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Elia Biganzoli

Publications and source records attributed to Elia Biganzoli.

13 recordsLinked to original sources
PubMed2026

Global downstream BMP15 pathway analysis in human ovarian granulosa cells reveals novel genetic variations associated with primary ovarian insufficiency.

OBJECTIVES: Primary ovarian insufficiency (POI) is a fertility disorder with a well-established genetic component, but many cases still remain idiopathic. Approximately 1.5-12% of patients with POI can carry a variant in the BMP15 gene, depending on the population and the diagnostic criteria. We hypothesize that genetic variations within pathways downstream of BMP15 activity in ovarian granulosa cells (GCs) may contribute to unexplained cases of POI. The main goal of this study is to identify novel variants associated with POI in genes induced by BMP15 in GCs. STUDY DESIGN: Primary cultures of human GCs were stimulated with recombinant human BMP15. Microarray analysis profiled the BMP15-induced transcriptome in GCs. Validation was achieved by qPCR and immunoblot. Further, target exome sequencing of the differentially expressed genes was performed on 64 women with early POI onset in search of novel variants. MAIN OUTCOME MEASURES: Transcriptome profiling of human GCs stimulated with BMP15 and target exome sequencing in women with early onset of POI. RESULTS: Transcriptome analysis revealed significant upregulation of 19 genes (p&#xa0;<&#xa0;0.05). Ontology analysis of these genes converged towards two main pathways: TGF-beta signaling and regulation of stem cell pluripotency. Target exome sequencing identified six novel rare variants in five BMP15-induced genes (SAMD11, SMAD6, ID1, USP35, GPCR137C) in 9 of the 64 women with early POI (14%). CONCLUSIONS: BMP15 action in human ovarian GCs defines TGF-beta signaling and pluripotency fate in ovarian follicles. In addition, this study uncovers new potential candidate genes for the pathogenesis of POI.

Humans↗
PubMed2006

Axillary lymph node nanometastases are prognostic factors for disease-free survival and metastatic relapse in breast cancer patients.

PURPOSE: Early breast cancer presents with a remarkable heterogeneity of outcomes. Undetected, microscopic lymph node tumor deposits may account for a significant fraction of this prognostic diversity. Thus, we systematically evaluated the presence of lymph node tumor cell deposits<or=0.2 mm in diameter [pN0(i+), nanometastases] and analyzed their prognostic effect. EXPERIMENTAL DESIGN: Single-institution, consecutive patients with 8 years of median follow-up (n=702) were studied. To maximize chances of detecting micrometastases and nanometastases, whole-axilla dissections were analyzed. pN0 cases (n=377) were systematically reevaluated by lymph node (n=6676) step-sectioning and anticytokeratin immunohistochemical analysis. The risk of first adverse events and of distant relapse of bona fide pN0 patients was compared with that of pN0(i+), pN1mi, and pN1 cases. RESULTS: Minimal lymph node deposits were revealed in 13% of pN0 patients. The hazard ratio for all adverse events of pN0(i+) versus pN0(i-) was 2.51 (P=0.00019). Hazards of pN1mi and pN0(i+) cases were not significantly different. A multivariate Cox model showed a hazard ratio of 2.16 for grouped pN0(i+)/pN1mi versus pN0(i-) (P=0.0005). Crude cumulative incidence curves for metastatic relapse were also significantly different (Gray's test chi2=5.54, P=0.019). CONCLUSION: Nanometastases are a strong risk factor for disease-free survival and for metastatic relapse. These findings support the inclusion of procedures for nanometastasis detection in tumor-node-metastasis staging.

Adult↗
PubMed2006

Allometric scaling law questions the traditional mechanical model for axillary lymph node involvement in breast cancer.

PURPOSE: To find a quantitative relationship between tumor size and frequency of axillary lymph node involvement. PATIENTS AND METHODS: The frequency of axillary node involvement versus primary tumor volume was analyzed in 10 selected series of patients incorporating a total of 57,244 women with resectable breast cancer. The average number of events per unit volume resulting in tumor spread to axillary lymph nodes before tumor surgical removal Theta(V)/V, was estimated under simple probabilistic assumptions. RESULTS: The allometric scaling law Theta(V)/V = 0.0586V(-0.7457) was estimated on the data, fitting the proportion of lymph node involvement on tumor volume V (in microliters). The estimate 0.7457 (95% CI, 0.7200 to 0.7713) suggests that the true scaling exponent, under the assumed model, may be the fractional value, which characterizes scaling relationships for a wide variety of biologic variables at both the whole organism level and organ level. CONCLUSION: Results suggest that the phenomenon should be related to some internal structural trait of the tumor. The vascular network seems to be the best candidate. This result does not support a mere mechanical model of lymphatic tumor spread. A more complex biology-based model of lymphohematogenous spread is suggested, in which the axillary nodes draining the lymph from the primary tumor may become activated by factors produced by both tumor cells and tumor stroma, thus favoring cell-selective homing of otherwise circulating tumor cells. The success of fractal features related to the internal architecture brings additional support to the consideration of primary breast cancer as an organ-like structure.

Axilla↗
PubMed2006

Molecular subtyping of breast cancer from traditional tumor marker profiles using parallel clustering methods.

PURPOSE: Recent small-sized genomic studies on the identification of breast cancer bioprofiles have led to profoundly dishomogenous results. Thus, we sought to identify distinct tumor profiles with possible clinical relevance based on clusters of immunohistochemical molecular markers measured on a large, single institution, case series. EXPERIMENTAL DESIGN: Tumor biological profiles were explored on 633 archival tissue samples analyzed by immunohistochemistry. Five validated markers were considered, i.e., estrogen receptors (ER), progesterone receptors (PR), Ki-67/MIB1 as a proliferation marker, HER2/NEU, and p53 in their original scale of measurement. The results obtained were analyzed by three different clustering algorithms. Four different indices were then used to select the different profiles (number of clusters). RESULTS: The best classification was obtained creating four clusters. Notably, three clusters were identified according to low, intermediate, and high ER/PR levels. A further subdivision in two biologically distinct subtypes was determined by the presence/absence of HER2/NEU and of p53. As expected, the cluster with high ER/PR levels was characterized by a much better prognosis and response to hormone therapy compared to that with the lowest ER/PR values. Notably, the cluster characterized by high HER2/NEU levels showed intermediate prognosis, but a rather poor response to hormone therapy. CONCLUSIONS: Our results show the possibility of profiling breast cancers by means of traditional markers, and have novel clinical implications on the definition of the prognosis of cancer patients. These findings support the existence of a tumor subtype that responds poorly to hormone therapy, characterized by HER2/NEU overexpression.

Adult↗
PubMed2006

In vivo T-cell immune response against anaplastic lymphoma kinase in patients with anaplastic large cell lymphomas.

BACKGROUND AND OBJECTIVES: Anaplastic lymphoma kinase (ALK) oncogenic fusion proteins, expressed in about 60% of anaplastic large cell lymphomas (ALCL), are tumor-specific molecular targets for such a malignancy. One of the promising ALK-targeted therapeutic options is cancer vaccination. In this study, we investigate whether ALK is a tumor-associated antigen suitable for immune interventions. DESIGN AND METHODS: The frequency and the functional phenotype of the anti-ALK CD8 precursor repertoire in freshly isolated peripheral blood mononuclear cells (PBMC) from healthy donors and ALK-positive patients were determined by major histocompatibility complex (MHC)/tetrameric analyses. The anti-ALK secondary immune responses were evaluated as PBMC-specific interferon (INF-gamma) release by ELISPOT. In addition, the ability of the anti-ALK immune response to specifically lyse ALK-positive lymphoma cells was investigated by in vitro stimulation with ALK-derived peptide p280-89. RESULTS: Tetrameric MHC/peptide complexes revealed high frequencies of CD8/ALK-tetramer-positive cells both in patients and in healthy individuals. However, the functional phenotype of the CD8/ALK-tetramer-positive lymphocytes showed the presence of effector and memory T lymphocytes only in patients. The anti-ALK cytotoxic T lymphocytes (CTL) of patients, but not healthy donors, displayed thresholds of activation comparable to those of CTL precursors of a recall antigen (influenza virus). A polyclonal ALK-specific tumor-reactive T-cell line was isolated from patients' peripheral blood lymphocytes. INTERPRETATION AND CONCLUSIONS: The presence of an anti-ALK effector/memory lymphocyte population in the peripheral blood of ALK-positive patients indicates an in vivo antigenic challenge. Thus, ALK is a lymphoma-associated antigen suitable for immune interventions. The high number of anti-ALK memory CD8 T cells present in patients' PBMC may represent a valid source of activated CTL suitable for cancer cell lysis.

Anaplastic Lymphoma Kinase↗
PubMed2005

A time-dependent discrimination index for survival data.

To derive models suitable for outcome prediction, a crucial aspect is the availability of appropriate measures of predictive accuracy, which have to be usable for a general class of models. The Harrell's C discrimination index is an extension of the area under the ROC curve to the case of censored survival data, which owns a straightforward interpretability. For a model including covariates with time-dependent effects and/or time-dependent covariates, the original definition of C would require the prediction of individual failure times, which is not generally addressed in most clinical applications. Here we propose a time-dependent discrimination index Ctd where the whole predicted survival function is utilized as outcome prediction, and the ability to discriminate among subjects having different outcome is summarized over time. Ctd is based on a novel definition of concordance: a subject who developed the event should have a less predicted probability of surviving beyond his/her survival time than any subject who survived longer. The predicted survival function of a subject who developed the event is compared to: (1) that of subjects who developed the event before his/her survival time, and (2) that of subjects who developed the event, or were censored, after his/her survival time. Subjects who were censored are involved in comparisons with subjects who developed the event before their observed times. The index reduces to the previous C in the presence of separation between survival curves on the whole follow-up. A confidence interval for Ctd is derived using the jackknife method on correlated one-sample U-statistics.The proposed index is used to evaluate the discrimination ability of a model, including covariates having time-dependent effects, concerning time to relapse in breast cancer patients treated with adjuvant tamoxifen. The model was obtained from 596 patients entered prospectively at Istituto Nazionale per lo Studio e la Cura dei Tumori di Milano (INT). The model discrimination ability was validated on an independent testing data set of 175 patients provided by Centro Regionale Indicatori Biochimici di Tumore (CRIBT) in Venice.

Breast Neoplasms↗
PubMed2005

Randomized trial of fenretinide (4-HPR) to prevent recurrences, new localizations and carcinomas in patients operated on for oral leukoplakia: long-term results.

We assessed the efficacy of fenretinide at preventing relapses, new lesions and carcinomas after surgical excision of oral leukoplakia. In a controlled multicenter study, 170 patients operated on for oral leukoplakias with benign postoperative histology were randomized to 200 mg fenretinide daily for 1 year vs. no intervention. Preliminary analysis indicated that fenretinide had good tolerability and was effective at preventing relapses and new lesions during treatment. Analysis after 5-year follow-up suggested that fenretinide protected against relapses and new lesions up to 19 months after randomization, with both limits of the 95% hazard ratio CI for fenretinide vs. control below 1 for 7 months after randomization. There was also a protective effect against all first events, including cancer, for 25 months, with both limits of the 95% CI below 1 up to 11 months after randomization. Subsequently, risk ratio estimates were unstable. Fenretinide was well tolerated and effective at preventing relapses and new leukoplakias during treatment and after. The trial had to be stopped prematurely for very low recruitment and had insufficient power to reveal any protective effect against oral carcinoma; nevertheless, continuing studies on this promising chemopreventive are justified.

Adult↗
PubMed2005

Multiple correspondence analysis in S-PLUS.

Multiple correspondence analysis (MCA) is a multivariate method for analyzing multidimensional contingency tables. General software procedures to perform MCA are available. Among them SAS Proc CORRESP, SPAD CORMU procedure and the mca function of the MASS library in S-PLUS are probably the most used. However, CORRESP and CORMU output is different from that of mca function. The aim of this short note is showing how to obtain from mca function results compatible with those achieved with SAS or SPAD. A modified code is proposed in order to obtain the same coordinate system computed by SAS and SPAD. Moreover, the computation of the contributions of the levels of the factors to the inertia explained by each axis, the squared cosine of each factor level and the re-evaluation of the inertia explained by each axis have been added in order to improve the interpretations of the results of the decomposition.

Programming Languages↗
PubMed2003

HER2 overexpression and doxorubicin in adjuvant chemotherapy for resectable breast cancer.

PURPOSE: Human epidermal growth factor receptor 2 (HER2) overexpression was found to predict a good response in breast carcinoma patients treated with doxorubicin (Adriamycin [ADM]). Evidence from our recent study indicates that node-positive patients respond to cyclophosphamide, methotrexate, and fluorouracil (CMF) regardless of HER2 status. We address the issue of whether therapy regimens including CMF and ADM versus CMF alone have the same therapeutic effect in patients with HER2+ and HER2- tumors in terms of relapse-free survival (RFS) and overall survival (OS). METHODS: Archival specimens of the primary tumors from 506 patients in a prospective clinical trial were stained with the anti-HER2 monoclonal antibody CB11. Originally, patients were randomly allocated to receive either 12 courses of intravenous CMF or eight courses of the same regimen followed by four cycles of ADM. RFS and OS were analyzed by a Cox model taking into account treatment, HER2 status, and the interaction between treatment and HER2 status, adjusting for the effect of other known clinical and biopathologic factors. RESULTS: Analysis of survival rates indicates a possible differential effect of treatment in the patients grouped according to HER2 status. Improved RFS and OS were observed in the HER2+ subgroup after treatment with CMF plus ADM versus CMF alone. With a median follow-up of 15 years, the hazard ratio (HR) for RFS was 0.83 in HER2+ tumors and 1.22 in HER2- tumors. The effect of treatment was more evident on OS in HER2+ patients (HR = 0.61; CI, 0.32 to 1.16) than in HER2- patients (HR = 1.26). CONCLUSION: Our data indicate that adding ADM to CMF might be beneficial for patients with HER2+ tumors.

Adult↗
PubMed2002

A general framework for neural network models on censored survival data.

Flexible parametric techniques for regression analysis, such as those based on feed forward artificial neural networks (FFANNs), can be useful for the statistical analysis of censored time data. These techniques are of particular interest for the study of the outcome dependence from several variables measured on a continuous scale, since they allow for the detection of complex non-linear and non-additive effects. Few efforts have been made until now to account for censored times in FFANNs. In the attempt to fill this gap, specific error functions and data representation will be introduced for multilayer perceptron and radial basis function extensions of generalized linear models for survival data.

Humans↗
PubMedDate not supplied

A comparative study of the toxicity of mercury dichloride and methylmercury, assayed by the Frog Embryo Teratogenesis Assay--Xenopus (FETAX).

The Frog Embryo Teratogenesis Assay-Xenopus (FETAX) is a powerful and flexible bioassay that makes use of the embryos of the anuran amphibian Xenopus laevis. The FETAX can detect xenobiotics that affect embryonic development, when mortality, teratogenicity and growth inhibition are used as endpoints. The FETAX was used to compare the embryotoxic and teratogenic potentials of two chemical species of mercury, inorganic mercury(II) chloride (HgCl2) and organic methylmercury chloride (MeHgCl). A higher toxicity of MeHgCl (the estimated median lethal concentration [LC50] and median teratogenic concentration [TC50] were 0.313microM and 0.236microM, respectively) over HgCl2, with estimated LC50 and TC50 values of 0.601microM and 0.513microM, respectively). On the basis of these results, HgCl2 and MeHgCl can be classified as "slightly teratogenic compounds", as the ratio of LC50/TC50 is less than 1.5. There was a significant deviation from the commonly described monotonic behaviour of the concentration-response curves, suggesting a hormetic effect of both species of mercury. Uptake experiments, followed by neutron activation analysis, showed a higher incorporation of mercury in embryos exposed to MeHgCl compared with those exposed to HgCl2. Interestingly, Hg- exposed embryos showed a higher content of selenium and zinc than did control embryos.

Abnormalities, Drug-Induced↗