Chemotherapy versus chemoradiotherapy in patients with limited small cell lung carcinoma

62 patients with a limited small cell lung cancer were randomly qualified into two groups. 32 patients of the first group were treated only with the chemotherapy regimen, consisted of three drugs (Carboplatine, Etoposide and Vincristine administered in 6 courses, on regular, 3-weeks basis). The second group of 30 patients had been treated with the identical chemotherapy schedule, but alternatively combined with a primary site irradiation in a total dose of 40Gy, applied in parts after the chemotherapy courses 2, 3, and 4. The significantly higher proportion of a complete remission results was observed in the alternate-treatment group: 14/30 (46.7%), compared with the chemotherapy-only group: 10/32 (31%). Alternate chemoradiotherapy resulted both in the increased median remission duration time, and the increased median survival time. Only in the alternate chemotherapy group, in 14/30 patients (46.7%) the pneumotoxicity symptoms appeared, whilst no differences in other organ-specific treatment-induced toxic effects were noted.     

Effect of transient cyclic AMP elevation on DNA synthesis in rat hepatocytes at G1 phase

Maintaining high levels of intracellular cyclic AMP (cAMP) is known to inhibit the growth of various proliferating cells including hepatocytes. We show here that transient (30 min) elevations of cAMP induced by addition of 8-bromo-cAMP (1 mmol/L) to rat hepatocytes in primary culture at three time points (12 h, 16 h and 20 h) after seeding stimulated DNA synthesis. Sustained levels of cAMP stimulated DNA synthesis to a lesser degree at a lower concentration (1 mumol/L), but inhibited it at concentrations higher than 100 mumol/L. We also determined cyclin-dependent kinase 2 (cdk2) activity in the hepatocytes during this incubation period. The transient addition of 8-bromo-cAMP at the late G1 phase increased cdk2 activity. This suggests that transient cAMP elevation in hepatocytes at the late G1 phase has a growth stimulation effect. Up-regulation of cdk2 activity may have a role in this process.     

DNA flow cytometric analysis in patients with operable non-small cell lung carcinoma

Fresh surgical specimens of tumors from 60 patients with previously untreated non-small cell lung carcinoma (NSCLC) who underwent radical surgery between January 1991 and October 1992 were investigated by means of flow-cytometry. The nuclear DNA measurement was carried out using a Facscan (Becton, Dickinson, USA). Analysis of the DNA content was performed in all 60 patients whilst cell cycle analysis was possible in 41 cases (68.3%). Forty-two of the 60 cases (70%) were aneuploid and 18 (30%) were diploid. The overall mean value of DNA index was 1.5. Diploid NSCLC were compared with aneuploid tumors: no significant differences in age distribution, sex ratio, histology and staging were found between the two groups (P > 0.05). An S-phase proportion of more than 10% was found in 30 out of 41 patients (73.2%). Early cancer deaths were reported in four patients (6.6%): the aneuploidy rate was very close in these patients (75%) and in the remaining surviving patients (69.6%). An S-phase proportion of more than 10% was found in 100% of early cancer deaths and in 70.2% of the remaining cases; such a difference seems of some importance although it was not statistically significant (P = 0.071). In conclusion, flow-cytometry studies seem to be a useful tool in the understanding of the biological behavior of patients with NSCLC. In the present prospective report there were no significant correlations between DNA measurements and clinical outcome, however, these results suggest that a high S-phase proportion should be seen as a possible prognostic indicator.(ABSTRACT TRUNCATED AT 250 WORDS)     

Allelotype and replication error phenotype of small cell lung carcinoma

Allelotype and replication error (RER) phenotype analyses were performed to clarify the pathogenetic significance of inactivation of tumor suppressor genes and genomic instability in the genesis and progression of small cell lung carcinoma (SCLC). We examined 37 cases of SCLC for loss of heterozygosity (LOH) and microsatellite instability at 49 loci on all 39 nonacrocentric chromosomal arms. LOH was frequently (>70%) detected on chromosomes 3p (29/32, 90.6%), 5q (15/21, 71.4%), 13q (25/26, 96.2%), 17p (22/25, 88.0%), and 22q (24/33, 72.7%). Frequent LOH (>70%) on these loci was observed even among seven cases of stage I tumors. The incidence of LOH on all 39 nonacrocentric chromosomal arms was not significantly different between primary tumors and metastases. These results suggest that inactivation of multiple tumor suppressor genes accumulates relatively early during progression of SCLC and it may be responsible for clinically and biologically aggressive phenotype of SCLC. RER was observed in 6/37 (16.2%) of SCLC, however, RER at multiple loci was observed only in two cases. Therefore, it was indicated that genomic instability is uncommon, but might play a role in the genesis of a small subset of SCLC.     

Steroid-dependent anti-Hu negative paraneoplastic encephalomyelitis and small cell lung carcinoma

Oslerus osleri tracheobronchitis was diagnosed in 4 young dogs following endoscopic visualization of tracheal nodules and identification of larvae in airway cytologic samples. All dogs improved when ivermectin was administered (200-400 micrograms/kg body weight); however, most (3/4) required serial treatments in order to achieve long-term resolution of clinical signs.     

Attenuation of gossypol cytotoxicity by cyclic AMP in a rat liver cell line

We showed previously that supplementation for 30 d with 800 IU (727 mg) vitamin E/d did not adversely affect healthy elderly persons. We have now assessed the effects of 4 mo of supplementation with 60, 200, or 800 IU (55, 182, or 727 mg) all-rac-alpha-tocopherol/d on general health, nutrient status, liver enzyme function, thyroid hormone concentrations, creatinine concentrations, serum autoantibodies, killing of Candida albicans by neutrophils, and bleeding time in 88 healthy subjects aged >65 y participating in a double-blind, placebo-controlled trial. No side effects were reported by the subjects. Vitamin E supplementation had no effect on body weight, plasma total proteins, albumin, glucose, plasma lipids or the lipoprotein profile, total bilirubin, alkaline phosphatase, serum aspartate aminotransferase, serum alanine aminotransferase, lactate dehydrogenase, serum urea nitrogen, total red blood cells, white blood cells or white blood cell differential counts, platelet number, bleeding time, hemoglobin, hematocrit, thyroid hormones, or urinary or serum creatinine concentrations. Values from all supplemented groups were within normal ranges for older adults and were not significantly different from values in the placebo group. Vitamin E supplementation had no significant effects on plasma concentrations of other antioxidant vitamins and minerals, glutathione peroxidase, superoxide dismutase, or total homocysteine. There was no significant effect of vitamin E on serum nonspecific immunoglobulin concentrations or anti-DNA and anti-thyroglobulin antibodies. The cytotoxic ability of neutrophils against Candida albicans was not compromised. Thus, 4 mo of supplementation with 60-800 IU vitamin E/d had no adverse effects. These results are relevant for determining risk-to-benefit ratios for vitamin E supplementation.     

First-line treatment of advanced nonsmall cell lung carcinoma with docetaxel and vinorelbine

BACKGROUND: Docetaxel and vinorelbine are active agents in the treatment of nonsmall cell lung carcinoma (NSCLC). The efficacy and toxicity of this combination was evaluated in a Phase II study in patients with advanced NSCLC. METHODS: Forty-six chemotherapy-naive patients (44 men and 2 women with a median age of 64 years) with NSCLC (11 with Stage IIIB and 35 with Stage IV disease) were entered into the study; the World Health Organization (WHO) performance status was 0, 1, and 2 in 32, 11, and 3 patients, respectively. Patients received vinorelbine (25 mg/m2) on Day 1 and docetaxel (100 mg/m2) on Day 2 in cycles repeated every 3 weeks. Granulocyte-colony stimulating factor was given to all patients from Day 3 to Day 10. RESULTS: One hundred and seventy-seven courses of chemotherapy were administered. Adverse events included WHO Grade 4 neutropenia (15 patients), Grade 3/4 thrombocytopenia (3 patients), Grade 3 anemia (2 patients), Grade 2 and 3 neurotoxicity (7 patients and 1 patient, respectively), and Grade 3 fatigue (2 patients). Twenty patients (43%) required hospitalization: 11 (24%) for neutropenic fever (2 deaths from sepsis), and 9 (20%) for nonneutropenic pulmonary infections (2 deaths from cardiopulmonary insufficiency). The median overall survival was 5 months and the 1-year survival was 24%. Four complete responses (9.8%) and 11 partial responses (26.8%) (overall response rate of 36.6%; 95% confidence interval, 21.8-51.3%) were documented in 41 evaluable patients (intent-to-treat: 32.6%). Stable and progressive disease occurred in 13 patients each (31.7%). The median duration of response was 5 months and the median time to progression was 3 months (6 months for the responders). CONCLUSIONS: This schedule of docetaxel and vinorelbine combination is effective but its relatively high incidence of complicated neutropenia precludes its general use in patients with advanced NSCLC.     

The results of treatment in 100 patients with limited-stage small cell lung cancer

Strain differences in midgut basal lamina thickness, assessed by measurement in transmission electron micrographs, and disseminated infection rates of dengue-1 virus were compared among three laboratory strains of Aedes albopictus (Skuse). Mean basal lamina thickness for the New Orleans and Houston strains were significantly greater than those for the Oahu strain, which exhibits a higher disseminated infection rate than the former two. Although basal lamina thickness among the F1 progeny of reciprocal crosses of the Oahu and Houston strains were intermediate between the parental strains, they were too variable to be useful as markers in genetic studies. Measurements of basal laminae among individuals of the New Orleans strain, with disseminated or nondisseminated infections, failed to demonstrate a role for basal lamina thickness as a modulator of dengue-1 virus dissemination across the midgut epithelium of Ae. albopictus.     

The value of diagnostic methods used to assess the response to treatment in patients with limited small cell lung carcinoma

Tumor response is used as a main criterion whether or not the treatment yields an anticancer activity. The tumor response criteria are defined by WHO recommendation but little is known about the tests must be used. The aim of this paper was to compare the degree of response to the treatment of 268 patients with limited small cell lung cancer, using independently 3 methods: radiological, bronchoscopic and cytological of bronchial material. Particular categories of response (CR, PR NR and presence or absence of carcinomatous cells) were related to survival time of patients independently to method of assessment. Multivarinte Cox analysis selected 3 parameters related to 3 different methods as independent survival risk factors. We conclude that each of diagnostic method (chest x-ray, bronchoscopy, cytological examination of bronchial material yield independent information correlated with survival risk of particular patient.     

The role of surgery in the management of small cell lung carcinoma

Small cell lung carcinoma is responsive to chemotherapy and radiotherapy, but long-term survival of patients is rarely seen. We analyzed resected 19 patients with small cell lung carcinoma. The overall 5-year survival rate of resected patients was approximately 30% and mean survival time (MST) was 50 months. 2 patients of them survived more than 5 years. The survivors were received chemotherapy and radiotherapy several times after surgery. When we consider the role of resection in the treatment of small cell lung carcinoma, we can realize multimodality therapy including resection is important to obtain long-term survival. Moreover, the surgical resection can identify mixed type with non-small cell elements or residual tumors after chemotherapy and determine optimal treatment methods from their histopathologic findings.     

A case of small cell carcinoma of the lung associated with hypertrophic pulmonary osteoarthropathy

AIM: To investigate the mechanisms of anti-inflammatory effect of matrine (Mat), its effects on mouse splenocyte proliferation, and release of interleukin-1 (IL-1) and interleukin-6 (IL-6) from mouse peritoneal macrophages. METHODS: Splenocyte proliferation was assayed by [3H] TdR incorporation. IL-1 and IL-6 activities were measured by thymocyte proliferation assay and B9 cell proliferation MTT colorimetric method, respectively. RESULTS: Mat (125-500 mg.L-1) obviously inhibited concanavalin A (Con A, 5 mg.L-1)- and lipopolysaccarides (LPS, 10 mg.L-1)-induced splenocyte proliferation and LPS-induced release of IL-1 and IL-6 from mouse peritoneal macrophages. CONCLUSION: Mat inhibited splenocyte proliferation and release of IL-1 and IL-6 in vitro.     

Potentiation of paclitaxel cytotoxicity by inostamycin in human small cell lung carcinoma, Ms-1 cells

A robust new analytical method has been developed for the determination of 5-fluorouracil (5-FU) in human plasma samples using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The method is based on a liquid-liquid extraction procedure, precolumn derivatization, reversed-phase HPLC separation, and detection using atmospheric pressure chemical ionization and selected reaction monitoring. The derivatization agent used was 4-bromomethyl-7-methoxycoumarin. The internal standard for the assay procedure was a stable isotope labeled analog of 5-FU. The lower limit of quantitation was 1.0 ng/mL using 500 microL aliquots of plasma. Sample throughput on the mass spectrometer was approximately 17 samples/h (3.5 min/sample). The method was fully validated. The recovery of 5-FU averaged 76.1%. The accuracy of the assay, assessed from quality control samples, ranged from 99.1% to 104.3% (% theoretical). The overall interassay precision (% RSD) was 2.7%, and the intraassay precision (% RSD) ranged from 1.5% to 3.9%. The derivatized samples were found to be stable under sample analysis conditions and during refrigerator storage. The method was specific for the determination of 5-FU.     

Radiotherapy in the treatment of brain metastasis from small cell lung carcinoma: study on appropriately controlled dose

Fifty-two brain metastatic lesions occurring in 20 patients with small cell lung carcinoma (SCLC) were irradiated, and then the relationship between tumor size, dose and control was clinically and histopathologically studied. Lesions of 8 mm in diameter and those of 10 mm in diameter were determined to be controllable by irradiation at about 38 Gy and 42 Gy, respectively. According to size-dependent curative minimum doses, the lesions could be divided by the 10 Gy/ 5fr/wk method into controlled and non-controlled groups with the curve expressed as dose (Gy) = 15.27 log10 [tumor volume (mm3)] +0.6. Based on these results, tumors of 2 mm and 3 mm in diameter were estimated to be controllable at 14 and 20 Gy, respectively. Thus prophylactic cranial irradiation (PCI) in the treatment of SCLC was thought to be not always necessary if early treatment of small metastatic lesions, detected by Gd-DTPA-enhanced MRI could be achieved. The optimal interval between follow-up examinations was thought to be 1 month during the first two years after the diagnosis of SCLC, and then 3 months after that. In addition, the omission of PCI can save many patients who do not actually require PCI from suffering its adverse effects.     

Effect of atrial natriuretic peptide and cyclic GMP phosphodiesterase inhibition on collagen synthesis by adult cardiac fibroblasts

1. Cardiac fibroblasts play an important role in the pathophysiology of cardiac remodelling induced by hypertension and myocardial infarction by undergoing proliferation and depositing extracellular matrix proteins such as collagen. We have examined the effects of atrial natriuretic peptide (ANP) on proliferation and collagen synthesis by adult rat and human cardiac fibroblasts in culture. 2. In cells from both species radioligand studies using 125I-ANP suggested that the majority of binding sites (> 85%) were non-guanylyl cyclase-linked (NPR-C subtype). Nonetheless ANP (10(-9) to 10(-6) M), in the presence of zaprinast, an inhibitor of phosphodiesterase 5 (PDE5), increased fibroblast cyclic GMP levels 3-5 fold in a concentration-dependent manner (P < 0.05). 3. ANP (10(-11) to 10(-6) M), a NPR-C ligand, C-ANF4-23 (10(-11) to 10(-6) M) and zaprinast alone had no significant effect on either basal or serum-stimulated DNA synthesis or fibroblast number. In combination with zaprinast (10(-5) M), however, ANP (10(-9) to 10(-6) M) but not C-ANF4-23 (10(-7) M) inhibited markedly both basal and stimulated fibroblast mitogenesis, an effect reproduced by 8-bromo-cyclic GMP (10(-5) to 10(-3) M). 4. Collagen synthesis, determined by measuring hydroxyproline levels, was stimulated with transforming growth factor-beta1 (40 pM), angiotensin II (10(-7) M) or 2% foetal bovine serum. The increase in collagen production, normalised by cell number, was reduced dramatically (to at or near basal production) by ANP (10(-9) to 10(-7) M) but not C-ANF4-23 (10(-7) M) in the presence of zaprinast. Again 8-bromo-cyclic GMP (10(-5) to 10(-3) M) reproduced the effect. 5. ANP is capable of inhibiting collagen synthesis in adult rat and human cardiac fibroblasts via cyclic GMP, a property unmasked and enhanced by inhibition of PDE5.     

Nuclear and kinetoplast DNA synthesis in Trypanosoma cruzi, autoradiographical study with DNA polymerase inhibitors

DNA synthesis in epimastigote forms of Trypanosoma cruzi was studied autoradiographically by incorporation of [3H]thymidine in the nuclear and kinetoplast DNA. Both DNA were heavily labelled. Three eukaryotic DNA polymerase inhibitors (aphidicolin, aracytidine, and dideoxythimidine) were chosen to study the nuclear and kinetoplast DNA synthesis in vivo. Inhibition was mainly observed with the nuclear DNA.     

Reduced expression of E-cadherin in oral squamous cell carcinoma: relationship with DNA methylation of 5'' CpG island

The caffeine-evoked effects on the intracellular Ca2+ concentration ([Ca2+]i) and on the release of dopamine by PC12 cells were investigated. Stimulation by caffeine resulted in a transient Ca2+ release which was followed by a sustained phase of Ca2+ entry through a non-voltage dependent pathway. Treatment with cyclopiazonic acid (CPA) or thapsigargin, inhibitors of the Ca2+ATPase pump of the endoplasmic reticulum, resulted in only a sustained rise in [Ca2+]i in the presence of extracellular Ca2+. Pretreatment of cells with CPA or thapsigargin abolished the subsequent Ca2+ responses to caffeine. Caffeine also evoked the release of dopamine from the cells only in the presence of extracellular Ca2+, which was mimicked by CPA. These results suggest that store-dependent Ca2+ entry evoked by caffeine has an indispensable role in the secretory response in an excitable cell line, PC12 cells.     

Reduced E-cadherin expression correlates with increased invasiveness in colorectal carcinoma cell lines

A reduction in cell adhesiveness and cell invasion are essential steps in tumour progression to metastasis. In the present study two out of seven colorectal carcinoma cell lines exhibited reduced expression of the cell-cell adhesion molecule E-cadherin as assessed by immunofluorescence. The same two cell lines were invasive in the collagen gel and membrane invasion culture system invasion assays. Addition of anti-E-cadherin antibody to a non-invasive carcinoma cell line caused the cells to assume a dissociated morphology on plastic and to become invasive in collagen gels. This demonstrates a causal role for E-cadherin in the maintenance of intercellular adhesion and the suppression of tumour cell invasion and possibly metastasis in colorectal tumour cells.     

Involvement of hydrogen peroxide production in erbstatin-induced apoptosis in human small cell lung carcinoma cells

Tyrosine kinase inhibitor, erbstatin, induced morphological apoptosis and DNA fragmentation in human small cell lung carcinoma (SCLC) cells. Erbstatin-induced apoptosis was inhibited by antioxidants, whereas erbstatin-inhibited tyrosine phosphorylation was not affected by them. Erbstatin was shown by means of flow cytometry to induce hydrogen peroxide generation. Furthermore, hydrogen peroxide induced morphological apoptosis and DNA fragmentation in the SCLC cells. We also demonstrated that erbstatin-induced hydrogen peroxide production and DNA fragmentation were partially suppressed by inhibition of protein synthesis. Thus, erbstatin-induced apoptosis would be due to hydrogen peroxide generation via newly synthesized protein.     

Full chemotherapy in elderly patients with small cell bronchial carcinoma

The changing distributions of collagens and glycosaminoglycans have been studied at the attachments of the medial collateral ligament during postnatal development. The ligament is of particular interest because it has a fibrocartilaginous attachment to the femoral epiphysis, but a fibrous one to the tibial metaphysis. Ligaments were examined in rats killed at birth and at 2, 4, 6, 8, 10, 20, 30, 45, 60, 90 and 120 days after birth. Cryosections were immunolabelled with monoclonal and polyclonal antibodies against types I and II collagen, chondroitin 4 and 6 sulfate, dermatan and keratan sulfate. Although the ligament is attached at both ends to bones that develop from cartilage, there was a striking difference in collagen labelling. Type II collagen was only found in spicules of calcified cartilage in bone beneath the tibial enthesis after ossification had commenced, but there was a continuous band of labelling at all stages of development at the femoral enthesis. Initially, the cartilage at the femoral attachment lacked type I collagen, but by 45 days labelling was continuous from ligament to bone. Continuity of labelling was seen much earlier at the tibial enthesis, as soon as bone had formed. There were also marked changes in glycosaminoglycan distribution. Keratan sulfate was present at both entheses up to 45 days, but only at the femoral enthesis thereafter. Both attachments labelled throughout life for dermatan sulfate, but chondroitin 4 and 6 sulfate were only found at the femoral end. The results suggest that enthesial cartilage at the femoral attachment was initially derived from the cartilaginous bone rudiment but was quickly eroded on its deep surface by endochondral ossification as bone formed at the attachment site. It was replaced by fibrocartilage developing in the ligament. This mechanism allows enthesis cartilage/fibrocartilage to contribute to the growth of a bone at a secondary centre of ossification in addition to dissipating stress at the ligament-bone junction.