Biomedical subjects

B Puig

Publications and source records attributed to B Puig.

35 records · Page 2Linked to original sources

PubMed2002

Active, phosphorylation-dependent MAP kinases, MAPK/ERK, SAPK/JNK and p38, and specific transcription factor substrates are differentially expressed following systemic administration of kainic acid to the adult rat.

Excitotoxicity is considered a major cell death inductor in neurodegeneration. Yet the mechanisms involved in cell death and cell survival following excitotoxic insults are poorly understood. Expression of active, phosphorylation-dependent mitogen-activated extracellular signal-regulated kinases (MAPK/ERKs), stress-activated c-Jun N-terminal kinases (SAPK/JNKs) and p38 kinases, as well as their putative active, phosphorylation-dependent specific transcriptional factor substrates CREB, Elk-1, ATF-2, c-Myc and c-Jun, has been examined following systemic administration of kainic acid (KA) at convulsant doses to rats. Increased phosphorylated MAPK (MAPK(P)) immunoreactivity has been found at 3 and 6 h in the vulnerable regions entorhinal cortex and CA3, in which neurons are committed to die, as well as in sensitive regions dentate gyrus and gyrus cinguli, in which neurons will survive. JNK(P) has been observed in the entorhinal cortex and dentate gyrus, and p38(P) immunoreactivity occurs in the entorhinal cortex. Strong c-Myc(P) expression parallels MAPK(P) immunoreactivity in the entorhinal cortex, CA3, dentate gyrus and gyrus cinguli, showing that enhanced c-Myc(P) expression does not preclude cell death or cell survival. Selective decrease of CREB(P) immunoreactivity in entorhinal cortex and CA3 indicates CREB(P) reduction associated with cell death. Strong c-Jun(P) immunoreactivity has been found in the entorhinal cortex, CA3 and dentate gyrus, thus suggesting that regulation of two opposing cellular programs (cell death or cell survival) of c-Jun(P) depends on c-Jun interactions with other factors. Interestingly, ATF-2(P), and to a lesser extent Elk-1(P), is selectively increased in the dentate gyrus. These results suggest ATF-2(P) involvement in cell survival of dentate gyrus granule cells. The present results demonstrate activation of specific MAPK pathways in association with either cell death or cell survival triggered by KA. Furthermore, increased Ras activation, as seen with p21 Ras activation assay, indicates a crucial role for Ras in activating MAP kinases following excitotoxic insult.

Activating Transcription Factor 2↗

PubMed2001

Cleaved caspase-3, caspase-7 and poly (ADP-ribose) polymerase are complementarily but differentially expressed in human medulloblastomas.

Expression of cleaved caspase-3, cleaved caspase-7 and specific product of caspase-dependent Poly (ADP-Ribose) Polymerase (PARP) cleavage have been examined by immunohistochemistry in seven human medulloblastomas. Cleaved caspase-3 and cleaved PARP expression parallels apoptosis as revealed with classical morphological criteria and with the method of in situ end-labelling of nuclear DNA fragmentation. Cleaved PARP co-localizes cleaved caspase-3 in the majority of tumors and areas thus indicating that caspase-3 is a major effector caspase leading to apoptosis in these tumors. Yet cleaved caspase-7 was also expressed in a small number of cells in four of seven tumors, but was the predominant caspase associated with cleaved PARP in one medulloblastoma. These findings indicate that effector caspase-3 and -7 may act in association, although caspase-7 may be exceptionally dominant in selected tumors.

Apoptosis↗

PubMed2001

Methylazoximethanol acetate-induced cell death in the granule cell layer of the developing mouse cerebellum is associated with caspase-3 activation, but does not depend on the tissue-type plasminogen activator.

Methylazoximethanol (MAM) acetate-induced cell death in the external granule cell layer of the developing cerebellum affects clusters of cells with morphological features of apoptosis. This is accompanied by selective induction of active caspase-3 expression and increased c-Jun/AP-1 (N) immunoreactivity in dying cells, as revealed with immunohistochemistry. Since the antibody to cJun/AP-1 (N) cross-reacts with epitopes emerging after caspase-mediated proteolysis during apoptosis, these results indicate that MAM-induced cell death is associated with active caspase-3 expression and function in dying cells. In order to investigate the involvement of tissue-type plasminogen activator (tPA), which has been implicated in certain forms of neuronal cell death, MAM-induced cell death has been examined in tPA-/- and tPA+/+ mice. No differences in the number of dying cells, as seen with haematoxylin and eosin staining and in situ end-labelling of fragmented nuclear DNA-processed sections, were seen between tPA-/- and tPA+/+ mice. These results indicate that tPA is not involved in MAM-induced cell death in the developing brain.

Animals↗

PubMed2001

Prion protein expression in senile plaques in Alzheimer's disease.

Prion protein (PrPC) is a glycolipid-anchored cell membrane sialoglycoprotein that localises in presynaptic membranes. Since synapses are vulnerable to Alzheimer's disease (AD), the present study examines PrPC expression in senile plaques, one of the major structural abnormalities in AD, by single- and double-labelling immunohistochemistry. Punctate PrPC immunoreactivity is found in diffuse plaques, whereas isolated large coarse PrPC-positive granules reminiscent of dystrophic neurites are observed in neuritic plaques. Finally, PrPC deposition also occurs as dense filamentous and amorphous precipitates in amyloid cores of senile plaques, but not in the walls of blood vessels with amyloid angiopathy. In contrast to PrPC, betaA4-amyloid immunoreactivity is preserved and even enhanced following incubation of the tissue sections with proteinase K prior to immunohistochemistry, thus indicating no PrPC and betaA4-amyloid cross-reactivity in dense amyloid cores of senile plaques. Punctate PrPC deposition in diffuse plaques is similar to that of synaptophysin, a synaptic vesicle-associated protein, as already reported in other studies. Immunoprecipitation, electrophoresis and Western blot studies have shown that synaptophysin, amyloid precursor protein (APP) and betaA4 do not co-precipitate with PrP. These results suggest that synaptophysin, APP and betaA4 are likely not bound to PrP. PrPC accumulation in betaA4-amyloid dense cores may be the consequence of the release of PrP into the extracellular space. Whether PrPC accumulation in the extracellular space is the result of impaired endocytosis and subsequent hydrolysis in the endosomal compartment, in contrast to normal degradation of PrPC, resulting from or occurring in parallel to abnormal APP degradation, deserves further study.

Aged↗

PubMed2001

Fas and Fas ligand expression in Alzheimer's disease.

The Fas/Fas ligand (L) signaling system has been implicated in the control of cell death and cell survival of T and B lymphocytes and in a variety of cell types under particular pathological conditions. In the present study we examined the expression of Fas and Fas-L, by Western blotting and immunohistochemistry, in the human frontal cortex and hippocampus of individuals with advanced Alzheimer's disease (AD) and age-matched controls. Expression levels of Fas and Fas-L, as seen in Western blots, are preserved in the frontal cortex but decreased in the hippocampus in AD when compared with age-matched controls. Yet Fas and Fas-L immunoreactivity is found in remaining AD neurons in the frontal cortex and hippocampus. Moreover, Fas and Fas-L are expressed equally in tangle-bearing and non-tangle-bearing neurons, as revealed with double-labeling immunohistochemistry to Fas or Fas-L and tau or phosphorylated neurofilament epitopes. Dystrophic neurites of senile plaques are not stained with Fas and Fas-L antibodies. A moderate increase in Fas and a strong increase in Fas-L immunoreactivity occur in reactive astrocytes in AD. Yet there is no relationship between Fas or Fas-L expression and increased nuclear DNA vulnerability as revealed with double-labeling immunohistochemstry and in situ end-labeling of nuclear DNA fragmentation. Although the Fas/Fas-L system may have some effect in the control of reactive astrocytosis in AD, the present results show no evidence that Fas/Fas-L signals participate in specific processes of the disease, including neurofibrillary degeneration, dystrophic neurite formation, and cell death.

Aged↗

PubMed2001

Active, phosphorylation-dependent mitogen-activated protein kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in Parkinson's disease and Dementia with Lewy bodies.

The expression of mitogen-activated protein kinases, extracellular signal-regulated kinases (MAPK/ERK), stress-activated protein kinases, c-Jun N-terminal kinases (SAPK/JNK), and p38 kinases is examined in Parkinson disease (PD), in Dementia with Lewy bodies (DLB), covering common and pure forms, and in age-matched controls. The study is geared to gaining understanding about the involvement of these kinases in the pathogenesis of Lewy bodies (LBs) and associated tau deposits in Alzheimer changes in the common form of DLB. Active, phosphorylation dependent MAPK (MAPK-P) is found as granular cytoplasmic inclusions in a subset of cortical neurons bearing abnormal tau deposits in common forms of DLB. Phosphorylated p-38 (p-38-P) decorates neurons with neurofibrillary tangles and dystrophic neurites of senile plaques in common forms of DLB. Phosphorylated SAPK/JNK (SAPK/JNK-P) expression occurs in cortical neurons with neurofibrillary tangles in the common form of DLB. Lewy bodies (LBs) in the brain stem of PD and DLB are stained with anti-ERK-2 antibodies, but they are not recognized by MAPK-P, SAPK/JNK-P and p-38-P. Yet MAPK-P, p-38-P and SAPK/JNK-P immunoreactivity is found in cytoplasmic granules in the vicinity of LBs or in association with irregular-shaped or diffuse alpha-synuclein deposits in a small percentage of neurons, not containing phosphorylated tau, of the brain stem in PD and DLB. MAPK-P, p-38-P and SAPK-P are not expressed in cortical LBs or in cortical neurons with alpha-synuclein-only inclusions in DLB. MAPK-P, p-38-P and SAPK/JNK-P are not expressed in alpha-synuclein-positive neurites (Lewy neurites) in PD and DLB as revealed by double-labeling immunohistochemistry. These results show that MAPKs are differentially regulated in neurons with alpha-synuclein-related inclusions and in neurons with abnormal tau deposits in DLB. Moreover, different kinase expression in brain stem and cortical LBs suggest a pathogenesis of brain stem and cortical LBs in LB diseases. Finally, no relationship has been observed between MAPK-P, p-38-P and SAPK/JNK-P expression and increased nuclear DNA vulnerability, as revealed with the method of in situ end-labeling of nuclear DNA fragmentation, and active, cleaved caspase-3 expression in neurons and glial cells in the substantia nigra in PD and DLB.

Aged↗

PubMed2001

Phosphorylated mitogen-activated protein kinase (MAPK/ERK-P), protein kinase of 38 kDa (p38-P), stress-activated protein kinase (SAPK/JNK-P), and calcium/calmodulin-dependent kinase II (CaM kinase II) are differentially expressed in tau deposits in neurons and glial cells in tauopathies.

Calcium/calmodulin-dependent kinase II (alpha- and beta-CaM kinase II), and phosphorylated mitogen-activated extracellular signal-regulated protein kinase (MAPK/ERK-P), phosphorylated protein kinase of 38 kDa (p38-P) and phosphorylated stress-activated protein kinase (SAPK/JNK-P) expression have been examined in Alzheimer disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The study was carried out to increase understanding of the signals that may regulate tau phosphorylation in tauopathies. MAPK/ERK-P was found in a subset of neurons and glial cells bearing abnormal tau deposition, but rarely in neurofibrillary tangles. Strong p38-P immunoreactivity was observed in about 50-70% of neurons with neurofibrillary tangles and in dystrophic neurites of senile plaques in AD. Strong p38-P immunoreactivity was seen in practically all Pick bodies in PiD, and in most neurons with neurofibrillary degeneration or with tau deposits (pre-tangle neurons) in PSP and CBD, as revealed with single and double-labeling immunohistochemistry to p38-P and tau. In addition, strong p38-P immunoreactivity was present in tau-positive astrocytes and in coiled bodies in PSP and CBD. Single and double-labeling immunohistochemistry to MAPK/ERK-P and p38-P disclosed that MAPK/ERK-P appeared at early stages of tau phosphorylation in neurons and glial cells in tauopathies, and that MAPK/ERK-P and p38-P co-localize only in a subset of neurons and glial cells with phosphorylated tau deposits. SAPK/JNK-P immunoreactivity was seen in a subset of neurons, including many neurons with neurofibrillary degeneration, and in glial cells accumulating abnormal tau, in AD, PiD, PSP and CBD. Double-labeling immunohistochemistry disclosed partial co-localization of SAPK/JNK-P and either MAPK/ERK-P or p-38-P immunoreactivity. These findings indicate that MAPK/ERK-P, SAPK/JNK-P and p-38-P are differentially expressed in association with tau deposits in tauopathies. Finally, CaM kinase II is present in neurons but not in glial cells, thus suggesting no role of CaM kinase II in tau phosphorylation of glial cells. These observations, together with previous results of in vitro studies, support the idea that several MAPK/ERK, SAPK/JNK, p38 and CaM kinase II may participate in tau phosphorylation in tauopathies. Lack of co-localization between MAPK/ERK-P, SAPK/JNK-P and p-38-P over-expression, and staining with the method of in situ end-labeling of nuclear DNA fragmentation in individual cells indicate that over-expression of these kinases is not linked with increased nuclear DNA vulnerability in AD, PiD, PSP and CBD.

Aged↗

PubMed2001

Phosphorylated c-MYC expression in Alzheimer disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration.

Phosphorylated c-Myc (c-Myc-P) expression has been examined by immunohistochemistry, using an antibody that recognizes phosphorylated c-Myc at Thr58 and Ser62, in the brains of Alzheimer disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and age-matched control cases, as well as in human medulloblastomas and central neuroblastomas. Strong c-Myc-P immunoreactivity was seen in dystrophic neurites and neurones with neurofibrillary tangles in AD, and in neurones and glial cells bearing abnormal tau deposits in PiD, PSP and CBD. Previous studies have shown active Ras and increased mitogen-activated protein kinase (MAPK/ERK) expression in neurones and glial cells with abnormal tau deposition in AD and other tauopathies. Since MAPKs phosphorylate c-Myc at Thr58 and Ser62, these observations implicate the Ras/MAP kinase pathway in c-Myc phosphorylation and accumulation in AD and other tauopathies. Previous studies have also shown activation of cell cycle associated proteins in neuronal death. The present results have shown colocalization of nuclear c-Myc-P and active, cleaved caspase-3, a major executioner of apoptosis, in medulloblastomas and central neuroblastomas, thus suggesting phosphorylated c-Myc expression in caspase-3-dependent apoptosis of tumour cells. However, no evidence of caspase-3 activation has been observed in neurones and glial cells with strong phosphorylated c-Myc immunoreactivity in AD, PiD, PSP and CBD. Therefore, it is not clear that the activation of the Ras/MAPK/c-Myc subprogramme leads to neuronal death in AD and other tauopathies.

Aged↗

PubMed2001

Phosphorylated map kinase (ERK1, ERK2) expression is associated with early tau deposition in neurones and glial cells, but not with increased nuclear DNA vulnerability and cell death, in Alzheimer disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration.

Abnormal tau phosphorylation and deposition in neurones and glial cells is one of the major features in taupathies. The present study examines the involvement of the Ras/MEK/ERK pathway of tau phosphorylation in Alzheimer disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), by Western blotting, single and double-labelling immunohistochemistry, and p21Ras activation assay. Since this pathway is also activated in several paradigms of cell death and cell survival, activated ERK expression is also analysed with double-labelling immunohistochemistry and in situ end-labelling of nuclear DNA fragmentation to visualise activated ERK in cells with increased nuclear DNA vulnerability. The MEK1 antibody recognises one band of 45 kD that identifies phosphorylation-independent MEK1, whose expression levels are not modified in diseased brains. The ERK antibody recognises one band of 42 kD corresponding to the molecular weight of phosphorylation-independent ERK2; the expression levels, as well as the immunoreactivity of ERK in individual cells, is not changed in AD, PiD, PSP and CBD. The antibody MAPK-P distinguishes two bands of 44 kD and 42 kD that detect phosphorylated ERK1 and ERK2. MAPK-P expression levels, as seen with Western blotting, are markedly increased in AD, PiD, PSP and CBD. Moreover, immunohistochemistry discloses granular precipitates in the cytoplasm of neurones in AD, mainly in a subpopulation of neurones exhibiting early tau deposition, whereas neurones with developed neurofibrillary tangles are less commonly immunostained. MAPK-P also decorates neurones with Pick bodies in PiD, early tau deposition in neurones in PSP and CBD, and cortical achromatic neurones in CBD. In addition, strong MAPK-P immunoreactivity is found in large numbers of tau-positive glial cells in PSP and CBD, as seen with double-labelling immunohistochemistry. Yet no co-localisation of enhanced phosphorylated ERK immunoreactivity and nuclear DNA fragmentation is found in AD, PiD, PSP and CBD. Finally, activated Ras expression levels are increased in AD cases when compared with controls. These results demonstrate increased phosphorylated (active) ERK expression in association with early tau deposition in neurones and glial cells in taupathies, and suggest activated Ras as the upstream activator of the MEK/ERK pathway of tau phosphorylation in AD.

Aged↗

PubMed2001

Cell death signaling in the cerebellum in Creutzfeldt-Jakob disease.

Examination of the expression of proteins linked with signaling pathways commanding cell death and cell survival has been carried out to increase understanding on the mechanisms leading to cell death in the cerebellum in Creutzfeldt-Jakob disease (CJD). Expression of Fas, Fas ligand (Fas-L), ERK, MEK, Bcl-2, Bax, N-myc, c-myc, pro-caspase-2 and active caspase-3 was examined by immunohistochemistry in the cerebellum of six patients with sporadic CJD, three patients with olivopontocerebellar atrophy (OPCA) and six age-matched controls. No modifications in the expression of these proteins were observed in granule cells in CJD and OPCA when compared with controls, except in a few cells in the molecular and granular layers in CJD that displayed dense homogeneous active caspase-3 immunostaining. This suggests selective activation of caspase-3 in association with increased cellular vulnerability in CJD. No modifications in pro-caspase-2 and c-myc immunoreactivity were observed in Purkinje cells in diseased brains when compared with controls. However, increased diffuse Fas, Fas-L, MEK, ERK and Bax expression, and enhanced granular active caspase-3 immunoreactivity was found in the cytoplasm of Purkinje cells in CJD. Increase in Bcl-2 and N-myc occurred in Purkinje cells in CJD and OPCA. These results indicate that enhanced Fas, Fas-L, MERK, ERK, Bax and granular active caspase-3 expression is not lethal to Purkinje cells in CJD, whereas increased Bcl-2 and N-myc does not preclude per se cell death or death survival in CJD and OPCA. These findings point to the likelihood that expression of these cell death proteins in neurodegeneration has functional roles differing from those related with apoptosis.

Apoptosis↗

PubMed2000

Local and distant failures after limited surgery with positive margins and radiotherapy for node-negative breast cancer.

PURPOSE: To determine the outcome of patients with positive margins after lumpectomy for breast cancer and to address the issue of the relationship between local recurrences and distant metastasis in the absence of chemotherapy. METHODS AND MATERIALS: Among 3697 patients with primary breast cancer, we retrospectively analyzed 152 patients who had undergone conservative surgery with axillary dissection, had infiltrating carcinomas with positive margins, were node-negative, and received radiotherapy without chemotherapy. One-third received hormonal therapy. Endpoints were local failure and distant metastasis. Median follow-up was 72 months. RESULTS: Five- and 10-year recurrence-free survival were 0.80 and 0.71 respectively for local recurrences, and 0.85 and 0.73 respectively for metastasis. Infiltrating carcinoma on the margins was associated with early local relapse as opposed to intraductal carcinoma. Local and distant recurrences had similar patterns of yearly-event probabilities. Hazard of relapsing from metastasis was 2.5 times higher after a local recurrence. In the multivariate analysis, negative estrogen receptors (ER-)(p = 0.0012), histologic multifocality (p = 0.0028), and no hormonal therapy (p = 0.017) predicted local relapses, while ER- (p = 0.004) and pathologic grade (p = 0.009) predicted metastasis. Hormonal therapy did not prevent early local recurrences. CONCLUSION: In this population, reexcision is advisable for local purposes and because the data support the hypothesis that local and distant recurrences are tightly connected.

Adult↗

PubMed2000

Prognosis of breast-carcinoma lymphagenesis evaluated by immunohistochemical investigation of vascular-endothelial-growth-factor receptor 3.

Very few studies have yet addressed the question of the existence and role of lymphagenesis in tumor growth; it is generally overshadowed by the greater emphasis placed on the blood vascular system. Monoclonal antibodies against vascular endothelial-growth-factor receptor 3 (VEGFR3) have been shown to provide a specific antigenic marker for lymphatic endothelium. By comparison with the microvascular count (MVC), we investigated the prognostic value of the microlymphatic count (MLC) in a series of 60 cases of 2-cm-diameter breast carcinomas. The mean value of MVC was 72.5 and of MLC, 40.5. There was no quantitative correlation between these 2 parameters. The MVC but not the MLC had a prognostic value in overall survival. Neither the MLC nor the MVC had any correlation with axillary-lymph-node invasion.

Biomarkers↗

PubMed2000

Prion protein deposition and abnormal synaptic protein expression in the cerebellum in Creutzfeldt-Jakob disease.

Prion protein (PrP(C)) is a cell membrane-anchored glycoprotein, which is replaced by a pathogenic protease-resistant, beta-sheet-containing isoform (PrP(CJD) or PrP(SC)) in human and animal prion encephalopathies, including sporadic Creutzfeldt-Jakob disease. Cell fractionation methods show that PrP(C) localizes in presynaptic membrane-enriched fractions. Following infection, abnormal PrP accumulates in nerve cell processes and synaptic regions. The present study examines the possible correlation between abnormal PrP deposition and the expression of synaptic proteins controlling neurotransmission in the cerebellum of six 129 Met/Met sporadic cases of Creutzfeldt-Jakob disease. Aggregates of protease-resistant PrP-positive granules, reminiscent of cerebellar glomeruli, were found in the granular cell layer, whereas fine punctate PrP-immunoreactive deposits occurred in the molecular layer. Small numbers of diffuse, irregular plaque-like PrP deposits in the molecular and granular cell layers were present in every case. The somas of Purkinje cells, and stellate, basket and Golgi neurons, were not immunostained. PrP-immunoreactive fibres were found in the album of the cerebellum and hilus of the dentate nucleus. Punctate PrP deposition decorated the neuropil of the dentate nucleus and the surface of dentate neurons. Synaptic protein expression was examined with synaptophysin, synapsin-1, synaptosomal-associated protein of 25,000 mol. wt, syntaxin-1 and Rab3a immunohistochemistry. Reduced synaptophysin, synapsin-1, synaptosomal-associated protein of 25,000 mol. wt, syntaxin-1 and Rab3a immunoreactivity was noted in the granular cell layer in every case, but reduced expression was inconstant in the molecular layer. Synaptophysin accumulated in axon torpedoes, thus indicating abnormal axon transport. Expression of synaptic proteins was relatively preserved in the dentate nucleus, although synaptophysin immunohistochemistry disclosed large coarse pericellular terminals in Creutzfeldt-Jakob disease, instead of the fine granular terminals in control cases, around the soma of dentate neurons. Finally, Rab3a accumulated in the cytoplasm of Purkinje cells, thus suggesting major anomalies in Rab3a transport. These observations demonstrate, for the first time, abnormal expression of crucial synaptic proteins in the cerebellum of cases with Creutzfeldt-Jakob disease. However, abnormal PrP deposition is not proportional to the degree of reduction of synaptic protein expression in the different layers of the cerebellar cortex and in the dentate nucleus. Therefore, it remains to be elucidated how abnormal PrP impacts on the metabolism of proteins linked to exocytosis and neurotransmission, and how abnormal PrP deposition results in eventual synaptic loss.

Aged↗

PubMed1999

Association of angiogenesis and poor prognosis in node-positive patients receiving anthracycline-based adjuvant chemotherapy.

UNLABELLED: Tumoral angiogenesis has been described as associated with poor prognosis in breast cancer, particularly for node negative breast cancer. The purpose of this study was to evaluate the influence of angiogenesis in node-positive breast cancer and particularly its potential impact on adjuvant chemotherapy. PATIENTS AND METHODS: One hundred and thirty-five node-positive breast cancer patients who received anthracycline or derivative based adjuvant chemotherapy were selected from the data base of the Institut Paoli Calmettes. Angiogenesis was evaluated using CD31 antibody. Other prognosis variables studied were: hormonal status, tumor size, hormonal receptors, Elston and Ellis grade, and number of involved lymph nodes. RESULTS: In multivariate analysis, a high level of angiogenesis was independently associated with a diminution of survival (p = 0.007), and of metastasis-free survival (p = 0.003). Other variables associated with poor survival were progesterone receptor status (p = 0.003) and Elston's grade (p = 0.003), and with metastasis-free survival, progesterone receptor status (p = 0.018). CONCLUSION: Tumoral angiogenesis appears to be an independent prognostic factor for node-positive breast cancer, when treated with adjuvant chemotherapy. Adjuvant strategies for patients with a high level of angiogenesis should be discussed.

Adult↗

PubMed1998

Local and distant recurrence after conservative management of "very low-risk" breast cancer are dependent events: a 10-year follow-up.

PURPOSE: To determine the risk factors associated with recurrence after breast-conserving treatments, and the relationship between occurrence of a local recurrence and subsequent distant metastases. METHODS AND MATERIALS: Among the 3697 patients with primary breast cancer treated at Institut Paoli-Calmettes Cancer Center, Marseille, between 1980 and 1995, we retrospectively analyzed 756 patients who had been treated with conservative surgery with uninvolved margins of excision, were node-negative, and had received uniform radiotherapy and no chemotherapy. One third of the patients received hormonal therapy via tamoxifen or surgical castration. The endpoints considered were local failures and distant metastases. All tumors were reviewed by our pathologists. The median follow-up for the 700 survivors was 62 months. RESULTS: In the multivariate analysis, histological multifocality (p = 0.0076), peritumoral vessel invasion (p = 0.0215), and young age (p = 0.0245) were associated with an increased risk of local recurrences, whereas tumor size (p = 0.0013), young age (p = 0.003), and histological multifocality (p = 0.0414) were associated with an increased risk of distant metastases. Local recurrences and distant metastases had similar yearly-event probabilities. Median time to distant metastases was shorter after a local recurrence. Early timing of local recurrences did not mark a higher risk of distant metastases. Hazard of relapsing from distant metastases was 4.4 times higher after a local recurrence. CONCLUSION: our results support the hypothesis that, in this subset of patients, local recurrences favor further dissemination of cancer cells. We are unable to clearly identify a group who would benefit from more aggressive local therapy.

Adult↗

PubMedDate not supplied

Prognostic value of simultaneous expression of p21 and mdm2 in breast carcinomas treated by adjuvant chemotherapy with antracyclin.

One hundred and sixty-two breast carcinomas treated by adjuvant chemotherapy were investigated in immunohistochemistry for expression of p53 and two wild-type p53-regulated induced proteins, mdm2 and p21/waf1. p21 and mdm2 were expression stongly correlated with Ki67 but not with survival. The p53+/p21+, p53+/p21- and p53+/mdm2- phenotypes were associated with the worst prognosis. The p53+/p21+/ mdm2+ tumors were associated with a better outcome than the other phenotypes, they may be tumors expressing wild-type p53 and p21, and a form of mdm2 that might lead to the stabilization of p53. It is suggested that p21/mdm2 expression should be investigated in all cases of p53 positive breast cancer.

Antibiotics, Antineoplastic↗

PubMedDate not supplied

Peritumoral vascular invasion in women with node-negative breast cancer, receiving no adjuvant therapy.

BACKGROUND: The prognostic value of peritumoral vascular invasion (PVI) in node negative breast cancer (N-) is a controversial issue. Considerable debate has focused on how PVI should be defined, and the techniques used to detect them have differed considerably from one study to another. MATERIAL AND METHODS: In our study, 167 cases of N- breast cancers were reviewed, with a view to determining whether or not PVI, as defined in the recently published European recommendations, were present. RESULTS: Based on the results of the subsequent statistical study, the presence of PVI was not found to constitute a reliable prognostic index to the outcome of N- breast cancer. CONCLUSION: Referring each case to the data available in the literature, the difficulties encountered when searching for PVI of this kind are described, the results of various studies on the topic are reviewed and whether it is worth pursuing studies along these lines is discussed.

Adult↗