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1.
Support Care Cancer ; 31(4): 228, 2023 Mar 23.
Article in English | MEDLINE | ID: mdl-36952029

ABSTRACT

BACKGROUND: Pain is one of the most common and distressing symptoms experienced by children and adolescents diagnosed with cancer. It is vital that children and adolescents receive adequate pain management early on in their cancer treatments to mitigate pain and cancer-related symptoms. Exercise training shows particular promise in the management of acute and chronic pain among children and adolescents diagnosed with cancer. METHODS: This position paper comes to outline the challenge of mitigating pain in children and adolescents diagnosed with cancer, and the potential benefits of integrating exercise training to the management of chronic pain in this population in need. RESULTS: Integrating exercise training into the care and pain management of children and adolescents diagnosed with cancer who have chronic pain would have the advantage of addressing several shortcomings of pain medication. Pain medication aims to temporarily manage or reduce pain; it does not have the potential to directly improve a patient's physical condition in the way that exercise training can. The current paucity of data available on the use of exercise training as a complementary treatment to pain medications to reduce chronic pain in children and adolescents diagnosed with cancer allows only for hypotheses on the effectiveness of this pain management modality. CONCLUSION: More research on this important topic is necessary and mitigating pain effectively while also reducing the use of opioid pain medication is an important goal shared by patients, their families, clinicians, and researchers alike. Future research in this area has great potential to inform clinical care, clinical care guidelines, and policy-making decisions for pain management in children and adolescents diagnosed with cancer who experience chronic pain.


Subject(s)
Chronic Pain , Neoplasms , Humans , Child , Adolescent , Chronic Pain/etiology , Chronic Pain/therapy , Pain Management , Neoplasms/complications , Exercise , Decision Making
2.
Cancer ; 126(8): 1749-1757, 2020 04 15.
Article in English | MEDLINE | ID: mdl-31967673

ABSTRACT

BACKGROUND: The prognosis for children with recurrent solid tumors generally is poor. Targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor A with everolimus and bevacizumab, respectively, synergistically improves progression-free survival and is well tolerated in adults with solid tumors. METHODS: In the current phase 1 study, a total of 15 children with recurrent or refractory solid tumors were treated with bevacizumab and everolimus to establish the maximum tolerated dose, toxicity, and preliminary antitumor response (ClinicalTrials.gov identifier NCT00756340). The authors also evaluated everolimus-mediated inhibition of the mTOR pathway in the peripheral blood mononuclear cells of treated patients. RESULTS: Tumors predominantly were soft tissue and/or bone sarcomas (8 cases) and brain tumors (5 cases). The first 2 patients enrolled at dose level 1 (10 mg/kg of bevacizumab and 4 mg/m2 of everolimus) experienced dose-limiting toxicities (DLTs). The next 5 patients were enrolled at dose level 0 (8 mg/kg of bevacizumab and 4 mg/m2 of everolimus), and DLTs occurred in 2 patients. The authors then modified the protocol to permit expansion of dose 0, and 8 additional patients were added, with no DLTs reported. Of all the patients, stable disease occurred in 4 patients (30.8%; median, 2 courses), and progressive disease occurred in 9 patients (69.2%). Overall survival was 0.59 years (95% CI, 0.24-1.05 years). The mTOR biomarker phospho-4EBP1 Thr/37/46 significantly decreased from baseline to day 27 in peripheral blood mononuclear cells (P = .045). Phospho-AKT levels also decreased from those at baseline. CONCLUSIONS: The maximum tolerated dose of cotreatment with bevacizumab and everolimus was 8 mg/kg of bevacizumab and 4 mg/m2 of everolimus in a 4-week cycle for children with recurrent solid tumors.


Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab/therapeutic use , Everolimus/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Neoplasms/drug therapy , Adolescent , Child , Child, Preschool , Female , Humans , Male , Maximum Tolerated Dose , Neoplasm Recurrence, Local/pathology , Neoplasms/pathology , Prognosis , Progression-Free Survival
3.
J Adolesc Young Adult Oncol ; 9(1): 47-54, 2020 02.
Article in English | MEDLINE | ID: mdl-31600095

ABSTRACT

Purpose: Adolescents and young adults (AYAs) with cancer are a vulnerable population with decreased attendance at National Cancer Institute (NCI) comprehensive cancer centers and Children's Oncology Group (COG) facilities. Decreased attendance at NCI/COG facilities has been associated with poor cancer outcomes. The objective of this study was to evaluate cancer care patterns of AYAs compared with children, within Pennsylvania, and factors associated with attending an NCI/COG facility. Methods: Data from the Pennsylvania Cancer Registry between 2010 and 2015 for patients aged 0-39 years at cancer diagnosis were used. Primary analyses focused on age at diagnosis, insurance status, race, ethnicity, gender, cancer type, stage, diagnosis year, and distance to the NCI/COG facility. The primary outcome was receipt of care at an NCI/COG facility. Odds ratios (ORs) were calculated using multivariable logistic regression models. Sensitivity analyses were conducted to test and estimate robustness. Results: A sample of 15,002 patients, ages 0-39, was obtained, including 8857 patients (59%) who attended an NCI/COG facility. Patients were significantly less likely to attend an NCI/COG facility if they were aged 31-39 years (OR 0.054, 95% confidence interval [CI] 0.04-0.07), non-White (OR 0.890, 95% CI 0.80-0.99), Hispanic (OR 0.701, 95% CI 0.59-0.83), female (OR 0.915, 95% CI 0.84-1.00), had Medicaid insurance (OR 0.836, 95% CI 0.75-0.93), and lived further from an NCI/COG facility. Sensitivity analyses largely corroborated the performed estimates. Conclusions: AYAs with cancer in Pennsylvania have disproportionate attendance at specialized NCI/COG facilities across a variety of demographic domains. Enhancing the attendance of AYAs with cancer at these specialized centers is crucial to improve cancer outcomes.


Subject(s)
Child Health/trends , Health Services Accessibility/standards , Healthcare Disparities/standards , Patient Admission/statistics & numerical data , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , National Cancer Institute (U.S.) , Pennsylvania , United States , Young Adult
4.
J Pediatr Hematol Oncol ; 37(1): e6-e12, 2015 Jan.
Article in English | MEDLINE | ID: mdl-24633303

ABSTRACT

BACKGROUND: Most prior studies evaluating subsequent malignant neoplasms (SMNs) in patients with neuroblastoma are restricted to long-term survivors and/or their treatment exposures. This study investigates SMNs in patients diagnosed with neuroblastoma at our institution. METHODS: Records of 646 patients treated for neuroblastoma at St Jude Children's Research Hospital between 1961 and 2005 were reviewed. Data from patients with SMNs were analyzed and the 20- and 30-year cumulative incidence of SMNs and standardized incidence ratio were calculated. RESULTS: Twenty-one patients had a SMN. The 20- and 30-year cumulative incidences of a SMN were 2.6%±0.7% and 4.6%±1.1%, respectively. The standardized incidence ratio was 8.3 (95% confidence interval, 5.0-13.0). Five patients developed a SMN within 5 years from diagnosis. The median latency for the development of acute myeloid leukemia/myelodysplastic syndrome (n=4), sarcomas (n=7), and carcinomas (n=5) were 3.6, 9, and 24.2 years, respectively. Nine patients died from their SMN, including all with acute myeloid leukemia/myelodysplastic syndrome. CONCLUSIONS: Patients with neuroblastoma have an increased risk of secondary neoplasia. Modification of risk-adapted therapies will likely alter the affected patient population and the incidence of SMNs. Future studies are necessary to link SMNs to treatment exposures and to evaluate the risk of SMNs beyond 30 years from diagnosis.


Subject(s)
Neoplasms, Second Primary/epidemiology , Neuroblastoma/complications , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Incidence , Infant , Infant, Newborn , Male , Neoplasms, Second Primary/etiology , Risk
5.
J Pediatr Hematol Oncol ; 37(1): e13-8, 2015 Jan.
Article in English | MEDLINE | ID: mdl-24942022

ABSTRACT

Oxaliplatin, although related to cisplatin and carboplatin, has a more favorable toxicity profile and may offer advantages in combination regimens. We combined oxaliplatin, ifosfamide, and etoposide (IOE) and estimated the regimen's maximum tolerated dose (MTD) in children with refractory solid tumors. Dose-limiting toxicity (DLT) and MTD were assessed at 3 dose levels in a 21-day regimen: day 1, oxaliplatin 130 mg/m (consistent dose); days 1 to 3, ifosfamide 1200 mg/m/d (level 0) or 1500 mg/m/d (levels 1 and 2) and etoposide 75 mg/m/d (levels 0 and 1) or 100 mg/m/d (level 2). Course 1 filgrastim/pegfilgrastim was permitted after initial DLT determination, if neutropenia was dose limiting. Seventeen patients received 59 courses. Without filgrastim (n=9), DLT was neutropenia in 2 patients at dose level 1. No DLT was observed after adding filgrastim (n=8). There was no ototoxicity, nephrotoxicity >grade 1, or neurotoxicity >grade 2. One patient experienced a partial response and 9 had stable disease after 2 courses. In conclusion, the IOE regimen was well tolerated. Without filgrastim, neutropenia was dose limiting with MTD at ifosfamide 1200 mg/m/d and etoposide 75 mg/m/d. The MTD with filgrastim was not defined due to early study closure. Filgrastim allowed ifosfamide and etoposide dose escalation and should be included in future studies.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Child , Child, Preschool , Etoposide/administration & dosage , Etoposide/adverse effects , Female , Humans , Ifosfamide/administration & dosage , Ifosfamide/adverse effects , Infant , Male , Maximum Tolerated Dose , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/adverse effects , Oxaliplatin
6.
J Clin Oncol ; 32(14): 1445-52, 2014 May 10.
Article in English | MEDLINE | ID: mdl-24711551

ABSTRACT

PURPOSE: The addition of immunotherapy, including a combination of anti-GD2 monoclonal antibody (mAb), ch14.18, and cytokines, improves outcome for patients with high-risk neuroblastoma. However, this therapy is limited by ch14.18-related toxicities that may be partially mediated by complement activation. We report the results of a phase I trial to determine the maximum-tolerated dose (MTD), safety profile, and pharmacokinetics of hu14.18K322A, a humanized anti-GD2 mAb with a single point mutation (K322A) that reduces complement-dependent lysis. PATIENTS AND METHODS: Eligible patients with refractory or recurrent neuroblastoma received escalating doses of hu14.18K322A ranging from 2 to 70 mg/m(2) per day for 4 consecutive days every 28 days (one course). RESULTS: Thirty-eight patients (23 males; median age, 7.2 years) received a median of two courses (range, one to 15). Dose-limiting grade 3 or 4 toxicities occurred in four of 36 evaluable patients and were characterized by cough, asthenia, sensory neuropathy, anorexia, serum sickness, and hypertensive encephalopathy. The most common non-dose-limiting grade 3 or 4 toxicities during course one were pain (68%) and fever (21%). Six of 31 patients evaluable for response by iodine-123 metaiodobenzylguanidine score had objective responses (four complete responses; two partial responses). The first-course pharmacokinetics of hu14.18K322A were best described by a two-compartment linear model. Median hu14.18K322A α (initial phase) and ß (terminal phase) half-lives were 1.74 and 21.1 days, respectively. CONCLUSION: The MTD, and recommended phase II dose, of hu14.18K322A is 60 mg/m(2) per day for 4 days. Adverse effects, predominately pain, were manageable and improved with subsequent courses.


Subject(s)
Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/adverse effects , Brain Neoplasms/drug therapy , Neuroblastoma/drug therapy , Adolescent , Antibodies, Monoclonal/administration & dosage , Antineoplastic Agents/administration & dosage , Child , Child, Preschool , Female , Humans , Male , Maximum Tolerated Dose , Recurrence
7.
J Pediatr Surg ; 49(1): 149-53, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24439600

ABSTRACT

BACKGROUND: Renal insufficiency is a significant complication of Wilms tumor treatment in the 5% with bilateral disease. Nephron-sparing surgery (NSS) is recommended after neoadjuvant chemotherapy initially. However, the role of NSS in recurrent disease is unknown. We reviewed our experience to assess the feasibility and oncologic and functional outcomes of repeat NSS for children with recurrent disease. METHODS: A retrospective review was performed of all children treated at our institution for bilateral, favorable histology (FH) Wilms tumor. Patients undergoing repeat NSS for locally recurrent disease were identified. The outcomes evaluated included tumor recurrence, renal function, and patient survival. RESULTS: Since 2001, 36 children with bilateral FH Wilms tumor have been treated at our institution. Eight patients (22%) underwent repeat NSS for locally recurrent disease. Two patients had a second local recurrence and underwent a third NSS. Six patients are alive without disease (75%) with an average follow-up of 4.5years. Two patients have died, each with blastemal-predominant histology at repeat NSS. The surviving patients have normal renal function, although two patients require medical management of hypertension. CONCLUSIONS: Our experience suggests that repeat NSS for local recurrence of FH bilateral Wilms tumor is feasible and affords acceptable oncologic outcome with preservation of renal function. However, more aggressive therapy may be required for patients whose recurrence has blastemal-predominant histology, given the poor outcome for these patients in our series.


Subject(s)
Kidney Neoplasms/surgery , Neoplasm Recurrence, Local/surgery , Neoplasms, Multiple Primary/surgery , Nephrectomy/methods , Organ Sparing Treatments/methods , Wilms Tumor/surgery , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child, Preschool , Combined Modality Therapy , Dactinomycin/administration & dosage , Doxorubicin/administration & dosage , Female , Follow-Up Studies , Humans , Infant , Kidney Failure, Chronic/prevention & control , Kidney Neoplasms/drug therapy , Kidney Neoplasms/pathology , Male , Neoadjuvant Therapy , Neoplasms, Multiple Primary/drug therapy , Neoplasms, Multiple Primary/pathology , Nephrons/surgery , Postoperative Complications/prevention & control , Prognosis , Reoperation , Retrospective Studies , Survival Analysis , Treatment Outcome , Vinblastine/administration & dosage , Wilms Tumor/drug therapy , Wilms Tumor/pathology
8.
J Pediatr Surg ; 48(7): 1481-5, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23895958

ABSTRACT

PURPOSE: Nephron-sparing surgery (NSS) has been advocated for patients with bilateral Wilms tumor (BWT). We sought to determine whether margin status impacted local tumor recurrence. METHODS: A retrospective review of patients undergoing NSS for BWT from November 1999 to March 2009 at our institution in which local recurrence rates based on margin status were compared. RESULTS: Of 21 patients, five (23.8%) had positive margins. These and 2 (9.5%) with focal anaplasia received flank XRT. Seven (33%) patients developed recurrent disease, a mean of 18.0 (range 1.3-39.9) months after NSS. Recurrence rates were similar in patients with positive and negative margins (1/5 [20%] vs 6/16 [37.5%]; p = 0.47). Hypertension occurred more frequently in patients who received XRT (57.1% vs 28.6%). At a median follow-up of 28.6 months (range 5.2-142.3), 19 patients are alive, without evidence of disease; one patient (with a positive margin at initial NSS) died of metastatic anaplastic WT and another died of a brain tumor. One patient, with multiple risk factors, developed renal failure. CONCLUSIONS: In our experience, local recurrence rates after NSS were not affected by surgical margin status although all patients with positive margins received XRT. These results support the aggressive use of NSS for patients with BWT.


Subject(s)
Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Neoplasm Recurrence, Local/epidemiology , Nephrectomy/methods , Organ Sparing Treatments , Wilms Tumor/pathology , Wilms Tumor/surgery , Child, Preschool , Female , Humans , Infant , Male , Nephrons , Retrospective Studies , Survival Rate
9.
J Pediatr Surg ; 48(1): 47-55, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23331792

ABSTRACT

PURPOSE: Osteoprotegerin (OPG) is a decoy receptor for the Receptor of NF-κB (RANK) ligand that can inhibit osteoclastogenesis. Previous studies have suggested that Mammalian Target of Rapamycin (mTOR) inhibition upregulates OPG production. We tested the hypothesis that the mTOR inhibitor rapamycin could inhibit neuroblastoma bone metastases through its action on OPG. EXPERIMENTAL DESIGN: An orthotopic model of bone metastasis was established. Mice with established disease were subsequently treated with rapamycin (5mg/kg IP daily) or vehicle control (DMSO 1:1000). X-rays were obtained twice a week to detect pathologic fractures. Serum OPG levels were measured by ELISA after two weeks of treatment. RESULTS: Mice with bone disease receiving rapamycin had increased serum levels of OPG in the CHLA-20 mice compared to controls (36.89 pg/mL ± 3.90 vs 18.4 pg/mL ± 1.67, p=0.004) and NB1691 tumor-bearing groups (46.03 ± 2.67 pg/mL vs 17.96 ± 1.84pg/mL, p=0.001), and a significantly longer median time to pathologic fractures with CHLA-20 (103 days vs 74.5 days, p=0.014) and NB1691 xenografts. CONCLUSION: In a xenograft model, increased OPG expression correlated with a delay to pathologic fracture suggesting a potential role for mTOR inhibitors in the treatment of neuroblastoma bone metastases.


Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Bone Neoplasms/drug therapy , Bone Neoplasms/secondary , Neuroblastoma/drug therapy , Neuroblastoma/secondary , Osteoprotegerin/blood , Sirolimus/therapeutic use , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers/blood , Bone Neoplasms/blood , Bone Neoplasms/complications , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Administration Schedule , Enzyme-Linked Immunosorbent Assay , Fractures, Spontaneous/etiology , Fractures, Spontaneous/prevention & control , Humans , Injections, Intraperitoneal , Mice , Mice, SCID , Neuroblastoma/blood , Neuroblastoma/complications , Reverse Transcriptase Polymerase Chain Reaction , Treatment Outcome
10.
Pediatr Blood Cancer ; 60(5): 761-5, 2013 May.
Article in English | MEDLINE | ID: mdl-23024112

ABSTRACT

BACKGROUND: Locoregional failure is a significant concern in patients with high-risk abdominal neuroblastoma (NB) receiving radiotherapy. Locoregional control outcomes were studied in children with NB receiving intensity modulated radiotherapy (IMRT). PROCEDURE: Twenty children (11 females, 9 males) with NB (median age at diagnosis 3.4 years) receiving IMRT were analyzed for locoregional failure, outcomes, and toxicities. IMRT doses were 23.4 Gy (n = 12), 30 Gy (n = 1), 30.6 Gy (n = 5), and 36.0 Gy (n = 2) based on extent of resection. Five patients had tumors with MYCN amplification, and 19 had metastatic disease. All patients were treated consistently using reproducible immobilization techniques; physiological motion was assessed by 4D-CT, and target localization by cone-beam computed tomography. ICRU 62 volumetric conventions were employed based on institutional data for pediatric target volume and organ motion. RESULTS: No patient developed primary site infield or locoregional failure at a median follow-up of 2.2 years. Distant failure (median time to distant failure 1.6 years) occurred in the brain, lungs, or skeletal sites in eight patients, five of whom died. The 2-year event-free survival was 58.5 ± 13.3% and cumulative incidence of local and distant failures was 0% and 41.5 ± 11.9%, respectively. Asymptomatic loose stool during RT occurred in nearly all patients, but required no intervention. CONCLUSIONS: IMRT is feasible, safe in the short term, and yields excellent locoregional control. Despite subtotal resection in some cases, locoregional control appeared to be increased by conformal radiotherapy with ICRU 62-compliant volumes. Dose escalation beyond 30.6 Gy may be unnecessary with improved target volume coverage.


Subject(s)
Abdominal Neoplasms/radiotherapy , Neuroblastoma/radiotherapy , Radiotherapy, Intensity-Modulated , Abdominal Neoplasms/drug therapy , Abdominal Neoplasms/mortality , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Combined Modality Therapy , Cone-Beam Computed Tomography , Female , Humans , Infant , Male , N-Myc Proto-Oncogene Protein , Neoplasm Metastasis , Neuroblastoma/drug therapy , Neuroblastoma/mortality , Nuclear Proteins/genetics , Oncogene Proteins/genetics , Radiotherapy Dosage , Retrospective Studies , Treatment Outcome
11.
Clin Cancer Res ; 19(1): 236-46, 2013 Jan 01.
Article in English | MEDLINE | ID: mdl-23143218

ABSTRACT

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of sorafenib, bevacizumab, and low-dose oral cyclophosphamide in children and young adults with recurrent/refractory solid tumors. EXPERIMENTAL DESIGN: Sorafenib dose was escalated from 90 to 110 mg/m(2) twice daily with fixed doses of bevacizumab at 5 mg/kg every 3 weeks and cyclophosphamide at 50 mg/m(2) daily. Once sorafenib's MTD was established, bevacizumab dose was escalated. Each course was of 21 days. Pharmacokinetics and pharmacodynamics studies were conducted during the first course. RESULTS: Nineteen patients (11 males; median age, 9.2 years) received a median of four courses (range, 1-23). DLTs during course 1 included grade 3 rash (two), increased lipase (one), anorexia (one), and thrombus (one). With an additional 71 courses of therapy, the most common toxicities ≥ grade 3 included neutropenia (nine), lymphopenia (nine), and rashes (four). Five of 17 evaluable patients had partial tumor responses, and five had disease stabilization (>2 courses). Median day 1 cyclophosphamide apparent oral clearance was 3.13 L/h/m(2). Median day 1 sorafenib apparent oral clearance was 44 and 39 mL/min/m(2) at the 2 dose levels evaluated, and steady-state concentrations ranged from 1.64 to 4.8 mg/L. Inhibition of serum VEGF receptor 2 (VEGFR2) was inversely correlated with sorafenib steady-state concentrations (P = 0.019). CONCLUSION: The recommended phase II doses are sorafenib, 90 mg/m(2) twice daily; bevacizumab, 15 mg/kg q3 weeks; and cyclophosphamide, 50 mg/m(2) once daily. This regimen is feasible with promising evidence of antitumor activity that warrants further investigation.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Adolescent , Adult , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Bevacizumab , Child , Child, Preschool , Cyclophosphamide/administration & dosage , Female , Humans , Infant , Male , Niacinamide/administration & dosage , Niacinamide/analogs & derivatives , Phenylurea Compounds/administration & dosage , Recurrence , Sorafenib , Treatment Outcome , Young Adult
12.
Biomaterials ; 33(34): 8812-21, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22979989

ABSTRACT

Biomaterials for myocardial tissue engineering must balance structural, mechanical and bioactivity concerns. This work describes the interaction between HL-1 cardiomyocytes and a series of geometrically anisotropic collagen-GAG (CG) scaffolds with aligned tracks of ellipsoidal pores designed to mimic elements of the native geometric anisotropy of cardiac tissue. Here we report the role scaffold geometric anisotropy and pore size plays in directing cardiomyocyte bioactivity. Notably, HL-1 cardiomyocytes showed good proliferation and metabolic activity in all variants out to 14 days in culture. Critically, HL-1s exhibited significantly elevated 3D alignment and earlier spontaneous beating within anisotropic CG scaffolds relative to isotropic scaffold controls. This spontaneous beating occurred at significantly higher instances for larger pore size anisotropic variants. Gene expression and immunohistochemical analyses for key cardiac marker (α-myosin heavy chain, connexin-43) suggest that the isotropic and anisotropic scaffolds support expression of key transcriptomic markers of cardiomyocyte phenotype as well as the formation of gap junctions and elongated, aligned cell morphologies. Collectively, these results suggest that a geometrically anisotropic scaffold with sufficiently large pore size (>150 µm) provides a suitable microenvironment to induce cardiomyocyte alignment, beating, and bioactivity for cardiac tissue engineering applications.


Subject(s)
Collagen/chemistry , Glycosaminoglycans/chemistry , Myocytes, Cardiac/cytology , Tissue Scaffolds/chemistry , Animals , Anisotropy , Cell Adhesion , Cell Line , Cell Proliferation , Collagen/metabolism , Gap Junctions/ultrastructure , Gene Expression Regulation , Glycosaminoglycans/metabolism , Mice , Myocytes, Cardiac/metabolism , Porosity , Tissue Engineering/methods
13.
Pediatr Blood Cancer ; 58(3): 372-9, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21509928

ABSTRACT

BACKGROUND: Administration of an oral cephalosporin allowed advancement of the dosage of oral irinotecan. This study investigates whether administration of an oral cephalosporin increases the maximum tolerated dose (MTD) of intravenous irinotecan. PROCEDURE: Irinotecan was administered intravenously on Days 1-5 and Days 8-12 of a 21-day cycle with continuous oral cefpodoxime starting 2 days prior to irinotecan. Cohorts of 3-6 pediatric patients with refractory solid tumors were enrolled at 4 dosage levels, starting at the single-agent irinotecan MTD of 20 mg/m(2) /dose. RESULTS: The 17 evaluable patients received 39 courses of therapy. None of the patients treated with 20 mg/m(2) /dose experienced dose-limiting toxicity (DLT). One of six patients treated at 30 mg/m(2) /dose experienced dose-limiting neutropenia. Two of three patients treated with 45 mg/m(2) /dose and two of five treated with 40 mg/m(2) /dose experienced dose-limiting diarrhea, with associated dehydration and anorexia. Two unconfirmed partial responses were observed after one course in a patient with Ewing sarcoma and one with paraganglioma. A child with refractory neuroblastoma had disease stabilization through 12 courses of therapy. Median (range) systemic exposure to SN-38 at the MTD (30 mg/m(2) /dose) was 67 ng-h/mL (36 to 111 ng-h/mL). CONCLUSIONS: The MTD of intravenous irinotecan administered on a protracted schedule was increased by 50% from 20 to 30 mg/m(2) /dose with the addition of oral cefpodoxime. The most prominent DLT remained diarrhea. High interpatient variability in irinotecan pharmacokinetics was observed; however, SN-38 exposure at the MTD was greater than most reported exposures with the 20 mg/m(2) dosage.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Diarrhea/prevention & control , Neoplasms/drug therapy , Adolescent , Antibiotic Prophylaxis , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/analogs & derivatives , Camptothecin/pharmacokinetics , Ceftizoxime/administration & dosage , Ceftizoxime/analogs & derivatives , Child , Child, Preschool , Diarrhea/chemically induced , Female , Humans , Infusions, Intravenous , Irinotecan , Male , Maximum Tolerated Dose , Topoisomerase I Inhibitors/administration & dosage , Topoisomerase I Inhibitors/adverse effects , Topoisomerase I Inhibitors/pharmacokinetics , Young Adult , Cefpodoxime
14.
Invest New Drugs ; 30(4): 1660-70, 2012 Aug.
Article in English | MEDLINE | ID: mdl-21796439

ABSTRACT

BACKGROUND: Gefitinib potently inhibits neuroblastoma proliferation in vitro, and the gefitinib/irinotecan combination shows greater than additive activity against neuroblastoma xenografts. This Phase II pilot study estimated the rate of response to two courses of intravenous irinotecan plus oral gefitinib in children with untreated high-risk neuroblastoma. METHODS: Two courses of irinotecan [15 mg/m(2)/day (daily ×5)×2] were combined with 12 daily doses of gefitinib (112.5 mg/m(2)/day). Response was assessed after 6 weeks. A response rate >55% was sought. RESULTS: Of the 23 children enrolled, 19 were evaluable for response. Median age at diagnosis was 3.1 years (range, 18 days-12.7 years). Most patients were older than 24 months (n = 20; 87%), male (n = 18; 78%), white (n = 16; 70%), had INSS 4 disease (n = 19; 83%), and had adrenal primary tumors (n = 18; 78%); nine patients (39%) had amplified tumor MYCN. The toxicity of gefitinib/irinotecan was mild and reversible (nausea, 5/20; diarrhea, 8/20; vomiting, 7/20). Five patients had partial responses; 9 others had a 23%-60% decrease in primary tumor volume and/or improved MIBG scans or decreased bone or bone marrow tumor burden. Median (range) systemic irinotecan exposure (AUC) was 283 ng/ml*hr (range, 163-890 ng/ml*hr) and 28 ng/ml*hr (3.6-297 ng/ml*hr) for the active metabolite, SN-38. No relation was observed between response and tumor expression of EGFR, MRP2-4, ABCG2, and Pgp. CONCLUSIONS: Although the gefitinib/irinotecan combination was very tolerable and induced responses, it was not sufficiently active to warrant further investigation. Initial investigational studies of this type can preclude the necessity for larger, longer, and costlier trials.


Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Camptothecin/analogs & derivatives , Neuroblastoma/diagnosis , Neuroblastoma/drug therapy , Quinazolines/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Camptothecin/adverse effects , Camptothecin/pharmacokinetics , Camptothecin/pharmacology , Camptothecin/therapeutic use , Child , Child, Preschool , Female , Gefitinib , Homovanillic Acid/urine , Humans , Immunohistochemistry , Infant , Infant, Newborn , Irinotecan , L-Lactate Dehydrogenase/blood , Male , Neoplasm Proteins/metabolism , Neuroblastoma/blood , Neuroblastoma/urine , Pilot Projects , Quinazolines/adverse effects , Quinazolines/pharmacokinetics , Quinazolines/pharmacology , Risk Factors , Treatment Outcome , Tumor Burden/drug effects , Vanilmandelic Acid/urine
15.
Genes Chromosomes Cancer ; 50(12): 1054-62, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21987447

ABSTRACT

Cellular morphology of small cell osteosarcoma, an aggressive variant of osteosarcoma, is similar to Ewing sarcoma, but its molecular pathogenesis is largely unknown. We report the case of a 12-year-old girl with multifocal small cell osteosarcoma positive for the Ewing sarcoma breakpoint region 1 (EWSR1) gene rearrangement by interphase fluorescent in situ hybridization and negative for EWSR1-FLI1, EWSR1-ERG, and EWSR1-WT1 fusion transcripts by reverse transcriptase PCR. Rapid amplification of cDNA ends revealed exon 6 of the cAMP-responsive element binding protein 3-like 1 gene (CREB3L1, also known as "OASIS," NM_52854.2) fused in-frame to the EWSR1 exon 11, consistent with the EWSR1-CREB3L1 fusion transcript expressed in tumor tissue. The corresponding chimeric gene was confirmed by amplification and subsequent sequencing of the genomic breakpoint between introns 11 and 5 of EWSR1 and CREB3L1, respectively. An ∼70 kDa product in the tumor tissue lysate reacted with the CREB3L1 carboxyterminal antibody, consistent with a 656-amino acid predicted chimeric protein. Immunohistochemistry with the same antibody showed signal translocation from the physiologic perinuclear compartment observed in glia and unrelated osteoblasts to nuclei of tumor cells, consistent with the likely function of EWSR1-CREB3L1 as a transcriptional regulator predicted by its structure. This is the first report of a fusion transcript in osteogenic sarcoma; it demonstrates a relation between molecular mechanisms of small cell osteogenic and Ewing sarcomas. The 3'-end partner and the inferred structure of EWSR1-CREB3L1, however, are different from those of Ewing sarcoma, suggesting different targets of the new oncogene.


Subject(s)
Calmodulin-Binding Proteins/genetics , Cyclic AMP Response Element-Binding Protein/genetics , Nerve Tissue Proteins/genetics , Oncogene Proteins, Fusion/genetics , Osteosarcoma/genetics , RNA-Binding Proteins/genetics , Sarcoma, Small Cell/genetics , Base Sequence , Cell Nucleus/genetics , Child , Exons , Female , Humans , In Situ Hybridization, Fluorescence/methods , Introns , Molecular Sequence Data , Neuroglia/metabolism , RNA-Binding Protein EWS , Reverse Transcriptase Polymerase Chain Reaction/methods , Translocation, Genetic
16.
J Pediatr Surg ; 46(10): 2029-31, 2011 Oct.
Article in English | MEDLINE | ID: mdl-22008346

ABSTRACT

The pediatric malignancies most likely to metastasize to the skin are neuroblastoma, leukemia, and rhabdomyosarcoma. Cutaneous and subcutaneous metastases from osteosarcoma are extremely rare, with only a few cases reported in pediatric patients with multifocal synchronous osteosarcoma. We describe the case of a 19-year-old woman with a single subcutaneous nodule of the abdominal wall that, on histologic evaluation, proved to be a metastatic high-grade osteosarcoma 5 years after her initial diagnosis.


Subject(s)
Bone Neoplasms/pathology , Osteosarcoma/secondary , Skin Neoplasms/secondary , Tibia/pathology , Abdominal Wall , Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Neoplasms/drug therapy , Bone Neoplasms/surgery , Calcinosis/diagnostic imaging , Calcinosis/etiology , Cisplatin/administration & dosage , Combined Modality Therapy , Doxorubicin/administration & dosage , Female , Humans , Ifosfamide/administration & dosage , Lung Neoplasms/secondary , Lung Neoplasms/surgery , Methotrexate/administration & dosage , Neoadjuvant Therapy , Organ Sparing Treatments , Osteosarcoma/diagnostic imaging , Osteosarcoma/drug therapy , Osteosarcoma/surgery , Radiography , Razoxane/administration & dosage , Receptor, IGF Type 1/immunology , Skin Neoplasms/diagnostic imaging , Skin Neoplasms/surgery , Subcutaneous Tissue , Tibia/surgery , Time Factors , Young Adult
17.
Eur J Cancer ; 46(11): 2045-51, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20621735

ABSTRACT

PURPOSE: To investigate associations between germline genetic variations in the epidermal growth factor receptor (EGFR) and toxicity in paediatric patients treated with gefitinib. PATIENTS AND METHODS: Gefitinib treatment and toxicity data from five paediatric clinical trials were combined. EGFR genotypes evaluated included -191C>A, -216G>T, Arg497Lys and intron 1 CA sequence repeat number. The genetic variations were evaluated for associations with grade one or greater rash or diarrhoea during the first course of treatment. RESULTS: The analysis included 110 patients, 60 (55%) with grade one or greater rash and 47 (43%) with grade one or greater diarrhoea. Among patients with the -216 GG (n=51), GT (n=41) and TT (n=16) genotypes, grade one or greater rash occurred in 52.9%, 46.3% and 87.5% of patients (p=0.003, recessive model), respectively. Diarrhoea occurred in 27.5%, 58.5% and 43.8% of patients with respective GG, GT and TT genotypes (p=0.004, dominant model). The -191C>A, intron 1 CA repeat number and Arg497Lys genotypes were not significantly associated with either rash or diarrhoea. EGFR -216 and -191 polymorphisms were in linkage disequilibrium (D'=0.66, p=0.01). The haplotype (-191C, -216T) was associated with increased risk for rash (p=0.049), but was not more predictive of rash than the single -216 polymorphism. CONCLUSION: These findings indicate that EGFR -216G>T genotype is a predictive marker for the development of skin rash and diarrhoea in paediatric patients treated with gefitinib. Continued investigation of relationships between germline EGFR polymorphisms and the efficacy of EGFR inhibitors in paediatric patients is warranted.


Subject(s)
Antineoplastic Agents/adverse effects , ErbB Receptors/genetics , Neoplasms/genetics , Polymorphism, Genetic/genetics , Protein Kinase Inhibitors/adverse effects , Quinazolines/adverse effects , Adolescent , Child , Child, Preschool , Clinical Trials as Topic , Diarrhea/chemically induced , Drug Eruptions/genetics , Exanthema/chemically induced , Gefitinib , Germ-Line Mutation , Humans , Infant , Neoplasms/drug therapy , Risk Factors , Young Adult
18.
J Pediatr Surg ; 45(4): 678-86, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20385270

ABSTRACT

PURPOSE: The purpose of the study was to compare outcomes of pediatric patients with high-risk metastatic neuroblastoma who received radiotherapy (RT) with those of patients who did not. PATIENTS AND METHODS: We reviewed the records of 63 patients with newly diagnosed metastatic neuroblastoma treated at our institution (1989-2001) to investigate their characteristics at presentation, dose and field of RT, treatment response, and failure patterns. RESULTS: Seventeen patients received RT, and 46 did not. In the RT group, a greater percentage of patients had residual disease before consolidation than did those in the no-RT group (88.2% vs 69.6%, P = .008). Gross total resection was achieved less often in the RT group (65% vs 89%, P = .055), but the 5-year cumulative incidences of local failure were similar (35.3% +/- 12.4% vs 32.6% +/- 7.1%). Although there was no difference in 5-year event-free survival, overall survival was better in the no-RT group (47.8% +/- 7.2% vs 23.5% +/- 9.2%, P = .026). CONCLUSION: The addition of RT to the therapy of a group of patients with more residual locoregional disease appeared to improve the local failure rate to approximately that of patients with less residual disease. Radiotherapy may provide even greater benefit to those with less residual disease before consolidation.


Subject(s)
Neuroblastoma/radiotherapy , Neuroblastoma/secondary , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Male , Neoplasm Recurrence, Local/prevention & control , Neuroblastoma/pathology , Neuroblastoma/therapy , Radiotherapy/adverse effects , Radiotherapy Dosage , Retrospective Studies , Survival Analysis
19.
Diagn Microbiol Infect Dis ; 67(1): 92-4, 2010 May.
Article in English | MEDLINE | ID: mdl-20227220

ABSTRACT

The Zygomyces are an increasingly frequent cause of invasive mold infection in immunocompromised patients. Here we describe the first well-documented case of Rhizopus infection of odontogenic origin, which presented as a rapidly progressive soft tissue infection in a neutropenic child. The infection resolved with limited surgical debridement and antifungal therapy.


Subject(s)
Neoplasms/complications , Neutropenia/complications , Rhizopus/isolation & purification , Soft Tissue Infections/microbiology , Stomatognathic Diseases/complications , Zygomycosis/diagnosis , Child, Preschool , Head/diagnostic imaging , Humans , Immunocompromised Host , Male , Neoplasms/drug therapy , Neutropenia/chemically induced , Radiography , Tomography , Zygomycosis/microbiology
20.
J Clin Oncol ; 27(27): 4599-604, 2009 Sep 20.
Article in English | MEDLINE | ID: mdl-19687340

ABSTRACT

PURPOSE: To assess the maximum-tolerated dosages (MTDs), and dose-limiting toxicities (DLTs) of the epidermal growth factor receptor inhibitor gefitinib and of intravenous (IV) irinotecan when administered together in children with refractory solid tumors. To assess the effect of gefitinib on the pharmacokinetics of IV irinotecan and on the bioavailability of a single oral dose of irinotecan. PATIENTS AND METHODS: IV irinotecan (15 or 20 mg/m(2)) was given daily for 5 days of 2 consecutive weeks. Oral gefitinib (150 or 112.5 mg/m(2)) was concomitantly given daily for 12 or 21 days. A single oral dose of irinotecan was given on day 9 of course 2 to allow pharmacokinetic analysis. RESULTS: The study enrolled 29 patients with recurrent solid tumors. The 21-day regimen of oral gefitinib with irinotecan was not tolerated. Diarrhea was the most common DLT. The MTD of the combination regimen was 15 mg/m(2)/d of IV irinotecan for 5 days of 2 consecutive weeks and 112.5 mg/m(2)/d of gefitinib given for 12 days. Gefitinib increased the bioavailability of oral irinotecan by four-fold over that observed in historical controls (median, 0.09 v 0.42; P < .000001), reducing the apparent clearance (an inverse measure of exposure) of irinotecan and SN-38 by 37% and 38%, respectively (P < .0001). A partial response was observed in a patient with refractory Ewing sarcoma. CONCLUSION: IV irinotecan given with 12 days of oral gefitinib is well tolerated in children. We observed one partial response. Gefitinib significantly enhances the bioavailability of oral irinotecan. This combination warrants further investigation, particularly with orally administered irinotecan.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Camptothecin/analogs & derivatives , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacokinetics , Protein-Tyrosine Kinases/antagonists & inhibitors , Quinazolines/pharmacokinetics , Administration, Oral , Adolescent , Antineoplastic Agents/administration & dosage , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/pharmacokinetics , Biological Availability , Camptothecin/administration & dosage , Camptothecin/pharmacokinetics , Child , Child, Preschool , Drug Synergism , Female , Gefitinib , Humans , Infant , Infusions, Intravenous , Irinotecan , Male , Protein Kinase Inhibitors/administration & dosage , Quinazolines/administration & dosage , Toxicity Tests , Young Adult
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