A systematic review of the potential consequences of abnormal serum levels of vitamin B6 in people living with Parkinson's disease.

The prevalences of polyneuropathy and epilepsy are higher in people living with Parkinson's disease (PwPD) when compared to older adults. Vitamin B6 is widely available and affordable. PwPD are at higher risk of having abnormal serum levels of vitamin B6, which are associated with polyneuropathy and epilepsy that are potentially preventable and treatable. Potential contributors to abnormal B6 levels in PwPD include age, dietary habits, vitamin supplement misuse, gastrointestinal dysfunction and complex interactions with levodopa. The literature on the potential consequences of abnormal B6 levels in PwPD is limited by a small number of observational studies focused on polyneuropathy and epilepsy. Abnormal B6 levels have been reported in 60 of 145 PwPD (41.4% relative frequency). Low B6 levels were reported in 52 PwPD and high B6 levels were reported in 8 PwPD. There were 14 PwPD, polyneuropathy and low B6. There were 4 PwPD, polyneuropathy and high B6. There were 4 PwPD, epilepsy and low B6. Vitamin B6 level was low in 44.6% of PwPD receiving levodopa-carbidopa intestinal gel and in 30.1% of PwPD receiving oral levodopa-carbidopa. In almost all studies reporting low B6 in PwPD receiving oral levodopa-carbidopa, the dose of levodopa was ≥1000 mg/day. Rigorous epidemiological studies will clarify the prevalence, natural history and clinical relevance of abnormal serum levels of vitamin B6 in PwPD. These studies should account for diet, vitamin supplement use, gastrointestinal dysfunction, concurrent levels of vitamin B12, folate, homocysteine and methylmalonic acid, formulations and dosages of levodopa and other medications commonly used in PwPD.

Resection with intraoperative cesium-131 brachytherapy as salvage therapy for recurrent brain tumors.

OBJECTIVE: The authors' objective was to examine the safety and efficacy of salvage intracranial cesium-131 brachytherapy in combination with resection of recurrent brain tumors. METHODS: The authors conducted a retrospective chart review of consecutive patients treated with intraoperative intracranial cesium-131 brachytherapy at a single institution. Permanent suture-stranded cesium-131 seeds were implanted in the resection cavity after maximal safe tumor resection. The primary outcomes of interest were local, locoregional (within 1 cm), and intracranial control, as well as rates of overall survival (OS), neurological death, symptomatic adverse radiation effects (AREs), and surgical complication rate graded according to Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Between 2016 and 2020, 36 patients received 40 consecutive cesium-131 implants for 42 recurrent brain tumors and received imaging follow-up for a median (interquartile range [IQR]) of 17.0 (12.7-25.9) months. Twenty patients (55.6%) with 22 implants were treated for recurrent brain metastasis, 12 patients (33.3%) with 16 implants were treated for recurrent atypical (n = 7) or anaplastic (n = 5) meningioma, and 4 patients (11.1%) were treated for other recurrent primary brain neoplasms. All except 1 tumor (97.6%) had received prior radiotherapy, including 20 (47.6%) that underwent 2 or more prior radiotherapy treatments and 23 (54.8%) that underwent prior resection. The median (IQR) tumor size was 3.0 (2.3-3.7) cm, and 17 lesions (40.5%) had radiographic evidence of ARE prior to salvage therapy. Actuarial 1-year local/locoregional/intracranial control rates for the whole cohort and patients with metastases and meningiomas were 91.6%/83.4%/47.9%, 88.8%/84.4%/45.4%, and 100%/83.9%/46.4%, respectively. No cases of local recurrence of any histology (0 of 27) occurred after gross-total resection (p = 0.012, log-rank test). The 1-year OS rates for the whole cohort and patients with metastases and meningiomas were 82.7%, 79.1%, and 91.7%, respectively, and the median (IQR) survival of all patients was 26.7 (15.6-36.4) months. Seven patients (19.4%) experienced neurological death from progressive intracranial disease (7 of 14 total deaths [50%]), 5 (13.9%) of whom died of leptomeningeal disease. Symptomatic AREs were observed in 9.5% of resection cavities (n = 4), of which 1 (2.4%) was grade 3 in severity. The surgical complication rate was 16.7% (n = 7); 4 (9.5%) of these patients had grade 3 or higher complications, including 1 patient (2.4%) who died perioperatively. CONCLUSIONS: Cesium-131 brachytherapy resulted in good local control and acceptable rates of symptomatic AREs and surgical complications in this heavily pretreated cohort, and it may be a reasonable salvage adjuvant treatment for this patient population.

Essential statistical principles of clinical trials of pain treatments.

This article presents an overview of fundamental statistical principles of clinical trials of pain treatments. Statistical considerations relevant to phase 2 proof of concept and phase 3 confirmatory randomized trials investigating efficacy and safety are discussed, including (1) research design; (2) endpoints and analyses; (3) sample size determination and statistical power; (4) missing data and trial estimands; (5) data monitoring and interim analyses; and (6) interpretation of results. Although clinical trials of pharmacologic treatments are emphasized, the key issues raised by these trials are also directly applicable to clinical trials of other types of treatments, including biologics, devices, nonpharmacologic therapies (eg, physical therapy and cognitive-behavior therapy), and complementary and integrative health interventions.

Brachytherapy for meningiomas.

Interstitial intracranial radiotherapy implants, or brachytherapy, is an adjuvant option for treatment of recurrent high-grade meningiomas after resection. The implants are placed in the resection cavity following tumor resection. The most commonly used isotope is Iodine-125 (I-125). While there are no controlled studies comparing treatment of meningiomas with or without brachytherapy, several case series report good long-term survival, suggesting that this may be a useful adjuvant for recurrent high-grade tumors. Complications can occur including radiation necrosis, impaired wound healing, hydrocephalus and infection. In the future, new isotopes are being explored that may have fewer complications and better safety profiles.

Tic Disorders are Associated With Lower Child and Parent Quality of Life and Worse Family Functioning.

OBJECTIVE: Chronic tic disorders occur in approximately 3% of children. Neuropsychiatric symptoms of attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, anxiety, and depression are common. We evaluated the impact of tic disorders and comorbid symptoms on individual and parent quality of life and family functioning. METHOD: In two cross-sectional studies children with tic disorders were enrolled at the University of Rochester or the University of South Florida; data were pooled for analyses. Control subjects were enrolled at the University of Rochester. We compared quality of life and function in youth and families with and without tic disorders. We evaluated the associations between comorbid symptoms and individual quality of life and family impact in youth with tic disorders using multiple regression analyses. RESULTS: We enrolled 205 youths with tic disorders and 100 control subjects. Psychosocial (P < 0.0001) and physical (P < 0.0001) quality of life were lower in individuals with tic disorders compared with controls. Severity of attention-deficit/hyperactivity disorder (P < 0.0001) and depression (P = 0.046) symptoms were associated with lower psychosocial quality of life in youth with tic disorders. Families of youths with tic disorders had worse parent quality of life (P < 0.001) and family functioning (P < 0.001) than control families. Severity of attention-deficit/hyperactivity disorder (P < 0.0001), obsessive-compulsive disorder (P = 0.0004), and depression (P = 0.01) symptoms were associated with predicted worse family impact. CONCLUSION: Youths with tic disorders had lower individual and parent quality of life and worse family functioning than controls. The impact of tic disorders on the family may have significant implications for approaches to providing comprehensive care to these families.

Surgical Resection and Interstitial Iodine-125 Brachytherapy for High-Grade Meningiomas: A 25-Year Series.

BACKGROUND: Atypical and malignant meningiomas can recur despite resection and radiation. OBJECTIVE: To determine outcomes of patients with recurrent atypical or malignant meningioma treated with repeat resection and permanent iodine-125 ( 125 I) brachy-therapy. METHODS: Charts of patients who underwent surgical resection and 125 I brachyther-apy implantation for atypical and malignant meningiomas between 1988 and 2013 were retrospectively reviewed. The Kaplan-Meier actuarial method was used to calculate progression-free and overall survival. The log-rank test was used to compare groups. Significance was set at P < .05. RESULTS: Forty-two patients underwent 50 resections with 125 I brachytherapy im-plantations. All patients had undergone previous resections and 85% had previously undergone radiation. Median follow-up was 7.5 years after diagnosis and 2.3 years after brachytherapy. Median time to progression after resection with 125 I brachytherapy was 20.9 months for atypical meningioma, 11.4 months for malignant meningioma, and 11.4 months for the combined groups. Median survival after re-resection and 125 I brachytherapy was 3.5 years for atypical meningioma, 2.3 years for malignant menin-gioma, and 3.3 years for all subjects. Median overall survival after diagnosis was 11.1 years for atypical meningioma, 9.1 years for malignant meningioma, and 9.4 years for all subjects. Complications occurred in 17 patients and included radiation necrosis (n = 8, 16%), wound breakdown (n = 6, 12%), hydrocephalus (n = 4, 8%), infection (n = 3, 6%), and a pseudomeningocele (n = 2, 5%). CONCLUSION: This is the largest experience with adjuvant 125 I brachytherapy for recurrent high-grade meningiomas. The outcomes support the use of adjuvant brachytherapy as an option for these aggressive tumors.

A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease.

OBJECTIVE: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. METHODS: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. RESULTS: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. CONCLUSIONS: These data do not justify use of CoQ as a treatment to slow functional decline in HD. CLINICALTRIALSGOV IDENTIFIER: NCT00608881. CLASSIFICATION OF EVIDENCE: This article provides Class I evidence that CoQ does not slow the progressive functional decline of patients with HD.

Adverse event reporting in nonpharmacologic, noninterventional pain clinical trials: ACTTION systematic review.

Assessment of treatment safety is 1 of the primary goals of clinical trials. Organizations and working groups have created reporting guidelines for adverse events (AEs). Previous research examining AE reporting for pharmacologic clinical trials of analgesics in major pain journals found many reporting inadequacies, suggesting that analgesic trials are not adhering to existing AE reporting guidelines. The present systematic review documented AE reporting in 3 main pain journals for nonpharmacologic, noninterventional (NP/NI) trials examining pain treatments. To broaden our pool of nonpharmacologic trials, we also included trials examining acupuncture, leech therapy, and noninvasive stimulation techniques (eg, transcutaneous electrical nerve stimulation). We documented AE reporting at 2 levels of specificity using coding manuals based on the Consolidated Standards of Reporting Trials (CONSORT) harms reporting standards and Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) AE reporting checklist. We identified a number of inadequacies in AE reporting across the 3 journals. For example, using the ACTTION coding manual, we found that less than one-half of the trials reported specific AE assessment methods; approximately one-third of the trials reported withdrawals due to AEs for each study arm; and about one-fourth of the trials reported all specific AEs. We also examined differences in AE reporting across several trial characteristics, finding that AE reporting was generally more detailed in trials with patients versus those using healthy volunteers undergoing experimentally evoked pain. These results suggest that investigators conducting and reporting NP/NI clinical trials are not adequately describing the assessment and occurrence of AEs.

Deep arteriovenous malformations in the basal ganglia, thalamus, and insula: multimodality management, patient selection, and results.

OBJECTIVE: This study sought to describe a single institution's experience treating arteriovenous malformations (AVMs) of the basal ganglia, thalamus, and insula in a multimodal fashion. METHODS: We conducted a retrospective review of all deep AVMs treated at our institution between 1997 and 2011 with attention to patient selection, treatment strategies, and radiographic and functional outcomes. RESULTS: A total of 97 patients underwent initial treatment at our institution. 64% presented with hemorrhage with 29% located in the basal ganglia, 41% in the thalamus, and 30% in the insula. 80% were Spetzler-Martin grade III-IV. Initial treatment was microsurgical resection in 42%, stereotactic radiosurgery (SRS) in 45%, and observation in 12%. Radiographic cure was achieved in 54% after initial surgical or SRS treatment (71% and 23%, respectively) and in 63% after subsequent treatments, with good functional outcomes in 78% (median follow-up 2.2 years). Multivariate logistic regression analysis revealed treatment group and age as factors associated with radiographic cure, whereas Spetzler-Martin score and time to follow-up were significantly associated with improved/unchanged functional status at time of last follow-up. Posttreatment hemorrhage occurred in 11% (7% of surgical and 18% of SRS patients). CONCLUSIONS: Modern treatment of deep AVMs includes a multidisciplinary approach utilizing microsurgery, SRS, embolization, and observation. Supplementary grading adds meaningfully to traditional Spetzler-Martin grading to guide patient selection. Surgical resection is more likely to result in obliteration compared with SRS, and is associated with satisfactory results in carefully selected patients.

High-dosage ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A: results of a randomized, double-masked, controlled trial.

IMPORTANCE: No current medications improve neuropathy in subjects with Charcot-Marie-Tooth disease type 1A (CMT1A). Ascorbic acid (AA) treatment improved the neuropathy of a transgenic mouse model of CMT1A and is a potential therapy. A lower dosage (1.5 g/d) did not cause improvement in humans. It is unknown whether a higher dosage would prove more effective. OBJECTIVE: To determine whether 4-g/d AA improves the neuropathy of subjects with CMT1A. DESIGN: A futility design to determine whether AA was unable to reduce worsening on the CMT Neuropathy Score (CMTNS) by at least 50% over a 2-year period relative to a natural history control group. SETTING: Three referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins University, and University of Rochester). PARTICIPANTS: One hundred seventy-four subjects with CMT1A were assessed for eligibility; 48 did not meet eligibility criteria and 16 declined to participate. The remaining 110 subjects, aged 13 to 70 years, were randomly assigned in a double-masked fashion with 4:1 allocation to oral AA (87 subjects) or matching placebo (23 subjects). Sixty-nine subjects from the treatment group and 16 from the placebo group completed the study. Two subjects from the treatment group and 1 from the placebo group withdrew because of adverse effects. INTERVENTIONS: Oral AA (4 g/d) or matching placebo. MAIN OUTCOMES AND MEASURES: Change from baseline to year 2 in the CMTNS, a validated composite impairment score for CMT. RESULTS: The mean 2-year change in the CMTNS was -0.21 for the AA group and -0.92 for the placebo group, both better than natural history (+1.33). This was well below 50% reduction of CMTNS worsening from natural history, so futility could not be declared (P > .99). CONCLUSIONS AND RELEVANCE: Both treated patients and those receiving placebo performed better than natural history. It seems unlikely that our results support undertaking a larger trial of 4-g/d AA treatment in subjects with CMT1A. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00484510.

Cocaine-related attentional bias following trauma cue exposure among cocaine dependent in-patients with and without post-traumatic stress disorder.

AIMS: Although the co-occurrence of post-traumatic stress disorder (PTSD) and cocaine dependence is associated with a wide range of negative clinical outcomes, little is known about the mechanisms that underlie this association. This study investigated one potential mechanism-attentional bias to cocaine imagery following trauma cue exposure. DESIGN: Male and female cocaine-dependent in-patients with and without PTSD were exposed to both a neutral and personalized trauma script on separate days, followed by a visual dot-probe task. A 2 (PTSD versus non-PTSD) × 2 (neutral versus trauma script) × 2 (male versus female) design was used to examine hypotheses. SETTING: Participants were recruited from a residential substance use disorder (SUD) treatment center. PARTICIPANTS: Participants were 60 trauma-exposed cocaine dependent in-patients, 30 with current PTSD and 30 without a history of PTSD. MEASUREMENTS: Attentional bias was assessed using a visual dot-probe task depicting cocaine-related imagery following both a neutral script and personalized trauma script. FINDINGS: Following neutral script exposure, PTSD (versus non-PTSD) participants exhibited an attentional bias away from cocaine imagery. This effect was reversed following trauma script exposure, with PTSD participants exhibiting a greater attentional bias towards the location of cocaine imagery than non-PTSD participants. Severity of subjective distress following trauma script exposure predicted level of attentional bias among PTSD participants. CONCLUSIONS: Cocaine appears to serve an emotion-regulating function among post-traumatic stress disorder patients and may be a potential target for brief post-traumatic stress disorder-substance use disorder interventions that can facilitate residential substance use disorder treatment retention.

Identification of a new antinociceptive alkaloid isopropyl N-methylanthranilate from the essential oil of Choisya ternata Kunth.

ETHNOPHARMACOLOGICAL RELEVANCE: Mexican people employed infusion of leaves of Choisya ternata Kunth for their antispasmodic and "simulative properties". AIM OF THE STUDY: In the present study the detailed GC and GC-MS analyses of the essential oil of Choisya ternata Kunth (Rutaceae) were performed. The presence of a minor constituent isopropyl N-methylanthranilate (1) was revealed among other identified volatiles. A synthesis of 1 was undertaken in order to corroborate this find and obtain gram quantities that would allow the testing of its biological activity (peripheral and central antinociceptive activity). MATERIALS AND METHODS: The oils were investigated by GC and GC-MS. Synthesized compounds were spectrally characterized (UV-Vis, IR, 1D and 2D NMR, MS). The obtained synthetic samples of compounds were assayed for peripheral and central antinociceptive activity in two models (effects on acetic acid induced writhing in mice and the hot plate test for nociception). RESULTS: Detailed GC and GC-MS analyses of the essential oil of Choisya ternata Kunth (Rutaceae) among 157 other identified volatiles revealed the presence of a minor constituent isopropyl N-methylanthranilate (1). Compound 1, named ternanthranin, is therefore detected as a natural product for the first time with a very restricted occurrence (samples of several citrus oils were screened for the presence of 1). The antinociceptive activities were assayed for ternanthranin, the two other synthetic analogs, methyl and propyl N-methylanthranilate, as well as the essential oil and the crude ethanol extract of the leaves. The results clearly demonstrate a very high (even significant at 0.3 mg/kg) dose dependent activity for the anthranilates (and the extracts). Isopropyl N-methylanthranilate showed the highest, while methyl N-methylanthranilate showed the lowest activity (with the methyl ester at 3 mg/kg still better than acetylsalicylic acid, at 200 mg/kg, in the first, or comparable with morphine, at 5mg/kg, in the second test). CONCLUSION: This study once again revealed that detailed investigations of plant species with ethnopharmacologically documented activity may yield new natural compounds-a new alkaloid (ternanthranin), a volatile simple anthranilate that can be considered responsible for the antinociceptive activity of the crude plant extracts.

Safety and tolerability of high-dosage coenzyme Q10 in Huntington's disease and healthy subjects.

Coenzyme Q10 (CoQ(10)), a potential neuroprotective compound, was previously investigated at a dosage of 600 mg/day in Huntington's disease (HD) patients and demonstrated a trend toward slowing disease progression. Higher CoQ(10) dosages may prove beneficial. We investigated the tolerability and blood levels associated with 1,200, 2,400, and 3,600 mg/day of CoQ(10) in HD and healthy subjects. Twenty-eight subjects (20 HD, 8 healthy) enrolled in a 20-week open-label trial. Subjects started on 1,200 mg/day of CoQ(10), increasing every 4 weeks by 1,200 mg to a maximum dosage of 3,600 mg/day. Monthly evaluations included review of adverse events and CoQ(10) blood levels. Twenty-three subjects (82%) achieved the target dosage of 3,600 mg/day. Six subjects (2 healthy, 4 HD) withdrew prematurely (gastrointestinal (GI) symptoms in 3, worsening HD in 2, and 1 because of a fall). All three serious adverse events occurred in a single subject, and were deemed unrelated to CoQ(10). The most common adverse events seen were GI symptoms. Mean (± SD) CoQ10 blood levels achieved over the course of the trial were as follows: 1.26 ± 1.27 µg/mL (baseline, n = 28), 5.59 ± 2.24 µg/mL (1,200 mg/day, week 4, n = 26), 6.38 ± 3.25 µg/mL (2,400 mg/day, week 8, n = 25), 7.49 ± 4.09 µg/mL (3,600 mg/day, week 12, n = 23), and 6.78 ± 3.36 µg/mL (3,600 mg/day, week 20, n = 20). CoQ(10) was well tolerated with over 80% of subjects achieving the target dosage. Dosages of 2,400 mg/day may provide the best balance between tolerability and blood level achieved. Further studies examining the efficacy of 2,400 mg/day are planned.

Adjunctive chemotherapeutic suppression of mutans streptococci in the setting of severe early childhood caries: an exploratory study.

OBJECTIVES: This investigational study assessed the suppressive effect of 10 percent povidone iodine (PI) coupled with elimination of active carious lesions on salivary mutans streptococci (MS) populations in children with severe early childhood caries (S-ECC). METHODS: 77 children (38 females, 39 males) were treated for S- ECC in one session; a 0.2 ml PI solution was applied to the dentition after dental surgery was completed and immediately wiped off. The subjects aged from 2 to 5 years (mean = 3.78 years) at baseline. Whole nonstimulated saliva samples were obtained at baseline, 30 days, 60 days, and 90 days post dental surgery. Samples were placed on ice and processed within 2 hours. The MS level in each sample was expressed as colony forming units (CFUs) per ml of saliva. RESULTS: Approximately 50 percent of subjects had a >95 percent reduction in CFU/ml of saliva at each time point after baseline. The percentages of subjects with a >50 percent reduction in MS level were 85 percent at 30 days, 83 percent at 60 days, 84 percent at 90 days. The median (25th, 75th percentiles) CFUs/ml of saliva counts were 8.40 x 10(5) (1.49 x 10(5), 5.00 x 10(6)) at baseline (n= 77), 4.12 x 10(4) (8.40 x 10(3), 1.89 x 10(5)) at 30 days (n = 74), 4.62 x 10(4) (7.00 x 10(3), 1.36 x 10(5)) at 60 days (n = 70), and 5.09 x 10(4) (1.16 x 10(4), 1.00 x 10(5)) at 90 days (n = 70). The changes from baseline to 30 days, 60 days, and 90 days were statistically significant (P < 0.0001). CONCLUSIONS: PI coupled with dental surgery has a significant suppressive effect on salivary MS levels in the setting of S-ECC for at least 90 days. These data strongly suggest that treatment with PI may be an important adjunct to dental surgery for S-ECC.

Surgical resection and permanent iodine-125 brachytherapy for brain metastases.

PURPOSE: To evaluate the efficacy and toxicity of surgical resection and permanent iodine-125 brachytherapy without adjuvant whole brain radiation therapy (WBRT) for brain metastases. METHODS AND MATERIALS: Forty patients were treated with permanent iodine-125 brachytherapy at the time of resection of brain metastases from 1997 to 2003. Actuarial freedom from progression (FFP) and survival were measured from the date of surgery and estimated using the Kaplan-Meier method, with censoring at last imaging for FFP endpoints. RESULTS: The median survival was 11.3 months overall, 12.0 months in 19 patients with newly diagnosed brain metastases and 7.3 months in 21 patients with recurrent brain metastases. Twenty-two patients (55%) remained free of progression of brain metastases, three failed at the resection cavity (including one with leptomeningeal dissemination), two failed with leptomeningeal spread only, and 13 failed elsewhere in the brain including two who also had leptomeningeal disease. The 1-year resection cavity FFP probabilities were 92%, 86% and 88%; and brain FFP probabilities were 29%, 43% and 37% for the newly diagnosed, recurrent and all patients, respectively. Symptomatic necrosis developed 7.4-40.0 months (median, 19.5 months) after brachytherapy in 9 patients (23%), confirmed by resection in 6 patients. CONCLUSIONS: Excellent local control was achieved using permanent iodine-125 brachytherapy for brain metastasis resection cavities, although there is a high risk of radiation necrosis over time. These data support consideration of permanent brachytherapy without adjuvant WBRT as a treatment option in patients with symptomatic or large newly diagnosed or recurrent brain metastases.

Transcerebellar stereotactic biopsy for lesions of the brainstem and peduncles under local anesthesia.

OBJECTIVE: For certain brainstem lesions, a diagnostic biopsy is required for treatment planning. We reviewed the indications, safety, and diagnostic effectiveness of a transcerebellar stereotactic biopsy using local anesthesia and sedation. METHODS: We retrospectively reviewed hospital records for all adult patients with symptomatic lesions of the pons and/or cerebellar peduncle who underwent an awake transcerebellar stereotactic biopsy at our institution over a 7-year period. Our technique features several modifications from the standard method and was performed under local anesthesia with patients in the semi-sitting position. RESULTS: Our rate of diagnostic success (92%) was comparable to those in other published reports. However, only 5 (42%) of 12 biopsy-derived diagnoses were consistent with those predicted from preoperative magnetic resonance imaging. There were no deaths, and the only neurological complication was a cranial nerve palsy. Diagnoses in the 13 cases included infiltrative glioma (), metastases (), lymphoma (), encephalitis (), and reactive astrogliosis (). CONCLUSION: Tissue diagnosis of lesions in the brainstem and cerebellar peduncles continues to be a significant challenge, with the potential for major morbidity. With appropriate patient selection, however, awake transcerebellar biopsy is a safe and effective procedure that can change clinical management and provide important prognostic information.

Effects of L-isoleucine and L-valine on hot flushes and serum homocysteine: a randomized controlled trial.

OBJECTIVE: To investigate whether L-isoleucine was effective in the treatment of hot flushes and whether L-isoleucine, L-valine, or the combination of both amino acids reduced fasting serum homocysteine. METHODS: After a 1-week baseline period, 100 postmenopausal women experiencing at least five moderate-severe hot flushes per day were randomized with equal probability to one of four groups (phase 1/phase 2): placebo/L-valine, placebo/L-valine and L-isoleucine, L-isoleucine/L-valine, and L-isoleucine/L-valine and L-isoleucine. Phase 1 was 12 weeks long, and phase 2 was 10 weeks long. Patients took five capsules by mouth, twice a day throughout the study, with each capsule containing 500 mg of compound. Data were obtained from daily hot flush diaries, fasting blood work, and several questionnaires. The primary outcome variable was the percent change in hot flush composite score from baseline to week 12. RESULTS: In phase 1 of the study, there were no significant differences between the L-isoleucine and placebo groups for any of the outcome measures. At week 12, there was a mean 13.9% decrease in hot flush composite score compared with baseline in the L-isoleucine group and a mean 25% decrease in the placebo group (P=.28). In phase 2 of the study, there was no significant change in fasting serum homocysteine levels associated with any of the amino acid therapies. CONCLUSION: L-isoleucine therapy appears to be ineffective in the treatment of hot flushes in postmenopausal women. L-isoleucine and L-valine, either alone or in combination, appear to have no effect on fasting serum homocysteine levels. CLINCIAL TRIAL REGISTRATION: ClinicalTrials.gov, (www.clinicaltrials.gov), NCT00081952. LEVEL OF EVIDENCE: I.

Prevalence of vitamin D insufficiency in elderly ambulatory outpatients in Denver, Colorado.

BACKGROUND: Vitamin D insufficiency is common in the elderly. However, previous studies have utilized 25-hydroxvvitamin D (25[OH]D) concentrations as low as <16 ng/mL for defining vitamin D insufficiency. Moreover, most of the studies have been conducted in European patients, in certain geographic areas of the United States, or in institutionalized elderly. OBJECTIVE: The goal of this study was to characterize vitamin D concentrations in ambulatory elderly living in metropolitan Denver, Colorado, utilizing 25(OH)D concentrations <32 ng/mL as the definition for vitamin D insufficiency. METHODS: Ambulatory older adults (aged 65-89 years) with clinic visits during December 2005 and January 2006 were enrolled. Serum concentrations of 25(OH)D, parathyroid hormone (PTH), calcium, phosphorus, creatinine, and albumin were measured; height and weight were also measured. Data regarding dietary and over-the-counter vitamin D intake were collected, as well as information on body mass index, history of osteoporosis, osteoporosis treatment, and history of falls and fractures. RESULTS: Eighty patients (mean [SD] age, 77.8 [5.3] years; age range, 66-89 years) completed the study; there were no dropouts. The majority of patients were white (88%) and female (68%). Fifty-nine (74%) were found to have vitamin D insufficiency. Mean total and over-the-counter vitamin D intake was significantly higher in sufficient (P < 0.01) and insufficient (P < 0.05) patients compared with deficient patients, but dietary intake did not differ significantly between groups. The majority of patients who were vitamin D insufficient consumed more than the recommended 400 to 600 IU/d of vitamin D. Obese patients were found to have significantly lower 25(OH)D concentrations (P < 0.001) and higher PTH concentrations (P = 0.04) than nonobese patients. CONCLUSIONS: Vitamin D insufficiency is prevalent in ambulatory, and especially obese, elderly living in Denver, Colorado, despite vitamin D intake consistent with national recommendations. Dietary intake of vitamin D appeared to be unreliable to prevent insufficiency. Based on our results, along with other published data, we feel that national recommendations for vitamin D intake in the elderly should be increased to at least 800 to 1000 IU/d of over-the-counter supplemental cholecalciferol.

Neuroradiographic changes following convection-enhanced delivery of the recombinant cytotoxin interleukin 13-PE38QQR for recurrent malignant glioma.

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.