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Biomedical subjects

Victor M Santana

Publications and source records attributed to Victor M Santana.

At least 19 recordsLinked to original sources
PubMed2006

Concomitant administration of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide for high-risk sarcomas: the St. Jude Children's Research Hospital experience.

BACKGROUND: Intensified chemotherapy may improve the outcome of patients with high-risk pediatric sarcomas. Vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide are highly effective against pediatric sarcomas. The authors investigated the feasibility of administering these agents concomitantly within a defined period. METHODS: In the prospective high-risk sarcoma (HIRISA) Phase II trial HIRISA1, pediatric patients with high-risk sarcomas received 3 cycles of intensive vincristine, ifosfamide, etoposide, cyclophosphamide, and doxorubicin (VACIE) before radiotherapy and/or surgery began at Week 9 with concurrent vincristine, cyclophosphamide, and doxorubicin (Week 9) and vincristine and ifosfamide (Week 12). Three additional cycles of VACIE were then given. After delayed hematologic recovery in the first 11 patients, the protocol was modified (HIRISA2) to delay local control therapy until after 5 cycles of VACIE (to be completed within 18 weeks). Patients who responded to the protocols were eligible for myeloablative consolidation with autologous stem cell support. RESULTS: Eleven of 24 patients (median age, 14.9 years) had Ewing sarcoma family of tumors, 9 patients had rhabdomyosarcoma, and 4 patients had unresectable desmoplastic small round cell tumors. Seven of 13 patients on HIRISA2, but none of 11 patients on HIRISA1, completed therapy within the specified time. Reversible Grade 4 myelosuppression was the most common toxicity. Major nonhematologic toxic effects were mucositis, nutritional impairment, hypotension, and peripheral neuropathy. Three patients died of toxicity. The 5-year survival and 5-year event-free survival estimates both were 45.8% +/- 11.2%. CONCLUSIONS: The feasibility of administering intensive chemotherapy regimens like VACIE was dependent in part on the timing of local control therapy. This regimen was associated with significant toxicity.

Adolescent↗
PubMed2006

Cefixime allows greater dose escalation of oral irinotecan: a phase I study in pediatric patients with refractory solid tumors.

PURPOSE: Irinotecan is active against a variety of malignancies; however, severe diarrhea limits its usefulness. In our phase I study, the intravenous formulation of irinotecan was administered orally daily for 5 days for 2 consecutive weeks (repeated every 21 days) to children with refractory solid tumors. Our objectives were to determine the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of oral irinotecan and to evaluate whether coadministration of cefixime (8 mg/kg/d beginning 5 days before irinotecan and continuing throughout the course) ameliorates irinotecan-induced diarrhea. PATIENTS AND METHODS: In separate cohorts, irinotecan doses were escalated from 15 to 45 mg/m2/d without cefixime and then from 45 to 60 and 75 mg/m2/d with cefixime. RESULTS: Without cefixime, diarrhea was dose limiting at irinotecan 45 mg/m2/d. Myelotoxicity was not significant at any dose. The MTD was 40 mg/m2/d without cefixime but 60 mg/m2/d with cefixime. Systemic exposure to SN-38 at the MTD was significantly higher with cefixime than without cefixime (mean SN-38 area under the curve: 19.5 ng x h/mL; standard deviation [SD], 6.8 ng x h/mL v 10.4 ng x h/mL; SD, 4.3 ng x h/mL, respectively; P = .030). CONCLUSION: Cefixime administered with oral irinotecan is well tolerated in children and allows greater dose escalation of irinotecan. Because diarrhea is a major adverse effect of both intravenous and oral irinotecan, further evaluation of the use of cefixime to ameliorate this adverse effect is warranted.

Administration, Oral↗
PubMed2006

Pilot study to evaluate MYCN expression as a neuroblastoma cell marker to detect minimal residual disease by RT-PCR.

This pilot study was performed to determine whether MYCN expression warrants further investigation as a tumor marker to detect low levels of residual neuroblastoma (NB). Seven NB cell lines and 30 bone marrow (BM) samples from patients with high-risk NB were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) for MYCN expression, and for the established NB marker tyrosine hydroxylase. MYCN was expressed in all 7 NB cell lines, but not in normal peripheral blood, CD34 cells, or BM. In dilution studies using cell lines with or without DNA amplification of MYCN, 1 NB cell in 10 to 10 nucleated blood cells was detectable by RT-PCR. MYCN was identified in all 21 BM samples in which tumor cells were identified by histologic examination, including 4 samples in which tyrosine hydroxylase was not detected. Additionally, expression of both markers was detected in 5 samples that were negative by histology but presumably contained low levels of tumor cells, consistent with the greater sensitivity of RT-PCR compared with morphologic methods. Detection of MYCN RNA was independent of MYCN DNA amplification status. The selective expression of MYCN in tumor cells, and the sensitivity of detection of MYCN by RT-PCR noted in this and other studies, supports further evaluation of MYCN as a NB marker for molecular detection of minimal residual disease.

Biomarkers, Tumor↗
PubMed2006

Distinguishing benign from malignant pulmonary nodules with helical chest CT in children with malignant solid tumors.

PURPOSE: To retrospectively assess whether computed tomographic (CT) findings can indicate the benign or malignant nature of pulmonary nodules in pediatric patients with malignant solid primary tumors. MATERIALS AND METHODS: With institutional review board approval, waived parental and patient consent, and HIPAA compliance, the authors determined the incidence of malignancy among 81 pulmonary nodules that were sampled at biopsy within 3 weeks after chest CT (January 1999 to September 2003) in 41 young patients with malignant solid tumors. Three radiologists independently and retrospectively reviewed these scans and the available previously obtained scans, classifying nodules as benign, malignant, or indeterminate on the basis of their number, unilateral versus bilateral distribution, size, margins (indistinct vs distinct), calcification, growth, and associated adenopathy. These classifications were compared with nodule histologic type, and interreviewer agreement was assessed. RESULTS: The median patient age was 14.8 years (mean, 13.7 years; range, 5-21 years). Twenty-four of the 41 patients (58%) had at least one biopsy-proved malignant nodule. Four (10%) patients had both benign and malignant nodules; 17 (42%) had only benign nodules. Reviewer 1 classified 65% (39 of 60) of nodules correctly; reviewer 2, 57% (37 of 65); and reviewer 3, 67% (43 of 64). Interreviewer agreement was slight to moderate (kappa </= 0.43, P </= .03). In contrast to findings in adults, sharply defined nodules in younger individuals were more likely to be malignant (P = .03) and nodule size was not associated with malignancy (P >/= .32). CONCLUSION: The frequency of benign nodules and the inconsistency of predictions based on CT features suggest the need for better predictors of pulmonary nodules being malignant or benign, so as to reduce unnecessary thoracotomy in pediatric patients with solid malignancy. .

Adolescent↗
PubMed2005

The impact of early resection of primary neuroblastoma on the survival of children older than 1 year of age with stage 4 disease: the St. Jude Children's Research Hospital Experience.

BACKGROUND: It remains unclear whether primary tumor resection benefits patients with metastatic neuroblastoma. The authors assessed the impact of extent and timing of resection on outcome in these patients. METHODS: The authors reviewed the records of 124 patients > 1 year of age at diagnosis of International Neuroblastoma Staging System Stage 4 neuroblastoma. The survival estimates of those who did and did not have a gross total resection (GTR) and of those who had initial versus delayed GTR were compared. Surgical complications were reviewed. RESULTS: The 5-year survival estimates were comparable for the 90 patients who had a GTR and the 17 who underwent surgery but did not have a GTR (29.9% +/- 5.1% [standard error] vs. 29.4% +/- 10.1%). The 7 patients who underwent GTR at the time of diagnosis had a higher 5-year survival estimate than the 83 patients who had a GTR after induction chemotherapy (83.3% +/- 13.9% vs. 25.2% +/- 5.0%) (P = 0.001). Five-year event-free survival estimates were similarly higher in the initial-GTR group (57.1% +/- 18.7% vs. 14.5% +/- 4.2%) (P = 0.002). These two groups did not differ significantly in age at diagnosis (P = 0.118), site of primary tumor (P = 0.34), MYCN amplification status (P = 1), serum lactate dehydrogenase activity at diagnosis (P = 0.34), or treatment protocol (P = 0.22). Twenty-two (21%) patients had a surgical complication. CONCLUSIONS: In this small cohort of patients with metastatic neuroblastoma, GTR at the time of diagnosis offered a survival benefit. Further prospective studies are warranted before this approach can be applied to all patients with metastatic neuroblastoma.

Adolescent↗
PubMed2005

Phase I study of the combination of topotecan and irinotecan in children with refractory solid tumors.

PURPOSE: We have shown in xenograft studies that the antitumor activities of topotecan and irinotecan are highly schedule- and dose-dependent, with a high frequency of response at low, protracted dose schedules. Preclinical and clinical data suggest that topotecan and irinotecan have different antitumor activities and mechanisms of resistance, and non-overlapping toxicities, providing a rationale for their combination. Combining both agents may increase the amount of camptothecin delivered to the tumor, without additive toxicity. METHODS: We conducted a phase I study in children with refractory solid tumors to determine the maximum tolerated dose (MTD) of irinotecan when administered with a targeted systemic exposure (TSE) of topotecan and to define the dose-limiting toxicity (DLT) of this combination. Irinotecan was administered IV over 60 min followed by topotecan over 30 min daily for 5 days for two consecutive weeks. We initially fixed the topotecan-TSE to 80+/-10 ng*h/ml and investigated the ability to escalate irinotecan (starting dose 16 mg/m2/d). Topotecan and irinotecan pharmacokinetics were determined. RESULTS: Eleven patients (median age 10 years) were enrolled. Owing to DLT, irinotecan was de-escalated to 12 (level -1; n = 3) and 9 (level -2; n = 3) mg/m2/day, and topotecan-TSE was reduced to 60+/-10 ng*h/ml (level -3; n = 2). DLTs were neutropenia (n = 8), typhlitis (n = 5), and skin rash (n = 1). MTD could not be reached. Median (range) irinotecan and topotecan lactone systemic clearances were 50.3 (16.6-76.2) l/h/m2 and 27.6 (14.7-55.9) l/h/m2, respectively. The pharmacokinetics profile of each agent was similar to that seen in previous single agent studies. One patient with neuroblastoma and one with rhabdomyosarcoma had a partial and a complete response, respectively. CONCLUSION: Despite promising antitumor activity, the combination of topotecan and irinotecan given on a protracted schedule does not warrant further development in children due to unacceptable toxicity.

Adolescent↗
PubMed2005

Percutaneous biopsy of pediatric solid tumors.

BACKGROUND: The objective of the current study was to determine the diagnostic accuracy of percutaneous biopsy of pediatric solid tumors, a procedure that is less invasive than open biopsy. METHODS: The authors conducted a retrospective analysis of clinical data related to 202 percutaneous core-needle biopsies of solid tumors at St. Jude Children's Research Hospital over 5.5 years (from 1997 to 2003). In 103 patients, the procedure was performed to establish an initial diagnosis of a suspected malignancy; and, in 99 patients, disease recurrence was suspected. Biopsies were guided by ultrasound, computed tomography, or fluoroscopic imaging. From each tumor, 1-17 core biopsy samples (median, 6 samples) were obtained; the median needle size was 15 gauge (range, 13-20 gauge). The specimens were submitted for histopathologic analysis and other ancillary procedures (molecular pathology and/or cytogenetic analyses). The accuracy of the diagnoses from the biopsies was determined by subsequent surgery with or without pathologic assessment or by outcome. RESULTS: When the biopsy samples were assessed for the presence of malignancy, there were 121 true-positive results (90% sensitivity), 67 true-negative results (100% specificity), and 14 false-negative results (93% accuracy). In 103 tumors, when the procedure was performed for initial diagnosis, percutaneous needle biopsy showed a sensitivity of 97%, a specificity of 100%, and an accuracy of 98%. The 99 procedures for suspected recurrence were less reliable (sensitivity, 83%; specificity, 100%; accuracy, 88%). CONCLUSIONS: Image-guided percutaneous biopsy was highly accurate and safe in the diagnosis of pediatric malignant solid tumors. This technique may be able to supplant diagnostic open biopsy.

Adolescent↗
PubMed2005

Development and validation of limited sampling models for topotecan lactone pharmacokinetic studies in children.

PURPOSE: To develop and validate a pharmacokinetic limited sampling model (LSM) for intravenous and oral topotecan pharmacokinetic studies in children. METHODS: Topotecan lactone concentration-time data from five trials were used to develop and validate LSM for intravenous and oral topotecan. Based on full sampling from one intravenous study (30 patients; 195 studies), a LSM for intravenous topotecan was determined using a modification of the D-optimality algorithm. For oral topotecan we used full sampling data from one oral topotecan study (27 patients; 47 studies) to develop an LSM. Accuracy and bias of each LSM were determined relative to the full sampling method. Predictive performance of the LSM was validated using additional data and Monte-Carlo simulations based on these data. RESULTS: LSM for intravenous topotecan includes: 5 min, 1.5, and 2.5 h after the end of the 30 min infusion. The median accuracy (absolute predicted error) and bias (predicted error) are < or =8% and < or =6.1%, respectively. For oral topotecan, the optimal LSM includes: 15 min, 1.5, and 6 h. The median accuracy and bias are 6% and 4%, respectively. CONCLUSIONS: Our results indicate that the optimal sampling times for the intravenous LSM for topotecan in children consist of: predose, and 5 min, 1.5, and 2.5 h after the end of infusion. For oral topotecan the sample times are predose, 15 min, 1.5, and 6 h after dose administration. These LSM are invaluable to children receiving topotecan because it minimizes inconvenience and blood collection.

Administration, Oral↗
PubMed2005

Improved response in high-risk neuroblastoma with protracted topotecan administration using a pharmacokinetically guided dosing approach.

PURPOSE: To estimate the response rate and toxicity associated with intravenous topotecan when it is administered on a protracted schedule according to a pharmacokinetically guided dosing approach to treat childhood high-risk neuroblastoma. PATIENTS AND METHODS: In this prospective phase II trial, topotecan was administered intravenously daily for 5 days for each of 2 consecutive weeks for two cycles. On the basis of topotecan systemic clearance, doses were individualized to attain a single-day topotecan lactone area under the plasma concentration-time curve (AUC) of 80 to 120 ng/mL . h. Patients subsequently received standard treatment. RESULTS: Both cycles were administered to 28 (93%) of the 30 enrolled patients (median age, 3.1 years). Target topotecan AUCs were achieved in 92 (72%) of the 127 measurements conducted after pharmacokinetically guided adjustment; the median dosage required to achieve target AUCs was 2.7 mg/m(2) (range, 0.95 to 3.8 mg/m(2)). The response rate was 60% (95% CI, 41% to 77%); there were one complete and 17 partial responses. No patient experienced disease progression during initial topotecan therapy. Primary tumor volumes decreased (median decrease, -58.2%; range, -95.1% to -4.9%) in the 26 patients with available size data. Homovanillic acid levels in 16 (89%) of 18 patients and vanillylmandelic acid levels in 14 (78%) of 18 patients were lower (P = .002 and P = .018, respectively) after topotecan therapy. Reversible grade 4 myelosuppression occurred in all patients, but no deaths occurred as a result of infection or toxicity. CONCLUSION: Topotecan is active against neuroblastoma when it is administered on a protracted schedule and targeted systemic exposure is achieved.

Adolescent↗
PubMed2005

Radiographic assessment of resectability of locoregional disease in children with high-risk neuroblastoma during neoadjuvant chemotherapy.

BACKGROUND: The optimal timing for attempting removal of the primary tumor and regional disease in patients with high-risk neuroblastoma is uncertain. The purpose of this study was to evaluate resectability of the primary tumor and regional disease, as determined radiographically, in children with high-risk neuroblastoma during neoadjuvant chemotherapy. PROCEDURE: Patients enrolled in our institutional high-risk neuroblastoma protocol were evaluated prospectively by CT scan and/or MRI to determine the resectability of their primary tumor and regional disease at diagnosis, after two cycles of experimental therapy and after standard induction therapy. Tumors were considered to be unresectable if there was significant involvement with major vascular structures or contiguous organs, or would likely require nephrectomy to remove the entire tumor. RESULTS: Twenty-four patients were referred prior to surgery for treatment of high-risk neuroblastoma. Seven of 24 (29%) patients were felt to be resectable at diagnosis, with an additional 9 patients becoming resectable after the initial experimental therapy. Thus, overall, 16 of 24 (67%) patients were felt to be resectable by the completion of the initial therapy. Only four additional patients of the remaining eight were considered resectable after the completion of standard induction therapy. CONCLUSIONS: Based on these data, we conclude that complete resection of the primary tumor and regional disease in children with high-risk neuroblastoma can be performed after an initial phase therapy in the majority of patients. Since earlier tumor removal may decrease the chance for the subsequent development of chemotherapy-resistant disease, we are recommending surgical resection as soon as the locoregional disease appears to be resectable.

Adolescent↗
PubMed2004

Combined use of erythropoietin and granulocyte colony-stimulating factor does not decrease blood transfusion requirements during induction therapy for high-risk neuroblastoma: a randomized controlled trial.

PURPOSE: To evaluate the efficacy of recombinant erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF) in reducing blood transfusion requirements and stimulating hematopoiesis in children with high-risk neuroblastoma. PATIENTS AND METHODS: Thirty-eight patients given six cycles of intensive induction chemotherapy for high-risk neuroblastoma were randomized to receive G-CSF (n = 20) or G-CSF + EPO (n = 18). Cytokines were given subcutaneously each day, starting 24 hours after each chemotherapy cycle and continuing until 48 hours before the start of the next cycle. The primary end point was the effect of EPO on total red cell transfusion requirements during induction therapy. RESULTS: Patients who received G-CSF + EPO had a higher red cell transfusion requirement (median, 161.0 mL/kg) than did those who received G-CSF alone (median, 106.6 mL/kg; P =.005). In addition, among patients given transfusions for hemoglobin < or = 8 g/dL, those in the G-CSF + EPO group received more red cell transfusions than did those given G-CSF alone (median per patient, 10 v 8, respectively; P =.044). The two treatment groups had similar cumulative durations of neutropenia, incidences of febrile neutropenia, platelet transfusion requirements, and numbers of platelet transfusions; they also received induction chemotherapy for similar durations and had similar probabilities of progression-free survival and overall survival. CONCLUSION: The addition of EPO to the G-CSF regimen provides no benefit for patients receiving intensive induction chemotherapy for high-risk neuroblastoma.

Adolescent↗
PubMed2004

Phase I and pharmacokinetic study of topotecan administered orally once daily for 5 days for 2 consecutive weeks to pediatric patients with refractory solid tumors.

PURPOSE: We conducted a phase I trial of the injectable formulation of topotecan given orally once daily for 5 days for 2 consecutive weeks (qd x 5 x 2) in pediatric patients with refractory solid tumors. PATIENTS AND METHODS: Cohorts of two to six patients received oral topotecan at 0.8, 1.1, 1.4, 1.8, and 2.3 mg/m(2)/d every 28 days for a maximum of six courses. Twenty patients (median age, 10.6 years) received a total of 51 courses. Eight patients received topotecan capsules during course 2 only. RESULTS: Dose-limiting toxicity occurred at 2.3 mg/m(2)/d and consisted of prolonged grade 4 neutropenia (n = 2), grade 3 stomatitis as a result of radiation recall (n = 1), grade 3 hemorrhage (epistaxis) in the presence of grade 4 thrombocytopenia (n = 1), and grade 3 diarrhea in the presence of Clostridium difficile infection (n = 1). Dose-limiting, prolonged grade 4 neutropenia and thrombocytopenia occurred in one patient at 1.4 mg/m(2)/d. Infrequent toxicities were mild nausea, vomiting, elevated liver ALT or AST, and rash. The maximum-tolerated dosage was 1.8 mg/m(2)/d; the mean (+/- standard deviation) area under the plasma concentration-time curve for topotecan lactone at this dosage was 20.9 +/- 8.4 ng/mL. h. The population mean (+/- standard error) oral bioavailability of the injectable formulation was 0.27 +/- 0.03; that of capsules was 0.36 +/- 0.06 (P =.16). Disease stabilized in nine of 19 assessable patients for 1.5 to 6 months. CONCLUSION: Oral topotecan (1.8 mg/m(2)/d) on a qd x 5 x 2 schedule is well tolerated and warrants additional testing in pediatric patients.

Administration, Oral↗
PubMed2004

Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors.

PURPOSE: The purpose is to estimate the maximum-tolerated dose (MTD) of temozolomide and irinotecan given on a protracted schedule in 28-day courses to pediatric patients with refractory solid tumors. EXPERIMENTAL DESIGN: Twelve heavily pretreated patients received 56 courses of oral temozolomide at 100 mg/m(2)/day for 5 days combined with i.v. irinotecan given daily for 5 days for 2 consecutive weeks at either 10 mg/m(2)/day (n = 6) or 15 mg/m(2)/day (n = 6). We assessed toxicity, the pharmacokinetics of temozolomide and irinotecan, and the DNA repair phenotype in tumor samples. RESULTS: Two patients experienced dose-limiting toxicity (DLT) at the higher dose level; one had grade 4 diarrhea, whereas the other had bacteremia with grade 2 neutropenia. In contrast, no patient receiving temozolomide and 10 mg/m(2)/day irinotecan experienced DLT. Myelosuppression was minimal and noncumulative. No pharmacokinetic interaction was observed. Drug metabolite exposures at the MTD were similar to exposures previously associated with single-agent antitumor activity. One complete response, two partial responses, and one minor response were observed in Ewing's sarcoma and neuroblastoma patients previously treated with stem cell transplant. Responding patients had low or absent O(6)-methylguanine-DNA methyltransferase expression in tumor tissue. CONCLUSIONS: The MTD using this schedule was temozolomide (100 mg/m(2)/day) and irinotecan (10 mg/m(2)/day), with DLT being diarrhea and infection. Drug clearance was similar to single-agent values, and clinically relevant SN-38 lactone and MTIC exposures were achieved at the MTD. As predicted by xenograft models, this combination and schedule appears to be tolerable and active in pediatric solid tumors. Evaluation of a 21-day schedule is planned.

Adolescent↗
PubMed2004

Aggressive bladder carcinoma in a child.

The brief report describes an unusual case of high grade bladder neoplasm with divergent differentiation in a 31 month-old child. The presentation included hematuria with tissue fragments and the tumor was confined to the bladder. The tumor behaved aggressively despite radical cystectomy, chemotherapy with agents known to be effective against epithelial and mesenchymal tumors and radiation therapy. Although rare, most malignant bladder neoplasms in children are low grade and present in early stages. Sarcomatoid differentiation in the setting of high-grade urothelial carcinoma portends a poor prognosis.

Black People↗
PubMed2004

Phase II trial of cladribine and cytarabine in relapsed or refractory myeloid malignancies.

To evaluate the efficacy of cladribine and cytarabine in children with relapsed or refractory myeloid malignancies, we administered cytarabine (200 mg/m2 per day) by continuous subcutaneous infusion and cladribine (8.9 mg/m2 per day) by continuous intravenous infusion concomitantly for 5 days to nine patients younger than 21 years. After one course, five patients had no response, two patients had partial responses, one had stable disease, and one had progressive disease. Two patients received a second course: one patient had stable disease after one course and progressive disease after the second; another patient had a partial response after one course and no response after the second. Despite the efficacy of the cladribine and cytarabine regimen in treating newly diagnosed acute myeloid leukemia (AML) in a previously reported study, the combination was not effective for relapsed or refractory childhood AML.

Adolescent↗
PubMed2004

Effect of fractionated ifosfamide on the pharmacokinetics of irinotecan in pediatric patients with osteosarcoma.

The combination of irinotecan (daily for 5 days for 2 consecutive weeks) and ifosfamide (daily on days 1 through 3) was investigated in children with osteosarcoma. Irinotecan pharmacokinetic investigations were performed before ifosfamide (day 1), after 3 days of ifosfamide (day 3), and 9 days after the end of ifosfamide (day 12). On day 3, the concentrations of irinotecan's active metabolite, SN-38, were below the limit of quantitation in two patients and were decreased in a third patient. The SN-38 area under the concentration-time curve remained below the day 1 value in two patients on day 12. The reduced area under the curve to the active metabolite SN-38 during ifosfamide therapy predicts a compromised efficacy of irinotecan in this combination.

Adolescent↗