Comparison of intraocular lens power calculation formulas with and without total keratometry and ray tracing in patients with previous myopic SMILE.

PURPOSE: To evaluate the prediction error (PE) variance and absolute median PE of different intraocular lens (IOL) calculation formulas including last-generation formulas such as Barrett True-K with K, Okulix and total keratometry (TK)-based calculations with Haigis, and Barrett True-K in a simulation model in post-small-incision lenticule extraction (SMILE) eyes. SETTINGS: Department of Ophthalmology, University Hospital Marburg, Marburg, Germany. DESIGN: Prospective study. METHODS: Preoperative measurements included IOL power calculation before and after SMILE surgery. The target refraction was set to be the lowest myopic refractive error in pre-SMILE eyes. The IOL power targeting at the lowest myopic refractive error in pre-SMILE eyes was selected for the post-SMILE IOL calculation of the same eye. The difference between the predicted refraction of pre- and post-SMILE eyes with the same IOL power was defined as IOL difference. The refractive change induced by SMILE was defined as the difference between preoperative and postoperative manifest refraction. RESULTS: 98 eyes from 49 patients underwent bilateral myopic SMILE. The PE variance of Okulix was not significantly different compared with Barrett True-K with TK ( P = .471). The SDs of the mean PEs were ±0.413 D (Haigis-TK), ±0.453 D (Okulix), ±0.471 D (Barrett True-K with TK), ±0.556 D (Haigis-L), and ±0.576 D (Barrett True-K with K). The mean absolute PE was 0.340 D, 0.353 D, 0.404 D, 0.511 D, and 0.715 D for Haigis-TK, Okulix, Barrett True-K with TK, Barrett True-K with K, and Haigis-L, respectively. The highest percentage of eyes within ±0.50 D was achieved by Okulix, followed by Haigis-TK, Barrett True-K with TK, Barrett True-K with K, and Haigis-L. CONCLUSIONS: Results suggest that Haigis in combination with TK, Okulix, and Barrett True-K with and without TK offer good options for accurate IOL power calculation after SMILE. Haigis-L showed a tendency for myopic shift in eyes after previous SMILE.

Transdermal Nicotine Treatment and Progression of Early Parkinson's Disease.

BACKGROUND: Epidemiologic studies show that smokers have a lower incidence of Parkinson's disease. Nicotine has been hypothesized to slow progression in early Parkinson's disease. METHODS: In a double-blind, placebo-controlled multicenter trial, we randomly assigned patients with Parkinson's disease, diagnosed within 18 months, who were in Hoehn and Yahr disease stage less than or equal to 2 (range from 0 to 5; higher scores indicate greater impairment), who were therapy naïve (except for stable monoamine-oxidase-B inhibition), and not requiring dopaminergic therapy, to transdermal nicotine or placebo. The primary end point was change in Unified Parkinson's Disease Rating Scale parts I­III (Total UPDRS) score (range from 0 to 172; higher scores indicate greater impairment) between baseline and 60 weeks (52 weeks of trial therapy, 8 weeks of washout). The first secondary end point was change in Total UPDRS from baseline to 52 weeks. Differences between groups were estimated using the Hodges­Lehmann (HL) method and tested with the exact two-sided stratified Mann­Whitney­Wilcoxon test according to the intention-to-treat principle. RESULTS: Among 163 participants, 101 were assessed for the primary end point. Mean worsening of Total UPDRS was 3.5 in the placebo versus 6.0 in the nicotine group (HL-difference with 95% CI: ­3 [­6 to 0], P=0.06). For the first secondary end point, analysis of 138 participants showed a mean worsening of 5.4 in the placebo versus 9.1 in the nicotine group (HL-difference with 95% CI: ­4 [­7 to ­1]). Dropout was mainly because of early treatment discontinuation or adverse events. Cutaneous adverse effects at the patch application site were common. In all, 34.6% of participants initiated dopaminergic therapy during participation. CONCLUSIONS: One-year transdermal nicotine treatment did not slow progression in early Parkinson's disease. (Funded by the Michael J. Fox Foundation for Parkinson's Research and others; ClinicalTrials.gov number, NCT01560754; EudraCT number, 2010-020299-42.)

Pulmonary inflammatory response and immunomodulation to multiple trauma and hemorrhagic shock in pigs.

BACKGROUND: Patients suffering from severe trauma experience substantial immunological stress. Lung injury is a known risk factor for the development of posttraumatic complications, but information on the long-term course of the pulmonary inflammatory response and treatment with mild hypothermia are scarce. AIM: To investigate the pulmonary inflammatory response to multiple trauma and hemorrhagic shock in a porcine model of combined trauma and to assess the immunomodulatory properties of mild hypothermia. METHODS: Following induction of trauma (blunt chest trauma, liver laceration, tibia fracture), two degrees of hemorrhagic shock (45 and 50%) over 90 (n = 30) and 120 min. (n = 20) were induced. Animals were randomized to hypothermia (33°C) or normothermia (38°C). We evaluated bronchoalveolar lavage (BAL) fluid and tissue levels of cytokines and investigated changes in microRNA- and gene-expression as well as tissue apoptosis. RESULTS: We observed a significant induction of Interleukin (IL) 1ß, IL-6, IL-8, and Cyclooxygenase-2 mRNA in lung tissue. Likewise, an increased IL-6 protein concentration could be detected in BAL-fluid, with a slight decrease of IL-6 protein in animals treated with hypothermia. Lower IL-10 protein levels in normothermia and higher IL-10 protein concentrations in hypothermia accompanied this trend. Tissue apoptosis increased after trauma. However, intervention with hypothermia did not result in a meaningful reduction of pro-inflammatory biomarkers or tissue apoptosis. CONCLUSION: We observed signs of a time-dependent pulmonary inflammation and apoptosis at the site of severe trauma, and to a lower extent in the trauma-distant lung. Intervention with mild hypothermia had no considerable effect during 48 hours following trauma.

Prognostic Significance of the Nodal Ratio and Number of Positive Nodes in Patients With Squamous Cell Carcinomas of the Head and Neck.

BACKGROUND/AIM: The lymph node status has high prognostic relevance in head and neck squamous cell carcinoma (HNSCC). This study aimed to address the hypothesis that the number of positive nodes and the nodal ratio have a prognostic impact on survival in HNSCC. PATIENTS AND METHODS: A retrospective analysis of 221 patients with HNSCC and clinical N+ status who underwent a neck dissection during primary surgery or after definitive radio(chemo)therapy was performed. The possible influence of age, sex, TNM stage, number of positive nodes and nodal ratio on survival was analyzed by univariate and multivariate Cox models and log-rank tests. RESULTS: On average, 30.1 lymph nodes were removed and 4.96 metastases were detected. The mean nodal ratio was 9.4%, the median nodal ratio was 5.3%. Multivariate analysis demonstrated a nodal ratio of ≥6-<12.5% [hazard ratio (HR)=2.33, 95% confidence interval (CI)=1.24-4.37; p=0.008] and of ≥12.5% (HR=2.86, 95% CI=1.40-5.84; p=0.004) compared to nodal ratio 0, number of positive nodes pN=1 compared to number of positive nodes=0 (HR=2.02, 95% CI=1.08-3.80. p=0.029), as well as N3 compared to N0 (HR=8.10, 95% CI=1.89-34.66; p=0.005), and Mx compared to M0 (HR of 2.76, 95% CI=1.59-4,79, p≤0.001) were of main importance for poor prognosis. Postoperative radio(chemo)therapy after surgery was associated with prolonged survival in multivariate analysis (HR=0.37, 95% CI=0.24-0.57; p≤0.001). CONCLUSION: The nodal ratio and number of positive nodes seem to have a high prognostic impact in patients with HNSCC and can be of value in identifying patients at high risk who warrant more aggressive therapy.

Intensive Care as an Independent Risk Factor for Infection after Reconstruction and Augmentation with Autologous Bone Grafts in Craniomaxillofacial Surgery: A Retrospective Cohort Study.

Autologous bone grafts for reconstruction and augmentation are routinely used for maintaining functionality and facial aesthetics. Associated complications, however, have a significant impact on patients and health care systems. This study aims to investigate the possible risk factors associated with the occurrence of complications in order to provide evidence for the outcome of autologous bone graft reconstructive procedures. Patients from 2008 to 2018 who underwent autologous (mostly mandibular) reconstruction were included in the observational study. Clinical, pathological, and therapeutic factors were examined in univariate and multivariate analysis for significance with occurring complications. A multivariate model was used to create a prognostic model predicting the occurrence of complications. Graft complications requiring revision were exhibited by 33/128 patients. Infections were most frequent, with 4/22 patients affected by multi-resistant germs. Multivariate analysis showed radiotherapy (OR = 5.714; 95% CI: 1.839-17.752; p = 0.003), obstructive pulmonary disease (OPD) (OR = 4.329; 95% CI: 1.040-18.021; p = 0.044) and length of defect (in mm) (OR = 1.016; 95% CI: 1.004-1.028; p = 0.009) as independent risk factors associated with graft complications with high accuracy of prediction (AUC = 0.815). Intensive care (OR = 4.419; 95% CI: 1.576-12.388; p = 0.005) with a coefficient between intensive care and OPD (0.214) being low was identified as the most relevant risk factor for infection. Although intensive care is not a classic risk factor, but rather a summation of factors not reaching significance in the individual case, a stay in ICU (intensive care unit) needs to be considered for graft complications. As a clinical consequence, we recommend using the best possible hygienic measures during procedures e.g., while performing dressing and drainage changes in ICU.

Trabeculectomy offers better intraocular pressure reduction in intrapatient comparison to transscleral cyclophotocoagulation.

PURPOSE: Both trabeculotomy (TE) as well as transscleral endodiode laser cyclophotocoagulation (CPC) are common approaches in glaucoma surgery. The purpose of this study was to perform an intraindividual comparison of these procedures carried out by the same surgeon in the same patient on the same day. METHODS: An observational monocentric retrospective cohort study was conducted. Patients with a bilateral refractory open-angle glaucoma who underwent trabeculectomy in one eye and transscleral endodiode laser cyclophotocoagulation in the fellow eye simultaneously were included and followed up with over the course of 1 year. RESULTS: Eighty-two eyes of 41 patients were included. Seventeen patients (41.5%) were men and 24 (58.5%) women. The mean age was 68.7 ± 9.5 years. The diagnosis comprised 33 (80.5%) patients with a primary open-angle glaucoma, five (12.2%) patients with pseudoexfoliation glaucoma, and three (7.3%) patients with pigment dispersion glaucoma. A reduction in intraocular pressure (IOP) was seen in both after TE (from 26.2 ± 13.2 to 10.6 ± 4.1 mmHg, 52 weeks post-treatment) as well as CPC (from 24.2 ± 9.9 to 15.0 ± 5.4 mmHg, 52 weeks post-treatment). In comparison to each other, TE was significantly more effective in lowering the IOP (10.6 ± 4.1 vs. 13.4 ± 5.0; p = 0.0030, 52 weeks post-treatment) and needed antiglaucomatous medications (0.45 ± 0.80 vs. 1.24 ± 1.13; p = 0.0009, 52 weeks post-treatment). Consistently, the achievement rate of an IOP ≤ 16 mmHg without antiglaucomatous medications was significantly higher in TE-treated eyes (65.8% vs. 31.6%; p = 0.0019). Re-interventions, including 10 secondary TEs, were commonly required in those eyes undergoing CPC, especially in younger patients. CONCLUSIONS: Trabeculectomy was demonstrated to be more effective in reducing IOP in comparison to fellow eyes receiving CPC. In particular, in younger patients, an additional TE in the CPC-treated eyes was necessary. The outcome of those secondary TEs however was comparable to the primarily performed TEs. Our study thus supports the use of CPC as tool to control IOP, especially in the context of bilateral refractive glaucoma.

Effect of iloprost inhalation on postoperative outcome in high-risk cardiac surgical patients: a prospective randomized-controlled multicentre trial (ILOCARD).

PURPOSE: Perioperative right ventricular (RV) failure due to pressure overload from pulmonary hypertension (PH) worsens postoperative outcomes after cardiac surgery. Inhaled iloprost is a potent pulmonary vasodilator improving RV performance, ameliorating myocardial and pulmonary ischemia-reperfusion injury and attenuating inflammation. We hypothesized that the prophylactic inhalation of iloprost would reduce postoperative ventilation times after cardiac surgery. METHODS: In this phase III, multicentre, randomized, double-blind, placebo-controlled trial, we randomly assigned 253 cardiac surgical patients at high risk of perioperative RV failure to the prophylactic inhalation of 20 µg iloprost or placebo before and during weaning from extracorporeal circulation. The primary endpoint was the duration of postoperative ventilation. Secondary endpoints included perioperative hemodynamics, intensive care unit and hospital length of stay, and 90-day mortality. Safety was assessed by the incidence of adverse events. RESULTS: Iloprost had no significant effect on the median [interquartile range] duration of postoperative ventilation compared with placebo (720 [470-1170] min vs 778 [541-1219] min, respectively; median decrease, 65 min; 95% confidence interval [CI], - 77 to 210; P = 0.37). While the nebulization of iloprost decreased RV afterload and improved cardiac index, major secondary endpoints were not significantly affected. Ninety-day mortality occurred in 14% of the iloprost patients compared with 14% of the placebo patients (hazard ratio, 0.97; 95% CI, 0.50 to 1.89; P = 0.93). The incidence of adverse events was comparable in both groups. CONCLUSIONS: The prophylactic inhalation of iloprost did not meaningfully improve the outcome in high-risk cardiac surgical patients. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT00927654); registered 25 June, 2009.

RéSUMé: OBJECTIF: L'insuffisance cardiaque droite périopératoire due à une surcharge de pression provoquée par l'hypertension pulmonaire (HP) a un impact négatif sur le pronostic postopératoire après une chirurgie cardiaque. L'iloprost administré par inhalation est un vasodilatateur pulmonaire puissant qui améliore la performance du ventricule droit (VD), réduisant ainsi la lésion d'ischémie-reperfusion myocardique et pulmonaire et atténuant l'inflammation. Nous avons émis l'hypothèse qu'une inhalation prophylactique d'iloprost réduirait les temps de ventilation postopératoire après une chirurgie cardiaque. MéTHODE: Dans cette étude multicentrique de phase III, contrôlée par placebo, à double insu et randomisée, nous avons distribué aléatoirement 253 patients chirurgicaux courant un risque élevé d'insuffisance cardiaque droite périopératoire à une prophylaxie de 20 µg d'iloprost ou d'un placebo par inhalation avant et pendant le sevrage de la circulation extracorporelle. Le critère d'évaluation principal était la durée de ventilation postopératoire. Les critères d'évaluation secondaires étaient les données hémodynamiques périopératoires, la durée de séjour à l'unité de soins intensifs et à l'hôpital, et la mortalité à 90 jours. L'innocuité a été évaluée en fonction de l'incidence d'événements indésirables. RéSULTATS: L'iloprost n'a pas eu d'effet significatif sur la durée médiane [écart interquartile] de ventilation postopératoire par rapport au placebo (720 [470­1170] min vs 778 [541­1219] min, respectivement; réduction médiane, 65 min; intervalle de confiance [IC] 95 %, − 77 à 210; P = 0,37). Bien que la nébulisation d'iloprost ait réduit la post-charge du VD et amélioré l'index cardiaque, cette manœuvre n'a pas eu d'impact significatif sur les critères d'évaluation secondaires majeurs. Une mortalité à 90 jours a été observée chez 14 % des patients ayant reçu de l'iloprost, comparativement à 14 % des patients ayant reçu un placebo (rapport de risque, 0,97; IC 95 %, 0,50 à 1,89; P = 0,93). L'incidence d'événements indésirables était comparable dans les deux groupes. CONCLUSION: L'inhalation prophylactique d'iloprost n'a pas amélioré le pronostic des patients de chirurgie cardiaque à haut risque. ENREGISTREMENT DE L'éTUDE: www.clinicaltrials.gov (NCT00927654); enregistrée le 25 juin 2009.

Acetylcholine Receptor Antibody Titers and Clinical Course after Influenza Vaccination in Patients with Myasthenia Gravis: A Double-Blind Randomized Controlled Trial (ProPATIent-Trial).

BACKGROUND: It is a continuous matter of discussion whether immune activation by vaccination in general and Influenza vaccination in particular increases the risk for clinical deterioration of autoimmune diseases. This prospective study investigated the serological and clinical course of autoimmune Myasthenia gravis (MG) after a seasonal influenza vaccination. METHODS: This randomized, placebo-controlled, double-blind study enrolled MG patients with antibodies against acetylcholine-receptors (AChR-ab). They were allocated to receive seasonal influenza vaccine or placebo. The primary endpoint was the relative change of AChR-ab-titer over 12weeks. A relative increase of 20% was set as non-inferiority margin. Secondary endpoints were clinical changes in the modified Quantitative Myasthenia Gravis Score (QMG), increase of anti-influenza-ELISA-antibodies, and changes of treatment. The study is registered with Clinicaltrialsregister.eu, EudraCT number 2006-004374-27. FINDINGS: 62 patients were included. Mean±standard deviation (median) in the vaccine and placebo group were AChR-ab-titer changes of -6.0%±23.3% (-4.0%) and -2.8%±22.0% (-0.5%) and QMG score changes of -0.08±0.27 (0.17) and 0.11±0.31 (0.00), respectively. The difference between groups (Hodges-Lehmann estimate with 95% CI) was - for the AChR-ab-titer change 4·0% [-13.3%, 4.5%] (p=0.28 for testing a difference, p<0.0001 for testing non-inferiority) and for the QMG change 0·00 [-0.17, 0.00] (p=0.79 for testing a difference). The occurrence of 74 adverse events (AE) was comparable between groups. The most common AE was flu-like symptoms. One serious AE (hospitalisation following gastrointestinal haemorrhage) in the verum group was not related to the vaccine. INTERPRETATION: Influenza vaccination in MG is safe. Uprating the potential risk of a severe course of MG exacerbation during influenza infection compared to the 95% CI differences for the endpoints, vaccination is principally indicated in this patient population.

Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors (PROMID): Results of Long-Term Survival.

BACKGROUND: Somatostatin analogs have been shown to control the growth of well-differentiated metastatic neuroendocrine tumors. Their effect on overall survival is a matter of debate. We analyzed the prognostic significance of early treatment with octreotide LAR and of hepatic tumor load in the PROMID trial cohort. PATIENTS AND METHODS: Between 2001 and 2008, 85 treatment-naïve patients were randomly assigned to monthly octreotide LAR 30 mg or placebo until tumor progression or death. Post-study treatment was at the discretion of the investigator. Upon disease progression, 38 out of 43 placebo patients (88.4%) received octreotide LAR. For survival, patients were followed until May 2014. RESULTS: Forty-eight out of 85 patients (56.5%) died. In 38 patients (79.2%), death was tumor related. The median overall survival (84.7 and 83.7 months) was only slightly different in patients assigned to octreotide and placebo [HR = 0.83 (95% CI: 0.47-1.46); p = 0.51]. The median overall survival was 84.7 months for all 85 patients, 107.6 months in the low-tumor-load (n = 64) and 57.5 months in the high-tumor-load (n = 21) subgroups [HR = 2.49 (95% CI: 1.36-4.55); p = 0.002]. There was a trend towards improved overall survival in patients with a low hepatic tumor load receiving octreotide compared to placebo ['median not reached' and 87.2 months; HR = 0.59 (95% CI: 0.29-1.2); p = 0.142]. CONCLUSION: The extent of tumor burden is a predictor for shorter survival. Overall survival was similar in patients receiving octreotide LAR or placebo treatment at randomization. Crossover of the majority of placebo patients to octreotide LAR may have confounded the data on overall survival.

Salvage Treatment of Adrenocortical Carcinoma with Trofosfamide.

Adrenocortical carcinoma (ACC) has a dismal prognosis in advanced stages. Despite treatment with the adrenal toxicant mitotane and/or aggressive chemotherapy, tumor control is often short-lived. Here, we examine trofosfamide as a salvage treatment of ACC in an observational cohort study within the German ACC registry. Response defined as progression-free survival (PFS) at first tumor evaluation was assessed by RECIST 1.1 or clinically, and PFS and overall survival (OS) were estimated by the Kaplan-Meier method. Twenty-seven patients (11 males; median age 46.9 years) progressing after mitotane and three (median, range 0-5) other systemic treatments were evaluated for safety. Trofosfamide (150 mg/day) was administered as monotherapy (n = 13) or in combination with mitotane (n = 14). Overall tolerability was good with only mild adverse events. Six patients did not meet criteria for response assessment. Of the 21 patients, 8 patients had clinically progressive disease (3 deaths from ACC); among the 13 patients evaluable by RECIST 1.1, best response to treatment was stable disease (SD, n = 3) or progressive disease (n = 10). Hence, predefined response criteria were met in 3/21 patients (14 %). Median PFS was 84 days (95 % confidence interval 74-95) and median OS survival 198 days (95 % CI 89-307). One prolonged disease stabilization (best response by RECIST 1.1 -26 %) was observed for 479 days. In conclusion, trofosfamide is overall well tolerated but disease stabilization is rather rare. Accordingly, it may be used in selected cases of ACC not amenable to other treatment options such as clinical trials.

Propionibacterium acnes in shoulder surgery: is loss of hair protective for infection?

BACKGROUND: Propionibacterium acnes (P acnes) has been linked to chronic infections in shoulder surgery. It was recently observed during first-time shoulder surgery in healthy patients at a rate between 36% and 56%. Male gender and the anterolateral approach were reported risk factors. Because the skin biology greatly differs, we aimed to correlate skin complaints with P acnes-positive intraoperative cultures from different tissue layer samples in patients undergoing shoulder surgery for the first time. METHODS: Intraoperative samples (1 skin, 1 superficial, 1 deep tissue, and 1 control sample) from 112 patients (70 men, 42 women; aged 59.2 years) were cultured. The association between the presence of P acnes in the deep or superficial tissue, or both, and 10 items of a validated preoperative questionnaire for skin pathology was explored. RESULTS: The cultures were positive for P acnes in 38.4% (n = 43) of the cases. Skin samples were positive for P acnes in 8% (n = 9), superficial samples were positive in 23% (n = 26), and deep samples were positive in 30% (n = 34). Self-reported "loss of hair" was significantly negatively associated with the presence of P acnes in the superficial or deep tissue sample (P = .00028). DISCUSSION: Patients who report having "loss of hair" show fewer P acnes-positive cultures in intraoperative tissue samples taken during open shoulder surgery. Whether this subgroup is at a lesser risk for P acnes infections remains to be substantiated. LEVEL OF EVIDENCE: Basic Science Study; Microbiology.

Comparison of 6% hydroxyethyl starch and 5% albumin for volume replacement therapy in patients undergoing cystectomy (CHART): study protocol for a randomized controlled trial.

BACKGROUND: The use of artificial colloids is currently controversial, especially in Central Europe Several studies demonstrated a worse outcome in intensive care unit patients with the use of hydroxyethyl starch. This recently even led to a drug warning about use of hydroxyethyl starch products in patients admitted to the intensive care unit. The data on hydroxyethyl starch in non-critically ill patients are insufficient to support perioperative use. METHODS/DESIGN: We are conducting a single-center, open-label, randomized, comparative trial with two parallel patient groups to compare human albumin 5% (test drug) with hydroxyethyl starch 6% 130/0.4 (comparator). The primary endpoint is cystatin C ratio, calculated as the ratio of the cystatin value at day 90 after surgery relative to the preoperative value. Secondary objectives are inter alia the evaluation of the influence of human albumin and hydroxyethyl starch on further laboratory chemical and clinical parameters, glycocalyx shedding, intensive care unit and hospital stay and acute kidney injury as defined by RIFLE criteria (risk of renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function, and end-stage kidney disease) criteria. DISCUSSION: There is a general lack of evidence on the relative safety and effects of hydroxyethyl starch compared with human albumin for volume replacement in a perioperative setting. Previously conducted studies of surgical patients in which researchers have compared different hydroxyethyl starch products included too few patients to properly evaluate clinical important outcomes such as renal function. In the present study in a high-risk patient population undergoing a major surgical intervention, we will determine if perioperative fluid replacement with human albumin 5% will have a long-term advantage over a third-generation hydroxyethyl starch 130/0.4 on the progression of renal dysfunction until 90 days after surgery. TRIAL REGISTRATION: EudraCT number 2010-018343-34. Registered on 11 January 2010.

Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection.

BACKGROUND: Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently. OBJECTIVE: The aim of this study was to identify markers with prognostic value for patients in this clinical setting. DESIGN, SETTING, AND PARTICIPANTS: From the German ACC registry, 319 patients with the European Network for the Study of Adrenal Tumors stage I-III were identified. As an independent validation cohort, 250 patients from three European countries were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical, histological, and immunohistochemical markers were correlated with recurrence-free (RFS) and overall survival (OS). RESULTS: Although univariable analysis within the German cohort suggested several factors with potential prognostic power, upon multivariable adjustment only a few including age, tumor size, venous tumor thrombus (VTT), and the proliferation marker Ki67 retained significance. Among these, Ki67 provided the single best prognostic value for RFS (hazard ratio [HR] for recurrence, 1.042 per 1% increase; P < .0001) and OS (HR for death, 1.051; P < .0001) which was confirmed in the validation cohort. Accordingly, clinical outcome differed significantly between patients with Ki67 <10%, 10-19%, and ≥20% (for the German cohort: median RFS, 53.2 vs 31.6 vs 9.4 mo; median OS, 180.5 vs 113.5 vs 42.0 mo). Using the combined cohort prognostic scores including tumor size, VTT, and Ki67 were established. Although these scores discriminated slightly better between subgroups, there was no clinically meaningful advantage in comparison with Ki67 alone. CONCLUSION: This largest study on prognostic markers in localized ACC identified Ki67 as the single most important factor predicting recurrence in patients following R0 resection. Thus, evaluation of Ki67 indices should be introduced as standard grading in all pathology reports of patients with ACC.

Does footprint preparation influence tendon-to-bone healing after rotator cuff repair in an animal model?

PURPOSE: The aim of this study was to investigate the influence of footprint spongialization and radiofrequency ablation on rotator cuff repair outcomes compared with an untreated group in a rat model. METHODS: We randomly assigned 189 Sprague-Dawley rats to either a spongialization, radiofrequency ablation, or untreated group. After separation of the supraspinatus tendon from the greater tubercle, the footprint was prepared by removing the cortical bone with a burr (spongialization), was prepared by ablating soft tissue with a radiofrequency ablation device, or was left unaltered (untreated). Biomechanical testing (after 7 weeks, n = 165) and histologic analysis after 1 and 7 weeks (n = 24) followed reinsertion. RESULTS: The mean load to failure was 17.51 ± 4.46 N/mm(2) in the spongialization group, 15.56 ± 4.85 N/mm(2) in the radiofrequency ablation group, and 19.21 ± 5.19 N/mm(2) in the untreated group. A significant difference was found between the spongialization and radiofrequency ablation groups (P = .0409), as well as between the untreated and radiofrequency ablation groups (P = .0014). There was no significant difference between the spongialization and untreated groups (P = .2456). The mean area of fibrocartilage transition, characterized by the presence of type II collagen, was larger after 1 and 7 weeks in the spongialization group (0.57 ± 0.1 mm(2) and 0.58 ± 0.1 mm(2), respectively) and untreated group (0.51 ± 0.1 mm(2) and 0.51 ± 0.2 mm(2), respectively) than in the radiofrequency ablation group (0.11 ± 0.1 mm(2) and 0.4 ± 0.1 mm(2), respectively) with P < .05 and P < .01. CONCLUSIONS: The results of this study show that radiofrequency ablation of the footprint results in a poor biomechanical and histologic outcome in an animal model. No preparation of the footprint has the same effect as spongialization. CLINICAL RELEVANCE: Different techniques of footprint preparation in rotator cuff repair may influence tendon-to-bone healing.

Incurable recurrences in patients with oropharyngeal and hypopharyngeal carcinomas.

BACKGROUND: Carcinomas of the oropharyngeal and hypopharynx are difficult to treat because of their aggressive tendency to metastasize and their high recurrence rate. METHODS: A retrospective review of 79 patients with recurrences of oropharyngeal or hypopharyngeal carcinomas was performed. The courses of disease from recurrence diagnosis to the valuation date or death were analyzed. RESULTS: The median survival for patients classified as incurable at recurrence diagnosis amounted to 8 months (95% confidence interval [CI], 5-10 months), patients initially classified as curable at the time of recurrence diagnosis survived an estimated 12 months (95% CI, 8-22 months). No significant differences regarding the survival after diagnosed recurrence could be observed depending on the tumor location or tumor stage. CONCLUSION: The knowledge about the courses of disease and especially the remaining lifetime after diagnosed incurability could facilitate the planning of the remaining lifetime in order to achieve the best possible quality of life.

Reoperations for primary hyperparathyroidism--improvement of outcome over two decades.

PURPOSE: Reoperations (R-PTX) for primary hyperparathyroidism (pHPT) are challenging, since they are associated with increased failure and morbidity rates. The aim was to evaluate the results of reoperations over two decades, the latter considering the implementation of Tc(99m)sestamibi-SPECT (Mibi/SPECT), intraoperative parathormone (IOPTH) measurement, and intraoperative neuromonitoring (IONM). PATIENTS AND METHODS: Data of 1,363 patients who underwent surgery for pHPT were retrospectively analyzed regarding reoperations. Causes of persistent (p) pHPT or recurrent (r) pHPT, preoperative imaging studies, surgical findings, and outcome were analyzed. Data of patients who underwent surgery between 1987 and 1997 (group 1; G1) and between 1998 and 2008 (group 2; G2) with the use of Mibi/SPECT, IOPTH, and IONM were evaluated. RESULTS: One hundred twenty-five patients with benign ppHPT (n = 108) or rpHPT (n = 17) underwent reoperations (R-PTX). Group 1 included 54, group 2 71 patients. Main cause of ppHPT (G1 = 65 % vs. G2 = 53 %) and rpHPT (G1 = 80 % vs. G2 = 60 %) was the failed detection of a solitary adenoma (p = 0.2). Group 1 patients had significantly less unilateral/focused neck re-explorations (G1 = 23 % vs. G2 = 57 %, p = 0.0001), and more sternotomies (G1 = 35 vs. G2 = 14 %, p = 0.01). After a median follow-up of 4 (range 0.9-23.4) years, reversal of hypercalcemia was achieved in 91 % (G1) and in 98.6 % in group 2 (p = 0.08, OR 7.14 [0.809-63.1]). The rates of permanent recurrent laryngeal nerve palsy (G1 = G2 = 9 %, p = 1) and of postoperative permanent hypoparathyroidism (G1 = 9 % vs. G2 = 6 %, p = 0.5) were not significantly different. Other complications such as wound infection, postoperative bleeding, and pneumonia were significantly lower in group 2 (p < 0.001). CONCLUSION: Nowadays, cure rates of R-PTX are nearly the same as in primary operations for pHPT. These results can be achieved in high-volume centers by routine use of well-established preoperative Mibi/SPECT and US in combination with IOPTH. However, morbidity is still considerably high.

High- versus low-stimulation current threshold for axillary plexus blocks: a prospective randomized triple-blinded noninferiority trial in 205 patients.

BACKGROUND: For nerve stimulator-guided regional anesthesia, one has to compromise between a presumed low success rate (using a high-current threshold) and a presumed increased risk of nerve damage (using a low-current threshold). We hypothesized that high-current thresholds in the range of 0.9 to 1.1 mA are not inferior with respect to the procedural and latency times compared with low threshold currents in the range of 0.3 to 0.5 mA for nerve stimulation in brachial plexus blocks. METHODS: Two hundred five patients scheduled for elective surgery were randomized to a low (0.3-0.5 mA, n = 103) or a high (0.9-1.1 mA, n = 102) stimulation current threshold for the axillary plexus block with 40 mL local anesthetic mixture (20 mL, each of prilocaine 1% and ropivacaine 0.75%). The primary end point was the time to complete sensory block. The secondary outcome measures were the time to readiness for surgery (defined as the time from the start of block procedure to complete sensory block) and the block performance time. The noninferiority margin was set at 5 minutes and was evaluated using the two-sided 95% bootstrap-confidence intervals ([CIs] 100,000 replications) for differences in means. RESULTS: The mean times to complete sensory block revealed a significant decrease with the low-current group (17.9 ± 12.1 (mean ± SD) versus 22.8 ± 12.4 minutes; 95% CI, 1.1 to 8.6; p = 0.012). The time to readiness for surgery was 30.3 ± 13.8 minutes in the low-current group and 31.7 ± 12.9 minutes in the high-current group (95% CI, -2.7 to 5.5; p = 0.49). The performance time was significantly shorter in the high-current threshold group (9.5 ± 4.7 versus 11.9 ± 5.7 minutes; 95% CI, -4 to 1.1; p = 0.001). CONCLUSION: Noninferiority for the high-current threshold technique could neither be confirmed for the primary end point nor for secondary end points. However, we consider a difference in mean times of approximately 8.5 minutes to achieve readiness for surgery acceptable for clinical practice.

Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial.

CONTEXT: Treatment of refractory adrenocortical carcinoma (ACC) is not established. Animal experiments pointed toward adrenal toxicity of sunitinib. OBJECTIVE: The objective of the study was to determine the antitumor effects of sunitinib in refractory ACC. DESIGN: This was a phase II, open-label trial using a two-stage accrual design. SETTING: The study was conducted at two tertiary referral centers. PATIENTS: Thirty-eight patients with refractory ACC progressing after mitotane and one to three cytotoxic chemotherapies participated in the study. INTERVENTION: The intervention included sunitinib at a standard dose (50 mg/d, 4 wk on, 2 wk off). MAIN OUTCOME MEASURE: Response was defined as progression-free survival (PFS) of 12 wk or longer (first tumor evaluation). RESULTS: Thirty-five patients could be evaluated for response. Five patients experienced stable disease, 24 had progressive disease, and six patients died from ACC before the first evaluation (naïve estimate five of 35=14.3%, median unbiased response rate 15.4%, 95% confidence interval 5.0-33.4%). The median PFS was 2.8 months. In responders, PFS ranged between 5.6 and 11.2 months and overall survival between 14.0 and 35.5 months. Of 36 serious adverse events, only nine were possibly related to sunitinib. Concomitant mitotane appeared to negatively impact on outcome. Furthermore, a negative correlation between the serum concentrations of sunitinib plus its active metabolite N-desethylsunitinib (SU12662) and mitotane (r=-0.650; P=0.114) was observed in seven evaluable patients suggestive of a relevant drug interaction. CONCLUSION: Sunitinib has modest activity in advanced refractory ACC, which compares favorably with other targeted treatments in these patients. Sunitinib serum levels might have been profoundly reduced by mitotane induced cytochrome P450-3A4 activity attenuating its antitumor activity and adverse effects. Together these findings suggest that sunitinib deserves further investigation in mitotane-naïve ACC patients.

Development of a formula to predict parathyroid carcinoma in patients with primary hyperparathyroidism.

BACKGROUND: Cure of parathyroid carcinoma (PC) requires initial en bloc resection, including resection of all tumor-bearing tissue, with hemithyroidectomy and dissection of the central lymph node compartment. Unfortunately, no reliable preoperative criteria have yet been assessed to indicate a high likelihood of PC. Thus, the aim of the present study was to develop a formula to indicate preoperatively the presence of PC. METHODS: A prospective database of 1,363 patients with primary hyperparathyroidism (pHPT) was screened for patients with PC. Age, gender, surgical procedures, laboratory data, and follow-up results were evaluated and compared to a group of patients with benign pHPT. Based on preoperative serum calcium (Ca) and parathyroid hormone (PTH) levels, as well as patients' age at the time of diagnosis, a formula was developed by a multivariate logistic model that estimates the individual risk for PC. RESULTS: Between 1987 and 2008, 19 patients with PC were identified. Ca (3.8 ± 0.3 vs 2.9 ± 0.3 mmo/l; p = 0.0002) and PTH levels (1,250 ± 769 vs 194 ± 204 pg/ml; p = 0.0030) were significantly higher in patients with PC than in those with benign pHPT. Patients with PC were also significantly younger than patients with benign pHPT (48.9 ± 12.1 vs 59.1 ± 13.8 years; p < 0.05). With a ≥5 % probability that a given patient suffered from PC, the sensitivity and specificity to identify the disease were 100 and 30 %, respectively, with the new Ca, PTH, and age based logarithmic formula. CONCLUSIONS: The new logarithmic formula can be used to calculate the individual risk for PC. If the calculated individual risk exceeds 5 %, en bloc resection seems to be justified to provide long-term cure in case of PC.

Combination chemotherapy in advanced adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment. METHODS: We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival. RESULTS: For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments. CONCLUSIONS: Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT ClinicalTrials.gov number, NCT00094497.).