Gábor Borgulya

Long-term Survival of Patients With Idiopathic Inflammatory Myopathies According to Clinical Features: A Longitudinal Study of 162 Cases

The idiopathic inflammatory myopathies are characterized by chronic muscle inflammation and involvement of internal organs, which contribute considerably to the morbidity and mortality of the disease. We conducted the current study to determine the survival data for patients with idiopathic inflammatory myopathies according to the presence of extramuscular clinical manifestations. We also determined the cumulative survival probability and the long-term prognosis and analyzed the causes of death at a single clinical immunology center.A survival analysis was performed using data for 162 patients diagnosed between 1976 and 1997 according to Bohan and Peter’s criteria. Patients were followed up for a minimum of 5 years (median, 101.5 mo) or to date of death. Cumulative survival probability was calculated by the Kaplan-Meier method. The influence of extraskeletal and extramuscular involvement was analyzed as prognostic factors for death by Cox proportional hazards survival model.Eighteen disease-specific deaths occurred; pulmonary and cardiac complications were the most frequent causes of death. Global survival rates were 95%, 92%, and 89% for 1, 5, and 10 years, respectively. Analysis for clinicopathologic subgroups revealed that cancer-associated myositis had the worst prognosis, while juvenile and overlap myositis had the best prognosis. Five- and 10-year survival rates were 94.2% and 89.4% for patients with primary polymyositis and 90.1% and 86.4% for primary dermatomyositis patients, respectively. In the whole group of patients with idiopathic inflammatory myopathy, cardiac (p < 0.01) and respiratory muscle involvement (p = 0.045) were significant prognostic factors for death. In the group of patients with primary polymyositis/dermatomyositis, cardiac involvement was the main prognostic factor for death (p < 0.01).Myositis patients described in this study have higher survival rates than reported previously worldwide. We examine the reasons for the differences between the data in the current study and the available survival data in the relevant literature.

Inhibiting poly(ADP-ribose) polymerase: a potential therapy against oligodendrocyte death

Oligodendrocyte loss and demyelination are major pathological hallmarks of multiple sclerosis. In pattern III lesions, inflammation is minor in the early stages, and oligodendrocyte apoptosis prevails, which appears to be mediated at least in part through mitochondrial injury. Here, we demonstrate poly(ADP-ribose) polymerase activation and apoptosis inducing factor nuclear translocation within apoptotic oligodendrocytes in such multiple sclerosis lesions. The same morphological and molecular pathology was observed in an experimental model of primary demyelination, induced by the mitochondrial toxin cuprizone. Inhibition of poly(ADP-ribose) polymerase in this model attenuated oligodendrocyte depletion and decreased demyelination. Poly(ADP-ribose) polymerase inhibition suppressed c-Jun N-terminal kinase and p38 mitogen-activated protein kinase phosphorylation, increased the activation of the cytoprotective phosphatidylinositol-3 kinase-Akt pathway and prevented caspase-independent apoptosis inducing factor-mediated apoptosis. Our data indicate that poly(ADP-ribose) polymerase activation plays a crucial role in the pathogenesis of pattern III multiple sclerosis lesions. Since poly(ADP-ribose) polymerase inhibition was also effective in the inflammatory model of multiple sclerosis, it may target all subtypes of multiple sclerosis, either by preventing oligodendrocyte death or attenuating inflammation.

Analysis of CSF shunting procedure requirement in children with posterior fossa tumors

ObjectThe authors analyze the factors that predispose to persistent hydrocephalus in children with posterior fossa tumors and compare their results and treatment policy with those described in the literature, particularly with regard to the higher postoperative shunt insertion rates, which have led some authors to the routine use of preoperative third ventriculostomy.MethodsThe clinical records of 180 children treated for posterior fossa tumors in the Department of Pediatric Neurosurgery of the National Institute of Neurosurgery, Budapest, Hungary, between 1990 and 2000 were retrospectively reviewed.ConclusionsThe low postoperative shunt insertion rate in our series (15.5%) led us to believe that the routine use of preoperative third ventriculostomy is not entirely justified. Factors such as patients age and tumor type, which showed a statistically significant association with the postoperative shunt requirement in our study, should be considered when the decision regarding treatment is made.

BclI polymorphism of the glucocorticoid receptor gene is associated with decreased bone mineral density in patients with endogenous hypercortisolism.

Objective  The hypothalamic–pituitary–adrenal axis setpoint and the glucocorticoid sensitivity of various tissues are at least partially genetically determined. We investigated the impact of glucocorticoid receptor (GR) gene polymorphisms, including the BclI, N363S, ER22/23EK and A3669G variants on bone turnover and/or mineral density (BMD) in patients with endogenous glucocorticoid excess.

Robust localization of the contralateral precentral gyrus in hemiparetic patients using the unimpaired ipsilateral hand : a clinical functional magnetic resonance imaging protocol

Tumor related contralateral motor deficits complicate preoperative functional magnetic resonance imaging (fMRI). In plegic patients the localization of the sensorimotor cortex is often impossible. In this context we developed a clinical fMRI protocol dedicated to patients with motor deficits using the unaffected ipsilateral hand. Based on the hypothesis that selfpaced finger movements recruit more and larger neuronal populations with rising task complexity, different motor tasks were tested regarding ipsilateral localization in ten right handed volunteers. Complex finger opposition localized the ipsilateral premotor cortex (Brodman area 6) robustly and was introduced to preoperative fMRI in hemiparetic patients as functional landmark to identify the precentral gyrus on the tumors side. Additional contralateral automated tactile stimulation localized the primary somatosensory cortex and completed the protocol.

Fermented wheat germ extract reduces chemotherapy-induced febrile neutropenia in pediatric cancer patients

Purpose:An open-label, matched-pair (by diagnosis, stage of disease, age, and gender) pilot clinical trial was conducted to test whether the combined administration of the medical nutriment MSC (Avemar) with cytotoxic drugs and the continued administration of MSC on its own help to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers compared with the same treatments without MSC. Methods:Between December 1998 and May 2002, 22 patients (11 pairs) were enrolled in this study. At baseline, the staging of the tumors was the same in each pair (mostly pTNM = T2N0M0), with the exception of two cases in which patients in the MSC group had worse prognoses (metastasis at baseline). There were no significant differences in the average age of the patients, the length of treatment time (MSC) or follow-up, the number of patients with central venous catheters, the number of chemotherapy cycles, the frequency of preventive counterneutropenic interventions, or the type and dosage of antibiotic and antipyretic therapy used in the two groups. Results:During the treatment (follow-up) period, there was no progression of the malignant disease, whereas at end-point the number and frequency of febrile neutropenic events significantly differed between the two groups: 30 febrile neutropenic episodes (24.8%) in the MSC group versus 46 (43.4%) in the control group (Wilcoxon signed rank test, P < 0.05). Conclusions:The continuous supplementation of anticancer therapies with the medical nutriment MSC helps to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers.

Primary radiotherapy of stage IIA/B-IIIB cervical carcinoma. A comparison of continuous versus sequential regimens.

Background:Comprehensive literature on cervical cancer demonstrates, even today, the need for optimization of the timing of external-beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDR-BT) in the treatment of stage IIA/B–IIIB cervical carcinoma.Patients and Methods:210 patients with carcinoma of the cervix were treated in the Municipal Center of Oncoradiology between January 1991 and December 1996 (FIGO IIA: n = 10, FIGO IIB: n = 113, and FIGO IIIB: n = 87). Two regimens were compared: sequential radiation therapy (SRT) with 4 × 8 Gy HDR-BT to point A followed by EBRT, and continuous radiation therapy (CRT) in which 5 × 6 Gy HDR-BT to point A, one session per week, was integrated into the EBRT. A total dose of 68–70 Gy to point A and 52–54 Gy to point B was given in EBRT with SRT, five fractions per week were applied. Four fractions per week were applied in CRT, i. e., no EBRT was performed on the day of HDR-BT. Total doses to points A and B were identical in both regimens. Overall treatment time (OTT) amounted to 56 days for SRT and 35 days for CRT. Median follow-up time was 3.4 (2.5–4.2) years.Results:Progression-free 5-year-survival (PFS) was 71% in the CRT and 56% in the SRT group. Nevertheless, this difference was not statistically significant (p = 1.00), and the same was found in a subgroup analysis of the different tumor stages, showing, however, an unequivocal trend. Late bladder and rectal injuries occurred in 13% and 25%, respectively. Late rectal injuries were significantly more frequent with SRT than CRT (35 patients in the SRT and 18 patients in the CRT group; p = 0.037). This was due to the higher doses per fraction of HDR-BT in the SRT group. No difference was found regarding late bladder injuries (p = 0.837).Conclusion:For the patients included in this study, no advantage has been found so far in using CRT, i. e., shortening the OTT by weekly integration of HDR-BT into EBRT. Nevertheless, an obvious trend exists. The dose of 8 Gy per fraction of HDR-BT in the SRT regimen was obviously too high. To achieve a significant improvement in local control and disease-free survival (DFS) as well as overall survival (OS), the combination with modern chemotherapy regimens and regional deep hyperthermia may rather be the treatment option.Hintergrund:Die umfangreiche Literatur zum Zervixkarzinom belegt, dass auch heute noch Optimierungsbedarf bezüglich der räumlichen und zeitlichen Interaktion von perkutaner Strahlentherapie (EBRT) und High-Dose-Rate-Brachytherapie (HDR-BT) bei der Behandlung des Zervixkarzinoms im Stadium IIA/B–IIIB besteht.Patienten und Methodik:Zwischen Januar 1991 und Dezember 1996 wurden 210 Patientinnen mit einem Zervixkarzinom FIGO IIA/B–IIIB am Uzsoki Hospital, Budapest, Ungarn, behandelt (FIGO IIA: n = 10, FIGO IIB n = 113 und FIGO IIIB n = 87). Zwei kombinierte Strahlentherapieregime wurden verglichen: eine sequentielle Therapie (SRT) mit 4 × 8 Gy HDR-BT am Punkt A, gefolgt von EBRT, und eine kontinuierliche Therapie (CRT), bei der die wöchentliche HDR-BT mit 5 × 6 Gy am Punkt A in die EBRT integriert war. Die EBRT erfolgte bei SRT fünfmal wöchentlich bis zu einer Gesamtdosis von 68–70 Gy am Punkt A und 52–54 Gy am Punkt B. Bei der CRT wurde viermal wöchentlich perkutan bestrahlt, d. h. nicht am Tag der HDR-BT. Die Gesamtdosen am Punkt A bzw. B waren bei beiden Regimen gleich. Die Gesamtbehandlungszeit (OTT) betrug bei SRT 56 Tage, bei CRT 35 Tage. Die mediane Nachbeobachtungszeit lag bei 3,4 (2,5–4,2) Jahren.Ergebnisse:Das progressionsfreie 5-Jahres-Überleben (DFS) betrug in der CRT-Gruppe 71% und in der SRT-Gruppe 56%. Dieser Unterschied erreichte allerdings keine statistische Signifikanz (p = 1,00), auch nicht in Untergruppenanalysen der einzelnen Tumorstadien. Der Trend war jedoch eindeutig. Spätfolgen an Blase und Rektum traten in 13% bzw. 25% auf. Die Spätfolgen am Rektum waren bei SRT statistisch signifikant häufiger als bei CRT (35 Patienten bei SRT und 18 Patienten bei CRT; p = 0,037). Dies wird auf die höhere HDR-BT-Fraktionsdosis bei SRT zurückgeführt. Bei den Spätfolgen an der Blase ergab sich kein Unterschied (p = 0,837).Schlussfolgerung:Bisher ist in dem hier vorgestellten Patientengut kein günstiger Effekt der CRT mit wöchentlich in die EBRT integrierter HDR-BT und verkürzter OTT nachweisbar; es besteht lediglich ein Trend. Die HDR-BT-Fraktionsdosis war im SRT-Regime mit 8 Gy zu hoch. Eine signifikante Verbesserung der lokalen Kontrollrate und der krankheitsfreien bzw. Gesamt-Überlebenszeit ist wohl nur durch die Kombination mit modernen chemotherapeutischen Regimen und der regionalen Tiefenhyperthermie erreichbar.

Red cell distribution width: a powerful prognostic marker in heart failure

We read the recent paper by Al-Najjar et al. on the prognostic value of red cell distribution width (RDW) in heart failure (HF) with great interest. The authors have shown in a population of 1087 ambulatory patients with HF due to left ventricular systolic dysfunction that RDW is a potent prognostic marker of all-cause mortality and has similar prognostic power to that of NT-proBNP. Two important open questions were raised at the end of the manuscript: whether the effect of RDW is independent of erythropoietin (EPO) levels, and what are the mechanisms of elevated RDW values in HF. The authors suggested that this new information may lead to novel approaches in treatment. We have also published similar results showing the prognostic value of RDW in chronic HF that appear to be in parallel with the study of Al-Najjar et al. Besides showing the prognostic power of RDW for all-cause mortality in our cohort, we were able to show the same for rehospitalization due to worsening HF symptoms. Furthermore, according to our analysis, RDW has NT-proBNP-independent predictive power for clinical events in chronic HF. In addition, we also provided observational data about the laboratory correlates of RDW in chronic HF and described novel data for delineation of the underlying mechanisms behind this observation. According to our data, RDW values are strongly related to signs of ineffective erythropoiesis, inflammation, impaired renal function, and under nutrition. Higher RDW values were associated with significantly lower serum iron and ferritin levels and decreased transferrin saturation and also with increased soluble transferrin receptor levels. The strongest correlate of RDW was soluble transferrin receptor concentration in the multiple linear regression model. Thus, based on these observations, RDW seems to be a prominent marker of anaemia of chronic diseases complicated by iron deficiency in patients with chronic HF. Furthermore, high serum EPO levels were associated with high RDW values in our cohort, indicating that the bonemarrow effects of EPO may also be compromised. In response to the questions raised by Al-Najjar et al., we have now performed an analysis to evaluate whether the prognostic effect of RDW is independent of EPO levels. The results of our Cox regression models (Table 3 in our paper) after addition of EPO as a further covariate suggest that the prognostic power of RDW is independent of EPO levels (for all-cause mortality HR 1.586 (95% CI 1.288–1.951; x 13.165 and P , 0.0001; for all-cause mortality or HF hospitalization HR 1.424 (95% CI 1.153–1.757; x 8.65 and P 1⁄4 0.003). Taken together, the results of these two recent independent studies in combination with the pioneering work of Felker et al. have now convincingly shown that future HF prognostic models should utilize RDW, a test available as part of the complete blood count. The effectiveness of this marker may lie, as supported by our observational data, on its relationship with ineffective red cell production, inflammation, impaired renal function, and under nutrition.

Primary Radiotherapy of Stage IIA/B–IIIB Cervical Carcinoma

Background:Comprehensive literature on cervical cancer demonstrates, even today, the need for optimization of the timing of external-beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDR-BT) in the treatment of stage IIA/B–IIIB cervical carcinoma.Patients and Methods:210 patients with carcinoma of the cervix were treated in the Municipal Center of Oncoradiology between January 1991 and December 1996 (FIGO IIA: n = 10, FIGO IIB: n = 113, and FIGO IIIB: n = 87). Two regimens were compared: sequential radiation therapy (SRT) with 4 × 8 Gy HDR-BT to point A followed by EBRT, and continuous radiation therapy (CRT) in which 5 × 6 Gy HDR-BT to point A, one session per week, was integrated into the EBRT. A total dose of 68–70 Gy to point A and 52–54 Gy to point B was given in EBRT with SRT, five fractions per week were applied. Four fractions per week were applied in CRT, i. e., no EBRT was performed on the day of HDR-BT. Total doses to points A and B were identical in both regimens. Overall treatment time (OTT) amounted to 56 days for SRT and 35 days for CRT. Median follow-up time was 3.4 (2.5–4.2) years.Results:Progression-free 5-year-survival (PFS) was 71% in the CRT and 56% in the SRT group. Nevertheless, this difference was not statistically significant (p = 1.00), and the same was found in a subgroup analysis of the different tumor stages, showing, however, an unequivocal trend. Late bladder and rectal injuries occurred in 13% and 25%, respectively. Late rectal injuries were significantly more frequent with SRT than CRT (35 patients in the SRT and 18 patients in the CRT group; p = 0.037). This was due to the higher doses per fraction of HDR-BT in the SRT group. No difference was found regarding late bladder injuries (p = 0.837).Conclusion:For the patients included in this study, no advantage has been found so far in using CRT, i. e., shortening the OTT by weekly integration of HDR-BT into EBRT. Nevertheless, an obvious trend exists. The dose of 8 Gy per fraction of HDR-BT in the SRT regimen was obviously too high. To achieve a significant improvement in local control and disease-free survival (DFS) as well as overall survival (OS), the combination with modern chemotherapy regimens and regional deep hyperthermia may rather be the treatment option.Hintergrund:Die umfangreiche Literatur zum Zervixkarzinom belegt, dass auch heute noch Optimierungsbedarf bezüglich der räumlichen und zeitlichen Interaktion von perkutaner Strahlentherapie (EBRT) und High-Dose-Rate-Brachytherapie (HDR-BT) bei der Behandlung des Zervixkarzinoms im Stadium IIA/B–IIIB besteht.Patienten und Methodik:Zwischen Januar 1991 und Dezember 1996 wurden 210 Patientinnen mit einem Zervixkarzinom FIGO IIA/B–IIIB am Uzsoki Hospital, Budapest, Ungarn, behandelt (FIGO IIA: n = 10, FIGO IIB n = 113 und FIGO IIIB n = 87). Zwei kombinierte Strahlentherapieregime wurden verglichen: eine sequentielle Therapie (SRT) mit 4 × 8 Gy HDR-BT am Punkt A, gefolgt von EBRT, und eine kontinuierliche Therapie (CRT), bei der die wöchentliche HDR-BT mit 5 × 6 Gy am Punkt A in die EBRT integriert war. Die EBRT erfolgte bei SRT fünfmal wöchentlich bis zu einer Gesamtdosis von 68–70 Gy am Punkt A und 52–54 Gy am Punkt B. Bei der CRT wurde viermal wöchentlich perkutan bestrahlt, d. h. nicht am Tag der HDR-BT. Die Gesamtdosen am Punkt A bzw. B waren bei beiden Regimen gleich. Die Gesamtbehandlungszeit (OTT) betrug bei SRT 56 Tage, bei CRT 35 Tage. Die mediane Nachbeobachtungszeit lag bei 3,4 (2,5–4,2) Jahren.Ergebnisse:Das progressionsfreie 5-Jahres-Überleben (DFS) betrug in der CRT-Gruppe 71% und in der SRT-Gruppe 56%. Dieser Unterschied erreichte allerdings keine statistische Signifikanz (p = 1,00), auch nicht in Untergruppenanalysen der einzelnen Tumorstadien. Der Trend war jedoch eindeutig. Spätfolgen an Blase und Rektum traten in 13% bzw. 25% auf. Die Spätfolgen am Rektum waren bei SRT statistisch signifikant häufiger als bei CRT (35 Patienten bei SRT und 18 Patienten bei CRT; p = 0,037). Dies wird auf die höhere HDR-BT-Fraktionsdosis bei SRT zurückgeführt. Bei den Spätfolgen an der Blase ergab sich kein Unterschied (p = 0,837).Schlussfolgerung:Bisher ist in dem hier vorgestellten Patientengut kein günstiger Effekt der CRT mit wöchentlich in die EBRT integrierter HDR-BT und verkürzter OTT nachweisbar; es besteht lediglich ein Trend. Die HDR-BT-Fraktionsdosis war im SRT-Regime mit 8 Gy zu hoch. Eine signifikante Verbesserung der lokalen Kontrollrate und der krankheitsfreien bzw. Gesamt-Überlebenszeit ist wohl nur durch die Kombination mit modernen chemotherapeutischen Regimen und der regionalen Tiefenhyperthermie erreichbar.

Intracardiac calcification is a marker of generalized atherosclerosis

Aortic valve calcification (AVC) and carotid artery calcification (CAC) are considered to be markers of generalized atherosclerosis. However, the role of intracardiac calcification (ICC) (valvular and perivalvular calcification) is unclear. The objective of this retrospective study was to analyze the relationship between ICC and CAC, risk factors, and clinical atherosclerotic disease. Risk factors included age, sex, diabetes mellitus, hypercholesterolemia, and hypertension; clinical atherosclerosis comprised stroke, coronary artery disease, and peripheral artery disease. Between January 1, 2001, and January 1, 2004, all consecutive patients were enrolled into the study who underwent both carotid ultrasonography and transthoracic echocardiography examinations within 2 months. Patients with renal failure, substantial aortic stenosis, and carotid artery occlusion were excluded. There were 320 patients (104 men; mean ± SEM age, 66.6 ± 0.76 years). Positive results on carotid ultrasonography are defined as any CAC. Patients were categorized as having mild, moderate, or severe CAC. Positive results on transthoracic echocardiography were defined as any ICC; AVC was defined as mitral anulus calcification (MAC) or both. Intracardiac calcification was found in 181 patients, AVC in 51 patients, MAC in 48 patients, and calcification of both structures in 82 patients. Using multiple logistic regression analysis, ICC (odds ratio, 1.9), age (10-year periods) (odds ratio, 2.0), and the presence of peripheral artery disease (odds ratio, 1.7) were independent predictors of CAC. Carotid ultrasonography results were positive in 227 patients. For CAC, the sensitivities of AVC, MAC, both, and any ICC were 52.4%, 52.0%, 33.5%, and 71.2%, respectively, and the specificities were 84.9%, 87.1%, 92.5%, and 78.5%, respectively. The extension of ICC as 0, 1 location (AVC or MAC) , or 2 locations (AVC and MAC) was associated with the severity of CAC (P < .001, τ = 0.42). There was no difference between patients with AVC vs patients with MAC in the presence of different stages of CAC (P = .62). Intracardiac calcification (MAC or AVC) is an independent predictor of CAC as a marker of atherosclerosis, although the lack of ICC does not rule out atherosclerosis. Intracardiac calcification is related to CAC, with high specificity. The extension of ICC is related to the severity of atherosclerosis. Based on our results, antiatherothrombotic therapy should be considered in patients with ICC even before obtaining a positive carotid ultrasonography result.