Second primary malignancies induced by radioactive iodine treatment of differentiated thyroid carcinoma - a critical review and evaluation of the existing evidence.

PURPOSE: Concern is growing about long-term side effects of differentiated thyroid cancer treatment, most notably radioactive iodine (RAI) therapy. However, published studies on the subject have had heterogeneous cohorts and conflicting results. This review seeks to provide an updated evaluation of published evidence, and to elucidate the risk of second primary malignancies (SPMs), especially secondary hematologic malignancies (SHMs), attributable to RAI therapy. METHODS: An extensive literature search was performed in Ovid MEDLINE, Ovid MEDLINE and In-Process & Other Non-Indexed Citations, Ovid MEDLINE Epub Ahead of Print, Cochrane Central Register of Controlled Trials (CENTRAL) and PubMed. Studies regarding RAI-induced SPMs or a dose-response relationship between RAI therapy and SPMs were identified, 10 of which were eligible for the analysis. We evaluated risk of bias in each study and judged quality of evidence (QOE) across all studies using the Grading of Recommendations, Assessment, Development and Evaluations approach. RESULTS: For the outcome "SPM", the relative effect (relative risk, hazard ratio, or odds ratio) of RAI vs. no RAI ranged from 1.14 to 1.84 across studies, but most results were not statistically significant. For the outcome "SHM", reported relative effects ranged from 1.30 to 2.50, with 2/3 of the studies presenting statistically significant results. In 7/8 of the studies, increased risk for SPM was shown with increasing cumulative RAI activity. QOE was "very low" regarding SPM after RAI and regarding a dose-response relationship, and "low" for SHM after RAI. CONCLUSION: Based on low quality evidence, an excess risk for the development of SPM cannot be excluded but is expected to be small.

Characteristics of a large sample of candidates for permanent ventricular pacing included in the Biventricular Pacing for Atrio-ventricular Block to Prevent Cardiac Desynchronization Study (BioPace).

AIMS: The general clinical profile of European pacemaker recipients who require predominant ventricular pacing (VP) is scarcely known. We examined the demographic and clinical characteristics of the 1808 participants (out of 1833 randomized patients) of the ongoing Biventricular Pacing for Atrio-ventricular Block to Prevent Cardiac Desynchronization (BioPace) study. METHODS AND RESULTS: BioPace recruited patients between May 2003 and September 2007 predominantly in European medical centres. We analysed demographic data and described clinical characteristics and electrophysiological parameters prior to device implantation in 1808 enrolled patients. The mean age ± standard deviation (SD) of the 1808 patients was 73.5 ± 9.2 years, 1235 (68%) were men, 654 (36%) presented without structural heart disease, 547 (30%) had ischemic, 355 (20%) hypertensive, 146 (8%) valvular, and 102 (6%) non-ischemic dilated cardiomyopathy. Mean left ventricular ejection fraction was 55.4 ± 12.3%. The main pacing indications were (a) permanent and intermittent atrioventricular (AV) block in 973 (54%), (b) atrial fibrillation with slow ventricular rate in 313 (17%), and (c) miscellaneous bradyarrhythmias in 522 (29%) patients. Mean QRS duration was 118.5 ± 30.5 ms, left bundle branch block was present in 316 (17%), and atrial tachyarrhythmias in 426 (24%) patients. CONCLUSION: To the best of our knowledge, this sample is a representative source of description of the general profile of European pacemaker recipients who require predominant VP. Patients' characteristics included advanced age, predominantly male gender, preserved left ventricular systolic function, high-grade AV block, narrow QRS complex, and atrial tachyarrhythmias, the latter being present in nearly one-fourth of the cohort.

Catheter ablation of concomitant atrial fibrillation improves survival of patients undergoing transcatheter edge-to-edge mitral valve repair.

Background: Atrial fibrillation (AF) is the most common concomitant disease in patients undergoing transcatheter edge-to-edge repair (TEER) for mitral regurgitation (MR) and detrimentally affects their outcome. While there is increasing evidence for prognostic improvement and safety of catheter ablation (CA) of AF in the overall cohort of heart failure patients, corresponding data in TEER patients are lacking. Objectives: To investigate the impact of treatment regimens for concomitant AF on survival of TEER patients. Methods: In a multicenter observational cohort study consecutive patients successfully undergoing TEER were analyzed and survival of patients receiving CA of concomitant AF was compared with that of patients on pharmacological AF treatment and with that of patients without a history of AF, using propensity score matching (PSM). Results: A total of 821 patients were analyzed. Of these, 608 (74.1%) had concomitant AF, of whom 48 patients received CA. Patients with CA in AF showed significantly higher 3-year-survival after TEER compared to PSM-patients on pharmacological AF treatment (75.5% [36/48] vs. 49.4% [166/336], p = 0.009). The 3-year-survival after TEER of patients with concomitant AF treated with CA was not significantly different from PSM-patients without AF (75.5% [36/48] vs. 68.3% [98/144], p = 0.36). Conclusions: CA of AF is superior to pharmacotherapy as it significantly improves the survival of TEER patients in a PSM analysis. CA even offsets the prognostic disadvantage of coexisting AF in TEER patients. Given the growing evidence of prognostic benefits in the overall cohort of HF patients, our data point out the importance of treating concomitant AF and support CA as an essential part of a holistic management of TEER patients.

Treatment Approaches and Outcome of Patients with Neuroendocrine Neoplasia Grade 3 in German Real-World Clinical Practice.

BACKGROUND: Neuroendocrine neoplasia grade 3 (NEN G3) represents a rare and heterogeneous cancer type with a poor prognosis. The aim of our study was to analyze real-world data from the German NET Registry with a focus on therapeutic and prognostic aspects. METHODS: NEN G3 patients were identified within the German NET Registry. Demographic data and data on treatments and outcomes were retrieved. Univariate analyses were performed using the Kaplan-Meier-method. Multivariate analysis was performed using a Cox proportional hazard model. RESULTS: Of 445 included patients, 318 (71.5%) were diagnosed at stage IV. Well-differentiated morphology (NET G3) was described in 31.7%, 60% of cases were classified as neuroendocrine carcinoma (NEC), and the median Ki67 value was 50%. First-line treatment comprised chemotherapy in 43.8%, with differences in the choice of regimen with regard to NET or NEC, and surgery in 41.6% of patients. Median overall survival for the entire cohort was 31 months. Stage, performance status and Ki67 were significant prognostic factors in multivariate analysis. CONCLUSIONS: The survival data of our national registry compare favorably to population-based data, probably mainly because of a relatively low median Ki67 of 50%. Nevertheless, the best first- and second-line approaches for specific subgroups remain unclear, and an international effort to fill these gaps is needed.

Forced needle advancement during needle-nerve contact in a porcine model: histological outcome.

BACKGROUND: In this study, we determined whether needle advancement during needle-nerve contact (forced needle-nerve contact) is associated with a higher risk of nerve injury compared with needle-nerve contact without needle advancement (nonforced needle-nerve contact). METHODS: In 8 anesthetized pigs, the brachial plexus nerves underwent forced (0.15 Newton) or nonforced (0.0 Newton) needle-nerve contact without nerve penetration. The grade of nerve injury was histologically assessed using an objective score ranging from 0 (no injury) to 4 (severe injury). RESULTS: Sixty-nine nerves, including controls, were examined. Histology revealed a significant difference between forced and nonforced needle-nerve contact (median [interquartile range] 3 [2-4] vs 2 [1-2]; P = 0.004). Myelin damage and intraneural hematoma occurred only after forced needle-nerve contact. CONCLUSIONS: The severity of structural nerve injury after needle-nerve contact was directly related to force exposure via needle advancement.

Impact of Rhythm vs. Rate Control in Atrial Fibrillation on the Long-Term Outcome of Patients Undergoing Transcatheter Edge-to-Edge Mitral Valve Repair.

Atrial fibrillation (AF) is a highly prevalent comorbidity in patients with severe mitral valve regurgitation (MR) undergoing transcatheter mitral valve repair (TMVR) and has been shown to significantly worsen their outcome. However, data on the impact of AF treatment strategy in this rapidly growing cohort of patients is unknown. In a multicenter, observational cohort study, 542 consecutive patients undergoing TMVR were enrolled, and subsequently, comprehensive survival analyses according to AF status and therapy were performed using propensity score matching and Cox regression. In the analyzed cohort, 373 (73.3%) of the TMVR patients had concomitant AF. Of these patients, 212 (59%) were on rate control therapy and 161 (41%) were on rhythm control therapy. At 3 years, significantly reduced cumulative survival was observed for patients on rhythm compared to patients on rate control (46.7% (75/161) vs. 56.5% (91/161), p = 0.032). Amiodarone was used to a substantial extent for rhythm control and found to be an independent mortality predictor (Hazard Ratio 1.5, 95%CI 1.1-2.1, p = 0.04). The adverse outcome of concomitant AF in TMVR patients was confirmed (AF: 47.3% (126/266) vs. non-AF: 58.3% (78/133), p = 0.047). Rhythm control achieved almost exclusively pharmacologically is associated with an adverse outcome compared to the rate control of AF in TMVR. This raises awareness of the importance of AF and its treatment, as this seems to be a promising key point for improving the prognosis of TMVR patients.

Modulation of human motor cortex excitability by single doses of amantadine.

Amantadine-sulfate has been used for several decades to treat acute influenza A, Parkinson's disease (PD), and acute or chronic drug-induced dyskinesia. Several mechanisms of actions detected in vivo/in vitro including N-methyl-D-aspartate (NMDA)-receptor antagonism, blockage of potassium channels, dopamine receptor agonism, enhancement of noradrenergic release, and anticholinergic effects have been described. We used transcranial magnetic stimulation (TMS) to evaluate the effect of single doses of amantadine on human motor cortex excitability in normal subjects. Using a double-blind, placebo-controlled, crossover study design, motor thresholds, recruitment curves, cortical stimulation-induced silent period (CSP), short intracortical inhibition (ICI), intracortical facilitation (ICF), and late inhibition (L-ICI) in 14 healthy subjects were investigated after oral doses of 50 and 100 mg amantadine with single and paired pulse TMS paradigms. Spinal cord excitability was investigated by distal latencies and M-amplitudes of the abductor digiti minimi muscle. After intake of amantadine, a significant dose-dependent decrease of ICF was noticed as well as a significant increase of L-ICI as compared to placebo. The effect on ICF and L-ICI significantly correlated with amantadine serum levels. ICI was slightly increased after amantadine intake, but the effect failed to be significant. Furthermore, amantadine had no significant effects on motor thresholds, MEP recruitment curves, CSP, or peripheral excitability. In conclusion, a low dose of amantadine is sufficient in modulating human motor cortex excitability. The decrease of ICF and increase of L-ICI may reflect glutamatergic modulation or a polysynaptic interaction of glutamatergic and GABA-ergic circuits. Although amantadine has several mechanisms of action, the NMDA-receptor antagonism seems to be the most relevant effect on cortical excitability. As L-ICI can be influenced by this type of drug, it may be an interesting parameter for studies of motor learning and use-dependent plasticity.

Levetiracetam influences human motor cortex excitability mainly by modulation of ion channel function--a TMS study.

PURPOSE: Levetiracetam (LEV) is a new compound with anticonvulsive efficacy in focal and generalized epilepsies. Recent in vitro studies suggest LEV to act as a selective N-type-calcium-channel blocker. METHODS: We used transcranial magnetic stimulation (TMS) in order to investigate if ion-channel blockade is relevant to the inhibitory CNS effects of LEV in vivo and if motor thresholds (MTs) are a valid TMS parameter to detect this mode of action. In a double blind, placebo-controlled, crossover study, the effects of single oral doses of 500 and 2000 mg LEV on motor thresholds, recruitment curves (REC), cortical induced silent period (CSP) and on intracortical inhibition (ICI) and facilitation (ICF) were studied in 10 healthy subjects. RESULTS: A significant increase of motor thresholds was noticed after 2000 mg LEV as compared to placebo. The recruitment curve showed a trend towards motor evoked potential (MEP) amplitude reduction after LEV. LEV had no significant effect on CSP or on intracortical excitability as measured by inhibition and facilitation. CONCLUSIONS: We conclude that the modulation of ion-channel function, reflected by motor threshold elevation and a trend towards recruitment curve suppression, is relevant to the inhibitory CNS effects of LEV in vivo, and therefore, may contribute to the anticonvulsive efficacy of LEV. GABAergic or glutamatergic mechanisms seem to be less important in vivo as measured by TMS.

Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy, and it was only in 2004 that the International Union Against Cancer (UICC) defined TNM criteria and published the first staging classification. However, to date, the prognostic value of the proposed classification has not been evaluated. METHODS: The German ACC Registry comprising 492 patients was searched for patients who were diagnosed between 1986 and 2007 with detailed information on primary diagnosis and a minimum follow-up of 6 months. Patients were assigned to UICC tumor stage, and disease-specific survival (DSS) was assessed. In addition, the contribution of potential risk factors for DSS was evaluated. RESULTS: In total, 416 patients with a mean follow-up of 36 months met the inclusion criteria (stage I, n=23 patients; stage II, n=176 patients; stage III, n=67 patients; stage IV, n=150 patients). Kaplan-Meier analysis revealed a stage-dependent DSS. However, DSS in patients with stage II ACC did not differ significantly from DSS in patients with stage III ACC (hazard ratio, 1.38; 95% confidence interval, 0.89-2.16). Furthermore, patients who had stage IV ACC without distant metastases had an improved DSS compared with patients who had metastatic disease (P=.004). An analysis of different potential risk factors for defining stage III ACC revealed important roles in DSS for tumor infiltration in surrounding tissue, venous tumor thrombus (VTT), and positive lymph nodes; whereas tumor invasion in adjacent organs carried a prognosis similar to that of infiltration in surrounding tissue only. CONCLUSIONS: The 2004 UICC staging classification for ACC has significant limitations. On the basis of the current analysis, a revised classification with superior prognostic accuracy is proposed (the European Network for the Study of Adrenal Tumors classification). In this system, stage III ACC is defined by the presence of positive lymph nodes, infiltration of surrounding tissue, or VTT; and stage IV ACC is restricted to patients with distant metastasis.

Does fine-needle aspiration cytology optimize the surgical management of thyroid disorders in endemic goiter region?

AIM: The aim of this study was to determine the diagnostic value of fine-needle aspiration cytology (FNAC) before thyroidectomy in an endemic goiter region. METHODS: One hundred patients with preoperative FNAC of thyroid nodules who underwent thyroidectomy were recruited. FNAC were classified into five groups. 0, no thyroid cells; 1, normal thyroid cells; 2, degenerative thyroid cells without evidence of malignacy; 3, follicular or oncocytary neoplasia; and 4, malignant thyroid cells. FNAC was compared with postoperative histopathological diagnoses. RESULTS: Only 76% of the FNAC allowed an adequate cytological examination. In 15 patients (15%), carcinomas were found in the postoperative histopathological diagnosis (including four follicular carcinomas). In the 48 patients of FNAC groups 3 and 4, nine carcinomas (18.7%) were found (including four follicular carcinomas). In the 28 patients of groups 1 and 2, there was only one papillary carcinoma (3.5%). In the 24 patients of group 0, there were two papillary, two follicular, and one anaplastic carcinomas (total of 20.8%). The sensitivity, specificity, and likelihood ratio (LR) of the FNAC for benign nodules were 90%, 40.9%, 0.24, respectively. The LR for malignant nodules was 13.2, and that for follicular neoplasia was 0.55. CONCLUSIONS: Despite the high prevalence of carcinoma in an endemic goiter region, FNAC disappointed its diagnostic expectation. The lower specificity of FNAC may be caused by a higher prevalence of thyroid nodules in an endemic goiter region or by the absence of a specialized cytopathologist.

Biventricular stimulation to prevent cardiac desynchronization: rationale, design, and endpoints of the 'Biventricular Pacing for Atrioventricular Block to Prevent Cardiac Desynchronization (BioPace)' study.

Despite the deleterious effects of cardiac dyssynchrony and the positive effects of cardiac resynchronization therapy, patients with high-degree atrioventricular block continue to receive desynchronizing right ventricular (RV) pacing systems. Although it is unclear whether the negative effects of RV pacing and left bundle branch block (LBBB) are comparable, and whether they depend on the presence and the degree of structural heart disease, one may hypothesize that RV pacing may have similar effects to LBBB. In the BioPace trial, the long-term effects of RV pacing vs. biventricular pacing will be prospectively compared in 1200 pacemaker patients with high likelihood of mostly paced ventricular events, regardless of whether in sinus rhythm or in atrial fibrillation (AF). After echocardiographic examination of left ventricular (LV) function, patients will be randomly assigned to the implantation of an RV vs. a biventricular pacing system and followed for up to 5 years. Primary study endpoints are survival, quality of life (QoL), and the distance covered in a 6-min hall walk (6-MHW) at 24 months after implantation. Secondary endpoints are QoL and the 6-MHW result at 12 months after implantation, hospitalization rate, LV dimensions, LV ejection fraction, and the development of chronic AF and other adverse events.

Prognostic significance of serum cholesterol levels in patients with idiopathic dilated cardiomyopathy.

AIMS: Previous studies indicate that low cholesterol levels are associated with adverse prognosis in heart failure patients, because elevated lipoprotein levels may negate bacterial endotoxin load induced by gastrointestinal congestion. METHODS AND RESULTS: We examined the prognostic significance of lipid levels in a cohort of 422 patients with idiopathic dilated cardiomyopathy (iDCM) [50+/-12 years, 342 males, 80 females, left ventricular ejection fraction (LV-EF): 31.6+/-10.6%]. During 42 months of follow-up, 86 patients (20.3%) died or received a heart transplant. In univariate Cox regression analysis, reduced LV-EF, high New York Heart Association (NYHA) class, and increased LV end-diastolic diameter (LVEDD) were strong risk factors associated with that endpoint, whereas decreased total cholesterol, HDL-cholesterol, and apoprotein I levels were identified as weak risk predictors. After step-wise multivariable analysis, only LVEDD, NYHA class, and LV-EF emerged as parameters independently contributing to the model predicting risk for death or heart transplantation (P<0.05). Cholesterol levels were positively associated with LV-EF and negatively associated with LVEDD (P<0.05). Circulating sCD14 levels, a marker of endotoxin exposure, were related to cholesterol levels (P<0.05) and LV-EF (P<0.05). CONCLUSION: Decreased cholesterol levels do not independently predict adverse prognosis in patients with iDCM. Our findings indicate that low cholesterol levels are dependent on the severity of cardiac disease.

Extracorporeal shock wave therapy for plantar fasciitis: randomised controlled multicentre trial.

OBJECTIVE: To determine the effectiveness of extracorporeal shock wave therapy compared with placebo in the treatment of chronic plantar fasciitis. DESIGN: Randomised, blinded, multicentre trial with parallel group design. SETTING: Nine hospitals and one outpatient clinic in Germany. PARTICIPANTS: 272 patients with chronic plantar fasciitis recalcitrant to conservative therapy for at least six months: 135 patients were allocated extracorporeal shock wave therapy and 137 were allocated placebo. MAIN OUTCOME MEASURES: Primary end point was the success rate 12 weeks after intervention based on the Roles and Maudsley score. Secondary end points encompassed subjective pain ratings and walking ability up to a year after the last intervention. RESULTS: The primary end point could be assessed in 94% (n=256) of patients. The success rate 12 weeks after intervention was 34% (n=43) in the extracorporeal shock wave therapy group and 30% (n=39) in the placebo group (95% confidence interval - 8.0% to 15.1%). No difference was found in the secondary end points. Few side effects were reported. CONCLUSIONS: Extracorporeal shock wave therapy is ineffective in the treatment of chronic plantar fasciitis.