Prognostic value of Bcl‐2 in breast cancer patients treated with neoadjuvant anthracycline based chemotherapy

We have analyzed the predictive/prognostic value of Bcl‐2 protein in breast cancer patients treated with neoadjuvant chemotherapy. One hundred and ten patients were submitted to two different chemotherapeutic regimens: a) 5‐fluorouracil, adriamycin or epirubicin, and cyclophosphamide (FAC/FEC) during 2–6 cycles before surgery and 3 or 4 additional cycles of FAC/FEC after surgery (n=40) and b) doxorubicin (D) 75mg/m2 or epirubicin (E) 120mg/m2 during 4 cycles before surgery, and 6 cycles of cyclophosphamide, methotrexate, and 5‐fluorouracil (CMF) after surgery (n=70). Bcl‐2 expression, evaluated by immunohistochemistry, did not change significantly after chemotherapy and was not related to clinical/pathological response. In FAC/FEC group, Bcl‐2 positive expression after chemotherapy correlated with better disease free survival (DFS) and overall survival (OS) (P=0.008 and P=0.001). In D/E group, Bcl‐2 also correlated with better DFS and OS (P=0.03 and P=0.054) in the post‐chemotherapy biopsies. An unusual nuclear localization of Bax was observed in some biopsies, but this localization did not correlate with the tumor response or outcome of the patients. We found that a high Bcl‐2 expression had no predictive value but had prognostic value in breast cancer patients treated with neoadjuvant anthracycline based chemotherapy.     

Central vestibular projections of primary cervical fibers in the frog

The origin of cervicovestibular inputs was documented in frogs, as well as the number of fibers, site of projection, and their distribution within the nuclei. The first spinal nerve in 15 frogs was labeled with extracellular injections of horseradish peroxi-dase. The brain stem and the posterior root were sectioned serially. The trajectories of the fibers in the central nervous system were reconstructed, and the number and diameters of the fibers in the posterior root were determined. The average number of fibers in the first posterior root was 143 ±6.2, their number decreasing exponentially with increased diameter. After entering the spinal cord the fibers were located in the dorsal funiculus. The thick and medium-sized fibers coursed medially in relation to the thin ones, giving collaterals to the spinal cord and to the obex region. The thinnest fibers projected to the reticular formation and nucleus of the solitary tract. Only collaterals from fibers of medium and thick caliber reached the vestibular area in their trajectory to the cerebellum (spinocerebellar fibers). All the vestibular nuclei received collaterals and endings from the spinocerebellar fibers, the ventral nucleus being the most innervated. The total number of branches for the vestibular area, however, was very small. The results of this experiment are correlated with physiological and anatomical findings described in the literature.     

Collagen induced MMP-2 activation in human breast cancer

Summary Matrix metalloproteinase-2 (MMP-2), a zymogen requiring proteolytic activation for catalytic activity, has been implicated broadly in the invasion and metastasis of many cancer model systems, including human breast cancer (HBC). MMP-2 has been immunolocalized to carcinomatous human breast, where the degree of activation of MMP-2 correlates well with tumor grade and patient prognosis. Using Matrigel assays, we have stratified HBC cell lines for invasivenessin vitro, and compared this to their potential for metastatic spread in nude mice. HBC cell lines expressing the mesenchymal marker protein vimentin were found to be highly invasivein vitro, and tended to form metastases in nude mice. We have further discovered that culture on collagen-I gels (Vitrogen^TM; Vg) induces MMP-2-activator in highly invasive but not poorly invasive HBC cell lines. As seen for other MMP-2-activator inducing regimens, this induction requires protein synthesis and an intact MMP-2 hemopexin-like domain, appears to be mediated by a cell surface activity, and can be inhibited by metalloproteinase inhibitors. The induction is highly specific to collagen I, and is not seen with thin coatings of collagen I, collagen IV, laminin, or fibronectin, or with 3-dimensional gels of laminin, Matrigel, or gelatin. This review focuses on collagen I and MMP-2, their localization and source in HBC, and their relationship(s) to MMP-2 activation and HBC metastasis. The relevance of collagen I in activation of MMP-2in vivo is discussed in terms of stromal cell: tumor cell interaction for collagen I deposition, MMP-2 production, and MMP-2-activation. Such cooperativity may existin vivo for MMP-2 participation in HBC dissemination. A more complete understanding of the regulation of MMP-2-activator by type I collagen may provide new avenues for improved diagnosis and prognosis of human breast cancer.     

Benign salivary gland tumors: A cytogenetic study of 21 cases

Cytogenetic findings of 21 benign salivary gland tumors, including 14 pleomorphic adenomas, 5 Warthin's tumors, 1 myoepithelioma, and 1 cystadenoma, are reported. The present study confirms that pleomorphic adenomas characteristically have highly specific rearrangements involving only a few chromosome regions (3p21, 8q12 and 12q13–15) which suggests their specific role in the mixed tumors genesis. Warthin's tumors also show nonrandom numerical and structural alterations that were concurrent in one of the cases studied. To our knowledge no cytogenetic data are available in myoepitheliomas and cystadenomas. The former reveals a normal karyotype and the latter shows only clonal numerical alterations (gain of chromosomes 2 and 18). © 1995 Wiley-Liss, Inc.     

Results of treatment with an intensive induction regimen using idarubicin in combination with cytarabine and etoposide in children with acute myeloblastic leukemia

We report results achieved in our institution with a study opened in July 1990 (similar to the German AML-BFM-87 in which daunorubicin was replaced by idarubicin in the induction phase and cranial preventive radiotherapy was omitted) and closed in December 1994, for the treatment of newly diagnosed acute myeloblastic leukemia (AML), without prior malignancies except for myelodysplasia.This evaluation included 68 patients, whose mean age was 6 years (range: 1 month–16 years). Thirty-nine were boys and 29 were girls. Complete remission rate was 80.9% (55/68), death on induction rate was 14.7% and induction failure rate was 4.4%. At median follow up of 38 months (range: 12–66 months), the 4-year event-free survival (EFS) estimate was 0.428 (S.E.: 0.062), event-free interval (EFI) estimate was 0.529 (S.E.: 0.07) and overall survival (OS) estimate was 0.44 (S.E.: 0.071).We conclude that idarubicin in combination with cytarabine and etoposide is a highly effective regimen for induction in children with AML. Although preventive cranial irradiation was not delivered, we have observed only one combined CNS relapse. Finally, we corroborate that in this setting two definite risk groups may be identified in children with AML.     

Clinical and angiographic findings in three patients with serpiginous choroiditis

PURPOSE/METHODS: Serpiginous choroiditis is a rare, chronic, progressive, and recurrent bilateral disorder primarily involving the choriocapillaris and the retinal pigment epithelium. Progression typically occurs as pseudopodia extensions away from the optic discs and usually infringes upon the macula and foveal region. RESULTS/CONCLUSIONS: We studied three cases of geographic choroidopathy, showing the ophthalmoscopic picture and the fluorescein angiographic of the fundus oculi, characterised by typical disease lesions. Finally, some considerations in differential diagnosis between pigment epithelium inflammatory diseases will be reported.     

Treatment of patients with recurrence or who do not respond to the first treatment against hepatitis C

The current criteria to confirm the absence of therapeutic response to HCV is based on the viral findings. Lack of response is defined as the failure to achieve a negative serological response to the virus in peripheral blood (serum or plasma) after 12 weeks of treatment with interferon alpha (2a or 2b), or 24 weeks of treatment with IFN and ribavirin. Up to 60% of patients treated with standard IFN alpha and ribavirin are considered non-responders. According to viral genotype, figures are still worse in the group with genotype 1. Recently, the use of pegylated interferon allowed the reduction of the number of non-responding patients. The investigators propose different approaches in the search for better therapeutic strategies. The most effective of them all are the addition of ribavirin to the therapeutic scheme and the use of pegylated interferon which greatly increased the number of responders. Nevertheless, there are still many patients who are resistant to therapy. These are the proposed therapeutic alternatives for non-respondent patients: 1. Another tretment cycle with standard IFN and ribavirin (low probability) 2. Another treatment cycle with pegylated IFN and ribavirin. 3. Another treatment cycle with IFN, ribavirin and amantadine. 4. Another treatment cycle with IFN, ribavirin and timosine. 5. Other antiviral agents. It's important to clarify that "real non-responders" are those patients who remain positive in the viral load tests after 12-24 months of treatment. On the other hand, patients who "escape from treatment" or those with "recurrence" are not real non-responders, compared to those who are negative after 12-24 weeks of treatment.     

Bcl-6 p53 mutations in lymphomas carrying the bcl-2/Jh rearrangement

BACKGROUND AND OBJECTIVES: The t(14;18)(q32;q21) chromosomal translocation is the hallmark of follicular lymphomas (FL). The translocation induces the overexpression of the Bcl-2 protein and prolongs the survival of clonogenic cells. Tumor cells may acquire additional molecular alterations that may be associated with histologic progression or with chemo-resistance. DESIGN AND METHODS: We analyzed the distribution and association of bcl-6 and p53 mutations in 55 consecutive bcl-2/Jh+ lymphoma samples derived from 43 patients obtained at the time of diagnosis and, in 5 of these patients, during follow-up. A total of 29 bcl-6 point mutations were detected in seventeen patients (40%) associated with major or minor breakpoints of the bcl-2/Jh fusion gene. In seven cases a p53 mutation was detected. Three cases corresponded to FL with the minor breakpoint in the bcl-2 gene and these patients had a favorable clinical evolution, whereas the 4 patients with p53 mutations and the major breakpoint had a bad clinical outcome with morphologic transformation to high-grade lymphoma in three cases. The sequential analysis of 5 patients showed a different timing in the acquisition of mutations: one patient showed bcl-6 and p53 mutations at diagnosis, another patient showed bcl-6 mutations at diagnosis and acquired a p53 mutation later whereas the third patient had a p53 mutation before the appearance of the bcl-6 mutation. RESULTS: We did not find significant differences in survival between patients with FL who showed exclusively bcl-6 mutations and those without bcl-6 mutations, but those patients with a high International Progostic Index score and p53 mutations showed the lowest overall survival (p = 0.002). INTERPRETATION AND CONCLUSIONS: These findings suggest that bcl-2/Jh lymphomas show molecular heterogeneity and that bcl-6 and p53 mutations may be acquired during the evolution of such lymphomas. Bcl-6 mutations, by themselves, do not seem to be associated with a bad prognosis. Rearrangements at the minor bcl-2 locus may have a different molecular evolution.