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1.
Ann Oncol ; 32(8): 1005-1014, 2021 08.
Article in English | MEDLINE | ID: mdl-33932503

ABSTRACT

BACKGROUND: In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. PATIENTS AND METHODS: KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). RESULTS: The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR = 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. CONCLUSIONS: T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.


Subject(s)
Breast Neoplasms , Neoadjuvant Therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Female , Humans , Neoplasm Recurrence, Local/drug therapy , Receptor, ErbB-2 , Trastuzumab/adverse effects
2.
Eur J Surg Oncol ; 46(10 Pt A): 1861-1866, 2020 10.
Article in English | MEDLINE | ID: mdl-32723610

ABSTRACT

Breast cancer treatment has deeply changed in the last decades, since clinical and oncological cure cannot be achieved without patient's satisfaction in term of aesthetic outcomes. Several methods have been proposed to objectively assess these results. However, Italian breast centers have not yet agreed on measurable, reproducible and validated aesthetic outcome indicators to monitor their performance. METHODS: The study was designed and conducted by Senonetwork, a not-for-profit association of Italian breast centers. Ten breast centers were selected based on specific eligibility criteria. This multicentre observational prospective study recruited 6515 patients with diagnosis of in situ or invasive breast cancer who underwent breast surgery in the years 2013-2016. Thirteen indicators of aesthetic results and of related quality of care were analyzed. Data collection and analysis were conducted using a common study database. RESULTS: On average, seven out of ten centers were able to collect data on the proposed indicators with a proportion of missing values < 25%. By expert consensus based on study results, some seven indicators have been defined as "mandatory" while the remaining six have been defined as "recommended" because they require further refinement before they can be proposed for monitoring aesthetic outcomes or because there are doubts on the feasibility of data collection. The minimum standard is reached for 5 of 13 indicators. This finding and the wide range between centers reveal that there is ample room for improvement. CONCLUSIONS: From the present study useful measurable aesthetic parameters have emerged, leading to the definition of target objectives that breast centers can use for benchmarking and improvement of quality of care.


Subject(s)
Breast Neoplasms/surgery , Mammaplasty/methods , Mastectomy, Segmental/methods , Mastectomy/methods , Physical Appearance, Body , Quality Indicators, Health Care , Breast Implantation/methods , Cicatrix , Data Collection , Esthetics , Female , Humans , Italy , Nipples , Organ Sparing Treatments , Patient Outcome Assessment , Quality of Health Care , Skin Pigmentation , Surgical Flaps , Tissue Scaffolds
3.
Clin Radiol ; 75(8): 622-628, 2020 08.
Article in English | MEDLINE | ID: mdl-32321646

ABSTRACT

AIM: To evaluate the association between 11C-methionine positron-emission tomography (11C-methionine PET) findings, isocitrate dehydrogenase (IDH) gene mutation, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in patients with grade II and III gliomas. MATERIALS AND METHODS: Data were collected from 40 patients with grade II and III gliomas who underwent both magnetic resonance imaging (MRI) and 11C-methionine PET as part of their pre-surgical examination. IDH mutation was examined via DNA sequencing, and MGMT promoter methylation via quantitative methylation-specific polymerase chain reaction (PCR). RESULTS: A threshold of MGMT promoter methylation of 1% was significantly associated with tumour/normal tissue (T/N) ratio. The T/N ratio in samples with MGMT promoter methylation ≥1% was higher than that in samples with MGMT promoter methylation <1%, and the difference was statistically significant (p=0.011). Reliable prediction of MGMT promoter methylation (<1% versus ≥1%) was possible using the T/N ratio under the receiver operator characteristic (ROC) curve with a sensitivity and specificity of 75% each (cut-off value=1.6: p=0.0226, area under the ROC curve [AUC]=0.76172). Conversely, the T/N ratio had no association with IDH mutation (p=0.6). The ROC curve revealed no reliable prediction of IDH mutation using the T/N ratio (p=0.606, AUC=0.60577). CONCLUSION: 11C-methionine PET parameters can predict MGMT promoter methylation but not IDH mutation status. 11C-methionine uptake may have limited potential to reflect DNA methylation processes in grade II and III gliomas.


Subject(s)
Brain Neoplasms/genetics , DNA Modification Methylases/genetics , DNA Repair Enzymes/genetics , Glioma/genetics , Isocitrate Dehydrogenase/genetics , Methionine/pharmacokinetics , Mutation , Neoplasm Staging/methods , Tumor Suppressor Proteins/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Brain Neoplasms/diagnosis , Brain Neoplasms/metabolism , DNA Modification Methylases/metabolism , DNA Mutational Analysis , DNA Repair Enzymes/metabolism , DNA, Neoplasm/genetics , Female , Glioma/diagnosis , Glioma/metabolism , Humans , Isocitrate Dehydrogenase/metabolism , Magnetic Resonance Imaging , Male , Middle Aged , Positron-Emission Tomography , Prognosis , Promoter Regions, Genetic , Retrospective Studies , Tumor Suppressor Proteins/metabolism , Young Adult
4.
Public Health ; 149: 81-88, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28577441

ABSTRACT

OBJECTIVE: To evaluate whether a country's Human Development Index (HDI) can help explain the differences in the country's breast cancer and gynecological cancer incidence and mortality rates in the Pan-American region. STUDY DESIGN: Ecological analysis. METHODS: Pan-American region countries with publicly available data both in GLOBOCAN 2012 and the United Nations Development Report 2012 were included (n = 28). Incidence and mortality rates age-standardized per 100,000 were natural log-transformed for breast cancer, ovarian cancer, corpus uteri cancer, and cervical cancer. The mortality-to-incidence ratio (MIR) was calculated for each site. Pearson's correlation test and a simple linear regression were performed. RESULTS: The HDI showed a positive correlation with breast cancer and ovarian cancer incidence and mortality rates, respectively, and a negative correlation with cervical cancer incidence and mortality rates. The HDI and corpus uteri cancer showed no association. MIR and the HDI showed a negative correlation for all tumor types except ovarian cancer. An increment in 1 HDI unit leads to changes in cancer rates: in breast cancer incidence ß = 4.03 (95% confidence interval [CI] 2.61; 5.45) P < 0.001, breast cancer mortality ß = 1.76 (95% CI 0.32; 3.21) P = 0.019, and breast cancer-MIR ß = -0.705 (95% CI 0.704; 0.706) P < 0.001; in cervical cancer incidence ß = -3.28 (95% CI -4.78; -1.78) P < 0.001, cervical cancer mortality ß = -4.63 (95% CI -6.10; -3.17) P < 0.001, and cervical cancer-MIR ß = -1.35 (95% CI -1.83; -0.87) P < 0.001; in ovarian cancer incidence ß = 3.26 (95% CI 1.78; 4.75) P < 0.001, ovarian cancer mortality ß = 1.82 (95% CI 0.44; 3.20) P = 0.012, and ovarian cancer-MIR ß = 5.10 (95% CI 3.22; 6.97) P < 0.001; in corpus uteri cancer incidence ß = 2.37 (95% CI -0.33; 5.06) P = 0.83, corpus uteri cancer mortality ß = 0.68 (95% CI -2.68; 2.82) P = 0.96, and corpus uteri cancer-MIR ß = -2.30 (95% CI -3.19; -1.40) P < 0.001. CONCLUSIONS: A country's HDI should be considered to understand disparities in breast cancer and gynecological cancer in the Pan-American region.


Subject(s)
Breast Neoplasms/epidemiology , Genital Neoplasms, Female/epidemiology , Health Status Disparities , Adult , Aged , Americas/epidemiology , Breast Neoplasms/mortality , Caribbean Region/epidemiology , Female , Genital Neoplasms, Female/mortality , Humans , Incidence , Middle Aged
5.
Braz. j. med. biol. res ; 48(5): 479-485, 05/2015. tab, graf
Article in English | LILACS | ID: lil-744381

ABSTRACT

Neoadjuvant chemotherapy has practical and theoretical advantages over adjuvant chemotherapy strategy in breast cancer (BC) management. Moreover, metronomic delivery has a more favorable toxicity profile. The present study examined the feasibility of neoadjuvant metronomic chemotherapy in two cohorts [HER2+ (TraQme) and HER2− (TAME)] of locally advanced BC. Twenty patients were prospectively enrolled (TraQme, n=9; TAME, n=11). Both cohorts received weekly paclitaxel at 100 mg/m2 during 8 weeks followed by weekly doxorubicin at 24 mg/m2 for 9 weeks in combination with oral cyclophosphamide at 100 mg/day (fixed dose). The HER2+ cohort received weekly trastuzumab. The study was interrupted because of safety issues. Thirty-six percent of patients in the TAME cohort and all patients from the TraQme cohort had stage III BC. Of note, 33% from the TraQme cohort and 66% from the TAME cohort displayed hormone receptor positivity in tumor tissue. The pathological complete response rates were 55% and 18% among patients enrolled in the TraQme and TAME cohorts, respectively. Patients in the TraQme cohort had more advanced BC stages at diagnosis, higher-grade pathological classification, and more tumors lacking hormone receptor expression, compared to the TAME cohort. The toxicity profile was also different. Two patients in the TraQme cohort developed pneumonitis, and in the TAME cohort we observed more hematological toxicity and hand-foot syndrome. The neoadjuvant metronomic chemotherapy regimen evaluated in this trial was highly effective in achieving a tumor response, especially in the HER2+ cohort. Pneumonitis was a serious, unexpected adverse event observed in this group. Further larger and randomized trials are warranted to evaluate the association between metronomic chemotherapy and trastuzumab treatment.


Subject(s)
Humans , Decontamination/methods , Geobacillus stearothermophilus/drug effects , Hydrogen Peroxide/administration & dosage , Infection Control/methods
6.
Braz J Med Biol Res ; 48(5): 479-85, 2015 May.
Article in English | MEDLINE | ID: mdl-25760024

ABSTRACT

Neoadjuvant chemotherapy has practical and theoretical advantages over adjuvant chemotherapy strategy in breast cancer (BC) management. Moreover, metronomic delivery has a more favorable toxicity profile. The present study examined the feasibility of neoadjuvant metronomic chemotherapy in two cohorts [HER2+ (TraQme) and HER2- (TAME)] of locally advanced BC. Twenty patients were prospectively enrolled (TraQme, n=9; TAME, n=11). Both cohorts received weekly paclitaxel at 100 mg/m(2) during 8 weeks followed by weekly doxorubicin at 24 mg/m(2) for 9 weeks in combination with oral cyclophosphamide at 100 mg/day (fixed dose). The HER2+ cohort received weekly trastuzumab. The study was interrupted because of safety issues. Thirty-six percent of patients in the TAME cohort and all patients from the TraQme cohort had stage III BC. Of note, 33% from the TraQme cohort and 66% from the TAME cohort displayed hormone receptor positivity in tumor tissue. The pathological complete response rates were 55% and 18% among patients enrolled in the TraQme and TAME cohorts, respectively. Patients in the TraQme cohort had more advanced BC stages at diagnosis, higher-grade pathological classification, and more tumors lacking hormone receptor expression, compared to the TAME cohort. The toxicity profile was also different. Two patients in the TraQme cohort developed pneumonitis, and in the TAME cohort we observed more hematological toxicity and hand-foot syndrome. The neoadjuvant metronomic chemotherapy regimen evaluated in this trial was highly effective in achieving a tumor response, especially in the HER2+ cohort. Pneumonitis was a serious, unexpected adverse event observed in this group. Further larger and randomized trials are warranted to evaluate the association between metronomic chemotherapy and trastuzumab treatment.


Subject(s)
Administration, Metronomic , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Carcinoma, Ductal, Breast/drug therapy , Neoadjuvant Therapy , Receptor, ErbB-2 , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/chemistry , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/chemistry , Carcinoma, Ductal, Breast/pathology , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Female , Hand-Foot Syndrome/etiology , Humans , Kaplan-Meier Estimate , Middle Aged , Neoadjuvant Therapy/adverse effects , Neoplasm Grading , Paclitaxel/administration & dosage , Pneumonia/etiology , Prospective Studies , Receptors, Estrogen/analysis , Trastuzumab
8.
J Gen Virol ; 93(Pt 7): 1474-1482, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22442113

ABSTRACT

Although inserting exogenous viral genome segments into rotavirus particles remains a hard challenge, this study describes the in vivo incorporation of a recombinant viral capsid protein (VP6) into newly assembled rotavirus particles. In vivo biotinylation technology was exploited to biotinylate a recombinant VP6 protein fused to a 15 aa biotin-acceptor peptide (BAP) by the bacterial biotin ligase BirA contextually co-expressed in mammalian cells. To avoid toxicity of VP6 overexpression, a stable HEK293 cell line was constructed with tetracycline-inducible expression of VP6-BAP and constitutive expression of BirA. Following tetracycline induction and rotavirus infection, VP6-BAP was biotinylated, recruited into viroplasms and incorporated into newly assembled virions. The biotin molecules in the capsid allowed the use of streptavidin-coated magnetic beads as a purification technique instead of CsCl gradient ultracentrifugation. Following transfection, double-layered particles attached to beads were able to induce viroplasm formation and to generate infective viral progeny.


Subject(s)
Biotinylation/methods , Rotavirus/growth & development , Staining and Labeling/methods , Virology/methods , Virus Assembly , Capsid Proteins/genetics , Capsid Proteins/metabolism , Cell Line , Humans , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Recombination, Genetic , Rotavirus/genetics , Rotavirus/physiology
9.
J Virol ; 85(6): 2781-92, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21228236

ABSTRACT

The ubiquitin-proteasome system has been shown to play an important role in the replication cycle of different viruses. In this study, we describe a strong impairment of rotavirus replication upon inhibition of proteasomal activity. The effect was evidenced at the level of accumulation of viral proteins, viral RNA, and yield of infective particles. Kinetic studies revealed that the early steps of the replicative cycle following attachment, entry, and uncoating were clearly more sensitive to proteasome inhibition. We ruled out a direct inhibition of the viral polymerase activities and stability of viral proteins and found that the crucial step that was impaired by blocking proteasome activity was the assembly of new viroplasms. This was demonstrated by using chemical inhibitors of proteasome and by gene silencing using small interfering RNAs (siRNAs) specific for different proteasomal subunits and for the ubiquitin precursor RPS27A. In addition, we show that the effect of proteasome inhibition on virus infection is not due to increased levels of beta interferon (IFN-ß).


Subject(s)
Proteasome Endopeptidase Complex/metabolism , Rotavirus/physiology , Virus Internalization , Virus Replication , Animals , Cell Line , Gene Silencing , Proteasome Inhibitors , RNA, Viral/metabolism , Viral Proteins/metabolism
10.
Acta Clin Belg ; 66(6): 426-8, 2011.
Article in English | MEDLINE | ID: mdl-22338305

ABSTRACT

We report the case of a woman with a metastatic breast cancer, who started a third-line treatment with dasatinib, a new oral tyrosine kinase inhibitor, and who developed, one week later, a progressive breathless sensation. Workup demonstrated pleuropericardial effusion that turned out to be a side effect of this new investigational drug. Although this dasatinib-induced side effect is well known, this case clearly illustrates the importance of an accurate diagnosis and adequate treatment of complications of new agents which are easy to use since most of them are orally taken, and the difficulty to clearly separate drug origin and cancer morbidities. The patient recovered completely one month after discontinuation of dasatinib. In this report, we will review the differential diagnosis and management of pleuropericardial effusion.


Subject(s)
Breast Neoplasms/drug therapy , Dyspnea/chemically induced , Protein Kinase Inhibitors/adverse effects , Pyrimidines/adverse effects , Thiazoles/adverse effects , Dasatinib , Female , Humans , Middle Aged
11.
Pathol Res Pract ; 207(2): 97-103, 2011 Feb 15.
Article in English | MEDLINE | ID: mdl-21185131

ABSTRACT

The role of the stromal constituents in the natural history of breast cancers is still poorly defined. The aim of the present study was to evaluate the expression of proteoglycan versican, a constituent of desmoplastic stroma of invasive carcinomas, in preinvasive breast lesions. We selected 41 cases of breast carcinoma: 28 pure in situ lesions and 13 invasive lesions with in situ-associated lesions. The study provided evidence that versican is strongly expressed in the perilesional stroma of a subclass of ductal in situ carcinomas, and that the extension of versican immunostaining is statistically related to the high grade (G3) category (54% of diffuse expressors; p=0.01), and with a comedo pattern (67% of diffuse expressors, p=0.003). On the other hand, the expression of versican in the cases of classic lobular in situ carcinomas that we selected for the study was confined to the anatomical structures that usually contain the proteoglycan in adult breast tissues. In our cohort, versican synthesis was found to be associated with spindle-shaped elements with myofibroblastic phenotype, as in the stroma of invasive carcinoma. These data, taken together with evidence from previous studies on proteins strongly related to versican, suggest that various histotypes of breast in situ carcinomas could follow different pathways of epithelial stromal interactions. In particular a category of in situ lesions shows constituents of desmoplastic stroma before the manifestation of the morphological signs of invasion. Study of the connective tissue modifications that trigger the pivotal phase of invasion could provide new prospects in oncology.


Subject(s)
Breast Neoplasms/chemistry , Carcinoma in Situ/chemistry , Carcinoma, Intraductal, Noninfiltrating/chemistry , Carcinoma, Lobular/chemistry , Stromal Cells/chemistry , Versicans/analysis , Adult , Aged , Aged, 80 and over , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Carcinoma in Situ/pathology , Carcinoma in Situ/surgery , Carcinoma, Intraductal, Noninfiltrating/pathology , Carcinoma, Intraductal, Noninfiltrating/surgery , Carcinoma, Lobular/pathology , Female , Humans , Immunohistochemistry , Middle Aged , Neoplasm Invasiveness , Stromal Cells/pathology
12.
Eur J Cancer ; 46(13): 2344-56, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20675120

ABSTRACT

To define a set of quality indicators that should be routinely measured and evaluated to confirm that the clinical outcome reaches the requested standards, Eusoma has organised a workshop during which twenty four experts from different disciplines have reviewed the international literature and selected the main process and outcome indicators available for quality assurance of breast cancer care. A review of the literature for evidence-based recommendations have been performed by the steering committee. The experts have identified the quality indicators also taking into account the usability and feasibility. For each of them it has been reported: definition, minimum and target standard, motivation for selection and level of evidence (graded according to AHRO). In overall 17 main quality indicators have been identified, respectively, 7 on diagnosis, 4 on surgery and loco-regional treatment, 2 on systemic treatment and 4 on staging, counselling, follow-up and rehabilitation. Breast Units in Europe are invited to comply with these indicators and monitor them during their periodic audit meetings.


Subject(s)
Breast Neoplasms/therapy , Quality Indicators, Health Care , Antineoplastic Agents/therapeutic use , Early Detection of Cancer , Female , Genetic Counseling , Health Services Misuse , Humans , Long-Term Care/standards , Magnetic Resonance Imaging , Neoplasm Staging/standards , Patient Care Team , Postoperative Care/standards , Preoperative Care/standards , Waiting Lists
13.
Mol Cell Endocrinol ; 284(1-2): 1-10, 2008 Mar 12.
Article in English | MEDLINE | ID: mdl-18255222

ABSTRACT

Leptin stimulates fatty acid oxidation via the phosphorylation of AMPK (AMP-activated protein kinase) and ACC (acetyl-CoA carboxylase). Obesity is associated with resistance to the effects of leptin. We determined the action of leptin on AMPKalpha and ACCbeta phosphorylation and lipid metabolism in soleus (SOL) and extensor digitorum longus (EDL) muscles from lean and obese Wistar rats after 1 and 100 nM leptin. Both leptin doses stimulated phosphorylation of AMPKalpha and ACCbeta (P

Subject(s)
Acetyl-CoA Carboxylase/metabolism , Fatty Acids/metabolism , Leptin/metabolism , Multienzyme Complexes/metabolism , Muscle, Skeletal/metabolism , Obesity/metabolism , Protein Serine-Threonine Kinases/metabolism , AMP-Activated Protein Kinases , Acyl Coenzyme A/metabolism , Adipose Tissue/pathology , Animals , Body Weight , Dietary Fats/administration & dosage , Disease Models, Animal , Dose-Response Relationship, Drug , Energy Metabolism , Enzyme Activation , Glycolysis , Humans , Insulin/blood , Leptin/blood , Leptin/pharmacology , Male , Malonyl Coenzyme A/metabolism , Muscle Fibers, Skeletal/enzymology , Muscle Fibers, Skeletal/metabolism , Muscle, Skeletal/drug effects , Muscle, Skeletal/enzymology , Obesity/enzymology , Obesity/etiology , Obesity/pathology , Oxidation-Reduction , Phosphorylation , Rats , Rats, Wistar
14.
Eur J Clin Nutr ; 62(8): 968-77, 2008 Aug.
Article in English | MEDLINE | ID: mdl-17538539

ABSTRACT

OBJECTIVE: To test the dose-response effect on low-density lipoprotein cholesterol (LDL-c) of plant sterols (PS) from different sources in a low-fat spread. METHODS: Dose responses of soybean oil (BO), tall oil (TO) and a mix of tall oil and rapeseed oil (TO/RP) as fatty acid esters were tested in a parallel design in free-living subjects recruited from the general community who had elevated cholesterol concentrations. Subjects received either control for 6 weeks or 1.6 g PS per day for 3 weeks, then 3.0 g/day for 3 weeks. RESULTS: LDL-c was lowered significantly by consumption of 1.6 g/day of PS (-10.4%, range -7.3 to -11.4%). Increasing the dose to 3.0 g/day modestly reduced LDL-c concentrations further to -14.7%. TO, containing 78% sitosterol, produced an increase in serum sitosterol of 6.5 nmol/ml, while BO, containing only 27% campesterol, produced an increase in serum campesterol of 9.5 nmol/ml in 6 weeks. After PS withdrawal, serum sterols declined by 50% within 2 weeks. CONCLUSION: Different PS sources were equally effective in lowering serum LDL-c concentrations. The decrease in absolute concentrations of LDL-c was dependent on the baseline concentrations.


Subject(s)
C-Reactive Protein/analysis , Cholesterol, LDL/blood , Hypercholesterolemia/therapy , Phytosterols/analysis , Phytosterols/pharmacology , Adult , Aged , Cholesterol/analogs & derivatives , Cholesterol/blood , Cholesterol, HDL/blood , Cholesterol, HDL/drug effects , Cholesterol, LDL/drug effects , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Female , Food, Fortified , Humans , Hypercholesterolemia/blood , Male , Margarine , Middle Aged , Sitosterols/analysis , Sitosterols/pharmacology , Triglycerides/blood , Young Adult
15.
Br J Cancer ; 96(10): 1504-13, 2007 May 21.
Article in English | MEDLINE | ID: mdl-17453008

ABSTRACT

The Ki-67 antigen is used to evaluate the proliferative activity of breast cancer (BC); however, Ki-67's role as a prognostic marker in BC is still undefined. In order to better define the prognostic value of Ki-67/MIB-1, we performed a meta-analysis of studies that evaluated the impact of Ki-67/MIB-1 on disease-free survival (DFS) and/or on overall survival (OS) in early BC. Sixty-eight studies were identified and 46 studies including 12 155 patients were evaluable for our meta-analysis; 38 studies were evaluable for the aggregation of results for DFS, and 35 studies for OS. Patients were considered to present positive tumours for the expression of Ki-67/MIB-1 according to the cut-off points defined by the authors. Ki-67/MIB-1 positivity is associated with higher probability of relapse in all patients (HR=1.93 (95% confidence interval (CI): 1.74-2.14); P<0.001), in node-negative patients (HR=2.31 (95% CI: 1.83-2.92); P<0.001) and in node-positive patients (HR=1.59 (95% CI: 1.35-1.87); P<0.001). Furthermore, Ki-67/MIB-1 positivity is associated with worse survival in all patients (HR=1.95 (95% CI: 1.70-2.24; P<0.001)), node-negative patients (HR=2.54 (95% CI: 1.65-3.91); P<0.001) and node-positive patients (HR=2.33 (95% CI: 1.83-2.95); P<0.001). Our meta-analysis suggests that Ki-67/MIB-1 positivity confers a higher risk of relapse and a worse survival in patients with early BC.


Subject(s)
Biomarkers, Tumor/analysis , Breast Neoplasms/diagnosis , Carcinoma/diagnosis , Ki-67 Antigen/analysis , Biomarkers, Tumor/metabolism , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Carcinoma/mortality , Carcinoma/pathology , Carcinoma/therapy , Disease-Free Survival , Female , Follow-Up Studies , Humans , Ki-67 Antigen/metabolism , Prognosis , Survival Analysis
16.
Int J Gynecol Cancer ; 17(2): 316-24, 2007.
Article in English | MEDLINE | ID: mdl-17362309

ABSTRACT

Ovarian carcinosarcomas (OCS), also known as malignant mixed müllerian tumors, are uncommon malignancies that carry a poor prognosis. The presentation of OCS is usually indistinguishable from that of epithelial ovarian cancer. Due to its low frequency, prospective trials have been difficult to perform, but there is evidence that OCS are sensitive to platinum-based chemotherapy. Recent studies have shown encouraging results with platinum-ifosfamide and platinum-taxane schedules, which are usually considered the treatment of choice. However, poor performance status at presentation is also a common problem, so that many patients may be unsuitable for combination chemotherapy but may still benefit from single-agent platinum or ifosfamide or, occasionally, from nonplatinum schedules such as ifosfamide plus paclitaxel. Aggressive cytoreductive surgery appears to have a positive impact on outcome and should probably be offered to most patients. However, this procedure has been associated with higher rates of complication in OCS and should only be attempted by experienced (gynecological) surgeons in centers with expertise in the management of gynecological malignancies.


Subject(s)
Carcinosarcoma/therapy , Ovarian Neoplasms/therapy , Antineoplastic Agents/therapeutic use , Carcinosarcoma/diagnosis , Carcinosarcoma/etiology , Clinical Trials as Topic , Female , Humans , Ovarian Neoplasms/diagnosis , Ovarian Neoplasms/etiology , Prognosis
17.
Br J Cancer ; 95(9): 1265-8, 2006 Nov 06.
Article in English | MEDLINE | ID: mdl-17043685

ABSTRACT

We enrolled all 2162 in situ and 21 148 invasive cases of breast cancer in 17 areas of Italy, diagnosed in 1997-2001. Rates of early cancer increased by 13.7% in the screening age group (50-69 years), and breast conserving surgery by 24.6%. Advanced cancer rates decreased by 19.4%, and mastectomy rates by 24.2%. Service screening did not increase mastectomy rates in the study population.


Subject(s)
Breast Neoplasms/surgery , Mass Screening/statistics & numerical data , Mastectomy/statistics & numerical data , Aged , Breast Neoplasms/epidemiology , Carcinoma in Situ/epidemiology , Carcinoma in Situ/surgery , Carcinoma, Ductal, Breast/epidemiology , Carcinoma, Ductal, Breast/surgery , Humans , Italy/epidemiology , Logistic Models , Mastectomy/trends , Middle Aged , Multivariate Analysis
18.
Br J Cancer ; 92(10): 1855-61, 2005 May 23.
Article in English | MEDLINE | ID: mdl-15870716

ABSTRACT

BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor (VEGFR) inhibitor that targets tumour cell proliferation and tumour angiogenesis. This Phase I study was undertaken to determine the safety profile, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and tumour response profile of oral BAY 43-9006 in patients with advanced, refractory solid tumours. BAY 43-9006 was administered daily for repeated cycles of 21 days on/7 days off. A total of 44 patients were enrolled at doses from 50 to 800 mg b.i.d. Pharmacokinetic profiles of BAY 43-9006 in plasma were determined during the first treatment cycle. The most frequently reported adverse events over multiple cycles were gastrointestinal (75%), dermatologic (71%), constitutional (68%), pain (64%), or hepatic (61%) related. A MTD of 400 mg b.i.d. BAY 43-9006 was defined. BAY 43-9006 was absorbed rapidly; steady-state conditions were reached within 7 days. BAY 43-9006 exposure increased nonproportionally with increasing dose. In all, 32 patients were evaluated for tumour response: 15 patients showed tumour progression, 16 patients experienced stable disease (>6 months in eight patients), and one patient with renal cell carcinoma achieved a partial response. BAY 43-9006 given for 21 days with 7 days off treatment was safe, well tolerated, and showed antitumour activity.


Subject(s)
Benzenesulfonates/adverse effects , Benzenesulfonates/pharmacokinetics , Neoplasms/drug therapy , Pyridines/adverse effects , Pyridines/pharmacokinetics , Adult , Aged , Benzenesulfonates/administration & dosage , Carcinoma, Renal Cell/drug therapy , Drug Administration Schedule , Female , Humans , Kidney Neoplasms/drug therapy , Male , Maximum Tolerated Dose , Middle Aged , Niacinamide/analogs & derivatives , Phenylurea Compounds , Pyridines/administration & dosage , Sorafenib
19.
Biosens Bioelectron ; 20(5): 975-84, 2004 Nov 15.
Article in English | MEDLINE | ID: mdl-15530794

ABSTRACT

Complexes between short oligodeoxynucleotides (ODN) with a variable dG(x)dC(y) base composition and liposomes composed of the cationic lipid DOTAP (ODN lipoplexes) were studied by differential pulse voltammetry at a glassy carbon electrode. Since lipoplexes are spontaneously formed by electrostatic interactions, the objective of the voltammetric study was to investigate their behaviour at the electrode surface/solution interface. It was verified that the peak current in the voltammograms for ODN lipoplexes was due to guanosine oxidation and that it was influenced both by the applied adsorption potential and the lipoplex (+/-) charge ratio used. It was found that for low ODN lipoplexes (+/-) charge ratios the peak current obtained was enhanced when compared to that registered with free ODN for the same concentration. This allowed a higher sensitivity in the determination of ODN by differential pulse voltammetry and a limit of detection of 5.5 ng/mL was achieved. A model that explains the organisation of ODN lipoplexes at the electrode surface/solution interface is proposed. The electrochemical results presented account for a better physicochemical characterisation of lipoplexes at charged interfaces, which can be important for the understanding and development of gene therapy vectors based on ODN lipoplexes.


Subject(s)
Biosensing Techniques/methods , Coated Materials, Biocompatible/chemistry , Electrochemistry/methods , Fatty Acids, Monounsaturated/chemistry , Liposomes/chemistry , Oligonucleotides/chemistry , Quaternary Ammonium Compounds/chemistry , Biosensing Techniques/instrumentation , Electrochemistry/instrumentation , Fatty Acids, Monounsaturated/analysis , Liposomes/analysis , Macromolecular Substances/chemistry , Materials Testing , Oligonucleotides/analysis , Quaternary Ammonium Compounds/analysis , Static Electricity , Structure-Activity Relationship , Surface Properties
20.
Int J Oncol ; 25(5): 1473-9, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15492841

ABSTRACT

Topoisomerase-IIalpha (topo-II) is a molecular target for topo-II inhibitors, which makes it a potential predictive marker of responsiveness to these agents. We aim to correlate topo-II gene and protein status on 103 HER-2 amplified breast cancer samples. Paraffin-embedded blocks were screened by FISH for topo-II gene amplification (topo-II: CEP17 ratio >/=1.5; triple probe by Vysis inc.) and analyzed by IHC for topo-II protein expression (continuous variable; clone KiS1) and Ki-67 (positive if >25% of stained cells; clone MIB-1). Topo-II gene amplification was observed in 36.9% (38/103) of the HER-2 amplified study population. HER-2 amplification level (e.g. copy number) was not shown to be predictive for topo-II amplification. The median percentage of topo-II positively stained cells by IHC for topo-II non-amplified and amplified cases were 5% and 10%, respectively. A weak but significant correlation was observed between topo-II gene amplification level and percentage of positively stained cells (Spearman's ranks correlation coefficient of 0.23, p=0.02), the observed correlation being higher in patients with positive staining for Ki-67. Contrary to HER-2, where gene amplification is almost always correlated with protein overexpression in breast cancer, topo-II gene amplification apparently does not always lead to protein overexpression, at least when the latter is evaluated by IHC. Other factors, specifically the tumor proliferation status, may interfere with the topo-II protein status. Although the great majority of topo-II gene aberrations occur in HER-2 positive tumors, the level of HER-2 amplification does not predict for topo-II amplification.


Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/physiopathology , Carcinoma/genetics , Carcinoma/physiopathology , DNA Topoisomerases, Type II/genetics , Gene Amplification , Gene Expression Profiling , Receptor, ErbB-2/biosynthesis , Antigens, Neoplasm , DNA-Binding Proteins , Female , Humans , In Situ Hybridization, Fluorescence , Isoenzymes , Poly-ADP-Ribose Binding Proteins
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