Chemotherapy-induced neutropenia as a prognostic factor in advanced non-small-cell lung cancer: results from Japan Multinational Trial Organization LC00-03.

BACKGROUND: Neutropenia is a common adverse reaction of chemotherapy. We assessed whether chemotherapy-induced neutropenia could be a predictor of survival for patients with non-small-cell lung cancer (NSCLC). METHODS: A total of 387 chemotherapy-naïve patients who received chemotherapy (vinorelbine and gemcitabine followed by docetaxel, or paclitaxel and carboplatin) in a randomised controlled trial were evaluated. The proportional-hazards regression model was used to examine the effects of chemotherapy-induced neutropenia and tumour response on overall survival. Landmark analysis was used to lessen the bias of more severe neutropenia resulting from more treatment cycles allowed by longer survival, whereby patients who died within 126 days of starting chemotherapy were excluded. RESULTS: The adjusted hazard ratios for patients with grade-1 to 2 neutropenia or grade-3 to 4 neutropenia compared with no neutropenia were 0.59 (95% confidence interval (CI), 0.36-0.97) and 0.71 (95% CI, 0.49-1.03), respectively. The hazard ratios did not differ significantly between the patients who developed neutropenia with stable disease (SD), and those who lacked neutropenia with partial response (PR). CONCLUSION: Chemotherapy-induced neutropenia is a predictor of better survival for patients with advanced NSCLC. Prospective randomised trials of early-dose increases guided by chemotherapy-induced toxicities are warranted.

Bone metabolic changes in Antarctic wintering team members.

Bone mass, bone metabolic markers, and calcium regulation hormones were measured in members of an Antarctic wintering team who stayed at the Japanese Antarctic station, Syowa (latitude: south 69 degrees 00', longitude: east 39 degrees 35') for 1 year. Subjects included 31 healthy Japanese males, aged 24-51 years (mean age 34.5 years) at the beginning of this study, ingesting 488 IU/day of vitamin D and 550.9 mg/day of calcium per person. The long-term coefficient of variation (CV) of the equipment used in the assessments of bone mass was 0.67% in single X-ray absorptiometry (SXA), 0.17% in the speed of sound (SOS) by quantitative ultrasound method (QUS), and 0.63% in broadband ultrasound attenuation (BUA) by QUS. The seasonal changes in the calcaneal bone mineral density (BMD) by SXA were not significant, whereas the SOS measured by QUS decreased during the measurement period (0.55%, p < 0.001), and BUA increased (1.9%, p < 0.01). Bone-specific alkaline phosphatase and osteocalcin levels increased significantly during summer (p < 0.001) and urinary calcium level decreased significantly during winter (p < 0.05). Urinary pyridinoline and deoxypyridinoline levels decreased significantly at the end of winter (p < 0.001). Serum 1,25(OH)2D3 level did not change significantly, whereas serum 25(OH)D3 level decreased significantly during winter (p < 0.001). Serum parathyroid hormone (PTH) level significantly increased at the end of winter (p < 0.01), although both PTH level and 25(OH)D3 level remained within the normal range. We concluded that the 25(OH)D3 level in subjects who stayed in Antarctica for 1 year decreased significantly with the reduction in duration of sunshine, but there were no clear changes in bone mass.

Fucosylated Thomsen-Friedenreich antigen in alpha-anomeric configuration in human gastric surface epithelia: an allogeneic carbohydrate antigen possibly controlled by the Se gene.

Human gastric surface epithelial cells display the ABH blood group antigens with the core structure of N-acetyllactosamine (NAcLc). Their expression is under the control of the secretor gene Se. The Thomsen-Friedenreich (T)-antigen (Gal beta 1-3GalNAc) is another core structure of the ABH antigens. We examined the gastric surface epithelial expression of T- and alpha 1-2 fucosylated T (FucT) histochemically with peanut agglutinin (PNA) and monoclonal antibody (MAb) MBr1, respectively. Eight of 24 individuals exhibited the PNA-reactive antigen (i.e., T-expressers) and others the MBr1-reactive antigen (i.e., FucT-expressers). alpha-L-fucosidase digestion of the FucT-positive tissues and beta-galactosidase digestion of the T-positive tissues, respectively, made them reactive with PNA and the antibody specific for GalNAc alpha-O-Ser/Thr. There was a remarkable correlation among reactivities with MBr1, Ulex europaeus lectin 1 (UEA1), and anti-Leb MAb CO-431. ABH blood group status had no correlation with this expression. We conclude that human gastric surface epithelial cells constitutionally synthesize T in alpha configuration (i.e., Gal beta 1-3GalNAc alpha-O-Ser/Thr) and that it was alpha 1-2 fucosylated only in the FucT-expressers. alpha 1-2 fucosylation of T is suggested to be regulated by the Se gene.

Long-term results of combination chemotherapy with or without irradiation in small cell lung cancer: a 5- to 11-year follow-up.

Between April 1981 and December 1987, 148 patients with newly diagnosed small cell lung cancer (SCLC) were treated using combination chemotherapy with or without thoracic irradiation and prophylactic cranial irradiation (PCI) in a series of cooperative therapeutic trials. With a minimum follow-up of 4.7 years, 13 (9%) patients survived and were free of SCLC. These included 11 (15%) of 76 patients with limited disease and two (3%) of 72 patients with extensive disease. Three died without any evidence of SCLC (one each from second leukemia, non-small cell lung cancer, and unrelated disease). The remaining 10 (7%) patients are currently alive and free of SCLC beyond 4.7 years. Since late relapse beyond 5 years is a very rare event, these patients may have been cured. However, late toxicity of PCI must be kept in mind. Three among the 10 patients have suffered from neuropsychologic symptoms of varying degrees in severity. Although the long-term survival rate is a benchmark in the treatment of SCLC, modifications of therapy that may potentially avoid such toxicities should be considered hereafter.

Increased urinary excretion of non-albumin antigen detected with YO-2, a novel monoclonal antibody, in diabetic patients.

Monoclonal antibodies were raised against urine proteins from diabetic patients. An antibody, YO-2, stained three protein bands with apparent molecular weights of 66, 49, and 36 kDa. These bands were not reactive with an anti-human albumin antibody. The urine levels of YO-2-reactive antigen in the normal control were 0.97 +/- 0.37 U/g-Cr (units per gram of urine creatinine) (mean +/- SD). Those of the normo-, micro-, and macroalbuminuric diabetic patients, respectively, were 1.38 +/- 1.36, 2.87 +/- 2.07, and 3.92 +/- 3.33 U/g-Cr. They were significantly higher in the micro- and macroalbuminuric patients. The urine levels of YO-2-reactive antigen had no significant correlation with the urine albumin levels and hemoglobin A1c. We concluded that; a) monoclonal antibody YO-2 recognized a non-albumin urine antigen increasingly excreted in diabetic patients with nephropathy, b) recent glycemic control of diabetes would not significantly affect the urinary excretion rate of YO-2-reactive antigen, and c) the excretion rate and probably the mechanism of YO-2-reactive protein differed from those of albumin. The urine levels of YO-2-reactive antigen could be a clinical marker of diabetic nephropathy.

Anticancer drug sensitivity by human tumor clonogenic assay.

The anticancer drug sensitivity of human cancers was tested by the human tumor clonogenic assay (HTCA). Of 152 human cancer specimens tested, 63 (41%) formed more than 30 tumor cell colonies in control plates and could be used to evaluate the drug sensitivity of tumor cells. In 42 (93%) of 45 clinical trials in 24 patients, a parallel correlation was observed between the in vitro anticancer drug sensitivity measured by the HTCA and the clinical response of tumors to anticancer drugs. These results suggest that the HTCA is a good technique for the in vitro test of the anticancer drug sensitivity of human cancers.

Antitumor activity of platinum analogs against human lung cancer cell lines and tumor specimens.

Antitumor activities of five platinum analogs, including cisplatin, carboplatin, 254-S, DWA2114R, and NK121, were compared using five human lung cancer cell lines and 19 tumor specimens obtained from lung cancer patients. The antitumor activity was evaluated by determining the ratio of the maximum tolerated dose of each drug to the 70% tumor growth inhibitory concentration in a colony assay. Cisplatin was the most potent agent, followed by 254-S and carboplatin. DWA2114R and NK121 were less potent than cisplatin and 254-S. Cross-resistance to adriamycin was also investigated using an adriamycin-resistant small cell lung cancer subline, SBC -3/ADM30. SBC-3/ADM30 was 1.7- to 4.0-fold more resistant to cisplatin, carboplatin, NK121, and DWA2114R, than was the parent line, SBC-3, and the subline was 2.0-fold more sensitive to 254-S. Using SBC-3, in vitro combination effects of etoposide and cisplatin, carboplatin, or 254-S were evaluated by the median-effect principle. Synergism was noted when cisplatin and etoposide were combined at a fixed molar ratio of 1:1. Combination of carboplatin and etoposide showed an additive effect. The combination of 254-S and etoposide was antagonistic at low concentrations, but was markedly synergistic at higher concentrations. These data suggested the efficacy of 254-S in the treatment of lung cancer.

Mortality and morbidity in two-year disease-free survivors of small cell lung cancer after treatment with combination chemotherapy with or without irradiation.

We evaluated the long-term outcome of 148 patients with small cell lung cancer (SCLC) who had been entered into clinical trials of chemotherapy with or without thoracic and prophylactic cranial irradiation (PCI) between 1981 and 1987. Eighteen patients (12%) survived for 2 or more years. With a minimum follow-up of 4.5 years, 10 of the 18 patients who remained disease-free at 2 years are currently alive and free of SCLC. Seven of these 10 patients currently function as they did before diagnosis. However, three suffer from central nervous system changes of varying degrees in severity which appeared 2-3 years after PCI. Eight of the 18 patients who were disease-free at 2 years have died. Two died of isolated relapse in the brain at 3.6 and 4.2 years after initiation of chemotherapy. Five died of other malignancies while continuing their complete response to SCLC; two of non-small cell lung cancer, two of acute myelogenous leukemia, and one of hepatocellular carcinoma. Another patient died of an unrelated disease without any evidence of SCLC. A small but substantial proportion of patients who underwent intensive treatment will achieve long-term survival; however, these patients remain at higher risk for second cancers and late toxicities. Therefore, attention must be directed to defining the safest way to employ such treatment in the management of SCLC.

Disappearance of pulmonary metastases by OK-432 treatment in a case of hepatocellular carcinoma.

We report here a case of hepatocellular carcinoma (HCC) with multiple lung metastases, which were disappeared by treatment of OK-432. The patient was a 65-year-old man and was diagnosed in 1986 with a small (17 x 11 mm) HCC in the anterior-superior segment of the liver. A part of the right hepatic lobe including the tumor was surgically removed, and transarterial injections of adriamycin (10 mg/week) and subcutaneous injections of OK-432 (10 KE/week) were given. Two and a half years later, recurrence of HCC in the liver and its invasion to vena cava inferior (IVC) were found. OK-432 administration was then stopped and percutaneous ethanol injection therapy (PEIT) was performed 10 times. Six months later, the PEIT was effective and the liver tumor with IVC invasion diminished. However, multiple lung metastases were visible on roentgenograms of the chest, and serum alphafetoprotein (AFP) concentration increased to 50,000 ng/ml. The OK-432 treatment resumed. After 6 months of OK-432 treatment, the multiple lung metastases were disappeared and the serum AFP level decreased to 100 ng/ml. At present, the patient is surviving without any sign of recurrence in either the liver or the lung. The clinical course of this case suggests that OK-432 might have effectively treated lung metastases of HCC, although the exact mechanisms are at present unclear.

[Induction of psoriasis by human recombinant granulocyte colony stimulating factor in a patient with small cell lung cancer].

A 70-year-old man with small cell lung cancer was admitted to our hospital. He received chemotherapy consisting of cisplatin plus etoposide with concurrent chest irradiation. Because the patient had leukocytopenia after the first course of chemotherapy, he was treated subcutaneously with filgrastim (human recombinant granulocyte colony stimulating factor, G-CSF). Three days later, he developed psoriasiform skin eruptions mainly on the surface of the chest radiation field. When filgrastim was replaced with lenograstim (G-CSF), the skin lesions improved. But, after a second course of chemotherapy, lenograstim caused generalized psoriasiform eruptions. The patient had no previous history of psoriasis or any pre-existing skin disease. A skin biopsy revealed a Munro microabscess and spongiform pustules of Kogoj, which are the findings characteristic of the pathology of psoriasis. The MEDLINE report search has revealed, this is the first report of induction of psoriasis by G-CSF in a patient with small cell lung cancer.

[A case of chronic hypersensitivity pneumonitis induced by shiitake mushroom spores].

A 73-year-old woman was admitted to our hospital with a low-grade fever, dry cough and dyspnea on exertion as the chief complaints. She had been a professional shiitake mushroom grower for 50 years. Three years before visiting our hospital, she had been suspected of having hypersensitivity pneumonitis as a result of chest X-ray examination, bronchoalveolar lavage and transbronchial lung biopsy performed at another clinic. No antigens were identified at that time, but prednisolone was administered. On admission to our hospital, chest radiography and chest computed tomography revealed an interstitial shadow with subpleural honey-combing in both lower lung fields. After steroid pulse therapy, dyspnea on exertion and hypoxia improved moderately. Because of recurrence of the dyspnea, however, she was admitted on four separate occasions. On the second admission, an increase in lymphocytes was found by bronchoalveolar lavage, and septal lymphocytic infiltration accompanying fibrosis was demonstrated by transbronchial lung biopsy. On the fourth admission, a detailed immunological examination and an environmental survey were performed. The environmental provocation test yielded clinical symptoms similar to those experienced at the mushroom farm. Furthermore, tests of precipitation and lymphocyte proliferation in response to shiitake mushroom extracts were positive. Finally a diagnosis of chronic hypersensitivity pneumonitis induced by shiitake mushrooms was confirmed.

[Sensitivity testing of anticancer drugs using the human tumor clonogenic assay].

The response to cancer chemotherapy varies from patient to patient with the same histologic type of tumor. However, anticancer drugs are considerably toxic to the patient, and it is therefore very important to have an accurate knowledge of the sensitivity of anticancer drugs against an individual patient's tumor in establishing successful chemotherapy. We have investigated the sensitivity testing of anticancer drugs using the human tumor clonogenic assay since 1980. Specimens were obtained by aspiration of ascites, pleural effusions and bone marrow and by biopsy of primary and metastatic tumors. Drugs tested in the present study were adriamycin, aclarubicin, THP-adriamycin, mitoxantrone, 40497s (an active compound derived from ifosfamide), mitomycin C, cisplatinum and methotrexate. One hundred and fifty-two specimens were obtained from cancer patients and tested for their drug sensitivity using the assay. Of the 152 specimens, 63 (41%) formed more than 30 colonies in control plates and could be used to evaluate drug sensitivity. Of these, 45 instances were evaluable for examination in an in vitro-in vivo association, and 42 (93%) showed a correlation between in vitro sensitivity and clinical response. In summary, the results indicated that the human tumor clonogenic assay was an excellent technique for testing the in vitro sensitivity of anticancer drugs. However, technical developments yielding higher colony efficiency would be required to facilitate practical use of the assay.

[A case of lung cancer with pericardial effusion without cardiac tamponade].

Cardiac tamponade as an initial manifestation of primary lung cancer is uncommon. All such cases had shown symptoms of cardiac tamponade at the first visit of the hospital. We report a case of lung cancer with pericardial effusion without cardiac tamponade. Echocardiography, revealed little pericardial effusion and it has not increased for 3 months. Pericardiotomy revealed adenocarcinoma and lung cancer was confirmed by bronchial biopsy. It is necessary to further examine patients with even slight amounts of pericardial effusion.

[Cytotoxic effect of topoisomerase II inhibitors against adriamycin- and etoposide-resistant small cell lung cancer sublines].

Using reverse transcription polymerase chain reaction, we determined mRNA expression of topoisomerase (topo) II alpha and beta in adriamycin- and etoposide-resistant small cell lung cancer sublines, SBC-3/ADM 100 and SBC-3/ETP. The expression of topo II alpha mRNA decreased substantially in SBC-3/ADM 100 and SBC-3/ETP as compared with the parent cell line, SBC-3; 0.71-fold in the former and 0.38-fold in the latter. Similarly, that of topo II beta mRNA decreased to an extent of 0.68-fold in SBC-3/ADM 100 and 0.28-fold in SBC-3/ETP as compared with the parent cell line. SBC-3/ADM 100 and SBC-3/ETP were highly resistant to topo II inhibitors such as daunorubicin, epirubicin, pirarubicin, mitoxantrone, and teniposide. However, SBC-3/ADM 100 showed a less resistance to aclarubicin, and SBC-3/ETP was as sensitive to the drug as was in the parent cell line. The resistance to topo II inhibitors excluding for aclarubicin might be partially explained by the decreased expression of topo II alpha and beta mRNA.

[Small cell lung cancer: a retrospective analysis of results of chemotherapy and combined modality treatment].

In order to assess the development of treatments and the curability of SCLC, we analyzed a total of 181 patients entered in our protocol studies since 1976. Between 1976 and 1981, 37 patients (20 LD and 17 ED) were treated with COMP, a 4-drug combination of cyclophosphamide (CTX), vincristine (VCR), methotrexate, and procarbazine. During the period, chest irradiation (RT) was administered optionally to those with LD. Between 1981 and 1986, 112 patients (56 each of LD and ED) were treated with a cyclic alternating chemotherapy of the COMP and VAN, a 3-drug combination of etoposide (VP-16), adriamycin (ADM), and nimustine. In this study, we randomized LD patients either to receive CT alone or CT plus chest RT of 40 Gy to assess the role of chest RT in the treatment of patients in LD. Complete responders were also randomized either to receive prophylactic cranial irradiation (PCI) or not. Thereafter, a pilot phase II study of a hybrid regimen has been conducted in 32 patients (16 each of LD and ED), in which CTX, ADM and VCR (CAV) was given on day 1, and cisplatine and VP-16 (PVP) on days 8 and 9. Chest RT was administered mandatory to LD in this study. The median survival time (MST) has been prolonged with an improvement in response rate over CT in both LD and ED: MST of LD was 10 months for COMP, 14 months for COMP-VAN, and not achieved for CAV-PVP hybrid regimen (13 of 16 patients alive between 10 and months), while that of ED was 8 months for COMP, 11 months for COMP-VAN, and 13 months for CAV-PVP hybrid regimen. The randomized study comparing CT alone and CT plus chest RT revealed that chest RT played a substantial, but not significant, for long survival in LD. Finally 13 of 149 patients treated between 1976 and 1986 were long-term, disease-free survivors beyond 2 years (12 LD and 1 ED). Two of them who had not received PCI had a relapse in the brain, but the remaining 11 patients are alive and disease-free between 28 and 84 months. These results imply that SCLC is potentially curable, but it will be difficult to achieve a cure in a substantial proportion of patients with the disease.

[Beneficial effect of cisplatin based combination chemotherapy on adenocarcinoma of the lung].

Cisplatin (CDDP) based combination chemotherapy has improved the response rate of non-small cell lung cancer (NSCLC). However, the survival benefit of CDDP-based chemotherapy in patients with NSCLC is still controversial. In order to determine whether CDDP had a meaningful impact on the course of NSCLC, the survival of patients treated by combination chemotherapy containing CDDP (CDDP arm: PVB; CDDP + vindesine + bleomycin, VIP; vindesine + ifosfamide + CDDP) was compared with that treated by chemotherapy without CDDP (no CDDP arm: COMP; cyclophosphamide + vincristine + methotrexate + procarbazine, MVB; mitomycin C + vindesine + bleomycin), retrospectively. Survival in CDDP arm (median survival time [MST]; 10.2 months) was significantly longer than in the no-CDDP arm (MST; 6.9 months) (p less than 0.01). These results indicate that CDDP-based combination chemotherapy can not only improve response rate but also prolong survival of NSCLC.

[Phase II study of a three-drug combination of ifosfamide, cisplatin and vindesine in non-small-cell lung cancer].

Between February 1986 and April 1987, we conducted a phase II clinical trial of a three-drug combination of ifosfamide, cisplatin, and vindesine in advanced non-small-cell lung cancer. The combination consisted of ifosfamide, 1,300 mg/m2, on days 1 through 5, cisplatin, 20 mg/m2, on days 1 through 5, and vindesine, 3 mg/m2, on days 1 and 8. Courses were repeated at 4-week intervals until disease progression or unacceptable toxicity occurred. Of 21 patients evaluated, one had a complete response and 12 had partial response, with an overall response rate of 62%. The projected median response duration was 30 weeks. The median survival for all patients has not been reached: 14 of 21 patients are still alive with a median follow-up period of 41 weeks (range, 12 to 73 weeks). The major toxicity was myelosuppression. One patient died of septicemia while neutropenic, but the toxicity was well tolerated in the rest. These results indicate that this three-drug combination is active against non-small-cell lung cancer and warrants further clinical trials.

[Pilot phase II study of hybrid chemotherapy of CAV-PVP in small cell lung cancer (SCLC)].

A pilot phase II study of a hybrid chemotherapy for SCLC has been conducted between October 1986 and March 1988. Dose and schedule of the regimen were as follows: CTX, 700 mg/m2, on day 1; ADM 30 mg/m2, on day 1; VCR, 1.4 mg/m2, on day 1 (CAV); and CDDP, 60 mg/m2, on day 8; VP-16, 100 mg/m2, on days 8 and 9 (PVP). Courses were repeated q. 4 weeks up to 6 cycles. Patients with LD received chest irradiation at a dose of 50 Gy when maximal response was achieved. Thirty-six patients were fully evaluated for tumor response and toxicity. All 18 patients with LD responded to the regimen including 11 CRs (61%); there were 7 CRs (39%) and 9 PRs (50%) in patients with ED. Fourteen of the 18 patients with LD have survived for 7 to 22 months, against 12.8 months in ED patients. The major toxicity was myelosuppression, but it was well tolerated. These results indicate that hybrid chemotherapy is highly effective for SCLC, and warrants further clinical trials.

[Clinical evaluation of benign asbestos pleurisy].

Seventeen cases of benign asbestos pleurisy were evaluated clinically. All cases were male and almost all cases were more than 60 years-old. Most cases presented with chief complaints of chest pain and dyspnea, but 2 cases had no complaints. Pleural effusion appeared predominantly in the right side. Six cases had 2 or 3 episodes of pleural effusion, and 1 case had 5. Ten cases had an occupational history of asbestos exposure in shipyards and 5 other cases had a history in building construction. Almost all cases had more than 30 years of exposure to asbestos and benign asbestos pleurisy appeared after more than 30 years from the first exposure to asbestos. Among the patients, 6 cases had diffuse pleural thickening and 2 cases had malignancies. Pleural fluid was bloody in 14 of 17 cases (82%) and all pleural fluid showed an exudate. Lymphocytes represented 70% and eosinophils 15% of the cellular population of the pleural fluid. Hyaluronic acid in pleural fluid in cases of benign asbestos pleurisy averaged 29.5 micrograms/ml, which was significantly (p < 0.05) lower than in malignant pleural mesothelioma. Leukocytosis in peripheral blood and a high CRP value were uncommon in benign asbestos pleurisy.

[Small cell lung cancer; a retrospective analysis of results of chemotherapy and chemo-radiotherapy].

In order to assess the development of treatments and the curability of small cell lung cancer, we analysed a total of 239 patients entered in our protocol study since 1976. Median survival time was 68 weeks for 127 patients with limited disease and 48 weeks for 112 with extensive disease. Three-year survival rate was 18% for those with limited disease, whereas it was only 5% for extensive disease. The median survival time and long-term disease-free survival rate has been improved with an introduction of aggressive chemotherapy including new drugs such as etoposide and cisplatin. Chest irradiation in addition to intensive chemotherapy played a substantial, but not significant, role for prolonging patient survival in those with limited disease. Nevertheless, the pace of therapeutic advances has been slowed and appears to reach a plateau. In this paper, the authors try to find some obstacles in the treatment of the disease, and to indicate some strategies to gain a progress.