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Biomedical subjects

M G Daidone

Publications and source records attributed to M G Daidone.

At least 55 records · Page 3Linked to original sources
PubMed1999

Clinical studies of Bcl-2 and treatment benefit in breast cancer patients.

Interest in translational studies aimed at investigating the role of biologic markers in predicting clinical outcome of breast cancer patients and, in particular, response to specific treatments, has progressively increased. Among biologic variables presently under investigation, apoptosis markers, in particular Bcl-2 and Bax expression, are receiving much attention for their relationship with the cellular response to genotoxic damage in experimental tumors. Retrospective, independent studies were carried out by several research groups on about 5000 patients with breast cancer at different stages and with an adequate follow-up. The outcome of separate analyses as a function of treatment generally demonstrated that Bcl-2 overexpression, which correlates with biologic features of a differentiated phenotype (slow proliferation, high steroid receptor levels, absence of p53 and c-erB-2 expression), is associated with a favorable outcome. Such a finding is mainly evident following surgery as well as endocrine treatment. Conversely, no or weak Bcl-2 expression, alone or in association with bax overexpression, appears indicative of a radiation response, and preliminary emerging evidence supports the involvement of such an association of apoptosis-related markers even as predictors of long-term response to neoadjuvant cytotoxic treatment. Although the findings of an involvement of Bcl-2 and Bax as determinants of treatment response should be confirmed within the context of randomized clinical trials, they indicate a combined consideration of proteins that negatively and positively regulate apoptosis in translational studies on the effect of chemical and physical agents at a cellular level.

Antineoplastic Agents, Hormonal↗
PubMed1998

Biological markers as indicators of pathological response to primary chemotherapy in oral-cavity cancers.

The predictive role in terms of pathological response and prognostic role of biomarkers such as GST-pi, p53, bcl-2 and bax expression, immuno-histochemically detected, and of the S-phase cell fraction, autoradiographically determined as thymidine labeling index (TLI), were investigated within a prospective randomized phase III clinical trial on squamous-cell carcinoma of the oral cavity, including surgery or primary chemotherapy (PCT), which foresaw the prospective determination of biological markers. Pathological response was defined as the achievement after PCT of a pathological complete remission or the presence of microresidual disease. The study was performed on tumors obtained from a series of 100 previously untreated patients with resectable T2-4N0-2M0 carcinoma. All biomarkers were unrelated, except for an inverse relation between TLI and GST-pi and a direct relation between bcl-2 and bax expression. In patients treated with surgery alone, 3-year disease-free survival (DFS) appeared to be weakly, but not significantly, related only to GST-pi and p53 expression. In patients treated with PCT, pathological response and DFS were independent of p53 expression and cell proliferation. Conversely, low GST-pi and bax expression were indicative of pathological response but lost relevance as predictors of DFS, whereas absence of bcl-2 was associated with high probability of 3-year DFS in the overall series as well as in non-responding patients. Within this latter sub-set, all patients with bcl-2-positive tumors relapsed within 1 year of surgery, whereas a 60% probability of 3-year DFS was observed for patients with bcl-2-negative tumors (p = 0.02). This interim analysis appears to indicate that some biofunctional markers can provide information on pathological response to PCT and could help in understanding treatment efficacy at a cellular level.

Biomarkers↗
PubMed1998

The clinical predictivity of biomarkers of stage III-IV epithelial ovarian cancer in a prospective randomized treatment protocol.

BACKGROUND: The aim of this study was to define the clinical relevance of functional biomarkers, prospectively assessed in a randomized clinical protocol, in patients with Stage III-IV epithelial ovarian cancer. The protocol compared cisplatin with polychemotherapy that included cisplatin and cyclophosphamide. METHODS: In a subset of 168 patients with invasive epithelial ovarian cancer cell proliferation was determined by the 3H-thymidine labeling index, DNA ploidy was assessed by flow cytometry, and the expression of p53, bcl-2, and glutathione S-transferase-pi (GST-pi) was evaluated by immunohistochemistry using the antibodies PAb1801, anti-bcl-2, and GST-pi, respectively. RESULTS: Cell proliferation, DNA ploidy, and the expression of p53, bcl-2, and GST-pi were generally unrelated to one another and unrelated to clinicopathologic features, except for an association between DNA ploidy and the rate of cell proliferation. All biologic variables except bcl-2 were slightly related to tumor grade. DNA ploidy emerged as a predictor of clinical complete response and 3-year overall survival, regardless of treatment type or residual disease. Conversely, except for a favorable outcome for patients with tumors not expressing bcl-2 who were treated with cisplatin, no definitive patterns of predictivity for short term or long term clinical outcomes were observed for the other biomarkers studied. CONCLUSIONS: DNA ploidy appears to be the most clinically relevant biomarker for epithelial ovarian cancer. More information is needed to understand the role of the other markers studied in this tumor type.

Aged↗
PubMed1998

Association between [18F]fluorodeoxyglucose uptake and postoperative histopathology, hormone receptor status, thymidine labelling index and p53 in primary breast cancer: a preliminary observation.

To investigate the possible role of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) in the prognostic evaluation of primary breast cancer, we studied 86 patients with T1-3 (TNM classification) breast tumours before surgery and compared the tumour FDG uptake, calculated as a standardized uptake value (SUV), with postoperative histopathological findings, steroid hormone receptor status of the tumour, thymidine labelling index (LI) and tissular expression of p53. SUV was significantly higher in infiltrating ductal carcinomas (n = 68; median SUV = 5.6) than in lobular ones (n = 18; median SUV = 3.8), and in grade 3 carcinomas (n = 26; median SUV = 6.2) than in grade 1-2 ones (n = 60; median SUV = 4.9). Moreover, SUV was significantly higher in carcinomas with high levels of p53 (n = 12; median SUV = 9.5) than in those with low levels (n = 48; median SUV = 4.25). By contrast, there was no significant correlation between SUV and the steroid hormone receptor status or LI of tumours. Our data demonstrate that FDG uptake, expressed as SUV, is associated with certain prognostic factors in breast cancer, such as histopathological grading and p53 expression, which can be assessed only by means of postoperative in vitro examinations. Hence, the information provided by FDG-PET is to some extent related to relevant information on tumour biology. The clinical value of these data will have to be confirmed by analysis of the independence of SUV from other prognostic factors by means of a multivariate analysis performed on a larger series of patients with adequate follow-up. If SUV is confirmed as an independent variable, FDG-PET could assume an important role in the determination of appropriate therapeutic strategies for primary breast cancer.

Adult↗
PubMed1998

P53 accumulation in primary breast cancer: a comparison between immunohistochemistry and a novel luminometric immunoassay.

The accumulation of p53 protein was evaluated by a novel luminometric immunoassay (LIA) in cytosol samples from a series of 245 primary breast cancers. The cytosolic p53 content was not related to nodal status or hormone receptor status, but it was significantly and directly associated with tumor size and cell proliferation. A matched comparison between immunohistochemistry (IHC) and LIA results of individual tumors showed a significant association, albeit with a correlation coefficient of only 0.41. The agreement of results from the two assays was higher in node-positive, estrogen-receptor-negative and rapidly proliferating tumors than in the complementary subgroups. Overall, there was a significant trend in favor of an increase in p53 levels as determined by LIA with the increase in p53-positive cells shown by IHC. However, taking IHC detection as a reference, the sensitivity of the LIA was better for negative (86%) than for positive (61%) values. Based on these findings, a comparative assessment of the clinical relevance of LIA versus IHC results has to be recommended.

Antibodies, Monoclonal↗
PubMed1997

int-2 oncogene amplification and prognosis in node-negative breast carcinoma.

The role of int-2 oncogene amplification on the prognosis of breast cancer patients was investigated in 128 patients with node-negative primary breast cancers given first-line local-regional treatments until relapse and with a median follow-up of 65 months. Tumours had been previously characterised for oestrogen (ER) and progesterone receptor (PgR) status and proliferative activity (3H-thymidine labelling index). Amplification of the int-2 oncogene occurred in 18% of cases and was significantly related to the presence of hormone receptors and to menopausal status or age, but not to proliferative status. Patients with tumours exhibiting int-2 amplification had a lower probability of disease-free survival than patients with non-amplified tumours and frequently developed local-regional recurrence. Disease-free survival analysis, adjusted for the prognostic contribution provided by tumour size, steroid receptors and proliferative rate, indicated that the association between int-2 amplification and risk of relapse was maintained and remained constant even in the presence of the other co-variates. Interestingly, int-2 amplification was a further prognostic discriminant within subsets of patients with a putatively good (i.e., tumour size <20 mm, ER+ and PgR+) or poor prognosis (i.e., high labelling index). Our exploratory study suggests that within node-negative patients, int-2 amplification could be a valuable and independent prognosticator, useful to identify patients at high risk of local-regional recurrence.

Analysis of Variance↗
PubMed1997

Expression of p53, glutathione S-transferase-pi, and Bcl-2 proteins and benefit from adjuvant radiotherapy in breast cancer.

BACKGROUND: In clinical breast cancer research, the utility of certain biomarkers as predictors of response to surgery, chemotherapy, or hormonal therapy has been studied intensively. Much less research has been done on the relevance of biologic predictors of response to radiotherapy, which represents an effective local-regional treatment for breast cancer. PURPOSE: The utility of biomarkers involved in DNA damage repair (p53 protein), control of programmed cell death (p53 and Bcl-2 proteins), and cellular detoxification (glutathione S-transferase-pi [GST-pi] enzyme) in predicting local breast cancer recurrence was analyzed retrospectively in two cohorts of breast cancer patients. These patients had had no detectable metastases in the axillary lymph nodes (i.e., node-negative) or in distant sites and had had similar distributions of clinicopathologic and biologic prognostic features. They had been treated by conservative surgery alone (139 case patients) or by conservative surgery followed by adjuvant radiotherapy (496 case patients) during the period from 1984 through 1990. METHODS: The expression of the p53, GST-pi, and Bcl-2 proteins in the specimens of primary breast tumor obtained from these patients was determined by use of immunohistochemistry; cell proliferation activity and levels of steroid receptors were determined by use of a [3H]thymidine-labeling index assay and the dextran-coated charcoal technique, respectively. The median time of follow-up of patients was 6 years. In the analyses of patient outcomes, only local failures that presented as first events were considered. RESULTS: After surgery alone, the risk of local recurrence at 6 years was higher for patients with tumors exhibiting elevated levels of p53 and GST-pi protein expression than for patients with low levels (hazard ratio [HR] = 3.1, 95% confidence interval [CI] = 1.3-7.7, two-sided P = .012; HR = 2.7, 95% CI = 1.1-6.4, two-sided P = .026, respectively). Weak or no observable expression of Bcl-2 protein was only suggestive of a higher frequency of local failures. Adjustment for patient age, tumor size, cell proliferation, and estrogen receptor status did not change these findings. Conversely, in the series of patients given conservative surgery followed by radiotherapy, there was no difference in local tumor recurrence between patients with tumors expressing or not expressing each of the three markers. CONCLUSIONS: Our study provides indirect evidence of a benefit from radiation therapy in preventing local breast cancer relapse, particularly among node-negative patients with tumors that express elevated levels of the p53 or GST-pi proteins or that express little or no Bcl-2 protein.

Biomarkers, Tumor↗
PubMed1997

Cell proliferation in 3,800 node-negative breast cancers: consistency over time of biological and clinical information provided by 3H-thymidine labelling index.

For breast cancer, many prognostic markers that initially appeared promising have failed to maintain their clinical predictive value. Few reports have analyzed the consistency over time of biological and clinical information provided by biomarkers. Tumour cell proliferation has acquired relevance as an indicator of prognosis and of response to treatment. Since its clinical role has been investigated for some decades, cell proliferation represents an ideal marker for an over-time validation. In 3,800 node-negative breast cancers recruited between 1972 and 1991, the consistency of information provided by the 3H-thymidine labelling index (TLI), in terms of basic relations with other clinico-pathological and biological variables and clinical predictivity, was evaluated using a combined analysis of results previously published by our group for distinct series of patients. Clinical predictivity was analyzed on a subset of 2,067 patients given local-regional therapy until relapse and followed for a median time from 6 to 10 years. Over the entire period TLI maintained a weak direct relation with tumour size and an inverse strong relation with steroid receptors. An increase in TLI was observed for tumours in post-menopausal patients up to the mid 1980s. During 3 different accrual periods (1972-1983; 1984-1987; 1988-1991), TLI was a consistent and independent predictor of relapse-free time, distant metastasis and overall survival, regardless of its consideration as a continuous variable or with a cutoff value of 3%. The reproducibility of our results over time provides support to the consistency of the methodology used and of the biological and clinical information obtained when using TLI as an indicator of breast cancer cell proliferation.

Adult↗
PubMed1997

Expression of high-affinity 67-kDa laminin receptors in primary breast cancers and metachronous metastatic lesions or contralateral cancers.

The presence of high-affinity 67-kDa laminin receptors, detected immunohistochemically, was determined on 63 primary breast cancers and on metachronous metastatic lesions or contralateral cancers from the same patients. A disagreement was observed in two-thirds of the cases. In particular, laminin receptor content was significantly lower (P = 0.02) in local recurrences and slightly higher in lymph node metastasis than in the corresponding primary tumours.

Breast Neoplasms↗
PubMed1996

p53 expression, DNA content and cell proliferation in primary and synchronous metastatic lesions from ovarian surface epithelial-stromal tumours.

The aim of this study was to investigate biological heterogeneity between primary and metastatic ovarian cancer lesions from individual patients as a means of elucidating steps in clinical progression. Cancer tissue from 61 untreated patients with ovarian surface epithelial-stromal tumours was examined. p53 expression detected immunocytochemically by the PAb1801 antibody, DNA content evaluated by flow cytometry, and cell proliferation evaluated as the [3H]thymidine labelling index were investigated in primary tumours and corresponding synchronous metastases. The frequency of p53 positivity was similar in primary (62%) and metastatic (66%) sites, with an agreement between the two lesions from the same patient in 97% of the cases. Similarly, aneuploidy frequency (80%) and DNA indices were superimposable in primary and metastatic lesions from the same patient, with a 94% agreement. The frequency of aneuploidy was higher in p53-positive than in p53-negative lesions. An overall poor agreement (rs = 0.44) was observed for proliferative activity of primary and metastatic lesions, due to a heterogeneous profile in omental with respect to primary tumours, which was mainly evident in p53-positive cancers. Conversely, cell proliferation of peritoneal, abdominal and pelvic lesions was qualitatively similar to that of the primary tumour in 88% of patients.

Cell Division↗
PubMed1996

p53 and bcl-2 expression correlates with clinical outcome in a series of node-positive breast cancer patients.

BACKGROUND AND PURPOSE: The tumor-suppressor gene TP53 and the proto-oncogene bcl-2 encode, respectively, for a nuclear phosphoprotein and for a mitochondrial protein involved in multiple cellular functions. The proteins provide prognostic information in node-negative breast cancer and are supposed to influence treatment responsiveness. We analyzed the predictive role of p53 and bcl-2 expression, alone and in association with other variables, in postmenopausal women with node-positive, estrogen receptor-positive (ER+) breast cancers treated with radical or conservative surgery plus radiotherapy and adjuvant tamoxifen for at least 1 year. PATIENTS AND METHODS: On 240 resectable cancers, we determined the expression of p53 and bcl-2, using immunohistochemistry, cell proliferation (3H-thymidine labeling index [3H-dT LI]), and ER and progesterone receptors (PgR). RESULTS: p53 expression and 3H-dT LI were weakly related to one another and both were unrelated to bcl-2. Relapse-free and distant metastasis-free survival at 5 years were significantly lower for patients with tumors that highly expressed p53 (P = .0001) and for those that weakly expressed or did not express bcl-2 (P = .02). However, p53, but not bcl-2, provided prognostic information independent of tumor size, axillary node involvement, steroid receptors, and 3H-dT LI. Moreover, the simultaneous p53 overexpression and lack of PgR identified patients at maximum risk of relapse, whereas bcl-2 overexpression, associated with a low 3H-dT LI or the presence of PgR, improved the prognostic resolution for low-risk patients. CONCLUSION: p53 expression appears to be indicative of clinical outcome in postmenopausal patients treated with tamoxifen. Whether p53 overexpression and weak bcl-2 expression are indicators of biologic aggressiveness, regardless of treatment, or of hormone resistance remains to be defined.

Aged↗
PubMed1996

Validation of p53 accumulation as a predictor of distant metastasis at 10 years of follow-up in 1400 node-negative breast cancers.

Most studies are in favor of a prognostic relevance of p53 accumulation determined by immunohistochemistry in breast cancer, but negative results are not lacking. On a series of 1400 patients with lymph node-negative cancers treated with local-regional therapy alone until relapse and with a median follow-up of 10 years, we validated the prognostic relevance for overall relapse and death of p53 accumulation observed in a pilot study and analyzed its predictivity on different adverse events. p53 protein accumulation was immunocytochemically detected using PAb1801. The case series had also been previously characterized for hormone receptor content [estrogen receptors (ERs) and progesterone receptors (PgRs)] and for cell proliferation [[3H]thymidine labeling index ([3H]dT LI)]. p53 expression, considered as a dichotomous variable with a cutoff value of 5% positive cells, significantly predicted the occurrence of overall relapse, distant metastasis, and death with an interaction with cell proliferation. p53 accumulation, cell proliferation, and their interaction term, along with tumor size and patient age, retained a predictive role for overall relapse, and together with tumor size and PgR, also for overall survival. When considered as continuous variables, we observed that the hazard of metastasis increased linearly with the increase of [3H]dT LI and decreased linearly with the increase of ER and PgR. Conversely, the hazard increased with the increase of p53-positive cells only for tumors with a [3H]dT LI lower than 7.5%. In multivariate analysis, the same prognostic factors for distant metastasis were identified when the biomarkers were considered as continuous or dichotomous variables.

Adult↗
PubMed1995

Contribution of ploidy and cell kinetics from fine-needle aspirates for the diagnosis of breast lesions: study of 606 consecutive cases.

A total of 606 consecutive patients with palpable breast lesions underwent physical examination, mammography, and fine-needle aspiration for cytologic and flow-cytometric (FCM) DNA analyses. FCM determinations included DNA ploidy and the fraction of cells in S + G2 + M phases. Aneuploid clones were considered indicative of malignancy; diploid, rapidly proliferating (S+G2+M>12%) clones were considered suggestive of malignancy; and diploid, slowly proliferating clones were considered indicative of benignancy. Sensitivity, specificity, and the predictive accuracy for positive or negative results of FCM information were 82%, 90%, 93.1% and 69.8%, respectively. These values were lower than those observed for the three conventional diagnostic assays owing to the presence of false-positive results (in 23 cases) or unassessable DNA plots (in 90 cases). FCM information alone detected five cases in which the other tests gave inconclusive results and in association to the conventional diagnostic triple test, increased the incidence of positive conclusive cases from 97.9% to 99.2%. However, further refinements are needed before this approach can be used as a routine diagnostic tool.

Adult↗
PubMed1995

Changes in biological markers after primary chemotherapy for breast cancers.

The profiles of functional (proliferative rate and cell distribution in the cell cycle) and phenotypic (nuclear DNA content and hormone receptor status) biological markers and the expression of P53 and Bcl-2 proteins were prospectively evaluated in breast cancers before and after different regimens of primary chemotherapy. Overall, changes induced on the 2 proliferation indices (3H-thymidine labelling index, 3H-dT LI, and flow-cytometric S-phase fraction, FCM-S) mainly consisted of a decrease for rapidly proliferating tumours and an increase or no change for slowly proliferating tumours. However, when considered as a function of treatment type, changes of 3H-dT LI and FCM-S were superimposable in rapidly proliferating tumours, regardless of the type of treatment, and in slowly proliferating tumours only after anthracycline-including regimens. Conversely, following CMF, FCM-S was increased in 90% of the cases and 3H-dT LI in only 50%. Our data imply that the 2 proliferation indices could reflect different phenomena: an actual variation of proliferative activity by 3H-dT LI and an accumulation of cells in the S-phase by FCM-S. In addition, a higher accumulation of cells in G2-M phases could be detected by FCM after anthracycline-including regimens than after CMF. The fraction of P53-positive cells was reduced by primary chemotherapy in about 50% of P53-positive tumours, whereas Bcl-2 expression was only marginally affected. DNA ploidy and hormone receptor status did not change in about 75% of cases, regardless of the chemotherapeutic regimen.

Aneuploidy↗