P. Casalini - Academia.edu (original) (raw)

Papers by P. Casalini

European Journal of Cancer Supplements, 2008

Anticancer research

Polyomaviruses are expressed in both human tumors and immunodepressed patients. Malignant and non... more Polyomaviruses are expressed in both human tumors and immunodepressed patients. Malignant and nonmalignant pleural effusions create an environment that could favor the expression of opportunistic viral infections. We studied if SV40, JC, and BK viral DNA can be amplified from biopsies obtained from different pleural diseases. DNA was extracted from mesotheliomas (MM), nonspecific inflammatory and tubercular pleural biopsies, blood and urinary sediments from patients with MM, and pleural effusion cytological specimens. SV40, JC and BK viral early regions were amplified by PCR and analyzed by Southern Blot hybridization with specific probes. SV40 was positive in 9/23 MM, 5/18 tubercular and 1/7 nonspecific inflammatory biopsies, and 5/12 pleural effusion cytological specimens. JC was positive in 2/23 MM and in 7/15 urinary sediments. All blood samples were negative and BK was also negative in all samples. Tissue specific factors, characteristic of MM and TB, may contribute to expressi...

British Journal of Haematology, 1995

Lymphocyte activation antigens, such as CD30, rcpresent suitable target molecules for antibody-dr... more Lymphocyte activation antigens, such as CD30, rcpresent suitable target molecules for antibody-driven drug delivery in haemopoietic malignancies. A ribosomeinactivating protein (RIP) type 1 of potential interest for mAb targeting is gelonin, which displays a lower toxicity, as compared to other RIPs. In this study, two anti-CD30/antigelonin bispecific monoclonal antibodies (bimAbs), secreted by hybrid hybridomas, were used to deliver this RIP to CD30+ tumour cells. The two bimAbs, termed D4 and A18, were produced using the same anti-CD30 mAb and two anti-gelonin mAbs, directed to unrelated epitopes of the gelonin molecule. These bimAbs enhanced gelonin toxicity (ICs0 5 x M, in the absence of mAbs) against the CD30+ L540 Hodgkii's lymphoma cell line in a protein synthesis inhibition assay. Thus, in the presence of M D4 bimAb, protein synthesis was inhibited with an ICso of 5 x 1 0 -l '~ as gelonin, whereas with A18 bimAb the ICs0 was 8 x lo-" M. More interestingly, the combined use of the two bimAbs had a synergistic effect, since the lCso of gelonin reached 6 x 1 0 -I '~. Among CD30 tumour cell lines, the Hodgkin's lymphoma L428 was also sensitive to gelonin delivered by bimAbs (IC50 6 x lo-" M), whereas the COLE Hodgkin's cell line and the T-ALI. Jurkat were completely resistant to the toxic effect of gelonin and bimAbs. COLE and Jurkat cells were also resistant to a gelonin/anti-CD30 conventional immunotoxin, whereas they were sensitive to a saporin/anti-CD30 immunotoxin. This suggests that the resistance to gelonin is not related to a lack of internalization through the CD30 molecule but is associated with some property of the RIP.

Journal of B.U.ON. : official journal of the Balkan Union of Oncology, 2009

Every cellular process is likely to be regulated by microRNAs (miRNAs), and an aberrant expressio... more Every cellular process is likely to be regulated by microRNAs (miRNAs), and an aberrant expression signature of these small non-coding RNAs is a hallmark of several diseases, including cancer. miRNA expression profiling by microarray techniques has provided a powerful tool to reveal the involvement of these tiny molecules in tumor development and progression, showing that they are differentially expressed in tumors as compared to normal tissues. Moreover, specific miRNA signatures have been associated with histopathological and clinical features, suggesting a potential role of these molecules as prognostic and predictive markers. Focusing then on their biological effects and role in cancer, it has been shown that miRNAs can function as potential oncogenes or oncosuppressor genes, depending on the cellular context and on the target genes they regulate. The possibility to modulate miRNA expression either in vitro and in vivo by developing synthetic pre-miRNA molecules or antisense oli...

British journal of cancer, 1998

Pretargeting techniques using the avidin-biotin system have shown encouraging results in both dia... more Pretargeting techniques using the avidin-biotin system have shown encouraging results in both diagnostic and therapeutic clinical trials. It has been shown that in cancer therapy the ideal agent to be used for pretargeting should have a plasma half-life longer than avidin and lower immunogenicity than streptavidin in order for these procedures to be applied safely and repeatedly in patients. We prepared a recombinant form of avidin with no carbohydrates and avidins, biochemically modified either by decreasing the positive charges with succinic anhydride or by linking polyethylene glycol (PEG) at three different molar ratios and evaluated their in vivo behaviour after i.p. administration in mice. The succinylation and PEGylation of avidin increased the plasma half-life proportionally to the degree of protein modification. The procedures, however, affected the biotin binding to some extent. The biodistribution studies showed that, for all six time points (ranging from 20 min to 18 h p...

Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2011

Molecular Cancer Therapeutics, 2009

The retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), a metabolite of fenretinide (4-HP... more The retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), a metabolite of fenretinide (4-HPR) present in plasma of 4-HPR-treated patients, is very effective in inducing growth inhibition and apoptosis in several cancer cell lines. 4-Oxo-4-HPR and 4-HPR have different mechanisms of action because 4-oxo-4-HPR, unlike 4-HPR, causes marked cell accumulation in G2-M phase. Here, we investigated the molecular events involving 4-oxo-4-HPR-induced cell cycle perturbation in ovarian (A2780 and IGROV-1) and breast (T47D, estrogen receptor+ and BT-20, estrogen receptor-) cancer cells. 4-Oxo-4-HPR induced a delay of mitosis (with mitotic index increasing 5- to 6-fold in all cell lines) without progression beyond the anaphase, as shown by cyclin B1 expression. 4-Oxo-4-HPR induced multipolar spindle formation and phosphorylation of BUBR1, resulting in activation of the spindle checkpoint. Multipolar spindles were not due to impairment of pole-focusing process, loss of centrosome integrity, or modulation of the expression levels of molecules associated with spindle aberrations (Kif 1C, Kif 2A, Eg5, Tara, tankyrase-1, centractin, and TOGp). We show here that 4-oxo-4-HPR targets microtubules because, in treated cells, it interfered with the reassembly of cold-depolymerized spindle microtubules and decreased the polymerized tubulin fraction. In cell-free assays, 4-oxo-4-HPR inhibited tubulin polymerization (50% inhibition of microtubule assembly at 5.9 micromol/L), suggesting a direct molecular interaction with tubulin. In conclusion, by showing that 4-oxo-4-HPR causes mitotic arrest through antimicrotubule activities, we delineate a new molecular mechanism for a retinoid.

European Journal of Surgical Oncology (EJSO), 2013

It has recently been reported that, using axillary reverse mapping (ARM), the lymphatics from the... more It has recently been reported that, using axillary reverse mapping (ARM), the lymphatics from the arm can be spared to reduce the incidence of breast-cancer-related lymphoedema (BCRL). The aim of this study was to assess the feasibility of selective axillary dissection (SAD) after using ARM and partially preserving arm drainage, and to assess the occurrence of BCRL. Using a radioisotope and lymphoscintigraphy, ARM was performed in 60 patients scheduled for SAD, who were subsequently divided for the purpose of comparing the BCRL rates into: group A, comprising 45 patients who successfully underwent SAD with a residual lymphatic hot spot; and group B with 15 whose hot nodes were removed as is normally the case during complete axillary lymph node dissection (ALND). SAD was feasible in 75% of the 60 patients. SAD was completed successfully in 19 of the first 30 patients, and in 26 of the second 30 patients (p = 0.072). The median follow-up was 16 months (6-36), during which 9 patients developed a BCRL, 4 in group A (9%) and 5 in group B (33%); p = 0.035. None of the patients had nodal relapses during the follow-up. Using a radioisotope enables an effective and safe SAD in a large proportion of patients. There was evidence of a trend to suggest a learning curve. The rate of BCRL after SAD was less than one third of the rate recorded after ALND, a result that should encourage the development of the former technique.

European Journal of Cancer Supplements, 2008

Endocrine-related cancer, 2005

The association between expression of the 67 kDa laminin receptor (67LR) and tumor aggressiveness... more The association between expression of the 67 kDa laminin receptor (67LR) and tumor aggressiveness has been convincingly demonstrated although the exact function of this molecule in the metastatic process has remained unclear. In this study, we tested whether the laminin-1, upon interaction with 67LR, promotes tumor cell aggressiveness; the investigation was based on: (i) the previous demonstration that soluble 67LR, as well as a 20-amino-acid peptide corresponding to the 67LR laminin binding site, changes the conformation of laminin upon interaction with this adhesion molecule and (ii) the known relevance of microenvironment remodeling by the tumor, leading to structural modification of extracellular matrix components in tumor progression. MDAMB231 breast carcinoma cells plated on peptide G-treated laminin-1 exhibited a polygonal array of actin filament bundles compared with cells seeded on native laminin-1 which presented the actin bundles organized as multiple cables parallel to m...

British journal of cancer, Jan 7, 2003

Examination of parity, age at menarche and at menopause by HER2 status in a large series of breas... more Examination of parity, age at menarche and at menopause by HER2 status in a large series of breast carcinomas showed a statistically significant increased-frequency of HER2-positive tumours in lower risk subgroups. The findings suggest a difference in the protective role of hormone-related risk factors between HER2-positive and -negative tumours.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 15, 2001

There is considerable interest in biologic markers able to predict the response of cancer patient... more There is considerable interest in biologic markers able to predict the response of cancer patients to therapy. HER2 overexpression is a potential indicator of responsiveness to doxorubicin and paclitaxel and of unresponsiveness to tamoxifen in breast carcinoma patients. However, the significance of HER2 overexpression in responsiveness to cyclophosphamide, methotrexate, and fluorouracil (CMF) has remained unclear. In this study, we investigated this issue in the 386 breast cancer patients in the first CMF controlled clinical trial with a 20-year follow-up. Node-positive breast carcinoma patients were randomly assigned to receive either no further treatment after radical mastectomy (179 women) or 12 monthly cycles of adjuvant CMF chemotherapy (207 women). Overexpression of HER2 and the status of other tumor variables was assessed by immunohistochemistry in at least 324 (84%) of the 386 patients. Statistical analyses were performed to assess the efficacy of CMF treatment for the subgr...

Clinical cancer research : an official journal of the American Association for Cancer Research, 1999

We previously reported that a 660-bp sequence that is homologous to the env gene of the mouse mam... more We previously reported that a 660-bp sequence that is homologous to the env gene of the mouse mammary tumor virus (MMTV) but not to endogenous retroviruses or to other known genes was present in 38% of human breast cancers and in some breast cancer cell lines studied (Y. Wang et al., Cancer Res., 55: 5173-5179, 1995). Here, we have investigated whether the MMTV-like sequences were associated with the clinical, pathological, and molecular parameters that have been reported to define two subsets of human breast cancers. Archival breast carcinoma samples were analyzed for four clinical parameters, obtained from patients' records, and for six pathological characteristics. Expression of c-erbB-2, p53, bcl-2, progesterone receptor, laminin receptor, and cathepsin D was detected by immunochemistry using monoclonal antibodies. PCRs were used to amplify 250 bp of the MMTV env gene-like sequence. The chi2, log-rank, and generalized Wilcoxon tests were used to analyze the data. The MMTV en...

Clinical cancer research : an official journal of the American Association for Cancer Research, 1997

Infiltration by lymphoid cells is a common feature of many human tumors, including breast carcino... more Infiltration by lymphoid cells is a common feature of many human tumors, including breast carcinomas, and the degree of infiltration has been suggested to be a measure of the host immune response. Our analyses in a series of 1919 cases of primary ductal and lobular infiltrating breast carcinomas from women with a long-term follow-up revealed: (a) a 16-17% frequency of infiltrated tumors independent of the patient's age at diagnosis; and (b) a strong positive correlation between survival rates and the presence of lymphocytes at the tumor site in patients less than 40 years of age (P = 0.0002) but no association with prognosis in patients 40 years of age or older. Multivariate analysis indicated that lymphoid infiltration is independent of other conventional prognostic factors such as nodal status and tumor size in predicting survival. Thus, a possible immune response against the tumor seems to be relevant only in women with early-onset tumors. Because the immune system is functio...

FEBS letters, Jan 30, 1998

Analysis of the fate of the p185HER2 oncoprotein following activation by heregulin beta1 revealed... more Analysis of the fate of the p185HER2 oncoprotein following activation by heregulin beta1 revealed the induction of the tyrosine-phosphorylation, down-modulation, and polyubiquitination of p185HER2. Receptor ubiquitination was suppressed in cells treated with heregulin beta1 in the presence of sodium azide, an inhibitor of ATP-dependent reactions, or genistein, a tyrosine kinase protein inhibitor, indicating the requirement for kinase activity and ATP in p185HER2 polyubiquitination. Ubiquitinated p185HER2 was degradated by the 26S proteasome proteolytic pathway. Kinetics and inhibition experiments indicated that endocytosis of the receptor occurs downstream of the initiation of the degradation process.

Cancer research, 1994

The MOv18 (gamma 1, kappa) and MOv19 (gamma 2a, kappa) murine monoclonal antibodies (MAbs) recogn... more The MOv18 (gamma 1, kappa) and MOv19 (gamma 2a, kappa) murine monoclonal antibodies (MAbs) recognize different epitopes on the human folate binding receptor which is overexpressed on 90% of nonmucinous epithelial ovarian tumors. A chimeric murine-human (human gamma 1, kappa) version of both antibodies was constructed and expressed. The genes encoding the murine heavy and light chain variable regions of the MOv18 and MOv19 MAbs were cloned from the parental hybridomas, fused with genes encoding the human heavy (gamma 1) and light (kappa) chain constant regions, respectively, and expressed in the SP2/0 murine myeloma cell line. Using human peripheral blood mononuclear cells as effector cells and conditions that provide for maximum lysis (effector target = 50:1, saturating antibody concentration), the murine MOv18 MAb (IgG1) mediated variable levels of specific cytolysis of the target ovarian cancer cell line IGROV1. In contrast, the chimeric MOv18 MAb mediated higher and more consiste...

The Breast, 2011

A woman's risk of breast cancer is strongly affected by her reproductive history. The hormonal mi... more A woman's risk of breast cancer is strongly affected by her reproductive history. The hormonal milieu is also a key determinant of the course of the disease. Combining mouse genetics with tissue recombination techniques, we have established that the female reproductive hormones, estrogens, progesterone, and prolactin, act sequentially on the mammary epithelium to trigger distinct developmental steps. The hormones impinge directly on a subset of luminal mammary epithelial cells that express the respective hormone receptors and act as sensor cells translating and amplifying systemic signals into local stimuli. Local signaling is stage and age specific. During puberty, estrogens promote proliferation using the EGF family member, amphiregulin, as essential paracrine mediator. In adulthood, progesterone, rather than estrogen, is the major inducer of stem cell activation and cell proliferation of the mammary epithelium. Hormonal signaling modulates crucial developmental pathways that impinge on mammary stem cell populations, while Notch signaling, by inhibiting p63, is central to mammary cell fate determination. Cell proliferation occurs in two waves. The first results from direct stimulation of the small fraction of hormone receptor positive cells. It is followed by a second wave of progesterone-induced proliferation involving mostly hormone receptor negative cells, in which RANKL is a key mediator. A model in which repeated activation of paracrine signaling by progesterone with resulting stem cell activation promotes breast carcinogenesis is proposed.

European Journal of Cancer Supplements, 2010

To evaluate the outcomes of the PET detected hypermetabolic lesions in the lungs of breast cancer... more To evaluate the outcomes of the PET detected hypermetabolic lesions in the lungs of breast cancer patients, as correlated with follow up CT findings and to analyze the PET and CT findings of hypermetabolic lesions in PET-CT for differentiation benign from malignancy.

Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2015

Forkhead box P3 (FOXP3), a gene member of the forkhead/winged-helix family of transcription regul... more Forkhead box P3 (FOXP3), a gene member of the forkhead/winged-helix family of transcription regulators, is implicated in regulating immune system development and function. This gene has been found to be of crucial importance for the generation of CD4 + CD25 + regulatory T cells (Tregs). In addition to its expression in the lymphocyte lineage, studies have recently described FOXP3 expression in normal and cancer cells nonhematopoietic-derived, suggesting that FOXP3 exerts a broader function than that on Tregs. A role for FOXP3 as an onco-suppressor gene in human cancers has been suggested based on in vitro studies showing that FOXP3 is implicated in repressing various oncogenes and enhancing expression of tumorsuppressor genes. However, numerous studies in samples from human cancer patients showed a positive correlation between FOXP3 expression and poor prognosis, especially with metastasis. Further investigations are required to clarify the significance of FOXP3 expression in tumor cells and to identify the mechanisms by which it affects prognosis. Uva V, et al.

European Journal of Cancer Supplements, 2008

Anticancer research

Polyomaviruses are expressed in both human tumors and immunodepressed patients. Malignant and non... more Polyomaviruses are expressed in both human tumors and immunodepressed patients. Malignant and nonmalignant pleural effusions create an environment that could favor the expression of opportunistic viral infections. We studied if SV40, JC, and BK viral DNA can be amplified from biopsies obtained from different pleural diseases. DNA was extracted from mesotheliomas (MM), nonspecific inflammatory and tubercular pleural biopsies, blood and urinary sediments from patients with MM, and pleural effusion cytological specimens. SV40, JC and BK viral early regions were amplified by PCR and analyzed by Southern Blot hybridization with specific probes. SV40 was positive in 9/23 MM, 5/18 tubercular and 1/7 nonspecific inflammatory biopsies, and 5/12 pleural effusion cytological specimens. JC was positive in 2/23 MM and in 7/15 urinary sediments. All blood samples were negative and BK was also negative in all samples. Tissue specific factors, characteristic of MM and TB, may contribute to expressi...

British Journal of Haematology, 1995

Lymphocyte activation antigens, such as CD30, rcpresent suitable target molecules for antibody-dr... more Lymphocyte activation antigens, such as CD30, rcpresent suitable target molecules for antibody-driven drug delivery in haemopoietic malignancies. A ribosomeinactivating protein (RIP) type 1 of potential interest for mAb targeting is gelonin, which displays a lower toxicity, as compared to other RIPs. In this study, two anti-CD30/antigelonin bispecific monoclonal antibodies (bimAbs), secreted by hybrid hybridomas, were used to deliver this RIP to CD30+ tumour cells. The two bimAbs, termed D4 and A18, were produced using the same anti-CD30 mAb and two anti-gelonin mAbs, directed to unrelated epitopes of the gelonin molecule. These bimAbs enhanced gelonin toxicity (ICs0 5 x M, in the absence of mAbs) against the CD30+ L540 Hodgkii's lymphoma cell line in a protein synthesis inhibition assay. Thus, in the presence of M D4 bimAb, protein synthesis was inhibited with an ICso of 5 x 1 0 -l '~ as gelonin, whereas with A18 bimAb the ICs0 was 8 x lo-" M. More interestingly, the combined use of the two bimAbs had a synergistic effect, since the lCso of gelonin reached 6 x 1 0 -I '~. Among CD30 tumour cell lines, the Hodgkin's lymphoma L428 was also sensitive to gelonin delivered by bimAbs (IC50 6 x lo-" M), whereas the COLE Hodgkin's cell line and the T-ALI. Jurkat were completely resistant to the toxic effect of gelonin and bimAbs. COLE and Jurkat cells were also resistant to a gelonin/anti-CD30 conventional immunotoxin, whereas they were sensitive to a saporin/anti-CD30 immunotoxin. This suggests that the resistance to gelonin is not related to a lack of internalization through the CD30 molecule but is associated with some property of the RIP.

Journal of B.U.ON. : official journal of the Balkan Union of Oncology, 2009

Every cellular process is likely to be regulated by microRNAs (miRNAs), and an aberrant expressio... more Every cellular process is likely to be regulated by microRNAs (miRNAs), and an aberrant expression signature of these small non-coding RNAs is a hallmark of several diseases, including cancer. miRNA expression profiling by microarray techniques has provided a powerful tool to reveal the involvement of these tiny molecules in tumor development and progression, showing that they are differentially expressed in tumors as compared to normal tissues. Moreover, specific miRNA signatures have been associated with histopathological and clinical features, suggesting a potential role of these molecules as prognostic and predictive markers. Focusing then on their biological effects and role in cancer, it has been shown that miRNAs can function as potential oncogenes or oncosuppressor genes, depending on the cellular context and on the target genes they regulate. The possibility to modulate miRNA expression either in vitro and in vivo by developing synthetic pre-miRNA molecules or antisense oli...

British journal of cancer, 1998

Pretargeting techniques using the avidin-biotin system have shown encouraging results in both dia... more Pretargeting techniques using the avidin-biotin system have shown encouraging results in both diagnostic and therapeutic clinical trials. It has been shown that in cancer therapy the ideal agent to be used for pretargeting should have a plasma half-life longer than avidin and lower immunogenicity than streptavidin in order for these procedures to be applied safely and repeatedly in patients. We prepared a recombinant form of avidin with no carbohydrates and avidins, biochemically modified either by decreasing the positive charges with succinic anhydride or by linking polyethylene glycol (PEG) at three different molar ratios and evaluated their in vivo behaviour after i.p. administration in mice. The succinylation and PEGylation of avidin increased the plasma half-life proportionally to the degree of protein modification. The procedures, however, affected the biotin binding to some extent. The biodistribution studies showed that, for all six time points (ranging from 20 min to 18 h p...

Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2011

Molecular Cancer Therapeutics, 2009

The retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), a metabolite of fenretinide (4-HP... more The retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR), a metabolite of fenretinide (4-HPR) present in plasma of 4-HPR-treated patients, is very effective in inducing growth inhibition and apoptosis in several cancer cell lines. 4-Oxo-4-HPR and 4-HPR have different mechanisms of action because 4-oxo-4-HPR, unlike 4-HPR, causes marked cell accumulation in G2-M phase. Here, we investigated the molecular events involving 4-oxo-4-HPR-induced cell cycle perturbation in ovarian (A2780 and IGROV-1) and breast (T47D, estrogen receptor+ and BT-20, estrogen receptor-) cancer cells. 4-Oxo-4-HPR induced a delay of mitosis (with mitotic index increasing 5- to 6-fold in all cell lines) without progression beyond the anaphase, as shown by cyclin B1 expression. 4-Oxo-4-HPR induced multipolar spindle formation and phosphorylation of BUBR1, resulting in activation of the spindle checkpoint. Multipolar spindles were not due to impairment of pole-focusing process, loss of centrosome integrity, or modulation of the expression levels of molecules associated with spindle aberrations (Kif 1C, Kif 2A, Eg5, Tara, tankyrase-1, centractin, and TOGp). We show here that 4-oxo-4-HPR targets microtubules because, in treated cells, it interfered with the reassembly of cold-depolymerized spindle microtubules and decreased the polymerized tubulin fraction. In cell-free assays, 4-oxo-4-HPR inhibited tubulin polymerization (50% inhibition of microtubule assembly at 5.9 micromol/L), suggesting a direct molecular interaction with tubulin. In conclusion, by showing that 4-oxo-4-HPR causes mitotic arrest through antimicrotubule activities, we delineate a new molecular mechanism for a retinoid.

European Journal of Surgical Oncology (EJSO), 2013

It has recently been reported that, using axillary reverse mapping (ARM), the lymphatics from the... more It has recently been reported that, using axillary reverse mapping (ARM), the lymphatics from the arm can be spared to reduce the incidence of breast-cancer-related lymphoedema (BCRL). The aim of this study was to assess the feasibility of selective axillary dissection (SAD) after using ARM and partially preserving arm drainage, and to assess the occurrence of BCRL. Using a radioisotope and lymphoscintigraphy, ARM was performed in 60 patients scheduled for SAD, who were subsequently divided for the purpose of comparing the BCRL rates into: group A, comprising 45 patients who successfully underwent SAD with a residual lymphatic hot spot; and group B with 15 whose hot nodes were removed as is normally the case during complete axillary lymph node dissection (ALND). SAD was feasible in 75% of the 60 patients. SAD was completed successfully in 19 of the first 30 patients, and in 26 of the second 30 patients (p = 0.072). The median follow-up was 16 months (6-36), during which 9 patients developed a BCRL, 4 in group A (9%) and 5 in group B (33%); p = 0.035. None of the patients had nodal relapses during the follow-up. Using a radioisotope enables an effective and safe SAD in a large proportion of patients. There was evidence of a trend to suggest a learning curve. The rate of BCRL after SAD was less than one third of the rate recorded after ALND, a result that should encourage the development of the former technique.

European Journal of Cancer Supplements, 2008

Endocrine-related cancer, 2005

The association between expression of the 67 kDa laminin receptor (67LR) and tumor aggressiveness... more The association between expression of the 67 kDa laminin receptor (67LR) and tumor aggressiveness has been convincingly demonstrated although the exact function of this molecule in the metastatic process has remained unclear. In this study, we tested whether the laminin-1, upon interaction with 67LR, promotes tumor cell aggressiveness; the investigation was based on: (i) the previous demonstration that soluble 67LR, as well as a 20-amino-acid peptide corresponding to the 67LR laminin binding site, changes the conformation of laminin upon interaction with this adhesion molecule and (ii) the known relevance of microenvironment remodeling by the tumor, leading to structural modification of extracellular matrix components in tumor progression. MDAMB231 breast carcinoma cells plated on peptide G-treated laminin-1 exhibited a polygonal array of actin filament bundles compared with cells seeded on native laminin-1 which presented the actin bundles organized as multiple cables parallel to m...

British journal of cancer, Jan 7, 2003

Examination of parity, age at menarche and at menopause by HER2 status in a large series of breas... more Examination of parity, age at menarche and at menopause by HER2 status in a large series of breast carcinomas showed a statistically significant increased-frequency of HER2-positive tumours in lower risk subgroups. The findings suggest a difference in the protective role of hormone-related risk factors between HER2-positive and -negative tumours.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 15, 2001

There is considerable interest in biologic markers able to predict the response of cancer patient... more There is considerable interest in biologic markers able to predict the response of cancer patients to therapy. HER2 overexpression is a potential indicator of responsiveness to doxorubicin and paclitaxel and of unresponsiveness to tamoxifen in breast carcinoma patients. However, the significance of HER2 overexpression in responsiveness to cyclophosphamide, methotrexate, and fluorouracil (CMF) has remained unclear. In this study, we investigated this issue in the 386 breast cancer patients in the first CMF controlled clinical trial with a 20-year follow-up. Node-positive breast carcinoma patients were randomly assigned to receive either no further treatment after radical mastectomy (179 women) or 12 monthly cycles of adjuvant CMF chemotherapy (207 women). Overexpression of HER2 and the status of other tumor variables was assessed by immunohistochemistry in at least 324 (84%) of the 386 patients. Statistical analyses were performed to assess the efficacy of CMF treatment for the subgr...

Clinical cancer research : an official journal of the American Association for Cancer Research, 1999

We previously reported that a 660-bp sequence that is homologous to the env gene of the mouse mam... more We previously reported that a 660-bp sequence that is homologous to the env gene of the mouse mammary tumor virus (MMTV) but not to endogenous retroviruses or to other known genes was present in 38% of human breast cancers and in some breast cancer cell lines studied (Y. Wang et al., Cancer Res., 55: 5173-5179, 1995). Here, we have investigated whether the MMTV-like sequences were associated with the clinical, pathological, and molecular parameters that have been reported to define two subsets of human breast cancers. Archival breast carcinoma samples were analyzed for four clinical parameters, obtained from patients' records, and for six pathological characteristics. Expression of c-erbB-2, p53, bcl-2, progesterone receptor, laminin receptor, and cathepsin D was detected by immunochemistry using monoclonal antibodies. PCRs were used to amplify 250 bp of the MMTV env gene-like sequence. The chi2, log-rank, and generalized Wilcoxon tests were used to analyze the data. The MMTV en...

Clinical cancer research : an official journal of the American Association for Cancer Research, 1997

Infiltration by lymphoid cells is a common feature of many human tumors, including breast carcino... more Infiltration by lymphoid cells is a common feature of many human tumors, including breast carcinomas, and the degree of infiltration has been suggested to be a measure of the host immune response. Our analyses in a series of 1919 cases of primary ductal and lobular infiltrating breast carcinomas from women with a long-term follow-up revealed: (a) a 16-17% frequency of infiltrated tumors independent of the patient's age at diagnosis; and (b) a strong positive correlation between survival rates and the presence of lymphocytes at the tumor site in patients less than 40 years of age (P = 0.0002) but no association with prognosis in patients 40 years of age or older. Multivariate analysis indicated that lymphoid infiltration is independent of other conventional prognostic factors such as nodal status and tumor size in predicting survival. Thus, a possible immune response against the tumor seems to be relevant only in women with early-onset tumors. Because the immune system is functio...

FEBS letters, Jan 30, 1998

Analysis of the fate of the p185HER2 oncoprotein following activation by heregulin beta1 revealed... more Analysis of the fate of the p185HER2 oncoprotein following activation by heregulin beta1 revealed the induction of the tyrosine-phosphorylation, down-modulation, and polyubiquitination of p185HER2. Receptor ubiquitination was suppressed in cells treated with heregulin beta1 in the presence of sodium azide, an inhibitor of ATP-dependent reactions, or genistein, a tyrosine kinase protein inhibitor, indicating the requirement for kinase activity and ATP in p185HER2 polyubiquitination. Ubiquitinated p185HER2 was degradated by the 26S proteasome proteolytic pathway. Kinetics and inhibition experiments indicated that endocytosis of the receptor occurs downstream of the initiation of the degradation process.

Cancer research, 1994

The MOv18 (gamma 1, kappa) and MOv19 (gamma 2a, kappa) murine monoclonal antibodies (MAbs) recogn... more The MOv18 (gamma 1, kappa) and MOv19 (gamma 2a, kappa) murine monoclonal antibodies (MAbs) recognize different epitopes on the human folate binding receptor which is overexpressed on 90% of nonmucinous epithelial ovarian tumors. A chimeric murine-human (human gamma 1, kappa) version of both antibodies was constructed and expressed. The genes encoding the murine heavy and light chain variable regions of the MOv18 and MOv19 MAbs were cloned from the parental hybridomas, fused with genes encoding the human heavy (gamma 1) and light (kappa) chain constant regions, respectively, and expressed in the SP2/0 murine myeloma cell line. Using human peripheral blood mononuclear cells as effector cells and conditions that provide for maximum lysis (effector target = 50:1, saturating antibody concentration), the murine MOv18 MAb (IgG1) mediated variable levels of specific cytolysis of the target ovarian cancer cell line IGROV1. In contrast, the chimeric MOv18 MAb mediated higher and more consiste...

The Breast, 2011

A woman's risk of breast cancer is strongly affected by her reproductive history. The hormonal mi... more A woman's risk of breast cancer is strongly affected by her reproductive history. The hormonal milieu is also a key determinant of the course of the disease. Combining mouse genetics with tissue recombination techniques, we have established that the female reproductive hormones, estrogens, progesterone, and prolactin, act sequentially on the mammary epithelium to trigger distinct developmental steps. The hormones impinge directly on a subset of luminal mammary epithelial cells that express the respective hormone receptors and act as sensor cells translating and amplifying systemic signals into local stimuli. Local signaling is stage and age specific. During puberty, estrogens promote proliferation using the EGF family member, amphiregulin, as essential paracrine mediator. In adulthood, progesterone, rather than estrogen, is the major inducer of stem cell activation and cell proliferation of the mammary epithelium. Hormonal signaling modulates crucial developmental pathways that impinge on mammary stem cell populations, while Notch signaling, by inhibiting p63, is central to mammary cell fate determination. Cell proliferation occurs in two waves. The first results from direct stimulation of the small fraction of hormone receptor positive cells. It is followed by a second wave of progesterone-induced proliferation involving mostly hormone receptor negative cells, in which RANKL is a key mediator. A model in which repeated activation of paracrine signaling by progesterone with resulting stem cell activation promotes breast carcinogenesis is proposed.

European Journal of Cancer Supplements, 2010

To evaluate the outcomes of the PET detected hypermetabolic lesions in the lungs of breast cancer... more To evaluate the outcomes of the PET detected hypermetabolic lesions in the lungs of breast cancer patients, as correlated with follow up CT findings and to analyze the PET and CT findings of hypermetabolic lesions in PET-CT for differentiation benign from malignancy.

Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2015

Forkhead box P3 (FOXP3), a gene member of the forkhead/winged-helix family of transcription regul... more Forkhead box P3 (FOXP3), a gene member of the forkhead/winged-helix family of transcription regulators, is implicated in regulating immune system development and function. This gene has been found to be of crucial importance for the generation of CD4 + CD25 + regulatory T cells (Tregs). In addition to its expression in the lymphocyte lineage, studies have recently described FOXP3 expression in normal and cancer cells nonhematopoietic-derived, suggesting that FOXP3 exerts a broader function than that on Tregs. A role for FOXP3 as an onco-suppressor gene in human cancers has been suggested based on in vitro studies showing that FOXP3 is implicated in repressing various oncogenes and enhancing expression of tumorsuppressor genes. However, numerous studies in samples from human cancer patients showed a positive correlation between FOXP3 expression and poor prognosis, especially with metastasis. Further investigations are required to clarify the significance of FOXP3 expression in tumor cells and to identify the mechanisms by which it affects prognosis. Uva V, et al.