Changes in microtubule-related proteins and autophagy in long-term vitamin E-deficient mice.

Vitamin E deficiency induces neuronal dysfunction and while oxidative stress is likely to be involved in mediating this process, the detailed mechanisms remain to be elucidated. Previously, we found axonal degeneration in the hippocampal CA1 region in vitamin E-deficient mice of 6 months of age (long-term). However, 3 month-old (short-term) vitamin E-deficient mice did not exhibit axonal degeneration in same region. In order to characterize the mechanisms involved in axonal degeneration in long-term vitamin E-deficient mice, we examined changes in microtubule-related proteins. Long-term vitamin E-deficiency led to significantly increased expression of the phosphorylated form of collapsin response mediator protein (CRMP)-2 compared to short-term deficiency. It is well known that CRMP-2 plays a crucial role in the maintenance of neurite function. Similarly, long-term vitamin E-deficiency significantly decreased the expression of silent mating type information regulation (SIRT)-2 mRNA compared to short-term deficiency. SIRT-2 belongs to a family of class III histone deacetylases (HDACs) and functions in the deacetylation of tubulins. Furthermore, the expression of microtubule-associated protein light chain (MAP-LC)3-2, which is a key autophagy protein was significantly higher in the short-term vitamin E-deficiency than the long-term deficiency. These results indicate that the mechanisms of axonal injury in long-term vitamin E-deficient mice are related to dysfunction in microtubules assembly via alterations in microtubule-related proteins and autophagy.

Phase III study (MONET1) of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC): Asian subgroup analysis.

BACKGROUND: This preplanned subset analysis of the phase III MONET1 study aimed to determine whether motesanib combined with carboplatin/paclitaxel (C/P) would result in improved overall survival (OS) versus chemotherapy alone, in a subset of Asian patients with nonsquamous nonsmall-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with nonsquamous NSCLC (stage IIIB/IV or recurrent) and no prior systemic therapy for advanced disease were randomized to IV carboplatin (AUC, 6 mg/ml min) and paclitaxel (200 mg/m2) for up to six 3-week cycles, plus either oral motesanib 125 mg q.d. or placebo. Primary end point was OS; secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS: Two hundred twenty-seven Asian patients from MONET1 were included in this descriptive analysis. Median OS was 20.9 months in the motesanib plus C/P arm and 14.5 months in the placebo plus C/P arm (P=0.0223); median PFS was 7.0 and 5.3 months, respectively, (P=0.0004); and ORR was 62% and 27%, respectively, (P<0.0001). Grade≥3 adverse events were more common in the motesanib plus C/P arm versus placebo plus C/P (79% versus 61%). CONCLUSION: In this preplanned subset analysis of Asian patients with nonsquamous NSCLC, motesanib plus C/P significantly improved OS, PFS, and ORR versus placebo plus C/P. CLINICAL TRIAL NUMBER: NCT00460317.

Possible association of nicotinic acetylcholine receptor gene (CHRNA4 and CHRNB2) polymorphisms with nicotine dependence in Japanese males: an exploratory study.

INTRODUCTION: Smoking is a leading global cause of avoidable mortality. It has been reported that the nicotinic acetylcholine receptor (CHRNA4 and CHRNB2) genes might be associated with smoking behavior in several ethnic populations. However, no study between the 2 genes and nicotine dependence (ND) using a Japanese population has been reported. METHODS: We examined the association between ND and 5 single nucleotide polymorphisms (SNPs) within the CHRNA4 and 3 SNPs within the CHRNB2 using a well characterized sample of 558 Japanese healthy male workers with a relatively homogeneous background. The Fagerström test for nicotine dependence (FTND) was used to quantify the degree of ND. Additionally, we explored the effect of gene-gene interactions of the 2 genes on ND. RESULTS: We found CHRNB2 rs4845652 genotypes to be associated with FTND scores under an additive genetic model: rs4845652 T-allele carriers had lower ND levels (p=0.038; when adjusted for smoking duration: p=0.052). Furthermore, we demonstrated a possible gene-gene interaction of CHRNA4 and CHRNB2 on ND in a dose-dependent manner: those smokers with CHRNA4 rs1044397 GG or GA genotypes along with CHRNB2 rs4845652 CC genotype are likely to demonstrate higher ND scores. DISCUSSION: These findings suggest that CHRNB2 rs4845652 T-allele carriers may be associated with lower levels of ND, and that certain allelic combinations of CHRNA4 and CHRNB2 might be correlated with higher ND levels. This preliminary study has certain limitations (issues such as sample size/power and multiple testing) that need to be taken into account, and the present work thus has an experimental nature.

Quality of life and disease-related symptoms in previously treated Japanese patients with non-small-cell lung cancer: results of a randomized phase III study (V-15-32) of gefitinib versus docetaxel.

BACKGROUND: This report describes quality of life (QoL) findings of a randomized study comparing gefitinib with docetaxel in patients with advanced/metastatic pretreated non-small-cell lung cancer. PATIENTS AND METHODS: This open-label, phase III study randomized 490 Japanese patients to gefitinib (250 mg/day) or docetaxel (60 mg/m(2)/3 weeks), with survival as the primary outcome. Preplanned QoL analyses included Functional Assessment of Cancer Therapy-Lung (FACT-L), Trial Outcome Index (TOI) and Lung Cancer Subscale (LCS) improvement rates, and mean change from baseline. RESULTS: Gefitinib showed statistically significant benefits over docetaxel in QoL improvement rates (FACT-L 23% versus 14%, P = 0.023; TOI 21% versus 9%, P = 0.002) and mean change from baseline score [mean treatment difference: FACT-L 3.72 points, 95% confidence interval (CI) 0.55-6.89, P = 0.022; TOI 4.31 points, 95% CI 2.13-6.49, P < 0.001], although differences did not meet the clinically relevant six-point change. There were no significant differences between treatments in LCS improvement rates (23% versus 20%, P = 0.562) or mean change from baseline score (0.63 points, 95% CI -0.07 to 1.34, P = 0.077). CONCLUSIONS: Gefitinib improved aspects of QoL over docetaxel, with superior objective response rate and a more favorable tolerability profile and no statistically significant difference in overall survival (although noninferiority was not statistically proven).

Comparison in prognosis after VATS lobectomy and open lobectomy for stage I lung cancer: retrospective analysis focused on a histological subgroup.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) has become an attractive surgical procedure, but several issues remain to be resolved. Prognosis after VATS lobectomy is important to evaluate the adequacy of VATS lobectomy as a cancer operation. Interestingly, several investigators, including us, have reported that prognosis after VATS lobectomy was superior to that after open lobectomy in early non-small-cell lung cancer (NSCLC). One of the possible reasons is the low invasiveness of VATS lobectomy. But we considered that patient bias might have some influence favoring VATS lobectomy. To evaluate our hypothesis, we reviewed medical records of stage I NSCLC patients undergoing operation between 1993 and 2002. We compared and evaluated the relationship between patient characteristics and prognosis after VATS and open lobectomy. We focused particularly on histological type, classifying it into four subgroups; (1) bronchioloalveolar carcinoma (BAC), (2) mixed BAC + papillary adenocarcinoma (BAC + Pap), (3) other adenocarcinoma (Other adeno), (4) squamous cell carcinoma + others (Sq + others). RESULTS: A total of 165 patients underwent VATS lobectomy, and 123 patients underwent open lobectomy. The 5-year survival rate of the VATS lobectomy group was 94.5% and that of the open lobectomy group was 81.5%. Univariate Cox regression of survival revealed that male, CEA > 5, Other adeno, Sq + others, open lobectomy, and tumor size > 3 cm were significant negative prognostic variables. Multivariate Cox regression of survival revealed that histological subtype and tumor size were independent prognostic factors, but surgical procedure was not an independent prognostic factor. COMMENTS: Prognosis after VATS lobectomy was superior to that after open lobectomy, but patient bias influenced the prognosis in favor of VATS lobectomy, and the surgical procedure itself was not a prognostic factor.

Second primary cancer in survivors following concurrent chemoradiation for locally advanced non-small-cell lung cancer.

Long-term cancer survivors risk development of second primary cancers (SPC). Vigilant follow-up may be required. We report outcomes of 92 patients who underwent chemoradiation for unresectable stage III non-small-cell lung cancer, with a median follow-up of 8.9 years. The incidence of SPC was 2.4 per 100 patient-years (95% confidence interval: 1.0-4.9).

Multi-institutional phase II trial of irinotecan, cisplatin, and etoposide for sensitive relapsed small-cell lung cancer.

Irinotecan (CPT-11) has been shown to exhibit excellent antitumour activity against small-cell lung cancer (SCLC). A multi-institutional phase II study was therefore conducted to evaluate the efficacy and toxicity of CPT-11 combined with cisplatin (CDDP) and etoposide (ETOP) (PEI regimen) for the treatment of sensitive relapsed SCLC. Patients who responded to first-line chemotherapy but relapsed more than 8 weeks after the completion of first-line therapy (n=40) were treated using the PEI regimen, which consisted of CDDP (25 mg m(-2)) weekly for 9 weeks, ETOP (60 mg m(-2)) for 3 days on weeks 1, 3, 5, 7, and 9, and CPT-11 (90 mg m(-2)) on weeks 2, 4, 6, and 8 with granulocyte colony-stimulating factor support. Five complete responses and 26 partial responses were observed, and the overall response rate was 78% (95% confidence interval 61.5-89.2%). The median survival time was 11.8 months, and the estimated 1-year survival rate was 49%. Grade 3/4 leucocytopenia, neutropenia, and thrombocytopenia were observed in 55, 73, and 33% of the patients, respectively. Nonhaematological toxicities were mild and transient in all patients. In conclusion, the PEI regimen is considered to be highly active and well tolerated for the treatment of sensitive relapsed SCLC.

Phase I/II trial of weekly cisplatin, etoposide, and irinotecan chemotherapy for metastatic lung cancer: JCOG 9507.

Combinations of cisplatin-irinotecan and cisplatin-etoposide are active and well tolerated in patients with both small-cell lung cancer (SCLC) and nonsmall-cell lung cancer (NSCLC). To define the recommended dose for phase II trials of irinotecan combined with cisplatin and etoposide in chemonaive patients with stage IV disease, 56 patients (11 having SCLC and 45 NSCLC) received cisplatin 25 mg m(-2) weekly for 9 weeks, etoposide 60 mg m(-2) for 3 days on weeks 1, 3, 5, 7 and 9, and irinotecan 20-100 mg m(-2) (levels 1-8) on weeks 2, 4, 6 and 8, together with a prophylactical granulocyte colony-stimulating factor support (50 microg m(-2) on days 4-7 on weeks 1, 3, 5, 7 and 9, and on days 2-7 on weeks 2, 4, 6 and 8). Grade 3-4 leukocytopenia, neutropenia and thrombocytopenia were noted in 20 (36%), 28 (50%) and nine (16%) patients, respectively. Grade 3 diarrhoea, grade 3 cardiac toxicity, and grade 4 transaminase elevation developed in one (1.8%) patient each. Totally, four of 56 patients were removed from the study because of toxicity and recovered, and two other patients died in situations where drug toxicity might contribute to their death. Dose-limiting toxicity was noted in less than one-third of patients at dose levels 1-7, but in all patients at dose level 8. Thus, the recommended dose was determined to be level 7 (irinotecan 90 mg m(-2)). The response rates for SCLC and NSCLC were 91% (10/11) and 38% (17/45), respectively. The median survival time and 1-year survival rate were 11.9 months and 46% for SCLC and 10.1 months and 40% for NSCLC, respectively. This regimen was considered to be feasible and promising for the treatment of stage IV SCLC and NSCLC.

Retrospective study of hyponatremia in gastric cancer patients treated with a combination chemotherapy of 5-fluorouracil and cisplatin: a possible warning sign of severe hematological toxicities?

BACKGROUND: Some anti-neoplastic agents induce hyponatremia. The relationship between hyponatremia and other toxicities in gastric cancer patients treated with 5-fluorouracil and cisplatin (FP) was investigated retrospectively to clarify its clinical significance. METHODS: The subjects were 50 advanced gastric cancer patients treated with FP. Patients' performance status, oral intake, nausea/vomiting, diarrhea, fever, urine volume, presence of ascites or pleural effusion, laboratory data and administration of diuretics, corticosteroid and contents and volume of hydration before and during the first 5 days after chemotherapy were reviewed. RESULTS: The serum sodium level decreased after initiation of chemotherapy in all patients and the lowest level (nadir) was most frequently observed on day 8 (range, days 2-14), which preceded hematological toxicities. In 10 patients (20%) the nadir of serum sodium was lower than 125 mEq/l. We classified these 10 patients as a low-sodium group and the others into a normal-sodium group. Six (60%) and seven (70%) of the 10 patients in the low-sodium group had complications with grade 3 or 4 leukopenia and thrombocytopenia, whereas only one (3%) and two (5%) were seen in the normal-sodium group (p < 0.0001). Stomatitis and diarrhea were also slightly more severe in the former than the latter group. With respect to sensitivity and probability, receiver operating characteristic curves showed the nadir ((> or = ) or <125 mEq/l) of the serum sodium level was the best marker for both leukopenia and thrombocytopenia. CONCLUSION: Hyponatremia after initiation of chemotherapy with FP may be a warning sign of subsequent severe hematological toxicity.

A phase I/II trial of cisplatin, docetaxel and ifosfamide in advanced or recurrent non-small cell lung cancer.

This trial was initiated to evaluate the toxicity and activity of combination chemotherapy employing cisplatin (CDDP), docetaxel (DCT) and ifosfamide (IFX) in non-small cell lung cancer (NSCLC), and to determine the maximum tolerated dose (MTD) of IFX. Chemotherapy-naive patients with advanced or recurrent NSCLC received 60 mg/m(2) DCT followed after a 3-h interval by 60 mg/m(2) CDDP on chemotherapy day 1, and IFX at an escalating dose with mesna protection on days 2-4. The chemotherapy was repeated every 3 weeks. Granulocyte colony-stimulating factor (GCSF) was administered in the event of grade 3 leukopenia/neutropenia. The patients tolerated the treatment well up to level 4 of IFX dosing 1.5 g/day, but not the IFX dose at level 6 (2.0 g/day). Additional patients were enrolled in level 5 (IFX 1.7 g/day) to evaluate the toxicity of the drugs around the MTD. Level 5 was also judged as having exceeded the MTD, with febrile neutropenia and hepatic toxicity being observed as the dose-limiting toxicities. No toxicity-related deaths occurred. The majority of the chemotherapy courses were supported by GCSF administration. A total of 33 eligible patients were entered into the trial; the overall response rate was 10/33 or 30% among all eligible cases, and the rate for patients treated with the MTD or higher (levels 4-6) was 8/24, or 33% (90% confidence limit: 18-52%). The MTD of IFX was 1.5 g/m(2) administered for 3 days in this triplet combination. The clinical activity does not seem to justify the toxicity profile.

Phase I and pharmacological study of paclitaxel given over 3 h with cisplatin for advanced non-small cell lung cancer.

BACKGROUND: To establish the toxicities and maximum tolerated dose of paclitaxel given over 3 h in combination with cisplatin, to determine the pharmacokinetic profiles of these two drugs and to observe their antitumor activity, we conducted a combination phase I study in non-small cell lung cancer. METHODS: Patients received paclitaxel doses of 150-210 mg/m2 given over 3 h and cisplatin doses of 60-80 mg/m2 as a 1 h infusion 2 h after the end of the paclitaxel infusion. RESULTS: A total of 25 patients with previously untreated non-small cell lung cancer were enrolled. Granulocytopenia was the most frequent hematological toxicity and the most prominent non-hematological toxicity was sensory dominant neuropathy. Two of six patients experienced dose limiting toxicities (leukopenia, infection and neuropathy) at a dose of paclitaxel 210 mg/m2 and cisplatin 60 mg/m2, which was considered the maximum tolerated dose. There were seven partial responses among 24 evaluable patients, for an overall response rate of 29%. The median survival time was 341 days and the 1 year survival rate was 45.8%. As the paclitaxel pharmacokinetic parameters in this study were consistent with those of our previous single agent study, we found no significant drug-drug interaction between the 3 h infusion paclitaxel and cisplatin. CONCLUSION: The recommended doses for further study are determined to be paclitaxel 180 mg/m2 and cisplatin 80 mg/m2. This is a well-tolerated and active regimen for non-small cell lung cancer. In view of the promising survival outcome, further evaluation in prospective randomized trials versus other regimens is warranted.

Japanese experience of telemedicine in oncology.

We started telemedicine projects from 1990 with a telepathology system within Tsukiji Campus of National Cancer Center. In 1994, we connected Tsukiji Campus and Kashiwa Campus by 6 Mbps optical fiber leased line using IP protocol for data transmission, for teleconference, telepathology, and teleradiology projects. We also started connection of regional cancer centers and are now forming a cancer center network of 14 cancer centers. We are at present organizing 130 teleconferences per year with an attendance of more than 16000 people as summary. We have also used a high-resolution image transferring system, such as SHD (2000 pixelsx2000 pixels resolution) system on one side, and an economical telemedicine system using JAVA and a WWW browser (NCC_image) on the other side. We think that providing information is another field of telemedicine. We began the experimental gopher and WWW service in 1993. We are now providing official up-to-date cancer information for patients and healthcare professionals. We are getting more than 400000 hits per month. We are also providing a teleconference video session which is held every week on the Internet using a Real Video system with synchronized slide presentation on the WWW browser. We are also organizing a Cancer Image Reference Database System including DICOM images with viewer software. This paper is a summary of the telemedicine projects performed at the National Cancer Center.

[Tumor markers in lung cancer].

Carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), neuron-specific enolase (NSE), cytokeratin 19 fragment (CYFRA), and pro-gastrin-releasing peptide (proGRP) can be used as tumor markers for lung cancer. CEA is sensitive for adenocarcinoma, SCC and CYFRA for squamous cell carcinoma, and NSE and proGRP for small cell carcinoma. A tumor marker is generally used as a marker to monitor the clinical course. Serum levels of pro-GRP, reflect the disease course of patients with small cell lung cancer more accurately than NSE or CEA. Among the patients with clinical N0-1 non-small cell lung cancer high serum CEA levels, adenocarcinoma histology, and large tumor dimension were significant predictors of pathologic N2 disease. CEA played a new role in predicting metastasis to mediastinal lymph nodes A more effective treatment may enhance the value of tumor markers to predict relapse.

Platinum-based chemotherapy with or without thoracic radiation therapy in patients with unresectable thymic carcinoma.

BACKGROUND: Thymic carcinoma is a rare mediastinal neoplasm with poor prognosis. Although the clinical benefit of chemotherapy for thymic carcinoma is controversial, cisplatin-based chemotherapy with or without radiation therapy is ordinarily adopted in advanced cases. We evaluated the clinical outcome of platinum-based chemotherapy with or without radiation therapy in unresectable thymic carcinoma patients. METHODS: Ten patients with unresectable thymic carcinoma were treated with platinum-based chemotherapy with or without radiation therapy in the National Cancer Center Hospital between 1989 and 1998. We reviewed the histological type, treatment, response and survival of these patients. RESULTS: Four of the 10 patients responded to chemotherapy and both the median progression-free survival period and the median response duration were 6.0 months. The median survival time was 11.0 months. There was no relationship between histological classification and prognosis. CONCLUSIONS: Platinum-based chemotherapy with or without thoracic radiation is, regardless of tumor histology, marginally effective in advanced thymic carcinoma patients, giving only a modest tumor response rate and short response duration and survival.

Clinical evaluation of 99mTc-Technegas SPECT in thoracoscopic lung volume reduction surgery in patients with pulmonary emphysema.

UNLABELLED: 99mTc-Technegas (Tcgas) SPECT is useful for evaluating the patency of the airway and highly sensitive in detecting regional pulmonary function in pulmonary emphysema. The aim of this study is to evaluate regional ventilation impairment by this method pre and post thoracoscopic lung volume reduction surgery (LVRS) in patients with pulmonary emphysema. METHODS: There were 11 patients with pulmonary emphysema. The mean age of patients was 64.1 years. All patients were males. LVRS was performed bilaterally in 8 patients and unilaterally in 3 patients. Post inhalation of Tcgas in the sitting position, the subjects were placed in the supine position and SPECT was performed. Distribution of Tcgas on axial images was classified into 4 types, A: homogeneous, B: inhomogeneous, C: hot spot, D: defect. Three slices of axial SPECT images, the upper, middle and lower fields were selected, and changes in deposition patterns post LVRS were scored (Tcgas score). RESULTS: Post LVRS, dyspnea on exertion and pulmonary function tests were improved. Pre LVRS, inhomogeneous distribution, hot spots and defects were observed in all patients. Post LVRS, improvement in distribution was obtained not only in the surgical field and other fields, but also in the contralateral lung of unilaterally operated patients. In 5 patients some fields showed deterioration. The Tcgas score correlated with improvements in FEV1.0, FEV1.0% and %FEV1.0. CONCLUSION: Tcgas SPECT is useful for evaluating changes in regional pulmonary function post LVRS.

[Cancer therapy and processing information].

The National Cancer Center Japan started to provide free, computer-based cancer information, through a service called the National Cancer Center--Cancer Information Service (NCC-CIS), to patients and their families, physicians and other health professionals via fax (telephone) and the Internet in 1996. NCC-CIS in Japanese is modeled on the Physician Data Query service produced by the National Cancer Institute in the United States and is produced from an independent standpoint adopted to the medical and social environment in Japan. NCC-CIS provides up-to-date cancer treatment information (staging, prognosis and state-of-the-art treatment by stage of disease), supportive care for each type of cancer, an image reference database, and a directory of organizations and lecture meeting reports in Japan in order to facilitate better understanding of cancer among people and support the decision-making process for physicians in order to achieve a reduction in cancer deaths.

Phase I study of a weekly infusion of irinotecan hydrochloride (CPT-11) and a 14-day continuous infusion of etoposide in patients with lung cancer: JCOG trial 9408.

BACKGROUND: The aim was to determine the maximum tolerated dose (MTD) and recommended dose of irinotecan hydrochloride (CPT-11) in combination with a 14-day continuous infusion of etoposide in patients with refractory advanced lung cancer (LC), especially small cell lung cancer (SCLC). METHODS: Etoposide was administered continuously at 25 mg/m2/day for 14 days. The initial dose of CPT-11 was 40 mg/m2 given as a 90 min intravenous infusion on days 1, 8 and 15 and the dose escalation of CPT-11 was planned in increments of 20 mg/m2 until severe or life-threatening toxic effects were observed. RESULTS: Nine refractory or advanced LC patients (eight at level 1, one at level 2) were entered in this study, of whom two at level 1 were not assessable for toxicity because of patient's refusal and progressive disease. One treatment-related death due to pulmonary toxicity and one patient with hypotension who needed catecholamine for more than 48 h were observed at level 1, a CPT-11 dose of 40 mg/m2. The MTD of CPT-11 was 40 mg/m2. Therapeutic efficacy could be assessed in seven patients, of whom two achieved a partial response. CONCLUSIONS: This regimen was too toxic and the recommended dose was outside the levels in this study. One has to consider pulmonary toxicity when using CPT-11, especially for patients previously treated with cytotoxic agents for which pulmonary toxicity has been reported.

Histologic types of lung carcinoma and related family history of anatomic sites and histologic types of cancers.

BACKGROUND: Familial factors are suggested to play roles in lung carcinogenesis, but may well be different for each histologic cell type. METHODS: Information regarding smoking, past medical history, and family history of malignant diseases among first-degree relatives was collected from a total of 1188 patients with primary lung carcinoma (participants) who were treated in the thoracic oncology ward at the National Cancer Center Hospital, Tokyo, Japan. These data were analyzed for associations with the histologic type of the lung carcinoma. The main outcome measures were the relative risk of developing a malignancy, at any site or at certain specific sites, in first-degree relatives of participants who had a specific histologic type of lung carcinoma compared with the relative risk in those first-degree relatives of participants with other cell types. RESULTS: Participants with multiple malignant lesions reported significantly more first-degree relatives with a malignancy than those without multiple tumors (P = 0.008 by the Wilcoxon rank sum test). There was no statistically significant correlation between age, gender, smoking history, or histologic tumor type in the participant and the overall family history of malignancy. Site specific analyses revealed that participants with adenocarcinoma reported a family history of colorectal carcinoma, and those with squamous cell carcinoma reported a family history of head and neck carcinoma, more frequently than other participants (P = 0.041 and 0. 001, respectively, by chi-square analysis). CONCLUSIONS: The data from the current study suggest an association between familial factors and histologic type of lung carcinoma. Genetic factors to determine individual susceptibility to lung carcinogenesis should be investigated according to each histologic type.

Progressive disease rate as a surrogate endpoint of phase II trials for non-small-cell lung cancer.

BACKGROUND: Although the potential activity of anticancer agents has been traditionally assessed by the response rate (RR) in phase II trials, there is an increasing need to identify alternative endpoints to evaluate the efficacy of novel types of antineoplastic agents such as cytostatic agents. However, none of the proposed alternatives have been validated. DESIGN: RR, rate of progressive disease (PD), and median survival time (MST) were obtained from 44 treatment arms in 42 single-agent phase II trials for non-small-cell lung cancer (NSCLC). Correlations between these parameters and their significance in selection of promising drugs were evaluated. RESULTS: The median (range) RR and PD rate per treatment arm were 17% (0%-40%) and 41% (8%-93%), respectively. The PD rate correlated more closely with MST (correlation coefficient (r) = 0.80, P < 0.001) than did the RR (r = 0.62, P < 0.001). The RR of active agents against NSCLC ranged broadly from 7% to 40%, whereas their PD rates were all 50% or less. In addition, all treatment arms with a PD rate over 50% had a poor MST of six months or shorter. CONCLUSIONS: The PD rate was potentially as good an endpoint as RR, and it may be a good candidate for the primary endpoint of phase II trials for novel types of anticancer agents.

A puzzling case of seizures and visual hallucinations during clomipramine treatment with a high dose but causing a low serum concentration.

We present a puzzling case of a 25-year-old depressive man suffering from seizures and visual hallucinations during clomipramine treatment with a high dose but causing a low serum concentration. We examined alleles of cytochrome P450 (CYP) isozymes. It was revealed that he was not an ultrarapid metabolizer for CYP2D6, and that the genotypes were homozygous for CYP2D6J and heterozygous for CYP2C19m1. Throughout the treatment period, his compliance was good. Since he was a smoker, it seems likely that his low clomipramine level was due to smoking-induced CYP1A2 activity. These findings suggest that smoking-induced CYP1A2 activity overcomes the possibly inhibiting effects of homozygosity for CYP2D6J and heterozygosity for CYP2C19m1, and that high-dose clomipramine is not always a direct cause of seizures.