Biomedical subjects
L Orlando
Publications and source records attributed to L Orlando.
Vinorelbine, cisplatin and continuous infusion of 5-fluorouracil (ViFuP) in metastatic breast cancer patients: a phase II study.
PURPOSE: Chemotherapy regimens for patients with advanced breast cancer or large primary tumours (including locally advanced disease) usually contain anthracyclines, taxanes or both. We investigated a multi-agent regimen for patients for whom anthracyclines and/or taxanes may not be suitable. We assessed efficacy in terms of response rate and time to progression of a combination with continuous infusion 5-fluorouracil (5-FU), vinorelbine and cisplatin (ViFuP regimen), as a first or subsequent line treatment for metastatic breast cancer patients. PATIENTS AND METHODS: One hundred consecutive patients with advanced breast cancer were treated with 5-FU 200 mg/m2 administered continuously through a permanent central venous line; vinorelbine was given on days 1 and 3 at a dose of 20 mg and cisplatin was administered at 60 mg/m2 on day one. Therapy was given every three weeks. The median age was 50 years (range 23-72). Fifty-two patients had received prior chemotherapy for metastatic breast cancer, and sixty-one percent had previously received anthracyclines, thirty-five percent taxanes and twenty-nine percent 5-FU as a bolus injection. All patients were assessable for toxicity, four patients were not assessable for response. RESULTS: There were four complete responses (4%). Forty-nine patients had a partial response (overall response rate, 55%; 95% confidence interval (CI): 45%-65%). After a median follow-up of 10.2 months, median duration of response is 5.2 months (range 1.5-20.7+ months), time to progression (TTP) is 6.8 months (range 0.3-24.7 months). Acute toxicity, including myelosuppression, was mild: only 18% of patients had grade 4 granulocytopenia and one patient experienced grade 4 diarrhea. Only 15% of patients had any non-hematological grade 3 toxicity including nausea (4%), stomatitis (4%), diarrhea (2%), fatigue (1%), fever (1%), photosensitivity (1%), hand-foot syndrome (1%). Grade 2 alopecia was observed only in six patients (6%). Eleven patients developed a right diaphragmatic supra elevation, while deep vein thrombosis, central venous catheter associated, occurred in eight patients. CONCLUSIONS: We identified a combination chemotherapy with noteworthy efficacy and well tolerated subjectively as either a first- or second-line treatment for metastatic breast cancer patients. The regimen warrants further development focusing on the comparison with either continuous administration of oral fluoropyrimidine derivatives.
Britain's [correction of Britian's] embryo cloning law passed.
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AD gene accelerates MS.
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Attention mediated by synchrony of neurons.
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Treatment of infrabony pocket with a collagen membrane supported by cancellous bovine bone.
BACKGROUND: Treatment of infrabony pockets with guided tissue regeneration (GTR) methods using absorbable membranes supported by bone substitutes has gained wide acceptance. Our objective is to observe the clinical variations obtained with the use of these materials in a prospective clinical study. METHODS: Nine patients were treated with GTR at nine infrabony pockets using a double layered collagen membrane and deproteinized cancellous bovine bone associated with root conditioning by application of tetracycline-HCl. The nine patients included in this study had adult periodontitis, were non-smokers and responded well to initial therapy. The sites evaluated had probing pocket depths of at least 5 mm and an angular defect of at least 2 mm. The clinical parameters considered were probing pocket depth (PPD), clinical attachment level (CAL) and gingival recession (REC). Some indexes were also evaluated: the modified Quigley and Hein's Plaque index (PI), O'Leary's bleeding index (FMBS) and the Löe and Sillness gingival index (GI). These parameters were measured one week before surgery and at the control visit after an average of 22.9 months. After the removal of the sutures on the eighth day the patients received professional oral hygene every four months at their private dentists' offices. The baseline and the final measurements were compared with the Student OtO-test to verify the statistical significance of this case series. RESULTS: The mean values of PI, FMBS and GI remained unvaried (p>0.05). Results showed an average decrease in PPD of 4.0+/-2.7 mm (p=0.0002), an average increase of CAL of 4.1+/-2.1 mm (p=0.0001) and an average decrease in recession of 0.2+/-1.2 mm (p=0.594). The value of statistical significance was set at p=0.05. CONCLUSIONS: We can conclude that the materials used in this study behaved well clinically and that the surgical technique described has given results that, within the limits of the number of cases reported, has modified the PPD and CAL in a significant manner.
Unexpected right phrenic nerve injury during 5-fluorouracil continuous infusion plus cisplatin and vinorelbine in breast cancer patients.
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Novel role for the NMDA receptor redox modulatory site in the pathophysiology of seizures.
Redox-active compounds modulate NMDA receptors (NMDARs) such that reduction of NMDAR redox sites increases, and oxidation decreases, NMDAR-mediated activity. Because NMDARs contribute to the pathophysiology of seizures, redox-active compounds also may modulate seizure activity. We report that the oxidant 5, 5'-dithio-bis(2-nitrobenzoic acid) (DTNB) and the redox cofactor pyrroloquinoline quinone (PQQ) suppressed low Mg(2+)-induced hippocampal epileptiform activity in vitro. Additionally, in slices exposed to 4-7 microM bicuculline, DTNB and PQQ reversed the potentiation of evoked epileptiform responses by the reductants dithiothreitol and Tris(2-carboxyethyl)phosphine (TCEP). NMDA-evoked whole-cell currents in CA1 neurons in slices were increased by TCEP and subsequently decreased by DTNB or PQQ at the same concentrations that modulated epileptiform activity. However, DTNB and PQQ had little effect on baseline NMDA-evoked currents in control medium, and PQQ did not alter NMDAR-dependent long-term potentiation. In contrast, in slices returned to control medium after low Mg(2+)-induced ictal activity, DTNB significantly inhibited NMDAR-mediated currents, indicating endogenous reduction of NMDAR redox sites under this epileptogenic condition. These data suggested that PQQ and DTNB suppressed spontaneous ictal activity by reversing pathological NMDAR redox potentiation without inhibiting physiological NMDAR function. In vivo, PQQ decreased the duration of chemoconvulsant-induced seizures in rat pups with no effect on baseline behavior. Our results reveal endogenous potentiation of NMDAR function via mass reduction of redox sites as a novel mechanism that may enhance epileptogenesis and facilitate the transition to status epilepticus. The results further suggest that redox-active compounds may have therapeutic use by reversing NMDAR-mediated pathophysiology without blocking physiological NMDAR function.
Response to primary chemotherapy in breast cancer patients with tumors not expressing estrogen and progesterone receptors.
BACKGROUND: We recently demonstrated that in premenopausal patients with estrogen receptors (ER)-absent tumors, early initiation of systemic chemotherapy after primary surgery might improve outcome. These data indicate a different responsiveness to chemotherapy for tumors not expressing hormone receptors. To test this hypothesis we evaluated the responsiveness to preoperative chemotherapy in patients with ER and progesterone receptors (PgR)-absent tumors. PATIENTS AND METHODS: Patients with biopsy-proven T2-T3, N0-2 breast cancer treated at a single institution from January 1995 to August 1999 with preoperative chemotherapy were retrospectively evaluated. ER and PgR were determined immunohistochemically and classified for this purpose as absent (0% of the cells positive) or positive (> or = 1% of the cells). RESULTS: On 117 evaluable patients 72 had an objective response (61%). A significant difference in response was observed for patients with ER and PgR absent compared with those with ER and/or PgR-positive tumors (82% vs. 57%, P = 0.03 Fishers's exact test). Pathological complete remission rates were also significantly different in the two groups (23% vs. 7%, respectively; P = 0.04). CONCLUSIONS: The different degree of response according to hormone receptors expression supports the hypothesis that tumors not expressing both ER and PgR might represent a different clinical entity in terms of chemotherapy responsiveness.
Incidence of venous thromboembolism in breast cancer patients during chemotherapy with vinorelbine, cisplatin, 5-fluorouracil as continuous infusion (ViFuP regimen): is prophylaxis required?
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Introducing taxanes in the adjuvant treatment of breast cancer: expectations and reality.
Adjuvant chemotherapy in early breast cancer significantly improves disease-free and overall survival. However, a recent update of the world-wide overview indicated that improvements, though statistically significant, are of modest magnitude. Considering the results of individual clinical trials, further improvements in disease-free survival through introduction of new drugs as part of adjuvant treatment for breast cancer are expected to be small. Phase III studies in advanced, measurable disease, each involving several hundreds of patients, have been conducted with both paclitaxel and docetaxel and these results are now available. The high level of efficacy observed, especially with docetaxel, has led to their prompt introduction into adjuvant trials, and the results of one trial with paclitaxel are already available. In this trial, which included 3170 patients, paclitaxel was given every three weeks for four courses following an adjuvant treatment with four courses of doxorubicin and cyclophosphamide (AC) combination. The sequential use of the AC following by the taxane showed an early significant improvement of disease-free survival as compared to AC alone, but the difference observed was exclusively in the 40% of patients who had oestrogen receptor (OR)-negative disease. These patients, and a few of those with OR-positive primaries, did not receive tamoxifen following chemotherapy. Differences in duration of the entire adjuvant treatment programme might have influenced results leading to potentially the wrong conclusion being drawn that the taxane made the difference and other treatment variables had a negligible influence on outcome. Taxanes deserve a 'fair trial' in the adjuvant setting. Moreover, potential cardiotoxicity and long-term impact of high-dose steroids suggest that caution and longer follow-up are required before the definitive introduction of taxanes into the routine care of patients with early breast cancer.
Detection by denaturant gradient gel electrophoresis of tumor-specific mutations in biopsies and relative bronchoalveolar lavage fluid from resectable non-small cell lung cancer.
A PCR-denaturant gradient gel electrophoresis (DGGE) method was developed for the detection of p53 and K-ras mutations in primary operable tumors and paired BAL samples of non-small cell lung cancer. Among 36 patients, 9 showed p53 exon V mutations in biopsies and in three paired bronchoalveolar lavage (BAL) specimens with a 33% concordance. Five patients presented p53 exon VI mutations in biopsies and in two paired BALs with a 40% concordance. No mutations were found in p53 exon VII either in biopsies or in paired BAL samples with 100% concordance. Exon VIII mutations were found in six primary tumors and in two BALs with a 33% concordance. Of 36 patients, we detected 7 (19.4%) with K-ras exon I mutations on tumor samples. DGGE analysis of DNA from BAL samples revealed three mutations distributed on K-ras exon I with a 42% overall concordance with respect to tumor tissue. Molecular screening by DGGE of p53-amplified DNA from BAL had cumulative 46.6% sensitivity, 100% specificity, and 77.7% accuracy. DGGE K-ras detection showed 43% sensitivity, 100% specificity, and 88.8% test accuracy. The method proposed demonstrated to be specific, accurate, and at relatively low cost but limited by low sensitivity in detecting the presence of neoplastic cells in patients with resectable non-small cell lung cancer.
Prediction of response to primary chemotherapy for operable breast cancer.
The use of primary systemic cytotoxics leads to a high remission rate in patients with breast cancer. Response was identified as an important variable associated with survival. Thus, features which predict response, are potentially relevant for planning treatments and improving survival. Retrospectively, we investigated several histopathological features (expression of oestrogen and progesterone receptors, Mib1, bcl-2, c-erbB-2, and p53) prior to two programmes of either sequential preoperative chemotherapy (doxorubicin plus cyclophosphamide) and radiotherapy (Group A), or preoperative chemotherapy (5-fluorouracil, folinic acid and vinorelbine) alone (Group B) in patients with operable breast cancer. After three courses, patients with a partial or complete response were given a further three courses, which was followed for patients in Group A by radiotherapy 50 Gy plus a boost of 10 Gy. All patients were submitted to surgery after completion of preoperative treatment and pathology material from 73 patients (median age, 49 years, range, 30-70; performance status, 0-1; 68 T2, 5 T3) was obtained. The overall response rate according to radiological and clinical evaluation was 59% (68% for Group A and 49% for Group B). 12 of 14 patients with p53-positive tumours and 31 of 59 with p53-negative tumours responded (P = 0.04). 6 of 7 patients with elevated c-erbB-2 had a response compared with 37 of 66 patients in the group with c-erbB-2 negative tumours (P = 0.03). Mib1 expression decreased substantially (> or = 50%) in 25 patients during treatment, of whom 20 responded compared with 21 of 48 patients with a lower decrease (P = 0.04). Response was observed in 28 of 37 patients with high baseline Mib1 (> 20%) and in 15 of 36 patients in the low Mib1 group (P = 0.05). Finally, 32 of 44 tumours with low expression of progesterone receptors responded compared with 11 of 29 tumours with high receptors expression (P = 0.05). These markers might be useful for tailoring primary and postsurgical systemic treatments.
Hepatic toxicity from cyclophosphamide, methotrexate, fluorouracil (CMF regimen)
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High-dose ifosfamide plus adriamycin in the treatment of adult advanced soft tissue sarcomas: is it feasible?
BACKGROUND: Adriamycin (ADM) and ifosfamide (IFO) are the two most active agents in the treatment of soft tissue sarcomas (STS) with a clear dose-response relationship. We evaluated the feasibility and toxicity of a high-dose IFO-plus-ADM combination. PATIENTS AND METHODS: Fourteen patients with advanced disease and nine patients in adjuvant setting received IFO 12.5 g/m2 in 120-hour continuous infusion with Mesna uroprotection and ADM 20 mg/m2 on days 1-3 and G-CSF every three weeks. RESULTS: Twenty-three patients received 89 chemotherapy cycles (70 cycles at full dose). Seventeen patients received the planned treatment, and nine patients required dose reductions. We observed grade 3-4 neutropenia in 52 cycles (59%)/20 patients; grade 3-4 thrombocytopenia in 16 cycles (18%)/nine patients; grade 3-4 anaemia in 24 cycles (27%)/11 patients. Eight patients experienced febrile neutropenia and six patients required blood transfusions. CONCLUSIONS: While feasible, this regimen showed heavy toxicity. Nevertheless, 74% of the patients were able to complete the planned treatment. Adjustment of the schedule of IFO continuous infusion to improve this combination is currently under investigation.
Assessment of response in primary chemotherapy for breast cancer.
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