Early responses to chemotherapy of normal and malignant hematologic cells are prognostic in children with acute lymphoblastic leukemia.

PURPOSE: Improved cure rates for children with acute lymphoblastic leukemia (ALL) have resulted from better relapse prediction, using clinical and laboratory features at diagnosis, and more intensive therapy in high-risk patients. More recently, measurements of the variation in the response of malignant lymphoblasts to chemotherapy in vivo have further improved relapse prediction. It is unknown whether the variation in the response of nonmalignant hematologic cells after chemotherapy correlates with the response of lymphoblasts or risk of relapse. PATIENTS AND METHODS: We retrospectively evaluated myelosuppression during induction and consolidation chemotherapy in 227 children uniformly treated for ALL on consecutive Australian and New Zealand Children's Cancer Study Group protocols. The early response to treatment was assessed in a representative subset (n = 62) by determining minimal residual disease (MRD) level by molecular techniques on the end-of-induction bone marrow sample. RESULTS: We found that a slow rate of myeloid recovery at the end of induction chemotherapy, reflected in a low absolute neutrophil count (ANC), was highly predictive of relapse (P < .0001). Additionally, patients with a high end-of-induction MRD level had a high risk of relapse (P = .001). Multivariate analysis confirmed the independent prognostic significance of MRD and ANC at the end of induction chemotherapy (P < .05). There was no significant association between other measures of myelotoxicity and MRD or relapse. CONCLUSION: We conclude that the responses of normal myeloid cells and malignant lymphoblasts to chemotherapy predict outcome by distinct mechanisms. While these results are promising, their use in the clinical setting needs to be examined in a future randomized controlled trial.     

Independent and court-ordered forensic neuropsychological examinations: Official statement of the National Academy of Neuropsychology

Independent forensic neuropsychological examinations are performed by neuropsychologists who are hired as independent contractors by third parties to make determinations regarding neuropsychological functioning. The responsibilities of neuropsychologists when performing independent or court-ordered forensic examinations differ from those of clinical examinations. Because neuropsychological training typically occurs in clinical contexts, the transition to forensic contexts may result in uncertainty about how to negotiate the unique responsibilities of the forensic examiner role. Neuropsychologists are responsible for maintaining the highest standards of professional practice when performing independent and court-ordered forensic examinations. To reach and maintain the highest standards of practice, neuropsychologists must understand the unique relationships with retaining parties and examinees and strive to maintain true independence and objectivity. Although a true neuropsychologist-patient relationship is not considered to exist within the context of a forensic neuropsychological evaluation, neuropsychologists have ethical responsibilities to both the retaining party and the examinee.     

Localized primary (AL) amyloid tumor of the breast. Cytologic, histologic, immunocytochemical and ultrastructural observations

Two examples of localized primary amyloid tumor of the breast are presented, including one patient with metachronous bilateral lesions. Our findings and review of the literature indicate that this rare lesion occurs predominantly in elderly females and can be mammographically and clinically confused with carcinoma. Fine-needle aspiration biopsy can be a useful procedure to make a preliminary diagnosis. Congo red staining with prior potassium permanganate incubation confirmed the AL type of amyloid in our two cases; this might be the predominant type in the localized form involving the breast. Immunofluorescence studies demonstrated IgA, with kappa and lambda light-chain deposition within the amyloid foci in one case, and intracytoplasmic IgG with both light chains within plasma cells and amyloid deposits of the second case. Ultrastructural examination of one of the cases showed characteristic findings of straight, nonbranching fibrils of 4-9 nm, diagnostic of amyloid. From our findings and a review of the literature, we conclude that amyloid tumors of the breast can occur in three separate settings: secondary amyloidosis, systemic or multiple myeloma associated amyloidosis, and as a localized primary type having a benign course.     

FPL 62064, a topically active 5-lipoxygenase/cyclooxygenase inhibitor

FLP 62064 [N-(4-methoxyphenyl)-1-phenyl-1H-pyrazole-3-amine] is a dual inhibitor of prostaglandin synthetase and 5-lipoxygenase. The compound had anti-inflammatory activity in vivo in a number of models. It inhibited peritoneal inflammation induced by immune-complex when given locally. When applied to the skin, FPL 62064 inhibited UV irradiation-induced erythema and PGE2 formation in the guinea pig and also oedema formation and eicosanoid production in the mouse ear produced by arachidonic acid. Co-injected with arachidonic acid in rabbit skin, FPL 62064 inhibited oedema and eicosanoid formation.     

Tau protein induces bundling of microtubules in vitro: comparison of different tau isoforms and a tau protein fragment.

Expression of tau protein in non-neuronal cells can result in a redistribution of the microtubule cytoskeleton into thick bundles of tau-containing microtubules (Lewis et al.: Nature 342:498-505, 1989; Kanai et al.: J Cell Biol 109:1173-1184, 1989). We reconstituted microtubule bundles using purified tubulin and tau in order to study the assembly of these structures. Taxol-stabilized tubulin polymers were incubated with various concentrations of recombinant human tau and examined by electron microscopy. With increasing concentrations of tau 3 (tau isoform containing three microtubule binding domains) or tau 4 (isoform containing four microtubule binding domains) the microtubules changed orientation from a random distribution to loosely and tightly packed parallel arrays and then to thick cables. In contrast, tau 4L, the tau isoform containing four microtubule binding domains plus a 58-amino acid insert near the N-terminus, showed minimal bundling activity. tau 4-induced bundling could be inhibited by the addition of 0.5 M NaCl or 0.4 mM estramustine phosphate, conditions which are known to inhibit tau binding to microtubules. A tau construct that contained only the microtubule binding domains plus 19 amino acids to the C-terminus was fully capable of bundling microtubules. Phosphorylation of tau 3 with cAMP-dependent protein kinase had no effect on its ability to induce microtubule bundling. These results indicate that tau protein is directly capable of bundling microtubules in vitro, and suggests that different tau isoforms differ in their ability to bundle microtubule filaments.