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Biomedical subjects

Larry E Kun

Publications and source records attributed to Larry E Kun.

At least 19 recordsLinked to original sources
PubMed2006

A model for quantitative changes in the magnetic resonance parameters of muscle in children after therapeutic irradiation.

PURPOSE/OBJECTIVE: This study aimed to develop objective models of radiation effects on musculature in children with soft tissue sarcoma using treatment dosimetry and clinical and quantitative magnetic resonance imaging (MRI) parameters that may be used to guide treatment planning or predict side effects. METHODS: In the initial 13 patients undergoing external beam radiation therapy (RT) on a Phase II study of conformal or intensity-modulated RT for the treatment of soft tissue sarcoma approved by an Institutional Review Board, we evaluated quantitative MRI changes in the musculature to assess radiation-related treatment effects. Patients with soft tissue sarcoma, including Ewing's sarcoma, had quantitative T1, T2 and dynamic enhanced MRI (DEMRI) performed before, during (Week 4) and after RT (Week 12). Regions of interest were selected in consistent locations within and outside the high-dose regions (on ipsilateral and contralateral sides when available). Mean RT dose, T1, T2 and DEMRI parameters were calculated and modeled using a mixed random coefficient dose model. RESULTS: The mean doses to the high- and low-dose regions were 56.4 Gy (41.8-75.3 Gy) and 13.0 Gy (0.1-37.5 Gy), respectively. Compared with tissues distant from the tumor bed, maximal enhancement was significantly increased in tissues adjacent to the tumor/tumor bed prior to RT (60.6 vs. 44.2, P=.045) and remained elevated after 12 weeks. T1 was significantly elevated in tissues adjacent to the tumor bed prior to RT (942.4 vs. 759.0, P=.0078). The slope of longitudinal change in T1 was greater for tissues that received low-dose irradiation than those that received high-dose irradiation (P=.0488). The effect of dose on the slope of T2 was different (P=.0333) when younger and older patients are compared. CONCLUSIONS: Acute affects of irradiation in muscle are quantifiable via MRI. These models provide evidence that quantifiable MRI parameters may be correlated with patient parameters of radiation dose and clinical factors including patient age. Long-term follow-up will be required to determine if acute changes correlate with clinically significant late effects.

Child↗
PubMed2006

Intratumoral hemorrhage among children with newly diagnosed, diffuse brainstem glioma.

BACKGROUND: Children with diffuse brainstem glioma (BSG) commonly undergo novel therapies because their outcome is poor with radiation therapy (RT). Although recent clinical trials using new biologic agents documented intratumoral hemorrhage (IH) among several children with BSG, to the authors' knowledge little is known regarding this phenomenon. In the current study, the authors assessed the characteristics and estimated the cumulative incidence of IH among children with BSG. METHODS: All available brain imaging studies and medical records of 48 consecutive patients with newly diagnosed BSG treated at the study institution over a 10-year interval (1992-2002) were reviewed. Treatment was comprised of RT and various regimens of conventional chemotherapy; none of these patients received biologic agents. At the time of last follow-up, all patients had died of tumor progression. RESULTS: The authors reviewed 319 imaging studies (251 magnetic resonance imaging scans and 68 computed tomography scans). IH was present in 6.25% of patients at the time of diagnosis. The 6-month and 12-month cumulative incidence estimates of IH regardless of the associated symptoms were 15.5% +/- 5.5% and 24.4% +/- 6.5%, respectively. The same estimates for symptomatic cases were 8.9% +/- 4% and 17.8% +/- 6%, respectively. All cases of IH at the time of diagnosis and 78% of symptomatic cases that developed after diagnosis were located in necrotic areas. CONCLUSIONS: Although IH is uncommon at the time of diagnosis, symptomatic IH may occur among nearly 20% of children after the diagnosis of BSG. The uniform occurrence of IH among patients treated with various chemotherapeutic regimens and its association with necrotic areas suggests that tumor biology plays a significant role in this event.

Adolescent↗
PubMed2006

Phase I trial of intrathecal spartaject busulfan in children with neoplastic meningitis: a Pediatric Brain Tumor Consortium Study (PBTC-004).

PURPOSE: A phase I trial of intrathecal Spartaject Busulfan (SuperGen, Inc., San Ramon, CA) was conducted in children with neoplastic meningitis following recurrent primary brain tumors to describe toxicities, estimate the maximum tolerated dose (MTD), and document evidence of responses to this agent. EXPERIMENTAL DESIGN: The continuous reassessment method was used to assign cohorts of patients to doses of intrathecal Spartaject Busulfan via an Ommaya reservoir and/or lumbar puncture twice weekly for 2 weeks followed by an assessment of toxicity and response. Patients with stable disease or an objective response continued to receive intrathecal Spartaject Busulfan plus systemic chemotherapy at regular intervals. Cerebrospinal fluid and blood were obtained for pharmacokinetic studies in patients with Ommaya reservoirs after the first dose of intrathecal Spartaject Busulfan. Seven evaluable patients were assigned to the starting dose of 5 mg, two patients to 7.5 mg, three patients to 10 mg, seven patients to 13 mg, and four patients to 17 mg. RESULTS: Between September 2000 and May 2003, 28 patients were enrolled in this study. Twenty-three patients (median age, 8.8 years; range, 2.5-19.5 years) were evaluable for estimating the MTD, and dose-limiting toxicities were observed in three and included grade 3 vomiting (n = 1 at 5 mg), grade 3 headache (n = 1 at 17 mg), and grade 3 arachnoiditis (n = 1 at 17 mg). Pharmacokinetic data showed that post-infusion concentrations of busulfan ranged from 50 to 150 microg/mL and declined to <1 microg/mL within 5 hours. CONCLUSIONS: Intrathecal Spartaject Busulfan was well tolerated in children with neoplastic meningitis from brain tumors, and the recommended dose for future phase II studies is 13 mg.

Adolescent↗
PubMed2006

Temozolomide after radiotherapy for newly diagnosed high-grade glioma and unfavorable low-grade glioma in children.

Chemotherapy is commonly used in the treatment of children with high-grade glioma, although its usefulness is uncertain. We conducted a multi-institutional study to evaluate the efficacy of temozolomide given after radiotherapy in children with newly diagnosed high-grade glioma and unfavorable low-grade glioma (gliomatosis cerebri or bithalamic involvement). Optional window therapy of intravenous irinotecan (10 doses of 20 mg/m2 per cycle x 2) was given over 6 weeks. The 5-day schedule of temozolomide (200 mg/m2 per day) started 4 weeks after the completion of radiotherapy and continued for a total of 6 cycles. Thirty-one eligible patients (median age: 12.3 years) participated. Tumors most commonly involved cerebral hemispheres (n = 13, 42%) and thalamus (n = 14, 45%). Whereas six patients underwent radical resection, the remainder had limited surgery, including biopsy (n = 14, 45%). The predominant histologic diagnoses were glioblastoma multiforme (n = 15, 48%) and anaplastic astrocytoma (n = 10, 32%). Two patients had bithalamic grade II astrocytoma. Twenty-seven patients received radiotherapy (median dose: 59.4 Gy), including craniospinal irradiation in 3 because of leptomeningeal spread. Four patients did not receive radiotherapy in this study because of consent withdrawn (n = 2), toxicity during window therapy (n = 1), or at the physician's discretion (n = 1). Twenty-three patients received 112 cycles of temozolomide therapy. The 2-year progression-free and overall survival estimates were 11 +/- 5% and 21 +/- 7%, respectively. Although the heterogeneity of prognostic factors in our patients made assessment of treatment outcome more difficult, the addition of 6 cycles of temozolomide after radiotherapy did not seem to alter the poor outcome of these patients.

Adolescent↗
PubMed2006

A phase II window trial of procarbazine and topotecan in children with high-grade glioma: a report from the children's oncology group.

The role of chemotherapy in the treatment of high-grade gliomas in children is unclear. Early reports were suggestive of improved outcome in children with high-grade glioma with the addition of chemotherapy after surgery and radiation therapy. Subsequent studies did not show similar favorable contribution of chemotherapy to the outcome of these children. Further efforts to identify active chemotherapy agents in children include use of agents that have shown efficacy in adult patients with high-grade glioma and agents that have shown promise in mice bearing human xenografts of brain tumors. A Pediatric Oncology Group (POG 9431) trial tested the activity of two such agents, procarbazine and topotecan in newly diagnosed patients with high-grade glioma who had measurable disease after diagnostic surgery. Neither agent showed efficacy within the confines of the statistical design of the study. This study showed that children with high-grade glioma have an innate resistance to alkylating agents based on mismatch repair deficiency and high levels of alkyguanine transferase (AGT). Future trials should consider strategies to overcome the resistance mechanisms in children with high-grade glioma.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial.

BACKGROUND: Current treatment for medulloblastoma, which includes postoperative radiotherapy and 1 year of chemotherapy, does not cure many children with high-risk disease. We aimed to investigate the effectiveness of risk-adapted radiotherapy followed by a shortened period of dose-intense chemotherapy in children with medulloblastoma. METHODS: After resection, patients were classified as having average-risk medulloblastoma (< or = 1.5 cm2 residual tumour and no metastatic disease) or high-risk medulloblastoma (> 1.5 cm2 residual disease or metastatic disease localised to neuraxis) medulloblastoma. All patients received risk-adapted craniospinal radiotherapy (23.4 Gy for average-risk disease and 36.0-39.6 Gy for high-risk disease) followed by four cycles of cyclophosphamide-based, dose-intensive chemotherapy. Patients were assessed regularly for disease status and treatment side-effects. The primary endpoint was 5-year event-free survival; we also measured overall survival. This study is registered with ClinicalTrials.gov, number NCT00003211. FINDINGS: Of 134 children with medulloblastoma who underwent treatment (86 average-risk, 48 high-risk), 119 (89%) completed the planned protocol. No treatment-related deaths occurred. 5-year overall survival was 85% (95% CI 75-94) in patients in the average-risk group and 70% (54-84) in those in the high-risk group (p=0.04); 5-year event-free survival was 83% (73-93) and 70% (55-85), respectively (p=0.046). For the 116 patients whose histology was reviewed centrally, histological subtype correlated with 5-year event-free survival (p=0.04): 84% (74-95) for classic histology, 77% (49-100) for desmoplastic tumours, and 57% (33-80) for large-cell anaplastic tumours. INTERPRETATION: Risk-adapted radiotherapy followed by a shortened schedule of dose-intensive chemotherapy can be used to improve the outcome of patients with high-risk medulloblastoma.

Adolescent↗
PubMed2006

Phase II trial of conformal radiation therapy for pediatric patients with craniopharyngioma and correlation of surgical factors and radiation dosimetry with change in cognitive function.

OBJECT: A Phase II trial of conformal radiation therapy (CRT) for craniopharyngioma was conducted to determine whether the irradiated volume could be safely reduced to decrease effects on cognitive function. METHODS: Between July 1997 and January 2003, 28 pediatric patients (median age 7.3 +/- 4.12 years) received CRT in whom doses (54-55.8 Gy) were administered to the gross tumor volume (solid and cystic components) surrounded by a 1-cm clinical target volume margin. Patients were evaluated serially with neuropsychometric testing. Statistical analyses were performed to determine the effect of clinical factors and radiation dosimetry on intelligence quotient (IQ). The median follow-up period was 36.6 months (range 24.4-80 months). The estimated 3-year progression-free survival rate was 90.3 +/- 7.3%. Three patients experienced local disease progression. Cognitive outcome for patients was adversely affected by the following factors: age younger than 7.4 years (p = 0.001), an interval between symptoms and diagnosis of more than 73 days (p = 0.06), more extensive surgery (p = 0.014), multiple surgical procedures (p = 0.002), diabetes insipidus (p = 0.02), hydrocephalus at diagnosis (p = 0.009), a cerebrospinal fluid shunt (p = 0.005), shunt revisions (p = 0.01), Ommaya reservoir laterality (p = 0.005), and cyst aspirations (p = 0.02). The percentage of total brain, supratentorial brain, or left temporal lobe volumes receiving a dose in excess of 45 Gy had a significant impact on longitudinal IQ. CONCLUSIONS: The use of CRT with a 1-cm margin for clinical target volume results in tumor control equivalent to that achieved using conventionally planned radiation therapy. Surgical morbidity and a volume-receiving dose more than 45 Gy are factors affecting longitudinal IQ after CRT in patients treated for craniopharyngioma.

Adolescent↗
PubMed2005

Patterns of treatment failure in pediatric and young adult patients with Hodgkin's disease: local disease control with combined-modality therapy.

PURPOSE: Refinement in managing pediatric Hodgkin's disease (HD) requires understanding of factors associated with local treatment failure. This study defines the cumulative incidence (CI) of local failure (LF) and prognostic factors for pediatric patients treated for HD with combined-modality therapy (CMT). PATIENTS AND METHODS: We enrolled 195 patients onto two prospective studies at St Jude Children's Research Hospital between 1990 and 2000. Patients received CMT with chemotherapy (vinblastine, doxorubicin, methotrexate, and prednisone [VAMP]; vinblastine, etoposide, prednisone, and doxorubicin; or VAMP/cyclophosphamide, vincristine, and procarbazine) and involved-field radiation therapy delivered to initial site(s) of disease on the basis of early response. Sites of disease involvement, treatment, and sites of failure were confirmed from the patients' medical record, imaging, and radiotherapy treatment records. We estimated the overall survival, event-free survival, and CI of LF. RESULTS: With a median follow-up of 7.6 years, the CI of LF was 10.9% and 11.6% at 5 and 10 years, respectively. Twenty-seven (14%) of 195 patients experienced recurrence of HD, and 22 (81%) of those experienced LF. Bulky mediastinal disease greater than one third transthoracic diameter predicted a higher incidence of LF, but did not predict failure in the mediastinum. Male sex, low initial hemoglobin, and bulky mediastinal disease were prognostic indicators of LF. Attenuation of radiation dose to 15 Gy based on response provides excellent infield control. CONCLUSION: CMT provides excellent local disease control in children and young adults with HD. LF remains a primary site of disease recurrence, with male sex, low initial hemoglobin, and bulky mediastinal disease predicting for LF.

Adolescent↗
PubMed2005

Intellectual and functional outcome of children 3 years old or younger who have CNS malignancies.

PURPOSE: To evaluate the impact of tumor location, clinical parameters, and therapy on neurocognitive, neuroendocrine, and functional outcomes in children < or = 3 years old with intracranial CNS malignancies who survived at least 2 years after diagnosis. PATIENTS AND METHODS: Records were retrospectively reviewed for 194 children diagnosed from 1985 to 1999 at St Jude Children's Research Hospital (Memphis, TN). RESULTS: The median age at diagnosis was 1.8 years (range, 0.1 to 3.5 years). Median follow-up was 7.64 years (2.0 to 19.4 years). Tumors were infratentorial (102), diencephalic (53), and hemispheric (39); 47% required ventriculoperitoneal shunts, 36% developed seizure disorders, and 20% developed severe ototoxicity. Therapy included no radiation therapy (RT) in 57 (30%), local RT in 87 (45%), and craniospinal irradiation (CSI) in 49 (25%). Overall survival at 10 years was 78 +/- 4%. In a longitudinal analysis of 126 patients with at least one neurocognitive evaluation (NE), the mean rate of intelligence quotient (IQ) change for patients who received CSI (-1.34 points per year) and local RT (-0.51 points per year) was significantly different from the no RT group (0.91 points per year; P = .005 and P = .036, respectively). Patients with hemispheric tumors had a significantly greater IQ decline (-1.52 points per year) than those with midline tumors (0.59 points per year; P = .038). Among those with NE > or = 5 years after diagnosis, 71.4% of CSI recipients compared with 23% of local RT recipients had IQ less than 70 (P = .021). Patients undergoing CSI were more likely to develop endocrinopathies (P < .0001) and to require special education (P = .0007). CONCLUSION: In young children with CNS tumors, CSI and hemispheric location are associated with significant declines in IQ scores.

Age of Onset↗
PubMed2005

Maintenance of certification for radiation oncology.

Maintenance of Certification (MOC) recognizes that in addition to medical knowledge, several essential elements involved in delivering quality care must be developed and maintained throughout one's career. The MOC process is designed to facilitate and document professional development of American Board of Radiology (ABR) diplomates in the essential elements of quality care in Radiation Oncology and Radiologic Physics. ABR MOC has been developed in accord with guidelines of the American Board of Medical Specialties. All Radiation Oncology certificates issued since 1995 are 10-year, time-limited certificates; diplomates with time-limited certificates who wish to maintain specialty certification must complete specific requirements of the American Board of Radiology MOC program. Diplomates with lifelong certificates are not required to participate but are strongly encouraged to do so. Maintenance of Certification is based on documentation of participation in the four components of MOC: (1) professional standing, (2) lifelong learning and self-assessment, (3) cognitive expertise, and (4) performance in practice. Through these components, MOC addresses six competencies-medical knowledge, patient care, interpersonal and communication skills, professionalism, practice-based learning and improvement, and systems-based practice. Details of requirements for components 1, 2, and 3 of MOC are outlined along with aspects of the fourth component currently under development.

Certification↗
PubMed2005

Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy.

PURPOSE: To describe clinical features, therapeutic approaches, and prognostic factors in pediatric patients with atypical teratoid/rhabdoid tumors (ATRT) treated at St Jude Children's Research Hospital (SJCRH). PATIENTS AND METHODS: Primary tumor samples from patients diagnosed with ATRT at SJCRH between July 1984 and June 2003 were identified. Pathology review included histologic, immunohistochemical analysis, and fluorescence in situ hybridization for SMARCB1 (also known as hSNF5/INI1) deletion. Clinical records of patients with pathologic confirmation of ATRT were reviewed. RESULTS: Thirty-seven patients were diagnosed with ATRT at SJCRH during the 19-year study interval. Six patients were excluded from this clinical review based on pathologic or clinical criteria. Of the remaining 31 patients, 22 were younger than 3 years. Posterior fossa primary lesions and metastatic disease at diagnosis were more common in younger patients with ATRT. All patients underwent surgical resection; 30 received subsequent chemotherapy. The majority of patients aged 3 years or older received postoperative craniospinal radiation. Two-year event-free (EFS) and overall survival (OS) of children aged 3 years or older (EFS, 78% + 14%; OS, 89% +/- 11%) were significantly better than those for younger patients (EFS, 11% +/- 6%; OS, 17% +/- 8%); EFS, P = .009 and OS, P = .0001. No other clinical characteristics were predictive of survival. Three of four patients 3 years or older with progressive disease were successfully rescued with ifosfamide, carboplatin, and etoposide therapy. CONCLUSION: Children presenting with ATRT before the age of 3 years have a dismal prognosis. ATRT presenting in older patients can be cured using a combination of radiation and high-dose alkylating therapy. Older patients with relapsed ATRT can have salvage treatment using ICE chemotherapy.

Central Nervous System Neoplasms↗
PubMed2005

Lymphoid gene expression as a predictor of risk of secondary brain tumors.

Gene expression profiles are tissue-specific but may also reflect germ-line-driven expression patterns across tissue types. Previously, using a targeted pharmacologic approach, we identified germ-line polymorphisms in a single gene (thiopurine methyltransferase) associated with the risk of irradiation- and chemotherapy-induced secondary brain tumors in children with acute lymphoblastic leukemia (ALL). To identify additional candidate genetic risk factors, in identically treated patients, we compared the gene expression profiles of diagnostic ALL blasts of those who did develop irradiation-associated brain tumors (n = 9) with the profiles from those who did not (n = 33). Weighted rank regression was used to identify 33 probe sets associated with the time-dependent development of brain tumors; k-means clustering (k = 2) identified 2 groups that differed significantly in cumulative incidence of brain tumors (P = 0.012). Permutation analysis was used to estimate the probability (P = 0.18) of obtaining 2 such clusters by chance. Linear discriminant analysis (time-independent categorization of outcome) was used to identify 70 probe sets whose expression differentiated between the 2 groups of patients. Permutation analyses (n = 1,000) was used to estimate the probability of selecting these probe sets by chance (P = 0.055). Five probe sets were in common between the time-independent and time-dependent methods. The distinguishing genes are involved in neural growth (FGFR1) and in nuclear trafficking (HNRPL, KPNB1). These data suggest that gene expression profiling from accessible tissues may identify targets involved in therapy-related malignancies in unrelated tissues.

Adolescent↗
PubMed2005

Intracranial germinoma: on whole-ventricular irradiation.

BACKGROUND: A current focus in the treatment of intracranial germinoma is on decreasing the volume of radiotherapy. We studied the theoretical impact of selecting different target volumes and treatment techniques. PROCEDURE: Retrospectively, five cases of localized germinoma were identified. Treatment plans were produced for three target volumes: involved field plans (i.e., targeting only gross disease), whole brain plans, and plans of increasing complexity targeting the ventricles (lateral-opposed, four-field and intensity-modulated (IMRT)). A second series of patients was processed similarly except that no involved field plans were produced. RESULTS: When target volumes were compared, normal structures were substantially spared by ventricular irradiation but maximally spared by involved field radiation. When treatment techniques were assessed for ventricular irradiation, the greatest gain in tissue sparing occurred when switching from two to four fields. This gain was at the higher doses levels at the expense of an increased volume of tissue irradiated to lower doses. IMRT plans always spared a small additional amount of normal brain. Whole ventricular plans were compared to similar plans excluding the fourth ventricle. Whole brain dose was only improved by 4-6% by excluding the fourth ventricle. CONCLUSIONS: The substitution of whole-ventricular irradiation for whole-brain irradiation can spare a significant amount of normal tissue, thus providing a theoretical advantage with respect to the risk of late effects. Ventricular irradiation is best achieved with at least a four-field 3D configuration, and optimally through an IMRT plan. Exclusion of the fourth ventricle in the target volume had only a minimal impact on normal tissue doses.

Brain Neoplasms↗
PubMed2005

Seizures in children with primary brain tumors: incidence and long-term outcome.

PURPOSE: To estimate the incidence and long-term outcome of brain tumor related seizures in children and to identify risk factors for adverse seizure outcome. METHODS: Analysis of medical records of children treated for brain tumor and seizures in a single institution. Children were identified from hospital database and neurology clinic records. Seizure status was characterized for the 6 months prior to most recent follow-up. RESULTS: Median follow-up after first seizure of the 157 analyzed children was 3.3 years. Tumor location was supratentorial in 81% and posterior fossa in 19%. Initial anti-epileptic drugs were phenytoin (n=52), carbamazepine (n=38), phenobarbital (n=14), gabapentin (n=31), or others (n=22). Seizures were controlled in 65% of the children and uncontrolled in 35% (17% intractable). Gabapentin showed a trend toward better seizure control (p=0.06). Neurologic deficit, T2 peri-cavity hyperintensity, and EEG slow waves were independently predictive of uncontrolled seizures by multivariate analysis. CONCLUSIONS: T2 peri-cavity hyperintensity, focal neurologic deficits, and EEG slow waves predict poor seizure control in children with brain tumors. Seizures can be controlled in most patients with brain tumors. Gabapentin use as first anti-epileptic drug needs to be studied prospectively.

Adolescent↗
PubMed2005

Hearing loss as a late complication of radiotherapy in children with brain tumors.

Late postirradiation hearing loss has been well described in the adult population. Few reports exist on the pediatric population. We conducted a retrospective review of 157 consecutive children with brain tumors treated exclusively with irradiation at St Jude Children's Research Hospital. Twenty-six patients developed a hearing loss, 74 did not, and 57 were excluded because of incomplete records. We report a statistically significant 27.41% cumulative risk of a stringent 20-dB hearing loss in the voice frequency range by the fifth year after radiotherapy. The right side demonstrated a significant frequency effect, with a higher incidence of loss in the higher-frequency region. We found no difference in cumulative incidence of hearing shift between the low-, middle-, and high-frequency ranges for either ear. This risk should be anticipated and managed as part of the treatment plan for radiotherapy for the treatment of malignancies. Radiation-induced hearing loss is important to acknowledge so that techniques of hyperfractionation, total dose, ports, preservative infusion medical therapy, or prolonged medical intervention (such as anticoagulants) can be developed that might reduce this disabling problem of postirradiation sensorineural hearing loss in future patients.

Adolescent↗