Biomedical subjects

E Villa

Publications and source records attributed to E Villa.

At least 55 records · Page 3Linked to original sources

PubMed2000

Paclitaxel and carboplatin in combination with gemcitabine: a phase I-II trial in patients with advanced non-small-cell lung cancer. Gruppo Studio Tumori Polmonari Veneto (GSTPV).

BACKGROUND: The combination of paclitaxel (P) and carboplatin (C) is an effective treatment for advanced NSCLC. Gemcitabine (G) is an active new drug. We planned a phase I study to find the maximum tolerated dose (MTD) of the PCG combination. A phase II study was subsequently conducted to evaluate the activity and toxicity of PCG. PATIENTS AND METHODS: Forty-five patients entered the study. Twenty-eight had stage IIIA-B disease, 17 stage IV. In the phase I study, with a fixed dose of C at AUC = 6 on day 1, P was escalated using increments of 25 mg/m2 starting from 175 mg/m2 on day 1 and G with increments of 200 mg/m2 starting from 800 mg/m2 on day 1 and 8. RESULTS: Fourteen patients entered the phase I study. The MTD was reached at P 200 mg/m2, C AUC = 6 and G 1000 mg/m2. Neutropenic fever and grade 3 diarrhea were the dose limiting toxicities. Thirty-one patients were treated in the phase II study with P 175 mg/m2, C AUC = 6 and G 1000 mg/m2. Response rate was 57% (68% in stage III and 47% in stage IV). Myelosuppression was the main toxicity, with grade 3-4 leukopenia occurring in 35% of cases. Grade 3 anemia was observed in 24% of cases and grade 3-4 thrombocytopenia occurred in 34% of patients. Non-hematological toxicity was mild. Median survival and one-year actuarial survival were 20.5 months and 74% for stage III and 11.5 months and 47% for stage IV. CONCLUSIONS: PCG is a promising regimen for treating advanced NSCLC. A phase III study comparing PCG to paclitaxel plus carboplatin in advanced NSCLC is ongoing. On the other hand, we are planning to introduce the PCG regimen in the treatment of stage II-III patients in the setting of a multimodality treatment.

Adult↗

PubMed2000

Natural history of inoperable hepatocellular carcinoma: estrogen receptors' status in the tumor is the strongest prognostic factor for survival.

Clinical course in hepatocellular carcinoma may be very different. We prospectively evaluated 96 patients with hepatocellular carcinoma unsuitable for radical therapy to investigate factors that could influence survival. Clinical, pathologic, and molecular data of patients were analyzed by univariate and multivariate analysis. The overall actuarial probability of survival at year 1, 2, 3, 4, 5, and 6 was 72%, 41%, 38%, 24%, 20%, and 9%. At univariate analysis, alpha-fetoprotein (AFP) (P =.0082); alkaline phosphatase (P =.0281); bilirubin (P =.0076); etiology (P =.0001); increment of tumor mass at month 3 (P =.0051); type of estrogen receptor (ER) in the tumor (P =.0000); prothrombin time (P =.0003); and portal vein thrombosis (P =.0000) had prognostic significance. At multivariate analysis, only type of ER (P =.0000) and bilirubin (P =.0030) showed independent predictive value for mortality. Survival was significantly longer in patients with wild-type estrogen receptors (P =.0000). Cumulative probability of survival at year 1, 2, 3, 4, 5, and 6 was 94%, 66%, 52%, 43%, 35%, and 18% for wild-type and 51%, 21%, 16%, and 9% for variant estrogen receptors (no patients alive after 4 years). Hepatitis B surface antigen (HBsAg)-positive patients with variant ERs had a median survival of 8 months versus 45 months in anti-hepatitis C virus-positive patients with wild-type ERs (P =.0001). In conclusion, (1) the presence of variant liver ER transcripts in the tumor was the strongest negative predictor of survival in inoperable hepatocellular carcinoma; (2) their presence was associated with spontaneous survival significantly worse than in patients with wild-type estrogen receptors; and (3) HBsAg-positive patients with variant receptors were characterized by the worst survival.

Aged↗

PubMed2000

Consolidation radiotherapy to bulky or semibulky lesions in the management of stage III-IV diffuse large B cell lymphomas.

BACKGROUND: To assess the impact on survival of consolidation radiotherapy to bulky or semibulky lesions in patients with advanced diffuse large B cell lymphoma (DLCL) in complete remission after primary chemotherapy. PATIENTS AND METHODS: Ninety-four patients with stage III-IV DLCL and bulky ( > or =10 cm) or semibulky lesions (6-9 cm) in complete remission after primary chemotherapy were reviewed. Forty patients received consolidation radiotherapy to bulky (n = 20) or semibulky lesions (n = 20), while 54 (18 with bulky disease) did not. Twenty-eight patients were irradiated to the involved field and 12 to the extended field with a dose of 30-46 Gy. RESULTS: In patients with bulky disease, consolidation radiotherapy prevented relapses involving exclusively the bulky area, prolonged time to relapse (TTR) (median 41+ vs. 18 months; p = 0.05) and improved 5-year overall survival (OS) (73 vs. 57%; p = 0.05). Consolidation radiotherapy reduced relapses within the semibulky area, prolonged TTR (median 26+ vs. 20 months; p = 0.01) and improved 5-year OS (59 vs. 41%; p = 0.09) also in patients with semibulky lesions. Multivariate analyses confirmed the independent association between consolidation radiotherapy and survival, and showed that a dose > or =36 Gy was related to a longer OS, while the extension of the radiotherapy field did not modify outcome. No treatment-related deaths were observed. Four patients developed a second malignancy, none of whom had undergone consolidation radiotherapy. CONCLUSIONS: Consolidation radiotherapy to bulky or semibulky lesions significantly improved the outcome in patients with advanced DLCL in complete remission after primary chemotherapy. Involved-field irradiation with 36-45 Gy made a prolonged disease control possible without either lethal toxicity or a higher incidence of second malignancies.

Adult↗

PubMed2000

A retrospective analysis of postradiation chemotherapy in 133 patients with glioblastoma multiforme.

The impact on survival of postradiation nitrosourea-containing chemotherapy (CHT) in patients with glioblastoma multiforme (GM) was analyzed retrospectively in 133 patients who completed the planned radiotherapy out of 173 observed cases. Thirty-five patients were < 50 years old, 89 were males, 20 had performance status (PS) < 70 and 72 > or = 70. Surgery was followed by radiotherapy in all cases (50-60 Gy in 95 patients, 61-70 Gy in 38 patients). At the end of radiotherapy, 43 patients received CHT, whereas 90 patients did not receive further therapy. At univariate analysis, age < 50 years, feminine gender, subtotal or total resection, radiotherapy doses > 60 Gy, and CHT had an independent prognostic value. Our results suggest that chemotherapy improves 2-year survival rates from 12% to 28% in GM. The sequence of treatment, new drugs, and combinations should be further explored.

Adult↗

PubMed1999

Fine-resolution mapping by haplotype evaluation: the examples of PFIC1 and BRIC.

Loci for two inherited liver diseases, benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis type 1 (PFIC1), have previously been mapped to 18q21 by a search for shared haplotypes in patients in two isolated populations. This paper describes the use of further haplotype evaluation with a larger sample of patients for both disorders, drawn from several different populations. Our assessment places both loci in the same interval of less than 1 cM and has led to the discovery of the PFIC1/BRIC gene, FIC1; this discovery permits retrospective examination of the general utility of haplotype evaluation and highlights possible caveats regarding this method of genetic mapping.

Cholestasis, Intrahepatic↗

PubMed1999

Docetaxel neuropathy: a distal axonopathy.

Docetaxel has been implicated as a causative agent in peripheral neuropathy, but pathological changes in peripheral nerve have not been described. During docetaxel treatment a 54-year-old man developed a sensorimotor polyneuropathy when the overall docetaxel dosage was 540 mg/m(2). Neurophysiological investigation revealed a sensorimotor axonal neuropathy. Fascicular sural nerve biopsy showed an axonal neuropathy with a preferentially loss of large myelinated fibers. There was evidence of considerable fiber regeneration. Sensory and motor symptoms progressively improved after docetaxel withdrawal.

Antineoplastic Agents, Phytogenic↗

PubMed1999

In-vivo dosimetry by diode semiconductors in combination with portal films during TBI: reporting a 5-year clinical experience.

BACKGROUND AND PURPOSE: In-vivo dosimetry is vital to assure an accurate delivery of total body irradiation (TBI). In-vivo lung dosimetry is strongly recommended because of the risk of radiation-induced interstitial pneumonia (IP). Here we report on our 5-year experience with in-vivo dosimetry using diodes in combination with portal films and assessing the effectiveness of in-vivo dosimetry in improving the accuracy of the treatment. Moreover, we wished to investigate in detail the possibility of in-vivo portal dosimetry to yield individual information on the lung dose and to evaluate the impact of CT planning on the correspondence between stated and in-vivo measured doses. MATERIALS AND METHODS: From March 1994 to March 1999, 229 supine-positioned patients were treated at our Institute with TBI, using a 6 MV X-rays opposed lateral beam technique. 146 patients received 10 Gy given in three fractions, once a day (FTBI), shielding the lungs by the arms; 70 received 12-13.2 Gy, given in 6-11 fractions, 2-3 fractions per day (HFTBI): in this case about 2/3 of the lungs were shielded by moulded blocks (mean shielded lung dose equal to 9 or 9.5 Gy). Thirteen patients received 8 Gy given in a single fraction (SFTBI, lung dose: 7 Gy). For all HFTBI and FTBI patients, midline in-vivo dosimetry was performed at the first fraction by positioning two diodes pairs (one at entrance and one at the exit side) at the waist (umbilicus) and at the pelvis (ankles). If at least one of the two diodes doses (waist-pelvis) was outside +/-5% from the prescribed dose, actions could be initiated, together with possible checks on the following fractions. Transit dosimetry by portal films was performed for most patients; for 165 of them (117 and 48, respectively for FTBI and HFTBI) the midline in-vivo dose distribution of the chest region was derived and mean lung dose assessed. As a CT plan was performed for all HFTBI patients, for these patients, the lung dose measured by portal in-vivo dosimetry was compared with the expected value. RESULTS: Concerning all diodes data, 528 measurements were available: when excluding the data of the first fraction(s) of the patients undergoing corrections (n = 392), mean and SD were respectively 0.0% and 4.5% (FTBI: -0.3 +/- 4.8%; HFTBI: 0.4 +/- 3.9%). In total 105/229 patients had a change after the first fraction and 66/229 were controlled by in-vivo dosimetry for more than one fraction. Since January 1998 a CT plan is performed for FTBI patients too: when comparing the diodes data before and after this date, a significant improvement was found (i.e. rate of deviations larger than 5% respectively equal to 30.7% and 13.1%, P = 0.007). When considering only the patients with a CT plan, the global SD reduced to 3.5%. Concerning transit dosimetry data, for FTBI, the mean (midline) lung dose was found to vary significantly from patient to patient (Average 9.13 +/- 0.81 Gy; range 7.4-11.4 Gy); for the HFTBI patients the mean deviation between measured and expected lung dose was 0.0% (1 SD = 3.8%). CONCLUSIONS: In vivo dosimetry is an effective tool to improve the accuracy of TBI. The impact of CT planning for FTBI significantly improved the accuracy of the treatment delivery. Transit dosimetry data revealed a significant inter-patient variation of the mean lung dose among patients undergoing the same irradiation technique. For patients with partial lung shielding (HFTBI), an excellent agreement between measured and expected lung dose was verified.

Ankle↗

PubMed1999

Second-line treatment for primary central nervous system lymphoma.

Failure after first-line treatment was reported in 35-60% of immunocompetent patients with primary central nervous system lymphoma (PCNSL). There are currently no reports focusing on salvage therapy. This review analyses prognostic factors and the efficacy of salvage therapy by focusing on data from papers reporting results of first-line treatment in 355 cases. The study group consisted of 173 patients presenting treatment failure. The interval between failure and death (TTD) was compared for age at relapse (< or =60 vs. >60 years), type of failure (relapse vs. progression), time to relapse (< or =12 vs. >12 months) and salvage treatment (yes vs no). Median TTD was similar in younger and older patients (P = 0.09). Relapsed patients had a longer TTD than patients with progressive disease (P = 0.002). Early relapse led to a shorter TTD than late relapse (P = 0.005). Median TTD was 14 months for patients who underwent salvage therapy and 2 months for untreated cases (P<0.00001). A multivariate analysis showed an independent prognostic role for salvage therapy and time to relapse. Age and type of failure had no predictive value. Salvage therapy significantly improves outcome and, possibly, quality of life. As many different treatments were used conclusions cannot be made regarding an optimal treatment schedule.

Aged↗

PubMed1999

Prostacyclin: its pathogenic role in essential hypertension and the class effect of ACE inhibitors on prostaglandin metabolism.

Angiotensin-converting enzyme inhibitors (ACEI) block degradation of bradykinin, and bradykinin stimulates prostacyclin synthesis. Therefore, we set out to determine whether the effects of ACE inhibitors on prostaglandin production in essential hypertensive patients are class effects or are dependent on ACE inhibitor structure. In addition, we studied whether hypertensives show an impaired capacity to synthesize vasodilator prostaglandins. To address these questions, we compared the effects of captopril (sulfhydryl-containing inhibitor), enalapril and ramipril (carboxyl-containing inhibitors) and fosinopril (phosphoryl-containing inhibitor) on blood pressure and urinary excretion of 6-keto-prostaglandin (PG) F1-alpha (the breakdown product of prostacyclin) in 44 mild-to-moderate essential hypertensive subjects before and 8 weeks after administration of an ACEI. We also studied prostacyclin excretion in 15 normotensive healthy controls. Levels of urinary 6-keto-PGF1-alpha (pg/ml) were measured by specific radioimmunoassay. Hypertensive subjects showed a lower excretion of 6-keto-PGF1-alpha than normotensive controls (212+/-147 vs 353+/-98 pg/ml, p < 0.001). All ACEI induced a significant decrease in MAP and increased the rate of excretion of the prostacyclin metabolite: C, 211+/-200 to 338+/-250 pg/ml, p < 0.05; E, 202+/-133 to 296+/-207 pg/ml, p < 0.05; R, 205+/-127 to 342+/-211 pg/ml, p < 0.05; F, 235+/-128 to 347+/-241 pg/ml, p < 0.05. In hypertensives (n = 44) the decrease in blood pressure correlated negatively with the rise in 6-keto-PGF1-alpha excretion (r = -0.51, p < 0.001). These data suggest that impaired prostacyclin biosynthesis in hypertensive patients could account for haemodynamic changes leading to the hypertensive state. Moreover, the hypotensive mechanisms of ACEI may be mediated by an increase in prostacyclin production; this effect seems to be class-dependent.

6-Ketoprostaglandin F1 alpha↗

PubMed1999

Gross pathologic types of hepatocellular carcinoma in Italy.

The prevalence and independent predictors of the different macroscopic types of hepatocellular carcinoma (HCC) were assessed in 1,073 unselected patients of 14 hospitals in Italy from May 1996 to May 1997. Solitary HCC was the most common cancer type (44.6%), followed by multinodular (44.2%), diffuse (8.4%) and massive (2.8%) types. After adjustment for the influence of confounders by multiple logistic regression analysis, Child-Pugh grades B and C were found to be independent predictors of multinodular (odds ratio, OR, 2.0; 95% confidence interval (CI) = 1.5-2.6) and diffuse (OR 2.6; 95% CI = 1.6-4.4) HCC types. These findings indicate that the majority of HCC cases are not detected at a potentially treatable stage. Delayed detection of HCC is associated with a higher likelihood of the multinodular or diffuse gross pathologic type.

Carcinoma, Hepatocellular↗

PubMed1999

Therapeutic management of stage I-II high-grade primary gastric lymphomas.

The best treatment for primary gastric lymphomas (PGL) has not yet been defined. Eighty-three patients with stage I/II PGL are documented, focusing on prognostic factors, treatment-related morbidity and mortality, and therapeutic outcome. Chemotherapy improved survival in comparison to local treatments, i.e. gastrectomy (n = 15) or gastrectomy and radiotherapy (n = 5). Patients treated with primary chemotherapy and/or radiotherapy (n = 21), with gastrectomy and chemotherapy (n = 26) or with gastrectomy and chemotherapy and radiotherapy (n = 16) showed a similar survival rate. Conservative treatment obtained a 5-year actuarial survival of 82% with a stomach preservation rate of 100%. Two treatment failures and 19 relapses (24%) were observed. Sixty patients (72%) are alive (59 no evidence of disease) at a median follow-up of 58 months. Ten-year actuarial survival is 64%. Local control was influenced by stage, tumor size, depth of infiltration, LDH ratio, and therapeutic modality, while age, stage, LDH ratio, and the use of chemotherapy had independent prognostic value. Because of its efficacy and safety, conservative strategy should be considered as first-line treatment for high-grade PGL. Gastrectomy should be indicated only for urgent cases, in which surgery followed by chemotherapy appears the best choice, followed by radiotherapy in patients with stage II2 disease.

Adult↗

PubMed1999

Use of dose-volume histograms and biophysical models to compare 2D and 3D irradiation techniques for non-small cell lung cancer.

For non-small cell lung cancer (NSCLC), unsatisfactory local control (LC) still remains an important cause of failure. It has been suggested that improved LC can be achieved with both higher radiation dosage and adequate target coverage. Modern three-dimensional treatment planning systems (3D-TPSs) offer many tools for planning optimization. Biophysical models, which estimate the normal tissue complication probability (NTCP), are gaining in importance in comparing plans. This study compares conventional two-dimensional (2D) with 3D irradiation techniques using parameters related to volumetric dose distribution and two different biophysical models predicting normal tissue tolerance to radiotherapy (RT). Nine patients with inoperable locally advanced NSCLC were treated with a beam's eye view-based 3D technique. For the same patients, a conventional treatment was simulated; the irradiation geometry and beam contour were fully defined at the simulator and then transferred to the 3D-TPS to calculate the dose distribution. Both techniques gave the same prescribed dose at the reference point. Dose-volume histograms (DVHs) and dose statistics of organs at risk (OARs) (heart, lung(s), parenchyma lung, spinal cord and oesophagus) were analysed. The probability of side effects was estimated using two different biophysical models: the integrated normal ("empirical") model and the relative seriality model. Apart from contralateral lung, the 3D irradiation technique significantly reduced the average mean doses to all OARs. The current analysis suggests that in the treatment of locally advanced NSCLC, the use of 3D irradiation techniques allows a large sparing of OARs; this advantage is confirmed by both dose statistics analysis and NTCP values.

Aged↗

PubMed1999

Non-surgical treatment with primary chemotherapy, with or without radiation therapy, of stage I-II high-grade gastric lymphoma.

Morbidity, mortality and discomfort related to gastrectomy has led some investigators to treat patients with stage I-II primary gastric high-grade lymphoma (PGL) with a conservative strategy. Here we report a retrospective series of 21 patients with PGL treated with primary chemotherapy alone or followed by radiation therapy and analyze previously reported series, focusing on therapeutic results, treatment-related morbidity and stomach preservation rate. All 21 patients with stage I-II PGL received an initial anthracycline-containing chemotherapy, which was followed by involved field-radiation therapy in 8 cases. Data regarding toxicity, response and relapse rates and survival of this patient group and 14 previously published series, involving 316 patients treated with conservative modality, were also analyzed. In the present series two patients did not complete the planned treatment, while the remaining 19 achieved a complete remission (response rate: 90%). Three patients relapsed, all of whom had been treated with chemotherapy alone. Two patients died of lymphoma, one of sepsis and the other of lung cancer while still relapse-free. The survival rate at 50 months is 81%, and the 5-year actuarial cause-specific survival is 82%. The stomach preservation rate is 100%. Previously reported series showed a response rate ranged between 76% and 100%. Gastrointestinal bleeding was observed in only 3% of cases, while no cases of gastric perforation were reported. Treatment mortality rate was 2.5%. 5-year actuarial survival ranged between 73% and 90% and stomach preservation rate was 97%. Short-term chemotherapy obtained similar results to more prolonged treatment. In conclusion, conservative treatment with primary chemotherapy followed by involved field-radiation therapy should be used for the first-line treatment of patients with stage I/II PGL considering that it is associated with a high response and survival rates, and with an insignificant risk of bleeding or perforation, high stomach preservation rate and good quality of life.

Adult↗

PubMed1999

[Integration of computerized tomography imaging with single photon emission in a commercial system for developing radiotherapy fields: application to conformational irradiation for lung carcinoma].

PURPOSE: Single photon emission computed tomography (SPECT) of lung perfusion permits to map functioning lung parenchyma with higher sensitivity than CT. Delivering higher radiation doses is used to increase local control in lung carcinoma; this strategy is based on radiobiological and clinical studies. Lung parenchyma is a dose-limiting tissue in patients irradiated for lung cancer. Functional mapping based on SPECT and CT findings permits to design radiation beams such as to minimize irradiation of functioning lung. MATERIAL AND METHODS: CT and SPECT were used to examine a patient with non small cell lung carcinoma (stage IIIB, T4N0, left lung) candidate to conformal irradiation. Images were spatially correlated based on lung contours and using CT findings as reference. SPECT images were normalized to mean right lung value and expressed as perfusion (functional) contours. CT images and perfusion contours were transferred to the treatment planning system (Cadplan V 2.79, Varian-Dosetek Oy): in this way both functional (SPECT) and anatomical (CT) data were available for planning. A comparison was made between two irradiation techniques defined at TPS with (technique B) or without (technique A) SPECT contour information. The prescribed dose was 70.2 Gy. Rival plans were compared using dose volume histograms of target and risk organs. Both functional and anatomical regions were considered in the lung, together with single lung(s) and lung parenchyma. A second perfusion SPECT was obtained 5 months after irradiation and correlated with pretreatment CT images. RESULTS: SPECT lung scans showed marked heterogeneity in the left lung, which was found neither at CT nor at classic lung function tests. The lung volume with perfusion exceeding 80% of average corresponds to about 70% of the anatomical volume. Mean doses to anatomical and to functional lung parenchyma were 24 Gy and 19 Gy, respectively, with technique A and 23 Gy and 18 Gy, respectively, with technique B. Thirty-five percent and 20%, respectively of anatomical and functional lung parenchyma received > or = 25 Gy (V25) with technique B. The figure for functional lung parenchyma was reduced by 5% with technique B. Optimal design of irradiation field geometry decreased the area of functional parenchyma given high doses, which sparing was greater with smaller irradiation volumes. CONCLUSIONS: We have integrated the functional data provided by SPECT lung perfusion into a commercial irradiation planning system. Lung function mapping permits to design irradiation portals sparing larger areas of functional lung parenchyma.

Carcinoma, Non-Small-Cell Lung↗

PubMed1999

[High-risk pulmonary surgery in potential candidates for a heart transplant].

Severe ventricular dysfunction and concomitant infection are considered absolute contraindications for major thoracic operations and immunosuppressive therapy, respectively. However, cardiac transplantation represents the first-choice treatment in advanced heart failure. We report the case of a patient with dilated cardiomyopathy and severe left ventricular dysfunction (ejection fraction = 25%), initially not considered as a potential heart transplant candidate due to the presence of a lung abscess. The patient subsequently underwent atypical pulmonary resection with intraoperative and perioperative intraaortic balloon counter-pulsation for circulatory support and was then listed for cardiac transplant. Pitfalls and intra/postoperative strategy, all of which are potentially important aspects in minimizing operative risk, are discussed.

Cardiomyopathy, Dilated↗

PubMed1998

Variant liver estrogen receptor transcripts already occur at an early stage of chronic liver disease.

Variant estrogen receptors may be found in hepatocellular carcinoma and may influence its natural history. Because it is not known whether their occurrence is an early or a late event during the course of chronic liver disease or whether they cluster in some subgroups of patients, we investigated a series of patients in different stages of chronic liver disease. One hundred eleven consecutive patients were studied for variant estrogen receptor transcripts by reverse-transcription polymerase chain reaction of RNA extracted from liver biopsy specimens. In chronic active hepatitis, variant estrogen receptor transcripts were coexpressed with wild-type significantly more often in men than in women (P = .029) and in hepatitis B surface antigen (HBsAg)-positive subjects than in subjects positive for antibody to hepatitis C virus (P = .0006). In hepatocellular carcinoma, again in men (P = .004) and in HBsAg-positive patients (P = .0015), the variant estrogen receptor transcript was overexpressed or remained the only one expressed. Patients with liver cell dysplasia presented with the same estrogen receptor pattern than patients with hepatocellular carcinoma. This further reinforces the significance of liver cell dysplasia as a preneoplastic condition. The significantly higher occurrence of variant estrogen receptor in men (especially in HBsAg-positive men) already at an early stage of disease, like chronic active hepatitis, suggests that the alteration of estrogen receptors, favoring uncontrolled proliferation and development of hyperplasia, might constitute a prominent mechanism facilitating neoplastic transformation especially in men.

Adult↗

PubMed1998

Italian Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group Trials. GROCTA Trials.

The first GROCTA trial compared 5-year tamoxifen treatment to ten chemotherapy cycles in a group of 504 pre-/post-menopausal, node-positive, ER-positive breast cancer patients. This study also included an arm combining tamoxifen with chemotherapy. Fifteen-year results showed no difference between tamoxifen and tamoxifen plus chemotherapy, while both treatments were significantly superior to chemotherapy alone. A confirmatory study (GROCTA 02) was performed in 244 pre-/perimenopausal patients by comparing 5 years of tamoxifen treatment (plus 2 years of goserelin) to six CMF cycles. No difference has emerged so far between the tamoxifen and CMF arms at a median follow-up time of 62 months. Post-menopausal women were scheduled to receive 3 years of tamoxifen treatment and then to be randomly allocated to further 2 years of tamoxifen or to 2 years of low-dose aminoglutethimide (GROCTA 04B). So far 662 patients have been entered, 375 of whom have been randomized to tamoxifen (n = 188) or aminoglutethimide (n = 187). Preliminary results (median follow-up time 32 months) show no major difference in patients' outcome. A new trial (ITA trial) with a similar design but employing anastrozole in place of aminoglutethimide has been activated in 1998. The GROCTA 03 study investigated the potential superiority of alternating adjuvant chemotherapy over standard CMF. This study, which included 107 node-positive ER-negative pre-menopausal women, was prematurely closed because more patients allocated to the triple alternated chemotherapy appeared to have relapsed and died at the first interim analysis. The use of high-dose chemotherapy (HDC) was explored by the GROCTA 06 trial which included 53 patients with ten or more involved nodes and a maximum age of 55 years. These patients were scheduled to receive three standard CEF cycles followed by one cycle of HDC (cyclophosphamide 5 g/m2; etoposide 1.5 g/m2; cisplatin 150 mg/m2) without any form of bone marrow rescue. This HDC program proved to be feasible but was not superior to CMF-based chemotherapy we had previously employed in a comparable group of patients in previous GROCTA trials. These findings prompted us to explore new HDC programmes with the use of peripheral stem cell support and in addition the possible value of new drugs such as Taxol and vinorelbine. New-generation trials will also explore the value of new prognostic indicators such as tumor proliferative activity, which are prospectively used to allocate patients to different treatment options.

Antineoplastic Agents, Hormonal↗

PubMed1998

Salt sensitivity: concept and pathogenesis.

Almost two decades ago, the existence of a subset of essential hypertensive patients, who were sensitive (according to the increase in blood pressure levels) to the intake of a diet with a high salt content, was described. These patients are characterized by an increase in blood pressure and in body weight when switched from a low to a high sodium intake. The increase in body weight is due to the incapacity of the kidneys to excrete the whole intake of sodium until renal perfusion pressure (mean blood pressure) attains a level that is able to restore pressure-natriuresis relationship to values that enable the kidney to excrete the salt ingested or administered intravenously. Salt sensitivity does not seem to depend on the existence of an intrinsic renal defect to handle sodium, but on the existence of subtle abnormalities in the regulation of the sympathetic nervous system, the renin-angiotensin system or endothelial function. It is also relevant that organ damage secondary to arterial hypertension, has been shown in animal models and in hypertensive humans sensitive to a high salt intake to be significantly higher when compared with that of salt-resistant animals or humans. Interestingly, in humans, salt sensitivity has been shown to correlate with microalbuminuria, an important predictor of cardiovascular morbidity and mortality, which correlates with most of the cardiovascular risk factors commonly associated with arterial hypertension. One of these factors is insulin resistance, that usually accompanies high blood pressure in overweight and obese hypertensives. Insulin resistance and hyperinsulinism are present in a significant percentage of hypertensive patients developing cardiovascular symptoms or death. For these reasons, therapy of arterial hypertension must be directed, not only to facilitate the lowering of BP level, but also, to halt the mechanisms underlying the increase in BP, when salt intake is increased. Furthermore, therapy must preferably improve the diminished insulin sensitivity present in salt-sensitive subjects that contribute independently to increased cardiovascular risk.

Animals↗