Biomedical subjects
Publications and source records attributed to Michael McDermott.
We report a case of successful allogeneic hematopoietic stem cell transplantation (HSCT) with full myeloablative conditioning in a patient with pre-existing invasive mucormycosis. The mucormycosis involved the maxilla, the nasal septum, and the hard palate. Sustained antifungal therapy and aggressive surgery both before and after HSCT were required.
Although neuroblastoma is characterized by numerous recurrent, large-scale chromosomal imbalances, the genes targeted by such imbalances have remained elusive. We have applied whole-genome oligonucleotide array comparative genomic hybridization (median probe spacing 6 kb) to 56 neuroblastoma tumors and cell lines to identify genes involved with disease pathogenesis. This set of tumors was selected for having either 11q loss or MYCN amplification, abnormalities that define the two most common genetic subtypes of metastatic neuroblastoma. Our analyses have permitted us to map large-scale chromosomal imbalances and high-level amplifications at exon-level resolution and to identify novel microdeletions and duplications. Chromosomal breakpoints (n = 467) generating imbalances >2 Mb were mapped to intervals ranging between 6 and 50 kb in size, providing substantial information on each abnormality. For example, breakpoints leading to large-scale hemizygous loss of chromosome 11q were highly clustered and preferentially associated with segmental duplications. High-level amplifications of MYCN were extremely complex, often resulting in a series of discontinuous regions of amplification. Imbalances (n = 540) <2 Mb long were also detected. Although the majority (78%) of these imbalances mapped to segmentally duplicated regions and primarily reflect constitutional copy number polymorphisms, many subtle imbalances were detected that are likely somatically acquired alterations and include genes involved with tumorigenesis, apoptosis, or neural cell differentiation. The most frequent microdeletion involved the PTPRD locus, indicating a possible tumor suppressor function for this gene.
BACKGROUND: Increased susceptibility for developing alcohol dependence (AD) might be related to structural differences in brain circuits that influence the salience of rewards and/or modify the efficiency of information processing. The role of the cerebellum in regulating cognitive functions is being increasingly recognized along with its well-known influence on motor performance. Additionally, developmental changes in cerebellar volume during adolescence have been reported. METHODS: Magnetic resonance imaging was used to measure the cerebellum in 17 high-risk adolescent and young adult offspring from multiplex alcohol dependence families and 16 control subjects matched for gender, age, and IQ. RESULTS: High-risk (HR) adolescents/young adults showed increased total cerebellum volume and total grey in comparison with control subjects. Age-related decreases in total grey volume were seen with age, a pattern that was not seen in HR offspring. CONCLUSIONS: Offspring from multiplex families for AD manifest genetic susceptibility by having larger cerebellar volume, which seems to be related to lesser grey matter pruning for age. Larger cerebellar volumes in adult obsessive compulsive disorder (OCD) patients have been reported. This suggests a possible similarity in structural underpinnings for alcohol dependence and OCD.
Primary CNS lymphoma is an aggressive form of non-Hodgkin lymphoma whose growth is restricted to the central nervous system. We used cDNA microarray analysis to compare the gene expression signature of primary CNS lymphomas with nodal large B-cell lymphomas. Here, we show that while individual cases of primary CNS lymphomas may be classified as germinal center B-cell, activated B-cell, or type 3 large B-cell lymphoma, brain lymphomas are distinguished from nodal large B-cell lymphomas by high expression of regulators of the unfolded protein response (UPR) signaling pathway, by the oncogenes c-Myc and Pim-1, and by distinct regulators of apoptosis. We demonstrate that interleukin-4 (IL-4) is expressed by tumor vasculature as well as by tumor cells in CNS lymphomas. We also identify high expression in CNS lymphomas of several IL-4-induced genes, including X-box binding protein 1 (XBP-1), a regulator of the UPR. In addition, we demonstrate expression of the activated form of STAT6, a mediator of IL-4 signaling, by tumor cells and tumor endothelia in CNS lymphomas. High expression of activated STAT6 in tumors was associated with short survival in an independent set of patients with primary CNS lymphoma who were treated with high-dose intravenous methotrexate therapy.
We describe bilateral pulmonary vein stenosis in a 5-year-old boy. He initially presented with haemoptysis secondary to left upper lobe pulmonary vein atresia and left lower lobe stenosis and subsequently he underwent left-sided pneumonectomy. He underwent repeat cardiac catheterizations with repeated balloon angioplasty of the right-sided venous stenoses using a cutting balloon. Despite satisfactory initial results the pulmonary venous stenosis reoccurred as early as 2 months following balloon angioplasty. Although cutting balloon angioplasty has demonstrated effective immediate alleviation of pulmonary venous stenosis its utility in providing sustained improvement in pulmonary vein stenosis is limited.
We report a 7-day-old boy referred to our institution with tachypnea and cardiomegaly who was discovered to have an intrapericardial extra-lobar pulmonary sequestration containing a cystic pulmonary adenomatoid malformation type II. He underwent successful surgical resection of the intrapericardial mass, which we believe represents the first reported case of this rare entity.
A convergence of advances in patient immobilization and localization, patient imaging, beam shaping and delivery, and treatment planning has led to considerable improvement in the ability to deliver highly conformal radiation treatments by radiosurgical or fractionated radiotherapy techniques. The selection of the "best" treatment technique for any given patient needs to consider the morphology of the target and regional organs at risk as well as available technology and institutional expertise.
BACKGROUND & AIMS: Recent studies suggest that the mouth may be involved frequently in patients with Crohn's disease (CD). The aim of this study was to document prospectively the proportion of children with oral lesions at diagnosis of CD, to describe the type of lesions found, and to examine the ability of gastroenterologists to identify correctly oral Crohn's manifestations. METHODS: In a prospective 3-year study, systematic dental examinations were performed on all children with suspected inflammatory bowel disease. Each child underwent upper endoscopy, colonoscopy, and barium follow-through radiography. RESULTS: Forty-eight of 49 children with CD were examined by the dentist. Oral CD was found in 20 patients (41.7%). Oral findings included mucogingivitis (12 patients), mucosal tags (4 patients), deep ulceration (4 patients), cobblestoning (3 patients), lip swelling (3 patients), and pyostomatitis vegetans (1 patient). Noncaseating granulomas were found in all 8 oral biopsy specimens from oral CD lesions (100%). Two patients with granulomas in oral biopsy specimens had no granulomas found in any other biopsy specimens. The presence of oral manifestations was associated with perianal disease. In only 9 patients (45%) with oral CD was the mouth found to be abnormal by the consultant gastroenterologists. Only nonspecific oral changes were seen in children with ulcerative colitis and indeterminate colitis. CONCLUSIONS: More than one third of all children presenting with CD had involvement of the mouth. The ability of physicians to recognize oral lesions was poor. Expert dental evaluation may be useful during the investigation of patients with suspected inflammatory bowel disease.
OBJECT: Convection-enhanced delivery (CED) is a novel method for delivering therapeutic agents to infiltrative brain tumor cells. For agents administered by CED, changes on magnetic resonance (MR) imaging directly resulting from catheter placement, infusion, and the therapeutic compound may confound any interpretation of tumor progression. As part of an ongoing multiinstitutional Phase I study, 14 patients with recurrent malignant glioma underwent CED of interleukin (IL) 13-PE38QQR, a recombinant cytotoxin consisting of human IL-13 conjugated with a truncated Pseudomonas exotoxin. Serial neuroradiographic changes were assessed in this cohort of patients. METHODS: Patients were treated in two groups: Group 1 patients received IL13-PE38QQR before and after tumor resection; Group 2 patients received infusion only after tumor resection. Preoperative and postinfusion MR images were obtained prospectively at specified regular intervals. Changes were noted along catheter tracks on postresection MR images obtained in all patients. A simple grading system was developed to describe these changes. When MR imaging changes appeared to be related to IL1 3-PE38QQR, patients were followed up without instituting new antitumor therapy. CONCLUSIONS: As CED of therapeutic agents becomes more common, clinicians and investigators must become aware of associated neuroimaging changes that should be incorporated into toxicity assessment. We have developed a simple grading system to facilitate communication about these changes among investigators. Biological imaging modalities that could possibly distinguish these changes from recurrent tumor should be evaluated. In this study the authors demonstrate the challenges in determining efficacy when surrogate end points such as time to tumor progression as defined by new or progressive contrast enhancement on MR imaging are used with this treatment modality.
BACKGROUND: The best way to initiate dopaminergic therapy for early Parkinson disease remains unclear. OBJECTIVE: To compare initial treatment with pramipexole vs levodopa in early Parkinson disease, followed by levodopa supplementation, with respect to the development of dopaminergic motor complications, other adverse events, and functional and quality-of-life outcomes. DESIGN: Multicenter, parallel-group, double-blind, randomized controlled trial. SETTING: Academic movement disorders clinics at 22 sites in the United States and Canada. PATIENTS: Patients with early Parkinson disease (N = 301) who required dopaminergic therapy to treat emerging disability, enrolled between October 1996 and August 1997 and observed until August 2001. INTERVENTION: Subjects were randomly assigned to receive 0.5 mg of pramipexole 3 times per day with levodopa placebo (n = 151) or 25/100 mg of carbidopa/levodopa 3 times per day with pramipexole placebo (n = 150). Dosage was escalated during the first 10 weeks for patients with ongoing disability. Thereafter, investigators were permitted to add open-label levodopa or other antiparkinsonian medications to treat ongoing or emerging disability. MAIN OUTCOME MEASURES: Time to the first occurrence of dopaminergic complications: wearing off, dyskinesias, on-off fluctuations, and freezing; changes in the Unified Parkinson's Disease Rating Scale and quality-of-life scales; and adverse events. RESULTS: Initial pramipexole treatment resulted in a significant reduction in the risk of developing dyskinesias (24.5% vs 54%; hazard ratio, 0.37; 95% confidence interval [CI], 0.25-0.56; P<.001) and wearing off (47% vs 62.7%; hazard ratio, 0.68; 95% CI, 0.49-0.63; P =.02). Initial levodopa treatment resulted in a significant reduction in the risk of freezing (25.3% vs 37.1%; hazard ratio, 1.7; 95% CI, 1.11-2.59; P =.01). By 48 months, the occurrence of disabling dyskinesias was uncommon and did not significantly differ between the 2 groups. The mean improvement in the total Unified Parkinson's Disease Rating Scale score from baseline to 48 months was greater in the levodopa group than in the pramipexole group (2 +/- 15.4 points vs -3.2 +/- 17.3 points, P =.003). Somnolence (36% vs 21%, P =.005) and edema (42% vs 15%, P<.001) were more common in pramipexole-treated subjects than in levodopa-treated subjects. Mean changes in quality-of-life scores did not differ between the groups. CONCLUSIONS: Initial treatment with pramipexole resulted in lower incidences of dyskinesias and wearing off compared with initial treatment with levodopa. Initial treatment with levodopa resulted in lower incidences of freezing, somnolence, and edema and provided for better symptomatic control, as measured by the Unified Parkinson's Disease Rating Scale, compared with initial treatment with pramipexole. Both options resulted in similar quality of life. Levodopa and pramipexole both appear to be reasonable options as initial dopaminergic therapy for Parkinson disease, but they are associated with different efficacy and adverse-effect profiles.
The Infevers database (http://fmf.igh.cnrs.fr/infevers/) was established in 2002 to provide investigators with access to a central source of information about all sequence variants associated with periodic fevers: Familial Mediterranean fever (FMF), TNF Receptor Associated Periodic Syndrome (TRAPS), Hyper IgD Syndrome (HIDS), Familial Cold Autoinflammatory Syndrome/Muckle-Wells Syndrome/Chronic Infantile Neurological Cutaneous and Articular Syndrome (FCAS/MWS/CINCA). The prototype of this group of disorders is FMF, a recessive disease characterized by recurrent bouts of unexplained inflammation. FMF is the pivotal member of an expanding family of autoinflammatory disorders, a new term coined to describe illnesses resulting from a defect of the innate immune response. Therefore, we decided to extend the Infevers database to genes connected with autoinflammatory diseases. We present here the biological content of the Infevers database, including the introduction of two new entries: Crohn/Blau and Pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA syndrome). Infevers has a range of query capabilities, allowing for simple or complex interrogation of the database. Currently, the database contains 291 sequence variants in related genes (MEFV, TNFRSF1A, MVK, CARD15, PSTPIP1, and CIAS1), consisting of published data and personal communications, which has revealed or refined the preferential mutational sites for each gene. This database will continue to evolve in its content and to improve in its presentation.
To determine the safety and evaluate the efficacy of repeated administration of virus-producing cells (GLI 328) containing the herpes simplex virus thymidine-kinase gene followed by ganciclovir treatment in adults with recurrent glioblastoma multiforme, we conducted a phase I/II multi-institutional trial. Eligible patients underwent surgical resection of tumor, followed by injections of vector producing cells (VPC) into the brain adjacent to the cavity. An Ommaya reservoir placed after surgery was used to inject a further dose of VPC seven days after surgery, followed seven days later by ganciclovir. Further gene therapy was given at 28-day intervals for up to a total of five cycles. Toxicity and anti-tumor effect were assessed. Of 30 patients who enrolled in the study, 16 experienced serious adverse events possibly related to the experimental therapy. Laboratory testing, including polymerase chain reaction analysis to detect replication-competent retrovirus in peripheral blood lymphocytes and tissues, as well as co-cultivation bioassays, were negative. Before receiving ganciclovir, 37% of the patients showed evidence of transduced peripheral blood leukocytes, but only 12% showed a persistence of transduced cells at the end of the first cycle of ganciclovir. Median survival was 8.4 months. Twenty percent of the patients (n = 6) survived more than 12 months from the date of study entry. This treatment modality is feasible and appears to have some evidence of efficacy. Toxicity may be related in part to the method of gene delivery.
OBJECT: In many new clinical trials of patients with malignant gliomas surgical intervention is incorporated as an integral part of tumor-directed interstitial therapies such as gene therapy, biodegradable wafer placement, and immunotherapy. Assessment of toxicity is a major component of evaluating these novel therapeutic interventions, but this must be done in light of known complication rates of craniotomy for tumor resection. Factors predicting neurological outcome would also be helpful for patient selection for surgically based clinical trials. METHODS: The Glioma Outcome Project is a prospectively compiled database containing information on 788 patients with malignant gliomas that captured clinical practice patterns and patient outcomes. Patients in this series who underwent their first or second craniotomy were analyzed separately for presenting symptoms, tumor and patient characteristics, and perioperative complications. Preoperative and intraoperative factors possibly related to neurological outcome were evaluated. There were 408 patients who underwent first craniotomies (C1 group) and 91 patients who underwent second ones (C2 group). Both groups had similar patient and tumor characteristics except for their median age (55 years in the C1 group compared with 50 years in the C2 group; p = 0.006). Headache was more common at presentation in the C1 group, whereas papilledema and an altered level of consciousness were more common at presentation in patients undergoing second surgeries. Perioperative complications occurred in 24% of patients in the C1 group and 33% of patients in the C2 group (p = 0.1). Most patients were the same or better neurologically after surgery, but more patients in the C2 group (18%) displayed a worsened neurological status than those in the C1 group (8%; p = 0.007). The Karnofsky Performance Scale score and, in patients in the C2 group, tumor size were important neurological outcome predictors. Regional complications occurred at similar rates in both groups. Systemic infections occurred more frequently in the C2 group (4.4 compared with 0%; p < 0.0001) as did depression (20 compared with 11%; p = 0.02). The perioperative mortality rate was 1.5% for the C1 group and 2.2% for the C2 group (p = not significant). The median length of the hospital stay was 4 days in each group. CONCLUSIONS: Perioperative complications occur slightly more often following a second craniotomy for malignant glioma than after the first craniotomy. This should be considered when evaluating toxicities from intraoperative local therapies requiring craniotomy. Nevertheless, most patients are neurologically stable or improved after either their first or second craniotomy. This data set may serve as a benchmark for neurosurgeons and others in a discussion of operative risks in patients with malignant gliomas.
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Most lymphomas that involve the central nervous system are B-cell neoplasms that express the cell surface molecule CD20. After intravenous administration, rituximab can be reproducibly measured in the cerebrospinal fluid (CSF) in patients with primary central nervous system lymphoma; however, the CSF levels of rituximab are approximately 0.1% of serum levels associated with therapeutic activity in patients with systemic non-Hodgkin lymphoma. Because lymphomatous meningitis is a frequent complication of non-Hodgkin lymphoma, we have conducted an analysis of the safety and pharmacokinetics of direct intrathecal administration of rituximab using cynomolgus monkeys. No significant acute or delayed toxicity, neurologic or otherwise, was detected. Pharmacokinetic analysis suggests that drug clearance from the CSF is biphasic, with a terminal half-life of 4.96 hours. A phase 1 study to investigate the safety and pharmacokinetics of intrathecal rituximab in patients with recurrent lymphomatous meningitis will be implemented based on these findings.
Our objective was to assess the test-retest reliability of the Unified Parkinson's Disease Rating Scale (UPDRS). The UPDRS is the most widely used instrument for measuring severity of parkinsonian symptoms in clinical research and in practice. The validity and inter-rater reliability of this scale have been previously studied. We examined the test-retest (intrarater) reliability of the UPDRS and derived subscales. Four hundred patients with early-stage Parkinson's disease (PD) who were participating in a multicenter clinical trial were evaluated using the UPDRS on two separate occasions (screening and baseline visits) prior to receiving treatment. The same neurologist at each center rated the subjects at both examinations that were, on average, 14.6 +/- 7.6 days apart (range 3-36 days). Test-retest reliability was estimated using the intraclass correlation coefficient (ICC) for the total UPDRS score, the mental, ADL, and motor subscale scores, and other derived subscale scores. Weighted kappa statistics were calculated for individual UPDRS items. The ICCs for the UPDRS scores were as follows: total score, 0.92; mental, 0.74; ADL, 0.85; motor, 0.90. ICCs for derived symptom-based scales ranged from 0.69-0.88. Reliability of specific items was generally lower than for summary scales. Reliability was slightly better in patients for whom the testing interval was within 14 days. Based on conventional standards, the UPDRS scores were found to have excellent test-retest reliability in this sample of patients with early PD rated by academic movement disorder specialists. The findings are in agreement with previous reports on interrater reliability.