Phase I study of topotecan for pediatric patients with malignant solid tumors

PURPOSE: To determine the dose-limiting toxicity and potential efficacy of topotecan in pediatric patients with refractory malignant solid tumors. PATIENTS AND METHODS: In this phase I clinical trial, 27 patients received topotecan 0.75-1.9 mg/m2 by continuous intravenous infusion daily for 3 days. Fifty-three treatment courses were given to these patients. RESULTS: Myelosuppression was the dose-limiting toxicity at levels of 1.3 to 1.9 mg/m2 for 3 days, requiring significant support with transfused packed RBCs and platelets. Myelosuppression was variable in severity at the 1.0-mg/m2 dosage level; thus, additional patients were treated with this dosage, followed by human recombinant granulocyte-colony stimulating factor (G-CSF). Other toxicities were not significant. One patient with neuroblastoma had a complete response that lasted for 8 months. Stable disease activity was recorded for other patients with neuroblastoma, rhabdomyosarcoma, and islet cell carcinoma. Pharmacokinetic studies showed that topotecan plasma concentrations ranged from 1.6 to 7.5 ng/mL during infusions of 1.0 mg/m2/d, and that there was a biphasic plasma distribution with a mean terminal half-life of 2.9 +2- 1.0 hours. CONCLUSION: Topotecan is a promising anticancer agent that deserves phase II testing in pediatric solid tumors. We recommend that pediatric phase II topotecan trials use 1.0 mg/m2/d for 3 days as a constant intravenous infusion, followed by G-CSF for 14 days, and that these treatment courses be repeated every 21 days.     

Phase I trial of 9-aminocamptothecin in children with refractory solid tumors: a Pediatric Oncology Group study

PURPOSE: A phase I trial of 9-aminocamptothecin (9-AC) was performed in children with solid tumors to establish the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and the pharmacokinetic profile in children and to document any evidence of activity. PATIENTS AND METHODS: A 72-hour infusion of 9-AC dimethylacetamide formulation was administered every 21 days to 23 patients younger than 21 years of age with malignant tumors refractory to conventional therapy. Doses ranged from 36 to 62 microg/m2 per hour. Pharmacokinetics were to be performed in at least three patients per dose level. The first course was used to determine the DLT and MTD. RESULTS: Nineteen patients on four dose levels were assessable for toxicities. At 62 microg/m2 per hour, three patients experienced dose-limiting neutropenia and one patient experienced dose-limiting thrombocytopenia. Pharmacokinetics were performed on 15 patients (nine patients had complete sets of plasma sampling performed). The pharmacokinetics of both lactone and total 9-AC were highly variable. The percentage of 9-AC lactone at steady-state was 10.8% +/- 3.6%. Total 9-AC and its lactone form had a terminal half-life of 8.1 +/- 3.8 and 7.1 +/- 3.9 hours, respectively, and a volume of distribution at steady-state (Vdss) of 21.2 +/- 13.3 L/m2 and 135.3 +/- 52.5 L/m2, respectively. Hepatic metabolism and biliary transport had an important role in 9-AC disposition. CONCLUSION: The recommended phase II dose of 9-AC administered as a 72-hour infusion every 21 days to children with solid tumors is 52 microg/m2 per hour. Neutropenia and thrombocytopenia were dose limiting.     

Phase I study of corynebacterium parvum in patients with solid tumors

Nineteen patients with various solid tumors were treated with Corynebacterium parvum for 10 consecutive days at doses ranging from 0.5 to 6 mg/m2. Major toxic effects included rigors and cyanosis, hypertension, headache, nausea, and vomiting. Toxicity was maximal during the first 3 days of treatment and decreased or even disappeared when, on subsequent days, increasing doses of the vaccine were given. Objective tumor regressions were observed in four patients.     

Phase II study of topotecan in patients with extensive-stage small-cell carcinoma of the lung: an Eastern Cooperative Oncology Group Trial

PURPOSE: To determine the response rate and survival of chemotherapy-naive patients with extensive-stage small-cell lung cancer (SCLC) treated with topotecan, and to determine the relationship of topotecan pharmacokinetics with response and toxicity. PATIENTS AND METHODS: Forty-eight patients with previously untreated, extensive-stage SCLC received 2.0 mg/m2 of topotecan daily for 5 days. The first 13 patients were treated without colony-stimulating factor (CSF) support; the next 35 patients received 5 micrograms/kg of granulocyte-colony-stimulating factor (G-CSF) for 10 to 14 days starting on day 6. Cycles were repeated every 3 weeks for a maximum of four cycles. Patients who had a partial response to topotecan after four cycles, stable disease after two cycles, or progressive disease at any time received salvage chemotherapy with cisplatin and etoposide. Topotecan pharmacokinetics were measured using a four-point sampling scheme. RESULTS: Of 48 patients, none had a complete response and 19 had a partial response, for an objective response rate of 39% (95% confidence interval [CI], 25.2% to 53.0%). The median response duration was 4.8 months (95% CI, 3.0 to 7.3). After a median follow-up duration of 18.2 months, the overall median survival time was 10.0 months (95% CI, 8.2 to 12.7); the 1-year survival rate was 39% (95% CI, 25.2% to 53.0%). Eight of 34 patients (24%) who received salvage chemotherapy responded. Four of 17 patients who did not respond to first-line therapy with topotecan responded to cisplatin and etoposide. The most common toxicity was hematologic. Ninety-two percent of patients treated without G-CSF developed grade 3 or 4 neutropenia, compared with 29% who received G-CSF. However, the incidence of neutropenic fevers was similar between the two groups (8% and 11%, respectively), and one patient in each group died of neutropenic fevers. There were no differences in objective tumor response, duration of response, time to treatment failure, or survival between the 13 patients who entered the study before G-CSF administration was mandated and the 35 patients who entered after and received G-CSF. There was poor correlation between the WBC count and absolute neutrophil counts (ANCs) and both the area under the curve (AUC) and maximum concentration++ (Cmx) of total topotecan in plasma. There was no correlation between the tumor response and either AUC or Cmx of total topotecan. CONCLUSION: The activity of topotecan in extensive-stage SCLC noted in this study warrants further investigation of this agent in phase III clinical trials.     

Oral topotecan given once or twice daily for ten days: a phase I pharmacology study in adult patients with solid tumors

The development of a highly sensitive method for detection of telomerase activity, telomeric repeat amplification protocol (TRAP), has provided knowledge on telomerase activity in normal and cancer tissues. Subsequent several modifications have been achieved, including an introduction of the internal standard and hybridization protection technique that leads to simplicity and improvement of reproducibility and linearity of this method, and application of TRAP to in situ analysis to identify the cells responsible for telomerase activity. As for measurement of telomere length, fluorescence in situ hybridization technique appeared to give an information of telomere length on an individual chromosome in contrast to analysis of terminal restriction fragment, a conventional method which can express mean telomere length of all chromosomes. Further methodological improvement in this field is ongoing and showing a new sight on cell mortality and immortality.     

Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors

PURPOSE AND METHODS: Tirapazamine (SR4233, WIN 59075) is a benzotriazine-di-N-oxide bioreductive agent that is selectively activated to a reactive DNA-damaging species in hypoxic tumors. Preclinical studies show that synergistic antitumor activity results from a schedule-dependent interaction between tirapazamine and several cytotoxic drug classes, including cisplatin. In a phase I combination study, tirapazamine (130 to 260 mg/m2) was administered as a 1-hour intravenous (IV) infusion beginning 3 hours before cisplatin (75 to 100 mg/m2). Thirteen patients received 41 courses of therapy. These patients had an excellent performance status and were not heavily pretreated. The predominant diagnosis was lung cancer. RESULTS: The major acute side effects were nausea and vomiting, which were controlled with an intensive antiemetic regimen. Other acute effects included diarrhea and muscle cramping, while with repeated dosing, anorexia and fatigue predominated. Full doses of each agent were well tolerated in combination, although in this previously treated population, fatigue increased markedly after three cycles of therapy. Partial responses were observed in two patients (one with non-small-cell lung cancer and one with breast cancer), and a minor response occurred in a patient with mesothelioma. Tirapazamine pharmacokinetics were linear with respect to increasing dose with a mean maximum plasma concentration (Cmax) of 5.97 +/- 2.25 microg/mL and an area under the concentration-time curve (AUC) of 811.4 +/- 311.9 microg/mL.min at 260 mg/m2. These results are consistent with other ongoing single-agent and combination studies and indicate that therapeutically relevant levels of tirapazamine are achievable in patients based on animal models. The mean cisplatin AUC was 285.6 +/- 46.4 microg/mL.min with mean Cmax values of 3.38 +/- 0.43 microg/mL at 75 mg/m2. The clearance of cisplatin was unaffected by coadministration with tirapazamine. CONCLUSION: This trial shows that in previously treated patients, full doses of cisplatin are well tolerated with increasing doses of tirapazamine up to 260 mg/m2. The observation of clinical responses in this trial supports the phase II investigation of this regimen.     

Phase I and pharmacologic study of topotecan in patients with impaired renal function

PURPOSE: To determine the toxicities, pharmacokinetics, and recommended doses of the topoisomerase I inhibitor, topotecan, in patients with varying degrees of renal excretory dysfunction. PATIENTS AND METHODS: Fourteen patients with normal renal function [creatinine clearance (CrCl) > or = 60 mL/min] and 28 patients with varying degrees of renal dysfunction were treated with topotecan 0.4 to 2.0 mg/m2/d as a 30-minute infusion for 5 consecutive days every 3 weeks. Plasma and urine samples were obtained to determine the disposition of topotecan. RESULTS: In patients with mild renal dysfunction (CrCl = 40 to 59 mL/min), dose-limiting hematologic toxicity was observed in three of eight patients receiving topotecan 1.0 mg/m2/d and in two of five patients receiving topotecan 1.5 mg/m2/d. In patients with moderate renal dysfunction (CrCl = 20 to 39 mL/min), dose-limiting hematologic toxicity was observed in three of eight patients who received topotecan 0.5 mg/m2/d, and in two of four patients receiving topotecan 1.0 mg/m2/d; these events were more frequently observed in extensively pretreated patients. Pharmacokinetic analyses showed significant correlations between CrCl and the plasma clearance of both total topotecan [Spearman's correlation coefficient (r2) = 0.65, P = .00001] and topotecan lactone (r2 = 0.65, P = .00003). Mean systemic plasma clearance of total topotecan was significantly reduced in patients with mild (P = .04) and moderate (P = .00006) renal dysfunction. There was no evidence of changes in the pharmacodynamic relationship between topotecan exposure (AUC) and myelotoxicity. CONCLUSION: Dose adjustments are required in patients with moderate, but not mild, renal impairment. For patients with moderate renal dysfunction, the recommended starting dose of topotecan is 0.75 mg/m2/d for 5 days every 3 weeks. Moreover, extensively pretreated patients need further dose reductions.     

Phase I and pharmacologic study of penclomedine, a novel alkylating agent, in patients with solid tumors

PURPOSE: To determine the maximum-tolerated dose (MTD), principal toxicities, and pharmacologic behavior of penclomedine, a novel alkylating agent. PATIENTS AND METHODS: Penclomedine (45 to 550 mg/ m2/d every 3 weeks) was administered as a 1- or 3-hour intravenous (IV) infusion for 5 consecutive days to patients with solid tumors. RESULTS: On a 1-hour dosing schedule, ataxia, vertigo, nystagmus, and a motor aphasia were the principal toxicities of penclomedine. These neurologic effects were dose-related, and evolved from complaints of somnolence and dizziness, to more pronounced signs and symptoms of cerebellar dysfunction. Up to and including doses of 415 mg/m2, these effects were well tolerated and resolved within 2 hours posttreatment. In contrast, both patients treated at the 550-mg/m2 dose level experienced a dose-limiting constellation of perinfusional aphasia and vertigo, with either ataxia of over 2 weeks' duration or recurrent dizziness. Prolongation of the infusion duration to 3 hours at this dose level resulted in less neurotoxicity; however, delayed trilineage hematologic toxicity precluded timely administration on this schedule. A statistically significant relationship was demonstrated between the development of ataxia and maximum plasma concentrations of penclomedine. CONCLUSION: Neurotoxicity was the dose-limiting toxicity (DLT) of penclomedine administered as a 1-hour infusion daily for 5 days every 3 weeks, and the recommended dose for further evaluations was 415 mg/m2. The nature of the principal toxicities and the lack of any detectible antitumor activity indicate that phase II evaluations of penclomedine on this administration schedule should be focused on specific disease settings, such as breast cancer and intracerebral tumors, in which antitumor activity has been demonstrated.     

Phase I study of the orally administered butyrate prodrug, tributyrin, in patients with solid tumors

Butyrates have been studied as cancer differentiation agents in vitro and as a treatment for hemoglobinopathies. Tributyrin, a triglyceride with butyrate molecules esterified at the 1, 2, and 3 positions, induces differentiation and/or growth inhibition of a number of cell lines in vitro. When given p.o. to rodents, tributyrin produces substantial plasma butyrate concentrations. We treated 13 patients with escalating doses of tributyrin from 50 to 400 mg/kg/day. Doses were administered p.o. after an overnight fast, once daily for 3 weeks, followed by a 1-week rest. Intrapatient dose escalation occurred after two courses without toxicity greater than grade 2. The time course of butyrate in plasma was assessed on days 1 and 15 and after any dose escalation. Grade 3 toxicities consisted of nausea, vomiting, and myalgia. Grades 1 and 2 toxicities included diarrhea, headache, abdominal cramping, nausea, anemia, constipation, azotemia, lightheadedness, fatigue, rash, alopecia, odor, dysphoria, and clumsiness. There was no consistent increase in hemoglobin F with tributyrin treatment. Peak plasma butyrate concentrations occurred between 0.25 and 3 h after dose, increased with dose, and ranged from 0 to 0.45 mM. Peak concentrations did not increase in three patients who had dose escalation. Butyrate pharmacokinetics were not different on days 1 and 15. Because peak plasma concentrations near those effective in vitro (0.5-1 mM) were achieved, but butyrate disappeared from plasma by 5 h after dose, we are now pursuing dose escalation with dosing three times daily, beginning at a dose of 450 mg/kg/day.     

Phase II evaluation of topotecan in patients with advanced colorectal cancer. A Southwest Oncology Group trial (SWOG 9241)

By using the indirect immunofluorescence assay and the tissue cells infected with coxackie virus Group B as antigen, the authors detected the antibodies type IgM to coxsackie virus Group B (CVB-IgM) of the sera of 105 children with viral myocarditis (VMC), 59 children with other diseases (COD) and 67 healthy children (HC). The results showed that in VMC, the genometric mean titre (GMT) of CVB-IgM in female (1:16.58) was higher than that in male (1:9.28, P < 0.05); not only in female, but also in male the GMT of VMC was higher than that of HC; also the GMT in female of VMC was higher than the GMT in female of COD, but no considerable difference existed between male of VMC and COD. Without sex distinction the GMT of HC was 0.289, its standard variance was 0.9335, the upper limit titre of normal range was 1:8.6. The authors took 1:10 as the positive criterion, the sensitivity of CVB-IgM in diagnosing VMC was 79.05%, the specialities of differentiating VMC from COD and HC were 42.3% and 91.04%, the consistancy rates of diagnosing VMC from COD and HC were 65.85% and 83.72% respectively.     

Phase I clinical and pharmacologic study of weekly cisplatin combined with weekly irinotecan in patients with advanced solid tumors

PURPOSE: In vitro synergy between cisplatin and irinotecan (CPT-11) has been reported. We designed a combination schedule of these agents to maximize the potential for synergistic interaction. PATIENTS AND METHODS: To maximize the opportunity for synergy, we divided the cisplatin into four consecutive weekly treatments, followed by a 2-week rest. Each dose of cisplatin was immediately followed by a dose of irinotecan. The dose of cisplatin was fixed at 30 mg/m2/wk. The initial irinotecan dose was 50 mg/m2/wk and this was escalated by 30% increments in successive cohorts of three to six patients to establish the maximum-tolerated dose (MTD). Pharmacokinetics of irinotecan and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were analyzed. RESULTS: Of 35 patients with solid tumors enrolled onto this trial, 30 were assessable for toxicity and response. The MTD for this regimen was 30 mg/m2/wk of cisplatin plus 50 mg/m2/wk of irinotecan in previously treated patients and 30 mg/m2/wk of cisplatin plus 65 mg/m2/wk of irinotecan in chemotherapy-naive patients. Neutropenia was the dose-limiting toxicity (DLT) encountered in this trial. Diarrhea was infrequent and rarely dose-limiting. Seven of 30 assessable patients achieved a partial response. No alteration in irinotecan, SN-38, or SN-38G pharmacokinetics resulted from the administration of cisplatin with irinotecan. CONCLUSION: The administration of cisplatin and irinotecan on this weekly schedule provides a practical and well-tolerated regimen that has the potential to maximize any clinical synergy between the two agents. Evidence of substantial clinical activity was seen in this phase I study.     

Phase II trial of paclitaxel and granulocyte colony-stimulating factor in patients with pancreatic carcinoma: a Southwest Oncology Group study

PURPOSE: Pancreatic cancer is difficult to treat, with most patients surgically unresectable at the time of diagnosis. Radiotherapy and chemotherapy can offer palliation, but more effective therapy is needed. This trial evaluated the effects of an aggressive schedule of paclitaxel given with granulocyte colony-stimulating factor (G-CSF) to patients with advanced pancreatic cancer. PATIENTS AND METHODS: All patients were required to have a histologic diagnosis of pancreatic adenocarcinoma with measurable disease and no prior chemotherapy or radiation therapy. Patients had to have performance status of 0 to 2, pretreatment absolute granulocyte count > or = 1,500/microL, and platelet count greater than or equal to the institutional lower limit of normal. Following pretreatment with dexamethasone, diphenhydramine, and cimetidine, patients received paclitaxel at a dose of 250 mg/m2 by 24-hour infusion on day 1, repeated every 21 days. G-CSF was given at a dose of 5 microg/kg/d on days 3 to 18 or until two consecutive absolute neutrophil counts (ANCs) > or = 10,000/microL were obtained. Doses of paclitaxel were modified depending on nadir counts. RESULTS: Forty-five patients were entered onto this study, with six ineligible. For the 39 eligible patients, there was one complete response (CR) and two partial responses (PRs), five stable/no responses, 23 increasing disease, two early deaths, and six patients whose assessment was inadequate to determine response. The response rate was therefore three of 39 or 8% (95% confidence interval [CI], 2% to 21%). The median survival time for the 39 eligible patients was 5 months. The most common toxicities were anemia, leukopenia/granulocytopenia, malaise/fatigue, nausea/vomiting, alopecia, thrombocytopenia, paresthesias, and liver function abnormalities. There was one death due to sepsis. CONCLUSION: Single-agent paclitaxel in this dose and schedule has minimal activity in pancreatic adenocarcinoma patients.     

Phase I clinical and pharmacokinetic study of titanocene dichloride in adults with advanced solid tumors

This Phase I dose-escalation clinical trial of a lyophilized formulation of titanocene dichloride (MKT4) was conducted to determine the maximum tolerated dose, the dose-limiting toxicity (DLT), and pharmacokinetics of titanium (Ti) after a single i.v. infusion of MKT4. Forty patients with refractory solid malignancies were treated with a total of 78 courses. Using a modified Fibonacci scheme, 15 mg/m2 initial doses of titanocene dichloride were increased in cohorts of three patients up to level 11 (560 mg/m2) if DLT was not observed. The maximum tolerated dose was 315 mg/m2, and nephrotoxicity was DLT. Two minor responses (bladder carcinoma and non-small cell lung cancer) were observed. The pharmacokinetics of plasma Ti were assessed in 14 treatment courses by atomic absorption spectroscopy. The ratio for the area under the curve(0-infinity) in plasma and whole blood was 1.2. The following pharmacokinetic parameters were determined for plasma, as calculated in a two-compartment model: biological half-life t1/2beta in plasma was 22.8+/-11.2 h (xh +/- pseudo-SD), peak plasma concentration cmax approximately 30 microg/ml at a dose of 420 mg/m2, distribution volume Vss= 5.34+/-2.1 L (xa +/- SD), and a total clearance CItotal = 2.58+/-1.23 ml/min (xa +/- SD). There was a linear correlation between the area under the curve(0-infinity) of Ti in plasma and the titanocene dichloride dose administered with a correlation coefficient r2 of 0.8856. Plasma protein binding of Ti was in the 70-80% range. Between 3% and 16% of the total amount of Ti administered were renally excreted during the first 36 h. The recommended dose for Phase II evaluation is 240 mg/m2 given every 3 weeks with i.v. hydration to reduce renal toxicity.     

Five days of oral topotecan (Hycamtin), a phase I and pharmacological study in adult patients with solid tumours

Topotecan is a specific inhibitor to topoisomerase I. An oral formulation of topotecan is available with a bioavailability of 32-44% in humans. A phase I and pharmacological study of the oral formulation of topotecan administered daily for 5 days every 21 days was performed in adult patients with solid tumours to determine the maximum tolerated dose (MTD). Adult patients with a WHO performance status < or = 2 adequate haematological, hepatic and renal functions, with malignant solid tumours refractory to standard forms were entered into the study. Pharmacokinetics were performed on days 1 and 4 of the first course using a validated high performance liquid chromatographic assay. 29 patients entered the study, all patients were evaluable for toxicity and response. The doses studied in the 29 patients were 1.2, 1.8, 2.3, 2.7 mg/m2/day and a fixed dose of 4 mg/day without surface area adjustment. A total of 109 courses were given. Dose limiting toxicity (DLT) was reached at a dose of 2.7 mg/m2/day and consisted of CTC (NCI-Common Toxicity Criteria) grade IV granulocytopenia. The regimen was well tolerated. Non-haematological toxicities were mild, including fatigue, anorexia, nausea, vomiting and diarrhoea. A significant correlation was observed between the percentage decrease in white blood cells versus the area under the curve (AUC(t)) of topotecan lactone (R = 0.76 P < 0.01) which was modelled by a sigmoidal Emax function. The correlation coefficient between the absolute topotecan dose administered and the AUC(t) was R = 0.52 (P = 0.04). Pharmacokinetics of the fixed dose of 4 mg/day were comparable to the 2.3 mg/m2/day dose. DLT in this phase I study of five daily doses of oral topotecan every 21 days was granulocytopenia. The recommended dose for phase II studies is 2.3 mg/m2/day or alternatively, a fixed dose of 4 mg/day.     

Consolidation therapy with antimetabolite-based therapy in standard-risk acute lymphocytic leukemia of childhood: a Pediatric Oncology Group Study

PURPOSE: To develop antimetabolite-based consolidation regimens that minimize acute and long-term toxicities and improve the survival rate of children with standard-risk B-lineage acute lymphocytic leukemia (ALL). PATIENTS AND METHODS: Seven hundred twenty-seven eligible patients with standard-risk early pre-B ALL were registered onto the study. Seven hundred sixteen patients attained a complete remission (CR) after induction therapy. Of these, 114 patients were randomized to a different regimen and were the subject of a separate report. Six hundred two patients were randomized to receive one the following regimens: intermediate-dose methotrexate (IDMTX) with leucovorin rescue on weeks 7, 10, 13, 16, 19, and 22 (regimen A); regimen A plus asparaginase (ASP) administered intramuscularly (i.m.) weekly for 24 weeks (regimen B); or regimen A plus a 24-hour infusion of cytarabine (AraC) with each IDMTX (regimen C). After consolidation, patients were placed on maintenance therapy through week 156. Regimens A and C were opened in February 1986, and regimen B in May 1987. Comparisons are based on concurrently randomized patients (May 1987 to January 1991 between regimens A and B, and February 1986 to January 1991 between regimens A and C). RESULTS: The 5-year continuous CR (CCR) rates were not significantly different: A versus B, 78.1% (3.9 +/- SE) versus 83.3% +/- 3.5% and A versus C, 79.4% +/- 3.2% versus 83.5% +/- 2.9%; P by one-sided log-rank tests were .27 and .34, respectively. Significant treatment differences were not found with regard to sex, rate of testicular and CNS relapse, or CNS complications. During consolidation, regimen C had significantly more bacterial infections (P = .0032) and days spent in the hospital (P < .001) compared with regimen A. CONCLUSION: We were unable to show a statistical advantage of adding either ASP or AraC to IDMTX in terms of improvement in event-free survival (EFS).     

Trisomy 21 in childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study (8602)

Of 1,036 children with newly diagnosed non-T, non-B acute lymphoblastic leukemia (ALL) and a demonstrated cytogenetic abnormality treated on the frontline Pediatric Oncology Group (POG) therapeutic trial 8602, there were 33 patients with trisomy 21 as the sole abnormality. Of these 33, 14 had Down syndrome (DS). Although the non-DS (NDS) trisomy 21 cases tended to be older than the DS cases, there were no other significant differences in clinicobiologic features nor in treatment outcomes between the DS and NDS groups, nor between the entire trisomy 21 group and the other chromosome abnormality group. Among NDS patients with +21 and one additional abnormality, +X, +16, -20, and structural abnormalities involving 6q or 12p were common findings. Kaplan-Meier event-free survival (EFS) curves showed a 4-year EFS of 80% (SE, 12%) in NDS trisomy 21 cases, 71% (SE, 22%) in DS cases with trisomy 21 as the sole abnormality, and 69% (SE, 2%) in cases with other chromosome abnormalities. Trisomy 21 as a sole acquired abnormality in NDS patients suggests a good prognosis.     

Phase I study of intraperitoneal metalloproteinase inhibitor BB94 in patients with malignant ascites

This was an open Phase I study of i.p. matrix metalloproteinase inhibitor BB94 in patients with malignant ascites. The objective of the study was to determine the effect of increasing i.p. doses of BB94 with reference to the tolerance, safety, and pharmacokinetics of the compound. Twenty-three patients with malignant ascites had BB94 instilled into the peritoneal cavity after paracentesis. The compound was well tolerated; no serious adverse events were seen, and no specific toxicities were observed. High plasma concentrations were seen an hour after dosing, and BB94 was still present in the plasma at day 28 after treatment at levels in excess of the IC50 identified in preclinical studies. Five of the 23 patients neither reaccumulated ascites nor died up to 112 days after dosing. Seven patients died without reaccumulating ascites. Although the study was not designed to demonstrate clinical efficacy, the results were encouraging and support the further therapeutic evaluation of matrix metalloproteinase inhibitors in the management of malignant ascites.     

Infection after pediatric heart transplantation: results of a multiinstitutional study. The Pediatric Heart Transplant Study Group

BACKGROUND: Detailed information regarding the spectrum and predictors of infection after heart transplantation in children is limited because of relatively small numbers of patients at any single institution. We therefore used combined data obtained from the Pediatric Heart Transplant Study Group to gain additional information regarding infectious complications in the pediatric population. METHODS: To determine the time-related risk of infection and death related to infection in a large pediatric patient population, we analyzed data related to 332 pediatric patients (undergoing heart transplantation between January 1, 1993, and December 31, 1994) from 22 institutions in the Pediatric Heart Transplant Study Group. RESULTS: Among the 332 total patients, 276 infections were identified in 136 patients. Of those patients with development of infection, a single infection episode was reported in 54% of patients, 21% had two infections, and 25% had three or more infections. Of the 276 infections, 164 (60%) were bacterial, 51 (18%) were due to cytomegalovirus, 35 (13%) were other viral (noncytomegalovirus) infections, 19 (7%) were fungal, and 7 (2%) were protozoal. Bacterial infections were more common in infants younger than 6 months of age at time of transplantation, comprising 73% of all infections as compared with 49% in patients older than 6 months of age. The incidence of bacterial infection peaked during the first month after transplantation, with the actuarial likelihood of a bacterial infection among all patients reaching 25% at 2 months. The most common sites of bacterial infection were blood and lung (74% of bacterial infections). Cytomegalovirus accounted for 59% of viral infections, with a peak hazard occurring at 2 months after transplantation. Among all infections, cytomegalovirus was less common in infants younger than 6 months of age (8% of all infections) than in older patients (25%). By multivariate analysis, risk factors for early infection included younger recipient age (p = 0.05), mechanical ventilation at time of transplantation (p = 0.0002), positive donor cytomegalovirus serologic study result with negative recipient result (p = 0.004), and longer donor ischemic time (p = 0.04). The overall mortality rate from infection was 5%, with an actuarial freedom from death related to infection of 92% at 1 year after transplantation. The mortality rate was high in patients with fungal infections (52%), yet was low for those with cytomegalovirus infection (6%). Infections accounted for 27% of the overall mortality rate in infants younger than 6 months of age, compared with 16% for older patients. CONCLUSIONS: Although most infections in pediatric heart transplant recipients are successfully treated, infection remains an important cause of posttransplantation morbidity and death, especially in infants. Bacterial infections predominate within the first month after transplantation, whereas the peak hazard for viral infections occurs approximately 2 months after transplantation. Cytomegalovirus infections are common in the pediatric transplant population, but death related to cytomegalovirus is low.