Methods: Patients having pathologically proven small cell lung cancer (SCLC) relapsed after one or two chemotherapies, and Eastern Cooperative Oncology Group performance status of 0 to 2 were eligible for the study. CPT-11 was delivered as 50 mg/m 2 on days 1 and 8, every 21 days. AMR was delivered on day 1. Doses of AMR were level 1: 80 mg/m 2 , level 2: 90 mg/m 2 , and level 3: 100 mg/m 2 . Dose elevation was determined using the modified continuous reassessment method. Tolerability was assessed after the first cycle. Another two cycles were conducted when disease progression or unacceptable toxicities were not observed. Results: Eighteen patients (mean age: 66.3 years) were enrolled. A total of 40 courses were conducted. Grade 3/4 toxicities of the first cycle were leukocytopenia: 11 (61%, grade 3/4: 8/3); neutropenia: 15 (83%, grade 3/4: 6/9); and thrombocytopenia: three (17%, grade 3/4: 2/1). Other grade 3 toxicities observed were febrile neutropenia, one; infection, three; diarrhea, one; and dyspnea, one. Dose-limiting toxicity was observed in two of six patients at level 2 (neutropenia and febrile neutropenia) and in one of six at level 3 (thrombocytopenia and infection). The maximum tolerated dose was level 3, and so, the recommended dose for phase II trials was judged to be 90 mg/m 2 . Objective response was obtained in four of eight patients who were able to evaluate responses. Median survival time was 13 months, with 68% at 1-year survival rate. Conclusions: This combination was well tolerated and showed encouraging activities in SCLC. Randomized phase II trials are being planned in chemonaive SCLC.

Background A randomized trial of vinorelbine plus gemcitabine followed by docetaxel (VGD) versus paclitaxel plus carboplatin (PC) in patients with advanced non-small-cell lung cancer showed no difference in overall survival (median survival time: 13.6 versus 14.1 months) between the two treatment groups. We report here the results of quality-of-life (QOL) study initiated in the mid-course of this randomized trial. Methods The patients themselves assessed the Functional Assessment of Cancer Therapy (FACT)-Lung (FACT-L), FACT-Taxane and the Functional Assessment of Chronic Illness Therapy - Spirituality (FACIT-Sp) QOL instruments at baseline and 6, 12 and 18 weeks after the treatment. The primary endpoint was a comparison of total QOL score for each assessment instrument between the two groups. Results Sixty-eight patients from the trial (VGD, 34; PC, 34) who submitted baseline questionnaires and at least one questionnaire over the course of treatment were eligible. Longitudinal analysis showed a significant difference in slope of the FACT-Taxane score (p = 0.004) between treatment regimens over time, but no difference was found in FACT-L score (p = 0.311) and FACIT-Sp score (p = 0.466) between the two groups. Conclusions The significant difference in slope of FACT-Taxane score favored the VGD regimen. These data should be considered in treatment decision-making for patients with advanced non-small-cell lung cancer. Trial registration NCT00242983.

A structure which shows a nearly constant mode coupling peak for a wide guide asynchronism range is described. The device exhibits low drive voltage and crosstalk

神経鞘腫は神経原性の良性腫瘍で顎口腔領域に好発すると言われている。われわれは比較的まれな左側頬部に発生した80×50×30mmの大きさの本腫瘍を経験した。本症例は顔貌の非対称, X線写真上で上顎の吸収が見られ, 病理学的にAntoni分類の混在型であった。過去30年間に本邦で報告された頬部から翼口蓋窩, 側頭下窩にかけて発生した神経鞘腫は女性に多く, 平均年齢は37.7歳で, 病理学的には混在型が多かった。

Ectopic antidiuretic hormone syndrome is a medical emergency characterized by dilutional hyponatremia. Clinical effectiveness of the vasopressin V2 receptor antagonist mozavaptan was evaluated in 16 patients. In short-term (7-day) treatment with the drug, serum sodium concentration (mean ± standard deviation) significantly (P = 0.002) increased from 122.8 ± 6.7 to 133.3 ± 8.3 mEq/l, and symptoms due to hyponatremia were improved. On the basis of these results, mozavaptan (Physuline(®)) was approved as an orphan drug for the treatment of the syndrome in 2006 in Japan. During the 43 months following its launch, 100 patients have been treated with the drug; overall clinical effects of the drug were found similar to those of this clinical trial. Clinically, mozavaptan may allow hyponatremic patients to be treated by aggressive cancer chemotherapy with platinum-containing drugs. Moreover, the drug may free patients from strict fluid-intake restrictions and thereby improve their quality of life.

Purpose: To evaluate motion artifacts, tissue contrasts, and lesion detectability in the neck with the periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) (BLADE) technique. Materials and Methods: A total of 46 patients referred for MRI of the neck were included in a comparison of T2-weighted BLADE (T2W-BLADE) sequence and T2W fast spin-echo (T2W-FSE) sequence. All examinations were performed at 3T using the same parameters. Two observers evaluated unlabelled images for motion artifacts, the preferred image quality, and lesion detectability. Region of interest (ROI)-based quantitative measurements were performed to assess tissue contrasts. The frequency of occurrence of the different assessed artifacts and the lesion detectability was tested using McNemar's test. Tissue contrasts were compared using the Wilcoxon paired test. Reader agreement was assessed using kappa test. Results: T2W-BLADE showed less ghosting and pulsation artifacts than T2W-FSE (P < 0.01). T2W-BLADE images were rated as better than or equal to T2W-FSE images in majority cases (93.5%; kappa = 0.64). There was not significant difference in tissue contrasts between T2W-BLADE and T2W-FSE. A total of 32 lesions were present in 32 patients and equally well seen on T2W-BLADE and T2W-FSE. Conclusion: T2W-BLADE can reduce motion artifacts and provide tissue contrasts and lesion detectability equivalent to T2W-FSE. J. Magn. Reson. Imaging 2010;32:1061–1067. © 2010 Wiley-Liss, Inc.

Objective: It is important to identify optimal regimens of cisplatin-based, third-generation chemotherapy and thoracic radiotherapy for patients with unresectable, Stage III, non-small cell lung cancer. Methods: Patients with unresectable, Stage III non-small cell lung cancer were treated with the following regimen: cisplatin 80 mg/m 2 on days 1 and 29, with irinotecan 60 mg/m 2 on days 1, 8, 15, 29, 36, and 43 and 30 mg/m 2 on days 57, 64, 71, 78, 85 and 92. Thoracic radiotherapy was started on day 57 at 2 Gy/day (total 60 Gy). Results: From February 1998 to January 1999, 68 patients were enrolled. Grade 3/4 toxicities during induction chemotherapy primarily included neutropenia (73.5%) and diarrhea (20.6%), while Grade 3/4 toxicities during concomitant thoracic radiotherapy with irinotecan consisted of neutropenia (18.4%), esophagitis (4.1%) and hypoxia (6.5%). There was one treatment-related death due to radiation pneumonitis. The response rate was 64.7% (95% confidence interval, 52.2‐75.9%). The median survival time was 16.5 (95% confidence interval, 12.6‐19.8) months. The 1- and 2 year survival rates were 65.8% (95% confidence interval, 54.4‐77.1%) and 32.9% (95% confidence interval, 21.6‐44.1%), respectively. Overall, only 36 (56%) completed both the scheduled chemotherapy and thoracic radiotherapy. Conclusions: Induction chemotherapy with cisplatin plus irinotecan followed by low-dose irinotecan and concomitant thoracic radiotherapy was feasible according to the prespecified decision criteria in this study for patients with unresectable Stage III non-small cell lung cancer. We did not decide to select this regimen for further investigations because approximately half of the patients completed the scheduled treatment.

Aprepitant is a new neurokinin-1 (NK1) receptor antagonist developed as a treatment for chemotherapy-induced nausea and vomiting (CINV). To evaluate the efficacy and safety of aprepitant used in combination with standard therapy (granisetron and dexamethasone), we conducted a multicenter, phase II, placebo-controlled, double-blind, randomized study in Japanese cancer patients who received cancer chemotherapy including cisplatin (≥70 mg/m2). Aprepitant was administered for 5 days. A total of 453 patients were enrolled. In the three study groups, (i) standard therapy, (ii) aprepitant 40/25 mg (40 mg on day 1 and 25 mg on days 2–5) and (iii) aprepitant 125/80 mg (125 mg on day 1 and 80 mg on days 2–5), the percentage of patients with complete response (no emesis and no rescue therapy) was 50.3% (75/149 subjects), 66.4% (95/143 subjects) and 70.5% (103/146 subjects), respectively. This shows that efficacy was significantly higher in the aprepitant 40/25 mg and 125/80 mg groups than in the standard therapy group (χ2 test [closed testing procedure]: P = 0.0053 and P = 0.0004, respectively) and highest in the aprepitant 125/80 mg group. The delayed phase efficacy (days 2–5) was similar to the overall phase efficacy (days 1–5), indicating that aprepitant is effective in the delayed phase when standard therapy is not very effective. In terms of safety, aprepitant was generally well tolerated in Japanese cancer patients. (ClinicalTrials.gov number, NCT00212602.) (Cancer Sci 2010; 101: 2455–2461)

BackgroundThere has been a growing interest in lung cancer in never-smokers.MethodsUtilizing a database from the National Hospital Study Group for Lung Cancer, information for never-smokers and ever-smokers with advanced non-small cell lung cancer was obtained from 1990 to 2005, including clinicopathologic characteristics, chemotherapy response, and survival data. Time of diagnosis was classified into two periods: 1990–1999 and 2000–2005. Multivariate analysis was performed using the Cox regression and logistic regression method, including gender, age, performance status, histology, stage, and period of diagnosis.ResultsThere were 1499 never-smokers and 3455 ever-smokers with advanced stage IIIB and IV diseases who received cytotoxic chemotherapy. Never-smokers generally included more females, were younger, with better performance status and more adenocarcinoma diagnosed (p < 0.0001 for all). Smoking status was a significant prognostic factor (never-smoker versus ever-smoker; hazard ratio [HR] = 0.880, 95% confidence interval [CI]: 0.797–0.970; p = 0.0105). In separate multivariate analysis for never-smokers and ever-smokers, female gender and better performance status (p < 0.0001 for both) were both favorable prognostic factors. However, adenocarcinoma histology (versus squamous cell carcinoma; HR = 0.790, 95% CI: 0.630–0.990; p = 0.0403) and the period after 2000 (versus before 2000; HR = 0.846, 95% CI: 0.731–0.980; p = 0.0254) were significant only in the never-smokers, and younger age (HR = 1.007, 95% CI: 1.003–1.011; p = 0.0010) was significant only in the ever-smokers. In an exploratory analysis, different profiles were observed in predictive factors for chemotherapy response between the two groups.ConclusionsNever-smokers with non-small cell lung cancer lived longer than ever-smokers. Gender, histology, and time of diagnosis are important factors for prognosis in these patients.