Biomedical subjects

P Bevilacqua

Publications and source records attributed to P Bevilacqua.

At least 19 recordsLinked to original sources

PubMed1998

Ventricular late potentials, interstitial fibrosis, and right ventricular function in patients with ventricular tachycardia and normal left ventricular function.

We examined 40 patients with ventricular tachycardia (VT) and no evidence of heart disease, and found a 50% prevalence of ventricular late potentials (VLPs) on the signal-averaged electrocardiogram. This finding was associated with a significantly higher content of fibrous tissue on endomyocardial biopsy and a lower right ventricular ejection fraction. Thus, VLPs are frequently found in idiopathic VT, are a marker for subclinical anatomic and functional abnormalities of the right ventricle, and may be associated with a worse outcome.

Adult↗

PubMed1998

Arrhythmic profile, ventricular function, and histomorphometric findings in patients with idiopathic ventricular tachycardia and mitral valve prolapse: clinical and prognostic evaluation.

BACKGROUND: In patients with ventricular tachycardia (VT) and apparently normal hearts, mitral valve prolapse (MVP) is discovered fairly often, raising the question of whether or not it is an occasional finding. HYPOTHESIS: This issue was analyzed in a series of patients with VT and apparently normal hearts in order to define the prevalence of MVP in this condition, the existence of specific diagnostic features suggesting a nonrandom association between idiopathic VT and MVP, and the prognostic implications of this finding. METHODS: We studied 28 consecutive patients with documented VT and no history of heart disease. Two-dimensional (2-D) echocardiogram, cardiac catheterization, morphometric examination of endomyocardial biopsy and arrhythmologic evaluation (24-h Holter monitoring, electrophysiologic study, and signal-averaged electrocardiogram) were performed. Inclusion criteria for all patients were angiographically normal coronary arteries, normal biventricular function, and absence of histologic evidence of myocarditis. Data obtained in patients found to have MVP at 2-D echo were compared with those of the remaining patients. Long-term follow-up data were also collected. RESULTS: The prevalence of MVP in our study group was 25% (7 patients). It was not associated with leaflet dysplasia or significant regurgitation. Biventricular function (ventricular volumes and ejection fraction) was comparable in patients with and without MVP. Patients with MVP had a significantly higher prevalence of ventricular late potentials at signal-averaged electrocardiogram (86 vs. 29%, p = 0.027), more interstitial fibrosis at morphometry (8.5 +/- 3.7 vs. 5.4 +/- 2.7% p = 0.028), and VT of right bundle-branch block morphology (100 vs. 48%; p = 0.044). Other arrhythmologic findings were similar in the two groups. After a mean follow-up of > 5 years, no patient in either group died, and none developed heart failure or severe mitral regurgitation. CONCLUSIONS: Mitral valve prolapse is frequently detected in idiopathic VT. The distinguishing features of this association are (1) VT of right bundle-branch block morphology, (2) high prevalence of ventricular late potentials, and (3) increased fibrosis on endomyocardial biopsy. Ventricular function and other arrhythmologic findings are not specific of this association. Prognosis remains substantially benign, as is true for most cases of idiopathic VT.

Adolescent↗

PubMed1998

Assessment of right ventricular function and interstitial fibrosis in idiopathic dilated cardiomyopathy: hemodynamic correlates and prognostic value.

BACKGROUND: Right ventricular (RV) function and morphometric quantitation of interstitial fibrosis in idiopathic dilated cardiomyopathy (IDC) have not been the subject of specifically designed clinical observations. In particular, their role in routine assessment and prognostic evaluation of patients (pts) with IDC remains to be settled. METHODS: Eighty-one consecutive IDC patients (63 M, 18 F; mean age 52 +/- 11 yrs) with left ventricular (LV) systolic dysfunction (angiographic ejection fraction - EF - < 55%), normal coronary arteries and no histologic evidence of myocarditis were studied. Cardiac catheterization and endomyocardial biopsy (EMB) were routinely performed in all cases. RV volumes and EF were obtained by angiography according to Ferlinz' method and interstitial fibrosis was quantitated by computer-assisted morphometric analysis. These data were analyzed in order to study correlations with hemodynamic parameters and to assess their prognostic value in a long-term follow-up. RESULTS: In the study population, right ventricular EF was significantly lower than in normal controls (35 +/- 11% vs 53 +/- 6%, p < 0.0001) and showed a significant positive correlation with LV EF (r = 0.54; p < 0.0001), and a weak but significant negative correlation with fibrosis (r = -0.29; p = 0.03). RV volumes, but not EF, were significantly related to mean pulmonary pressure. At multivariate analysis, RV end-diastolic volume (EDV) and EF were the two independent predictors of severe heart failure (NYHA class III-IV). After a mean follow-up of 64 +/- 36 months, 20 pts died and 9 had heart transplantation, for a 63% transplant-free survival rate (TFS). Multivariate analysis identified three independent predictors of TFS: LV stroke work index (p < 0.0001), RV stroke work index (p = 0.02) and RV EDV (p = 0.03). Fibrosis was predictive of survival only in the subgroup with LV EF < 20%. CONCLUSIONS: Assessment of RV function provides useful information in the evaluation of hemodynamic profile and prognosis of pts with IDC. Quantitation of interstitial fibrosis by morphometry provides little additional data.

Adult↗

PubMed1997

The combined evaluation of p53 accumulation and of Ki-67 (MIB1) labelling index provides independent information on overall survival of ovarian carcinoma patients.

BACKGROUND: The prognostic implications of p53 accumulation, bcl-2 immunoreactivity and tumour proliferative fraction in ovarian carcinomas are still debated. PATIENTS AND METHODS: One hundred twelve ovarian carcinomas were immunostained for p53 protein, for bcl-2 and for the cell cycle-associated Ki-67 antigen. The immunostaining results were correlated with conventional clinico-pathological variables, response to induction chemotherapy, and patient survival. RESULTS: p53 accumulation and bcl-2 immunoreactivity in more than 10% of neoplastic cells were detected in 61 (54.5%) and 42 (37.5%) cases, respectively. A positive correlation between p53 accumulation and high (more than 30% neoplastic cells) MIB1 labelling index (r = 0.235; P = 0.015) was ascertained, whereas no significant association was found between bcl-2 immunoreactivity and p53 accumulation or MIB1 labeling index. Both p53 accumulation and MIB1 immunoreactivity correlated significantly with a reduced overall survival, but the association was lost in multivariate analysis. However, patients with tumours simultaneously showing p53 accumulation and MIB1 labelling index higher than 30% had significantly reduced overall survivals, in both univariate and multivariate analyses. CONCLUSION: The simultaneous evaluation of p53 accumulation and MIB1 labelling index has independent prognostic implications in common epithelial malignancies of the ovary, irrespective of the disease stage.

Cell Division↗

PubMed1997

Cellular acetylcholine content and neuronal differentiation.

N18TG2 neuroblastoma clone is defective for biosynthetic neurotransmitter enzymes; its inability to establish functional synapses is overcome in the neuroblastoma x glioma 108CC15, where acetylcholine synthesis is also activated. These observations suggest a possible relation between the ability to produce acetylcholine and the capability to advance in the differentiation program and achieve a fully differentiated state. Here, we report the characterization of several clones after transfection of N18TG2 cells with a construct containing a cDNA for rat choline acetyltransferase (ChAT). The ability of these clones to synthesize acetylcholine is demonstrated by HPLC determination on cellular extracts. In the transfected clones, northern blot analysis shows increased expression of mRNAs for a specific neuronal protein associated with synaptic vesicles, synapsin I. Fiber outgrowth of transfected clones is also evaluated to establish whether there is any relation between ChAT levels and morphological differentiation. This analysis shows that the transfected clone 1/2, not expressing ChAT activity, displays a very immature morphology, and its ability to extend fibers also remains rather poor in the presence of "differentiation" agents such as retinoic acid. In contrast, clones 2/4, 3/1, and 3/2, exhibiting high ChAT levels, display higher fiber outgrowth compared with clone 1/2 in both the absence and the presence of differentiating agents.

Acetylcholine↗

PubMed1996

Prognostic and predictive value of tumour angiogenesis in ovarian carcinomas.

Experimental studies suggest that angiogenesis plays an important role in the pathogenesis of ascites and progression of ovarian cancer. To evaluate the association of intratumoral microvessel density (IMD) with the conventional clinicopathologic features and to determine the capability of these factors in predicting responsiveness to platinum-based chemotherapy and overall survival (OS) we studied 112 ovarian carcinomas. IMD was determined using the anti-CD31 antibody and immunocytochemistry. In the entire series, we correlated IMD with the other features. In the subgroup of patients with FIGO stage III-IV (60 cases), we correlated the factors studied, determined prior of treatment, with response to therapy and prognosis. The median IMD value, in the "hot spot", in the entire series was of 48 microvessels/field. IMD values were significantly higher in mucinous carcinomas than in the other histologic types. In FIGO stage III-IV patients IMD, age and performance status (PS) were significantly associated with the probability of pathologic response to chemotherapy in univariate analysis. However, only IMD and PS retained significance in multivariate analysis. The overall capability of the 2 variables to predict response was high. In FIGO stage III-IV patients IMD, age, PS, the amount of post-operative residual disease (PORD), histologic type and response to chemotherapy were significant prognostic indicators of OS in univariate analysis. In multivariate analysis only histologic type, PORD and PS retained significance. The overall capability of these 3 variables to predict OS was satisfactory.

Adult↗

PubMed1996

Prediction of recovery after abstinence in alcoholic cardiomyopathy: role of hemodynamic and morphometric parameters.

The aim of the study is to describe the hemodynamic and morphometric characteristics of patients with alcoholic cardiomyopathy (ACM) and to evaluate whether these parameters can identify the subgroup of patients in whom recovery of cardiac function after abstinence will occur. Nineteen male patients (mean age 52.4 years, range 39-64 years) with symptomatic left ventricular dysfunction (LVD) [ejection fraction (EF) <50%] and a history of chronic heavy alcohol intake were submitted to a full invasive work-up including right ventricular endomyocardial biopsy (EMB). Counseling aimed at obtaining abstention and clinical follow-up were regularly performed in all patients. The two requisites necessary to define recovery were (1) an increase in left ventricular EF, and (2) improvement of symptoms. The former was defined as a gain in left ventricular EF > 15% from baseline; the latter, as a gain of at least one New York Heart Association (NYHA) functional class. Using these criteria, 9 alcoholic patients (48%) (Group A) improved significantly, while 10 (52%) (Group B) either stabilized or deteriorated at 2 years' follow-up. Group A patients had significantly lower pulmonary artery mean pressure (27.8 mmHg +/- 13.3 vs. 40.3 mmHg +/- 12.4; p < 0.05) and pulmonary capillary wedge pressure (18.4 mmHg +/- 8.9 vs. 26.5 mmHg +/- 7.7; p < 0.05) compared with Group B. All other hemodynamic data did not show statistically significant differences in the two groups. Quantitative evaluation of myocardial hypertrophy and interstitial fibrosis performed on EMB tissue samples using the morphometric approach was not predictive of recovery. Improvement in cardiac performance and functional class was detected in about one-half of patients with ACM who abstained from alcohol, and occurred even in cases presenting with severe LVD. Recovery is associated with significantly lower pulmonary artery and pulmonary wedge pressures. The morphometric evaluation of EMB does not provide adjunctive prognostic information in these patients.

Adult↗

PubMed1996

Lack of prognostic significance of the monoclonal antibody Ki-S1, a novel marker of proliferative activity, in node-negative breast carcinoma.

In a series of 205 node-negative breast cancers (NNBC), we determined staining by the novel antibody Ki-S1, a marker of tumor cell proliferation, in order to test its association with other prognostic variables and its prognostic significance. Ki-S1 was determined in routinely formalin-fixed paraffin-embedded tumor samples. Ki-S1 gave a nuclear staining in the majority of the carcinomas (188 of 205), with percentages of reacting nuclei ranging from 2% to 90% (median value of 7%). In 107 tumors frozen sections were available to also assess the Ki-67 antibody. Among these, 94 had a nuclear staining of cancer cells ranging from 5% to 80% (median value of 7%). In 46 tumors we also determined the MIB-1 antibody. The percentage of MIB-1 nuclear staining ranged from 1% to 50% (median value of 20%). There was no significant relationship between Ki-S1 and the other two cell kinetic markers. Ki-S1 labeling was significantly associated only with tumor size (p = 0.03). With a median follow-up of 6 years, Ki-S1 had no significant prognostic value for either relapse-free survival (RFS) or overall survival (OS) (Ki-S1 as continuous logarithmic variable; p = 0.86 and p = 0.23, respectively). For RFS the following variables had a significant prognostic value: Ki-67 (< or = 10% vs > 10%; p = 0.037); progesterone receptor (PgR) expression (- vs+/++; p = 0.041); tumor size (pT1 vs pT2-3; p = 0.042) and grading (GI vs GII-III; p = 0.047). For OS, tumor size (p = 0.0044), age (continuous variable; p = 0.0060), and Ki-67 (p = 0.043) were significantly prognostic. In multivariate analysis (final model), only tumor size retained a significant and independent prognostic value for RFS (p = 0.0042). For OS, both tumor size (p = 0.0029) and age (< or = 55 years vs > 55 years; p = 0.041) retained significance in the multivariate model. In conclusion, Ki-S1 does not seem to have prognostic relevance in this series of NNBC. Possible hypotheses to explain this observation are discussed.

Antibodies, Monoclonal↗

PubMed1996

Clinical significance of cyclin D1 expression in patients with node-positive breast carcinoma treated with adjuvant therapy.

BACKGROUND: Experimental and clinical studies suggest that cyclin D1 is involved in transformation and tumour progression. However, there is little and contradictory data on the clinical significance of cyclin D1 in human invasive breast carcinoma. PATIENTS AND METHODS: We investigated whether the determination of cyclin D1 has prognostic value in a series of 180 patients with node-positive breast carcinoma and treated with adjuvant therapy with a median follow-up exceeding 6 years. We assessed cyclin D1 expression using the CDS-6 monoclonal antibody and a highly sensitive immunohistochemical technique. RESULTS: We found that most of the evaluable tumours (117 of 167; 70.1%) presented nuclear cyclin D1 staining and that its expression was significantly associated with both the hormone receptors (P = 0.009 and P = 0.005 for ER and PgR, respectively). Furthermore, 29 (17%) of 167 tumours had a weak (15 cases) or strong (9 cases) cytoplasmic cyclin D1 staining. In a subgroup of cases we also studied the amplification of the cyclin D1 gene and a moderate agreement between cyclin D1 nuclear overexpression assessed immunohistochemically and the gene amplification was found. In univariate analysis, cyclin D1 nuclear positivity was significantly associated with improved 6-year relapse-free survival (RFS) (P = 0.004), but not with overall survival (OS) (P = 0.12). The results of the Cox multivariate analysis (final model) indicate that cyclin D1 expression (P = 0.0049) as well as the number of involved nodes (P < 0.001) and tumour size (P = 0.036) are significant prognostic indicators for RFS. Only the number of involved nodes retained significance (P < 0.001) for OS in our series. The joint assessment of the variables considered in the final model of the multivariate analyses had a moderate prognostic capability as determined using the Harrell c statistic (c = 0.66 and 0.64 for RFS and OS, respectively). CONCLUSIONS: The patients with node-positive breast cancer who have a higher likelihood of gaining benefit from adjuvant therapy are those with tumours with cyclin D1 nuclear expression, small size and less than 3 metastatic nodes. Further studies are needed to verify the prognostic value of cyclin D1 in relation to different adjuvant treatments and to deepen the biological pathways that regulate its activation/ suppression in human breast carcinoma.

Adult↗

PubMed1996

Determination of angiogenesis adds information to estrogen receptor status in predicting the efficacy of adjuvant tamoxifen in node-positive breast cancer patients.

There is experimental and clinical evidence that angiogenesis is involved in breast cancer progression and metastasis. To investigate whether the determination of angiogenesis adds prognostic information to the estrogen receptor (ER) status, we studied a series of 178 node-positive breast cancer patients, with a median follow-up time exceeding 5 years, treated with adjuvant tamoxifen (TAM). We assessed angiogenesis by the quantification of the intratumoral microvessel density and the determination of the Chalkley score using light microscopy. Microvessels were immunostained using the anti-CD31 antibody. The other features studied were ER status and the conventional clinicopathological prognostic indicators. Results were pooled from two collaborating Centers using Chalkley counts to convert intratumoral microvessel density to a common quantification system. We found that Chalkley score was not associated with any other feature studied. In univariate analysis, Chalkley score was significantly predictive of both relapse-free survival (RFS) and overall survival (OS; P < 0. 00001 and P = 0.00004, respectively). Likewise, ER status, the number of metastatic axillary nodes, histological grading, and tumor size were significantly predictive for RFS and OS. Cox multivariate analysis showed that Chalkley score was the strongest significant independent predictor of outcome. For RFS, ER status, the number of metastatic nodes, and histological grading also retained significance. For OS, the number of metastatic nodes, tumor size, and histological grading were independent prognostic factors. The joint assessment of the above variables had a satisfactory prognostic capability, as found using the Harrel statistics (c = 0. 77). These results suggest the validity of using Chalkley counts to assess and compare angiogenesis for prognostic purposes between different Centers. We found that angiogenesis adds significant prognostic information to ER status in predicting the outcome of breast cancer patients treated with adjuvant TAM. In fact, irrespective of the ER status, the patients with highly angiogenic tumors had a poor outcome, even if treated with TAM. For these patients, the inhibition of angiogenesis with specific angioinhibitory drugs may be a promising new therapeutic strategy.

Breast Neoplasms↗

PubMed1995

67-kDa laminin-receptor expression adds prognostic information to intra-tumoral microvessel density in node-negative breast cancer.

Experimental studies have shown that the 67-kDa laminin receptor (LRec) is an important molecule for the interaction of tumour cells with the extracellular matrix, and that it plays a role in the early steps of angiogenesis and in tumour invasion and metastasis. We performed a multi-parametric study in 171 node-negative breast cancers, followed for a median time of 6 years, to verify whether determination of the LRec provides prognostic information in addition to intra-tumoral microvessel density (IMD), a measure of tumour angiogenesis, and to other biological and conventional indicators. A positive association between LRec expression and high neovascularization was found, although it did not reach significance. LRec was not associated either with other biological markers (oestrogen receptor, progesterone receptor and p53 expression) or to the conventional prognostic features [menopausal status, tumour size, histological types, grading and peri-tumoral lymphatic vessel invasion (PLVI)]. In univariate analysis, IMD, p53, PgR, PLVI, grading and tumour size were significant prognostic indicators of relapse-free survival (RFS). LRec expression approached significance when considered as a dichotomous variable, after having selected the optimum cutoff of 10% to distinguish high-risk from low-risk patients. For overall survival (OS), tumour size and IMD (continuous variable) were significant prognostic factors, and p53 approached significance. In multivariate analysis for RFS, the joint variable LRec and vascularization was the strongest independent prognostic factor, followed by PgR, PLVI and p53. For OS, tumour size was the only independent prognostic indicator in this series.

Adult↗

PubMed1995

Prognostic value of intratumoral microvessel density, a measure of tumor angiogenesis, in node-negative breast carcinoma--results of a multiparametric study.

In the present study we update previous results on the prognostic value of intratumoral microvessel density (IMD), determined immunocytochemically using the monoclonal antibody CD-31 and a standard streptavidin-immunoperoxidase technique, published in the J Clin Oncol 12:454-466, 1994. This study was undertaken in those 211 node-negative breast cancer (NNBC) cases of that series of which we had pathological material available to determine all the prognostic indicators. The median period of follow-up has been extended to 78 and 80 months for relapse-free survival (RFS) and overall survival (OS), respectively, and new biological indicators (i.e. Ki-67 labeling and 67 kDa laminin receptor expression) were included in the analysis. The main results obtained are: i) a confirmation that IMD is not associated with the other biological markers studied, i.e. expression of p53 protein, c-erbB-2 protein, 67 kDa laminin receptor, and cell kinetics; IMD was weakly associated only with histological grade (p = 0.053); ii) IMD remains a highly significant prognostic factor for RFS and OS (p < 0.0001 and p = 0.018, respectively) in univariate analysis; iii) in multivariate analysis on RFS, IMD (likelihood ratio test (LRT) = 30.16; p < 0.0001), 67 kDa laminin receptor (LRT = 9.80; p = 0.0017), the IMD/67 kDa laminin receptor interaction (LRT = 8.62; p = 0.0033), tumor size (LRT = 8.56; p = 0.0034), and p53 protein (LRT = 4.96; p = 0.025) are significant and independent prognostic indicators. For OS, only tumor size (LRT = 8.34; p = 0.0038), menopausal status (LRT = 5.16; p = 0.023), p53 protein (LRT = 4.37; p = 0.036), and IMD (LRT = 4.05; p = 0.044) retain a significant and independent prognostic value. The results of this study confirm the prognostic importance on RFS of the variables previously tested, but not of peritumoral lymphatic vessel invasion. A novel finding is that 67 kDa laminin receptor and the IMD/67 kDa laminin receptor interaction are also significant and independent variables. For OS, the results confirm that both IMD and tumor size are significant and independent variables. With prolonged follow-up the novel finding that emerges is the prognostic importance of menopausal status and p53 protein. This new information could be useful for a more accurate selection of high-risk NNBC patients who require careful follow-up and may benefit from adjuvant therapy.

Analysis of Variance↗

PubMed1995

Characterization of acetylcholinesterase secretion in neuronal cultures and regulation by high K+ and soluble factors from target cells.

We have observed that cultured neurons from chick spinal cord and the neuroblastoma hybrid line 108CC15 released lower amounts of acetylcholinesterase (AChE) when compared with the parental line, N18TG2. AChE activity extracted by hypotonic buffer, which can be regarded as the source of the released enzyme, was considerably higher in the parental than in the hybrid 108CC15 (respectively, approximately 80% and approximately 40% of cellular activity). On the other hand, evaluation of ectocellular, with respect to total, AChE activity showed that in N18TG2 cells only 7% of AChE was localized on the plasmalemma, whereas in the hybrid line the percentage of ectocellular activity was 3.7 times higher than in the parental line. We have also examined the effect of cytochalasin B and nocodazole. In the N18TG2 line, the former did not affect AChE release, which was significantly reduced by the latter. High K+ level in the culture medium, of both N18TG2 and hybrid 108CC15 cultures, induced an increase in AChE secretion; Ca2+ presence was required for high K(+)-induced release. Muscle extracts increased AChE secretion in both the hybrid 108CC15 and the spinal cord neurons. The present data suggest that AChE secretion during neuronal development is modulated by depolarizing stimuli and by soluble factors produced by target cells and may be involved in the control of neuronal differentiation.

Acetylcholinesterase↗

PubMed1995

Predictive and prognostic markers in a series of patients with head and neck squamous cell invasive carcinoma treated with concurrent chemoradiation therapy.

It has been proposed that diverse anticancer drugs and radiation therapy may induce a mode of cell death with the characteristics of apoptosis. Since apoptosis is under the control of several oncogenes, we analyzed the expression of the protein encoded by the proto-oncogenes bcl-2 and p53. Furthermore, we studied cell proliferation [using PC-10 mAb to proliferating cell nuclear antigen (PCNA)] and vascularization [using the CD-31 mAb and by counting intratumoral microvessel density (IMD)] using immunocytochemistry. A series of 73 patients with clinical stage II-IV squamous cell invasive carcinoma of the head and neck (H&N) were treated with concurrent chemoradiation therapy (cisplatin, 80 mg/m2, versus carboplatin, 375 mg/m2, three times every 3 weeks and a total dose of radiation therapy of 64 Gy in 6-8 weeks). We correlated the expression of these markers, determined prior to treatment, with response to the therapy and prognosis. Bcl-2 protein was expressed in 37.4% of the carcinomas (25/67 evaluable), and it was not significantly associated with any other feature studied. Forty (56. 4%) of the 71 carcinomas evaluable for p53 were p53 positive; the median IMD was 38 microvessels/field at the hot spot (range, 18-80), and the median percentage of nuclei labeled by the PC-10 mAb was 50% (range, 0-95%). In the univariate analysis, regional lymph node negativity (P = 0.016), good performance status (PS) (PS >/= 90; P = 0.044), bcl-2 positivity (P = 0.070), and low vascularization (P = 0. 085) were significantly associated with a higher probability of complete remission. In the multivariate analysis (final model), only IMD (continuous variable; P = 0.045) and PS (P = 0.017) retained significance. As far as prognosis is concerned, in the univariate analysis, patients with tumors with low histological grading (grades 1-2; P = 0.006), p53 negative (P = 0.09), bcl-2 positive (P = 0.08), and high PCNA labeling (P = 0.06) had a significantly better disease-free survival. In the multivariate analysis, only grading (P = 0.003) and p53 (P = 0.04) retained significance for disease-free survival. For overall survival, in the univariate analysis, the following markers were significantly prognostic when only deaths due to progression are considered: response to therapy (P = 0.00001), PS (P = 0.04), nodal status (P = 0.028), PCNA (P = 0.04), p53 (P = 0. 08), and grading (P = 0.01). In the multivariate analysis, only patients who achieved complete response (P = 0.00002), high PCNA values (P = 0.002), and low histological grading (P = 0.01) retained a statistically significant probability of better overall survival. Our results suggest that in this series of H&N cancer patients the markers capable of predicting response to therapy are distinct from those associated with prognosis, once the remission has been achieved. This information is potentially useful to the clinician for developing a more rational therapeutic approach for H&N cancer patients eligible for concurrent chemoradiation therapy.

Adult↗

PubMed1995

Expression of bcl-2 protein predicts efficacy of adjuvant treatments in operable node-positive breast cancer.

The proto-oncogene bcl-2 encodes a protein that inhibits apoptosis, a common mechanism of cell death caused by hormone and chemotherapy. We have analyzed bcl-2 protein expression by immuno-cytochemistry in primary node-positive breast cancers in two groups of patients (for a total of 180 cases). One group received adjuvant hormone therapy, the other chemotherapy (cyclophosphamide, methotrexate, and fluorouracil), and both groups were followed for a median time of 63 months. We compared our findings with conventional clinicopathological indicators [menopausal status, number of axillary nodes, histological grade, tumor size and type, estrogen receptor (ER), and progesterone receptor] and with p53 protein expression. bcl-2 protein was present in 65% of the carcinomas (117/180) and it was significantly associated with ER and progesterone receptor and inversely associated with p53 in both the groups of patients treated with adjuvant chemotherapy and tamoxifen. In patients treated either with adjuvant chemotherapy or tamoxifen, relapse-free survival at 5 years was significantly better among patients with bcl-2-positive tumors than in those with bcl-2 negative ones (P = 0.05 and 0.02, respectively). As far as overall survival is concerned, patients with bcl-2-positive tumors had a significantly better outcome in the group treated with adjuvant chemotherapy (P = 0.03). Multivariate analyses were performed for the two treatment groups. In the group treated with tamoxifen, lack of expression of ER and of bcl-2 was the only significant and independent predictor for poor relapse-free survival (P < 0.01). A number of nodes above 3 was the only significant and independent predictor for poor overall survival (P < 0.01). In the cyclophosphamide-methotrexate-fluorouracil-treated group, bcl-2 absence was significant for poor overall survival (P = 0.02) as well as a number of nodes above 3 (P = 0.04) and a tumor size above 2 cm (P = 0.05). For poor relapse-free survival only a number of nodes above 3 (P < 0.01) and progesterone negativity (P = 0.02) were significant and independent predictors of a higher probability of relapse. Thus, in contrast to in vitro data on drug resistance, bcl-2 expression was associated with better outcomes in patients treated with hormone and chemotherapy. Overall, these results suggest that expression of bcl-2 protein and the number of metastatic lymph nodes are independent features predictive of clinical outcome in patients with node-positive breast cancer, irrespective of the type of adjuvant treatment. The determination of bcl-2 protein may prove to be a useful tool to distinguish patients for whom conventional forms of adjuvant therapy are beneficial from those with bcl-2 negative and ER-negative tumors for whom novel therapeutic strategies are needed.

Adult↗

PubMed1994

Cell kinetics in human breast cancer: comparison between the prognostic value of the cytofluorimetric S-phase fraction and that of the antibodies to Ki-67 and PCNA antigens detected by immunocytochemistry.

The determination of cell proliferation is one of the more widely used tools for assessing prognosis. However, additional research in this field is warranted because today there are several methodological procedures available for monitoring cell kinetics and it has still not been established which is the most reliable marker of proliferation and which possesses the greatest prognostic value. We performed this study in a series of primary invasive breast cancers to compare the prognostic value of S-phase fraction (SPF) by flow cytometry, the most widely used method for detecting proliferation at present, with that of antibodies to Ki-67 and PC-10 to proliferating-cell nuclear antigen (PCNA) detected by immunocytochemical methods. A significant linear relationship was observed only between SPF and Ki-67. In univariate analysis SPF and Ki-67 values, nodal status, histological grading and peritumoral lymphatic-vessel invasion were significant predictors of relapse-free survival (RFS). As far as overall survival (OS) is concerned, only SPF, Ki-67 and nodal status were significantly associated with the risk of death. PCNA had no prognostic value for either RFS or OS. In multivariate analysis only SPF and nodal status retained a significant and independent prognostic value. Neither the cell-kinetics parameters assessed by immunocytochemistry (i.e. Ki-67 and PCNA) nor histological grading were independent prognosticators. In conclusion, our results provide evidence that the determination of SPF by flow cytometry was the strongest cell-kinetics marker used to assess prognosis in this series of breast cancers. However, different and novel markers of cell kinetics need to be compared in larger series in order to identify the best one.

Breast Neoplasms↗

PubMed1994

Lack of correlation between N-myc and MAX expression in neuroblastoma tumors and in cell lines: implication for N-myc-MAX complex formation.

Detectable levels of MAX messenger RNA were found in a set of human neuroblastoma tumors and established cell lines. MAX mRNA levels were independent of tumor stage and N-myc genomic amplification. By contrast, N-myc mRNA transcripts were detectable only in tumors with amplification of N-myc gene and in cell lines. Analysis by reverse transcriptase polymerase chain reaction and hybridization to specific oligodeoxynucleotide probes revealed approximately equal amounts of two MAX transcripts in all cases analyzed. Immunoprecipitations with a specific antibody to MAX detected two proteins of M(r) 21,000 and 22,000 in approximately equal amounts in all neuroblastoma lines regardless of N-myc amplification and/or expression. On the other hand, protein binding to the myc DNA consensus sequence correlated with N-myc expression in neuroblastoma cells. Thus, N-myc expression might be a limiting factor in the formation of the N-myc-MAX heterodimer in neuroblastomas.

Amino Acid Sequence↗

PubMed1994

A multiparametric study on the prognostic value of epidermal growth factor receptor in operable breast carcinoma.

Epidermal growth factor receptor (EGFR) is a potentially useful new biological prognostic and predictive indicator in human breast cancer. Additional research on EGFR is warranted to enhance our information on: i) the method of choice for its detection and quality control issues; ii) its association with novel pathobiological markers of prognosis; iii) its prognostic value in multivariate analysis; and iv) its capability to predict response to hormone therapy and, in the future, to biological treatments using antibodies against the specific receptor or its ligands. In the present study we update previous data on EGFR status, determined immunocytochemically, by prolonging the period of observation up to 5 years and by including, in the multivariate analysis, several new biological indicators. The main results obtained are: i) EGFR is weakly associated with Ki-67 score (p = 0.073) and with p53 expression (p = 0.06); ii) EGFR is a significant indicator for recurrence (p < 0.01 and odds ratio of 2.82) but not for death (p = 0.27 and odds ratio of 1.49); iii) the prognostic power of EGFR is enhanced when combined with the knowledge of S-phase fraction; and iv) in multivariate analysis on relapse-free survival, EGFR and S-phase fraction (likelihood ratio test = 26.40; p < 0.01), c-erB-2 protein and p53 mutant protein expression (likelihood ratio test = 5.94; p = 0.05), cathepsin D (likelihood ratio test = 9.78; p < 0.01), and nodal status (likelihood ratio test = 7.32: p < 0.01) are significant and independent prognostic factors in early-stage breast carcinoma. This new information could be of help for a more rational approach in the use of EGFR as a marker in future clinical research.

Age Factors↗