Circulating asymmetric dimethylarginine and lipid profile in pre-pubertal children with growth hormone deficiency: effect of 12-month growth hormone replacement therapy.

OBJECTIVE: Growth hormone deficiency (GHD) in adults is associated with cardiovascular complications, which lead to reduced life expectancy. At present, data on cardiovascular risk factors in GHD children are limited. The aim of this study was to evaluate whether pre-pubertal GHD children have increased cardiovascular risk factors, and whether 12-month growth hormone (GH) treatment can reverse them. DESIGN: Twenty pre-pubertal GHD children (6 boys, mean (±SD) age: 9.5±1.8 years) were matched for sex and age with 20 healthy controls (6 boys, mean (±SD) age: 8.8±1.5 years). Asymmetric dimethylarginine (ADMA), lipid profile, glucose metabolism parameters, IGF-1, blood pressure and anthropometric parameters were assessed at baseline and after 12 months of GH treatment. RESULTS: At baseline, GHD patients showed significantly higher ADMA levels (median [interquartile range]: 78.5 [69.6-123.5] vs 54.0 [38.3-60.8] ng/ml, p<0.001), total cholesterol (mean±SD: 177.5±30.4 vs 150.1±21.4 mg/dl; p=0.004) and LDL-cholesterol (mean±SD: 111.2±22.2 vs 84.9±15.9 mg/dl; p<0.001) than controls. After 12-month GH treatment, ADMA (median [interquartile range]: 55.4 [51.2-73.8] ng/ml), total cholesterol (mean±SD: 155.6±43.2 mg/dl), and LDL-cholesterol (mean±SD: 95.4±32.1 mg/dl) significantly decreased in GHD children, reaching values comparable to those in controls. CONCLUSIONS: This study showed that, as in adults, pre-pubertal GHD children manifest increased cardiovascular risk markers and that 12-month GH treatment can improve them.

The combination of carboplatin and weekly paclitaxel: a safe and active regimen in advanced non small-cell lung cancer patients. A phase I-II study.

The combination of carboplatin and paclitaxel given every three weeks is a tolerated and reasonably active regimen in advanced non-small cell lung cancer (NSCLC). This study was designed to evaluate the maximum tolerated dose (MTD) of a fixed dose of carboplatin with an area under the curve (AUC) of 6 and escalating doses of weekly paclitaxel with an initial dose of 50 mg/m2 with 10 mg/m2 increments at each level in untreated NSCLC patients (phase I study). The study continued with a phase II study. Thirty patients entered the phase I study. The MTD was: carboplatin AUC = 6 on days 1 and 28 plus paclitaxel 100 mg/m2 (1 hour) on days 1, 8,15, 28. The dose-limiting toxicity (DLT) was severe neutropenia and cardiological toxicity. Subsequently, 42 patients entered the phase II study with the same treatment schedule. The 2-drug combination was globally well tolerated. The overall response rate (RR) was 42% [CI 95%: 26.3-57.7], stable disease (SD) 29% and progression (PD) 29%. The median duration of response was 8.0 mos (range: 1.0-19.0). The median time to progression was 8.0 mos (range: 7.0-19.0) and the median survival was 14.0 months (range: 9.0-19.0). The association of carboplatin AUC = 6 and weekly paclitaxel 100 mg/m2 proved to be manageable, active and extremely safe even in elderly patients (one third of all patients in our cohort). The survival results were interesting: the median survival time was 14 months (9-19 months) and the 1- and 2-year survival was 59% and 16%, respectively.

Cisplatin and escalating doses of paclitaxel and epirubicin in advanced ovarian cancer. A phase I study.

PURPOSE: The combination of paclitaxel and cisplatin is considered the standard regimen for advanced ovarian cancer (AOC). A meta-analysis has shown that the incorporation of anthracyclines into first-line chemotherapy might improve long-term survival by 7-10%. We designed a phase I-II study in patients with AOC using a combination of a fixed dose of cisplatin with paclitaxel and epirubicin both given at escalating doses every 3 weeks. The objectives of this study were to determine both the maximum tolerated dose (MTD) and the antitumor activity of this combination. METHODS: Six different dose levels were planned. The starting doses were cisplatin 75 mg/m2, paclitaxel 140 mg/m2, and epirubicin 50 mg/m2. The doses of paclitaxel were escalated in 20-mg/m2 increments, alternating with 20-mg/m2 increments of epirubicin. Ten patients with AOC entered the phase I study. Three patients each were enrolled at level I and level II and four patients at level III, and at each level, 15 courses were administered. Patients received a median of five courses. RESULTS: Nonhematological toxicity was generally mild, except for grade 3 mucositis in one course at levels II and III, and grade 3 vomiting in one course at levels I and III. Hematological toxicities were grade 3-4 neutropenia in 60%, 47% and 60% of courses at levels I, II and III, respectively, and grade 3 anemia in one course at level III. At level III two of four patients developed a dose-limiting toxicity which was grade 4 neutropenia lasting more than 1 week. CONCLUSIONS: The MTD was reached at level II with cisplatin 75 mg/m2, paclitaxel 160 mg/m2, and epirubicin 50 mg/m2. The phase II part of the study is currently ongoing.

Oral glycoprotein IIb/IIIa antagonism in patients with coronary artery disease.

Dose-finding studies and trials of interaction of oral glycoprotein IIb/IIIa antagonists with other antiplatelet agents have been limited. We hypothesized that these detailed assessments could be first performed in patients with stable coronary artery disease (CAD) and then extrapolated to the target population. To this end, we performed 2 sequential studies. The first study examined the dose-related effects on indexes of platelet and vascular function induced by the oral inhibitor RPR 109891, when given alone and in combination with aspirin, in patients (n = 100) with stable CAD. The second study (the Antagonism of the FIbrinogen Receptor after Myocardial Events trial) assessed the pharmacodynamics and safety of derived regimens in patients (n = 320) with unstable coronary syndromes. In patients with stable CAD, platelet aggregation was dose dependently inhibited by RPR 109891, and the dose-response relation was shifted to the right by the concomitant administration of aspirin (p = 0.0001). The degree of platelet inhibition induced by 3 doses of RPR 109891 (plus aspirin) was lower in patients with unstable than stable CAD. No drug-related major bleeding occurred in either study. RPR 109891 treatment was associated with acute and delayed thrombocytopenia. In conclusion, chronic treatment with an oral glycoprotein IIb/IIIa antagonist (1) induces antiplatelet effects that are potentiated by concomitant administration of aspirin, (2) may require dose adjustment in syndromes of platelet activation, (3) is associated with a low rate of clinically significant bleeding when doses inducing incomplete inhibition of platelet aggregation are used, and (4) requires frequent monitoring of platelet count unless reliable predictors of delayed thrombocytopenia become available.

Formestane, a steroidal aromatase inhibitor after failure of non-steroidal aromatase inhibitors (anastrozole and letrozole): is a clinical benefit still achievable?

BACKGROUND: There are few clinical data on the sequential use of aromatase inhibitors (AI). This paper focuses on the relevance of clinical benefit CB (CR + PR + SD > or = 6 months) in postmenopausal metastatic breast cancer (MBC) patients treated with the steroidal aromatase inhibitor (SAI) formestane (FOR). who had already received non-steroidal aromatase inhibitor (nSAI): letrozole (LTZ) or anastrozole (ANZ). PATIENTS AND METHODS: Twenty postmenopausal women with MBC were analysed in this retrospective two-centre study with the sequence nSAI-FOR. When receiving ANZ, 1 of 11 achieved a complete response and 9 of 11 a stable disease > or = 6 months, and receiving LTZ 1 of 9 achieved a partial response and 4 of 9 a stable disease > or = 6 months. The analysis of the entire population treated with FOR showed an overall CB of 55% (11 of 20) with a median duration of 15 months and median time to progression (TTP) of 6 months. CONCLUSIONS: Formestane 250 mg once bi-weekly seems to be an attractive alternative third-line hormonal therapy for the treatment of patients with MBC, previously treated with nSAI.

Weekly schedule of vinorelbine in pretreated breast cancer patients.

PURPOSE: In this phase II study, we explored tolerability and activity of vinorelbine administered according to a dose-dense weekly schedule with hematopoietic growth factor support in pretreated, advanced breast cancer patients. PATIENTS AND METHODS: From January 1994 to March 1996, 40 patients with metastatic breast cancer, pretreated with at least one prior anthracycline-containing regimen, were entered into the study. PATIENT CHARACTERISTICS: median age 53 years (range 32-70); ECOG performance status 0-1: 34 patients, 2: 6 patients; dominant visceral metastatic disease: 15 patients, dominant non-visceral: 25; anthracycline-refractory/resistant: 2 patients, sensitive: 38 patients. Six patients were treated as first-line therapy for metastatic disease and 34 in second- or subsequent lines. All patients received vinorelbine at the dose of 25 mg/m2/week as a short intravenous infusion, together with routine antiemetic medication. Granulocyte-colony stimulating factor (Lenograstim) at the dose of 150 microg/m2 subcutaneously on day 3 was included in the treatment schedule. RESULTS: The median number of treatment weeks was 23 (range: 4-24), with a delivered dose-intensity (DDI) of 23.8 mg/m2/week (range: 18.7-25, 95.2% of projected dose-intensity). Toxicity was mild, with non-complicated neutropenia being the main toxicity observed (grade 3-4 in 25% of the patients but only 2% of treatment weeks). Overall response rate was 52.5%, with complete responses in 12.5% of patients. Median duration of the response and median time to progression were 10 and 9 months, respectively. Median overall survival was 19 months. CONCLUSION: Dose-dense weekly vinorelbine is safe and effective with minimal toxicity in pretreated advanced breast cancer patients.

Ifosfamide and vinorelbine in advanced pretreated ovarian cancer: a phase II study.

PURPOSE: The response rate to salvage chemotherapy in advanced ovarian cancer (AOC) has been disappointing in patients who do not respond or relapse after platinum-containing regimens. Ifosfamide (IFO) showed an overall response rate of 20% and vinorelbine (VNR) 15.6%. Trials of the association of these two drugs for AOC have not yet been published. PATIENTS AND METHODS: Between April 1996 and August 1997, 17 patients with AOC were treated with intravenous IFO 2000 mg/m2 per day, days 1 to 3, with mesna uroprotection, and VNR 25 mg/m2 per day, days 1 and 8, every 3 weeks. All patients but one had been heavily pretreated. All patients had been treated with platinum compounds and 16/17 with taxanes. RESULTS: All 17 patients were evaluable for toxicity, and 16 for response (one lost to follow-up). One patient showed a partial response, 12 progressive disease and three stable disease. No complete responses were observed. The main toxicity was neutropenia (grade 3-4 in 82% of patients) with neutropenic fever in 17.6% of patients. In 70.5% of patients (19/59 of courses) VNR was not administered on day 8. In four patients (10/59 courses) the dose was reduced by 25% for persistent leukopenia grade 2-3. Other toxicities were not significant. CONCLUSIONS: This combination showed no activity in this set of patients. The poor outcome, as compared with the significant activity reported with the agents used singly, could be ascribed to the patients' characteristics, the low dose intensity of VNR administered and possible cross-resistance between the study drugs and previously used agents.

Brachial plexus neuropathy as unusual onset of diffuse neurolymphomatosis.

We present a patient with a large B cell gastric lymphoma in total remission who, after 4 months, developed a fatal progressive peripheral neuropathy with an unusual early involvement of the right brachial plexus. No evidence of lymphoma was found at whole body computed tomography, magnetic resonance imaging of the head, cervical spine and right brachial plexus, bone marrow biopsy or repeated lumbar punctures. The diagnosis of neurolymphomatosis was made only at postmortem examination.

Oral iron chelating therapy. A single center interim report on deferiprone (L1) in thalassemia.

BACKGROUND AND OBJECTIVE: Deferiprone (L1) is a largely studied oral chelator in clinical setting, however, no definite conclusions concerning efficacy and toxicity still could be drawn. In an ongoing prospective trial with L1, we evaluated the efficacy and tolerance-toxicity in patients with thalassemia major previously treated by desferrioxamine (DFO); the specific aim of the study is to demonstrate that L1 could be an alternative to DFO in some patients with an acceptable toxicity. DESIGN AND METHODS: Sixty-nine patients over 13 years of age with poor compliance to DFO were considered for the study. The design included a liver biopsy before starting L1 in all patients in order to define liver siderosis either by histologic grading or by hepatic iron concentration (HIC); only patients with a minimum HIC of 4 mg/g dry weight entered the study. A repetition of the liver biopsy after one year of L1 was planned; further evaluations included serum ferritin, plasma iron, transferrin TIBC and iron urine excretion. L1 was given at 70 mg/kg/day in three divided doses. Toxicity was monitored either clinically or by controlling liver, kidney and marrow function by specific tests. Concerning clinical characteristics 52 patients showed hypogonadism (78%), 39 growth retardation (58%), 6 diabetes (9%), 4 cardiomyopathy (6%), 9 hypothyroidism (12%); 45 patients had chronic liver damage (65%). RESULTS: We focus this report on data collected in a group of 29 patients with a minimum follow-up of one year (14-33 months). The mean ferritin value was 3748 ng/mL (range: 200-10,000) and 2550 ng/mL (range: 80-14,500), before and while on L1 therapy, respectively (p = 0.001); the mean sideruria changed from 17.25 mg/dL (range: 5.4-50) to 20.98 mg/dL (range: 10-40), on DFO and L1, respectively (p = 0.078); the ratio between plasma iron (sideremia) and transferrin TIBC changed from 0.96 with DFO to 0.86 with L1 (0.014). A correlation with grade of liver siderosis and serum ferritin (p = 0.069) and iron urine excretion (p = 0.008) was recorded. The judgement of efficacy showed that L1 was effective (EF) in 9 patients, no assessable (UN) in 11 patients, not effective (NE) in 2 patients and with no advantages with respect to DFO in 7 patients. Liver biopsy was repeated in 20 patients showing a reduction of grade of liver siderosis and iron content in 7 patients. Clinical toxic effects of L1 were gastric intolerance (one patient), joint pain (three patients) and mild and temporary neutropenia (one patient). INTERPRETATION AND CONCLUSIONS: This preliminary experience shows that L1 is effective in several patients with thalassemia with poor compliance to DFO and to improve iron burden and iron excretion with generally minor side effects. L1 could be an alternative to DFO in some patients, however the recognition of neutropenia warrants a careful evaluation of patients and efforts finalized to early recognition of those to be addressed with this new and still experimental therapy.

Paclitaxel as salvage therapy in advanced pretreated ovarian cancer: a phase II study.

The response rate to salvage chemotherapy in advanced ovarian cancer has been disappointing in patients who do not respond or who relapse after platinum-containing regimens. In these cases, the identification of new drugs is a substantial challenge. The efficacy of one of these, paclitaxel, has already been assessed in many phase II trials. From July 1993 to October 1995, 33 patients with advanced ovarian cancer, recurrent or refractory after platinum-based regimens, entered our study. Paclitaxel was given by 3-hour intravenous infusion every 3 weeks. All the patients were evaluable for toxicity and 27 for response. Nine patients (33.3%) responded: 6 complete (22.2%) and 3 partial responses (11.1%). Six responses (35.3%) were observed in the 17 platinum-resistant patients and 3 (30%) in the 10 platinum-responders. World Health Organization (WHO) grade 3-4 neutropenia was common (13/33 patients, 39.4%) and peripheral neurotoxicity was observed in 29 patients (87.8%), but was WHO grade 3 in four cases (12.1%). Alopecia was ubiquitous, whereas other toxic effects were not significant. The overall response rate to paclitaxel in this study is similar to that reported in others and the high complete response (CR) rate should be emphasized. These data confirm the significant activity and safety of this drug in patients with advanced ovarian cancer, even in platinum-resistant cases.

Fitoplancton del Embalse Río Hondo (Tucumán-Santiago del Estero, Argentina): Variaciones espaciales y temporales

En el presente trabajo se estudió la distribución vertical de la comunidad fitoplanctónica de la zona limnética del embalse, para el período 1992-1993, en relación a la actividad azucarera

Iron overload in thalassemia: comparative analysis of magnetic resonance imaging, serum ferritin and iron content of the liver.

BACKGROUND: Iron overload in patients with thalassemia is a common feature which requires continuous chelation therapy and monitoring. Serum ferritin determination is widely accepted as a simple method for following iron load in patients with primary hemochromatosis; however, several reports on thalassemic patients emphasize that ferritinemia is not accurate and that other methods such as direct measurement of iron in the liver (HIC) and magnetic resonance imaging (MRI) are more precise. MATERIALS AND METHODS: In order to contribute to the general understanding of iron load in thalassemia we used liver MRI to study 33 thalassemic patients, most of whom were also evaluated for iron content by liver biopsy. The data were then compared with serum ferritin levels. RESULTS: Ferritin levels ranged between 276 and 8031 ng/mL, and liver iron content ranged from 1.6 to 31.0 mg/g dry weight; grade III or IV liver siderosis was recorded in 23/33 patients, just as 23/33 patients were found to have severe or very severe siderosis at MRI. Significant correlations with ferritin levels were recorded between grade IV and grades III, II and I (p < 0.01, p = 0.02, and p = 0.03, respectively). Ferritinemia also showed significant linearity with liver iron content (r = 0.603, p = 0.001). No significant differences of levels were recorded, however, between patients found to have severe and those with mild iron load at MRI (p = 0.073). CONCLUSIONS: Our study shows that serum ferritin levels exhibit a tendency to be significantly correlated with the true status of hemochromatosis in thalassemic patients; however, the discrepancies recorded in several patients and the scarce or total lack of correlation with MRI suggest exploring other approaches to this problem in order to make proper decisions about therapy.

Oral doxifluridine in elderly patients with metastatic colorectal cancer: a multicenter phase II study.

BACKGROUND: Cancer chemotherapy in elderly patients is an important and under-researched area. Doxifluridine is a fluoropyrimidine derivative and is activated to 5-fluorouracil by uridine phosphorylase, which is more highly expressed in malignant cells. Because of the high bioavailability and low toxicity of oral doxifluridine we conducted this phase II trial to evaluate the feasibility, toxicity and activity of a home therapy with oral doxifluridine in elderly metastatic colorectal cancer patients. PATIENTS AND METHODS: Forty-three elderly metastatic colorectal cancer patients entered the study: their median ECOG performance status was 1 (0-2) and median age 74 years (69-83), the predominant site of metastasis was liver and all but one of the patients had received no previous chemotherapy. Doxifluridine was given orally at the initial daily total dose of 2250 mg for 4 consecutive days every week. The daily dose was reduced to 1500 mg if toxicities greater than grade 2 (WHO) occurred. RESULTS: Forty-two patients are evaluable for toxicity: treatment was well tolerated, with the most common side effect being diarrhea, severe in 7 (17%) patients (6 grade 3 and 1 grade 4). Thirty-six patients are evaluable for response and 2 complete and 3 partial responses have been observed (response rate 14%; 95% confidence limit interval 5%-29%). CONCLUSIONS: This study demonstrates that a home therapy with oral doxifluridine in elderly advanced colorectal cancer patients is feasible, with a relatively low rate of toxicity, and has moderate activity, comparable to that of intravenous 5-fluorouracil. Therefore, this treatment may be considered for the management of advanced colorectal cancer in the elderly.

[Liver lipoma. Anatomo-histologic and radiologic study]. / Lipoma del fegato. Studio anatomo-istologico e radiologico.

An uncommon case of lipoma of the liver is described with reference to U.S., T.C. and M.R. features. The differential diagnosis with the capsular pseudolipomas and hepatic angiomyolipomas is discussed. The Authors emphasize the utility of the new techniques of image analysis as a diagnostic tool in focal hepatic lesions.

Takayasu's arteritis: low corticosteroid dosage and pregnancy--a case report.

The authors describe a case of Takayasu's arteritis in a twenty-five-year-old Italian woman, characterized by nonspecific symptoms (weakness, arthralgias, fever) and elevated erythrocyte sedimentation rate early onset of these symptoms at the age of about twenty-three years early diagnosis, only eighteen months after the onset of symptomatology absence of progression of the disease under corticosteroid therapy with a follow-up of three years uneventful pregnancy ending in cesarean section and birth of a baby without maternal and neonatal complications.

[Complete endocardial cushion defect and bone malformations of the hands. Holt-Oram syndrome]. / Difetto completo dei cuscinetti endocardici e malformazioni scheletriche delle mani. Sindrome di Holt-Oram.

A 44 year old woman with upper limb skeletal malformations and endocardial cushion defect is described. This congenital heart disease was rarely reported in association with Holt-Oram syndrome.

Clinical spectrum of accidental hemlock poisoning: neurotoxic manifestations, rhabdomyolysis and acute tubular necrosis.

In the past, hemlock poisoning was only known for its neurotoxic effects; quite recently non-neurological features, consisting of rhabdomyolysis and acute renal failure, have been also described. Here we report our experience with these clinical findings, which we frequently observe in accidental hemlock poisoning. Between 1972 and 1990 we studied 18 patients: 17 of them were poisoned by conline (an alkaloid of Conium maculatim) in Apulia (Italy), and one by cicutoxin (the active principle of water hemlock) in New Mexico (USA). In the non-rapidly-fatal cases we tested myoglobinuria, serum muscle enzymes, and renal function. In the patients with acute renal failure we performed microscopical examination of kidney specimens; immunohistochemistry was carried out to identify myoglobin and actin in tubules. Coniine was detected in urine, serum, or tissues. Neurological features were present in all of our cases: coniine had a curare-like effect on the neuromuscular junction, whereas cicutoxin was convulsant on the central nervous system. In addition rhabdomyolysis was noted in the 17 subjects poisoned by coniine. Acute renal failure was observed in five patients; it was confirmed by histological evidence of tubular necrosis with intratubular deposition of myoglobin and actin released by rhabdomyolysis. Our cases seem to be the first with histopathologically proven acute tubular necrosis in coniine intoxication. In conclusion, in hemlock poisoning neurotoxic manifestations may be accompanied by rhabdomyolysis and acute tubular necrosis; increased awareness of these clinical features is recommended in order to improve the diagnostic and therapeutic procedure.