Paul A. Caruso

Biexponential apparent diffusion coefficient parametrization in adult vs newborn brain

The decay of brain water signal with b-factor in adult and newborn brains has been measured over an extended b-factor range. Measurements of the apparent diffusion coefficient (ADC) decay curves were made at 16 b-factors from 100 to 5000 s/mm(2) along three orthogonal directions using a line scan diffusion imaging (LSDI) sequence to acquire data from 0.09 ml voxels in a mid-brain axial slice. Regions-of-interest (ROIs) in cortical gray (CG) and white matter in the internal capsule (IC) were selected for ADC decay curve analyses using a biexponential fitting model over this extended b-factor range. Measures of the fast and slow ADC component amplitudes and the traces of the fast and slow diffusion coefficients were obtained from CG and IC ROIs in both adults and newborns. The ADC decay curves from the newborn brain regions were found to have a significantly higher fraction of the fast diffusion ADC component than corresponding regions in the adult brain. The results demonstrate that post-natal brain development has a profound affect on the biexponential parameters which characterize the decay of water signal over an extended b-factor range in both gray and white matter.

Proton radiotherapy for pediatric central nervous system ependymoma: clinical outcomes for 70 patients

BACKGROUND Ependymoma is treated with maximal surgical resection and localized radiotherapy. Minimizing unnecessary exposure to radiation is of paramount importance for young children. Proton radiotherapy (PRT) spares healthy tissues outside the target region, but reports of clinical outcomes are scarce. We report outcomes for 70 patients treated with PRT for intracranial ependymoma. METHODS Seventy patients with localized ependymoma treated with involved-field PRT at the Massachusetts General Hospital between October 2000 and February 2011 were included. RESULTS Median age at diagnosis was 38 months (range, 3 mo-20 y). Nineteen (27%) patients had supratentorial ependymoma and 51(73%) had infratentorial ependymoma. Forty-six (66%) had gross total resection (GTR), and 24 (34%) had subtotal resection (STR). At a median follow-up of 46 months, 3-year local control, progression-free survival, and overall survival were 83%, 76%, and 95%, respectively. STR was significantly associated with worse progression-free survival (54% vs 88%, P = .001) and overall survival (90% vs 97% for GTR, P = .001). In a subset of patients (n = 14), mean intelligence was 108.5 at baseline and 111.3 after mean 2.05 years of follow-up. In a larger group of patients (n = 28), overall adaptive skills were 100.1 at baseline and 100.8 after 2.21 years of follow-up. Few patients developed evidence of growth hormone deficiency, hypothyroidism, or hearing loss. CONCLUSION Outcomes for children treated with PRT compare favorably with the literature. STR correlated with inferior outcome. The young age at diagnosis and the proximity of critical structures in patients with ependymoma make PRT an ideal radiation modality.

Cerebrovascular Involvement in Fabry Disease: Current Status of Knowledge

Fabry disease (FD) is a rare and highly debilitating lysosomal storage disorder that results from a total lack of, or deficiency in, the enzyme α-galactosidase A (α-Gal A) because of mutations in the GLA gene.1 FD is inherited as an X-linked trait; many of the male patients develop a classic severe phenotype with early onset of symptoms, whereas heterozygous females exhibit phenotypes ranging from asymptomatic to major involvement of vital organs.2 Most families inherit private mutations; to date, >600 mutations have been identified and are listed in the online FD database (Fabry-database.org).3 The deficiency in α-Gal A causes the accumulation of globotriaosylceramide (GL-3; also abbreviated Gb3) in various cellular compartments, particularly lysosomes, causing structural damage and cellular dysfunction, as well as triggering secondary, tissue-level responses, such as inflammation, ischemia, hypertrophy, and the development of fibrosis resulting in progressive organ dysfunction.4 Deacylated globotriaosylceramide (lyso- globotriaosylceramide [lyso-GL-3]) has also been shown to be present in increased concentrations in the plasma of patients with FD. It has been suggested that lyso-GL-3 promotes GL-3 accumulation, induces proliferation of smooth muscle cells in vitro, and may have deleterious effects on the intima and media of small arterioles.5 Many cell types are involved in FD pathology, including vascular cells (endothelial and smooth muscle cells), cardiac cells (cardiomyocytes and valvular cells), a variety of renal cells (tubular and glomerular cells, and podocytes), and nerve cells.2 The underlying pathophysiological mechanisms of FD are complex and incompletely understood.6 Early pathophysiological changes are thought to predominantly involve the microvasculature.7 As age increases, arterial remodeling and intima-media thickening in medium-to-large caliber vessels occur.2 The first clinical symptoms of FD occur in childhood (eg, neuropathic pain, hypohidrosis, and gastrointestinal problems)8 and are primarily because of autonomic neuropathy.9 As the disease …

Bevacizumab Treatment for Meningiomas in NF2: A Retrospective Analysis of 15 Patients

Bevacizumab treatment can result in tumor shrinkage of progressive vestibular schwannomas in some neurofibromatosis 2 (NF2) patients but its effect on meningiomas has not been defined. To determine the clinical activity of bevacizumab against NF2-related meningiomas, we measured changes in volume of meningiomas in NF2 patients who received bevacizumab for treatment of progressive vestibular schwannomas. A radiographic response was defined as a 20% decrease in tumor size by volumetric MRI analysis. In addition, we determined the expression pattern of growth factors associated with tumor angiogenesis in paraffin-embedded tissues from 26 unrelated meningiomas. A total of 48 meningiomas in 15 NF2 patients were included in this study with a median follow up time of 18 months. A volumetric radiographic response was seen in 29% of the meningiomas (14/48). Tumor shrinkage was not durable: the median duration of response was 3.7 months and the median time to progression was 15 months. There was no significant correlation between pre-treatment growth rate and meningioma response in regression models. Tissue analysis showed no correlation between tumor microvascular density and expression of VEGF pathway components. This data suggests that, in contrast to schwannomas, activation of VEGF pathway is not the primary driver of angiogenesis in meningiomas. Our results suggest that a minority of NF2-associated meningiomas shrink during bevacizumab therapy and that these responses were of short duration. These results are comparable to previous studies of bevacizumab in sporadic meningiomas.

Patterns of Failure After Proton Therapy in Medulloblastoma; Linear Energy Transfer Distributions and Relative Biological Effectiveness Associations for Relapses

PURPOSE The pattern of failure in medulloblastoma patients treated with proton radiation therapy is unknown. For this increasingly used modality, it is important to ensure that outcomes are comparable to those in modern photon series. It has been suggested this pattern may differ from photons because of variations in linear energy transfer (LET) and relative biological effectiveness (RBE). In addition, the use of matching fields for delivery of craniospinal irradiation (CSI) may influence patterns of relapse. Here we report the patterns of failure after the use of protons, compare it to that in the available photon literature, and determine the LET and RBE values in areas of recurrence. METHODS AND MATERIALS Retrospective review of patients with medulloblastoma treated with proton radiation therapy at Massachusetts General Hospital (MGH) between 2002 and 2011. We documented the locations of first relapse. Discrete failures were contoured on the original planning computed tomography scan. Monte Carlo calculation methods were used to estimate the proton LET distribution. Models were used to estimate RBE values based on the LET distributions. RESULTS A total of 109 patients were followed for a median of 38.8 months (range, 1.4-119.2 months). Of the patients, 16 experienced relapse. Relapse involved the supratentorial compartment (n=8), spinal compartment (n=11), and posterior fossa (n=5). Eleven failures were isolated to a single compartment; 6 failures in the spine, 4 failures in the supratentorium, and 1 failure in the posterior fossa. The remaining patients had multiple sites of disease. One isolated spinal failure occurred at the spinal junction of 2 fields. None of the 70 patients treated with an involved-field-only boost failed in the posterior fossa outside of the tumor bed. We found no correlation between Monte Carlo-calculated LET distribution and regions of recurrence. CONCLUSIONS The most common site of failure in patients treated with protons for medulloblastoma was outside of the posterior fossa. The most common site for isolated local failure was the spine. We recommend consideration of spinal imaging in follow-up and careful attention to dose distribution in the spinal junction regions. Development of techniques that do not require field matching may be of benefit. We did not identify a direct correlation between lower LET values and recurrence in medulloblastoma patients treated with proton therapy. Patterns of failure do not appear to differ from those in patients treated with photon therapy.

Incidence of CNS Injury for a Cohort of 111 Patients Treated With Proton Therapy for Medulloblastoma: LET and RBE Associations for Areas of Injury

BACKGROUND Central nervous system (CNS) injury is a rare complication of radiation therapy for pediatric brain tumors, but its incidence with proton radiation therapy (PRT) is less well defined. Increased linear energy transfer (LET) and relative biological effectiveness (RBE) at the distal end of proton beams may influence this risk. We report the incidence of CNS injury in medulloblastoma patients treated with PRT and investigate correlations with LET and RBE values. METHODS AND MATERIALS We reviewed 111 consecutive patients treated with PRT for medulloblastoma between 2002 and 2011 and selected patients with clinical symptoms of CNS injury. Magnetic resonance imaging (MRI) findings for all patients were contoured on original planning scans (treatment change areas [TCA]). Dose and LET distributions were calculated for the treated plans using Monte Carlo system. RBE values were estimated based on LET-based published models. RESULTS At a median follow-up of 4.2 years, the 5-year cumulative incidence of CNS injury was 3.6% for any grade and 2.7% for grade 3+. Three of 4 symptomatic patients were treated with a whole posterior fossa boost. Eight of 10 defined TCAs had higher LET values than the target but statistically nonsignificant differences in RBE values (P=.12). CONCLUSIONS Central nervous system and brainstem injury incidence for PRT in this series is similar to that reported for photon radiation therapy. The risk of CNS injury was higher for whole posterior fossa boost than for involved field. Although no clear correlation with RBE values was found, numbers were small and additional investigation is warranted to better determine the relationship between injury and LET.

Case 9-2008: A 65-year-old woman with a nonhealing ulcer of the jaw

From the Departments of Oral and Maxillofacial Surgery (T.B.D.), Oncology (N.S.R.), Radiology (P.A.C.), and Pathology (A.E.R.), Massachusetts General Hospital; the Department of Radiology, Massachusetts Eye and Ear Infirmary (P.A.C.); the Department of Oral and Maxillofacial Surgery, Harvard School of Dental Medicine (T.B.D.); and the Departments of Oncology (N.S.R.), Radiology (P.A.C.), and Pathology (A.E.R.), Harvard Medical School.

Case records of the Massachusetts General Hospital. Case 9-2008. A 65-year-old woman with a nonhealing ulcer of the jaw.

From the Departments of Oral and Maxillofacial Surgery (T.B.D.), Oncology (N.S.R.), Radiology (P.A.C.), and Pathology (A.E.R.), Massachusetts General Hospital; the Department of Radiology, Massachusetts Eye and Ear Infirmary (P.A.C.); the Department of Oral and Maxillofacial Surgery, Harvard School of Dental Medicine (T.B.D.); and the Departments of Oncology (N.S.R.), Radiology (P.A.C.), and Pathology (A.E.R.), Harvard Medical School.

The neuroanatomical phenotype of tuberous sclerosis complex: focus on radial migration lines

IntroductionThe contribution of radial migration lines (RMLs) to the neuroanatomical and neurocognitive phenotype of tuberous sclerosis complex (TSC) is unclear. The aim of this study was to perform a comprehensive evaluation of the neuroradiological phenotype of TSC, distinguishing RMLs from normal-appearing white matter (NAWM) using diffusion tensor imaging (DTI) and volumetric fluid-attenuated inversion recovery imaging.MethodsMagnetic resonance images of 30 patients with TSC were evaluated. The frequencies of RMLs, tubers, and subependymal nodules (SENs) were determined for every hemispheric lobe. Cerebellar lesions and subependymal giant cell tumors were counted. DTI metrics were obtained from the NAWM of every hemispheric lobe and from the largest RML and tuber. Analyses of variance and correlations were performed to investigate the associations between neuroanatomical characteristics and relationships between RML frequency and neurocognitive outcomes. NAWM DTI metrics were compared with measurements of 16 control patients.ResultsA mean of 47 RMLs, 27 tubers, and 10 SENs were found per patient, and the frequencies of these lesions were strongly correlated (p < 0.001). RML fractional anisotropy and mean diffusivity were strongly inversely correlated (p = 0.003). NAWM DTI metrics were similar to the controls (p = 0.26). RML frequency was strongly associated with age of seizure onset (p = 0.003), intelligence outcomes (p = 0.01), and level of autistic features (p = 0.007).ConclusionA detailed neuroradiological phenotype is presented, showing that RMLs are the most frequent neuroanatomical lesion, are responsible for white matter DTI abnormalities, and are strongly associated with age of seizure onset, intelligence outcomes, and level of autistic features.

Case 24-2009 — A 26-Year-Old Woman with Painful Swelling of the Neck

Dr. John H. Stone: A 26-year-old woman was seen in the rheumatology clinic of this hospital because of painful swelling on both sides of the neck. She had been well until approximately 3 months earlier, when dry mouth and increased thirst developed. Two weeks later, submental swelling occurred that was associated with local tenderness, pain on swallowing (with solids more than with liquids), and decreased appetite. Approximately 4 weeks after the onset of symptoms, she saw a physician; cephalexin was prescribed, with no improvement. During the next 2 weeks, pain developed in both ears. Seven weeks before evaluation at this hospital, she went to the emergency department of the Massachusetts Eye and Ear Infirmary. On examination there, the vital signs were normal. Anterior rhinoscopy revealed a minimally deviated septum and mildly edematous turbinates. The submandibular glands were symmetrically enlarged, irregular, bosselated, and tender. There was mild discomfort in the temporomandibular joints, more on the left than on the right. The remainder of the physical examination and fiberoptic endoscopic inspection of the larynx were normal. The level of plasma sodium was 132 mmol per liter (reference range, 135 to 145); the results of other laboratory tests, including a complete blood count, levels of other electrolytes, and tests of liver and renal function, were normal. Computed tomography (CT) of the neck after the intravenous administration of contrast material showed prominently enhancing submandibular glands that were enlarged and prominently enhancing parotid glands, all of which appeared nodular. No sialoliths or sialodocholiths were observed. Periodontal disease was present in the tissue surrounding both third mandibular molars, which were partially impacted. Ibuprofen was prescribed, to be taken as needed. Ten days later, fine-needle aspiration of the left and right submandibular glands was performed. Cytologic examination revealed a paucicellular specimen with polymorphous lymphoid cells, normal salivary-gland tissue, and no malignant cells. Two weeks after the fine-needle aspiration, the patient was seen in the infectious disease clinic of this hospital. Additional history was obtained. She had been born in an urban area of Morocco and immigrated to the United States 22 months before presentation at this hospital; a chest radiograph was reportedly normal at Case 24-2009: A 26-Year-Old Woman with Painful Swelling of the Neck