Safety assessment of intensive induction therapy in childhood anaplastic large cell lymphoma: report of the ALCL99 randomised trial

Background

ALCL99 protocol including six courses of chemotherapy derived from the NHL‐BFM protocol is widely used for the treatment of paediatric anaplastic large‐cell lymphoma. In the ALCL99 trial, patients were randomised to receive MTX 1 g/m² in 24 hr with intrathecal injection (MTX1) versus MTX 3 g/m² in 3 hr without intrathecal (MTX3); then to receive or not vinblastine (high‐risk patients). The present study provides information about the acute adverse reactions (ARs) during the six courses of the ALCL99 treatment, assesses risk factors for ARs and evaluates the risk of overweight related to treatment.

Methods

Data concerning ARs were assessed using CTCv2 and analysed overall and according to the type of course.

Results

Between 1999 and 2005, 352 patients were recruited. Toxicity assessed after 2050 courses included grade 4 neutropaenia (70% of courses), grade 3–4 stomatitis (13%), grade 3–4 transaminase elevation (10%) and grade 3–4 infection (5%). Four patients (1%) died of toxicity. The toxicity profile differed between courses‐A (significantly more haematological toxicity) and courses‐B (significantly more stomatitis). The percentage of ARs was higher after the first course than after subsequent courses. Severe toxicity was more frequent after MTX1 than after MTX3 courses but did not differ between courses with or without vinblastine. Overall 20% of patients had a weight gain exceeding 20%.

Conclusions

The high rate of acute toxicity should be considered when using the ALCL99 protocol. Chemotherapy including MTX 3 g/m² in 3 hr was less toxic than the same regimen with MTX 1 g/m² in 24 hr. Adding vinblastine did not increase the risk of toxicity. Pediatr Blood Cancer 2011;56:1071–1077. © 2011 Wiley‐Liss, Inc.     

The effect of age on knowledge of HIV/AIDS and risk related behaviours among army personnel

Background

HIV/AIDS has been described as the fourth largest cause of death globally and leading cause of death in Africa^. HIV/AIDS has been a devastating inferno for nearly 30 years, and has particularly impacted countries in sub-Saharan Africa^. In most African countries, it has been reported that the HIV infection amongst the military has been shown to be about 2 to 5 times higher than their civilian counterparts.

Objective

To address the knowledge level of HIV/AIDS and risk-related behaviours in military personnel, a well-described high risk groups for HIV/AIDS.

Methods

A cross-sectional study among army personnel in 82 Division Nigerian Army Headquarters Enugu, which has a population of about 1777. A random sampling in all the departments of 82 Division Nigerian Army Headquarters was done using the ballot method to select the respondents. Approval for the study was obtained from the General Officer in Command (GOC) of the 82 Division Nigerian Army Headquarters Enugu.

Results

There were no significant differences between the risk related behavior variables when comparisons were made between those under 30 years, and those 30 years and above. Furthermore, more respondents under 30 years (48.0%) did not seek medical treatment when infected with another STI before having sex again as against 45% of those above 30 years. Most of the respondents (9.1%) under the age of 30 years believed that HIV/AIDS could be contracted through mosquito bites as against 2.8% of those above 30 years.

Conclusion

The knowledge level of HIV/AIDS among the army personnel was high, though misconceptions about transmission modes like getting HIV through the bites of mosquitoes and casual body contacts were noted, especially among those under 30 years of age.     

The management of stage I--II Hodgkin's disease with irradiation alone or combined modality therapy: the Stanford experience

At Stanford University, between 1968 and 1978, 230 patients with pathologic stage I--II Hodgkin's disease were treated on prospective clinical trials with either irradiation alone or irradiation followed by 6 cycles of adjuvant combination chemotherapy. The actuarial survival at 10 yr was 84% for patients in either treatment group. Freedom from relapse at 10 yr was 77% among patients treated with irradiation alone and 84% after treatment with combined modality therapy [p(Gehan) = 0.09]. Freedom from second relapse at 10 yr was 89% and 94%, respectively [p(Gehan) = 0.56]. Several prognostic factors were evaluated in order to identify patients at high risk for relapse or with poor ultimate survival after initial treatment with irradiation alone. Systemic symptoms, histologic subtype, age, and limited extranodal involvement (E-lesions) did not affect the prognosis of patients and failed to identify patients whose survival could be improved by the routine use of combined modality therapy. Patients with large mediastinal masses (mediastinal mass ratio greater than or equal to 1/3) had a significantly poorer freedom from relapse when treated with irradiation alone than when treated initially with combined modality therapy [45% versus 81% at 10 yr, p(Gehan) = 0.03). The 10-yr survival of these patients, however, was not significantly different (84% versus 74%). The implications of these observations on the management of patient with early stage Hodgkin's disease are discussed.     

锌酞菁脂质体光动力作用引起小鼠肿瘤的细胞程序性死亡

电镜观察了锌酞菁脂质体光动力作用引起小鼠ＭＳ－２纤维肉瘤的形态学变化。发现其作用很强，并对肿瘤细胞有明显的直接影响。肿瘤细胞的结构表现出明显的程序性细胞死亡（ａｐｏｐｔｏｓｉｓ，ｐｒｏｇｒａｍｍｅｄｃｅｌｄｅａｔｈ）的特点：胞核染色质凝聚边集、核固缩、核破裂、染色质凝块流失、胞质内吞噬现象、胞膜表面肿胀粗钝的胞突形成、细胞碎裂等。加深了对锌酞菁脂质体光敏作用机理的认识，但其详细的发生机制和调节途径有待阐明。     

An endogenous glycosylphosphatidylinositol-specific phospholipase D releases basic fibroblast growth factor-heparan sulfate proteoglycan complexes from human bone marrow cultures

Basic fibroblast growth factor (bFGF) is a hematopoietic cytokine that stimulates stromal and stem cell growth. It binds to a glycosylphosphatidylinositol (GPI)-anchored heparan sulfate proteoglycan on human bone marrow (BM) stromal cells. The bFGF- proteoglycan complex is biologically active and is released by addition of exogenous phosphatidylinositol-specific phospholipase C. In this study, we show the presence of an endogenous GPI-specific phospholipase D (GPI-PLD) that releases the bFGF-binding heparan sulfate proteoglycan and the variant surface glycoprotein (a model GPI-anchored protein) from BM cultures. An involvement of proteases in this process is unlikely, because released proteoglycan contained the GPI anchor component, ethanol-amine, and protease inhibitors did not diminish the release. The mechanism of release is likely to involve a GPI-PLD and not a GPI-specific phospholipase C, because the release of variant surface glycoprotein did not reveal an epitope called the cross- reacting determinant that is exposed by phospholipase C-catalyzed GPI anchor cleavage. In addition, phosphatidic acid (which is specifically a product of GPI-PLD-catalyzed anchor cleavage) was generated during the spontaneous release of the GPI-anchored variant surface glycoprotein. We also detected GPI-PLD-specific enzyme activity and mRNA in BM cells. Therefore, we conclude that an endogenous GPI-PLD releases bFGF-heparan sulfate proteoglycan complexes from human BM cultures. This mechanism of GPI anchor cleavage could be relevant for mobilizing biologically active bFGF in BM. An endogenous GPI-PLD could also release other GPI-anchored proteins important for hematopoiesis and other physiologic processes.     

Distribution and identity of neurons expressing the oxytocin receptor in the mouse spinal cord

Nurr1 is a member of the nuclear receptor superfamily and is a regulatory factor of differentiation, migration and maturation of mesencephalic dopaminergic neurons. The present study was designed to observe the dynamic changes in the protein expression of Nurr1 and the relationship between Nurr1 and proliferating cell nuclear antigen (PCNA) during rat brain and spinal cord development. And we also investigated the significance of Nurr1 in differentiation and migration of nerve cells. Paraffin-embedded sections, immunohistochemistry, immunohistochemical double staining and Western blot techniques were used. The results demonstrate that the presence of Nurr1-positive cells increased during embryo development and that these cells slowly migrated to locations far from the lateral ventricle. In postnatal rats, the presence of Nurr1-positive cells surrounding the lateral ventricle decreased markedly. The expression of Nurr1 in the cerebral cortex peaked at postnatal days 1-5 (P1-P5) and then decreased as the cells matured, becoming rare in the mature cerebral cortex. As the cells matured, a staircase-shaped migration of Nurr1-positive cells from dorsal areas to ventral areas of the spinal cord could be observed. As maturation continued, the presence of Nurr1-positive cells in the spinal cord decreased, and no Nurr1-positive cells were found in the mature spinal cord. The comparative observation of Nurr1 and PCNA showed that the two proteins were expressed in different regions and in different cells. Nurr1 was confined to differentiated and migrating immature cells and was not present in proliferating cells. We suggest that Nurr1 may play a regulatory role in the differentiation, migration and maturation of nerve cells in the rat brain and spinal cord.     

Substrate for endothelial prostacyclin production in the presence of platelets exposed to collagen is derived from the platelets rather than the endothelium

Interactions between vascular endothelial cells and blood platelets have been investigated using a model microcirculation consisting of microcarrier beads colonized with human umbilical vein endothelial cells (HUVECs) and perfused with washed platelet suspensions. To simulate the effects of endothelial desquamation and exposure of subendothelium, fibrillar collagen in suspension was coinjected with the platelets. In this model, neither the passage of platelets alone nor collagen alone stimulated prostacyclin (PGI2) production by the HUVECs. Platelets activated by coinjection with collagen released thromboxane A2 (TXA2), and this was associated with the simultaneous production of PGI2 by the HUVECs. By means of double-isotope experiments with [3H]arachidonic acid (AA) incorporated into platelets and [14C]-AA into HUVECs, it was shown that all the PGI2 generated was derived from platelet AA and/or endoperoxides. This interpretation was strengthened by the finding that PGI2 production was not prevented by treatment of HUVECs with indomethacin followed by perfusion with collagen-stimulated platelets. AA metabolites in double-isotope label experiments were further characterized by reverse-phase chromatography, and it was shown that both cyclooxygenase and lipoxygenase products of the HUVECs were derived from platelet membrane lipid. Thrombin regularly produced transient PGI2 release, but showed rapid tachyphylaxis. Platelet-derived compounds including ADP, ATP, and platelet-activating factor (PAF) did not produce PGI2 release by HUVECs in this system. Thus, the transfer of AA and metabolites from collagen- stimulated platelets is likely to be the mechanism for PGI2 production in the context of minor degrees of endothelial desquamation.     

Involvement of prostaglandin F2α in the adverse effect of PCB 77 on the force of contractions of bovine myometrium

Polychlorinated biphenyls (PCBs) stimulate in vitro both the force of myometrial contractions and endometrial secretion of PGF2α in cattle. Therefore, the goal of this study was to investigate the participation of PGF2α in the effect of PCBs on uterine contractility. For this aim, the myometrial strips were incubated (48 h) with PCB 77 at the dose of 1, 10 and 100 ng/ml (i.e., 0.0034, 0.034 and 0.34 nmol/ml) separately or jointly with indomethacin (INDO, 10⁻⁴ M), which blocks the PGF2α synthesis. Next, the force of myometrial strips contractions was measured. Further, the influence of PCB 77 (0.1, 1 and 10 ng/ml) on the PGF2α secretion from myometrial cells after 6, 24, and 48 h and PCB 77 (1 and 10 ng/ml) on the mRNA expression of cyclooxygenase 2 (COX-2) and PGF2α synthase (PGFS) in myometrial cells after 6 and 24 h, was investigated. The increase (P < 0.05–0.001) of the contractions force of myometrial strips evoked by each dose of PCB 77, was markedly reduced (P < 0.05–001) by INDO. There was an increase (P < 0.05–0.001) of both PGF2α secretion after all studied periods of cell incubation and mRNA expression for COX-2 and PGFS after 6 h treatment of myometrial cells with PCB 77. It can be concluded that myometrial synthesis of PGF2α and its further secretion is a part of the mechanism by means of which PCB 77 may affect the force of myometrial contractions in cattle.