Acute hepatitis due to brivudin: a case report.

BACKGROUND/AIMS: Brivudin is licensed in several European countries for the treatment of herpetic infections, and is considered safe (approximately 1% of patients with transient elevation of liver enzymes) in large multicenter trials. METHODS: We report a case of acute brivudin hepatitis documented with a liver biopsy in detail. RESULTS: Liver biopsy demonstrated acute liver injury with a predominant cytolytic pattern and features suggestive of a drug-induced immunoallergic hepatitis. Elevated ALT levels returned to normal within weeks. CONCLUSIONS: This is the first published case of acute immunoallergic hepatitis due to brivudin.

Prognostic significance of deep vein thrombosis in patients presenting with acute symptomatic pulmonary embolism.

RATIONALE: Concomitant deep vein thrombosis (DVT) in patients with acute pulmonary embolism (PE) has an uncertain prognostic significance. OBJECTIVES: In a cohort of patients with PE, this study compared the risk of death in those with and those without concomitant DVT. METHODS: We conducted a prospective cohort study of outpatients diagnosed with a first episode of acute symptomatic PE. Patients underwent bilateral lower extremity venous compression ultrasonography to assess for concomitant DVT. MEASUREMENTS AND MAIN RESULTS: The primary study outcome, all-cause mortality, and the secondary outcome of PE-specific mortality were assessed during the 3 months of follow-up after PE diagnosis. Multivariate Cox proportional hazards regression was done to adjust for significant covariates. Of 707 patients diagnosed with PE, 51.2% (362 of 707) had concomitant DVT and 10.9% (77 of 707) died during follow-up. Patients with concomitant DVT had an increased all-cause mortality (adjusted hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.24 to 3.38; P = 0.005) and PE-specific mortality (adjusted HR, 4.25; 95% CI, 1.61 to 11.25; P = 0.04) compared with those without concomitant DVT. In an external validation cohort of 4,476 patients with acute PE enrolled in the international multicenter RIETE Registry, concomitant DVT remained a significant predictor of all-cause (adjusted HR, 1.66; 95% CI, 1.28 to 2.15; P < 0.001) and PE-specific mortality (adjusted HR, 2.01; 95% CI, 1.18 to 3.44; P = 0.01). CONCLUSIONS: In patients with a first episode of acute symptomatic PE, the presence of concomitant DVT is an independent predictor of death in the ensuing 3 months after diagnosis. Assessment of the thrombotic burden should assist with risk stratification of patients with acute PE.

The essential role of radiotherapy in the treatment of Merkel cell carcinoma: a study from the Rare Cancer Network.

PURPOSE: To evaluate the role of postoperative radiotherapy (RT) in Merkel cell carcinoma (MCC). METHODS AND MATERIALS: A retrospective multicenter study was performed in 180 patients with MCC treated between February 1988 and September 2009. Patients who had had surgery alone were compared with patients who received surgery and postoperative RT or radical RT. Local relapse-free survival (LRFS), regional relapse-free survival (RRFS), and distant metastasis-free survival (DMFS) rates were assessed together with disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates. RESULTS: Seventy-nine patients were male and 101 patients were female, and the median age was 73 years old (range, 38-93 years). The majority of patients had localized disease (n = 146), and the remaining patients had regional lymph node metastasis (n = 34). Forty-nine patients underwent surgery for the primary tumor without postoperative RT to the primary site; the other 131 patients received surgery for the primary tumor, followed by postoperative RT (n = 118) or a biopsy of the primary tumor followed by radical RT (n = 13). Median follow-up was 5 years (range, 0.2-16.5 years). Patients in the RT group had improved LRFS (93% vs. 64%; p < 0.001), RRFS (76% vs. 27%; p < 0.001), DMFS (70% vs. 42%; p = 0.01), DFS (59% vs. 4%; p < 0.001), and CSS (65% vs. 49%; p = 0.03) rates compared to patients who underwent surgery for the primary tumor alone; LRFS, RRFS, DMFS, and DFS rates remained significant with multivariable Cox regression analysis. However OS was not significantly improved by postoperative RT (56% vs. 46%; p = 0.2). CONCLUSIONS: After multivariable analysis, postoperative RT was associated with improved outcome and seems to be an important component in the multimodality treatment of MCC.

Evaluation of a clinical tool for early etiology identification in status epilepticus.

OBJECTIVES: Because early etiologic identification is critical to select appropriate specific status epilepticus (SE) management, we aim to validate a clinical tool we developed that uses history and readily available investigations to guide prompt etiologic assessment. METHODS: This prospective multicenter study included all adult patients treated for SE of all but anoxic causes from four academic centers. The proposed tool is designed as a checklist covering frequent precipitating factors for SE. The study team completed the checklist at the time the patient was identified by electroencephalography (EEG) request. Only information available in the emergency department or at the time of in-hospital SE identification was used. Concordance between the etiology indicated by the tool and the determined etiology at hospital discharge was analyzed, together with interrater agreement. RESULTS: Two hundred twelve patients were included. Concordance between the etiology hypothesis generated using the tool and the finally determined etiology was 88.7% (95% confidence interval (CI) 86.4-89.8) (κ = 0.88). Interrater agreement was 83.3% (95% CI 80.4-96) (κ = 0.81). SIGNIFICANCE: This tool is valid and reliable for identification early the etiology of an SE. Physicians managing patients in SE may benefit from using it to identify promptly the underlying etiology, thus facilitating selection of the appropriate treatment.

Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: Results from the randomized controlled I-COME Trial

Introduction: Imatinib trough plasma concentrations (Cmin) have been correlated with treatment response in chronic myeloid leukemia (CML) patients. The use of Cmin monitoring for optimizing imatinib dosage (therapeutic drug monitoring [TDM]) is therefore proposed for patients with unsatisfying response or tolerance ("rescue TDM"). A cycle of "routine TDM" for dosage individualization could also be beneficial to prevent unfavorable events, yet its clinical usefulness has not been evaluated. We aimed to assess prospectively whether a "routine TDM" intervention targeting imatinib Cmin of 1000 ng/mL (tolerance, 750-1500 ng/mL) could improve efficacy, tolerance, and persistence on treatment compared with "rescue TDM" use only. Patients (or Materials) and Methods: The Swiss Imatinib COncentration Monitoring Evaluation (I-COME) study was a multicenter randomized controlled trial (ISRCTN31181395). Adult patients in chronic or accelerated phase CML receiving imatinib ≤5 years were eligible. Patients were randomly (1:1) allocated to receive "routine TDM" intervention or to serve as controls with access only to "rescue TDM". All had 1-year follow-up. The primary endpoint was a combined efficacy-safety outcome (failure- and toxicity-free survival without imatinib discontinuation), analyzed in intention-to-treat. Results: Among 56 CML recruited patients, 55 had their molecular and cytogenetic response measured. 14/27 of patients receiving "routine TDM" (52% [33%-71%]) remained event-free versus 16/28 of control patients with "rescue TDM" only (57% [39%-75%]; P=0.69). In the "routine TDM" group, dosage recommendations were adopted entirely in 50% of patients (median Cmin at study end, 895 ng/mL; CV = 33%). These patients had fewer unfavorable events (28% [5%-52%]) compared with patients not receiving the advised dosage (77% [54%-99%]; P = 0.03; median Cmin at study end, 648 ng/mL; CV = 38%). Conclusion: This first prospective target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" of imatinib, especially due to a small patient number and limited prescriber's adherence to dosage recommendations. Nevertheless, the patients receiving the advised dosage more often met target concentrations and the combined outcome (efficacy, tolerance, and persistence). A cycle of routine TDM could thus be favorable, at least in patients eligible for dosage adjustment. Its usefulness should, however, be further confirmed in larger trials.

Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group.

OBJECTIVE: The purpose of this study was to compare the short-term efficacy and safety of risperidone and clozapine in treatment-resistant chronic schizophrenic patients. METHOD: In a controlled double-blind, multicenter study, 86 inpatients with chronic schizophrenia (DSM-III-R), who were resistant to or intolerant of conventional neuroleptics, were randomly assigned to receive risperidone or clozapine for 8 weeks after a 7-day washout period. After a 1-week dose-titration phase, doses were fixed at 6 mg/day of risperidone and 300 mg/day of clozapine for 1 week and then adjusted according to each patient's response. The final mean doses were 6.4 mg/day of risperidone and 291.2 mg/day of clozapine. Treatment efficacy and safety were evaluated with several well-known rating scales. RESULTS: Both risperidone and clozapine significantly reduced the severity of psychotic symptoms (scores on the Positive and Negative Syndrome Scale and the Clinical Global Impression scale) from baseline, with no significant between-group differences. At endpoint, 67% of the risperidone group and 65% of the clozapine group were clinically improved (reduction of 20% or more in total Positive and Negative Syndrome Scale score). Risperidone appeared to have a faster onset of action. In both groups extrapyramidal symptoms and other adverse events were few, and their severity was generally mild. Neither group showed evidence of a relation between drug plasma concentrations and clinical effectiveness. CONCLUSIONS: Risperidone was well tolerated and as effective as medium doses of clozapine in patients with chronic schizophrenia who had been resistant to or intolerant of conventional neuroleptics.

Laparoscopic aortic surgery: Techniques and results.

OBJECTIVE: This review describes and evaluates the results of laparoscopic aortic surgery. METHODS: We describe the different laparoscopic techniques used to treat aortic disease, including (1) total laparoscopic aortic surgery (TLS), (2) laparoscopy-assisted procedures including hand-assisted laparoscopic surgery (HALS), and (3) robot-assisted laparoscopic surgery, with their current indications. Results of these techniques are analyzed in a systematic review of the clinical series published between 1998 and 2008, each containing >10 patients with complete information concerning operative time, clamping time, conversion rate, length of hospital stay, morbidity, and mortality. RESULTS: We selected and reviewed 29 studies that included 1073 patients. Heterogeneity of the studies and selection of the patients made comparison with current open or endovascular surgery difficult. Median operative time varied widely in TLS, from 240 to 391 minutes. HALS had the shortest operating time. Median clamping time varied from 60 to 146 minutes in TLS and was shorter in HALS. Median hospital stay varied from 4 to 10 days regardless of the laparoscopic technique. The postoperative mortality rate was 2.1% (95% confidence interval, 1.4-3.0), with no significant difference between patients treated for occlusive disease or for aneurysmal disease. Conversion to open surgery was necessary in 8.1% of patients and was slightly higher with TLS than with laparoscopy-assisted techniques (P = .07). CONCLUSIONS: Analysis of these series shows that laparoscopic aortic surgery can be performed safely provided that patient selection is adjusted to the surgeon's experience and conversion is liberally performed. The future of this technique in comparison with endovascular surgery is still unknown, and it is now time for multicenter randomized trials to demonstrate the potential benefit of this type of surgery.

Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study.

This study presents the results of a multicenter investigation of the efficacy of acamprosate in the treatment of patients with chronic or episodic alcohol dependence. One hundred eighteen patients were randomly assigned to either placebo or acamprosate, and both groups were stratified for concomitant voluntary use of disulfiram. Treatment lasted for 360 days, with an additional 360-day follow-up period. The primary efficacy parameters evaluated were: relapse rate and cumulative abstinence duration (CAD). Results were analyzed according to Intention-To-Treat principles using chi2, t, and multiple regression analyses where appropriate. After 30 days on study medication, 40 of 55 (73%) acamprosate-treated patients were abstinent, compared with 26 of 55 (43%) placebo-treated patients (p = 0.019). The treatment advantage remained throughout the study medication period and was statistically significant until day 270 (p = 0.028). Twenty-seven percent of patients on acamprosate and 53% of patients on placebo had a first drink within the first 30 days of the study. The mean CAD was 137 days (40% abstinent days) for the patients treated with acamprosate and 75 days (21% abstinent days) for the placebo group (p = 0.013). No adverse interaction between acamprosate and disulfiram occurred, and the subgroup who received both medications had a better outcome on CAD than the those on only one or no medication. Acamprosate was well tolerated. Diarrhea was the only significant treatment-induced effect. It was concluded that acamprosate was a useful and safe pharmacotherapy in the long-term treatment of alcoholism. Concomitant administration of disulfiram improved the effectiveness of acamprosate.

Endovascular aortic repair versus open surgical repair for descending thoracic aortic disease a systematic review and meta-analysis of comparative studies.

OBJECTIVES: The purpose of this study was to determine whether thoracic endovascular aortic repair (TEVAR) reduces death and morbidity compared with open surgical repair for descending thoracic aortic disease. BACKGROUND: The role of TEVAR versus open surgery remains unclear. Metaregression can be used to maximally inform adoption of new technologies by utilizing evidence from existing trials. METHODS: Data from comparative studies of TEVAR versus open repair of the descending aorta were combined through meta-analysis. Metaregression was performed to account for baseline risk factor imbalances, study design, and thoracic pathology. Due to significant heterogeneity, registry data were analyzed separately from comparative studies. RESULTS: Forty-two nonrandomized studies involving 5,888 patients were included (38 comparative studies, 4 registries). Patient characteristics were balanced except for age, as TEVAR patients were usually older than open surgery patients (p = 0.001). Registry data suggested overall perioperative complications were reduced. In comparative studies, all-cause mortality at 30 days (odds ratio [OR]: 0.44, 95% confidence interval [CI]: 0.33 to 0.59) and paraplegia (OR: 0.42, 95% CI: 0.28 to 0.63) were reduced for TEVAR versus open surgery. In addition, cardiac complications, transfusions, reoperation for bleeding, renal dysfunction, pneumonia, and length of stay were reduced. There was no significant difference in stroke, myocardial infarction, aortic reintervention, and mortality beyond 1 year. Metaregression to adjust for age imbalance, study design, and pathology did not materially change the results. CONCLUSIONS: Current data from nonrandomized studies suggest that TEVAR may reduce early death, paraplegia, renal insufficiency, transfusions, reoperation for bleeding, cardiac complications, pneumonia, and length of stay compared with open surgery. Sustained benefits on survival have not been proven.

Fonction surrénalienne après bolus d'étomidate en chirurgie cardiaque : une étude rétrospective [Adrenal function after induction of cardiac surgery patients with etomidate: A retrospective study]

Objectif Un bolus unique d'étomidate inhibe une enzyme mitochondriale impliquée dans la synthèse du cortisol. Au sein de notre institution, tout patient candidat à une chirurgie cardiaque reçoit de l'étomidate à l'induction de l'anesthésie. L'objectif de cette étude a été de déterminer l'incidence des dysfonctions surrénaliennes chez les patients bénéficiant d'une chirurgie cardiaque et nécessitant de hautes doses de noradrénaline au cours de la période postopératoire. Type d'étude Étude rétrospective descriptive dans l'unité de réanimation d'un centre hospitalier universitaire. Patients et méthodes Soixante-trois patients admis en réanimation après chirurgie cardiaque nécessitant plus de 0,2μg/kg par minute de noradrénaline au cours des premières 48 heures postopératoires ont été étudiés. L'insuffisance surrénalienne absolue a été définie par un cortisol basal inférieur à 414nmo/l (15μg/dl), l'insuffisance surrénalienne relative par un cortisol basal entre 414nmo/l (15μg/dl) et 938nmo/l (34μg/dl) avec une augmentation de la cortisolémie (à 60 minutes après un test de stimulation par 250μg de corticotropine de synthèse) inférieure à 250nmo/l (9μg/dl). Résultats Quatorze patients (22 %) ont présenté une fonction surrénalienne normale, 10 (16 %) une insuffisance surrénalienne absolue et 39 (62 %) une insuffisance surrénalienne relative. Tous les patients ont reçu une substitution stéroïdienne, sans aucune différence d'évolution clinique entre les différents groupes. Conclusion L'incidence de l'insuffisance surrénalienne chez les patients qui ont reçu un bolus d'étomidate à l'induction, lors d'une chirurgie cardiaque avec circulation extracorporelle, et présenté une défaillance circulatoire postopératoire, est élevée.

Transient Ischemic Dilation (TID) ratio measurement during Rb-82 cardiac PET: Comparison between three different software packages.

Background: TIDratio indirectly reflects myocardial ischemia and is correlated with cardiacprognosis. We aimed at comparing the influence of three different softwarepackages for the assessment of TID using Rb-82 cardiac PET/CT. Methods: Intotal, data of 30 patients were used based on normal myocardial perfusion(SSS<3 and SRS<3) and stress myocardial blood flow 2mL/min/g)assessed by Rb-82 cardiac PET/CT. After reconstruction using 2D OSEM (2Iterations, 28 subsets), 3-D filtering (Butterworth, order=10, ωc=0.5), data were automatically processed, and then manually processed fordefining identical basal and apical limits on both stress and rest images.TIDratio were determined with Myometrix®, ECToolbox® and QGS®software packages. Comparisons used ANOVA, Student t-tests and Lin concordancetest (ρc). Results: All of the 90 processings were successfullyperformed. TID ratio were not statistically different between software packageswhen data were processed automatically (P=0.2) or manually (P=0.17). There was a slight, butsignificant relative overestimation of TID with automatic processing incomparison to manual processing using ECToolbox® (1.07 ± 0.13 vs 1.0± 0.13, P=0.001)and Myometrix® (1.07 ± 0.15 vs 1.01 ± 0.11, P=0.003) but not using QGS®(1.02 ±0.12 vs 1.05 ± 0.11, P=0.16). The best concordance was achieved between ECToolbox®and Myometrix® manual (ρc=0.67) processing.Conclusion: Using automatic or manual mode TID estimation was not significantlyinfluenced by software type. Using Myometrix® or ECToolbox®TID was significantly different between automatic and manual processing, butnot using QGS®. Software package should be account for when definingTID normal reference limits, as well as when used in multicenter studies. QGS®software seemed to be the most operator-independent software package, whileECToolbox® and Myometrix® produced the closest results.

Combinations of prognostic tools for identification of high-risk normotensive patients with acute symptomatic pulmonary embolism.

Background: In haemodynamically stable patients with acute symptomatic pulmonary embolism (PE), studies have not evaluated the usefulness of combining the measurement of cardiac troponin, transthoracic echocardiogram (TTE), and lower extremity complete compression ultrasound (CCUS) testing for predicting the risk of PE-related death. Methods: The study assessed the ability of three diagnostic tests (cardiac troponin I (cTnI), echocardiogram, and CCUS) to prognosticate the primary outcome of PE-related mortality during 30 days of follow-up after a diagnosis of PE by objective testing. Results: Of 591 normotensive patients diagnosed with PE, the primary outcome occurred in 37 patients (6.3%; 95% CI 4.3% to 8.2%). Patients with right ventricular dysfunction (RVD) by TTE and concomitant deep vein thrombosis (DVT) by CCUS had a PE-related mortality of 19.6%, compared with 17.1% of patients with elevated cTnI and concomitant DVT and 15.2% of patients with elevated cTnI and RVD. The use of any two-test strategy had a higher specificity and positive predictive value compared with the use of any test by itself. A combined three-test strategy did not further improve prognostication. For a subgroup analysis of high-risk patients, according to the pulmonary embolism severity index (classes IV and V), positive predictive values of the two-test strategies for PE-related mortality were 25.0%, 24.4% and 20.7%, respectively. Conclusions: In haemodynamically stable patients with acute symptomatic PE, a combination of echocardiography (or troponin testing) and CCUS improved prognostication compared with the use of any test by itself for the identification of those at high risk of PE-related death.

Validation of the DRAGON Score in 12 Stroke Centers in Anterior and Posterior Circulation.

BACKGROUND AND PURPOSE: The DRAGON score predicts functional outcome in the hyperacute phase of intravenous thrombolysis treatment of ischemic stroke patients. We aimed to validate the score in a large multicenter cohort in anterior and posterior circulation. METHODS: Prospectively collected data of consecutive ischemic stroke patients who received intravenous thrombolysis in 12 stroke centers were merged (n=5471). We excluded patients lacking data necessary to calculate the score and patients with missing 3-month modified Rankin scale scores. The final cohort comprised 4519 eligible patients. We assessed the performance of the DRAGON score with area under the receiver operating characteristic curve in the whole cohort for both good (modified Rankin scale score, 0-2) and miserable (modified Rankin scale score, 5-6) outcomes. RESULTS: Area under the receiver operating characteristic curve was 0.84 (0.82-0.85) for miserable outcome and 0.82 (0.80-0.83) for good outcome. Proportions of patients with good outcome were 96%, 93%, 78%, and 0% for 0 to 1, 2, 3, and 8 to 10 score points, respectively. Proportions of patients with miserable outcome were 0%, 2%, 4%, 89%, and 97% for 0 to 1, 2, 3, 8, and 9 to 10 points, respectively. When tested separately for anterior and posterior circulation, there was no difference in performance (P=0.55); areas under the receiver operating characteristic curve were 0.84 (0.83-0.86) and 0.82 (0.78-0.87), respectively. No sex-related difference in performance was observed (P=0.25). CONCLUSIONS: The DRAGON score showed very good performance in the large merged cohort in both anterior and posterior circulation strokes. The DRAGON score provides rapid estimation of patient prognosis and supports clinical decision-making in the hyperacute phase of stroke care (eg, when invasive add-on strategies are considered).

Outcome and prognostic factors in olfactory neuroblastoma: a rare cancer network study.

Purpose: To assess the outcome in patients with olfactory neuroblastoma (ONB). Methods and Materials: Seventy-seven patients treated for nonmetastatic ONB between 1971 and 2004 were included. According to Kadish classification, there were 11 patients with Stage A, 29 with Stage B, and 37 with Stage C. T-classification included 9 patients with T1, 26 with T2, 16 with T3, 15 with T4a, and 11 with T4b tumors. Sixty-eight patients presented with N0 (88%) disease. Results: Most of the patients (n = 56, 73 %) benefited from surgery (S), and total excision was possible in 44 patients (R0 in 32, R1 in 13, R2 in 11). All but five patients benefited from RT, and chemotherapy was given in 21(27%). Median follow-up period was 72 months (range, 6-315). The 5-year overall survival (OS), disease-free survival (DES), locoregional control, and local control were 64%, 57%, 62%, and 70%, respectively. In univariate analyses, favorable factors were Kadish A or B disease, T1 T3 tumors, no nodal involvement, curative surgery, R0/R1 resection, and RT-dose 54 Gy or higher. Multivariate analysis revealed that the best independent factors predicting the outcome were T1 T3, N0, R0/R1 resection, and total RT dose (54 Gy or higher). Conclusion: In this multicenter retrospective study, patients with ONB treated with R0 or R1 surgical resection followed by at least 54-Gy postoperative RT had the best outcome. Novel strategies including concomitant chemotherapy and/or higher dose RT should be prospectively investigated in this rare disease for which local failure remains a problem.

Urinalysis and pre-renal acute kidney injury: time to move on.

Urinary indices are classically believed to allow differentiation of transient (or pre-renal) acute kidney injury (AKI) from persistent (or acute tubular necrosis) AKI. However, the data validating urinalysis in critically ill patients are weak. In the previous issue of Critical Care, Pons and colleagues demonstrate in a multicenter observational study that sodium and urea excretion fractions as well as urinary over plasma ratios performed poorly as diagnostic tests to separate such entities. This study confirms the limited diagnostic and prognostic ability of urine testing. Together with other studies, this study raises more fundamental questions about the value, meaning and pathophysiologic validity of the pre-renal AKI paradigm and suggests that AKI (like all other forms of organ injury) is a continuum of injury that cannot be neatly divided into functional (pre-renal or transient) or structural (acute tubular necrosis or persistent).