Publications by authors named "Harald Heinzl"

63 Publications

Three brief pieces of statistical advice for medical peer reviewers.

Eur J Clin Invest 2019 Nov;49(11):e13171

Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

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http://dx.doi.org/10.1111/eci.13171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899676PMC
November 2019

Patient-Sharing Relations in the Treatment of Diabetes and Their Implications for Health Information Exchange: Claims-Based Analysis.

JMIR Med Inform 2019 Apr 12;7(2):e12172. Epub 2019 Apr 12.

Section for Clinical Biometrics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.

Background: Health information exchange (HIE) among care providers who cooperate in the treatment of patients with diabetes mellitus (DM) has been rated as an important aspect of successful care. Patient-sharing relations among care providers permit inferences about corresponding information-sharing relations.

Objectives: This study aimed to obtain information for an effective HIE platform design to be used in DM care by analyzing patient-sharing relations among various types of care providers (ToCPs), such as hospitals, pharmacies, and different outpatient specialists, within a nationwide claims dataset of Austrian DM patients. We focus on 2 parameters derived from patient-sharing networks: (1) the principal HIE partners of the different ToCPs involved in the treatment of DM and (2) the required participation rate of ToCPs in HIE platforms for the purpose of effective communication.

Methods: The claims data of 7.9 million Austrian patients from 2006 to 2007 served as our data source. DM patients were identified by their medication. We established metrics for the quantification of our 2 parameters of interest. The principal HIE partners were derived from the portions of a care provider's patient-sharing relations with different ToCPs. For the required participation rate of ToCPs in an HIE platform, we determine the concentration of patient-sharing relations among ToCPs. Our corresponding metrics are derived in analogy from existing work for the quantification of the continuity of care.

Results: We identified 324,703 DM patients treated by 12,226 care providers; the latter were members of 16 ToCPs. On the basis of their score for 2 of our parameters, we categorized the ToCPs into low, medium, and high. For the most important HIE partner parameter, pharmacies, general practitioners (GPs), and laboratories were the representatives of the top group, that is, our care providers shared the highest numbers of DM patients with these ToCPs. For the required participation rate of type of care provide (ToCP) in HIE platform parameter, the concentration of DM patient-sharing relations with a ToCP tended to be inversely related to the ToCPs member count.

Conclusions: We conclude that GPs, pharmacies, and laboratories should be core members of any HIE platform that supports DM care, as they are the most important DM patient-sharing partners. We further conclude that, for implementing HIE with ToCPs who have many members (in Austria, particularly GPs and pharmacies), an HIE solution with high participation rates from these ToCPs (ideally a nationwide HIE platform with obligatory participation of the concerned ToCPs) seems essential. This will raise the probability of HIE being achieved with any care provider of these ToCPs. As chronic diseases are rising because of aging societies, we believe that our quantification of HIE requirements in the treatment of DM can provide valuable insights for many industrial countries.
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http://dx.doi.org/10.2196/12172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484263PMC
April 2019

Cancer incidence in an Austrian alpine valley 1983-2012 : A descriptive study.

Wien Klin Wochenschr 2019 May 14;131(9-10):200-204. Epub 2019 Mar 14.

Section for Clinical Biometrics, Center for Medical Statistics, Informatics and Intelligent Systems, Medical University Vienna, Vienna, Austria.

After one of Austria's largest environmental scandals in 2014, which involved the release of hexachlorobenzene (HCB) in the Carinthian valley Görtschitztal, concerns about increased cancer rates have arísen in the affected local population. A descriptive study was conducted to examine the cancer incidence rates between 1983 and 2012. Data from the affected area (Görtschitztal, district St. Veit) were compared to data from the neighboring area within the same district and Carinthia excluding St. Veit, considering incidence rates of liver, lung, kidney, thyroid cancer and mesothelioma. Prostate cancer and carcinoma in situ were both included and excluded from overall cancer incidents in order to prevent potential bias due to screening programs. Considering the observed variability at an overall level, no conspicuous differences in cancer incidences could be found (Carinthia: 495, St. Veit West: 408, St. Veit East: 572 cases per 100,000 person-years in 2012). For some cancer types, e. g. liver, thyroid cancer and mesothelioma, the affected region showed a higher increase in rates than the neighboring area or Carinthia overall; however, these increased rates date back to a time prior to the HCB exposure, suggesting other carcinogenic influences, such as asbestos exposure from antecedent years.
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http://dx.doi.org/10.1007/s00508-019-1476-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520313PMC
May 2019

Contribution to the discussion of "When should meta-analysis avoid making hidden normality assumptions?"

Biom J 2018 11 1;60(6):1085-1086. Epub 2018 Aug 1.

Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1002/bimj.201800189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282562PMC
November 2018

Visualizing the quantile survival time difference curve.

J Eval Clin Pract 2018 08 23;24(4):708-712. Epub 2018 May 23.

Section for Clinical Biometrics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.

The difference between the pth quantiles of 2 survival functions can be used to compare patients' survival between 2 therapies. Setting p = 0.5 yields the median survival time difference. Varying p between 0 and 1 defines the quantile survival time difference curve which can be straightforwardly estimated by the horizontal differences between 2 Kaplan-Meier curves. The estimate's variability can be visualized by adding either a bundle of resampled bootstrap step functions or, alternatively, approximate bootstrap confidence bands. The user-friendly SAS software macro %kmdiff enables the straightforward application of this exploratory graphical approach. The macro is described, and its application is exemplified with breast cancer data. The advantages and limitations of the approach are discussed.
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http://dx.doi.org/10.1111/jep.12948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099283PMC
August 2018

Assessing the effect of a partly unobserved, exogenous, binary time-dependent covariate on survival probabilities using generalised pseudo-values.

BMC Med Res Methodol 2018 01 19;18(1):14. Epub 2018 Jan 19.

Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Spitalgasse 23, A-1090, Vienna, Austria.

Background: Investigating the impact of a time-dependent intervention on the probability of long-term survival is statistically challenging. A typical example is stem-cell transplantation performed after successful donor identification from registered donors. Here, a suggested simple analysis based on the exogenous donor availability status according to registered donors would allow the estimation and comparison of survival probabilities. As donor search is usually ceased after a patient's event, donor availability status is incompletely observed, so that this simple comparison is not possible and the waiting time to donor identification needs to be addressed in the analysis to avoid bias. It is methodologically unclear, how to directly address cumulative long-term treatment effects without relying on proportional hazards while avoiding waiting time bias.

Methods: The pseudo-value regression technique is able to handle the first two issues; a novel generalisation of this technique also avoids waiting time bias. Inverse-probability-of-censoring weighting is used to account for the partly unobserved exogenous covariate donor availability.

Results: Simulation studies demonstrate unbiasedness and satisfying coverage probabilities of the new method. A real data example demonstrates that study results based on generalised pseudo-values have a clear medical interpretation which supports the clinical decision making process.

Conclusions: The proposed generalisation of the pseudo-value regression technique enables to compare survival probabilities between two independent groups where group membership becomes known over time and remains partly unknown. Hence, cumulative long-term treatment effects are directly addressed without relying on proportional hazards while avoiding waiting time bias.
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http://dx.doi.org/10.1186/s12874-017-0430-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775686PMC
January 2018

Exploring the possible relationship between ambient heat and sudden infant death with data from Vienna, Austria.

PLoS One 2017 6;12(9):e0184312. Epub 2017 Sep 6.

Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.

A non-linear relationship between maximum ambient temperature and number of sudden infant death syndrome (SIDS) cases had been reported for Montreal, Canada, for the warm season. In particular, high maximum ambient temperatures were found to be extra-hazardous for infants. The study was replicated with data from Vienna, Austria, applying the same statistical approach. Vienna is roughly comparable to Montreal with regard to temperatures in the warm season, size of population, and number of SIDS cases. Although the Viennese study was powerful enough to detect even smaller effects, the Montrealean results could not be confirmed. The Viennese results do not support the hypothesis of a strong effect of maximum ambient temperature on the risk of SIDS during the warm season.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184312PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587259PMC
October 2017

Chromosome 1q gain and tenascin-C expression are candidate markers to define different risk groups in pediatric posterior fossa ependymoma.

Acta Neuropathol Commun 2016 08 22;4(1):88. Epub 2016 Aug 22.

Institute of Neurology, Medical University of Vienna, Vienna, Austria.

Intracranial classic (WHO grade II) and anaplastic (WHO grade III) ependymomas are among the most common tumors in pediatric patients and have due to frequent recurrences and late relapses a relatively poor outcome. The impact of histopathological grading on patient outcome is controversial and therefore, molecular prognostic and predictive markers are needed to improve patient outcome. To date, the most promising candidate marker is chromosome 1q gain, which has been associated in independent studies with adverse outcome. Furthermore, gene expression and methylation profiles revealed distinct molecular subgroups in the supratentorial and posterior fossa (PF) compartment and Laminin alpha-2 (LAMA2) and Neural Epidermal Growth Factor Like-2 (NELL2) were suggested as surrogate markers for the two PF subgroups PF-EPN-A and PF-EPN-B. PF-EPN-A tumors were also characterized by tenascin-C (TNC) expression and tenascin-C has been suggested as candidate gene on 9q, involved in tumor progression. Therefore, we have analyzed the status of chromosome 1q, TNC, LAMA2, and NELL2 expression in a series of pediatric PF ependymomas in terms of their frequency, associations among themselves, and clinical parameters, as well as their prognostic impact. We confirm the negative prognostic impact of 1q gain and TNC expression and could classify PF ependymomas by these two markers into three molecular subgroups. Tumors with combined 1q gain and TNC expression had the poorest, tumors without 1q gain and TNC expression had a favorable and TNC positive 1q non-gained cases had an intermediate outcome. We found also differences in age and tumor grade in the three subgroups and thus, provide evidence that PF pediatric ependymomas can be divided by chromosome 1q status and TNC expression in three molecular subgroups with distinct clinico-pathological features. These analyses require only few amounts of tumor tissue, are broadly available in the routine clinical neuropathological setting and thus, could be used in further therapy trials to optimize treatment of ependymoma patients.
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http://dx.doi.org/10.1186/s40478-016-0349-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994287PMC
August 2016

Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in patients with brain metastases.

Oncoimmunology 2016;5(1):e1057388. Epub 2015 Jun 9.

Department for Medicine I/Clinical Division of Oncology; Medical University of Vienna; Vienna, Austria; Comprehensive Cancer Center - CNS Tumors Unit; Medical University of Vienna; Vienna, Austria.

The immune microenvironment of the brain differs from that of other organs and the role of tumor-infiltrating lymphocytes (TILs) in brain metastases (BM), one of the most common and devastating complication of cancer, is unclear. We investigated TIL subsets and their prognostic impact in 116 BM specimens using immunohistochemistry for CD3, CD8, CD45RO, FOXP3, PD1 and PD-L1. The Immunoscore was calculated as published previously. Overall, we found TIL infiltration in 115/116 (99.1%) BM specimens. PD-L1 expression was evident in 19/67 (28.4%) BM specimens and showed no correlation with TIL density ( > 0.05). TIL density was not associated with corticosteroid administration ( > 0.05). A significant difference in infiltration density according to TIL subtype was present ( < 0.001; Chi Square); high infiltration was most frequently observed for CD3+ TILs (95/116; 81.9%) and least frequently for PD1+ TILs (18/116; 15.5%; < 0.001). Highest TIL density was observed in melanoma, followed by renal cell cancer and lung cancer BM (p < 0.001). The density of CD8 TILs correlated positively with the extent of peritumoral edema seen on pre-operative magnetic resonance imaging ( = 0.031). The density of CD3+ (15 vs. 6 mo; = 0.015), CD8 (15 vs. 11 mo; = 0.030) and CD45RO+ TILs (18 vs. 8 mo; = 0.006) showed a positive correlation with favorable median OS times. Immunoscore showed significant correlation with survival prognosis (27 vs. 10 mo; < 0.001). The prognostic impact of Immunoscore was independent from established prognostic parameters at multivariable analysis (HR 0.612, < 0.001). In conclusion, our data indicate that dense TILs infiltrates are common in BM and correlate with the amount of peritumoral brain edema and survival prognosis, thus identifying the immune system as potential biomarker for cancer patients with CNS affection. Further studies are needed to substantiate our findings.
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http://dx.doi.org/10.1080/2162402X.2015.1057388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760339PMC
June 2015

Clinical Neuropathology practice guide 5-2015: MGMT methylation pyrosequencing in glioblastoma: unresolved issues and open questions.

Clin Neuropathol 2015 Sep-Oct;34(5):250-7

Institute of Neurology, Medical University of Vienna, Vienna, Austria, Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland, Department of Medicine I, Comprehensive Cancer Center-CNS Tumours Unit (CCC-CNS), and Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.

O6-methylguanine-methyltransferase (MGMT) promoter methylation status has prognostic and, in the subpopulation of elderly patients, predictive value in newly diagnosed glioblastoma. Therefore, knowledge of the MGMT promoter methylation status is important for clinical decision-making. So far, MGMT testing has been limited by the lack of a robust test with sufficiently high analytical performance. Recently, one of several available pyrosequencing protocols has been shown to be an accurate and robust method for MGMT testing in an intra- and interlaboratory ring trial. However, some uncertainties remain with regard to methodological issues, cut-off definitions, and optimal use in the clinical setting. In this article, we highlight and discuss several of these open questions. The main unresolved issues are the definition of the most relevant CpG sites to analyze for clinical purposes and the determination of a cut-off value for dichotomization of quantitative MGMT pyrosequencing results into "MGMT methylated" and "MGMT unmethylated" patient subgroups as a basis for further treatment decisions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4542181PMC
http://dx.doi.org/10.5414/np300904DOI Listing
July 2016

How to STATE suitability and START transarterial chemoembolization in patients with intermediate stage hepatocellular carcinoma.

J Hepatol 2014 Dec 10;61(6):1287-96. Epub 2014 Jul 10.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, AKH & Medical University of Vienna, Austria. Electronic address:

Background & Aims: We aimed to establish an objective point score to guide the decision for the first treatment with transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC).

Methods: 277 patients diagnosed with HCC and treated with transarterial treatments between 1/2002 and 12/2011 at the Medical Universities of Vienna (training cohort) and Innsbruck (validation cohort) were included. We investigated the impact of baseline liver function and tumour load on overall survival (OS, log-rank test) and developed a point score (STATE-score: Selection for TrAnsarterial chemoembolisation TrEatment) in the training-cohort (n=131, Vienna) by using a stepwise Cox regression model. The STATE-score was externally validated in an independent validation cohort (n=146, Innsbruck) and thereafter combined with the Assessment for Retreatment with TACE (ART)-score to identify patients who are (un)suitable for TACE.

Results: The STATE-score starts with the serum-albumin level (g/L), which is reduced by 12 points each, if the tumour load exceeds the up-to-7 criteria and/or C-reactive protein (CRP) levels are ⩾1 mg/dl (maximum reduction: 24 points). The STATE-score differentiated 2 groups (<18, ⩾18 points) with distinct prognosis (median OS: 5.3 vs. 19.5 months; p<0.001) and a lower STATE-score was associated with short-term harm and increased mortality after TACE-1 (39% vs. 14% p<0.001). Sequential use of the STATE and the ART-score (START-strategy) identified the most (un)suitable patients for TACE. Results were confirmed in the external validation-cohort and were independent from recently proposed baseline selection tools.

Conclusion: The STATE-score identifies patients who are (un)suitable for the first TACE. The START-strategy identified the best candidates for multiple TACE sessions.
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http://dx.doi.org/10.1016/j.jhep.2014.07.002DOI Listing
December 2014

The ART-strategy: sequential assessment of the ART score predicts outcome of patients with hepatocellular carcinoma re-treated with TACE.

J Hepatol 2014 Jan 3;60(1):118-26. Epub 2013 Sep 3.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, AKH and Medical University of Vienna, Austria. Electronic address:

Background & Aims: Recently, we developed the ART score (assessment for re-treatment with TACE) to guide the decision for a second transarterial chemoembolization (TACE-2) in patients with hepatocellular carcinoma (HCC). Patients with an ART score of 0-1.5 points gained benefit from a second TACE session, while patients with an ART score ≥2.5 points did not. Here, we investigated (1) the prognostic significance of the ART score prior to the third (TACE-3) and fourth TACE (TACE-4), and (2) the feasibility of an ART score guided re-treatment strategy by sequential assessment of the ART score in HCC patients treated with multiple TACE sessions.

Methods: 109 patients, diagnosed with intermediate stage HCC and treated with ≥3 TACE sessions between January 1999 and December 2009 at the Medical Universities of Vienna and Innsbruck, were included. The ART score prior to each TACE session was assessed in comparison to the TACE naïve liver. The prognostic performance of the ART score before TACE-3 and 4 was evaluated with and without stratification based on the ART score prior to the respective last intervention.

Results: The pre-TACE-3 ART score discriminated two groups with different prognosis and remained a valid predictor of OS independent of Child-Pugh score (5-7 points), CRP-levels and tumor characteristics. Even in patients with an initially beneficial ART score (0-1.5 points) before TACE-2, repeated ART score assessment before TACE-3 identified a subgroup of patients with dismal prognosis (median OS: 27.8 vs. 10.8 months, p<0.001). Similar results were observed when the ART score was applied before TACE-4.

Conclusions: The sequential assessment of the ART score identifies patients with dismal prognosis prior to each TACE session.
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http://dx.doi.org/10.1016/j.jhep.2013.08.022DOI Listing
January 2014

Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series.

Acta Neuropathol 2013 Sep 31;126(3):365-84. Epub 2013 Jul 31.

Institute of Neurology, Medical University Vienna, AKH 4J, Währinger Gürtel 18-20, 1097, Vienna, Austria.

Neurodegenerative diseases are characterised by neuronal loss and cerebral deposition of proteins with altered physicochemical properties. The major proteins are amyloid-β (Aβ), tau, α-synuclein, and TDP-43. Although neuropathological studies on elderly individuals have emphasised the importance of mixed pathologies, there have been few observations on the full spectrum of proteinopathies in the ageing brain. During a community-based study we performed comprehensive mapping of neurodegeneration-related proteins and vascular pathology in the brains of 233 individuals (age at death 77-87; 73 examined clinically in detail). While all brains (from individuals with and without dementia) showed some degree of neurofibrillary degeneration, Aβ deposits were observed only in 160 (68.7 %). Further pathologies included α-synucleinopathies (24.9 %), non-Alzheimer tauopathies (23.2 %; including novel forms), TDP-43 proteinopathy (13.3 %), vascular lesions (48.9 %), and others (15.1 %; inflammation, metabolic encephalopathy, and tumours). TDP-43 proteinopathy correlated with hippocampal sclerosis (p < 0.001) and Alzheimer-related pathology (CERAD score and Braak and Braak stages, p = 0.001). The presence of one specific variable (cerebral amyloid angiopathy, Aβ parenchymal deposits, TDP-43 proteinopathy, α-synucleinopathy, vascular lesions, non-Alzheimer type tauopathy) did not increase the probability of the co-occurrence of others (p = 0.24). The number of observed pathologies correlated with AD-neuropathologic change (p < 0.0001). In addition to AD-neuropathologic change, tauopathies associated well with dementia, while TDP-43 pathology and α-synucleinopathy showed strong effects but lost significance when evaluated together with AD-neuropathologic change. Non-AD neurodegenerative pathologies and their combinations have been underestimated, but are frequent in reality as demonstrated here. This should be considered in diagnostic evaluation of biomarkers, and for better clinical stratification of patients.
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http://dx.doi.org/10.1007/s00401-013-1157-yDOI Listing
September 2013

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

Ann Rheum Dis 2014 Jul 18;73(7):1340-9. Epub 2013 May 18.

Scleroderma Research Consultants LLC, Avon, Connecticut, USA.

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.
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http://dx.doi.org/10.1136/annrheumdis-2013-203301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078756PMC
July 2014

Clinical neuropathology practice guide 3-2013: levels of evidence and clinical utility of prognostic and predictive candidate brain tumor biomarkers.

Clin Neuropathol 2013 May-Jun;32(3):148-58

Institute of Neurology, Department of Neurosurgery, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Austria.

A large number of potential tissue biomarkers has been proposed for brain tumors. However, hardly any have been adopted for routine clinical use, so far. For most candidate biomarkers substantial controversy exists with regard to their usefulness in clinical practice. The multidisciplinary neurooncology taskforce of the Vienna Comprehensive Cancer Center Central Nervous System Unit (CCC-CNS) addressed this issue and elaborated a four-tiered levels-of-evidence system for assessing analytical performance (reliability of test result) and clinical performance (prognostic or predictive) based on consensually defined criteria. The taskforce also consensually agreed that only biomarker candidates should be considered as ready for clinical use, which meet defined quality standards for both, analytical and clinical performance. Applying this levels-of-evidence system to MGMT, IDH1, 1p19q, Ki67, MYCC, MYCN and β-catenin, only immunohistochemical IDH1 mutation testing in patients with diffuse gliomas is supported by sufficient evidence in order to be unequivocally qualified for clinical use. For the other candidate biomarkers lack of published evidence of sufficiently high analytical test performance and, in some cases, also of clinical performance limits evidence-based confirmation of their clinical utility. For most of the markers, no common standard of laboratory testing exists. We conclude that, at present, there is a strong need for studies that specifically address the analytical performance of candidate brain tumor biomarkers. In addition, standardization of laboratory testing is needed. We aim to regularly challenge and update the present classification in order to systematically clarify the current translational status of candidate brain tumor biomarkers and to identify specific research needs for accelerating the translational pace.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663466PMC
http://dx.doi.org/10.5414/np300646DOI Listing
June 2013

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

Hepatology 2013 Jun 3;57(6):2261-73. Epub 2013 May 3.

Division of Gastroenterology and Hepatology, Department of Internal Medicine III, AKH & Medical University of Vienna, Austria.

Unlabelled: 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).
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http://dx.doi.org/10.1002/hep.26256DOI Listing
June 2013

Short-term effect of macronutrient composition and glycemic index of a yoghurt breakfast on satiety and mood in healthy young men.

Forsch Komplementmed 2012 5;19(5):247-51. Epub 2012 Oct 5.

Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, Austria.

Background: Promoting satiety and repressing appetite is one major goal in the dietetic therapy of obesity. In the past, several studies investigated the effect of different macronutrients, especially protein and carbohydrates, on short- and long-term satiety in humans. This paper aims to directly compare the effect of protein, rolled oats (low glycemic index), sugar or cornflakes (high glycemic index), and walnuts (high amount of omega-3 fatty acids) as ingredients of a yoghurt breakfast on short-term hunger and satiety in one setting. A second objective was to study the effect of these yoghurt breakfasts on mental state.

Methods: 14 healthy male volunteers participated in this randomized, controlled, cross-over design study. After consuming the different test meals, volunteers repeatedly completed 2 questionnaires over a total of 3 h.

Results: The protein meal showed the highest satiety scores and the controls (low-calorie yoghurt) the lowest. The other test meals were not different among each other. Regarding mental state (mood, fatigue, and calmness), no significant difference between the test meals and the low-calorie control was observed.

Conclusion: The glycemic index does not seem to modify satiety in this short-term setting. The similar mental state between low- and high-calorie breakfasts deserves further investigations.
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http://dx.doi.org/10.1159/000343163DOI Listing
November 2013

Non-invasive algorithms for the diagnosis of pulmonary hypertension.

Thromb Haemost 2012 Dec 10;108(6):1037-41. Epub 2012 Oct 10.

Department of Cardiology, Medical University of Vienna, Austria.

Precapillary pulmonary hypertension (PH) is diagnosed when mean pulmonary arterial pressure (mPAP) equals or exceeds 25 mmHg and the pulmonary capillary wedge pressure (PCWP) is equal or lower than 15 mmHg. Because both parameters can only be derived from invasive hemodynamic assessment, right heart catheter (RHC) is still a gold standard for the diagnosis of PH. Severe precapillary PH corresponds to pulmonary vascular disease and carries a poor prognosis. Unfortunately, due to a generally low specificity of non-invasive estimates of systolic pulmonary pressure, at least 50% of patients with suspicion of PH need to undergo invasive RHC for exclusion of precapillary PH. Therefore, and also in order to manage the growing number of postcapillary PH due to heart and lung disease in the general population, pulmonary and cardiologic diagnostic algorithms combining multiple parameters have been developed. Recent disease scores are reviewed, and an outlook is given on emerging evidence from the DETECT clinical study holding the promise to non-invasively predict precapillary PH in vulnerable patients. These diagnostic trees help limit unnecessary procedures and help differentiate the current categories of PH. However, one has to keep in mind that the diagnosis of PH is still made by hemodynamic assessment.
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http://dx.doi.org/10.1160/TH12-04-0239DOI Listing
December 2012

Relevance of the type III error in epidemiological maps.

Int J Health Geogr 2012 Aug 18;11:34. Epub 2012 Aug 18.

Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.

Background: A type III error arises from a two-sided test, when one side is erroneously favoured although the true effect actually resides on the other side. The relevance of this grave error in decision-making is studied for epidemiological maps.

Results: Theoretical considerations confirm that a type III error may be large for regions with small numbers of expected cases even when no spatial smoothing has been performed. A simulation study based on infant mortality data in Austria reveals that spatial smoothing may additionally increase the risk of type III errors.

Conclusions: The occurrence of a type III error should be taken into account when interpreting results presented in epidemiological maps, particularly with regard to sparsely populated regions and spatial smoothing.
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http://dx.doi.org/10.1186/1476-072X-11-34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492026PMC
August 2012

Exploratory investigation of eight circulating plasma markers in brain tumor patients.

Neurosurg Rev 2013 Jan 5;36(1):45-55; discussion 55-6. Epub 2012 Jul 5.

Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Several blood biomarkers have been established for the early diagnosis, screening and follow-up of non central nervous system cancers. However, there is lack of knowledge on biochemical blood alterations in brain tumor patients. In this study, we prospectively collected blood plasma samples of 105 adult brain tumor patients with diffuse low-grade glioma (World Health Organization (WHO) II, n = 7), anaplastic glioma (WHO III, n = 10), glioblastoma multiforme (WHO IV, glioblastoma multiforme (GBM)) (n = 34), meningioma (WHO I, n = 8), atypical meningioma (WHO II, n = 5), and intracerebral metastasis (ICM; n = 41). In each case, we measured plasma concentrations of neuropeptide Y, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, placental growth factor (PlGF), S100B, secretagogin, interleukin 8, and glial fibrillary acidic protein (GFAP) using enzyme-linked immunosorbent assay. Plasma marker concentrations were correlated to patient parameters including neuropathological diagnosis and neuroradiological features. Most of the markers were detectable in all diagnostic categories in variable concentrations. GFAP plasma detectability was strongly associated with a diagnosis of GBM (p < 0.001). Plasma GFAP and plasma placental growth factor showed promising moderate potential in the differential diagnosis of unifocal GBM versus unifocal supratentorial ICM (area under the curve = 0.73, p < 0.05). To summarize, our data show that none of the investigated markers is suitable to substitute histological diagnosis. However, measurement of circulating GFAP and PlGF may support neuroradiological differential diagnosis of GBM versus ICM.
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http://dx.doi.org/10.1007/s10143-012-0401-6DOI Listing
January 2013

Influence of the American ODAC statement on Austrian bevacizumab prescribing practice for metastatic breast cancer.

Oncologist 2012 27;17(7):e13-7. Epub 2012 Jun 27.

Department of Medicine I, Medical University of Vienna General Hospital, Waehringer, Austria.

Background: Results of trial E2100 led to the accelerated approval of bevacizumab as first-line therapy for patients with metastatic breast cancer (MBC) in the U.S. in February 2008. Based on results from subsequent trials, the U.S. Food and Drug Administration Oncologic Drugs Advisory Committee (ODAC) issued a statement proposing to withdraw the license for bevacizumab in July 2010, whereas bevacizumab approval for MBC was not withdrawn in Europe. In this nationwide survey, we investigated the influence of the discrepancy between the ODAC and European Medicines Agency (EMA) positions on the prescription practice of bevacizumab for MBC in Austria during the period January 2006 to June 2011.

Methods: The absolute number of bevacizumab administrations for MBC patients per month in all Austrian hospitals within the mentioned time frame was retrieved from a comprehensive national database. Bevacizumab prescription numbers for other malignancies were retrieved in order to rule out that a change in bevacizumab prescribing practice might reflect general changes in Austrian health care policy.

Results: A steady increase in bevacizumab use was seen from January 2006 to June 2010 (42 versus 1,357 administrations per month) for MBC. Thereafter, a significant decline in bevacizumab prescriptions for MBC became evident, with numbers dropping to 842 in March 2011 and 662 in June 2011. Bevacizumab prescriptions showed only minor variations in control cohorts.

Conclusions: The Austrian bevacizumab prescribing practice in MBC patients was significantly influenced by the ODAC statement issued in July 2010, whereas the EMA position was accepted to a lesser degree.
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http://dx.doi.org/10.1634/theoncologist.2012-0115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399659PMC
February 2013

Clinical Neuropathology Practice News 4-2012: levels of evidence for brain tumor biomarkers.

Clin Neuropathol 2012 Jul-Aug;31(4):206-9

Medical University of Vienna, Vienna, Austria.

The National Comprehensive Cancer Network (NCCN) recently published a task force report on the evaluation of the clinical utility of tumor biomarkers in oncology. In this report, common terminology and the use of levels of evidence scores to aid the evaluation of biomarker tests in oncology were proposed. Furthermore, the task force applied a level of evidence system to selected biomarkers of several cancer types. According to this system, the highest level of evidence, IA, is granted to a biomarker only if it has been evaluated in at least one adequately powered and specifically designed prospective controlled trial. For gliomas, only 1p/19q testing in oligodendroglial tumors was classified as IA by the NCCN task force. For all of the following biomarkers the present evidence level for clinical utility was regarded as lower than that of 1p/19q status: MGMT gene promoter methylation testing (glioblastoma), IDH mutation testing (diffusely growing gliomas), BRAF fusion testing (pilocytic astrocytoma) and CIMP testing (diffusely growing gliomas). The task force acknowledged that the exact application of levels of evidence needs further refinement. To our mind, the implementation of a brain tumor expert panel seems vital to evaluate the evidence levels of neurooncological biomarkers according to generally accepted criteria on a regular basis. Systematic identification of current research needs and widely accepted up-to-date recommendations for efficient biomarker application in everyday practice could be gained.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663460PMC
http://dx.doi.org/10.5414/np300511DOI Listing
September 2012

Podoplanin-expressing cancer-associated fibroblasts are associated with poor prognosis in invasive breast cancer.

Breast Cancer Res Treat 2012 Jul 17;134(1):237-44. Epub 2012 Feb 17.

Department of Surgery, General Hospital, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

While cancer research has been focused on tumor cells for many years, evidence is growing that the tumor stroma and in particular cancer-associated fibroblasts (CAFs) in particular play essential roles in the progression of human malignant disease. In human lung cancer, CAFs expressing the transmembrane protein podoplanin were shown to have significant influence on the patients' prognosis. In this study, we investigated the presence and prognostic role of podoplanin-expressing CAFs in a large series of patients with invasive breast cancer. Podoplanin expression was evaluated immunohistochemically in 367 breast cancers. Tumors with ≥10% distinct podoplanin staining were considered as positive (CAF+). Cytoplasmic podoplanin expression of tumor cells was considered as positive when ≥5% of tumor cells showed a distinct podoplanin expression. In normal breast tissue, no podoplanin-expressing fibrocytes were found. Thirty-three patients (9%) with breast cancer showed podoplanin expression in CAFs. In 28 patients (8%), a podoplanin expression in tumor cells was observed. A strong negative correlation of CAF+ with estrogen receptor status (p<0.001), and a significant association with higher histological grading (p<0.001) was seen. In multivariable analysis, CAFs+ was an independent prognostic factor for disease free (1.78 Hazard ratio; p=0.026) and overall survival (2.304 Hazard ratio; p=0.002) in patients with breast cancer. Podoplanin-expressing CAFs contribute to the prognosis of invasive breast cancer, indicating a highly aggressive subgroup. CAFs may present a highly selective target for anti-cancer therapies in patients with invasive breast cancer.
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http://dx.doi.org/10.1007/s10549-012-1984-xDOI Listing
July 2012

Prognostic value of Ki67 index in anaplastic oligodendroglial tumours--a translational study of the European Organization for Research and Treatment of Cancer Brain Tumor Group.

Histopathology 2012 May 15;60(6):885-94. Epub 2012 Feb 15.

Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Aims: To evaluate the prognostic value and clinical utility of Ki67 tumour cell proliferation index in anaplastic oligodendroglial tumours (AOT).

Methods And Results: We performed anti-Ki67 immunostaining (MIB-1 antibody) of formalin-fixed and paraffin-embedded tumour tissue specimens of 128 patients with newly diagnosed AOT that were treated in a randomized Phase III trial. Ki67 index was assessed by three independent observers and was correlated to clinical, histopathological and molecular features (including 1p/19q co-deletion, epithelial growth factor receptor gene (EGFR) amplification, isocitrate dehydrogenase (IDH1) mutations, O6-methylguanine-DNA methyltransferase gene (MGMT) promoter methylation, and patient survival times. Intra- and inter-observer agreement of Ki67 index assessment was excellent. Univariable analysis (n = 79) showed that patients with a low Ki67 index had significantly more favourable progression-free survival (PFS) (P-value = 0.004, log-rank test) and overall survival (OS) (P-value = 0.003, log-rank test) than patients with a high Ki67 index, respectively. On multivariable analysis (n = 43), Ki67 index showed no independent association with PFS or OS.

Conclusions: In AOT the Ki67 index has a strong prognostic impact on univariable analysis, but no independent influence on multivariable analysis. However, further prospective studies including larger numbers of cases and standardized evaluation of Ki67 index in conjunction with other relevant prognostic parameters are needed to draw definitive conclusions.
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http://dx.doi.org/10.1111/j.1365-2559.2011.04134.xDOI Listing
May 2012

Association of age and gender with alphaherpesvirus infections of the central nervous system in the immunocompetent host.

J Clin Virol 2012 Apr 21;53(4):356-9. Epub 2012 Jan 21.

Department of Virology, Medical University of Vienna, A-1095 Vienna, Austria.

Background: The alphaherpesviruses Varicella-zoster virus (VZV) and human herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) can cause severe infections of the central nervous system (CNS).

Objectives: To analyze whether age and gender of immunocompetent individuals are associated with the incidence of herpesvirus CNS diseases.

Study Design: A total of 241 patients with virologically confirmed HSV-1, HSV-2 or VZV-infection of the CNS (excluding neonatal infection and varicella), diagnosed at the Department of Virology, Medical University Vienna, from 2001 to 2009 were analyzed retrospectively. The relative incidence of disease was evaluated statistically with respect to gender and age.

Results: The relative incidence of VZV CNS disease increased with age (p<0.0001), and nonlinear age dependences were observed for HSV-1 (p=0.005) and HSV-2 disease (p=0.002). These effects were influenced significantly by the patient's gender in VZV (p=0.0003) and HSV-1 disease (p=0.008). Overall, 50.7% of VZV infections in males, but only 23.5% of those in females, occurred before age 45, and 28.9% of HSV-1 infections in males and 8.8% of those in females occurred before age 30. Women represented 71.9% of HSV-2 CNS infections (p=0.02).

Conclusions: The patient's gender is clearly associated with the incidence of CNS disease caused by VZV, HSV-1 and HSV-2, and its influence varies over one's lifetime.
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http://dx.doi.org/10.1016/j.jcv.2011.12.015DOI Listing
April 2012

Combining difference and equivalence test results in spatial maps.

Int J Health Geogr 2011 Jan 10;10. Epub 2011 Jan 10.

Department of Epidemiology, Center for Public Health, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.

Background: Regionally partitioned health indicator values are commonly presented in choropleth maps. Policymakers and health authorities use them among others for health reporting, demand planning and quality assessment. Quite often there are concerns whether the health situation in certain areas can be considered different or equivalent to a reference value.

Results: Highlighting statistically significant areas enables the statement that these areas differ from the reference value. However, this approach does not allow conclusions which areas are sufficiently close to the reference value, although these are crucial for health policy making as well. In order to overcome this weakness a combined integration of statistical difference and equivalence tests into choropleth maps is suggested and the approach is exemplified with health data of Austrian newborns.

Conclusions: The suggested method will improve the interpretability of choropleth maps for policymakers and health authorities.
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http://dx.doi.org/10.1186/1476-072X-10-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032638PMC
January 2011

Immature and absolute platelet count changes and thrombocytopenia in malignant glioma.

Eur J Clin Invest 2011 May 15;41(5):539-45. Epub 2010 Dec 15.

Department of Medicine I, Medical University of Vienna, Austria.

Background: Temozolomide (TMZ) is commonly used for the therapy of malignant glioma and induces thrombocytopenia in a fraction of patients. Currently, no biomarkers predicting TMZ-induced thrombocytopenia are available. In this study, we investigated whether changes in platelet count (PLT) or the immature platelet fraction (IPF) may serve as predictor of TMZ-induced thrombocytopenia in malignant glioma patients.

Methods:  We prospectively included 52 malignant glioma patients receiving TMZ-containing therapy regimens in this study. Platelet counts and IPF were determined at each clinical follow-up visit (weekly during concomitant radiochemotherapy or at least monthly during TMZ monotherapy) using the Sysmex XE-2100 system. We explored the diagnostic utility of PLT change/day and IPF change/day from the last to the current follow-up visit for the prediction of clinically relevant thrombocytopenia (PLT < 100·000 μl(-1) ) at the next follow-up visit.

Results: Relevant thrombocytopenia was observed in 10 of 234 occasions. The areas under the receiver operating characteristic curves for PLT absolute change/day, PLT relative change/day and IPF relative change/day were 0·675, 0·703 and 0·663, respectively. The Youden indices (maximum sum of sensitivity and specificity minus one) were 0·31, 0·39, and 0·29, respectively. The corresponding positive predictive values were 16%, 57%, and 6·7%, and the negative predictive values were 97%, 97%, and 98%, respectively.

Conclusions: The rather moderate diagnostic potential of our data indicate that the time course of PLT counts and IPF measured at routine clinical follow-up are not useful for the prediction of thrombocytopenia in glioma patients treated with TMZ.
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http://dx.doi.org/10.1111/j.1365-2362.2010.02442.xDOI Listing
May 2011

Impaired anti-inflammatory efficacy of n-butyrate in patients with IBD.

Eur J Clin Invest 2011 Mar 10;41(3):291-8. Epub 2010 Nov 10.

Institute of Immunology, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

Background: The intestinal mucosa of patients with inflammatory bowel diseases (IBD) characteristically shows a high degree of inflammation when compared to healthy subjects. This appears to be attributable to an imbalance in local reactivity of inflammatory cells. In the present study, we tested the hypothesis that immune cells from patients with IBD are less sensitive to anti-inflammatory agents in the gut as exemplified by the short-chain fatty acid (SCFA) n-butyrate.

Material And Methods: Peripheral blood mononuclear cells (PBMC) of patients with IBD (22 Crohn`s Disease, CD; 9 Ulcerative Colitis, UC) and 20 healthy individuals were stimulated through TLR-4 and TLR-2 engagement, respectively, and the anti-inflammatory activity of n-butyrate (0·06-1 mM) on cytokine production (IL-1β, IL-10, IL-12/23p40, TNF-α) was assessed. Inhibition curves were generated, and effective doses (ED20-ED80) were determined.

Results: Hyperresponsiveness to TLR-2 activation reflected by increased IL-12/23p40 and TNF-α production was observed in patients with IBD. To inhibit the release of IL-12/23p40 from PBMC after activation via TLR2-agonists, higher concentrations of n-butyrate were required in patients with IBD , when compared to healthy subjects. With regard to TLR-4 activation, PBMC from patients with IBD and controls were equally responsive to the immunoregulatory effects of n-butyrate. Further analysis revealed that the impaired sensitivity of PBMC to the anti-inflammatory action of n-butyrate was independent from hyperreactivity of immunocompetent cells.

Conclusions: Impaired sensitivity to the inhibitory action of n-butyrate in IBD may constitute a determinant in the pathogenesis of these inflammatory diseases.
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http://dx.doi.org/10.1111/j.1365-2362.2010.02407.xDOI Listing
March 2011

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

Cancer 2011 Feb 15;117(3):534-44. Epub 2010 Sep 15.

Clinical Division of Oncology, Department of Medicine I and Cancer Center, Medical University of Vienna, Vienna, Austria.

Background: 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.

Methods: Eighty-seven consecutive patients with mRCC who were to receive treatment with sunitinib or sorafenib were included in a prospective analysis. Thyroid function was assessed in each patient every 4 weeks during the first 2 months of treatment and every 2 to 4 months thereafter. Assessment included serum levels of thyroid-stimulating hormone (TSH), tri-iodthyronine (T3), and thyroxine (T4). Subclinical hypothyroidism was defined as an increase in TSH above the upper limit of normal (>3.77 μM/mL) with normal T3 and T4 levels.

Results: Subclinical hypothyroidism was evident in 5 patients at baseline and occurred in 30 patients (36.1%) within the first 2 months after treatment initiation. There was a statistically significant correlation between the occurrence of subclinical hypothyroidism during treatment and the rate of objective remission (hypothyroid patients vs euthyroid patients: 28.3% vs 3.3%, respectively; P < .001) and the median duration of survival (not reached vs 13.9 months, respectively; hazard ratio, 0.35; 95% confidence interval, 0.14-0.85; P = .016). In multivariate analysis, the development of subclinical hypothyroidism was identified as an independent predictor of survival (hazard ratio, 0.31; P = .014).

Conclusions: The current results indicated that hypothyroidism may serve as a predictive marker of treatment outcome in patients with mRCC. Thus, the interpretation of hypothyroidism during treatment with sunitinib and sorafenib as an unwanted side effect should be reconsidered.
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http://dx.doi.org/10.1002/cncr.25422DOI Listing
February 2011

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

Cancer 2010 Dec 24;116(24):5725-32. Epub 2010 Aug 24.

Institute of Neurology, Medical University of Vienna, Vienna, Austria.

Background: 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.

Methods: A nation-wide survey of malignant high-grade CNS tumors (World Health Organization grade III/IV), diagnosed in children (aged birth to 14 years) from 1996 to 2006 was conducted by the Austrian Brain Tumor Registry. A central histopathology review was performed including the assessment of SMARCB1 (INI1) protein status.

Results: A total of 311 newly diagnosed, malignant CNS tumors were included. Atypical teratoid/rhabdoid tumors constituted the sixth most common entity (6.1%), referring to an age-standardized incidence rate of 1.38 per 1,000,000 person-years in children. Peak incidence was found in the birth to 2 years age group, where they were as common as CNS primitive neuroectodermal tumors and medulloblastomas. A total of 47.4% of atypical teratoid/rhabdoid tumors were initially diagnosed, whereas 52.6% were retrospectively detected by the central review. The 5-year survival of atypical teratoid/rhabdoid tumor patients was 39.5%, with 66.7% in the correctly diagnosed group versus 15.0% in the not recognized group (P = .0469).

Conclusions: Clinicians and pathologists should be aware of the high incidence of atypical teratoid/rhabdoid tumors in young children to optimize diagnostic and therapeutic management of patients with these tumors.
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http://dx.doi.org/10.1002/cncr.25540DOI Listing
December 2010