Ilona M. Schmalfuss

Preradiotherapy computed tomography as a predictor of local control in supraglottic carcinoma

PURPOSE To determine the utility of pretreatment computed tomography (CT) for predicting primary site control in patients with supraglottic squamous cell carcinoma (SCC) treated with definitive radiotherapy (RT). MATERIALS AND METHODS Pretreatment CT studies in 63 patients were reviewed. Minimum length of follow-up was 2 years. Local recurrence and treatment complications resulting in permanent loss of laryngeal function were documented. Tumor volume was calculated using a computer digitizer, and pre-epiglottic space (PES) spread was estimated. The data were analyzed using a combination of Fishers exact test, logistic regression modeling, and multivariate analyses. Five-year local control rates were calculated using the product-limit method. RESULTS Local control rates were inversely and roughly linearly related to tumor volume, although there seemed to be a threshold volume at which primary site prognosis diminished. Local control was 89% in tumors less than 6 cm3 and 52% when volumes were > or =6 cm3 (P = .0012). The likelihood of maintaining laryngeal function also varied with tumor volume: 89% for tumors less than 6 cm3 and 40% for tumors > or =6 cm3 (P = .00004). Pre-epiglottic space involvement by tumor of > or =25% was associated with a reduced chance of saving the larynx (P = .0076). Multivariate analyses revealed that only tumor volume independently altered these end points. CONCLUSION Pretreatment CT measurements of tumor volume permits stratification of patients with supraglottic SCC treated with RT alone (which allows preservation of laryngeal function) into groups in which local control is more likely and less likely. Pre-epiglottic space spread is not a contraindication to using RT as the primary treatment for supraglottic SCC.

Intracranial abnormalities detected by three-dimensional magnetic resonance imaging in Prader–Willi syndrome†

The neuropathologic abnormalities associated with Prader–Willi syndrome (PWS) are largely unknown. PWS is due to the loss of several paternally expressed genes in chromosome 15q11‐q13 region. Several of the imprinted genes in the 15q11‐q13 region are normally expressed in the brain and thought to be necessary for neuronal growth and development. Thus, we hypothesized that we would find abnormalities in gray and white matter growth in individuals with PWS. We evaluated three‐dimensional (3‐D) MRI scans of 20 individuals with PWS, aged three months to 39 years, and compared them to 3‐D MRI scans of 21 normal weight sibling controls and 16 individuals with early‐onset morbid obesity (EMO) of unknown etiology. The interpreters of the scans were blinded to the diagnosis of the subjects. Intracranial abnormalities in individuals with PWS included ventriculomegaly (100% of individuals), decreased volume of brain tissue in the parietal‐occipital lobe (50%), sylvian fissure polymicrogyria (60%), and incomplete insular closure (65%). None of the EMO or normal weight control subjects had any of these findings. We found multiple morphologic brain abnormalities in subjects with PWS suggesting that the loss of paternally expressed genes in chromosome 15q11‐q13 region may result in abnormalities of neuronal development. The specific mechanisms underlying these neuropathological abnormalities and their correlation with the clinical phenotype remain to be elucidated.

The Poor Prognosis of Central Nervous System Cryptococcosis among Nonimmunosuppressed Patients: A Call for Better Disease Recognition and Evaluation of Adjuncts to Antifungal Therapy

We describe 9 nonimmunosuppressed patients with central nervous system cryptococcosis. Morbidity and mortality were high, especially among patients with cerebral infarcts. This was attributed to delayed diagnosis and apparent sequelae of overwhelming host immune responses. We present clues suggesting the diagnosis. Increased recognition and timely diagnosis of this condition may improve outcomes.

Contrast-Enhanced MR Imaging of Brain Lesions: A Large-Scale Intraindividual Crossover Comparison of Gadobenate Dimeglumine versus Gadodiamide

BACKGROUND AND PURPOSE: The higher relaxivity of gadobenate dimeglumine compared with gadodiamide is potentially advantageous for contrast-enhanced brain MR imaging. This study intraindividually compared 0.1-mmol/kg doses of these agents for qualitative and quantitative lesion enhancement. MATERIALS AND METHODS: Adult patients with suggested or known brain lesions underwent 2 identical MR imaging examinations at 1.5T, one with gadobenate dimeglumine and the other with gadodiamide. The agents were administered in randomized order separated by 3–14 days. Imaging sequences and postinjection acquisition timing were identical for the 2 examinations. Three blinded readers evaluated images qualitatively for diagnostic information (lesion extent, delineation, morphology, enhancement, and global preference) and quantitatively for contrast-to-noise ratio (CNR). RESULTS: One hundred thirteen of 138 enrolled patients successfully underwent both examinations. Final diagnoses were intra-axial tumor, metastasis, extra-axial tumor, or other (47, 27, 18, and 21 subjects, respectively). Readers 1, 2, and 3 demonstrated global preference for gadobenate dimeglumine in 63 (55.8%), 77 (68.1%), and 73 (64.6%) patients, respectively, compared with 3, 2, and 3 patients for gadodiamide (P < .0001, all readers). Highly significant (P < .0001, all readers) preference for gadobenate dimeglumine was demonstrated for all qualitative end points and for CNR (increases of 23.3%–34.7% and 42.4%–48.9% [spin-echo and gradient-refocused echo sequences, respectively] for gadobenate dimeglumine compared with gadodiamide). Inter-reader agreement was good for all evaluations (κ = 0.47–0.69). Significant preference for gadobenate dimeglumine was demonstrated for all lesion subgroup analyses. CONCLUSION: Significantly greater diagnostic information and lesion enhancement are achieved on brain MR imaging with 0.1-mmol/kg gadobenate dimeglumine compared with gadodiamide at an equivalent dose.

Performance monitoring, error processing, and evaluative control following severe TBI.

Patients with severe traumatic brain injury (TBI) often demonstrate impairments in performance monitoring--an evaluative control process that can be measured using the error-negativity/error-related negativity (Ne/ERN) and post-error positivity (Pe). The Ne/ERN and Pe are event-related potential (ERP) components generated following errors, with current theories suggesting the Ne/ERN reflects automatic performance monitoring and the Pe reflects error processing and awareness. To elucidate the electrophysiological mechanisms of performance monitoring deficits following severe TBI, behavioral and ERP measurements were obtained, whereas participants with severe TBI and neurologically-healthy comparison participants performed a modified color-naming version of the Stroop task. Behaviorally, both groups demonstrated robust response-time (RT) and error-rate interference. Participants with TBI exhibited generalized RT slowing; no significant between-groups interactions were present for RTs or error rates. ERP results indicate Ne/ERN amplitude was attenuated in participants with TBI, whereas the pattern of Pe amplitude did not clearly differentiate groups. Findings suggest the Ne/ERN as a potential electrophysiological marker of evaluative control/performance monitoring impairment following TBI. Implications for future research and potential clinical application as well as potential limitations in conducting electrophysiological research in neurologically-impaired populations are discussed.

Pituitary abnormalities in Prader–Willi syndrome and early onset morbid obesity†

Prader–Willi syndrome (PWS) is a well‐defined syndrome of childhood‐obesity which can serve as a model for investigating early onset childhood obesity. Many of the clinical features of PWS (e.g., hyperphagia, hypogonadotropic hypogonadism, growth hormone deficiency) are hypothesized to be due to abnormalities of the hypothalamus and/or pituitary gland. Children who become severely obese very early in life (i.e., before age 4 years) may also have a genetic etiology of their obesity, perhaps with associated neuroendocrine and hypothalamo‐pituitary defects, as infants and very young children have limited access to environmental factors that contribute to obesity. We hypothesized that morphologic abnormalities of the pituitary gland would be seen in both individuals with PWS and other subjects with early onset morbid obesity (EMO). This case‐control study included individuals with PWS (n = 27, age 3 months to 39 years), patients with EMO of unknown etiology (n = 16, age 4–22 years; defined as body mass index greater than the 97th centile for age before age 4 years), and normal weight siblings (n = 25, age 7 months to 43 years) from both groups. Participants had 3‐dimensional magnetic resonance imaging to evaluate the pituitary gland, a complete history and physical examination, and measurement of basal pituitary hormones. Subjects with PWS and EMO had a higher prevalence of pituitary morphological abnormalities than did control subjects (74% PWS, 69% EMO, 8% controls; P < 0.001). Anterior pituitary hormone deficiencies were universal in individuals with PWS (low IGF‐1 in 100%, P < 0.001 PWS vs. controls; central hypothyroidism in 19%, P = 0.052, and hypoplastic genitalia or hypogonadotropic hypogonadism in 100%, P < 0.001), and was often seen in individuals with EMO (6%, P = 0.89 vs. control, 31%, P = 0.002, and 25%, P = 0.018, respectively). The presence of a hypoplastic pituitary gland appeared to correlate with the presence of anterior pituitary hormone deficiencies in individuals with EMO, but no correlation was apparent in individuals with PWS. In conclusion, the high frequency of both morphological and hormonal abnormalities of the pituitary gland in both individuals with PWS and EMO suggests that abnormalities in the hypothalamo‐pituitary axis are features not only of PWS, but also frequently of EMO of unknown etiology.

Aceruloplasminaemia with progressive atrophy without brain iron overload: treatment with oral chelation

Background: Hereditary aceruloplasminaemia is a disorder of iron metabolism that is characterised by iron accumulation in the brain and other visceral organs. In previously reported cases, individuals with the disorder were noted to have evidence of iron accumulation in the brain. Oral chelating agents have not been used in neurological diseases of iron metabolism. Methods: A 54-year-old woman who presented with ataxia, lower extremity spasticity and chorea was evaluated for evidence of the source of neurological dysfunction. Results: Blood studies revealed no detectable ceruloplasmin. Marked iron overload was defined by a liver biopsy, which showed a variegated pattern consistent with a primary cause of iron overload. Review of MRI scans showed progressive brain atrophy without visible iron accumulation occurring over a 5-year period. The history suggested that neurodegeneration was coincident with aggressive oral iron replacement. Oral chelation improved many symptoms. Conclusions: Our findings in this patient suggest that disorders of iron transport such as aceruloplasminaemia can be a cause of neurological symptoms such as chorea and cognitive decline, as well as progressive neurodegeneration in the absence of visible iron on MRI scans. We found that oral iron chelation was effective at improving symptoms.

Contouring the Middle and Inner Ear on Radiotherapy Planning Scans

The purpose of this study was to establish guidelines that help radiation oncologists contour the inner and middle ear on treatment planning scans. The radiotherapy computed tomography (CT) scans of 15 previously treated patients were reviewed for the ability to identify 3 separate auditory structures. The middle ear, the cochlea, and the vestibular apparatus were identified and contoured on each scan using anatomic landmarks. The volume and maximum axial dimension of each contour were calculated. The middle ear, cochlea, and vestibular apparatus were identified on all scans. The middle ear was defined by the tympanic membrane laterally and by the interface between air and the temporal bone in all other directions. The plane of the internal auditory canal through the temporal bone was the landmark distinguishing the vestibular apparatus from the cochlea. The mean volume of the middle ear, vestibular apparatus, and cochlea were 0.58 cm3, 0.44 cm3, and 0.14 cm3, respectively. The maximum axial dimension across the contour averaged 1.57 cm for the middle ear, 1.10 cm for the vestibular apparatus, and 0.69 cm for the cochlea. A reference atlas was constructed that shows the contour of each structure on 5 consecutive CT images. Accurate identification of the middle ear and inner ear structures on radiotherapy planning scans is possible and is necessary if critical auditory organs are to be spared during radiotherapy of targets that are located near the base of the skull. The information generated in this study will help radiation oncologists contour auditory structures accurately.

A pilot study evaluating presurgery neuroanatomical biomarkers for postoperative cognitive decline after total knee arthroplasty in older adults.

Background:Total knee arthroplasty improves quality of life but is associated with postoperative cognitive dysfunction in older adults. This prospective longitudinal pilot study with a parallel control group tested the hypotheses that (1) nondemented adults would exhibit primary memory and executive difficulties after total knee arthroplasty, and (2) reduced preoperative hippocampus/entorhinal volume would predict postoperative memory change, whereas preoperative leukoaraiosis and lacunae volumes would predict postoperative executive dysfunction. Methods:Surgery (n = 40) and age–education-matched controls with osteoarthritis (n = 15) completed pre- and postoperative (3 weeks, 3 months, and 1 yr) memory and cognitive testing. Hypothesized brain regions of interest were measured in patients completing preoperative magnetic resonance scans (surgery, n = 31; control, n = 12). Analyses used reliable change methods to identify the frequency of cognitive change at each time point. Results:The incidence of postoperative memory difficulties was shown with delay test indices (i.e., story memory test: 3 weeks = 17%, 3 months = 25%, 1 yr = 9%). Postoperative executive difficulty with measures of inhibitory function (i.e., Stroop Color Word: 3 weeks = 21%, 3 months = 22%, 1 yr = 9%). Hierarchical regression analysis assessing the predictive interaction of group (surgery, control) and preoperative neuroanatomical structures on decline showed that greater preoperative volumes of leukoaraiosis/lacunae were significantly contributed to postoperative executive (inhibitory) declines. Conclusions:This pilot study suggests that executive and memory declines occur in nondemented adults undergoing orthopedic surgery. Severity of preoperative cerebrovascular disease may be relevant for understanding executive decline, in particular.

Radiotherapy and concomitant intraarterial cisplatin (RADPLAT) for advanced squamous cell carcinomas of the head and neck.

Purpose:Review of the University of Florida experience in treating advanced squamous cell carcinomas of the head and neck with concurrent intraarterial cisplatin and radiotherapy (RADPLAT). Patients and Methods:Thirty-five patients with Stage III or IV head and neck squamous cell carcinomas were treated between November 2000 and October 2001 with 3 to 4 cycles of weekly intraarterial cisplatin (150 mg/m2) and a rapid infusion of the neutralizing agent sodium thiosulfate (9 g/m2), followed by a continuous infusion of sodium thiosulfate (12 g/m2), with concomitant radiotherapy (RT). The primary site was treated with 70 Gy in 35 fractions with 6 MV photons, and the low neck received 50 to 70 Gy depending on nodal involvement. Median follow-up for all patients was 4.06 years; median follow-up for living patients was 4.34 years. Results:The 4-year outcomes were: local-regional control, 78%; distant metastasis-free survival, 83%; cause-specific survival, 65%; and survival, 57%. The majority of patients with recurrent disease failed at the primary site (73%); the remaining 27% of patients with recurrent disease failed only in distant sites. Nine patients required a neck dissection after chemoradiation because of suspected residual disease; 2 of 9 patients had residual tumor in the neck nodes. Severe osteoradionecrosis occurred in 26% of patients, and 9 of 35 patients (26%) required a permanent gastrostomy. Conclusions:RADPLAT results in excellent local-regional control and survival in patients with advanced squamous cell carcinomas of the head and neck. Outcomes from the University of Florida are comparable to those reported by other institutions. However, in our limited experience, the likelihood of osteoradionecrosis and permanent gastrostomy may be higher than what might be anticipated after RT alone or combined with intravenous chemotherapy.