Low-grade astrocytomas in children: evolving management strategies

Developments in imaging and in neurosurgical techniques over the past decade have substantially altered the management of children with low-grade astrocytoma. Indications for surgery have become more clearly defined, and a larger proportion of children undergo complete or subtotal resection than in the past. Fewer receive adjuvant therapy, even though the options in this regard are more numerous now and theoretically likely to result in less morbidity than conventional external beam radiotherapy.

This review will address in particular the correlations between location, imaging appearance, and behavior that need to be more widely appreciated, and present recommendations regarding the management of these tumors.     

Preclinical in vivo antitumor activity of vinflunine, a novel fluorinated Vinca alkaloid

Vinflunine, or 20′,20′-difluoro-3′,4′-dihydrovino‐relbine, is a novel Vinca alkaloid obtained by hemisynthesis using superacidic chemistry. The most impressive structural modification of this vinorelbine derivative was the selective introduction of two fluorine atoms at the 20′ position, a part of the molecule previously inaccessible by classic chemistry. The antitumor activity of vinflunine was evaluated against a range of transplantable murine and human tumors. Vinflunine exhibited marked activity against murine P388 leukemia grafted i.v. when given i.p. in single or multiple doses according to various schedules or in single i.v. or p.o. doses. Increases in life span achieved with vinflunine, as assessed by T/C ratios, ranged from 200% to 457% and proved markedly superior to those of 129–186% obtained with the other Vinca alkaloids tested. Against s.c.-implanted B16 melanoma, multiple i.p. administration of vinflunine proved active in terms of both survival prolongation and tumor growth inhibition, with optimal T/C values and relative areas under the tumor growth curves (rAUC) being 24% and 36%, respectively. The extent of this activity was superior to that noted for vinorelbine under the same experimental conditions. Growth inhibition of human tumor xenografts LX-1 (lung) and MX-1 (breast) was also observed following four weekly i.p. injections of vinflunine as reflected by optimal T/C values of 23% and 26%, respectively, and significant differences in the rAUCs noted for treated versus control animals. It was also noticeable that vinflunine induced considerably more prolonged inhibitory effects on tumor growth than did vinorelbine. These results demonstrate that vinflunine is well tolerated and is definitively active against a range of experimental animal tumor models. Vinflunine activity has been documented in terms of both survival prolongation and tumor growth inhibition, with definite superiority over vinorelbine being shown in each tumor model evaluated. Received: 13 July 1997 / Accepted: 21 October 1997     

Antimicrobial activity of myotoxic phospholipases A2 from crotalid snake venoms and synthetic peptide variants derived from their C-terminal region.

A short peptide derived from the C-terminal region of Bothrops asper myotoxin II, a Lys49 phospholipase A(2) (PLA(2)), was previously found to reproduce the bactericidal activity of its parent molecule. In this study, a panel of eight PLA(2) myotoxins purified from crotalid snake venoms, including both Lys49 and Asp49-type isoforms, were all found to express bactericidal activity, indicating that this may be a common action of the group IIA PLA(2) protein family. A series of 10 synthetic peptide variants, based on the original C-terminal sequence 115-129 of myotoxin II and its triple Tyr-->Trp substituted peptide p115-W3, were characterized. In vitro assays for bactericidal, cytolytic and anti-endotoxic activities of these peptides suggest a general correlation between the number of tryptophan substitutions introduced and microbicidal potency, both against Gram-negative (Salmonella typhimurium) and Gram-positive (Staphylococcus aureus) bacteria. Peptide variants with high bactericidal activity also tended to be more cytolytic towards skeletal muscle C2C12 myoblasts, thus limiting their potential in vivo use. However, the peptide variant pEM-2 (KKWRWWLKALAKK) showed reduced toxicity towards muscle cells, while retaining high bactericidal potency. This peptide also showed the highest endotoxin-neutralizing activity in vitro, and was shown to functionally interact with lipopolysaccharide (LPS) using a chimeric bacteria model. The bactericidal and anti-endotoxic properties of pEM-2, combined with its relatively low toxicity towards eukaryotic cells, highlight it as a promising candidate for further evaluation of its antimicrobial potential in vivo.     

Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate.

PURPOSE: To determine the activity of decitabine, a DNA methylation inhibitor, in imatinib-refractory or intolerant chronic myelogenous leukemia. MATERIALS AND METHODS: Thirty-five patients were enrolled in this phase II study (12 in chronic phase, 17 in accelerated phase, and six in blastic phase). Decitabine was administered at 15 mg/m2 intravenously over 1 hour daily, 5 days a week for 2 weeks. DNA methylation was measured using a LINE1 bisulfite/pyrosequencing assay. RESULTS: Complete hematologic responses were seen in 12 patients (34%) and partial hematologic responses in seven patients (20%), for an overall hematologic response rate of 54% (83% in chronic phase, 41% in accelerated phase, and 34% in blastic phase). Major cytogenetic responses were observed in six patients (17%), and minor cytogenetic responses were seen in 10 patients (29%) for an overall cytogenetic response rate of 46%. Median response duration was 3.5 months (range, 2 to 13+ months). Myelosuppression was the major adverse effect, with neutropenic fever in 28 (23%) of 124 courses of therapy. LINE1 methylation decreased from 71.3% +/- 1.4% (mean +/- standard error of the mean) to 60.7% +/- 1.4% after 1 week, 50.9% +/- 2.4% after 2 weeks, and returned to 66.5% +/- 2.7% at recovery of counts (median, 46 days). LINE1 methylation at the end of week 1 did not correlate with subsequent responses. However, at day 12, the absolute decrease in methylation was 14.5% +/- 3.0% versus 26.8% +/- 2.7% in responders versus nonresponders (P = .007). CONCLUSION: Decitabine induces hypomethylation and has clinical activity in imatinib refractory chronic myelogenous leukemia. We hypothesize that the inverse correlation between hypomethylation 2 weeks after therapy and response is due to a cell death mechanism of response, whereby resistant cells can withstand more hypomethylation.     

Outcome of patients less than 55 years of age with high-risk acute leukemia who did not have an human leukocyte antigen-identical related donor: a long-term study of 97 consecutive patients.

Between January 1993 and December 2000, an unrelated donor search (UDS) was initiated for 97 consecutive patients [46 acute lymphoblastic leukemia (ALL) and 51 acute myeloid leukemia (AML)]. Leukemia was considered to be of poor prognosis in cases of refractory disease (n=70), unfavourable karyotype (n=22) or miscellaneous (n=5). All patients had previously received various chemotherapies and 9 had undergone an autologous stem cell transplantation (SCT). The median age at UDS initiation was 25 (range 2.7-55) years. The median time to identify a suitable living donor or cord blood (CB) was 60 days. Eventually, 33 patients received unrelated allo-SCT (including 9 CB), 12 auto-SCT, 39 chemotherapy and 13 palliative treatment. At a median of 54 months, 18 patients were alive, including 15 in remission. The 4-year overall survival rates were 32%, 37%, 15% and 0% for allo-SCT, auto-SCT, chemotherapy or palliative treatment, respectively. Patients who received either allo- or auto-SCT had better survival than those who did not (P<0.0001). For ALL, only allo-SCT significantly improved survival (P<0.007). Finally, patients who received allo-SCT died less often of relapse than patients who did not (P<0.0001). Unrelated allo-SCT gives a substantial long-term survival and cure in patients with high-risk acute leukemia. For patients who achieve remission and for whom UDS fails, auto-SCT may prove to be a good approach. For patients who fail to enter into remission, intensive salvage chemotherapy has a very limited effect.     

Familial transmission of longevity

The Tau model of phenotypic transmission has been used to analyze the familial correlations (nuclear families and extended families) of longevity at Arthez d'Asson (individuals born between 1686 and 1899). At birth, the transmissibility (t²) is very weak: 0·103; at 20 years old, t² = 0·167; at 50 years old, t² = 0·294. The effect of sibling environment on children's phenotype is s = 0·086 at birth, is thus null. A cohabitional effect between spouses: p = 0·167 appears after 50 years. There is no social homogamy effect via grandparents.     

L’ecmnésie entre faits et fiction

If we are indebted to Pitres for the term of ecmnesia, its current definition is restricted to the translation of a patient in his (her) past, heightened by a feeling of actually living it. Initially considered as a spontaneous hysterical phenomenon, or obtained by means of hypnosis, ecmnesia appears to be a neuropsychiatric syndrome which can also be due to organic etiologies. Meanwhile, the fascinating theme of age regression, and the popular success of many pseudo medical stories, coming from the US, explain the diffusion of the theme in literature and cinema.     

Mycobacterium Species Related to M. leprae and M. lepromatosis from Cows with Bovine Nodular Thelitis

Bovine nodular thelitis is a granulomatous dermatitis associated with infection with acid-fast bacteria. To identify the mycobacterium responsible for this infection, we conducted phylogenetic investigations based on partial sequencing of 6 genes. These bacteria were identified as an undescribed Mycobacterium species that was phylogenetically related to M. leprae and M. lepromatosis.