Everolimus in combination with vandetanib in children, adolescents, and young adults: a phase I study.

BACKGROUND: Combined use of inhibitors of mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF-2) receptors is a potential strategy to overcome resistance to either class of drugs when used alone. PATIENTS AND METHODS: We designed a phase 1 trial to test the drug combination of a multikinase VEGF receptor 2 inhibitor, vandetanib, and an mTOR inhibitor, everolimus, in a pediatric and young adult patient cohort with advanced cancers. Exceptional responders were probed for tumor mutational profile to explore possible molecular mechanisms of response. RESULTS: Among 21 enrolled patients, clinical benefit was observed in 38% (one patient with partial response and eight patients with stable disease) with a median progression-free survival of 3.3 months. The most common treatment-related adverse event was rash (n = 13). Other treatment-related toxicities included diarrhea, fatigue, hypertension, QT prolongation, hypertriglyceridemia/hypercholesterolemia, transaminitis, thrombocytopenia, and weight loss. None of the patients experienced dose-limiting toxicities. Three exceptional responders were analyzed and were found to harbor genetic alterations including kinase insert domain receptor (KDR) Q472H mutation, EWSR1-CREB3L1, CDKN2A/B loss, and ASPL/ASPSCR1-TFE3 fusion. CONCLUSIONS: The combination of vandetanib and everolimus showed early activity and tolerable toxicity profile in pediatric patients with advanced cancers.

Validation of the Kinetik Blood Pressure Monitor-Series 1 for use in adults at home and in clinical settings, according to the 2002 European Society of Hypertension International Protocol on the validation of blood pressure devices.

The aim of this study was to assess the blood pressure (BP) measurement accuracy of the Kinetik Blood Pressure Monitor-Series 1 (BPM-1) for use in home or clinical settings according to the 2002 European Society of Hypertension International Protocol (ESH-IP). Forty-two participants were recruited to fulfil the required number of systolic and diastolic BP measurements according to the ESH-IP. Nine sequential same-arm BP readings were measured and analysed for each participant using the test device and observer mercury standard readings according to the 2002 ESH-IP. Forty one participants were used to obtain 33 sets of systolic and diastolic BP readings and were included in the analysis. Mean difference between the device measurements and the observer (mercury standard) measurements was 1.1 ± 7.2/1.1 ± 6.8 mmHg (mean ± standard deviation; systolic/diastolic). The number of systolic BP differences between the test and observer measurements that fell within 5, 10 and 15 mmHg was 65, 86 and 92. For diastolic readings, the number of test-observer measurement differences within 5, 10 and 15 mmHg was 77, 91 and 94. The number of participants with at least two out of three differences within 5 mmHg was 28 for systolic and 40 for diastolic BP readings. Three participants had no differences between the test and observer measurements within 5 mmHg in both the systolic and diastolic measurement categories. The Kinetik BPM-1 device fulfilled the requirements of the ESH-IP validation procedure and can be recommended for clinical use and self-measurement within the home.

Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985-2000).

The Dana-Farber Cancer Institute (DFCI) acute lymphoblastic leukemia (ALL) Consortium has been conducting multi-institutional clinical trials in childhood ALL since 1981. The treatment backbone has included 20-30 consecutive weeks of asparaginase during intensification and frequent vincristine/corticosteroid pulses during the continuation phase. Between 1985 and 2000, 1457 children aged 0-18 years were treated on four consecutive protocols: 85-01 (1985-1987), 87-01 (1987-1991), 91-01 (1991-1955) and 95-01 (1996-2000). The 10-year event-free survival (EFS)+/-s.e. by protocol was 77.9+/-2.8% (85-01), 74.2+/-2.3% (87-01), 80.8+/-2.1% (91-01) and 80.5+/-1.8% (95-01). Approximately 82% of patients treated in the 1980s and 88% treated in the 1990s were long-term survivors. Both EFS and overall survival (OS) rates were significantly higher for patients treated in the 1990s compared with the 1980s (P=0.05 and 0.01, respectively). On the two protocols conducted in the 1990s, EFS was 79-85% for T-cell ALL patients and 75-78% for adolescents (age 10-18 years). Results of randomized studies revealed that dexrazoxane prevented acute cardiac injury without adversely affecting EFS or OS in high-risk (HR) patients, and frequently dosed intrathecal chemotherapy was an effective substitute for cranial radiation in standard-risk (SR) patients. Current studies continue to focus on improving efficacy while minimizing acute and late toxicities.

Direct observation of the phenomenology of a solid thermal explosion using time-resolved proton radiography.

We present a new phenomenology for burn propagation inside a thermal explosion based on dynamic radiography. Radiographic images were obtained of an aluminum cased solid cylindrical sample of a plastic bonded formulation of octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine. The phenomenology observed is ignition followed by cracking in the solid accompanied by the propagation of a radially symmetric front of increasing proton transmission. This is followed by a further increase in transmission through the sample, ending after approximately 100 micros. We show that these processes are consistent with the propagation of a convective burn front followed by consumption of the remaining solid by conductive particle burning.

Osteogenic sarcoma associated with Diamond-Blackfan anemia: a report from the Diamond-Blackfan Anemia Registry.

PURPOSE: Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia, usually presenting in infancy or early childhood. A review of the literature strongly supports a predisposition to hematopoietic malignancy. Recently, solid tumors have been reported, some attributable to hemosiderosis and/or androgen therapy. Two cases of osteogenic sarcoma have also been documented. An analysis from the Diamond-Blackfan Anemia Registry was performed to evaluate the cancer risk in patients with DBA. METHODS: The Diamond-Blackfan Anemia Registry of North America (DBAR) is a comprehensive database of patients with DBA enrolled, after informed consent, through outreach to pediatric hematologists and family groups. The patients and/or their families complete a detailed questionnaire, and a review of medical records and telephone interviews are performed to complete and clarify the information provided. RESULTS: Of the 354 patients registered in the DBAR, there were six patients meeting the accepted diagnostic criteria for DBA who were found to have malignancies. Three patients had osteogenic sarcoma diagnosed, one with myelodysplastic syndrome, one with colon carcinoma, and one with a soft tissue sarcoma. CONCLUSION: There appears to be an association of osteogenic sarcoma with DBA. A young age at presentation may be a feature of DBA-associated osteogenic sarcoma. Because of the immaturity of the database, the actuarial risk for osteogenic sarcoma and other cancers in individuals with DBA cannot be ascertained. Speculation is made regarding the nature of the molecular defect leading to the association of DBA and osteogenic sarcoma.

Improved response with higher corticosteroid dose in children with acute lymphoblastic leukemia.

PURPOSE: We investigated whether there was a dose-response relationship for the use of corticosteroids in childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Three hundred sixty-nine patients, ages 1 to 18 years with ALL, were randomly assigned to receive one of four different doses of corticosteroid (prednisolone 40 mg/m(2)/d or dexamethasone 6, 18, or 150 mg/m(2)/d) administered as a 3-day, single-drug window before initiation of standard, multidrug induction chemotherapy. Corticosteroid drug response was measured by reduction in bone marrow blast counts and absolute peripheral blast counts after 3 days. Glucocorticoid receptor (GCR) number and the effective concentration of dexamethasone resulting in a 50% reduction of leukemic cell viability in vitro (EC-50) were evaluated at days 0 and 3. RESULTS: Increasing dexamethasone doses resulted in greater marrow blast response (P =.007), with a similar trend in peripheral-blood blast response. High-dose corticosteroid regimens (dexamethasone 18 or 150 mg/m(2)/d) elicited better responses than standard doses of dexamethasone or prednisone (bone marrow, P =.002; peripheral blasts, P =.05). Among patients treated with standard-dose corticosteroids, 38% with resistant (EC-50 > 10(-7)) peripheral blasts had a good response compared with 92% with sensitive (EC-50 < 10(-7)) peripheral blasts (P =.01). In contrast, there was no differential response according to EC-50 group after high-dose corticosteroids. Similarly, an association between response and GCR on peripheral-blood blasts was noted after standard-dose corticosteroid regimens but not after high-dose corticosteroid regimens. CONCLUSION: Response of ALL to glucocorticoid therapy increased with dose. Higher-dose corticosteroid treatment abrogated the effect of relative drug insensitivity and of low GCR on peripheral blasts.

Aggressive surgery is unwarranted for biliary tract rhabdomyosarcoma.

BACKGROUND/PURPOSE: Rhabdomyosarcoma (RMS) of the biliary tract is rare, and, in addition to multiagent chemotherapy with or without radiotherapy (RT), some investigators recommend aggressive surgery. To assess the role of surgery, records of all 25 eligible patients with biliary RMS enrolled in IRSG studies I through IV from 1972 to 1998 were reviewed. METHODS: Treatment included surgery with or without vincristine, dactinomycin, cyclophosphamide, doxorubicin, cisplatin, etoposide, ifosfamide, and with or without RT. Data evaluated included clinical presentation, treatment, complications, and outcome. RESULTS: Diagnostic imaging identified the primary tumor but failed to identify regional metastases. Despite aggressive surgery, gross total resection at diagnosis was possible in only 6 cases, 2 of which had negative surgical margins. Although only 6 (29%) patients without distant metastases underwent gross total resection, estimated 5-year survival rate was 78% (95% CI 58%, 97%). Infectious complications were common and frequently associated with external biliary drains. Five (20%) died within the first 2 months, 3 of sepsis. CONCLUSIONS: Surgery is critical for establishing an accurate diagnosis and determining the extent of regional disease. Gross total resection is rarely possible despite aggressive surgery, and outcome is good despite residual disease after surgery. External biliary drains increase the risk of postoperative infectious complications.

Long-term survivors of childhood cancer: the late effects of therapy.

The successful treatment of pediatric malignancy by multimodality therapy has improved the outcome for children with cancer. It has been estimated that 0.1% of individuals 20 years of age are survivors of childhood cancer. This represents a large cohort nationally who, with maturation, may be increasingly beset by the medical and social consequences of treatment. The study of long-term effects of cancer chemotherapy has grown enormously in the past decade. Any side effect that does not resolve after the completion of therapy is a long-term effect of therapy. Side effects recognized during the therapeutic period are usually addressed by the treating physicians. More problematic are those effects of therapy that are subclinical at completion of therapy but manifest years later. These are the true late effects of therapy and are the focus of this review. The cytotoxic effects on maturing tissues become apparent only with development. Thus physical, intellectual and pubertal development as well as reproductive potential may be impossible to assess for a decade or more, depending upon the age at the time of treatment. Nonetheless, the ability to predict the likelihood of a given adverse outcome is enormously helpful to the survivor and may allow for the mitigation of severe effects. Organ injury may also be subclinical initially. With aging and additional stress, compensatory mechanisms may fail. The development of effective screening methodologies may be essential for early interventions. Lifestyle changes may reduce exposure to further toxins and mutagenic agents such as alcohol and cigarette smoke that may lead to secondary malignancy, particularly if compounded in some instances by genetic predisposition. Programs for survivors of childhood cancer were developed within pediatric oncology. As the children become adults, the likelihood of continued care at the initial treating institution decreases. Oncologists and other health care professionals who become responsible for the health care of this maturing cohort will need to understand the risks engendered by childhood cancer therapy.

Frequent detection of tumor cells in hematopoietic grafts in neuroblastoma and Ewing's sarcoma.

Many poor-risk neuroblastomas and tumours of the Ewing's sarcoma family (ET) recur despite autologous transplants. Recurrence may be due to tumor cells contained in the BM harvests or PBSC harvests. The objectives of this prospective study were to: (1) determine the incidence and degree of tumor cell contamination in paired BM and PBSC harvests; and (2) determine the efficacy of tumor cell purging by immunomagnetic CD34+ cell selection. 198 samples from 11 consecutive patients with neuroblastoma or Ewing's sarcoma were analyzed. We assayed tumor contamination by RT-PCR assay for PGP 9.5, plus immunohistochemistry for neuroblastoma-specific antigens (the latter in neuroblastoma only). None of these patients had tumor cells detected in their BM by clinical histology immediately before BM or PBSC harvests. However, 82% of PBSC and 89% of backup BM harvests were contaminated with tumor by RT-PCR and/or immunocytochemistry assays. Unselected PBSC and BM harvests contained similar quantities of tumor cells (median, approximately 200000 cells). Cyclophosphamide plus G-CSF mobilization did not affect the incidence or level of contamination in PBSC harvests, as compared to blood obtained before mobilization. Immunomagnetic CD34+ cell selection depleted tumor cells by a median of 3.0 logs for PBSC, and 2.6 logs for BM harvests.

Corrected QT interval prolongation in anthracycline-treated survivors of childhood cancer.

PURPOSE: Comprehensive cardiac evaluations are currently recommended for all anthracycline-treated patients to detect subclinical cardiac failure. A screening test is needed that would easily and inexpensively identify patients who are at risk for late cardiac decompensation. METHODS: We routinely reviewed the ECG and echocardiogram (ECHO) results of 52 of 56 anthracycline-treated long-term survivors of childhood cancer who had received > or = 100 mg/m2 of ANTH (ANTH = 1 mg/m2 of doxorubicin), and who were not in clinical heart failure. Exercise testing was performed in eight patients with a corrected QT interval (QTc) of > or = 0.43. RESULTS: Zero of 15 patients (without chest radiation) who received less than 300 mg/m2 of ANTH versus six of 22 who received > or = 300 mg/m2 of ANTH had a QTc > or = 0.43 (P = .03). Three of 15 patients (with chest radiation) who received less than 300 mg/m2 of ANTH versus 12 of 22 who received > or = 300 mg/m2 of ANTH had a QTc > or = 0.43 (P = .03). For all patients (including those with chest radiotherapy), zero of 19 who received less than 300 mg/m2 of ANTH versus eight of 33 who received > or = 300 mg/m2 of ANTH had a QTc of > or = 0.45 (P = .025). Three of 19 who received less than 300 mg/m2 of ANTH versus 19 of 33 who received > or = 300 mg/m2 of ANTH had a QTc of > or = 0.43 (P = .003). One patient had decreased fractional shortening (FS) and QTc prolongation. Cardiac decompensation (with a FS of 24%) occurred with propranolol in a patient with previously normal FS but prolonged QTc. With exercise, the QTc became further prolonged in all four patients with a QTc of 0.44 to 0.46 and in two of four patients with a QTc of 0.43. CONCLUSION: Prolongation of the QTc, a measure of myocardial repolarization, may reflect injury to myocardial cells. QTc prolongation may be predictive of an increased risk of late cardiac decompensation. If the utility of the QTc measure is confirmed, screening for evidence of myocardial damage can be easily and inexpensively performed by oncologists and primary caretakers.

The optic nerve as the site of initial relapse in childhood acute lymphoblastic leukemia.

Three children with acute lymphoblastic leukemia (ALL) developed isolated optic nerve relapse as the initial site of disease recurrence. They were part of an early cohort of 39 children with non-B-cell, non-T-cell ALL without central nervous system (CNS) involvement, treated regardless of initial leukocyte count with intrathecal chemotherapy for CNS prophylaxis. Although the optic nerve is a known site of relapse in patients with systemic and meningeal ALL, it has not been reported to occur in otherwise relapse-free patients. Early diagnosis and treatment prevented blindness and allowed for long-term survival (57+, 49+, and 97+ months, respectively) and possibly cure. Since these patients were treated in a new manner and exhibited a new pattern of relapse, their clinical courses were reviewed. Features considered worrisome, but not diagnostic of CNS leukemia may be of greater import when intrathecal medications are utilized as primary CNS prophylaxis. An expanded definition of CNS leukemia may be necessary.

Preleukemic syndromes and other syndromes predisposing to leukemia.

The myelodysplastic and myeloproliferative syndromes are syndromes in childhood that may precede leukemia. Clinical and biologic features are reviewed in this article. Although rare, they offer an unique opportunity to observe the evolution of leukemia and give clues that are helping us to understand the leukemogenic process.

Elimination of clonogenic malignant human T cells using monoclonal antibodies in combination with 2'-deoxycoformycin.

2'Deoxycoformycin (dCF) specifically inhibits adenosine deaminase (ADA) and causes selective cytotoxicity of normal and malignant T cells. In clinical trials, dCF caused rapid lysis of malignant T lymphoblasts. Although dCF has been associated with dose-limiting nonhematopoietic toxicities, myelosuppression has not been observed. Since dCF is relatively nontoxic to hematopoietic stem cells, we tested dCF for utility in the ex vivo purging of malignant T lymphoblasts from remission leukemic bone marrow for autologous bone marrow transplantation. We found that T lymphoblast cell lines were sensitive to dCF (plus deoxyadenosine [dAdo]) under conditions that did not ablate human hematopoietic colony-forming cells. Moreover, combined pharmacologic (dCF plus dAdo) and immunologic (anti-T cell monoclonal antibodies [McAb] plus complement) purging resulted in additive reduction in clonogenic T lymphoblasts. These results provide the basis for a clinical trial of bone marrow transplantation using combined pharmacologic/immunologic purging of T lymphoblasts from patients' harvested autologous marrow.