e15645 Background: Negligible advances for PC treatment have been done over the last decade and G... more e15645 Background: Negligible advances for PC treatment have been done over the last decade and G remains the standard. Proteolitic degradation of extracellular matrix (ECM) is essential for early local invasion, metastasis and desmoplastic reaction characterizing PC. Differently from MMPs, the serine proteases (uPA and TAT) action is earlier and larger, degradating not only ECM, but also basement membrane, and activating trypsin, plasmin, angiogenesis via TGF-β1 and proliferation via PAR-2. GM is an inhibitor of u-PA,TAT, trypsin and plasmin, used in Italy and Japan for prophylaxis of acute pancreatitis after ERCP. In a previous study, GM demonstrated antinvasion and antimetastatic activity. Study aim: to evaluate if GM increases G efficacy on pancreatic cancer cell line. Methods: In vitro study of phenotypic effects of GM and G in poor differentiated PANC-1 PC cell line using:1) Cell vitality test (Trypan blu);2) Invasion test (Matrigel invasion assay);3) Cell cycle analysis (cyto...
3694 Background: Bio-pathological studies of colorectal cancer (CRC) have provided informations i... more 3694 Background: Bio-pathological studies of colorectal cancer (CRC) have provided informations into pathogenesis, but it is unclear how important these markers are in predicting prognosis and in c...
Quadruple wild-type (WT) gastrointestinal stromal tumors (GIST) is a genomic subgroup lacking KIT... more Quadruple wild-type (WT) gastrointestinal stromal tumors (GIST) is a genomic subgroup lacking KIT/PDGFRA/RAS pathways mutations, with an intact succinate dehydrogenase (SDH) complex. The aim of this work is to perform a wide comprehensive genomic study on quadruple WT GIST to improve the characterization of these patients. We selected 14 clinical cases of quadruple WT GIST, of which nine cases showed sufficient DNA quality for Whole Exome Sequencing (WES). NF1 alterations were identified directly by WES. Gene expression from Whole Transcriptome Sequencing (WTS) and miRNA profiling were performed using fresh-frozen, quadruple WT GIST tissue specimens and compared to SDH and KIT/PDGFRAmutant GIST. WES identified an average of 18 somatic mutations per sample. The most relevant somatic oncogenic mutations identified were in TP53, MEN1, MAX, FGF1R, CHD4 and CTDNN2. No somatic alterations in NF1 were identified in the analyzed cohort. A total of 247 mRNA transcripts and 66 miRs were diffe...
Basal-like breast carcinoma is an aggressive form of breast cancer, characterized by the absence ... more Basal-like breast carcinoma is an aggressive form of breast cancer, characterized by the absence of oestrogen receptor and HER2 expression, the presence of cytokeratin 5 and epidermal growth factor receptor expression, and by the up-regulation of stem cell regulatory genes. We show here that tumour tissues expressing high levels of SLUG mRNA show a basal-like breast carcinoma phenotype and that such tumours also express high levels of stem cell-regulatory genes, ie CD133, Bmi1. Further, we show that stem/progenitor cells, isolated from ductal breast carcinoma and from normal mammary gland as mammospheres, express SLUG, CD133, and Bmi1 mRNA and show a phenotype similar to that of basal-like breast carcinoma. We also report that SLUG expression in tumour tissues correlates with that of the hypoxia survival gene carbonic anhydrase IX. In this regard, we report that the exposure of SLUG-negative/luminal-like MCF-7 cells to a hypoxic environment promotes the onset of the basal-like breast carcinoma phenotype, together with up-regulation of the SLUG gene, which in turn blunts oestrogen receptor-alpha and boosts carbonic anhydrase IX gene expression. Finally, we show that SLUG expression promotes the invasiveness of MCF-7 cells exposed to hypoxia and sustains the in vivo aggressiveness of hypoxia-selected, MCF-7-derived cells in xenografts. These data indicate that SLUG gene expression is part of a hypoxia-induced genetic programme which sets up a basal/stem cell-like, aggressive phenotype in breast cancer cells.
The epidermal growth factor receptor (EGFr) is considered a major target for treatment of colorec... more The epidermal growth factor receptor (EGFr) is considered a major target for treatment of colorectal cancer (CRC). We found a mean EGFr content significantly lower but more activated in colonic neoplastic tissue than in paired normal mucosa. Phosphorylated (pY1068) EGFr detection in CRC may be a better tool than EGFr detection to select patients for targeted therapies.
Gastrointestinal stromal tumors are malignancies originating from stromal/mesenchymal tissues, mo... more Gastrointestinal stromal tumors are malignancies originating from stromal/mesenchymal tissues, most commonly in the stomach and small intestine, although they can be located everywhere in the gastrointestinal tract. Diagnosis is based on histological and immunohistochemical examination, and these rare tumors are characterized by c-kit (CD117) staining. Complete removal of the tumor is often curative in localized gastrointestinal stromal tumors and is always recommended. Clinically, their behavior is difficult to predict, and mitotic count and tumor size seem to be the most effective prognostic factors. We performed a retrospective analysis of clinical presentation and course, surgical management and pathological features of patients with gastrointestinal stromal tumors treated in our institution from 1995 to 2003. Twenty-two patients were enrolled in the study, and all of them underwent surgery. There were two perioperative deaths, and global morbidity was about 13%. Nineteen patien...
Medical oncology (Northwood, London, England), 2012
In practice, relapses of gastrointestinal stromal tumours after long time of surgical resection o... more In practice, relapses of gastrointestinal stromal tumours after long time of surgical resection occur. However, few published data are available for duration, intensity and imaging sources of follow-up in radically excised patients with localized disease. Therefore, every single institution chooses the surveillance schedule according to its experience. The aim of this study was to describe the late recurrences of disease 5 years after the primary tumour's excision in a series of patients with recurrent GIST from our institution. We retrospectively reviewed 42 patients with "recurrent" GIST, collected since 2001. Ten patients were always followed at our institution, and 32 patients came to our attention at the time of recurrence. The analysed series were divided into two groups: patients who developed recurrence before 5 years and patients who developed recurrence 5 years after the primary tumour's excision. Among 42 patients, 36 patients developed the recurrence wi...
Large-scale studies have demonstrated that continuative treatment in advanced and adjuvant settin... more Large-scale studies have demonstrated that continuative treatment in advanced and adjuvant settings results in a gain-of-survival. However, the discontinuation, and the duration of treatment in disease-free patients who have undergone radical surgical resection of metastases from gastrointestinal stromal tumours (GISTs) have yet to be evaluated. We retrospectively reviewed 40 patients with advanced and recurrent GIST, included in our GIST database, focusing on patients (5 males and 2 females; median age 56 years) who continued medical treatment following radical surgical resection of metastatic lesions. Seven out of 40 patients underwent surgery and continued medical treatment following radical surgical resection of metastatic lesions. The duration of adjuvant therapy was 3, 12, 16, 24, 35, 37 and 52 months, respectively, with a median of 26 months. No patients discontinued therapy and all were disease-free at the final CT-scan evaluation. Considering that the discontinuation of ima...
Resistance to gemcitabine is one of the main causes of treatment failure in pancreatic cancer. Co... more Resistance to gemcitabine is one of the main causes of treatment failure in pancreatic cancer. Compelling evidences have shown the involvement of nuclear factor κB (NF-κB) activation in such phenomenon. The protease inhibitor gabexate mesilate has been shown to inhibit NF-κB. We here investigated if combined treatment with this drug could improve gemcitabine antitumoral efficacy in pancreatic cancer cells. The effect of gabexate mesilate and gemcitabine, both used at concentrations achievable in human plasma, was assessed on in vitro pancreatic cancer cell growth, invasion, and tumor angiogenesis. The molecular mechanism at the basis of these effects was also investigated. Gabexate mesilate significantly increased gemcitabine anti-invasive and antiangiogenic efficacy. This effect was related to inhibition of gemcitabine-induced NF-κB activation by gabexate mesilate, which prevented RelA/p65 nuclear translocation and resulted in metalloproteinase 2, metalloproteinase 9, vascular endothelial growth factor, and interleukin 8 down-regulation. Combined treatment with gabexate mesilate also inhibited gemcitabine-induced extracellular-regulated kinase 1/2 and AKT activation by increased expression of Raf kinase inhibitor protein and phosphatase and tensin homolog. Combined treatment with gabexate mesilate sensitizes pancreatic cancer cells to gemcitabine by inhibition of the NF-κB pathway. The efficacy of this therapeutic strategy in pancreatic cancer patients remains to be established and deserves future clinical investigation.
e15645 Background: Negligible advances for PC treatment have been done over the last decade and G... more e15645 Background: Negligible advances for PC treatment have been done over the last decade and G remains the standard. Proteolitic degradation of extracellular matrix (ECM) is essential for early local invasion, metastasis and desmoplastic reaction characterizing PC. Differently from MMPs, the serine proteases (uPA and TAT) action is earlier and larger, degradating not only ECM, but also basement membrane, and activating trypsin, plasmin, angiogenesis via TGF-β1 and proliferation via PAR-2. GM is an inhibitor of u-PA,TAT, trypsin and plasmin, used in Italy and Japan for prophylaxis of acute pancreatitis after ERCP. In a previous study, GM demonstrated antinvasion and antimetastatic activity. Study aim: to evaluate if GM increases G efficacy on pancreatic cancer cell line. Methods: In vitro study of phenotypic effects of GM and G in poor differentiated PANC-1 PC cell line using:1) Cell vitality test (Trypan blu);2) Invasion test (Matrigel invasion assay);3) Cell cycle analysis (cyto...
3694 Background: Bio-pathological studies of colorectal cancer (CRC) have provided informations i... more 3694 Background: Bio-pathological studies of colorectal cancer (CRC) have provided informations into pathogenesis, but it is unclear how important these markers are in predicting prognosis and in c...
Quadruple wild-type (WT) gastrointestinal stromal tumors (GIST) is a genomic subgroup lacking KIT... more Quadruple wild-type (WT) gastrointestinal stromal tumors (GIST) is a genomic subgroup lacking KIT/PDGFRA/RAS pathways mutations, with an intact succinate dehydrogenase (SDH) complex. The aim of this work is to perform a wide comprehensive genomic study on quadruple WT GIST to improve the characterization of these patients. We selected 14 clinical cases of quadruple WT GIST, of which nine cases showed sufficient DNA quality for Whole Exome Sequencing (WES). NF1 alterations were identified directly by WES. Gene expression from Whole Transcriptome Sequencing (WTS) and miRNA profiling were performed using fresh-frozen, quadruple WT GIST tissue specimens and compared to SDH and KIT/PDGFRAmutant GIST. WES identified an average of 18 somatic mutations per sample. The most relevant somatic oncogenic mutations identified were in TP53, MEN1, MAX, FGF1R, CHD4 and CTDNN2. No somatic alterations in NF1 were identified in the analyzed cohort. A total of 247 mRNA transcripts and 66 miRs were diffe...
Basal-like breast carcinoma is an aggressive form of breast cancer, characterized by the absence ... more Basal-like breast carcinoma is an aggressive form of breast cancer, characterized by the absence of oestrogen receptor and HER2 expression, the presence of cytokeratin 5 and epidermal growth factor receptor expression, and by the up-regulation of stem cell regulatory genes. We show here that tumour tissues expressing high levels of SLUG mRNA show a basal-like breast carcinoma phenotype and that such tumours also express high levels of stem cell-regulatory genes, ie CD133, Bmi1. Further, we show that stem/progenitor cells, isolated from ductal breast carcinoma and from normal mammary gland as mammospheres, express SLUG, CD133, and Bmi1 mRNA and show a phenotype similar to that of basal-like breast carcinoma. We also report that SLUG expression in tumour tissues correlates with that of the hypoxia survival gene carbonic anhydrase IX. In this regard, we report that the exposure of SLUG-negative/luminal-like MCF-7 cells to a hypoxic environment promotes the onset of the basal-like breast carcinoma phenotype, together with up-regulation of the SLUG gene, which in turn blunts oestrogen receptor-alpha and boosts carbonic anhydrase IX gene expression. Finally, we show that SLUG expression promotes the invasiveness of MCF-7 cells exposed to hypoxia and sustains the in vivo aggressiveness of hypoxia-selected, MCF-7-derived cells in xenografts. These data indicate that SLUG gene expression is part of a hypoxia-induced genetic programme which sets up a basal/stem cell-like, aggressive phenotype in breast cancer cells.
The epidermal growth factor receptor (EGFr) is considered a major target for treatment of colorec... more The epidermal growth factor receptor (EGFr) is considered a major target for treatment of colorectal cancer (CRC). We found a mean EGFr content significantly lower but more activated in colonic neoplastic tissue than in paired normal mucosa. Phosphorylated (pY1068) EGFr detection in CRC may be a better tool than EGFr detection to select patients for targeted therapies.
Gastrointestinal stromal tumors are malignancies originating from stromal/mesenchymal tissues, mo... more Gastrointestinal stromal tumors are malignancies originating from stromal/mesenchymal tissues, most commonly in the stomach and small intestine, although they can be located everywhere in the gastrointestinal tract. Diagnosis is based on histological and immunohistochemical examination, and these rare tumors are characterized by c-kit (CD117) staining. Complete removal of the tumor is often curative in localized gastrointestinal stromal tumors and is always recommended. Clinically, their behavior is difficult to predict, and mitotic count and tumor size seem to be the most effective prognostic factors. We performed a retrospective analysis of clinical presentation and course, surgical management and pathological features of patients with gastrointestinal stromal tumors treated in our institution from 1995 to 2003. Twenty-two patients were enrolled in the study, and all of them underwent surgery. There were two perioperative deaths, and global morbidity was about 13%. Nineteen patien...
Medical oncology (Northwood, London, England), 2012
In practice, relapses of gastrointestinal stromal tumours after long time of surgical resection o... more In practice, relapses of gastrointestinal stromal tumours after long time of surgical resection occur. However, few published data are available for duration, intensity and imaging sources of follow-up in radically excised patients with localized disease. Therefore, every single institution chooses the surveillance schedule according to its experience. The aim of this study was to describe the late recurrences of disease 5 years after the primary tumour's excision in a series of patients with recurrent GIST from our institution. We retrospectively reviewed 42 patients with "recurrent" GIST, collected since 2001. Ten patients were always followed at our institution, and 32 patients came to our attention at the time of recurrence. The analysed series were divided into two groups: patients who developed recurrence before 5 years and patients who developed recurrence 5 years after the primary tumour's excision. Among 42 patients, 36 patients developed the recurrence wi...
Large-scale studies have demonstrated that continuative treatment in advanced and adjuvant settin... more Large-scale studies have demonstrated that continuative treatment in advanced and adjuvant settings results in a gain-of-survival. However, the discontinuation, and the duration of treatment in disease-free patients who have undergone radical surgical resection of metastases from gastrointestinal stromal tumours (GISTs) have yet to be evaluated. We retrospectively reviewed 40 patients with advanced and recurrent GIST, included in our GIST database, focusing on patients (5 males and 2 females; median age 56 years) who continued medical treatment following radical surgical resection of metastatic lesions. Seven out of 40 patients underwent surgery and continued medical treatment following radical surgical resection of metastatic lesions. The duration of adjuvant therapy was 3, 12, 16, 24, 35, 37 and 52 months, respectively, with a median of 26 months. No patients discontinued therapy and all were disease-free at the final CT-scan evaluation. Considering that the discontinuation of ima...
Resistance to gemcitabine is one of the main causes of treatment failure in pancreatic cancer. Co... more Resistance to gemcitabine is one of the main causes of treatment failure in pancreatic cancer. Compelling evidences have shown the involvement of nuclear factor κB (NF-κB) activation in such phenomenon. The protease inhibitor gabexate mesilate has been shown to inhibit NF-κB. We here investigated if combined treatment with this drug could improve gemcitabine antitumoral efficacy in pancreatic cancer cells. The effect of gabexate mesilate and gemcitabine, both used at concentrations achievable in human plasma, was assessed on in vitro pancreatic cancer cell growth, invasion, and tumor angiogenesis. The molecular mechanism at the basis of these effects was also investigated. Gabexate mesilate significantly increased gemcitabine anti-invasive and antiangiogenic efficacy. This effect was related to inhibition of gemcitabine-induced NF-κB activation by gabexate mesilate, which prevented RelA/p65 nuclear translocation and resulted in metalloproteinase 2, metalloproteinase 9, vascular endothelial growth factor, and interleukin 8 down-regulation. Combined treatment with gabexate mesilate also inhibited gemcitabine-induced extracellular-regulated kinase 1/2 and AKT activation by increased expression of Raf kinase inhibitor protein and phosphatase and tensin homolog. Combined treatment with gabexate mesilate sensitizes pancreatic cancer cells to gemcitabine by inhibition of the NF-κB pathway. The efficacy of this therapeutic strategy in pancreatic cancer patients remains to be established and deserves future clinical investigation.
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Papers by Paola Paterini