"Valve-In-Valve" aórtico em bioprótese com fratura de folheto / Aortic "Valve-In-Valve" in bioprosthesis with leaflet fracture

INTRODUÇÃO: As biopróteses possuem durabilidade aproximada de 12 a 20 anos. Neste período, complicações relacionadas à degeneração protética podem exigir novas intervenções. Mas o elevado risco de uma reoperação, principalmente se o paciente estiver clinicamente descompensado, tornam a cirurgia convencional muito arriscada ou mesmo proibitiva. Neste cenário, o implante valvar dentro da bioprótese degenerada (valve in valve) se mostrou como opção alternativa e viável. Relatamos um caso de correção de insuficiência aórtica grave por falência estrutural de bioprótese através de valve in valve (ViV) com sucesso em paciente gravemente descompensado. DESCRIÇÃO DO CASO: Homem, 66 anos, hipertenso, implante de bioprótese aórtica e plastia mitral em 2011, devido dupla lesão aórtica e mitral, sem seguimento clínico. Procurou o pronto socorro por dispnéia aos mínimos esforços e anasarca há uma semana. Admitido em IC perfil B. Após tratamento com diuréticos, o ecocardiograma transtorácico (ecoTT) revelou: aumento atrial esquerdo importante (volume indexado de 96 mL/m²); fração de ejeção do VE (FEVE) de 45% - Simpson; bioprótese aórtica apresentava folhetos com hipermobilidade e prolapso, sugestivos de fratura, com refluxo importante, gradiente sistólico (GS) máximo de 69 mmHg, GS médio de 36mmHg e área valvar (AV) de 1,3 cm2. Valva mitral com aspecto de plastia exibindo refluxo de grau importante. Internado para programação cirúrgica a princípio, mas após discussão com Heart Team, e considerando STS de 27 %, indicada a realização de "Valve-in-valve". A angiotomografia com parâmetros anatômicos adequados para o tratamento percutâneo. Procedimento realizado com técnica simplificada e otimizada ("minimalista"), sob sedação. Gradientes pré implante de prótese: VE 120 x 15 mmHg e Aorta 100 x 30 mmHg. Implante de bioprótese Myval 20 e pós dilatação com cateter balão ATLAS GOLD 22 x 40mm com sucesso conforme parâmetros do ecoTT. Após implante valvar, novos gradientes foram adquiridos: VE 130 x 15 mmHg e Aorta 128 x 70 mmHg. Paciente evoluiu com melhora clínica significativa. EcoTT do 1o dia pós procedimento revelou refluxo mitral de grau discreto a moderado e ausência de refluxo aórtico, gradiente GS máximo 21 mmHg, GS médio 11 mmHg, AV 1,4 cm2. O paciente demostrou melhora rápida de sua classe funcional (CF I). CONCLUSÃO: No caso descrito, a realização de "Valve-in-valve" após complicação estrutural de bioprótese constituiu tratamento seguro, efetivo e alternativa à intervenção cirúrgica convencional.

Usability of daily SF36 questionnaires to capture the QALD variation experienced after vaccination with AS03A-adjuvanted monovalent influenza A (H5N1) vaccine in a safety and tolerability study.

BACKGROUND: This study aims to describe the short-term reactogenicity of the AS03-adjuvanted H5N1 vaccine expressed through adverse events (AEs) and quality-adjusted life-day (QALD) scores. The AEs are likely to be short-term and therefore the quality of life (QoL) questionnaire, SF-36v2, was administered daily to record changes over seven days. A more sensitive application of this instrument should allow for a better understanding of short-term tolerability of adjuvanted vaccines. METHODS: Participants (N = 50) received a 2-dose vaccination schedule. Solicited (collected daily: days 0 to 7 [post dose 1] and 21 to 28 [post dose 2]) and unsolicited (collected weekly until day 21) AEs were collected via diary cards. The QoL questionnaires were completed daily (days 0-6) and weekly (days 0, 6, 21, 27) after dose one. Questionnaire data were transformed into SF-6D scores to report QALDs. It was hypothesized post-hoc that the QALD and daily AEs scores should correlate if discrete QoL-changes were captured. RESULTS: Pain (92%) and muscle ache (66%) were the most commonly reported solicited local and general AEs respectively, neither increased in intensity nor in frequency after dose 2. No safety concerns were identified during the study. A correlation between the daily AEs and QALD scores existed (correlation coefficient, - 0.97 (p < 0.001)). The impact of the AEs scores on the QALD was marginal (- 0.02 max for one day). CONCLUSION: Similarly with other H5N1 studies, no safety concern was identified throughout the study. Some time-limited variations in QALD-scores were reported. Our results imply that daily administration of the SF-36v2 captures changes in QALD-scores. TRIAL REGISTRATION: ClinicalTrials.gov . NCT01788228. Registered 11 February 2013.

Cirrhotic cardiomyopathy: the liver affects the heart.

Cirrhotic cardiomyopathy historically has been confused as alcoholic cardiomyopathy. The key points for diagnosis of cirrhotic cardiomyopathy have been well explained, however this entity was neglected for a long time. Nowadays the diagnosis of this entity has become important because it is a factor that contributes significantly to morbidity-mortality in cirrhotic patients. Characteristics of cirrhotic cardiomyopathy are a hyperdynamic circulatory state, altered diastolic relaxation, impaired contractility, and electrophysiological abnormalities, particularity QT interval prolongation. The pathogenesis includes impaired function of beta-receptors, altered transmembrane currents and overproduction of cardiodepressant factors, such as nitric oxide, cytokines and endogenous cannabinoids. In addition to physical signs of hyperdynamic state and heart failure under stress conditions, the diagnosis can be done with dosage of serum markers, electrocardiography, echocardiography and magnetic resonance. The treatment is mainly supportive, but orthotopic liver transplantation appears to improve this condition although the prognosis of liver transplantation in patients with cirrhotic cardiomyopathy is uncertain.

Cirrhotic cardiomyopathy: the liver affects the heart

Cirrhotic cardiomyopathy historically has been confused as alcoholic cardiomyopathy. The key points for diagnosis of cirrhotic cardiomyopathy have been well explained, however this entity was neglected for a long time. Nowadays the diagnosis of this entity has become important because it is a factor that contributes significantly to morbidity-mortality in cirrhotic patients. Characteristics of cirrhotic cardiomyopathy are a hyperdynamic circulatory state, altered diastolic relaxation, impaired contractility, and electrophysiological abnormalities, particularity QT interval prolongation. The pathogenesis includes impaired function of beta-receptors, altered transmembrane currents and overproduction of cardiodepressant factors, such as nitric oxide, cytokines and endogenous cannabinoids. In addition to physical signs of hyperdynamic state and heart failure under stress conditions, the diagnosis can be done with dosage of serum markers, electrocardiography, echocardiography and magnetic resonance. The treatment is mainly supportive, but orthotopic liver transplantation appears to improve this condition although the prognosis of liver transplantation in patients with cirrhotic cardiomyopathy is uncertain.

Bleeding pattern and cycle control of a low-dose transdermal contraceptive patch compared with a combined oral contraceptive: a randomized study.

OBJECTIVE(S): The aim of this study was to investigate the bleeding pattern and cycle control of a contraceptive patch containing 0.55 mg ethinyl estradiol (EE) and 2.1 mg gestodene (GSD) compared with a combined oral contraceptive (COC) containing 0.02 mg EE and 0.1 mg levonorgestrel (LNG). STUDY DESIGN: In this phase III, randomized, controlled, double-blind, double-dummy, multicenter trial, healthy women aged 18-45 years (smokers aged 18-35 years) received either the EE/GSD patch and a placebo tablet (n=171), or a placebo patch and the COC (n=175) for seven 28-day cycles. Bleeding control was assessed in two 90-day reference periods. RESULTS: Mean number of bleeding/spotting days was comparable across treatment groups in both reference periods (p>.05). Mean number of bleeding/spotting episodes was also comparable in reference period 1; however, there were fewer bleeding/spotting episodes for COC in reference period 2 (3.4 versus 3.1; p=.01). Mean length of bleeding/spotting episodes was comparable across treatment groups for both reference periods (p>.05). Withdrawal bleeding occurred consistently in both groups over the entire treatment period, but its absence was more common in the COC group in cycles 4 and 6 of reference period 2 (p<.01). Intracyclic bleeding was comparable between groups. CONCLUSION(S): Bleeding pattern and cycle control with the EE/GSD patch was comparable to an EE/LNG-containing COC. IMPLICATIONS STATEMENT: The findings suggest that bleeding patterns with the EE/GSD patch are similar to an EE/LNG-containing COC, except for absence of withdrawal bleeding, which was less common in patch users. The EE/GSD patch may constitute an additional contraceptive option for women.

Clinical utility of ultrasound versus magnetic resonance imaging for deciding to proceed with uterine artery embolization for presumed symptomatic fibroids.

AIM: To compare the diagnostic utility of pelvic ultrasound (US) and magnetic resonance imaging (MRI) on the clinical decision to proceed with uterine artery embolization (UAE). MATERIALS AND METHODS: Over 2 years, 180 consecutive women (mean age 43) sought consultation for UAE, 116 underwent pelvic US and MRI before possible UAE. US was performed prior to MRI. Imaging was analysed for leiomyoma quantity, size and location, uterine volume, and the presence of potential contraindications to UAE. Discrepancies between imaging methods and cases where discrepancies could have altered management, were recorded. RESULTS: For the 116 patients who completed imaging, the average uterine volume was 701 cm(3) using MRI versus 658 cm(3) using US (p=0.48). The average dominant leiomyoma volume was 292 cm(3) using MRI versus 253 cm(3) using US (p=0.16). In 14 (12.1%) patients US did not correctly quantify or localize leiomyomas compared with MRI (p=0.0005). Thirteen patients did not undergo UAE (patient preference n=9, pre-procedural imaging findings n=4). In the four cases where UAE was not performed due to imaging findings, relevant findings were all diagnosed by MRI compared with two by US (p=0.5). The two cases not detected by ultrasound were adenomyosis and a pedunculate subserosal leiomyoma. Of the 103 patients who underwent UAE, 14 were treated (without complication) despite the presence of a relative contraindication; all 14 relative contraindications were identified by MRI compared with 13 by US (p=1.0). CONCLUSION: MRI is more accurate than US for characterizing uterine leiomyomas. In a small but statistically insignificant number of cases, MRI identified findings that were missed by US, which changed management. For patients that are unsuitable to be assessed with MRI, ultrasound alone is sufficient for pre-UAE assessment.

Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years.

BACKGROUND: Prophylactic human papillomavirus (HPV) vaccines have to provide sustained protection. We assessed efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. METHODS: Women aged 15-25 years, with normal cervical cytology, who were HPV-16/18 seronegative and oncogenic HPV DNA-negative (14 types) at screening participated in a double-blind, randomised, placebo-controlled initial study (n=1113; 560 vaccine group vs 553 placebo group) and follow-up study (n=776; 393 vs 383). 27 sites in three countries participated in the follow-up study. Cervical samples were tested every 6 months for HPV DNA. Management of abnormal cytologies was prespecified, and HPV-16/18 antibody titres were assessed. The primary objective was to assess long-term vaccine efficacy in the prevention of incident cervical infection with HPV 16 or HPV 18, or both. We report the analyses up to 6.4 years of this follow-up study and combined with the initial study. For the primary endpoint, the efficacy analysis was done in the according-to-protocol (ATP) cohort; the analysis of cervical intraepithelial neoplasia grade 2 and above (CIN2+) was done in the total vaccinated cohort (TVC). The study is registered with ClinicalTrials.gov, number NCT00120848. FINDINGS: For the combined analysis of the initial and follow-up studies, the ATP efficacy cohort included 465 women in the vaccine group and 454 in the placebo group; the TVC included 560 women in the vaccine group and 553 in the placebo group. Vaccine efficacy against incident infection with HPV 16/18 was 95.3% (95% CI 87.4-98.7) and against 12-month persistent infection was 100% (81.8-100). Vaccine efficacy against CIN2+ was 100% (51.3-100) for lesions associated with HPV-16/18 and 71.9% (20.6-91.9) for lesions independent of HPV DNA. Antibody concentrations by ELISA remained 12-fold or more higher than after natural infection (both antigens). Safety outcomes were similar between groups: during the follow-up study, 30 (8%) participants reported a serious adverse event in the vaccine group versus 37 (10%) in the placebo group. None was judged related or possibly related to vaccination, and no deaths occurred. INTERPRETATION: Our findings show excellent long-term efficacy, high and sustained immunogenicity, and favourable safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. FUNDING: GlaxoSmithKline Biologicals (Belgium).

Low density of CD1+ cells in the synovial tissue of patients with rheumatoid arthritis.

OBJECTIVE: CD1 molecules present microbial and self glycolipid antigens to a defined T cell subset with features of natural killer cells. CD1 molecules are up-regulated by inflammatory stimuli such as GM-CSF, and we would expect to find increased CD1 expression in the synovium of patients with rheumatoid arthritis (RA) as compared to osteoarthritis (OA). This study was initiated to compare the density of CD1a+, CD1b+, and CD1c+ synovial cells in RA and OA patients. METHODS: Expression of CD1a+, CD1b+, and CD1c+ molecules in synovial tissue was assessed by semiquantitative immunohistochemistry. For comparison, serological, functional, and typical immunohistochemical markers of inflammation were detected. RESULTS: Although patients with RA as compared to OA had highly significantly increased signs of inflammation, the density of CD1a+, CD1b+, and CD1c+ synovial cells was similar This was also true for the density of CD1+ cells in relation to that of activated CD163+ macrophages. There was a high correlation between the densities of CD1a,b,c positive cells, which suggests the existence of similar regulatory pathways. In a combined analysis of RA and OA patients, there existed a negative association between prior NSAID therapy and the density of CD1a+, CD1b+, and CD1c+ synoviocytes in relation to CD163+ macrophages. This is interesting because a similar immunosuppressive aspect of NSAID has never been shown before and this might represent a hitherto unrecognized immunosuppressive aspect of NSAID. CONCLUSION: Considering the high synovial inflammation in patients with RA, the densities of CD1a+, CD1b+, and CD1c+ synovial cells were low compared to patients with OA. Further studies in RA patients are needed to clarify whether a defect in CD1 regulation may exist. Such a defect may lead to an insufficient immune response against microbial glycolipids, which would support smoldering or repeated inadequately responded infection.

Evaluation of a unique oral contraceptive in the treatment of premenstrual dysphoric disorder.

Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome (PMS). This is the first trial of a unique oral contraceptive containing a combination of drospirenone (DRSP, 3 mg) and ethinyl estradiol (EE, 30 microg) for the treatment of PMDD. DRSP is a spironolactone-like progestin with antiandrogenic and antimineralocorticoid activity. Spironolactone has been shown to be beneficial in PMS, whereas oral contraceptives have shown conflicting results. In this double-blind, placebo-controlled trial, 82 women with PMDD (Diagnostic and Statistical Manual of Mental Disorders, 4th ed. [DSM IV]) were randomized to receive DRSP/EE or placebo for three treatment cycles. The primary end point was change from baseline in luteal phase symptom scores as assessed on the Calendar of Premenstrual Experiences (COPE) scale. Patients treated with DRSP/EE showed a numerically greater change from baseline compared with those treated with placebo on each of the 22 COPE items and each of the 4 symptom factors. Between-group differences in symptom improvement reached statistical significance in factor 3 only (appetite, acne, and food cravings, p = 0.027). The secondary end points, Beck Depression Inventory (BDI) and Profile of Mood States (PMS), were consistent with the primary end point in that patients treated with the oral contraceptive showed a numerically greater improvement from baseline compared with those treated with placebo. The results of this study show a consistent trend in the reduction of symptoms that suggested a beneficial effect of DRSP/EE for the treatment of PMDD, despite limitations of the study design.

Functional neuroimaging of cerebellar activation during single word reading and verb generation in stuttering and nonstuttering adults.

Articulatory discoordinations typically observed in fluent and disfluent speech of stuttering adults suggest an underlying deficiency in the precise timing needed for speech production. Positron emission tomography scans of stuttering adults showed generally higher cerebellar activations pre-treatment compared to nonstuttering control subjects. Intensive fluency treatment resulted in increased cerebellar activation during reading immediately post-treatment and a decrease to near normal levels at the 1 year follow scan. In contrast, verb generation resulted in a gradual but consistent decrease over the three scans. The results suggest that automaticity in motor and cognitive processes during speech production may need to be considered as an important factor in future investigations of stuttering.

Stuttering: an update for physicians.

Stuttering is a disturbance in the normal fluency and time patterning of speech. Developmental stuttering (DS), with or without associated psychiatric illness, is the most common form and includes all cases with gradual onset in childhood that are not the result of acquired brain damage. Persistent developmental stuttering (PDS) is DS that has not undergone spontaneous or speech-therapy-induced remission. Organic models of DS focus on incomplete lateralization or abnormal cerebral dominance. There is also evidence that DS has a significant genetic component to its cause. Neuroimaging research data and the effectiveness of dopamine receptor antagonists in DS seem to support the theory of a hyperdopaminergic origin. Speech therapy remains the main treatment for DS; however, antidepressants can be useful in selected cases. Risperidone, a serotonin-dopamine antagonist, has been shown to be more effective than placebo in decreasing the severity of stuttering. The long-term efficacy and safety of serotonin-dopamine antagonists in DS deserve further study.

Delayed administration of sodium thiosulfate in animal models reduces platinum ototoxicity without reduction of antitumor activity.

Platinum-based chemotherapeutic agents, such as carboplatin and cisplatin, are effective against many human tumors, but their use may be limited by a high incidence of ototoxicity. Delayed administration of the chemoprotective agent sodium thiosulfate (STS) reduces the ototoxicity of carboplatin in a guinea-pig model, when given up to 8 h after the chemotherapy, and also reduces hearing loss in patients given carboplatin with osmotic blood-brain barrier opening for treatment of brain tumors. We tested whether STS, given at times that achieved otoprotection, could impact the chemotherapeutic efficacy of carboplatin. The impact of STS was evaluated by measuring the onset of growth of LX-1 human small cell lung carcinoma s.c. xenografts in the nude rat. When STS was administered as two boluses, 2 and 6 h after treatment with carboplatin and etoposide, there was a decrease in the time to tumor progression. In contrast, when STS administration was delayed until 8 h after carboplatin/etoposide, there was no reduction in the antitumor cytotoxicity of the chemotherapy. STS infusion did not significantly affect ultrafilterable platinum pharmacokinetics in the guinea pig. To explore the potential wider applicability of STS, in a pilot study we tested its efficacy against cisplatin ototoxicity. Delayed administration of STS, 2 h after cisplatin, was protective against cisplatin-induced ototoxicity in the guinea pig model, as determined by electrophysiological measures. On the basis of these data, we suggest that delayed administration of STS may provide a mechanism to reduce the ototoxicity caused by administration of carboplatin or cisplatin for both central nervous system and systemic cancer chemotherapy.

Cladribine with or without prednisone in the treatment of previously treated and untreated B-cell chronic lymphocytic leukaemia - updated results of the multicentre study of 378 patients.

Between January 1992 and January 1999, we treated 378 B-chronic lymphocytic leukaemia (CLL) patients with cladribine (2-CdA), and 255 of the patients were also treated with prednisone. A total of 194 patients were previously untreated, and 184 had relapsed or refractory disease after previous other therapy. Complete response (CR) was obtained in 111 (29.4%) and partial response (PR) in 138 (36.5%) patients, giving an overall response (OR) rate of 65.9%. CR and OR were achieved more frequently in patients in whom 2-CdA was a first-line treatment (45.4% and 82.5% respectively) than in the pretreated group (12.5% and 48.4% respectively) (P < 0.0001). The median duration of OR for previously untreated patients was 14.7 months and for pretreated patients 13.5 months (P = 0.09). The median survival evaluated from the beginning of 2-CdA treatment was shorter in the pretreated group (16.3 months) than in the untreated group (19.4 months) (P < 0.0001). A total of 117 (63.9%) patients died in the pretreated group and 63 (32.6%) in the untreated group. In pretreated patients, 2-CdA + prednisone (P) and 2-CdA alone resulted in similar OR (51.0% and 45.0% respectively; P = 0.4). In contrast, in untreated patients, 2-CdA + P produced a higher OR (85.4%) than 2-CdA alone (72.1%) (P = 0.04). Infections and fever of unknown origin, observed in 91 (49.4%) pretreated and 74 (38.1%) untreated patients (P = 0.03), were the most frequent toxic effects. Our results indicate that 2-CdA is an effective, relatively well-tolerated drug, especially in previously untreated CLL.

A positron emission tomography study of silent and oral single word reading in stuttering and nonstuttering adults.

Over the last decade positron emission tomography (PET) has been used extensively for the study of language and other cognitive and sensorimotor processes in healthy and diseased individuals. In the present study, [15O]H2O PET scanning was used to investigate the lateralization and functional distribution of cortical and subcortical activity involved in single word reading in stuttering and nonstuttering individuals. Ten right-handed male stuttering adults and matched nonstuttering individuals were instructed to read individually presented single words either silently or out loud. Subtraction of functional brain images obtained during each of the two reading tasks, and during a non-linguistic baseline task, was used to calculate within-group and between-group differences in regional cerebral blood flow by means of statistical parametric mapping. Increased activation in the left anterior cingulate cortex (ACC) was observed during silent reading in the stuttering speakers but not in the nonstuttering group. Because of the hypothesized role of the ACC in selective attention and covert articulatory practice, it is suggested that the observed increased ACC activation in the stuttering individuals reflects the presence of cognitive anticipatory reactions related to stuttering. During the oral reading task, within-group comparisons showed bilateral cortical and subcortical activation in both the stuttering and the nonstuttering speakers. Between-group comparisons showed a proportionally greater left hemisphere activation in the nonstuttering speakers, and a proportionally greater right hemisphere activation in the stuttering individuals. The results of the present study provide qualified support for the hypothesis that stuttering adults show atypical lateralization of language processes.

A physiological barrier distal to the anatomic blood-brain barrier in a model of transvascular delivery.

BACKGROUND AND PURPOSE: Osmotic disruption of the blood-brain barrier (BBB) provides a method for transvascular delivery of therapeutic agents to the brain. The apparent global delivery of viral-sized iron oxide particles to the rat brain after BBB opening as seen on MR images was compared with the cellular and subcellular location and distribution of the particles. METHODS: Two dextran-coated superparamagnetic monocrystalline iron oxide nanoparticle contrast agents, MION and Feridex, were administered intraarterially in rats at 10 mg Fe/kg immediately after osmotic opening of the BBB with hyperosmolar mannitol. After 2 to 24 hours, iron distribution in the brain was evaluated first with MR imaging then by histochemical analysis and electron microscopy to assess perivascular and intracellular distribution. RESULTS: After BBB opening, MR images showed enhancement throughout the disrupted hemisphere for both Feridex and MION. Feridex histochemical staining was found in capillaries of the disrupted hemisphere. Electron microscopy showed that the Feridex particles passed the capillary endothelial cells but did not cross beyond the basement membrane. In contrast, after MION delivery, iron histochemistry was detected within cell bodies in the disrupted hemisphere, and the electron-dense MION core was detected intracellularly and extracellularly in the neuropil. CONCLUSION: MR images showing homogeneous delivery to the brain at the macroscopic level did not indicate delivery at the microscopic level. These data support the presence of a physiological barrier at the basal lamina, analogous to the podocyte in the kidney, distal to the anatomic (tight junction) BBB, which may limit the distribution of some proteins and viral particles after transvascular delivery to the brain.

Technique of, and complications attributable to, repeated hyperosmotic blood-brain barrier disruption in dogs.

OBJECTIVE: To design a repeatable technique for reversible, hyperosmotic blood-brain barrier disruption (BBBD) in dogs and evaluate clinical effects of multiple BBBD. ANIMALS: 10 healthy adult dogs. PROCEDURE: Using fluoroscopic guidance, an arterial catheter was directed into the internal carotid artery via the femoral artery of 10 dogs. Blood-brain barrier disruption was achieved in 5 dogs, using intracarotid infusion of mannitol. Five control dogs received only saline solution. After recovery, dogs were monitored for clinical signs of disease before a second, nonsurvival procedure was performed 2 to 3 weeks later. BBBD was estimated, using computed tomographic (CT) densitometry values, as well as Evan's blue dye staining on necropsy specimens. RESULTS: Seven dogs completed the entire study. Two treatment dogs were lost after the first infusion because of deteriorating neurologic function attributed to CNS edema and increased intracranial pressure. One control dog was lost because of vessel wall damage during catheterization. The remaining dogs had only transient neurologic, ocular, and vasculature injuries. Successful BBBD was documented in all treated dogs by use of CT and Evan's blue dye evaluation. CONCLUSION: Repeated catheterization of the internal carotid artery and disruption of the blood- brain barrier is possible in dogs. CLINICAL RELEVANCE: Refinement of this technique would be useful not only for improved delivery of chemotherapeutic agents in patients with brain tumors, but also would allow further investigation of new treatments involving genetically engineered retroviruses and monoclonal antibodies.

Improving drug delivery to intracerebral tumor and surrounding brain in a rodent model: a comparison of osmotic versus bradykinin modification of the blood-brain and/or blood-tumor barriers.

OBJECTIVE: To compare transient blood-brain barrier disruption (BBBD) by hypertonic mannitol with pharmacological modification of the blood-tumor barrier by the vasoactive peptide bradykinin for delivery of small and large agents to nude rat intracerebral xenografts. METHODS: Female nude rats (n = 104) with 6-day intracerebral human small cell lung carcinoma tumors were treated using BBBD (n = 24), intracarotid bradykinin (n = 38), or saline (controls, n = 32) administered intra-arterially. During or immediately after infusion, the rats were given radiolabeled agent (methotrexate or dextran 70; Dupont NEN, Boston, MA). The rats were killed 10 minutes later, and samples of tumor and brain regions were obtained for scintillation counting. Twenty-two additional rats were examined using magnetic resonance imaging after administering one of two contrast agents (gadoteridol or iron oxide nanoparticles) or saline (controls) in conjunction with BBBD or bradykinin. RESULTS: After BBBD, the delivery of both small (methotrexate) and large (dextran 70) radiolabeled tracers was increased 2- to 6-fold in the tumor and 3- to 20-fold in surrounding brain, as compared with saline controls. After bradykinin treatment, there was minimal change in delivery of methotrexate or dextran 70 to tumor and brain around tumor, with the greatest increase less than 60% over controls. Magnetic resonance imaging demonstrated increased delivery of both small and large contrast agents to the treated hemisphere after BBBD. In comparison, no increased tumor enhancement could be detected after bradykinin treatment. CONCLUSION: BBBD resulted in global delivery of a variety of agents in a wide range of sizes. In this human brain tumor xenograft model, bradykinin was not effective at increasing delivery to the tumor of any agent tested.

First evidence of otoprotection against carboplatin-induced hearing loss with a two-compartment system in patients with central nervous system malignancy using sodium thiosulfate.

Sodium thiosulfate (STS) provides protection against carboplatin-induced ototoxicity in an animal model. The purpose of this study was to determine the STS dose required for otoprotection, in patients with malignant brain tumors treated with carboplatin in conjunction with osmotic blood-brain barrier disruption. Twenty-nine patients received STS intravenously 2 hr after carboplatin. Doses were escalated from 4 g/m2 to 8, 12, 16 and 20 g/m2 on consecutive months. Audiologic assessment was performed at baseline and monthly. The audiograms were compared with those of 19 similarly treated historical control patients who did not receive STS. The incidence of ototoxicity in the historical control group of patients was 79% (15/19). This group had an average loss of 20.8 +/- 5.9 dB (n = 19) at 8 kHz after one treatment with carboplatin, whereas the STS treatment group lost only 3.7 +/- 2 dB (n = 15) after one treatment. This difference was statistically significant as assessed by Student's t test (P < .05). Furthermore, patients in the STS treatment group with excellent base-line hearing showed little change in hearing thresholds at 8 kHz after the second treatment (8.0 +/- 8.3 dB) (n = 5) compared with the historical control patients with excellent base-line hearing, (40.5 +/- 8.6 dB) (n = 11). Our data support that doses of 16 or 20 g/m2 of STS decrease carboplatin-induced hearing loss without central nervous system entry. Clinical demonstration of an otoprotective effect with a two-compartment system to prevent drug-induced hearing loss, while preserving central nervous system cytotoxicity, has not been reported previously.