Role of recombinant interferon-gamma maintenance in responding patients with small cell lung cancer. A randomised phase III study of the EORTC Lung Cancer Cooperative Group

This study was undertaken to determine if recombinant interferon-gamma (rIFN-gamma) given every other day as maintenance therapy could prolong the survival of patients with small cell lung cancer (SCLC) who achieved a complete or nearly-complete response to induction therapy. A secondary endpoint was to assess the toxicity of alternate day doses of this treatment. One hundred and seventy seven patients in complete or nearly-complete response following chemotherapy with or without thoracic radiotherapy were studied. Patients were randomised to receive either rIFN-gamma 4 million units (0.2 mg) subcutaneously every other day for 4 months or observation. One hundred and twenty of the 127 registered patients were eligible; 59 patients received IFN and 61 patients without maintenance therapy were followed. Alternate day IFN was reasonably well tolerated by the majority of patients, but in 12% substantial non-haematological toxicity (including flu-like syndrome) occurred. One of 3 patients with pneumonitis died after having received 3.6 mg IFN. The median survival time from the date of randomisation was 8.9 months for the IFN arm and 9.9 months for the observation arm. rIFN-gamma at the dose and schedule used in this study failed to prolong response duration and survival in SCLC patients in complete or nearly-complete response. The toxicity seen with every other day doses of IFN was less than that reported with daily dosing. The hypothesis that this agent may increase the deleterious effects of radiation on normal lung tissue was supported by the development of pneumonitis in 3 cases of whom 1 had a fatal outcome. The results do not warrant further studies with rIFN-gamma on maintaining response in SCLC.     

Molecular cloning of a new unc-33-like cDNA from rat brain and its relation to paraneoplastic neurological syndromes

Anti-CV2-autoantibodies from patients with paraneoplastic neurological syndromes were used to purify protein(s) related to this disease. A novel cDNA, c-22, was obtained by PCR with primers based on amino-acid sequence of peptides obtained from this protein and rat brain cDNA as template. The deduced amino-acid sequence of c-22 shows homology to the Unc-33 gene from C. elegans in which mutations lead to defects in neuritic outgrowth and axonal guidance and cause uncoordinated movements of the nematode. Several consensus sites for putative protein kinase C phosphorylation were found, suggesting that the c-22 gene product may be a phosphoprotein. Northern hybridizations show that the apparently unique 3.8-kb mRNA of c-22 is present in rat brain tissue and its expression is developmentally regulated: the levels of C-22 mRNA, detectable in brain at embryonic day 17 (E17), increase up to post-natal day 7 (P7) and decline rapidly to an almost undetectable level in adult.     

The best is yet to come

A 25-year-old woman is presented with hemifacial atrophy due to unilateral bulbar poliomyelitis infection. Although bulbar poliomyelitis is not an uncommon disease, it is rarely a cause of hemifacial asymmetry.     

The effects of topical calcipotriol on systemic calcium homeostasis in patients with chronic plaque psoriasis

BACKGROUND: Calcipotriol is an effective treatment of chronic plaque psoriasis. We have previously demonstrated that it has a small effect on systemic calcium homeostasis even at recommended doses. OBJECTIVE: We attempted to determine the mechanism of the effect of calcipotriol on systemic calcium homeostasis so we could assess the possible consequences of long-term use. METHODS: Sixteen patients with extensive chronic plaque psoriasis were hospitalized and treated with high-dose topical calcipotriol. Up to 360 gm of calcipotriol (50 micrograms/gm) ointment was applied per week for 2 weeks under controlled conditions. RESULTS: There was a dose-dependent rise in intestinal absorption of calcium. No effect on bone turnover was demonstrated over this short period. Five patients became hypercalcemic, and there was a dose-dependent rise in serum total adjusted calcium, serum ionized calcium, serum phosphate, urine calcium, and urine phosphate. There was a dose-dependent fall in serum parathyroid hormone and serum 1,25 dihydroxyvitamin D3. CONCLUSION: Calcipotriol exerts its effects on systemic calcium homeostasis by increasing intestinal absorption of calcium and probably phosphate. This results in suppression of parathyroid hormone and 1,25 dihydroxyvitamin D3.     

Two strategies for managing invasive aspergillosis: a decision analysis

We devised a diagnostic approach based on screening plasma for an Aspergillus antigen with use of a sandwich enzyme-linked immunosorbent assay (ELISA), thoracic computed tomographic scanning, and radionuclide imaging for managing patients at risk for invasive aspergillosis. We used a decision analytic model to compare this alternative strategy with the conventional strategy, which relies only on the presence of clinical symptoms, persistent fever, and chest roentgenographic findings. Use of the alternative strategy reduced the number of patients who would receive antifungal treatment empirically, but this strategy was more expensive. The specificity of the sandwich ELISA had a significant impact on cost, but the sensitivity did not. A 13% prevalence of infection resulted in equal costs for both strategies. As much as 43.3% of the patients treated empirically could be given liposomal amphotericin B (L-AmB) before the conventional strategy became the most expensive. The costs of the alternative strategy were less than those of the conventional strategy when >5.3% of all patients, irrespective of strategy, were treated with L-AmB.     

Bipotential primitive-definitive hematopoietic progenitors in the vertebrate embryo

The effects of the diatomic radical, nitric oxide (NO), on melphalan-induced cytotoxicity in Chinese hamster V79 and human MCF-7 breast cancer cells were studied using clonogenic assays. NO delivered by the NO-releasing agent (C2H5)2N[N(O)NO]- Na+ (DEA/NO; 1 mM) resulted in enhancement of melphalan-mediated toxicity in Chinese hamster V79 lung fibroblasts and human breast cancer (MCF-7) cells by 3.6- and 4.3-fold, respectively, at the IC50 level. Nitrite/nitrate and diethylamine, the ultimate end products of DEA/NO decomposition, had little effect on melphalan cytotoxicity, which suggests that NO was responsible for the sensitization. Whereas maximal sensitization of melphalan cytotoxicity by DEA/NO was observed for simultaneous exposure of DEA/NO and melphalan, cells pretreated with DEA/NO were sensitized to melphalan for several hours after NO exposure. Reversing the order of treatment also resulted in a time-dependent enhancement in melphalan cytotoxicity. To explore possible mechanisms of NO enhancement of melphalan cytotoxicity, the effects of DEA/NO on three factors that might influence melphalan toxicity were examined, namely NO-mediated cell cycle perturbations, intracellular glutathione (GSH) levels and melphalan uptake. NO pretreatment resulted in a delayed entry into S phase and a G2/M block for both V79 and MCF-7 cells; however, cell cycle redistribution for V79 cells occurred after the cells returned to a level of cell survival, consistent with treatment with melphalan alone. After 15 min exposure of V79 cells to DEA/NO (1 mM), GSH levels were reduced to 40% of control values; however, GSH levels recovered fully after 1 h and were elevated 2 h after DEA/NO incubation. In contrast, DEA/NO (1 mM) incubation did not reduce GSH levels significantly in MCF-7 cells (approximately 10%). Melphalan uptake was increased by 33% after DEA/NO exposure in V79 cells. From these results enhancement of melphalan cytotoxicity mediated by NO appears to be complex and may involve several pathways, including possibly alteration of the repair of melphalan-induced lesions. Our observations may give insights for improving tumour kill with melphalan using either exogenous or possibly endogenous sources of NO.     

DNA signals for G2 checkpoint response in diploid human fibroblasts

Mammalian eggs are ovulated in metaphase II of meiosis, in a state characterized by high levels of cyclin B and of active maturation promoting factor (MPF). This arrest is mediated by an activity referred to as cytostatic factor (CSF) which prevents the degradation of cyclin. Fertilization triggers a train of Ca2+ spikes which is responsible for the decrease in activity of both MPF and CSF. The decline in MPF however much precedes that in CSF. Experimental observations on mammalian eggs indicate that the kinetics of cell cycle resumption much depends on the temporal pattern of the repetitive Ca2+ spikes. Here, we propose a theoretical model which accounts for Ca(2+)-induced relief from metaphase II arrest in mammalian eggs. The model is based on the fact that Ca2+/calmodulin kinase II (CaMKII) activation is the primary event leading to inactivation of both CSF and MPF. To account for experimental observations, it has to be assumed that CaMKII activation affects the level of the active form of the anaphase promoting complex (APC), which initiates the degradation of cyclin, through two pathways characterized by different time scales. Thus, we hypothesize that CaMKII activation by Ca2+ leads to the transformation of a mediator protein from a form which stimulates the inactivation of the APC into a form which gradually and indirectly induces the deactivation of CSF. In consequence, a sufficient number of Ca2+ spikes first triggers the decrease of MPF, thus allowing the egg to enter in interphase, and later that of CSF. Finally, when CSF is low and when Ca2+ oscillations have stopped, the level of MPF can increase again, a phenomenon that would correspond to the first mitosis. This model also accounts for the observed dependence of the time of entry in interphase (marked by the appearance of the pronuclei) on the frequency of Ca2+ spikes, as well as for the possible entry in metaphase III arrest, a pathological state of the egg which results from an insufficient activation by Ca2+. This study provides some theoretical prediction as to the time of the first mitosis as a function of the temporal pattern of Ca2+ oscillations.     

An experimental model of small intestinal submucosa as a growing vascular graft

OBJECTIVE: The ideal vascular graft for use in children with congenital heart disease should not only be biocompatible and nonthrombogenic and present no infectious risk, but ideally it should grow at the same rate as the recipient. METHODS: We have tested autologous small intestine submucosa as a superior vena cava interposition graft in 11 piglets. The grafts were prepared from segments of jejunum, rendered nonthrombogenic by heparin bonding. The superior vena cava from the level of the azygos vein to the superior vena cava-right atrial junction was replaced. RESULTS: One early and 1 late death were not related to the graft material. At 90 days, the weight of the 9 survivors increased by 630%, from a mean of 10.3 +/- 2.0 kg to a mean of 59.2 +/- 16.7 kg (P < .001). The grafts increased in circumference by 184%, from a mean of 36.8 +/- 4.4 mm to a mean of 61.4 +/- 12.1 mm (P < .001) at late follow-up. Their length increased by 147%, from a mean of 9.9 +/- 2.1 mm at implantation to a mean of 15.8 +/- 5.5 mm at explantation (P = .002 ). At the time of explantation, all 11 grafts were patent and free of thrombus. Cavograms showed no anastomotic stricture or aneurysm formation in 7 of 9 cases. The luminal surface of all grafts was smooth, shiny, and indistinguishable from that of the native cava. Light microscopy showed a loosely textured collagen framework, with a dense capillary network and complete luminal coverage by a single, continuous cell layer displaying the ultrastructural features characteristic of endothelial cells. CONCLUSION: Small intestine submucosa provides a collagen framework that becomes remodeled, grows, and acquires a nonthrombogenic endothelial lining. This makes it potentially well suited as a cardiovascular substitute in children.     

Histologic appearance of transmyocardial laser channels after 4 1/2 weeks

Preliminary results of clinical studies suggest that transmyocardial laser revascularization is an effective treatment for patients with chronic angina that cannot be treated by other means. The mechanism of this effect remains controversial. We present autopsy results from a patient obtained 4 1/2 weeks after operation that show that the channels do not maintain patency. Further work is needed to determine the frequency of channel patency and its relation to clinical benefit.