Georgios C. Sakellaropoulos

A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease

OBJECTIVES Rituximab (RTX) may favorably affect lung function and skin fibrosis in patients with systemic sclerosis (SSc). We aimed to assess long-term efficacy and safety of RTX in SSc compared to standard treatment. METHODS A total of 51 patients with SSc-associated interstitial lung disease were recruited and treated with RTX (n = 33) or conventional treatment (n = 18). Median follow-up was 4 years (range: 1-7). Conventional treatment consisted of azathioprine (n = 2), methotrexate (n = 6), and mycophenolate mofetil (n = 10). RESULTS Patients in the RTX group showed an increase in FVC at 2 years (mean ± SD of FVC: 80.60 ± 21.21 vs 86.90 ± 20.56 at baseline vs 2 years, respectively, p = 0.041 compared to baseline). In sharp contrast, patients in the control group had no change in FVC during the first 2 years of follow-up. At the 7 year time point the remaining patients in the RTX group (n = 5) had higher FVC compared to baseline (mean ± SD of FVC: 91.60 ± 14.81, p = 0.158 compared to baseline) in contrast to patients in the control group (n = 9) where FVC deteriorated (p < 0.01, compared to baseline). Direct comparison between the 2 groups showed a significant benefit for the RTX group in FVC (p = 0.013). Improvement of skin thickening was found in both the RTX and the standard treatment group; however, direct comparison between groups strongly favored RTX at all-time points. Adverse events were comparable between groups. CONCLUSIONS Our data indicate that RTX has a beneficial effect on lung function and skin fibrosis in patients with SSc. Randomized controlled studies are highly needed.

Inheritance and perinatal consequences of inherited thrombophilia in Greece

To investigate the impact of inherited thrombophilic factors on the gestational outcome of unselected pregnant women.

Interictal alterations of cardiovagal function in chronic epilepsy

AIM To assess the function of parasympathetic heart control in patients with epilepsy by means of clinical routine neurophysiology. MATERIALS AND METHODS Seventy-one consecutive epileptic patients (mean age+/-S.D. 37.8+/-12.9 years) with partial or generalized seizures manifested for more than 6 months and receiving various therapeutic regimes and 71 matched for sex and age healthy controls undertook a battery of neurophysiological tests which consisted of sensory conduction of sural nerve; R-R interval variation during normal and deep breathing; Valsalva manoeuvre and tilt test for calculation heart rate changes to respiratory strain and standing. RESULTS The patient group showed a significant difference in all parasympathetic parameters studied compared to the control group. Overall, 42.2% of patients had abnormal measurement in at least one of the parameters and Valsalva was the most frequently abnormal one (31% of patients). Sural nerve amplitude was significantly lower in the patients than in the controls and its measurements were associated with those of the tilt test. Long epilepsy duration (more than 10 years) and treatment with phenytoin showed a negative effect on data of R-R interval variation during deep breathing. No other correlations between measurements of parasympathetic parameters and epilepsy related characteristics i.e. type and frequency of seizure, monotherapy or combined therapy with seven other antiepileptic medications, were proven. CONCLUSIONS Our results suggested that simple neurophysiological tests, suitable for screening purposes were able to demonstrate suppressed cardiovagal control in epileptic patients and to identify those in need for further analysis of cardiovagal function.

Heart rate variability in Parkinson's disease unaffected by deep brain stimulation.

Trachani E, Constantoyannis C, Sakellaropoulos GC, Stavrinou ML, Nikiforidis G, Chroni E. Heart rate variability in Parkinson’s disease unaffected by deep brain stimulation.
Acta Neurol Scand: 2012: 126: 56–61.
© 2011 John Wiley & Sons A/S.

Radiobiologic comparison of helical tomotherapy, intensity modulated radiotherapy, and conformal radiotherapy in treating lung cancer accounting for secondary malignancy risks

The aim of the present study is to examine the importance of using measures to predict the risk of inducing secondary malignancies in association with the clinical effectiveness of treatment plans in terms of tumor control and normal tissue complication probabilities. This is achieved by using radiobiologic parameters and measures, which may provide a closer association between clinical outcome and treatment delivery. Overall, 4 patients having been treated for lung cancer were examined. For each of them, 3 treatment plans were developed based on the helical tomotherapy (HT), multileaf collimator-based intensity modulated radiation therapy (IMRT), and 3-dimensional conformal radiation therapy (CRT) modalities. The different plans were evaluated using the complication-free tumor control probability (p+), the overall probability of injury (pI), the overall probability of control/benefit (pB), and the biologically effective uniform dose (D¯¯). These radiobiologic measures were used to develop dose-response curves (p-D¯¯ diagram), which can help to evaluate different treatment plans when used in conjunction with standard dosimetric criteria. The risks for secondary malignancies in the heart and the contralateral lung were calculated for the 3 radiation modalities based on the corresponding dose-volume histograms (DVHs) of each patient. Regarding the overall evaluation of the different radiation modalities based on the p+ index, the average values of the HT, IMRT, and CRT are 67.3%, 61.2%, and 68.2%, respectively. The corresponding average values of pB are 75.6%, 70.5%, and 71.0%, respectively, whereas the average values of pI are 8.3%, 9.3%, and 2.8%, respectively. Among the organs at risk (OARs), lungs show the highest probabilities for complications, which are 7.1%, 8.0%, and 1.3% for the HT, IMRT, and CRT modalities, respectively. Similarly, the biologically effective prescription doses (DB¯¯) for the HT, IMRT, and CRT modalities are 64.0, 60.9, and 60.8Gy, respectively. Regarding the risk for secondary cancer, for the heart, the lowest average risk is produced by IMRT (0.10%) compared with the HT (0.17%) and CRT (0.12%) modalities, whereas the 3 radiation modalities show almost equivalent results regarding the contralateral lung (0.8% for HT, 0.9% for IMRT, and 0.9% for CRT). The use of radiobiologic parameters in the evaluation of different treatment plans and estimation of their expected clinical outcome is shown to provide very useful clinical information. The radiobiologic analysis of the response probabilities showed that different radiation modalities appear to be more effective in different patient geometries and target sizes and locations. Furthermore, there is not a clear pattern between the plans that appear to be more effective for the treatment and the risk of secondary malignancy. It seems that radiobiologically based treatment planning taking into account the risk of secondary cancer can be established as an effective clinical tool for a more clinically relevant treatment optimization.

SAT0222 B Cell Depletion Therapy in Systemic Sclerosis Associated Interstitial Lung Disease. A Multicenter, Open Label, Comparative Study with A Follow up of 94 Patient-Years

Background We have previously shown that rituximab (RTX) may favorably affect lung function and skin fibrosis in patients with systemic sclerosis (SSc). Objectives To assess long term efficacy and safety of RTX in SSc compared to standard treatment. Methods Fifty one patients with SSc associated interstitial lung disease were recruited and treated with RTX (n=33) or standard treatment (n=18). RTX cycles were repeated every 6 months throughout follow up apart from 6 patients where RTX was discontinued following 2 years of continuous treatment. Mean follow up was 2.9 years (range 1–7). Standard treatment consisted of azathioprine (n=2), methotrexate (n=6) and mycophenolate (n=10). Results Patients in the RTX group showed an increase in FVC during the first year of treatment (mean ± SEM of FVC: 80.60 ± 3.69 vs 83.02 ± 3.37 at baseline vs 1-year, respectively, p=0.13); this beneficial effect was further augmented at 2 years (86.90 ± 4.72, p=0.04 compared to baseline). In sharp contrast, patients in the control group had no change in FVC during the first 2 years of follow up. At 2 years, the RTX group was numerically better than the control group; however, differences tended but did not reach statistical significance (p=0.063). At the 7 year time point patients in the RTX group had higher FVC compared to baseline (mean ± SEM of FVC: 91.60 ± 6.62, p=0.15 compared to baseline) in contrast to patients in the control group where FVC deteriorated (p<0.01, compared to baseline). Direct comparison between the 2 groups showed a significant benefit for the RTX group (p=0.013). DLCO also improved following 2 years of RTX treatment (mean ± SEM of DLCO: 59.22 ± 3.16 vs 61.51 ± 4.02 at baseline vs 2-years, respectively, p=0.05). In the standard treatment group DLCO constantly deteriorated throughout follow up. In 6 patients where RTX was stopped following 2 years of continuous treatment a decline in PFTs was evident. Improvement of skin thickening was found in both the RTX and the standard treatment group, however, direct comparison between groups strongly favored RTX at all time points (p=0.002, 0.015, 0.002, 0.053 0.029 for the 1, 2, 3, 4 and 5-year time point, respectively). In the RTX group, six cases of respiratory infection requiring hospitalization, one case of hepatitis B reactivation and one case of herpes zoster were recorded. Two patients were diagnosed with cancer (lung and prostate). Five deaths were recorded: end stage respiratory failure (n=2), lung cancer (n=1), sudden death (n=1), unknown (n=1). In the control group, five patients with respiratory and four patients with urinary infection were hospitalized. In four cases, infections were recurrent. Two deaths were reported due to respiratory infection. Conclusions Our data indicate that continuous treatment with RTX has a beneficial effect on lung function and skin fibrosis in patients with SSc. Treatment was well-tolerated. Randomized controlled studies are highly needed. Disclosure of Interest None declared

Non-coding RNA Sequences Identification and Classification Using a Multi-class and Multi-label Ensemble Technique

High throughput sequencing RNA-sequencing technologies and modern in silico techniques have expanded our knowledge on short non-coding RNAs. These sequences were initially split into various categories based on their cellular functionality and their sequential, thermodynamic and structural properties believing that their sequence can be used as an identifier to distinguish them. However, recent evidence has indicated that the same sequences can act and function as more than one type of non-coding RNAs with a striking example of mature microRNA sequences which can also be transfer RNA fragments. Most of the existing computational methods for the prediction of non-coding RNA sequences have emphasized on the prediction of only one type of noncoding RNAs and even the ones designed for multiclassification do not support multiple labeling and are thus not able to assign a sequence to more than one non-coding RNA type. In the present paper, we introduce a new multilabel- multiclass method based on the combination of multiobjective evolutionary algorithms and multi-label implementations of Random Forests to optimize the feature selection process and assign short RNA sequences to one or more non-coding RNA types. The overall methodology clearly outperformed other machine learning techniques which were used for the same purpose and it is applicable to data coming from RNA-sequencing experiments.

Clinical survey for registering treatment decision criteria in advanced non-small-cell lung cancer radiotherapy and determination of the dose–response relationship for 1-year survival

Purpose: Recent studies have suggested significant variations in radiotherapy schedules used to treat advanced non-small-cell lung cancer (NSCLC), both between different centers in one country as well as between countries. In this study, different treatment methodologies have been explored using management plans proposed by radiation oncologists regarding general questions and theoretical case histories for patients with advanced NSCLC. Materials and methods: The survey was conducted by sending a questionnaire to 24 radiotherapy centers in Europe. The questionnaire was composed of two sections. The first section concerned reasons for giving radiotherapy, parameters that influence the choice of total dose and fractionation for radiotherapy and kind of equipment used. The second section concerned the management of five theoretical patients (A–E) regarding the selection of the radiotherapy technique and the aim of treatment (radical or palliative). Furthermore, 19 trials comparing different regimens of palliative radiotherapy in patients with NSCLC were reviewed. There were marked differences in the doses of the investigated radiotherapy schemes, the patient characteristics and the assessed outcome measures. Results: 70% of the responders answered that the most important factors for deciding what dose and fractionation scheme to use were: metastases, performance status (PS) of the patient, lung function and size of the primary tumour. The most common reasons for giving the treatment were symptom relief, prolongation of life and, in some cases, possibly cure. More than 95% of the responders stated that they would give radiotherapy in each of these cases. The total doses proposed where 20 Gy in five fractions or 30 Gy in ten fractions in 2 weeks for the cases A and D. If the previous two schemes were converted to a fractionation scheme delivering 2 Gy per fraction, the equivalent doses would be 23 and 33 Gy, respectively. For the cases B, C and E, the proposed fractionation schemes were 2 Gy daily to 60–68 Gy in Correspondence to: Panayiotis Mavroidis, Division of Medical Physics, Department of Radiation Oncology, University of Texas Health Sciences Center at San Antonio, 7979 Wurzbach Rd, MC 7889, San Antonio TX 78229-4427, USA. Tel: 11 210-450-1027. Fax: 11 210-450-1076. E-mail: mavroidis@uthscsa.edu

Evaluation of conduction properties of somatic and sympathetic sudomotor fibers in patients with epilepsy.

To assess the function of fast somatic nerve fibers and sympathetic sudomotor system in patients with partial or generalized seizures, receiving various therapeutic regimes. The authors studied 60 patients (mean age 36.7 ± 12.5 years) and 60 matched healthy controls by clinical, conventional nerve conduction study, and sympathetic skin responses (SSR) from hand and foot. Compared with controls, patients showed a tendency, occasional reaching significant level, to conduction slowing and amplitude reduction in the sensory and less often in the motor nerve study. Clinical signs of neuropathy were disclosed in 8.3% of patients, whereas at least one abnormal sensory parameter was evident in 18.3%. Mean SSR latencies in the patients were significantly prolonged. At least one SSR abnormality was shown in 20 (33.3%) patients; six of these had absent SSR from the hand or/and the foot. Polytherapy (vs. monotherapy) and topiramate, but not any other particular drug, seemed to have a negative effect on SSR measurements. The results suggested that despite the insignificant clinical manifestations of neuropathy, an electrophysiological examination was able to demonstrate some subclinical abnormalities of the fast somatic fibers in the peripheral nerves and of the sympathetic sudomotor function in a considerable number of epileptic patients.