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ABSTRACT: Background. Colon cancer during pregnancy is a relatively rare occurrence. To date there has been sparse clinical evidence about the safety of chemotherapy in this setting because the available data derive only from single-institution case reports. Methods. Irinotecan and fluorouracil, as part of the FOLFIRI regimen, were administered to a 33-year-old pregnant woman at an estimated gestational age of 23+ weeks. She had been diagnosed with adenocarcinoma of the transverse colon with liver and lymph node metastases. Results. Chemotherapy was administered from the 23+th to the 28+th week of gestational age. Chemotherapy was stopped because of disease progression. At 30 weeks' gestational age, the patient underwent an emergency cesarean section and colon resection. She gave birth to a healthy male infant with no particular problems in neurological, respiratory, cardiovascular, digestive and nutritional function. At follow-up, the 13-month-old child had achieved all appropriate growth and developmental milestones. Conclusions. Our report demonstrates the safety of exposure to FOLFIRI for both mother and fetus. The absence of any abnormalities in the infant makes irinotecan and fluorouracil a valid therapeutic option for colon cancer during pregnancy.
Tumori. 11/2012; 98(6):155e-7e.
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ABSTRACT: When there is little hope of a clinical benefit, too delayed a withdrawal from chemotherapy might be detrimental for a patient's quality of life. We evaluated appropriately timed cessation of chemotherapy in our Oncology Department after integration of a Supportive and Palliative Care Unit.
We carried out a review of deceased patients in our department from January 2006 to December 2009. Activities of the Supportive and Palliative Care Unit started in late 2007. We analyzed the characteristics of patients near the end of life and chemotherapy use within 30 days of death as an aggressiveness of cure index.
During the considered period, 361 hospitalized patients died: 69 in 2006, 77 in 2007, 97 in 2008 and 118 in 2009; 102 never received chemotherapy. Sixty-one of the remaining 259 patients died within 30 days of the last drug administration. The percentage of patients receiving chemotherapy in their last 30 days fell from 19% in 2006 and 20% in 2007, to 16% in 2008 and 14% in 2009.
Supportive and Palliative Care Unit integration decreased chemotherapy use in the last 30 days of life. A careful evaluation of prognostic factors of advanced cancer patients and provision of appropriate supportive and palliative cares can reduce the use of futile anticancer chemotherapy and preserve a patient's qualify of life.
Tumori. 09/2011; 97(5):573-7.
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ABSTRACT: A new method for evoking the tail flick reflex is introduced, using short duration or "impulsive" nociceptive stimuli, which allow synchronization and recording of electrophysiological responses. Ten adult rats were studied, by means of thermal (CO(2) laser infrared pulse with 30 ms duration, 7.5 or 10W), electric (a 25 ms train of five 0.2 ms pulses, with 5 or 10 mA intensity) or mechanical (pin pressed with 5 g force) stimuli. Both electromyographic and strain gauge mechanical responses were recorded from the tail. All three types of stimulation gave rise to three components, named early, late and ultralate, respectively occurring in the range of 19-97 ms, 190-519 ms, 1,523-2,765 ms. Conduction velocities of the underlying afferent fibres were calculated by moving the stimulation site. The early component could be linked to Aδ afferents, while late and ultralate components were due to unmyelinated C afferents. Experiments with Fentanyl (20 μg/kg) showed that only the C linked components were depressed, with the ultralate component the most affected, possibly because supraspinally originated. Tail flick reflex evoked by impulsive stimuli is believed to be an important electrophysiological complement to behavioural procedures, useful in identifying the site of action of analgesics and other drugs upon the spinal and supraspinal centres involved in nociception.
Journal of neuroscience methods 07/2011; 199(1):69-77. · 2.30 Impact Factor
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ABSTRACT: Differences in hormone receptor and HER-2 status between primary tumour and corresponding relapse could have a substantial impact on clinical management of patients. The aim of this study was to evaluate change in expression of hormone receptors and HER-2 status between primary tumour and corresponding local recurrence or distant metastasis. We analysed 140 primary tumours and related recurrent or metastatic samples. Hormone receptors status was evaluated by immunohistochemistry, while HER-2 status by immunohistochemistry and silver in situ hybridisation. A change in HER-2 was rare; 3.7% of cases by immunohistochemistry and only 0.7% by silver in situ hybridisation analysis. A change in estrogen and progesterone receptors was seen in 6.4% and 21.4% of cases, respectively. Estrogen receptor change was not affected by adjuvant therapy, whereas progesterone receptor was influenced by adjuvant chemotherapy associated to hormone therapy (P = 0.0005). A change in progesterone receptor was more frequent in distant metastases than in local recurrences (P = 0.03). In the setting of estrogen receptor positive tumours, patients with progesterone receptor loss in local recurrence had a statistically significant lower median metastasis free survival compared to others patients; progesterone receptor positive, 112 months; progesterone receptor negative, 24 months (P = 0.005). A change between primary tumour and corresponding relapse is frequent for progesterone receptor, infrequent for estrogen receptor and rare for HER-2. In cases with changes in HER-2, it is worthwhile reassessing HER-2 status with both immunohistochemistry and in situ hybridisation analysis. Progesterone receptor loss seems to be influenced by therapy and to correlate with a worse prognosis.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 06/2011; 459(1):1-10. · 2.49 Impact Factor
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The Oncologist 01/2010; 15(12):1270-2. · 3.91 Impact Factor
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ABSTRACT: Somatostatin receptors (SSTR1-5) mediate antiproliferative effects. In C6 rat glioma cells, somatostatin is cytostatic in vitro via phosphotyrosine phosphatase-dependent inhibition of ERK1/2 activity mediated by SSTR1, -2, and -5. Here we analyzed the effects of SSTR activation on C6 glioma growth in vivo and the intracellular mechanisms involved, comparing somatostatin effects with selective agonists for SSTR1, -2, and -5 (BIM-23745, BIM-23120, BIM-23206) or receptor biselective compounds (SSTR1 and -2, BIM-23704; and SSTR2 and -5, BIM-23190). Nude mice subcutaneously xenografted with C6 cells were treated with somatostatin, SSTR agonists (50 μg, twice/day), or vehicle. Tumor growth was evaluated every 3 days for 19 days. The intracellular pathways responsible of SSTR effects in vivo were evaluated measuring Ki-67, phospho-ERK1/2, and p27(kip1) expression by immunohistochemistry in sections from explanted tumors. Somatostatin and SSTR1, -2, and -5 agonists strongly inhibited in vivo C6 tumor growth, intratumoral neovessel formation, Ki-67 expression, and ERK1/2 phosphorylation and induced upregulation of p27(Kip1), whereas only a modest activation of caspase-3 was observed. Somatostatin (acting on SSTR1, -2, and -5) displayed the highest efficacy; SSTR5 selective agonist showed a stronger effect than SSTR1 agonist, and SSTR2 agonist was less effective. On the other hand, SSTR1 and -2 agonists maximally reduced tumor neovascularization. The combined activation of SSTR1 and -2 showed a synergistic activity, reaching a higher efficacy than BIM-23206, whereas the simultaneous activation of SSTR2 and -5 resulted in a response resembling SSTR5 effects. Thus the simultaneous activation of different SSTRs inhibits glioma cell proliferation in vivo through both direct cytotostatic and antiangiogenic effects.
AJP Endocrinology and Metabolism 09/2009; 297(5):E1078-88. · 4.75 Impact Factor
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ABSTRACT: Intravenous temsirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is approved for the treatment of advanced renal cell carcinoma (RCC). Sirolimus, the principal metabolite of temsirolimus in humans, also exhibits mTOR inhibitory activity.
The purpose of this study was to compare the pharmacokinetics of temsirolimus and its metabolite, sirolimus, among patients with RCC not receiving dialysis and those receiving hemodialysis.
This was a single-center, unblinded, single-dose study. Patients with histologically confirmed metastatic RCC were eligible. A single 25-mg dose of temsirolimus was administered as a 30-minute intravenous infusion during the first round of chemotherapy. Blood samples were drawn at 0 (predose), 0.5 (end of infusion), 1.5, 2.5, 5.5, 24, 72, and 144 hours after infusion. In patients receiving hemodialysis, an additional blood sample was drawn 1 hour after each treatment to compare pre- and postconcentration. Temsirolimus concentrations were assayed in blood using HPLC coupled to mass spectrometry. Pharmacokinetic parameters (C(max), T(max), t((1/2)), AUC(0-infinity), total body clearance, volume of distribution at steady state, AUC ratio [the ratio of sirolimus to temsirolimus AUCs], and AUC sum [the algebraic sum of temsirolimus and sirolimus AUCs]) were calculated and analyzed statistically.
In total, 13 consecutive patients (11 men and 2 women; 11 not receiving dialysis and 2 receiving hemodialysis) were included. No patient refused to participate in the study. Of those not receiving dialysis, the median age was 54 years (range, 36-77 years), and of those receiving hemodialysis, the median age was 60.5 years (60-61 years). There were no significant between-group differences in the pharmacokinetic parameters of temsirolimus and sirolimus. Moreover, in patients receiving hemodialysis, blood drug concentrations assessed immediately before hemodialysis were similar to those assayed 1 hour after the treatment.
This study found that after single-dose administration of 25 mg of temsirolimus as a 30-minute intravenous infusion, neither temsirolimus nor sirolimus concentrations were significantly affected in these patients with RCC receiving hemodi-alysis compared with those not receiving dialysis.
Clinical Therapeutics 08/2009; 31(8):1812-9. · 2.32 Impact Factor
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Gianluigi Lunardi,
Salvatore Galati,
Domenicantonio Tropepi,
Vincenzo Moschella,
Livia Brusa,
Mariangela Pierantozzi,
Alessandro Stefani,
Silvia Rossi,
Francesco Fornai,
Ernesto Fedele,
Paolo Stanzione,
Atticus H Hainsworth,
Antonio Pisani
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ABSTRACT: To assess possible differences in dopamine metabolism that could parallel disease progression in Parkinson's disease (PD), we measured dopamine (DA) and its metabolites in the cerebrospinal fluid (CSF) in PD patients at different stages of disease: de novo (DEN), advanced not showing dyskinesias (ADV), and advanced with dyskinesias (DYS). DA, homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) were significantly higher in DEN patients compared with other groups. A negative exponential correlation related DA level and disease duration. The HVA/DA ratio was significantly higher in the ADV and DYS group than that found in DEN group. Our data show that disease progression produces an early large decay of DA levels, followed by a stabilization. On the contrary, a late change in DA turnover (increased HVA/DA ratio) is documented in patients with longer disease duration. Our results suggest that the appearance of dyskinesia may not be related to a further loss of DA terminals but to a different, abnormal, DA turnover.
Parkinsonism & Related Disorders 12/2008; 15(5):383-9. · 3.80 Impact Factor
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Journal of Clinical Oncology 12/2008; 26(34):5652-3; author reply 5653-4. · 18.37 Impact Factor
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Alessandra Pattarozzi,
Monica Gatti,
Federica Barbieri,
Roberto Würth,
Carola Porcile, Gianluigi Lunardi,
Alessandra Ratto,
Roberto Favoni,
Adriana Bajetto,
Angelo Ferrari,
Tullio Florio
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ABSTRACT: The coordinated activity of estrogens and epidermal growth factor receptor (EGFR) family agonists represents the main determinant of breast cancer cell proliferation. Stromal cell-derived factor-1 (SDF-1) enhances extracellular signal-regulated kinases 1 and 2 (ERK1/2) activity via the transactivation of EGFR and 17beta-estradiol (E2) induces SDF-1 production to exert autocrine proliferative effects. On this basis, we evaluated whether the inhibition of the tyrosine kinase (TK) activity of EGFR may control different mitogenic stimuli in breast tumors using the EGFR-TK inhibitor gefitinib to antagonize the proliferation induced by E2 in T47D human breast cancer cells. EGF, E2, and SDF-1 induced a dose-dependent T47D cell proliferation, that being nonadditive suggested the activation of common intracellular pathways. Gefitinib treatment inhibited not only the EGF-dependent proliferation and ERK1/2 activation but also the effects of SDF-1 and E2, suggesting that these activities were mediated by EGFR transactivation. Indeed, both SDF-1 and E2 caused EGFR tyrosine phosphorylation. The molecular link between E2 and SDF-1 proliferative effects was identified because 1,1'-(1,4-phenylenebis(methylene))-bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD3100), a CXCR4 antagonist, inhibited SDF-1- and E2-dependent proliferation and EGFR and ERK1/2 phosphorylation. EGFR transactivation was dependent on c-Src activation. E2 treatment caused a powerful SDF-1 release from T47D cells. Finally, in SKBR3, E2-resistant cells, EGFR was constitutively activated, and AMD3100 reduced EGFR phosphorylation and cell proliferation, whereas HER2-neu was transactivated by SDF-1 in SKBR3 but not in T47D cells. In conclusion, we show that activation of CXCR4 transduces proliferative signals from the E2 receptor to EGFR, whose inhibition is able to revert breast cancer cell proliferation induced by multiple receptor activation.
Molecular pharmacology 02/2008; 73(1):191-202. · 4.53 Impact Factor
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ABSTRACT: Assessment of the conduction velocity of motor fibers of the rat tail nerves has been used by some authors in the past, but very little is known about the sensory fibers. In 10 adult rats, weighing between 320 and 380 g, responses from the nerves and muscles of the tail have been recorded after stimulation at its root and tip. It was found that stimulation of the tip involved mainly sensory fibers, of which two main groups could be identified. One faster group, conducting within the range of 38-27 m/s, and one slower group with range 14-7 m/s. The bipolar recording configuration was found to be optimal for sensory recording. Stimulation of the tail root evoked a motor response, which was preceded by a very small neurographic activity, due to the fastest sensory fibers conducting antidromically. The conduction velocity of motor fibers was calculated to be approximately 19 m/s. Distance traveled by the volley can be assessed with excellent precision on the tail nerves; hence the calculated conduction velocities are highly reliable and reproducible. We propose that the tail nerves may be a useful tool for evaluation of conduction velocity of Abeta and Adelta afferents. As the technique is just minimally invasive, the test can be repeated a number of times in animals under chronic experimental conditions.
Experimental Neurology 02/2007; 203(1):148-57. · 4.70 Impact Factor
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FEDERICA BARBIERI,
ADRIANA BAJETTO,
CAROLA PORCILE,
ALESSANDRA PATTAROZZI,
ALESSANDRO MASSA, GIANLUIGI LUNARDI,
GIANLUIGI ZONA,
ALESSANDRA DORCARATTO,
JEAN LOUIS RAVETTI,
RENATO SPAZIANTE,
GENNARO SCHETTINI,
TULLIO FLORIO
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ABSTRACT: Recent evidence indicates that cancer cells express chemokine (CK) receptors and that their signaling is crucial for tumor proliferation, migration, and angiogenesis. The profiles of expression of CXC CK receptors (CXCR1-5) and their main ligands (growth-related oncogene, GRO1-2-3/CXCL1-2-3; interleukin 8, IL-8/CXCL8; monokine-induced -interferon MIG/CXCL9; -interferon-inducible-protein-10, IP-10/CXCL10; stromal cell-derived factor-1, SDF1/CXCL12; B-cell activating CK-1, BCA-1/CXCL13) were analyzed by reverse transcription polymerase chain reaction (RT-PCR) in surgical samples of human meningiomas. All the five receptors displayed high percentages of positive cases: 92% CXCR1, 89% CXCR2, 83% CXCR3, 78% CXCR4, and 94% CXCR5. Conversely, their ligands showed a lower pattern of expression: 40% IL-8, 42% GRO1-3, 42% IP-10, 28% MIG, 53% SDF1, and 3% BCA-1. SDF1/CXCR4 interaction plays a pivotal role in cancer proliferation. Thus, the signaling mechanisms activated by the exclusive binding between SDF1 and CXCR4 was investigated in 12 primary cultures from meningioma tissues. CXCR4 was functionally coupled as demonstrated by the significant increase of DNA synthesis in meningioma cells in response to SDF1, measured by [3H]-thymidine uptake. In three primary cultures, the SDF1-dependent mitogenic activity was associated with a marked phosphorylation of extracellular signal-regulated kinase (ERK1/2) as evaluated by Western blots. PD98059 (a MEK inhibitor) significantly reduced ERK1/2 activation, thus linking the SDF1/CXCR4 pathway to meningioma cell proliferation via ERK1/2 signal transduction. We demonstrate, for the first time in human meningiomas, the simultaneous expression of CXCR1-5 and their CKs and the mitogenic activity of SDF1/CXCR4, suggesting a pivotal role of these receptor–ligand pairs in meningeal tumors.
Annals of the New York Academy of Sciences 01/2007; 1090(1):332 - 343. · 3.15 Impact Factor
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Federica Barbieri,
Adriana Bajetto,
Carola Porcile,
Alessandra Pattarozzi,
Alessandro Massa, Gianluigi Lunardi,
Gianluigi Zona,
Alessandra Dorcaratto,
Jean Louis Ravetti,
Renato Spaziante,
Gennaro Schettini,
Tullio Florio
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ABSTRACT: Recent evidence indicates that cancer cells express chemokine (CK) receptors and that their signaling is crucial for tumor proliferation, migration, and angiogenesis. The profiles of expression of CXC CK receptors (CXCR1-5) and their main ligands (growth-related oncogene, GRO1-2-3/CXCL1-2-3; interleukin 8, IL-8/CXCL8; monokine-induced gamma-interferon MIG/CXCL9; gamma-interferon-inducible-protein-10, IP-10/CXCL10; stromal cell-derived factor-1, SDF1/CXCL12; B-cell activating CK-1, BCA-1/CXCL13) were analyzed by reverse transcription polymerase chain reaction (RT-PCR) in surgical samples of human meningiomas. All the five receptors displayed high percentages of positive cases: 92% CXCR1, 89% CXCR2, 83% CXCR3, 78% CXCR4, and 94% CXCR5. Conversely, their ligands showed a lower pattern of expression: 40% IL-8, 42% GRO1-3, 42% IP-10, 28% MIG, 53% SDF1, and 3% BCA-1. SDF1/CXCR4 interaction plays a pivotal role in cancer proliferation. Thus, the signaling mechanisms activated by the exclusive binding between SDF1 and CXCR4 was investigated in 12 primary cultures from meningioma tissues. CXCR4 was functionally coupled as demonstrated by the significant increase of DNA synthesis in meningioma cells in response to SDF1, measured by [3H]-thymidine uptake. In three primary cultures, the SDF1-dependent mitogenic activity was associated with a marked phosphorylation of extracellular signal-regulated kinase (ERK1/2) as evaluated by Western blots. PD98059 (a MEK inhibitor) significantly reduced ERK1/2 activation, thus linking the SDF1/CXCR4 pathway to meningioma cell proliferation via ERK1/2 signal transduction. We demonstrate, for the first time in human meningiomas, the simultaneous expression of CXCR1-5 and their CKs and the mitogenic activity of SDF1/CXCR4, suggesting a pivotal role of these receptor-ligand pairs in meningeal tumors.
Annals of the New York Academy of Sciences 01/2007; 1090:332-43. · 3.15 Impact Factor
