Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002).

BACKGROUND: NEJ002 study, comparing gefitinib with carboplatin (CBDCA) and paclitaxel (PTX; Taxol) as the first-line treatment for advanced non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation, previously reported superiority of gefitinib over CBDCA/PTX on progression-free survival (PFS). Subsequent analysis was carried out mainly regarding overall survival (OS). MATERIALS AND METHODS: For all 228 patients in NEJ002, survival data were updated in December, 2010. Detailed information regarding subsequent chemotherapy after the protocol treatment was also assessed retrospectively and the impact of some key drugs on OS was evaluated. RESULTS: The median survival time (MST) was 27.7 months for the gefitinib group, and was 26.6 months for the CBDCA/PTX group (HR, 0.887; P=0.483). The OS of patients who received platinum throughout their treatment (n=186) was not statistically different from that of patients who never received platinum (n=40). The MST of patients treated with gefitinib, platinum, and pemetrexed (PEM) or docetaxel (DOC, Taxotere; n=76) was around 3 years. CONCLUSIONS: No significant difference in OS was observed between gefitinib and CBDCA/PTX in the NEJ002 study, probably due to a high crossover use of gefitinib in the CBDCA/PTX group. Considering the many benefits and the risk of missing an opportunity to use the most effective agent for EGFR-mutated NSCLC, the first-line gefitinib is strongly recommended.

Efficacy and safety of single-dose fosaprepitant in the prevention of chemotherapy-induced nausea and vomiting in patients receiving high-dose cisplatin: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: We evaluated the efficacy and safety of single-dose fosaprepitant in combination with intravenous granisetron and dexamethasone. PATIENTS AND METHODS: Patients receiving chemotherapy including cisplatin (≥70 mg/m(2)) were eligible. A total of 347 patients (21% had received cisplatin with vomiting) were enrolled in this trial to receive the fosaprepitant regimen (fosaprepitant 150 mg, intravenous, on day 1 in combination with granisetron, 40 µg/kg, intravenous, on day 1 and dexamethasone, intravenous, on days 1-3) or the control regimen (placebo plus intravenous granisetron and dexamethasone). The primary end point was the percentage of patients who had a complete response (no emesis and no rescue therapy) over the entire treatment course (0-120 h). RESULTS: The percentage of patients with a complete response was significantly higher in the fosaprepitant group than in the control group (64% versus 47%, P = 0.0015). The fosaprepitant regimen was more effective than the control regimen in both the acute (0-24 h postchemotherapy) phase (94% versus 81%, P = 0.0006) and the delayed (24-120 h postchemotherapy) phase (65% versus 49%, P = 0.0025). CONCLUSIONS: Single-dose fosaprepitant used in combination with granisetron and dexamethasone was well-tolerated and effective in preventing chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic cancer chemotherapy, including high-dose cisplatin.

Phase II study of S-1, a novel oral fluorouracil, in advanced non-small-cell lung cancer.

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(-2)day(-1): BSA < 1.25 m(2), 40 mg b.i.d.; BSA> or =1.25 but <1.5 m(2); 50 mg b.i.d., and BSA> or =1.5 m(2): 60 mg b.i.d. One cycle consisted of consecutive administration of S-1 for 28 days followed by a 2-week rest period, and cycles were repeated up to 4 times. The partial response (PR) rate of the eligible patients was 22.0% (13/59); (95% confidence interval: 12.3-34.7%). A PR was observed in 22.7% (5/22) of the stage IIIB patients and 21.6% (8/37) of the stage IV patients. The median response duration was 3.4 months (1.1-13.7 months or longer). Grade 4 neutropenia was observed in one of the 59 patients (1.7%). The grade 3 or 4 toxicities consisted of decreased haemoglobin level in 1.7% of patients (1/59), neutropenia in 6.8% (4/59), thrombocytopenia in 1.7% (1/59), anorexia in 10.2% (6/59), diarrhoea in 8.5% (5/59), stomatitis in 1.7% (1/59), and malaise in 6.8% (4/59), and their incidences were relatively low. There were no irreversible, severe or unexpected toxicities. The median survival time (MST) of all patients was 10.2 months (95% confidence interval: 7.7-14.5 months), and the one-year survival rate was 41.1%. The MST of the stage IIIB patients was 7.9 months, and that of the stage IV patients was 11.1 months. The one-year survival rates of the stage IIIB and IV patients were 30.7% and 47.4%, respectively. S-1 was considered to be an active single agent against NSCLC. Further study of S-1 with other active agents is warranted.

Induction of aldose reductase in cultured human microvascular endothelial cells by advanced glycation end products.

Accelerated formation and accumulation of advanced glycation end products, as well as increased flux of glucose through polyol pathway, have been implicated in the pathogenesis of diabetic vascular complications. We investigated effects of advanced glycation end products on the levels of aldose reductase mRNA, protein, and activity in human microvascular endothelial cells. When endothelial cells were cultured with highly glycated bovine serum albumin, aldose reductase mRNA in endothelial cells demonstrated concentration-dependent elevation. The increase in aldose reductase mRNA was accompanied by elevated protein expression and enzyme activity. Significant increase in the enzyme expression was also observed when endothelial cells were cultured with serum obtained from diabetic patients with end-stage renal disease. Pretreatment of the endothelial cells with probucol or vitamin E prevented the advanced glycation end products-induced increases in aldose reductase mRNA and protein. Electrophoretic mobility shift assays using the nuclear extracts of the endothelial cells treated with advanced glycation end products showed enhancement of specific DNA binding activity for AP-1 consensus sequence. These results indicate that accelerated formation of advanced glycation end products in vivo may elicit activation of the polyol pathway, possibly via augmented oxidative stress, and amplify endothelial cell damage leading to diabetic microvascular dysfunction.

Serum autoantibodies against sulfatide and phospholipid in NIDDM patients with diabetic neuropathy.

OBJECTIVE: We investigated the presence of antisulfatide and antiphospholipid antibodies and the relationship between these antibodies and the results of quantitative tests of nerve function in NIDDM patients with diabetic neuropathy. RESEARCH DESIGN AND METHODS: Antisulfatide and antiphospholipid antibodies were measured in serum samples obtained from 68 NIDDM patients with diabetic neuropathy by an enzyme-linked immunosorbent assay (ELISA). Each patient was classified into one of three groups based on the combined neuropathy score (determined by the symptom score, the results of autonomic nerve function tests, and the vibration perception test), as follows: mild (n = 26), moderate (n = 22), and severe (n = 20). Nerve conduction studies were performed in a subgroup of 37 patients. RESULTS: The antisulfatide antibody was detected in 1 (4%) of 26 patients in the mild group, 4 (18%) of 22 patients in the moderate group, and 8 (40%) of 20 patients in the severe group (P < 0.01 vs. mild group). The antiphospholipid antibody was detected in none of the patients in the mild group, 8 (36%) of 22 patients in the moderate group (P < 0.001 vs. mild group), and 6 (30%) of 20 patients in the severe group (P < 0.01 vs. mild group). The threshold amplitude, determined by the vibration perception test, was significantly higher in antibody-positive patients than in antibody-negative patients: antisulfatide antibody, 55.9 +/- 46.8 microns (n = 13) vs. 22.9 +/- 13.7 microns (n = 55), P < 0.001; antiphospholipid antibody, 47.2 +/- 32.5 microns (n = 14) vs. 24.5 +/- 23.2 microns (n = 54), P < 0.01. The conduction velocity of the sural nerve was slower in the antisulfatide antibody-positive group (37.9 +/- 11.1 m/s, n = 12) than in the antisulfatide antibody-negative group (45.2 +/- 6.0 m/s, n = 19) (P < 0.05). CONCLUSIONS: These results suggest that autoimmune nerve destruction may be involved in diabetic neuropathy in NIDDM patients.

[Epstein-Barr virus-infected T-cell malignancy in an adult patient with Behçet's disease-like symptoms].

A 20-year-old woman was hospitalized on November 11, 1994 with Behçet's disease-like symptoms (fever, genital ulcer and aphtha in the oral cavity). Bilateral cervical lymph node swelling was also noted and diagnosed as lymphadenitis on biopsy. Chronic active Epstein-Barr virus infection (CAEBV) was diagnosed based on the high titer of antibodies to the EBV capsid antigen, early antigen, and nuclear antigen. She was treated with prednisolone and acyclovir and all symptoms improved. However, ten months after onset of symptoms, T-cell malignancy was diagnosed on bone marrow aspiration, which revealed 34.9% blast cells that had rearrangement of TCR-beta. She died on May 8, 1995, despite anticancer therapy. In analyzing the blast cells, the monoclonal junctional DNA structure of the EBV terminal repeat was analyzed by Southern blotting and provided definitive evidence for the monoclonality of EBV-infected T cells. These findings strongly suggest that EBV plays a pathogenic role in T-cell malignancy. EBV-infected T-cell malignancy, such as this case, is very rare in Japan, especially in adult.

High prevalence of mitochondrial diabetes mellitus in Japanese patients with major risk factors.

To identify diabetes mellitus caused by the mitochondrial gene substitution at genomic nucleotide pair 3243 (M3243A-->G) we selected 87 diabetic patients with high risk factors such as maternal inheritance and hearing loss. Total DNA was extracted from peripheral leukocytes, and mitochondrial DNA fragments containing M3243A-->G were amplified by polymerase chain reaction (PCR). The amplified fragments were digested with a restriction endonuclease Apa1 and analyzed by agarose gel electrophoresis. The incidence of the M3243A-->G mutation was 4.6% (four of 87) in diabetic patients with maternal inheritance and/or hearing loss. In a subgroup with both maternal inheritance and hearing loss, the incidence of the mutation was as high as 21.4% (three of 14). Cardiac disorders were also present in all four diabetic patients with the mutation. This study suggests that maternal inheritance and hearing loss are useful clinical findings to identify diabetic patients with the mutation, and that cardiac involvement is a high risk factor for the M3243A-->G mutation.

Antibodies to glutamic acid decarboxylase in Japanese diabetic patients with secondary failure of oral hypoglycaemic therapy.

Some patients with non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) are positive for antibodies to glutamic acid decarboxylase (anti-GAD), which have been shown to be a useful marker for the diagnosis and prediction of insulin-dependent (Type 1) diabetes mellitus (IDDM). Anti-GAD positive NIDDM patients tend to develop insulin deficiency. We investigated the prevalence of anti-GAD in 200 NIDDM with secondary failure of oral hypoglycaemic therapy (SF) and 200 NIDDM well controlled by diet and/or sulphonylurea agents (NSF). Twenty-two of 200 (11%, p < 0.05) SF patients and 6 of 200 (3%) NSF patients were anti-GAD positive. The positive. The positive rate for anti-GAD was as high as 23.8% in the non-obese and insulin deficient SF patients. The SF patients with anti-GAD tended to be non-obese and to have an impaired release of endogenous insulin. The internal before development of secondary failure was not associated with the presence of anti-GAD in this study. In conclusion we found that anti-GAD was positive in as many as 11% of the SF patients, suggesting that autoimmune mechanisms may play an important role in the pathogenesis of secondary failure or sulphonylurea therapy.

UFT plus cisplatin in advanced non-small-cell lung cancer: interim analysis of 67 patients.

A single-institution phase II study indicated that combination chemotherapy using UFT (tegafur and uracil) plus cisplatin (Platinol) in patients with non-small-cell lung cancer was active with less host toxicity than other cisplatin-based therapies. To confirm these observations, the Japan JFT Lung Cancer Study Group conducted a multi-institutional phase II trial. The number of patients planned for this trial is 110. Eligibility includes previously untreated stage IIIB or IV non-small-cell lung cancer and a good performance status. UFT 400 mg/m2 in two divided doses is administered orally on days 1 through 14, and cisplatin 80 mg/m2 is injected IV on day 8. This treatment is repeated every 3 or 4 weeks. Between April 1995 and May 1996, 67 patients were enrolled, and all 67 were considered eligible for an interim analysis performed in October 1996. Among 63 patients evaluable for response, there was an overall response rate of 30% (95% confidence interval, 19% to 41%), with one complete response and 18 partial responses. With a median follow-up duration of 44 weeks, the median survival time was 32 weeks and the 1-year survival rate was 25%. Grade 3 leukopenia occurred in only 1 of 67 patients (1.5%), and there was no thrombocytopenia of grade 3 or greater. Vomiting, the most common nonhematologic toxicity observed, reached grade 3 or 4 in only 6 patients (9%). This interim analysis seems to support the observations of the previous single-institution phase II trial.

Formation of crossline as a fluorescent advanced glycation end product in vitro and in vivo.

Crossline is one of the major advanced glycation end products resulting the reaction mixture of free amino group(s) such as epsilon-one in lysine with D-glucose in vitro. To study crossline formation on proteins in vitro and in vivo, polyclonal antiserum to the crossline hapten was prepared. This antiserum reacted with bovine and human serum albumin that had been modified by prolonged incubation with glucose as well as with crossline itself. Antisera did not react with unmodified serum albumin or the other Maillard-related compounds. Crossline was formed in a time-dependent manner when a mixture of six different proteins was incubated with glucose at pH 7.2 or 9.0. Crossline levels could be measured in rat lens proteins and the levels increased with age. The crossline content of lens proteins in diabetic rats was more than two-fold higher than that of age-matched controls. Results of this study suggest that most proteins containing advanced glycation end products have crossline-like structures. Measurement of crossline-like structures in biological specimens may provide an index of aging and of the development of diabetic complications.

[Giant cell interstitial pneumonia in a metal grinder with an abnormally high level of serum CA19-9].

Interstitial pneumonia and recurrent pneumothorax developed in a 48-year-old man who had worked as a metal grinder. He died of respiratory failure despite having received antibiotics and steroids, and despite having undergone pleural sclerosis therapy. Giant cell interstitial pneumonia was diagnosed; innumerable bizarre giant cells engulfing black granules were found within the alveoli. The results of high-energy dispersion X-ray microanalysis indicated that the patient had hard metal pneumoconiosis associated with tungsten in the black granules. When he was admitted to the hospital, his serum CA19-9 and SLEX concentrations were abnormally high (2600 and 200 ng/ml, respectively). Immunohistochemical analysis of lung tissue was done with anti-CA19-9 and SLEX antibodies. CA19-9 staining revealed strong bronchialization and squamous metaplasia in contrast to type II hyperplasia. SLEX staining showed strong type II hyperplasia. Further investigations will be needed to determine the mechanism of elevated tumor-associated carbohydrate antigens in serum.

Optical characteristics of a wind-roughened water surface: a two-dimensional theory.

We present a two-dimensional theory of thermal emission and light scattering from an anisotropic wind-roughened water surface that is described by the Gaussian-Joint North Sea Wave Project model. The theory is developed through the use of the first-order geometrical-optics approxmation modified with shadowing effects, and it is valid when the average slopes of the surface are smaller than unity. The theory allows us to evaluate the effective emissivity and the effective bistatic reflectivity of a full-gravity-capillary wave surface at large viewing angles, for any direction relative to the average propagation direction of the surface wave. We also present an application of the theory to the recently proposed method for obtaining thermal imagery of a wind-roughened water surface from low altitudes, which is called statistically corrected ocean thermography. Corrected thermal images of the ocean surface, obtained by our field experiment, are shown.

Statistically corrected ocean thermography.

A corrected thermal imaging method for a wind-roughened water surface is proposed. This method can be applied even if the imaging system is placed at low altitudes, say on a ship or on land, as well as on an airborne platform. Such a technique is desirable from the following points of view: the surveillance of bioresources (fish), environmental assessments of a seaside industrial zone (hot waste water), and temporal complement and spatial interpolation of satellite observations of thermal images. The method is based on the analysis of optical characteristics of a model of a wind-roughened water surface, namely, the Gaussian-Joint North Sea Wave Project (JONSWAP) model, where the surface displacement obeys Gaussian distribution while its spectrum is specified by the JONSWAP wave spectral model. We present the basic temperature-correction formula and the algorithm for correction. The correction takes into account thermal emission of the water's surface, radiation of the sky reflected on the water's surface, and both absorption and emission by the atmosphere along the light path. This formula can be used for temperature correction of an infrared image of sky and random water surface. The experimental results that we obtained are encouraging.

[An early phase II trial combining cisplatin and carboplatin in advanced non-small cell lung cancer].

We conducted an early phase II trial in advanced non-small cell lung cancer (NSCLC) to evaluate response efficacy of a combination of Cisplatin (CDDP) and Carboplatin (CBDCA). The twenty-six patients in the study had had no previous treatment. They received a sequential administration of 300 mg/m2 CBDCA and 80 mg/m2 CDDP with approximately 3,500 ml of hydration on day 1 every 4 weeks. All patients were evaluable for response and toxicity. Ten (38.5%) of all assessable patients achieved a partial response (95% confidence interval, 19.8-57.2%). Response rates for patients with stage III A, III B and IV- disease were 40.0 (2/5), 70.0 (7/10) and 9.1% (1/11), respectively. Response rates for patients with squamous cell carcinoma, adenocarcinoma and large cell carcinoma were 35.7 (5/14), 45.5 (5/11) and 0.0% (0/1), respectively. The median survival time (MST) of all patients was 11 months. The MST for patients with stage III disease was 14 months; for those with stage IV disease it was 7 months. The MST for responding patients was 15 months and for not responding patients 5 months. Major toxicities were hematologic and gastrointestinal, and the dose-limiting factor was thrombocytopenia. This combination chemotherapy was effective against NSCLC with tolerable toxicities. Further trials are warranted to determine the efficacy of the combination chemotherapy.

[A study to increase the therapeutic effects of adoptive immunotherapy in vivo. Influence on the generation of lymphokine activated killer (LAK) cells and therapeutic effects of LAK cells with anti-tumor drug (cyclophosphamide)].

To enhance the effect of adoptive immunotherapy (AIT), we investigated the induction and characteristics of lymphokine activated killer (LAK) cells and also analyzed the combined effects of AIT with an antitumor drug (cyclophosphamide: CPA) in mice models. LAK cells were generated from C57/BL/6 (B6) spleen cells. The spleen cells were passed through a nylon wool column and cultured in RPMI-1640 medium containing 10% FCS and 2 x 10(3) units of human recombinant IL-2 (hr IL-2) for up to 14 days. During this period, the time kinetic analyses of the LAK cells' cytotoxicity and motility were performed. The cytotoxicities against Lewis Lung Carcinoma (3LL), evaluated by standard 51Cr release assay, gradually increased during the cultured period, and the motilities, determined by a modified version of the Boyden chamber method, greatly increased within the first 7 days' incubation. Based on these in vitro findings, we examined the efficacy of AIT alone or in combination with chemotherapy (CPA) in in vivo studies. AIT was performed in the following way: LAK cells were intravenously infused and rIL-2 was intraperitoneally administered for 5 consecutive days following LAK cell administration. CPA was intraperitoneally administered. The therapy protocols were as follows. There were seven experimental groups. Group I; the mice were infused with 3-day cultured LAK cells (3DLAKs) on the second day after tumor inoculation (day 2). Group II; the mice were infused with 3DLAKs on day 5. Group III; 10-day cultured LAK cells (10DLAKs) on day 2. Group IV; 10DLAKs on day 5. Group V (AIT and CPA combination); AIT (10DLAKs) was started on day 5 followed by CPA on day 10. Group VI; CPA was performed on day 5 followed by AIT (10DLAKs) on day 10. Group VII; CPA was performed on day 5 without AIT. Each group consisted on 15 mice. The therapeutic efficacies were evaluated by calculating the median survival time of each group. The results of these experiments were as follows (mean +/- SD); Group I's median survival time was 16.8 +/- 3.2 days, Group II 15.1 +/- 2.1 days, Group III 19.2 +/- 5.4 days, Group IV 16.1 +/- 4.8 days, Group V 23 +/- 6.3 days, Group VI 32 +/- 8.4 days and Group VII 22 +/- 5.1 days. These results suggested that the efficacy of AIT is closely related to the LAK cells' cytotoxicity and motility. Although AIT alone in the advanced tumor bearing host had a limited effect, combination with CPA improved it's efficacy.(ABSTRACT TRUNCATED AT 400 WORDS)

[An experience of laser therapy of lung cancer complicated with hemophilia A].

We applied an endoscopic Nd-YAG laser therapy for an early hilar lung cancer complicated with hemophilia A in a patient of 62-year-old male. Abnormality was pointed out by means of sputum cytology. But, no shadow of tumor was observed by chest x-ray films and computed tomogram. By a bronchoscopy, a mild irregular mucomembrane and stenosis without tumor were exhibited. By means of cytological diagnosis of an abrasive-washing specimen of that region, the presence of squamous cell carcinoma was proved. Also, he was diagnosed as factor VIII deficient hemophilia A. So we performed him a laser therapy in place of the operation and with an intrabronchial arterial infusion. After the laser treatment, the conditions progressed better without any recurrence but about one and a half years later, an intrapulmonary metastasis occurred. Then, radiation and chemotherapy have been applied and at present, the patient is in a good state although under the tumor-bearing condition.

[Quality of life (QOL) and nutrition].

We thought that nutritional parameters in laboratory data might be able to express quality of life (QOL). Therefore, in 70 patients with malignant chest diseases (NSCLC, 42 patients; SCLC, 15; lung metastasis, 7; others, 6), the correlation between nutritional parameters of total protein (Tp), serum albumin (Alb), and serum (cholinesterase (ChE] and Karnofsky Performance Status scale (KPS) was investigated. Then, in 24 patients with them (NSCLC, 12; SCLC, 6; lung metastasis, 4; others 2), Alb and ChE were compared to the EORTC Core Quality of Life Questionnaire and Lung Cancer-Specific Questionnaire Module (QS). Results were as follows: 1) KPS and nutritional parameters correlated (Tp. r = 0.55, p less than 0.001; Alb, r = 0.60, p less than 0.001, ChE, r = 0.60; p less than 0.001). 2) The cores for Functional Status (FS) and Disease and Treatment-related symptoms (Sym) in QS and parameters of Alb and ChE correlate (FS v.s. Alb, p less than 0.01; Sym v.s. Alb, p less than 0.01; FS v.s. ChE, p less than 0.05; and Sym v.s. ChE, p less than 0.05). Moreover, the scores of Psychological Distress in QS and Alb showed a correlation (p less than 0.05). It is considered that nutrition and part of QOL (KPS and FS + Sym in QS, that is to say, "objective" functional activity and "subjective" functional activity and symptoms) correlate, and that nutritional parameters are useful to evaluate QOL.

[An early phase II study of CPT-11 in primary lung cancer].

An early phase II study of CPT-11 was carried out in patients with primary lung cancer in 15 institutions throughout Japan. The efficacy and safety of CPT-11 were studied at 200 mg/m2 based on the results of the previous phase I study. Thirty-eight of 52 enrolled patients were eligible. CPT-11 proved to be effective for primary lung cancer. The response rates were 20.0% (7/35) for non-small cell lung carcinoma and 33.3% (1/3 for small cell lung carcinoma. Hematological toxicities included leukopenia (less than or equal to 3,000) in 44.7% of the patients. Other major toxicities were nausea/vomiting (greater than or equal to grade 2) in 50.0% and diarrhea (greater than or equal to grade 2) in 47.4%.