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D Alberti

Publications and source records attributed to D Alberti.

At least 19 recordsLinked to original sources
PubMed1999

A pilot study of melphalan, tumor necrosis factor-alpha and 41.8 degrees C whole-body hyperthermia.

PURPOSE: To evaluate the feasibilitv of sequencing (based on preclinical modeling) tumor necrosis factor-a (TNF) at two dose levels with melphalan (L-PAM) and 41.8 C whole-body hyperthermia (WBH) for 60 min. PATIENTS AND METHODS: Nine patients with refractory cancer were treated from October 1995 to June 1997. The study encompassed a total of 20 trimodality treatment courses. Three patients were treated at TNF dose level I (50 microg/m2) and six patients were treated at TNF dose level II (100 microg/m2). TNF was delivered as a 24-h intravenous infusion, 48 h prior to the combination of L-PAM and WBH; L-PAM was given over 10 min at target temperature at a dose of 17.5 mg/ m2 based on a previous phase I WBH/L-PAM trial. WBH was administered with an Aquatherm radiant heat device. RESULTS: Myelosuppression was the major toxicity associated with therapy, but there were no instances of bleeding or neutropenic fevers. Grade 3 thrombocytopenia was seen with 15% of treatments. Regarding absolute neutrophil count, 15% of treatments were associated with grade 3 toxicity, and 45% with grade 4 toxicity, and regarding white blood cell count, 50% of treatments were associated with grade 3 toxicity and 10% with grade 4 toxicity. The myelosuppression observed was equivalent to that seen in our earlier phase I study of WBH and L-PAM (without TNF). Only mild toxicities (grade 1 or 2) were associated with TNF; these were seen with <25% of treatments and included nausea, vomiting, diarrhea, fevers, and headache. There were no instances of hypotension. There was no relationship between toxicities observed and the two TNF dose levels. Mild WBH toxicities were seen with less than 15% of treatments; these included nausea, vomiting, and herpes simplex I. Responses included two complete remissions (malignant melanoma, TNF dose level I; breast cancer, TNF dose level II), and two disease stabilizations (both malignant melanoma, TNF dose level I). CONCLUSION: We conclude that the combination of TNF, L-PAM, and WBH is well tolerated at the dose levels studied. The clinical results justify further clinical investigation for this trimodality treatment approach.

Adult↗
PubMed1999

The spleen in the Wiskott-Aldrich syndrome: histopathologic abnormalities of the white pulp correlate with the clinical phenotype of the disease.

The Wiskott-Aldrich syndrome (WAS) is a X-linked hematologic disorder characterized by thrombocytopenia, eczema, and immunodeficiency of variable severity. Reported here are the results of a morphologic, morphometric, and immunophenotypic analysis of splenic lymphoid tissue in 12 WAS patients with documented molecular defect and with different disease severity. Spleens from 29 age-matched patients with different diseases were used as controls. Paraffin-embedded tissue (from all cases) and fresh-frozen samples (from 5 WAS patients and 4 control subjects) were used to study the different white pulp compartments by classic morphologic, immunophenotyping, and image analysis techniques. Data were statistically analyzed by both parametric and nonparametric tests. Spleens from WAS patients showed a significant depletion of the total white pulp (p = 0.0008), T cell (p < 0.05), and B cell (p = 0.0002) areas and marginal zone (MZ) thickness (p < 0.0001). Among WAS patients, a negative correlation was found between the score of severity of the disease and all variables considered (Spearman's rank correlation coefficient, r = -0.79, r = -0.73, r = -0.68, and r = -0.56, respectively). In conclusion, this study shows that in WAS a general depletion of the splenic white pulp occurs, supporting the evidence that WAS is characterized by a combined immune defect. The significant reduction of the MZ may explain the inability of WAS patients to mount a response to T-independent antigens.

Antigens, CD↗
PubMed1999

Angiotensin-converting enzyme inhibitors and kidney protection: the AIPRI trial. The ACE Inhibition in Progressive Renal Insufficiency (AIPRI) Study Group.

A protective effect of angiotensin-converting enzyme (ACE) inhibitors has been shown in patients with diabetic nephropathy but has not been clearly established in nondiabetic renal disease. A multicenter European study was designed to determine whether the ACE inhibitor benazepril was safe and effective in protecting residual renal function in patients with various renal diseases and mild to moderate renal failure. The trial involved 583 patients from 49 centers in Italy, France, and Germany. The patients were randomized to receive benazepril or placebo plus other antihypertensive agents, the target being a diastolic blood pressure of less than 90 mm Hg. Thirty-one patients in the benazepril group and 57 patients in the placebo group reached the end point [the time elapsed from entry to (a) doubling of serum creatinine (SCr) concentrations and (b) start of renal replacement therapy; p < 0.001 at 3 years]. The associated reduction in the relative risk of reaching the end point was 53% in benazepril-treated patients, with actuarial renal survival probability significantly better at 3 years. The best survival of renal function was observed in patients with chronic glomerular diseases and proteinuria greater than 1.0 g/24 h. Benazepril is effective in slowing the rate of progression and improving the survival of renal function in patients with renal diseases of various origins. This protective effect is associated with a clinically relevant decrease in both blood pressure and proteinuria.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Adenomyomatosis of the gallbladder in childhood.

Adenomyomatosis of the gallbladder (ADMG) is defined as an acquired disease characterized by localized or diffuse hyperplastic extensions of the mucosa into, and often beyond, the thickened gallbladder muscular layer (Rokitansky-Aschoff's sinuses). In recent years, attention has been drawn to its malignant potential. The occurrence of ADMG has never been reported in children. The authors report the case of a 5-year-old boy with symptomatic ADMG, who was successfully treated by laparoscopic cholecystectomy.

Adenomyoma↗
PubMed1998

Direct bypassing of extrahepatic portal venous obstruction in children: a new technique for combined hepatic portal revascularization and treatment of extrahepatic portal hypertension.

BACKGROUND: Decompression of extrahepatic portal hypertension by directly bypassing the thrombosed portal vein has never been reported in cases of children with idiopathic (or neonatal) portal vein obstruction and cavernoma. METHODS: Seven children (15 years or younger) with portal vein obstruction requiring surgical decompression (urgently in two cases), and in whom preoperative Doppler had shown that the intrahepatic portal branches were hypoplastic but free of thrombus, were included in a pilot study. The cavernoma was bypassed by interposing a venous jugular autograft between the superior mesenteric vein and the distal portion of the left portal vein. Patients received follow-up using routine clinical parameters, upper gastrointestinal endoscopy, and Doppler ultrasound. RESULTS: The mesenterico-portal bypass restored a direct (physiological) hepatopetal portal flow. The operation resulted in effective portal decompression as demonstrated by decrease of the pressure gradient, rapid regression of clinical signs of portal hypertension, and definitive control of bleeding. CONCLUSIONS: This study shows that direct bypassing of portal cavernoma is possible and results in effective portal decompression. Restoration of the hepatic portal flow is a major advantage compared with conventional surgical shunting procedures. This new technique is potentially applicable to two thirds of children with portal vein thrombosis and should be considered when shunting procedures are indicated.

Adolescent↗
PubMed1998

Phase I clinical and pharmacokinetic trial of penclomedine using a novel, two-stage trial design for patients with advanced malignancy.

PURPOSE: A novel phase I trial design was used to determine the maximum-tolerated dose (MTD) and pharmacokinetics for penclomedine when administered as an intravenous (i.v.) infusion over 1 hour daily for 5 days, repeated every 28 days. This study also tests the feasibility of a novel two-stage design for phase I trials. PATIENTS AND METHODS: Twenty-eight patients with advanced malignancy who met standard eligibility criteria were treated with i.v. penclomedine. The initial daily dose was 50 mg/m2. Dose escalations were planned using a modified Fibonacci sequence. One patient was enrolled on each dose level during the first stage of this trial. In the second stage, patients were enrolled in cohorts of three, proceeding in an up-and-down manner based on toxicities observed. MTD was determined by logistic regression analysis. Pharmacokinetic assessment was performed during the first cycle of treatment. RESULTS: Dose-limiting toxicities (DLT) observed during this trial were principally neurologic and were self-limited. Although hematologic toxicity was rare, the few patients with significant hematologic changes experienced late nadirs with prolonged time to recovery. The MTD was estimated as 381 mg/m2 (80% CI, 343 to 415 mg/m2). Although there was a long elimination half-life, accumulation of penclomedine over the 5 days of administration was negligible. CONCLUSION: The novel trial design used in this study was safe and appeared effective in limiting the numbers of patients treated at lower-dose levels. Reversible neurotoxicity was dose-limiting. Although the estimated MTD was 381 mg/m2, any dose within the CI would be reasonable for phase II study.

Adult↗
PubMed1998

Growth, insulin-like growth factor I (IGF-I), and IGF-binding proteins 1 and 3 in children with severe liver disease before and after liver transplantation: a longitudinal and cross-sectional study.

We aimed to study the growth and growth factors of children with liver disease before and after liver transplantation (LT). Three observation intervals: 1) before LT (preLT), 2) after LT on daily prednisone treatment (dP), and 3) on alternate day prednisone (adP). A longitudinal study (LS) involved 17 infants (9 male) aged 0.73-2.38 y at LT; mean (+/- SD) height (Ht) SD score (SDS) at LT was -2.02 (+/- 1.25). In a cross-sectional study, there were 123 children (73 male) aged 0.16-14.88 y (mean 3.72 y). IGF-I and IGF binding proteins (BP) 1 and 3 were measured at the same intervals. The results were, for LS, preLT height velocity (HV) SDS (X +/- SD -0.8+/-1.4) lower (p < 0.01) than adP-HV SDS (3.1+/-1.8) but not different from dP-HV SDS (-1.0+/-1.9). For the cross-sectional study, dP-Ht SDS (X+/-SD -1.94+/-1.31) lower (p < 0.001) than preLT-Ht SDS (-1.03+/-1.06) and adP-Ht SDS (-0.98+/-1.20). Parental target SDS was not different from adP-Ht SDS. (Similar observations were made in the LS.) The dP- sitting height (SH) and subischial leg length (SLL) SDS were significantly lower than both preLT- and adP-SH SDS and SLL SDS (p = 0.02 and 0.002, respectively). There was a significant improvement of head circumference SDS and arm circumference SDS from preLT to adP. The dP and adP IGF-I and IGF-BP3 levels were greater than preLT levels (p < 0.001); no differences were found between preLT, dP, and adP IGF-BP1 levels. We conclude that growth in children with liver disease does not improve after LT on dP, but catch-up growth is shown on adP, appearing to depend mainly on the clinical course and corticosteroid regimen. IGF-I and IGF-BP3 increment on dP (and sustained on adP) is possibly due to liver regeneration, in contrast with inhibition of body growth on dP, possibly due to central and peripheral effects of corticosteroid.

Adolescent↗
PubMed1998

Phase I clinical trial of perillyl alcohol administered daily.

Perillyl alcohol (POH; NSC-641066), a naturally occurring monoterpene, has shown antitumor and preventive activity in preclinical studies in rodent models. Drug-related activities that have been observed include the induction of apoptosis, cell cycle arrest, the inhibition of posttranslational modification of proteins that are involved in signal transduction, and differential gene regulation. We treated 18 patients who had advanced malignancies with POH, which was given on a continuous three-times-a-day schedule at the following doses: (a) level 1 (L1), 800 mg/m2/dose; (b) level 2 (L2), 1600 mg/m2/dose; and (c) level 3 (L3), 2400 mg/m2/dose. The main toxicity, which seemed to be dose related, was gastrointestinal and included nausea and vomiting, anorexia, unpleasant taste, satiety, and eructation. Two heavily pretreated ovarian cancer patients experienced reversible > or =grade 3 granulocytopenia. Grade 1-2 fatigue was also noted. The parent drug was not detectable in the plasma. The mean peak plasma levels of the two main metabolites on days 1 and 29 were 175 and 139 microM (L1), 472 and 311 microM (L2), and 456 and 257 microM (L3) for perillic acid (PA) and 7.1 and 9.8 microM (L1), 34.2 and 34.0 microM (L2), and 26.2 and 23.4 microM (L3) for dihydroperillic acid (DHPA). Peak levels were noted 2-3 h postingestion for PA and 3-5 h postingestion for DHPA. Metabolite half-lives measured about 2 h for each. POH, PA, and DHPA were detectable in the urine of all patients at L3. About 9% of the total dose was recovered in the first 24 h. The majority was recovered as PA; less than 1% was recovered as POH. Disease stabilization for > or =6 months was seen, although no objective tumor responses were noted. Further study of POH continues with a more frequent dosing schedule.

Adult↗
PubMed1998

Renal clearance, tissue distribution, and CA-125 responses in a phase I trial of suramin.

Suramin was administered to 49 patients in a Phase I cancer trial with real-time pharmacokinetic monitoring and dose individualization to achieve targeted mean plasma concentrations of 210 and 155 mg/liter during the 7-day period between days 15 and 22. Pharmacokinetic sampling after doses on days 1, 3, 5, and 8 was used to modify weekly suramin doses, beginning on day 15, in an attempt to achieve specific averaged plasma concentrations of 210 and 155 mg/liter. A 200-mg test dose was not effective in prospectively determining individual pharmacokinetic parameters and dosage requirements. Patients with peak plasma suramin concentrations in excess of 350 mg/liter may be more likely to experience neurotoxicity (P = 0.06), but there was no statistically significant effect of peak suramin concentration or of cumulative dose. Biopsy and autopsy tissue samples demonstrated low penetration of suramin into brain tissue and muscle but good penetration into prostate and other visceral organs. Prospective use of surrogate substrates for CYP1A2, CYP3A3/4, and CYP2D6 showed no consistent effect of suramin on these enzymes. Although a correlation between creatinine clearance and suramin renal clearance was found (r2 = 0.38; P < 0.00005), there was no correlation between creatinine clearance and total suramin clearance (P = 0.21). No suramin dose modification for renal or hepatic dysfunction can be supported at this time. Three of four ovarian cancer patients demonstrated a drop in CA-125 serum concentrations during suramin treatment.

Adult↗
PubMed1997

Phase I study of continuous-infusion L-S,R-buthionine sulfoximine with intravenous melphalan.

BACKGROUND: Increased intracellular glutathione has long been associated with tumor cell resistance to various cytotoxic agents. An inhibitor of glutathione biosynthesis, L-S,R-buthionine sulfoximine (BSO), has been shown to enhance the cytotoxicity of chemotherapeutic agents in vitro and in vivo. We performed a phase I study of BSO administered with the anticancer drug melphalan to determine the combination's safety/tolerability and to determine clinically whether BSO produced the desired biochemical end point of glutathione depletion (<10% of pretreatment value). METHODS: Twenty-one patients with advanced cancers received an initial 30-minute infusion of BSO totaling 3.0 g/m2 and immediately received a continuous infusion of BSO on one of the following schedules: 1) 0.75 g/m2 per hour for 24 hours (four patients); 2) the same dose rate for 48 hours (four patients); 3) the same dose rate for 72 hours (10 patients); or 4) 1.5 g/m2 per hour for 48 hours (three patients). During week 1, the patients received BSO alone; during weeks 2 or 3, they received BSO plus melphalan (15 mg/m2); thereafter, the patients received BSO plus melphalan every 4 weeks. Glutathione concentrations in peripheral blood lymphocytes were determined for all patients; in 10 patients on three of the administration schedules, these measurements were made in multiple sections from tumor biopsy specimens taken before, during, and after continuous-infusion BSO. RESULTS: Continuous-infusion BSO alone produced minimal toxic effects, although BSO plus melphalan produced occasional severe myelosuppression (grade 4) and frequent low-grade nausea/vomiting (grade 1-2). This treatment also produced consistent, profound glutathione depletion (<10% of pretreatment value). The degree of glutathione depletion in peripheral lymphocytes was considerably less than that observed in tumor sections. CONCLUSIONS: Continuous-infusion BSO is relatively nontoxic and results in depletion of tumor glutathione.

Adult↗
PubMed1997

A phase I study of 5-fluorouracil, leucovorin and levamisole.

PURPOSE: The activity of 5-fluorouracil (5-FU) against colon cancer is enhanced by leucovorin and the combination of 5-FU and levamisole has activity in the adjuvant treatment of colonic malignancies. The combination of 5-FU with both leucovorin and levamisole may provide additional benefit in the treatment of colon cancer. METHODS: A phase I study to assess qualitative and quantitative toxicities of this three-drug combination and to determine a dose for further phase II testing was undertaken. The role of levamisole as an immunomodulator was also assessed. RESULTS: A group of 38 patients with incurable metastatic malignancies received 119 cycles of treatment at eight dose levels. 5-FU (375 mg/m2 per day) and leucovorin (200 mg/m2 per day) were administered intravenously (days 1-5). Levamisole was administered orally (days 1-3 and 15-17) at doses from 30 to 470 mg/m2 per day. Patients received both 5FU/leucovorin and 5-FU/leucovorin/levamisole in random order for their initial two cycles. All subsequent treatments were with the three-drug combination. Toxicities included nausea, vomiting, stomatitis, thrombocytopenia and granulocytopenia. Diarrhea was the dose-limiting toxicity at 470 mg/m2 per day levamisole. The addition of levamisole resulted in more toxicity than 5-FU and leucovorin alone. No clinical responses were seen with this regimen. The addition of levamisole resulted in more immunomodulation than 5-FU and leucovorin alone as evidenced by release of neopterin from monocytes. CONCLUSION: With this schedule and dose of 5-FU and leucovorin, the maximum tolerated dose of levamisole was 354 mg/m2. However, given the lack of response and the absence of dose-dependent immunomodulation, this may not be the appropriate dose for further phase 11 studies.

Adjuvants, Immunologic↗
PubMed1997

Phase I clinical trial of melphalan and 41.8 degrees C whole-body hyperthermia in cancer patients.

PURPOSE: To evaluate the biologic interactions and toxicities of melphalan (L-PAM) combined with 41.8 degrees C whole-body hyperthermia (WBH) for 60 minutes. PATIENTS AND METHODS: Sixteen patients with refractory cancer were treated (May 1992 to May 1995) with WBH alone during week 1) thereafter patients were randomized to receive either L-PAM alone on week 2 and L-PAM plus WBH on week 5, or the reverse sequence. Patients who demonstrated clinical improvement received WBH plus L-PAM monthly. Dose levels of L-PAM were 10 mg/m2 (n = 3), 15 mg/m2 (n = 3), 17.5 mg/m2 (n = 6), and 20 mg/m2 (n = 4). L-PAM was administered at target temperature; WBH was administered with an Aquatherm radiant-heat device (patent pending; Cancer Research Institute, New York, NY). RESULTS: Comparisons of mean WBC count and platelet nadirs for L-PAM alone and L-PAM plus WBH demonstrated that the addition of WBH resulted in nadir counts that were, on average, 25% lower. There were no instances of febrile neutropenia or bleeding. Toxicities allowed for escalation of L-PAM to 20 mg/m2; all four patients at this level experienced grade 4 myelosuppression. No significant myelosuppression was observed at 10 and 15 mg/m2. Grade 3 myelosuppression was observed in two of six patients at 17.5 mg/m2. Responses included complete remission (CR) of pancreatic cancer (10 mg/m2), partial remission (PR) of malignant melanoma in two patients (20 mg/m2), and transient clinical and/or serologic improvement in five patients. The pharmacokinetics of L-PAM were not altered by WBH. Observed cytokine induction by WBH is also discussed in detail. CONCLUSION: We conclude that L-PAM with 41.8 degrees C WBH is well tolerated. Clinical results are consistent with preclinical predictions and provide a foundation for second-generation trials now in progress.

Adult↗
PubMed1997

Phase I clinical and pharmacokinetic study of oral carboxyamidotriazole, a signal transduction inhibitor.

PURPOSE: We conducted a phase I trial of carboxyamidotriazole (CAI, NSC 609974), designed to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetic characteristics of CAI gelatin capsule (gelcap) formulation administered daily as a single oral dose. PATIENTS AND METHODS: Twenty-nine patients with advanced malignancy who met standard eligibility criteria were treated with once-daily CAI given in cycles of 28 days. Pharmacokinetic sampling was performed on days 1 and 29 and trough plasma CAI levels were assessed weekly. RESULTS: Patients were entered at dose levels of 50, 75, and 100 mg/m2. All three patients at the 100-mg/m2 level experienced dose-limiting neurocerebellar toxicity. Other neurotoxicities were mild. Gastrointestinal side effects were common, but generally mild, with 23 patients experiencing nausea and/or vomiting of any grade. Fatigue was a frequent complaint, with 19 patients experiencing mild to moderate symptoms. Six patients with nausea and vomiting and five with fatigue experienced relief of symptoms with a change to nocturnal administration of CAI. Peak plasma concentrations (Cp) occurred at 2.4 +/- 1.5 hours after administration of the oral gelcap dose. Patients approached steady-state trough plasma concentrations (Css) by days 8 to 15 and maintained a relatively constant Css throughout the course of treatment. For all patients, the mean variation in weekly CAI Cp was 12.4% +/- 5.3%. CONCLUSION: The MTD for the gelcap formulation was 75 mg/m2 with dose-limiting neurocerebellar toxicity (ataxia) seen at 100 mg/m2. Other prominent side effects, including nausea, vomiting, and fatigue, were partially alleviated through altering the administration schedule to nighttime dosing.

Antineoplastic Agents↗
PubMed1997

[Dental and oral aspects in pediatric liver transplant patients. A comparison between the effects of cyclosporine A and FK 506].

The evolution and the improvement of the surgical techniques and pharmacological therapies brought to new patients categories, also in odontoiatric field for example patients who underwent organ transplantation. Among the patients, we wanted to dwell our attention on pediatric patients after liver transplantation, by light of the new therapeutic outlines modifications. In fact in these young patients it is possible to observe, besides the severe systemic consequences, also the involvement of the oral cavity. After the transplantation, the immunosuppressive therapy is set up and it is based on the use of cyclosporine with the possible azotiopine or steroid association. The cyclosporine side-effects are well known and, among these, the gingival hyperplasia. FK506 is a drug recently introduced, it is a strong immunosuppressor. Therefore we began to estimate patients who assumed FK 506, in order to compare the effect at the gingival level among patients who follow a cyclosporine therapy.

Child↗