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1.
Clin Pharmacol Ther ; 98(5): 506-13, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26239772

ABSTRACT

We developed an algorithm (ANDI) for predicting regulatory marketing approval for new cancer drugs after phase II testing has been conducted, with the objective of providing a tool to improve drug portfolio decision-making. We examined 98 oncology drugs from the top 50 pharmaceutical companies (2006 sales) that first entered clinical development from 1999 to 2007, had been taken to at least phase II development, and had a known final outcome (research abandonment or regulatory marketing approval). Data on safety, efficacy, operational, market, and company characteristics were obtained from public sources. Logistic regression and machine-learning methods were used to provide an unbiased approach to assess overall predictability and to identify the most important individual predictors. We found that a simple four-factor model (activity, number of patients in the pivotal phase II trial, phase II duration, and a prevalence-related measure) had high sensitivity and specificity for predicting regulatory marketing approval.


Subject(s)
Algorithms , Antineoplastic Agents/therapeutic use , Clinical Trials, Phase II as Topic/legislation & jurisprudence , Drug Approval/legislation & jurisprudence , Machine Learning , Clinical Trials, Phase II as Topic/methods , Drug Approval/methods , Forecasting , Humans , Neoplasms/diagnosis , Neoplasms/drug therapy
3.
J Pediatr Hematol Oncol ; 21(4): 260-7, 1999.
Article in English | MEDLINE | ID: mdl-10445887

ABSTRACT

PURPOSE: To describe patterns of central venous catheter (CVC) use and determine the risk of infection associated with a catheter in children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Children with ALL (n = 1934), participating in Children's Cancer Group studies for good-prognosis ALL (CCG-1881) and intermediate-risk ALL (CCG-1891) were evaluated in a retrospective case-control study. The presence of a catheter and the occurrence of infectious complications were recorded after each treatment phase. RESULTS: Young age and enrollment in the intermediate-risk study were associated with higher rates of catheter use. During each of the first four phases of therapy, the adjusted risk of infection was two- to fourfold higher when a catheter was in place. The proportion of patients with infection during the first four phases of therapy was 2.6 times higher with a CVC (14.4% versus 5.7%). Catheter use was associated with significantly increased hospitalization rates during induction, consolidation, and interim maintenance, but not during delayed intensification. A catheter did not significantly increase the risk of fever during neutropenia. CONCLUSION: The presence of a CVC increases the risk of infection during the early phases of low-intensity therapy for ALL.


Subject(s)
Antineoplastic Agents/administration & dosage , Catheterization, Central Venous/adverse effects , Infections/etiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Case-Control Studies , Child , Child, Preschool , Female , Humans , Incidence , Male , Retrospective Studies , Risk , United States
4.
Am J Hematol ; 59(1): 5-8, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9723569

ABSTRACT

An important purpose of blood transfusion in patients with sickle cell disease is to improve arterial oxygen saturation (SaO2) and thereby reduce red cell sickling. To investigate the degree of improvement in SaO2 by blood transfusion, we determined the hemoglobin oxygen affinity, transcutaneous oxygen saturation (Tc-SO2), and pulse rate before and after automated partial exchange transfusion (erythrocytapheresis). In 13 patients with sickle cell disease who underwent 24 erythrocytapheresis procedures, the mean oxygen tension at half saturation (P50) was significantly reduced from 30.4 +/- 2.2 to 26.0 +/- 1.6 mm Hg (P< 0.01) immediately after exchange transfusion. Mean Tc-SO2 values increased from 96.2 +/- 2.8 to 98.5 +/- 2.1% (P< 0.01). Approximately 50% of the increase in Tc-SO2 after erythrocytapheresis could be explained by the increase in hemoglobin oxygen affinity. An increase in arterial oxygen pressure (PaO2) following erythrocytapheresis, suggested by the calculated PaO2 in this study, may explain some of the increase in Tc-SO2. We conclude that improvement in Tc-SO2 in patients with sickle cell disease resulted from changes in hemoglobin oxygen affinity as well as blood oxygen pressure following erythrocytapheresis.


Subject(s)
Anemia, Sickle Cell/blood , Blood Component Removal , Blood Gas Monitoring, Transcutaneous , Erythrocyte Transfusion , Hemoglobins/metabolism , Oxygen/metabolism , 2,3-Diphosphoglycerate/blood , Adolescent , Adult , Arteries/chemistry , Child , Erythrocytes/chemistry , Female , Humans , Male , Partial Pressure , Pulse
5.
J Pediatr Hematol Oncol ; 19(4): 309-12, 1997.
Article in English | MEDLINE | ID: mdl-9256829

ABSTRACT

PURPOSE: To determine the hematopoietic and nonhematopoietic toxicity of a novel dose-intensive chemotherapy regimen for the treatment of children with relapsed solid tumors. PATIENTS AND METHODS: The time to hematopoietic recovery and toxicity experienced during 46 courses of high-dose cyclophosphamide (4.0 g/m2), MESNA, and carboplatin (400 mg/m2) with granulocyte colony stimulating factor (G-CSF) support in 14 children with recurrent solid tumors was reviewed. RESULTS: All patients developed grade 4 neutropenia and thrombocytopenia. Recovery to an absolute neutrophil count (ANC) of 500/microliter and platelet count of 50,000/microliter occurred at a median of 15 days and 23 days respectively. Median time to ANC > 1,000/microliter and platelets > 100,000/microliter was 27 days. Hospitalization for fever and neutropenia occurred during 35 of 46 courses, with documented bacteremia in six courses. There was no grade II or greater nonhematopoietic organ toxicity. Responses (CR + PR) were observed in 6 of 11 evaluable patients. CONCLUSIONS: These data suggest that this regimen is tolerable in heavily pretreated children with solid tumors with myelosuppression as the primary toxicity. Due to the lack of significant nonhematopoietic toxicity, this is a good candidate regimen for dose escalation using peripheral blood progenitor cell infusions and deserves further evaluation for efficacy in children with both recurrent and newly diagnosed high-risk solid tumors.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Adolescent , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Brain Neoplasms/drug therapy , Carboplatin/administration & dosage , Child , Child, Preschool , Cyclophosphamide/administration & dosage , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Humans , Male , Neoplasm Recurrence, Local/drug therapy , Neuroblastoma/drug therapy , Neuroectodermal Tumors, Primitive/drug therapy , Salvage Therapy
6.
Blood ; 88(5): 1588-93, 1996 Sep 01.
Article in English | MEDLINE | ID: mdl-8781414

ABSTRACT

This report examines the effect of filgrastim (granulocyte colony-stimulating factor, [G-CSF] in 12 patients with neutropenia [absolute neutrophil count [ANC] < 1,000/mm3]) caused by Fanconi anemia (FA). Two of 14 patients who were evaluated for study entry were ineligible because of unsuspected cytogenetic abnormalities in their bone marrow (BM). G-CSF was started at 5 micrograms/kg/d. All patients had an increase in their ANC at week 8 (mean increase = 15,664/mm3). The median ANC during therapy was 5,030/mm3. Eight of 10 patients who completed 40 weeks on study maintained an ANC > 1,500/mm3 on G-CSF given every-otherday. Four patients had an increase in their platelet count by week 8 without transfusion (maximum increase = 23,000 to 45,000/mm3); however, platelet counts fell toward baseline levels as the G-CSF dose was reduced. BM CFU-MK were increased at week 8 in three of four evaluable patients. Four patients who did not receive red blood cell transfusions had an increase in their hemoglobin level of at least 2.0 g/dL. A fifth patient had a red blood cell transfusion in week 2 and then had a similar increase in hemoglobin level without subsequent transfusion. Eight of 10 patients who completed 40 weeks of treatment showed increases in the percentage of BM CD34+ cells measured by flow cytometry. The same proportion showed increases in peripheral blood CD34+ cells. Increased BM cellularity and myeloid hyperplasia were constant findings and were associated with increased expression of the proliferating cell nuclear antigen. Adverse experiences were mild fever (1 patient) and a new BM cytogenetic abnormality at week 40 (1 patient). This study shows that prolonged administration of G-CSF exerts a stimulatory effect on the BM of FA patients and may be used to maintain a clinically adequate ANC in these patients. G-CSF has beneficial effects on multiple hematopoietic lineages in some patients and may be a good candidate for use in combination cytokine protocols for FA patients with progressive aplastic anemia. G-CSF use results in an increase in circulating CD34+ cells, a finding with important implications for future gene transfer protocols.


Subject(s)
Fanconi Anemia/drug therapy , Granulocyte Colony-Stimulating Factor/therapeutic use , Adolescent , Blood Transfusion , Bone Marrow/pathology , Child , Child, Preschool , Combined Modality Therapy , Fanconi Anemia/complications , Fanconi Anemia/pathology , Fanconi Anemia/therapy , Female , Filgrastim , Granulocyte Colony-Stimulating Factor/administration & dosage , Humans , Leukocyte Count/drug effects , Male , Neutropenia/drug therapy , Neutropenia/etiology , Pilot Projects , Platelet Count/drug effects , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use
7.
J Clin Oncol ; 14(3): 919-24, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8622040

ABSTRACT

PURPOSE: We sought to identify factors assessable at the time of admission for fever and neutropenia that predict bacteremia in children with cancer. PATIENTS AND METHODS: One hundred fifteen consecutive episodes of fever and absolute neutrophil count (ANC) less than 500/microliter in 72 children with cancer were studied prospectively to determine the risk of bacteremia using data assessable at the time of presentation. After exploratory analysis identified admission temperature and absolute monocyte count (AMoC) as the strongest predictive factors, recursive partitioning was used to determine cutpoints for these variables that resulted in discrimination between episodes associated with a lower or higher risk of bacteremia. RESULTS: There were 24 episodes of bacteremia (21% of episodes). Episodes were grouped using the cutpoints for AMoC and temperature: 17% were classified as low risk for bacteremia (AMoC > or = 100/microliter), 65% as intermediate risk (AMoC < 100/microliter and temperature < 39.0 degrees C), and 18% as high risk (AMoC < 100/microliter and temperature > or = 39.0 degrees C). No episodes classified as low risk were associated with bacteremia; 19% of intermediate-risk and 48% of high-risk episodes were associated with bacteremia. The odds ratio of bacteremia for the high-risk versus the intermediate-risk group is 4.4 (95% confidence interval, 1.6 to 12.9). The risk classification was validated using data from 57 different episodes of fever and neutropenia treated in the same hospital. CONCLUSION: Three levels of risk for bacteremia are defined using the AMoC and temperature at the time of admission for fever and neutropenia. Trials now should be conducted to test whether these factors may be used to assign some children to less intensive or outpatient antibiotic therapy at the time of presentation with fever and neutropenia.


Subject(s)
Bacteremia/complications , Fever/complications , Neoplasms/complications , Neutropenia/complications , Adolescent , Bacteremia/diagnosis , Bias , Child , Child, Preschool , Hospitalization , Humans , Infant , Leukocyte Count , Monocytes , Odds Ratio , Predictive Value of Tests , Prospective Studies , Regression Analysis
8.
J Pediatr ; 127(1): 147-51, 1995 Jul.
Article in English | MEDLINE | ID: mdl-7608801

ABSTRACT

OBJECTIVE: To determine whether adding vancomycin to central venous catheter (CVC) flush solution would significantly reduce the incidence of bacteremia attributable to luminal colonization with vancomycin-susceptible organisms. STUDY DESIGN: Fifty-five children with cancer and eight children given total parenteral nutrition by the surgery or nutrition support services were randomly assigned to receive a heparin CVC flush solution (n = 31) or a heparin-vancomycin CVC flush solution (n = 32). RESULTS: During 9158 catheter days, 6.5% of the patients in the heparin group and 15.6% of the patients in the heparin-vancomycin group had bacteremia attributable to luminal colonization with vancomycin-susceptible organisms (p = 0.43). The mean rates of bacteremia attributable to luminal colonization with vancomycin-susceptible organisms were 0.6/1000 catheter days in the heparin group and 1.4/1000 catheter days in the heparin-vancomycin group (p = 0.25). There was no significant difference between the groups when the time to the first episode of bacteremia attributable to luminal colonization with a vancomycin-susceptible organism was compared by means of Kaplan-Meier survival estimates. Streptococcus viridans infection was not attributable to luminal colonization. CONCLUSION: The addition of vancomycin to heparin CVC flush solution did not reduce bacteremia with vancomycin-susceptible organisms. Bacteremia with Streptococcus viridans was not related to the use of a CVC.


Subject(s)
Bacteremia/drug therapy , Catheterization , Heparin/therapeutic use , Parenteral Nutrition , Solutions , Vancomycin/therapeutic use , Adolescent , Bacteremia/etiology , Bacteremia/microbiology , Child , Child, Preschool , Drug Combinations , Enterococcus/isolation & purification , Enterococcus/pathogenicity , Heparin/administration & dosage , Humans , Streptococcus/isolation & purification , Streptococcus/pathogenicity , Treatment Outcome , Vancomycin/administration & dosage
9.
Am J Pediatr Hematol Oncol ; 16(2): 132-7, 1994 May.
Article in English | MEDLINE | ID: mdl-7513135

ABSTRACT

PURPOSE: We conducted a retrospective case-control study to examine the effect of granulocyte-colony-stimulating factor (G-CSF) on the duration of the neutrophil nadir and other clinical parameters in children with neuroblastoma. PATIENTS AND METHODS: We retrospectively reviewed 85 courses of the same chemotherapy in 16 consecutive neuroblastoma patients. The first nine patients received no growth factor and the following seven patients received G-CSF. Data obtained included days of neutropenia, fever rate and duration, hospitalization rate and duration, antibiotic duration, and infection rate. RESULTS: Patients who received G-CSF had a significant decrease in the period of neutropenia (mean 5.4 +/- 2.6 days per course vs. 11.4 +/- 4.1 days per course in the control group; p < 0.001). There were no statistically significant differences in episodes of fever per course, rate of hospitalization per course, duration of hospitalization, or duration of antibiotic therapy. Control patients had documented infections during 16% (nine of 56) of their chemotherapy courses, whereas the patients receiving G-CSF had infections during 7% (two of 29) of their courses, but this difference was not statistically significant (p = 0.318). We calculated that a study of 220 courses in each group would be needed to have adequate power to confirm that this difference is statistically significant. CONCLUSIONS: The administration of G-CSF in this patient population did result in fewer days of neutropenia, a finding that has been reported previously in several adult studies. However, we conclude that the clinical benefit of more rapid hematologic recovery in children remains uncertain and deserves further investigation in a large, prospective multicenter trial.


Subject(s)
Granulocyte Colony-Stimulating Factor/therapeutic use , Neuroblastoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Case-Control Studies , Child , Humans , Neutrophils/drug effects , Retrospective Studies
10.
Am J Pediatr Hematol Oncol ; 16(2): 156-9, 1994 May.
Article in English | MEDLINE | ID: mdl-8166369

ABSTRACT

PURPOSE: We report that the use of alternate-day cyclosporine and prednisone improved the clinical course of a 6-year-old child with severe Evans syndrome. Before the use of cyclosporine the child had experienced life-threatening episodes of hemolytic anemia despite the use of multiple therapeutic modalities. METHODS: Cyclosporine was given at a dose of 10 mg/kg/day divided into two doses on alternate days. RESULTS: The use of cyclosporine resulted in increased hemoglobin levels, increased platelet counts, and the reduction of the patient's prednisone dose from 2 mg/kg/day to as low as 1 mg/kg every other day. With this regimen, the patient had less severe hemolytic anemia, was less thrombocytopenic, and had fewer hospitalizations. No major toxic effects were associated with cyclosporine therapy. CONCLUSION: The regimen of alternate-day cyclosporine and prednisone may prove to be useful in the treatment of other patients with refractory Evans syndrome.


Subject(s)
Anemia, Hemolytic, Autoimmune/drug therapy , Cyclosporine/administration & dosage , Prednisone/administration & dosage , Thrombocytopenia/drug therapy , Child , Drug Administration Schedule , Drug Therapy, Combination , Female , Humans , Syndrome
11.
Pediatr Emerg Care ; 10(2): 79-82, 1994 Apr.
Article in English | MEDLINE | ID: mdl-8029115

ABSTRACT

When considering an alternative site to the emergency department (ED) for the care of acutely ill patients with sickle cell disease, it is necessary first to determine utilization of and satisfaction with ED care. Such data serve as guidelines for the planning and evaluation of alternative treatment facilities. We reviewed 137 consecutive ED visits by 98 patients with sickle cell diseases at The Children's Hospital of Philadelphia over a three-month period to determine ED utilization and waiting times. A follow-up telephone survey determined reasons for coming to the ED, duration of symptoms, and patient satisfaction with the ED visit. Our results reveal that an alternative facility open only during regular working hours would not serve the majority of patients with sickle cell disease. We describe the services provided to acutely ill sickle cell disease patients, and identify areas for improved service delivery within our ED or an alternative facility.


Subject(s)
Anemia, Sickle Cell/therapy , Emergency Service, Hospital/statistics & numerical data , Pediatrics , Acute Disease , Child , Child, Preschool , Delivery of Health Care/organization & administration , Emergency Service, Hospital/standards , Hospitals, Pediatric/statistics & numerical data , Humans , Infant , Patient Satisfaction , Philadelphia , Time Factors
12.
Blood ; 81(12): 3422-7, 1993 Jun 15.
Article in English | MEDLINE | ID: mdl-7685205

ABSTRACT

The observation of low transcutaneous arterial oxygen saturation (SaO2) in otherwise well sickle cell patients has lead to questions about the interpretation of pulse oximetry values in these patients. We undertook a prospective study of children with sickle cell disease to (1) determine the prevalence of, and factors associated with, low transcutaneous SaO2 in clinically well patients, (2) develop an algorithm for the use of pulse oximetry in acutely ill patients, and (3) assess the accuracy of pulse oximetry in these patients. Eighty-six clinically well children with hemoglobin (Hb) SS had a lower mean transcutaneous SaO2 than 22 Hb SC patients and 10 control subjects (95.6% v 99.1% v 99.0%, respectively; p < .001). In Hb SS patients, a history of acute chest syndrome and age greater than 5 years were associated with lower transcutaneous SaO2 (mean 93.8% for those with a history of acute chest syndrome v 97.8% for those without a history of acute chest syndrome, and 94.0% for patients > 5 years old v 97.2% for those < or = 5 years old; P < .001). These associations were not seen in Hb SC patients. During acute illness, Hb SS patients with acute chest syndrome had transcutaneous SaO2 values that were less than 96% and at least 3 points lower than measurements made when they were well. A nomogram was designed to aid in the interpretation of transcutaneous SaO2 in acutely ill Hb SS patients when a comparison value is not available. The accuracy of pulse oximetry was shown by the correlation between SaO2 measured by pulse oximetry and calculated by using the patient's oxygen dissociation curve and PaO2 (r = .97). This study provides evidence that Hb oxygen desaturation is not a universal finding among children with sickle cell disease and identifies factors associated with Hb oxygen desaturation. We conclude that pulse oximetry may be useful to assess whether progressive pulmonary dysfunction begins at an early age in Hb SS patients, and to assess acutely ill patients for the presence of hypoxemia associated with acute chest syndrome.


Subject(s)
Anemia, Sickle Cell/blood , Hemoglobin, Sickle/metabolism , Oximetry , Oxygen/blood , Child , Child, Preschool , Fetal Hemoglobin/metabolism , Hemoglobin SC Disease/blood , Humans , Prospective Studies , Regression Analysis
13.
J Pediatr ; 120(6): 882-5, 1992 Jun.
Article in English | MEDLINE | ID: mdl-1593347

ABSTRACT

We describe six boys with homozygous sickle cell disease, aged 7 to 13 years, in whom acute, severe neurologic abnormalities developed 1 to 11 days after partial exchange transfusion was performed to treat priapism that was unresponsive to more conservative therapy. Hemoglobin levels were 10.5 to 13.4 gm/dl (mean 12.1 gm/dl), and hemoglobin S levels were 18% to 33% (mean 27%) before the onset of neurologic complications. Severe headache was the initial finding in five patients, four of whom had increased intracranial pressure and three of whom required tracheal intubation and hyperventilation. Four patients had seizures; three had focal neurologic deficits for more than 24 hours. Cerebral arteriography demonstrated vascular abnormalities, including irregularity, stenosis, and complete occlusion of vessels. Patients treated with regular erythrocyte transfusions had no recurrence of neurologic signs or symptoms when hemoglobin S levels were kept at 30% to 50%. The occurrence of serious neurologic complications after partial exchange transfusion in patients with homozygous sickle cell disease from three centers indicates the possibility of a causal relationship between the events. Early and thorough investigation of neurologic symptoms, especially severe headache, is warranted in this clinical setting.


Subject(s)
Anemia, Sickle Cell/complications , Cerebrovascular Disorders/etiology , Epilepsy/etiology , Exchange Transfusion, Whole Blood/adverse effects , Headache/etiology , Priapism/therapy , Anemia, Sickle Cell/genetics , Child , Hemoglobin, Sickle/analysis , Homozygote , Humans , Intracranial Pressure , Male , Priapism/etiology
17.
Mol Cell Endocrinol ; 34(2): 113-9, 1984 Feb.
Article in English | MEDLINE | ID: mdl-6325268

ABSTRACT

The 170 000 dalton hepatic epidermal growth factor (EGF) receptor is phosphorylated on serine and tyrosine residues. The evidence indicates that distinct protein kinases are involved. Since EGF and agents that elevate cAMP are believed to participate in the regulation of liver regeneration, we tested whether or not the catalytic subunit of cAMP-dependent protein kinase (catalytic subunit), a known serine kinase, would utilize the EGF receptor as a substrate. The catalytic subunit increased phosphorylation of the EGF receptor in purified rat liver plasma membranes. The serine specificity of the catalytic subunit was established by phosphoamino acid analysis of electrophoretically purified EGF receptor. The result was confirmed by catalytic subunit phosphorylation of affinity purified preparations of the EGF receptor. The rates of dephosphorylation of the membrane-associated EGF receptor phosphorylated on different residues were compared. Dephosphorylation of serine residues (after catalytic subunit phosphorylation) was considerably slower (t1/2 greater than 120 sec) than the removal of phosphotyrosine after stimulation with EGF (t1/2 less than 30 sec).


Subject(s)
Epidermal Growth Factor/metabolism , Liver/metabolism , Protein Kinases/metabolism , Receptors, Cell Surface/metabolism , Animals , Cell Membrane/metabolism , ErbB Receptors , Kinetics , Macromolecular Substances , Male , Molecular Weight , Phosphorylation , Rats , Rats, Inbred Strains
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