Preliminary report of the Asian-Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Asian-Oceanian Clinical Oncology Association Nasopharynx Cancer Study Group

BACKGROUND: The aim of this trial was to compare the outcome achieved with neoadjuvant chemotherapy followed by radiotherapy to that achieved with radiotherapy alone for patients with locoregionally advanced undifferentiated or poorly differentiated nasopharyngeal carcinoma (NPC) meeting one of the following criteria: Ho's T3 disease, Ho's N2-N3 disease, or lymph node size > or =3 cm. METHODS: Between September 1989 and August 1993, 334 patients were enrolled in the study, with equal numbers of patients randomized to the neoadjuvant chemotherapy arm (CT arm) and the radiotherapy arm (RT arm). Neoadjuvant chemotherapy consisting of 2-3 cycles of cisplatin (60 mg/m2 on Day 1) and epirubicin (110 mg/m2 on Day 1) followed by radiotherapy was given to the CT arm. For radiotherapy, a dose of 66-74 gray (Gy) (median, 71 Gy) was delivered to the primary tumor and 60-76 Gy (median, 66 Gy) to the neck. Two hundred eighty-six eligible patients completed the treatment and were evaluable for treatment response (134 in the CT arm, 152 in the RT arm). All patients were included in the survival analysis based on the intention to treat. The median follow-up was 30 months for the whole cohort and 41 months for the surviving patients. RESULTS: Analysis of the 334 patients based on the intention to treat showed no significant difference in relapse free survival (RFS) or overall survival (OS) between the 2 treatment arms (3-year RFS rate: 48% in the CT arm vs. 42% in the RT arm, P = 0.45; 3-year OS rate: 78% vs. 71%, P = 0.57). In an efficacy analysis based on only the 286 evaluable patients, a trend of improved RFS favoring the CT arm was observed (3-year RFS rate: 58% vs. 46%, P = 0.053), with again no significant difference in OS (3-year OS rate: 80% vs. 72%, P = 0.21). In the subgroup of 49 patients with bulky neck lymph nodes >6 cm, improved RFS (3-year RFS rate: 63% vs. 28%, P = 0.026) and OS (3-year OS rate: 73% vs. 37%, P = 0.057) were observed, favoring the CT arm. CONCLUSIONS: This multicenter randomized study did not demonstrate any benefit with the addition of cisplatin-epirubicin neoadjuvant chemotherapy for patients with locoregionally advanced nasopharyngeal carcinoma; therefore routine administration of neoadjuvant chemotherapy to this target group cannot be recommended. Although the overall incidence of recurrence was reduced with the addition of chemotherapy in the efficacy analysis, the overall survival was not affected. A more effective chemotherapy regimen, the selection of an appropriate target group, and the use of an alternative strategy for combining chemoradiotherapy should be explored in future trials.     

Transurethral cystotomy repair

We present a novel transurethral technique for cystotomy repair. This method can be used for immediate bladder repair following limited bladder injury and avoids the morbidity associated with laparotomy.     

Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer

Fas ligand (FasL) is produced by activated T cells and natural killer cells and it induces apoptosis (programmed cell death) in target cells through the death receptor Fas/Apol/CD95. One important role of FasL and Fas is to mediate immune-cytotoxic killing of cells that are potentially harmful to the organism, such as virus-infected or tumour cells. Here we report the discovery of a soluble decoy receptor, termed decoy receptor 3 (DcR3), that binds to FasL and inhibits FasL-induced apoptosis. The DcR3 gene was amplified in about half of 35 primary lung and colon tumours studied, and DcR3 messenger RNA was expressed in malignant tissue. Thus, certain tumours may escape FasL-dependent immune-cytotoxic attack by expressing a decoy receptor that blocks FasL.     

Active Wegener's granulomatosis is associated with HLA-DR+ CD4+ T cells exhibiting an unbalanced Th1-type T cell cytokine pattern: reversal with IL-10

Wegener's granulomatosis (WG) is a granulomatous vasculitis that affects the upper respiratory tract, lung, and kidney. Since T cells make up a significant proportion of cells infiltrating granulomatous lesions in WG, we investigated the proliferative response and cytokine profile of T cells from these patients. PBMCs were isolated from 12 patients with active WG, 7 patients with inactive disease, and 12 healthy normal donors. PBMCs from clinically active WG patients exhibited increased proliferation following stimulation with either PMA/ionomycin or anti-CD2 and anti-CD28, when compared with normal donors. In addition, these PBMCs exhibited increased secretion of IFN-gamma, but not of IL-4, IL-5, or IL-10. Furthermore, TNF-alpha production from PBMCs and CD4+ T cells isolated from patients with WG was elevated, when compared with healthy donors. In further studies, we investigated the ability of WG patients' monocytes to produce IL-12 and showed that both inactive and active patients produced increased amounts of IL-12. Finally, the in vitro IFN-gamma production by WG PBMC is inhibited in a dose-dependent manner by exogenous IL-10. These data suggest that T cells from WG patients overproduce IFN-gamma and TNF-alpha, probably due to dysregulated IL-12 secretion, and that IL-10 may therefore have therapeutic implications for this disease.     

Epidemiology of clonorchiasis in Ninh Binh Province, Vietnam

We present the spatial structure of binase, a small extracellular ribonuclease, derived from 1H-NMR* data in aqueous solution. The total of 20 structures were obtained via torsion angle dynamics using DYANA program with experimental NOE and hydrogen bond distance constraints and phi and chi1 dihedral angle constraints. The final structures were energy minimised with ECEPP/2 potential in FANTOM program. Binase consists of three alpha-helices in N-terminal part (residues 6-16, 26-32 and 41-44), five-stranded antiparallel beta-sheet in C-terminal part (residues 51-55, 70-75, 86-90, 94-99 and 104-108) and two-stranded parallel beta-sheet (residues 22-24 and 49-51). Three loops (residues 36-39, 56-67 and 76-83), which play significant role in biological functioning of binase, are flexible in solution. The differences between binase and barnase spatial structures in solution explain the differences in thermostability of binase, barnase and their hybrids.     

Proadrenomedullin N-terminal 20 peptide: minimal active region to regulate nicotinic receptors

Proadrenomedullin N-terminal 20 peptide (PAMP-[1-20]; ARLDVASEFRKKWNKWALSR-amide) is a potent hypotensive and catecholamine release-inhibitory peptide released from chromaffin cells. We studied the mechanism of PAMP action and how its function is linked to structure. We tested human PAMP-[1-20] on catecholamine secretion in PC12 pheochromocytoma cells and found it to be a potent, dose-dependent (IC50 approximately 350 nmol/L) secretory inhibitor. Inhibition was specific for nicotinic cholinergic stimulation since PAMP-[1-20] failed to inhibit release by agents that bypass the nicotinic receptor. Nicotinic cationic (22Na+,45Ca2+) signal transduction was disrupted by this peptide, and potencies for inhibition of 22Na+ uptake and catecholamine secretion were comparable. Even high-dose nicotine failed to overcome the inhibition, suggesting noncompetitive nicotinic antagonism. N- and C-terminal PAMP truncation peptides indicated a role for the C-terminal amide and refined the minimal active region to the C-terminal 8 amino acids (WNKWALSR-amide), a region likely to be alpha-helical. PAMP also blocked (EC50 approximately 270 nmol/L) nicotinic cholinergic agonist desensitization of catecholamine release, as well as desensitization of nicotinic signal transduction (22Na+ uptake). Thus, PAMP may exert both inhibitory and facilitatory effects on nicotinic signaling, depending on the prior state of nicotinic stimulation. PAMP may therefore contribute to a novel, autocrine, homeostatic (negative-feedback) mechanism controlling catecholamine release.     

The association of peripheral monocyte derived interleukin 1beta (IL-1beta), IL-1 receptor antagonist, and tumor necrosis factor-alpha with osteoarthritis in the elderly

OBJECTIVE: To examine the association of peripheral blood mononuclear cell (PBMC) derived interleukin 1beta (IL-1beta), IL-1 receptor antagonist (IL-1Ra), tumor necrosis factor alpha (TNF-alpha), and radiographic osteoarthritis (OA) in the elderly. METHODS: A total of 703 subjects (436 women, 267 men, mean age 78.5+/-4.5 yrs) had both knee and hand radiographs, and cytokines were measured during the 22nd biennial examination of the Framingham Cohort. PBMC derived IL-1beta , IL-1Ra, and TNF-alpha production was assessed using a non-cross reacting polyclonal radioimmunoassay. Knee OA was defined as a score of > 2 using a modified Kellgren and Lawrence scale. The presence of osteophytes and joint space narrowing were scored separately on a 0-3 scale, in which disease was defined a priori as a score > 0 for each feature. Sex-specific odds ratios were calculated for knee OA after adjusting for weight, history of knee injury, and use of estrogen and nonsteroidal antiinflammatory drugs. RESULT: No uniform associations were found for IL-1beta or IL-1Ra in men, or for TNF-alpha production and radiographic OA in either sex. We found possible associations for the highest levels of IL-1beta production and the presence of knee osteophytes [OR=2.0 (1.2-3.5)] and joint space narrowing [OR=1.7 (1.1-2.8)] in women. Our data suggested a possible protective effect for IL-1Ra production and hand OA in women [OR=0.6 (0.4-1.0)]. CONCLUSION: We found no consistent association of PBMC cytokine production and radiographic OA. However, women with the highest production of IL-1beta and IL-1Ra had respectively higher rates of knee OA and lower rates of hand OA than expected.     

Effects of compaction technique on processing response of aluminium PM alloys

The objective of this research was to assess the effects of compaction method (uni-axial die compaction and cold isostatic pressing) on two aluminium powder metallurgy alloys. Both systems were mixtures of elemental and master alloy powders. Mechanical and physical properties from samples prepared using both methods were compared. Analyses included the measurement of green and sintered densities, tensile properties and microstructural analyses. Results indicated that sintered products of a largely comparable quality could be realised for both alloys regardless of the compaction approach employed. PM2324 displayed sensitivity to compaction pressure such that low values were preferred for cold isostatic pressing (CIP) whereas higher values yielded superior sintered products when die compaction was implemented. Conversely, compaction pressure had no meaningful impact on the sintering behaviour of PM7075 for CIP or die pressed samples.

Le but de cette recherche consistait à évaluer les effets de la méthode de compaction (compaction uniaxe en moule et compression isostatique à froid) sur deux alliages d’aluminium de la métallurgie des poudres. Les deux systèmes consistaient en mélanges de poudres élémentaires et de poudres d’alliage mère. On a comparé les propriétés mécaniques et physiques des échantillons préparés en utilisant les deux méthodes. Les analyses incluaient la mesure de la densité à cru et frittée, les propriétés de traction et les analyses de la microstructure. Les résultats indiquaient que l’on pouvait réaliser des produits frittés d’une qualité très comparable pour les deux alliages, peu importe l’approche de compaction utilisée. PM2324 démontrait une sensitivité à la pression de compaction de telle sorte que des valeurs faibles étaient préférées pour le CIP alors que des valeurs plus élevées produisaient des produits frittés supérieurs avec la compaction en moule. Inversement, la pression de compaction n’avait pas d’impact significatif sur le comportement de frittage de PM7075 pour les échantillons pressés par CIP ou en moule.