Harald Heinzl

Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study

Objective Earlier detection of pulmonary arterial hypertension (PAH), a leading cause of death in systemic sclerosis (SSc), facilitates earlier treatment. The objective of this study was to develop the first evidence-based detection algorithm for PAH in SSc. Methods In this cross-sectional, international study conducted in 62 experienced centres from North America, Europe and Asia, adults with SSc at increased risk of PAH (SSc for >3 years and predicted pulmonary diffusing capacity for carbon monoxide <60%) underwent a broad panel of non-invasive assessments followed by diagnostic right heart catheterisation (RHC). Univariable and multivariable analyses selected the best discriminatory variables for identifying PAH. After assessment for clinical plausibility and feasibility, these were incorporated into a two-step, internally validated detection algorithm. Nomograms for clinical practice use were developed. Results Of 466 SSc patients at increased risk of PAH, 87 (19%) had RHC-confirmed PAH. PAH was mild (64% in WHO functional class I/II). Six simple assessments in Step 1 of the algorithm determined referral to echocardiography. In Step 2, the Step 1 prediction score and two echocardiographic variables determined referral to RHC. The DETECT algorithm recommended RHC in 62% of patients (referral rate) and missed 4% of PAH patients (false negatives). By comparison, applying European Society of Cardiology/European Respiratory Society guidelines to these patients, 29% of diagnoses were missed while requiring an RHC referral rate of 40%. Conclusions The novel, evidence-based DETECT algorithm for PAH detection in SSc is a sensitive, non-invasive tool which minimises missed diagnoses, identifies milder disease and addresses resource usage.

Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis

Background: Early treatment prevents progression of joint damage in rheumatoid arthritis (RA), but diagnosis in early disease is impeded by lack of appropriate diagnostic criteria. Objective: To study the value of rheumatoid factor (RF), anti-cyclic citrullinated peptide autoantibodies (anti-CCP), and anti-RA33 autoantibodies for diagnosis of RA and prediction of outcome in patients with very early arthritis. Methods: The prospective follow up inception cohort included 200 patients with very early (<3 months) inflammatory joint disease. Autoantibodies were measured at baseline and analysed in a tree based model which aimed at determining the added diagnostic value of testing for anti-CCP and anti-RA33 as compared with RF alone. Results: RA was diagnosed in 102 patients, while 98 developed other inflammatory arthropathies. Receiver operator curve analysis showed an optimum cut off level for RF at 50 U/ml, above which anti-CCP and anti-RA33 had no additional diagnostic value. Remarkably, RF ⩾50 U/ml and anti-CCP showed similar sensitivity and high specificity for RA, but overlapped considerably. Anti-RA33 was less specific and did not correlate with RF or anti-CCP. Among patients with RA, 72% showed at least one of these three autoantibodies, compared with 15% of non-RA patients. RF ⩾50 U/ml and anti-CCP were predictors of erosive disease, whereas anti-RA33 was associated with mild disease. Conclusions: Stepwise autoantibody testing in early inflammatory joint disease, starting with RF, followed by anti-CCP (in patients with RF <50 U/ml), and finally anti-RA33, should be used as a sensitive and effective strategy for distinguishing patients with RA at high risk for poor outcome.

Improved prediction of intraocular lens power using partial coherence interferometry

Purpose: To evaluate the feasibility of using a new optical biometry technique, dual‐beam partial coherence interferometry (PCI), to improve intraocular lens (IOL) power prediction in cataract surgery. Setting: Department of Ophthalmology, Vienna General Hospital, and Institute of Medical Physics, University of Vienna, Vienna, Austria. Methods: Preoperative axial length (AL) data obtained with PCI biometry and applanation ultrasound (US) biometry in 77 eyes of 51 patients was applied to 4 commonly used IOL power formulas. The refractive outcome and the mean absolute error (MAE) were calculated for each formula using both biometry methods. A linear multiple‐regression model based on preoperative PCI biometry data was derived to predict the postoperative anterior chamber depth (ACD). The predictive power of this regression model was assessed by adding the predicted ACD to the SRK/T formula. Predicted residuals were calculated to evaluate the feasibility and stability of this modified IOL power formula. Results: Using PCI instead of US biometry significantly improved the refractive outcome with all 4 IOL power formulas. The Holladay I and SRK/T formulas yielded an MAE of 0.44 diopter (D) using PCI AL data and 0.56 D and 0.57 D, respectively, using US biometry data. The SRK/T formula combined with the PCI regression model for postoperative ACD prediction performed slightly better (MAE 0.42 D) than the conventional SRK/T formula alone. Predicted residuals revealed an MAE of 0.46 D, proving the predictive performance of the new formula. Conclusions: Partial coherence interferometry biometry applied to several widely used IOL power formulas yielded significantly better IOL power prediction and therefore refractive outcome in cataract surgery than US biometry. Further improvement can be achieved by applying PCI to a modified SRK/T formula that predicts the postoperative ACD using PCI biometry data.

Gaining more flexibility in Cox proportional hazards regression models with cubic spline functions.

The Cox proportional hazards model is the most popular model for the analysis of survival data. The use of cubic spline functions allows investigation of non-linear effects of continuous covariates and flexible assessment of time-by-covariate interactions. Two main advantages are provided--no particular functional form has to be specified and standard computer software packages like SAS or BMDP can be used. A SAS macro which implements the method is presented.

Long-term followup of uncemented tumor endoprostheses for the lower extremity.

Between 1982 and 1989, 100 primary lower limb reconstructions were done using the Kotz Modular Femur Tibia Reconstruction System after resection of a malignant tumor. In 32 patients a proximal femur prosthesis was implanted, in 40 patients a distal femur prosthesis was implanted, in 19 patients a proximal tibia component was implanted, in four patients a total femur prosthesis was implanted, and in five patients a total knee prosthesis was implanted. The Kaplan-Meier estimate of the overall survival rate of the prostheses was 85% after 3 years, 79% after 5 years, and 71% after 10 years. The most common reason for implant failure was aseptic loosening in 27% of patients (11 patients; range, 10–121 months) after the initial operation. The other reasons for revision surgery were implant fracture (n 5 4) and infection (n 5 4). Early repair of prostheses-related minor complications, such as worn polyethylene bushings, resulted in a statistically significant reduction of implant failure. After a median followup of 127.5 months after the initial surgery, 51 patients had died and eight patients were lost to followup. Forty-one patients were evaluated clinically and radiologically using the Musculoskeletal Tumor Society score and the radiologic implant evaluation system of the International Symposium on Limb Salvage; these 41 patients had a mean of 80% (range, 40%–100%) of the normal functional capability.

Anti-O6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as clinical biomarker.

Silencing of O6‐methylguanine‐DNA methyltransferase (MGMT) protein expression because of MGMT gene promoter hypermethylation is considered to be associated with postoperative chemoradiotherapy benefits in glioblastoma multiforme (GBM) patients. The objective of this study was to clarify the usability of MGMT immunohistochemistry (IHC) as a clinical biomarker.

Hypothyroidism in patients with renal cell carcinoma: blessing or curse?

Sunitinib and sorafenib are tyrosine kinase inhibitors that have important antitumor activity in metastatic renal cell carcinoma (mRCC). Hypothyroidism constitutes a commonly reported side effect of both drugs, and particularly of sunitinib. The objective of this analysis was to investigate whether the occurrence of hypothyroidism during treatment with sunitinib and sorafenib affects the outcome of patients with mRCC.

The ART of decision making: Retreatment with transarterial chemoembolization in patients with hepatocellular carcinoma

We aimed to establish an objective point score to guide the decision for retreatment with transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). In all, 222 patients diagnosed with HCC and treated with multiple TACE cycles between January 1999 and December 2009 at the Departments of Gastroenterology/Hepatology of the Medical Universities of Vienna (training cohort) and Innsbruck (validation cohort) were included. We investigated the effect of the first TACE on parameters of liver function and tumor response and their impact on overall survival (OS, log rank test) and developed a point score (ART score: Assessment for Retreatment with TACE) in the training cohort (n = 107, Vienna) by using a stepwise Cox regression model. The ART score was externally validated in an independent validation cohort (n = 115, Innsbruck). The increase of aspartate aminotransferase (AST) by >25% (hazard ratio [HR] 8.4; P < 0.001), an increase of Child‐Pugh score of 1 (HR 2.0) or ≥2 points (HR 4.4) (P < 0.001) from baseline, and the absence of radiologic tumor response (HR 1.7; P = 0.026) remained independent negative prognostic factors for OS and were used to create the ART score. The ART score differentiated two groups (0‐1.5 points; ≥2.5 points) with distinct prognosis (median OS: 23.7 versus 6.6 months; P < 0.001) and a higher ART score was associated with major adverse events after the second TACE (P = 0.011). These results were confirmed in the external validation cohort and remained significant irrespective of Child‐Pugh stage and the presence of ascites prior the second TACE. Conclusion: An ART score of ≥2.5 prior the second TACE identifies patients with a dismal prognosis who may not profit from further TACE sessions. (HEPATOLOGY 2013;57:2261–2273)

Local tumor control and morbidity after one to three fractions of stereotactic external beam irradiation for uveal melanoma

BACKGROUND AND PURPOSE To evaluate prospectively local tumor control and morbidity after 1-3 fractions of stereotactic external beam irradiation (SEBI) in patients with uveal melanoma, unsuitable for ruthenium-106 brachytherapy or local resection. MATERIAL AND METHODS This phase I/II study includes 62 selected patients with uveal melanoma. The mean initial tumor height was 7.8+/-2.8 mm. With the Leskell gamma knife SEBI, 41 patients (66%) were irradiated with two equal fractions of 35, 30 or 25 Gy/fraction, 14 patients (22%) were treated with three fractions of 15 Gy each, and seven patients (11%) with small tumor volumes below 400 mm(3) were treated with one fraction of 45 Gy. The mean total dose was 54+/-8 Gy. The minimal follow-up period was 12 months, and the median follow-up was 28.3 months. Data on radiation-induced side-effects were analyzed with the Cox proportional hazards model for possible risk factors. RESULTS Local tumor control was achieved in 98% and tumor height reduction in 97%. The mean relative tumor volume reductions were 44, 60 and 72% after 12, 24 and 36 months, respectively. Seven patients developed metastases (11%). Secondary enucleation was performed in eight eyes (13%). Morbidity was significant in tumors exceeding 8 mm in initial height; it was comparable and acceptable in those smaller. In the stepwise multiple Cox model, tumor localization, height and volume, planning target volume (PTV), total dose and patient age were identified as the strongest risk factors for radiation-induced lens opacities, secondary glaucoma, uveitis, eyelash loss and exudative retinal detachment. In this model, the high-dose volume irradiated with more than 10 Gy/fraction was the strongest risk factor for radiation-induced uveitis. CONCLUSIONS Stereotactic external photon beam irradiation and a total dose of 45-70 Gy delivered in one to three fractions are highly effective at achieving local tumor control in uveal melanoma. Further clinical studies using smaller fraction doses, and consequent smaller high-dose volumes, are justified to optimize dose and fractionation. Fractionated stereotactic irradiation has a challenging potential as an eye-preserving treatment in uveal melanoma.

Incidence of atypical teratoid/rhabdoid tumors in children: a population-based study by the Austrian Brain Tumor Registry, 1996-2006.

Atypical teratoid/rhabdoid tumors are highly malignant embryonal central nervous system (CNS) tumors that were defined as an entity in 1996. As compared with other malignant CNS tumors, their biological behavior is particularly aggressive, but patients may benefit from an intensified treatment. Atypical teratoid/rhabdoid tumors display a complex histomorphology, which renders them prone to misdiagnosis. They occur predominantly in young children, with an estimated prevalence of 1% to 2% among all pediatric CNS tumors. However, population‐based data on the incidence of these tumors are not yet available.