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Background: Although a significant proportion of patients with metastatic renal cell carcinoma (mRCC) are elderly, the data on the outcomes of targeted therapies in this population are limited. The aim of the present retrospective registry-based study was to analyse efficacy and toxicity of sunitinib as the first-line targeted therapy of elderly mRCC patients., Patients and Methods: The national RENal information system registry of mRCC patients treated with targeted agents in the Czech Republic was used as the data source. Of the 1315 patients treated with sunitinib as first-line targeted therapy, 1016 and 299 patients were aged <70 and ≥70 years, respectively., Results: Elderly patients had a significantly longer interval from diagnosis to the initiation of therapy. Median progression-free survival was 10.8 months (95 % confidence interval 9.8-11.8) and 8.8 months (7.2-10.4) for patients aged <70 and ≥70 years, respectively (p = 0.321). Median overall survival was 31.9 months (27.9-35.9) and 26.3 months (21.3-31.2), respectively (p = 0.044). Significantly more elderly patients started on a reduced dose of sunitinib or discontinued the treatment prior to progression because of adverse events., Conclusions: The differences in patient profile and dose-reduction rates point to a different approach in the management of older and younger patients in daily clinical practice. The lower dose intensity of sunitinib in the elderly population may have translated into inferior survival.

Introduction: Wilson's disease (WD) is a hereditary disorder caused by ATP7B mutations resulting in systemic copper accumulation. WD may manifest as early-adulthood parkinsonism; and atypical cases may be difficult to distinguish from early-onset Parkinson's disease (EO-PD), a neurodegenerative disorder with onset ≤40 years of age. The aim of our study was to compare transcranial sonography (TCS)-magnetic resonance fusion imaging in WD and EO-PD and examine whether TCS can provide clinically useful information., Methods: We examined 22 WD, 16 EO-PD, and 24 healthy control subjects. We measured echogenicity and determined presence of MRI signal changes in T2-weighted images in the substantia nigra (SN) and lentiform nucleus (NL). TCS with the capability of magnetic resonance fusion and Virtual Navigator was used. The echogenicity indices of SN and NL were processed using digital image analysis to eliminate subjective evaluation errors., Results: Mean SN echogenicity index in EO-PD (39.8 ± 5.9 [SD]) was higher compared to WD (28.0 ± 4.6, p < 0.0001) and control subjects (28.8 ± 4.9, p < 0.0001). Mean NL echogenicity index was higher in WD (117.5 ± 37.0) compared to EO-PD (61.6 ± 5.4, p < 0.0001) and control subjects (54.9 ± 11.2, p < 0.0001). The SN hyperechogenicity had sensitivity 93.8%, and specificity 90.9%, while the NL hyperechogenicity had sensitivity 95.5% and specificity 93.8% for differentiation of WD and EO-PD. NL hyperechogenicity was more pronounced in WD subjects with putaminal MRI T2 hyperintensity (p < 0.05) but was also present in subjects without MRI abnormality., Conclusions: There are distinct TCS findings in WD and EO-PD complementary to MRI that can be utilized as highly sensitive and specific biomarkers of these disorders., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are found in 35-45 % of colorectal cancer (CRC) cases. Although the association between the RAS signaling and angiogenesis is well known, the negative predictive value of KRAS mutation has not been established in patients treated with bevacizumab. The aim of this study was to evaluate the association between specific KRAS mutation types and outcome of patients with metastatic CRC treated with bevacizumab. The study included 404 patients with metastatic CRC (mCRC) treated with bevacizumab. Clinical data obtained from the clinical registry CORECT were retrospectively analyzed. The shortest survival was observed in patients with tumors harboring G12V or G12A KRAS mutation (G12V/A). The median progression-free survival (PFS) and overall survival (OS) for patients with tumors harboring G12V/A KRAS mutation was 6.6 and 16.8 compared to 11.6 and 26.3 months for patients with tumors harboring other KRAS mutation type (p < 0.001 and p < 0.001), while the survival of patients harboring other KRAS mutation types was comparable to those with tumors harboring wild-type KRAS gene. In the Cox multivariable analysis, KRAS G12V/A mutation type remains a significant factor predicting both PFS (HR = 2.18, p < 0.001) and OS (HR = 2.58, p < 0.001). In conclusion, the results of the present study indicate that there is a significant difference in biological behavior between tumors harboring G12V/A and other KRAS mutations. Moreover, comparison of the survival of patients with tumors harboring G12V/A KRAS mutations with those harboring wild-type KRAS gene revealed that G12V/A KRAS mutations are prognostic biomarker for inferior PFS and OS in patients with mCRC treated with bevacizumab in univariate as well as multivariable analyses.

Background: Serum lactate dehydrogenase (LDH) has been reported as a prognostic biomarker in malignant diseases. However, little is known on the dynamics of serum LDH levels during systemic treatment. We focused on the association of changes in serum LDH with outcome of patients with advanced-stage non-small cell lung cancer (NSCLC) treated with erlotinib., Patients and Methods: Clinical data of 309 patients were analyzed. Serum samples were collected within one week before initiation and after one month of treatment., Results: The change in serum LDH during the first month of erlotinib treatment was independently associated with disease control rate (p=0.006), progression-free survival (PFS) (p=0.010) and overall survival (OS) (p<0.001)., Conclusion: LDH is a commonly used serum biomarker, that is cheap and easy to detect. The results of our study suggest that the change in LDH serum level during the first month is a surrogate marker on the efficacy of erlotinib in patients with advanced NSCLC., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Bone metastases develop in several malignancies (multiple myeloma, breast, prostate and lung carcinoma) and cause several complications. The aim of this study was to search for new biomarkers to use in monitoring of bone metastatic disease with the use of xMAP technology., Patients and Methods: We assessed 62 oncological patients: 23 with no bone metastases, 28 with metastatic disease not having undergone therapy and 11 with metastatic disease treated by denosumab. Serum levels of dickkopf-related protein 1 (DKK1), growth differentiation factor-15 (GDF15), neuron-specific enolase (NSE), osteoprotegerin (OPG), osteonectin, periostin, tartrate-resistant acid phosphatase (TRAP5), tumor necrosis factor related weak inducer of apoptosis (TWEAK), chitinase-3-like protein 1 (YKL40), carboxy-terminal telopeptide (CTX) and procollagen type 1 N-terminal propeptide (PINP) were measured in each sample., Results: The following biomarkers were observed to have significantly higher levels in the groups of patients with metastases in comparison to metastasis-free patients: GDF15 (p<0.0001), osteonectin (p=0.0311), TRAP5 (p<0.0046), TWEAK (p<0.0343) and YKL40 (p<0.0034). The changes in DKK1, NSE, OPG and periostin were not significant., Conclusion: We identified five new biomarkers: GDF15, osteonectin, TRAP5, TWEAK, and YKL40 as being promising markers for monitoring bone metastases., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: The first aim of this study was to search for new biomarkers to be used in gastric cancer diagnostics. The second aim was to verify the findings presented in literature on a sample of the local population and investigate the risk of gastric cancer in that population using a multivariant statistical analysis., Patients and Methods: We assessed a group of 36 patients with gastric cancer and 69 healthy individuals. We determined carcinoembryonic antigen, cancer antigen 19-9, cancer antigen 72-4, matrix metalloproteinases (-1, -2, -7, -8 and -9), osteoprotegerin, osteopontin, prothrombin induced by vitamin K absence-II, pepsinogen I, pepsinogen II, gastrin and Helicobacter pylori for each sample., Results: The multivariate stepwise logistic regression identified the following biomarkers as the best gastric cancer predictors: CEA, CA72-4, pepsinogen I, Helicobacter pylori presence and MMP7., Conclusion: CEA and CA72-4 remain the best markers for gastric cancer diagnostics. We suggest a mathematical model for the assessment of risk of gastric cancer., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aim: The prognostic and predictive value of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in non-small cell lung cancer (NSCLC) is not well established. The present study aimed at the elucidation of the role of KRAS mutation in prediction of outcome of patients with advanced NSCLC receiving second- or third-line chemotherapy., Patients and Methods: The outcome of 127 patients with advanced NSCLC who recieved pemetrexed or docetaxel at second- or third-line therapy was retrospectively analyzed., Results: Progression-free survival was not significantly different between patients with KRAS mutation and those with wild-type KRAS. The results were the same even when taking into account the specific KRAS mutation. Overall survival was significantly longer for patients with wild-type KRAS vs. those with KRAS mutation (16.1 vs. 7.2 months, p=0,008). We observed shorter overall survival for those with G12C KRAS mutation vs. other KRAS mutations (median 10.3 vs. 6.4 months, p=0.011)., Conclusion: The presence of KRAS mutation (especially KRAS G12C mutation) correlated with adverse prognosis in patients treated with second- or third-line pemetrexed or docetaxel., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: The aim of the study was to assess the degree to which tissue polypeptide antigen (TPA) and tissue polypeptide-specific antigen (TPS), as well as carcinoembryonic antigen (CEA), can assist in the detection of distant metastases., Patients and Methods: We assessed 157 patients with colorectal and breast cancer divided into two groups. The first was a group of patients with cancer at stages 1, 2 and 3; the second was a group of patients with cancer at stage 4 with metastasis., Results: We found significantly higher levels of all biomarkers in the metastatic group compared to the group with cancer at stages 1-3 (p<0.0001). The calculated area under the receiver operating characteristic (ROC) curve was 0.9929 for TPS, 0.9337 for TPA and 0.7234 for CEA. The cut-off was calculated for each biomarker at 95% specificity, TPS cut-off=255 IU/l (sensitivity 95%), TPA cut-off=200 IU/l (sensitivity 70%) and CEA cut-off=18 μg/l (sensitivity 37%)., Conclusion: We suggest combining CEA with TPS or TPA in the detection of distant metastases or using only cytokeratins. This approach can significantly increase the quality of detection of the metastatic process., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Pemetrexed and erlotinib represent different agents commonly used for the second-line treatment of patients with advanced-stage non-small cell lung cancer (NSCLC)., Patients and Methods: We analyzed data of 137 patients with advanced-stage non-squamous NSCLC treated with pemetrexed or erlotinib in the second line. All patients harbored a wild-type epidermal growth factor receptor gene. Genetic testing was performed using a combination of denaturing capillary electrophoresis and direct Sanger sequencing., Results: overall response rate and disease control rate in patients treated with pemetrexed was 20.8% and 62.5% vs. 6.3% and 53.2% in patients treated with erlotinib (p=0.022; p=0.358). Median progression-free and overall survival in patients treated with pemetrexed was 1.6 and 11.3 months vs. 1.9 and 11.4 months in patients treated with erlotinib (p=0.470 and p=0.942, respectively). Erlotinib was associated with skin rash and diarrhea; pemetrexed was associated with hematological toxicity and fatigue., Conclusion: A similar efficacy and different, although well-tolerated, toxicity profile of both pemetrexed and erlotinib was shown., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Tumor biomarkers represent effective tools for diagnostics and follow-up monitoring of patients with non-small cell lung cancer (NSCLC). We focused on evaluating the predictive and prognostic role of the seven following tumor biomarkers: carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA 21-1), fragments of cytokeratin 8, 18 and 19 (MonoTotal), neuron-specific enolase (NSE), chromogranin A, thymidine kinase (TK) and squamous cell carcinoma antigen (SCCA) in patients with advanced-stage NSCLC treated with pemetrexed-based chemotherapy., Patients and Methods: In total, 114 patients with advanced-stage (IIIB or IV) non-squamous NSCLC treated with pemetrexed-based chemotherapy (monotherapy or combination with a platinum derivative) were included. Comparison of progression-free (PFS) and overall survival (OS) according to the level of assessed tumor markers was performed using the log-rank test., Results: We recorded significantly shorter OS for patients with high pretreatment levels of CYFRA 21-1 (10.3 vs. 23.4 months; p<0.001), NSE (1.6 vs. 13.5 months; p=0.003) and TK (11.3 vs. 23.4 months; p=0.003)., Conclusion: CYFRA 21-1, NSE and TK are feasible biomarkers for estimation of a patient's overall prognosis, however, none of the measured serum tumor markers were able to predict the efficacy of pemetrexed-based chemotherapy., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Goblet cell carcinoid (GCC) of the appendix is extremely rare, representing approximately 5% of all primary appendiceal neoplasms. Histologically there are three groups of GCC: group A (typical GCC), adenocarcinoma ex GCC signet ring cell type (group B), and adenocarcinoma ex GCC poorly differentiated carcinoma type (group C), which is the most aggressive. GCC metastasizes in 15-60% of cases, mainly to the ovaries, pelvis, abdominal cavity, ribs, vertebrae, and lymph nodes. Hematogenous metastasis to the liver or other parenchymal organs can occur, but this is very rare. The different organs metastases havent been described yet. The primary mode of treatment is radical surgical resection or debulking, followed by chemotherapy; however, patients with unresectable or recurrent GCC are candidates for systemic therapy. Here, we report a case of very aggressive GCC of the appendix, which had metastazed to the liver at the time of diagnosis and subsequently metastasized to the orbit.

Background: Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) represent novel, effective tools in the management of advanced-stage non-small cell lung cancer (NSCLC). We aimed to evaluate the incidence and predictive role of EGFR gene amplification in patients with advanced-stage NSCLC treated with EGFR-TKIs., Patients and Methods: The study included 290 patients with advanced-stage (IIIB or IV) NSCLC. Multiplex ligation-dependent probe amplification (MLPA) and polymerase chain reaction (PCR) were used for detection of EGFR gene amplification and EGFR mutations, respectively., Results: EGFR amplification was detected in 26 (9.0%) patients. EGFR amplification was found more frequently in patients harboring the EGFR mutation (p<0.001). No significant corelation between EGFR gene amplification and survival was observed., Conclusion: EGFR gene amplification is associated with EGFR gene mutation. EGFR gene amplification is not a feasible predictive biomarker for treatment with EGFR-TKIs in patients with advanced-stage NSCLC., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

The aim of our retrospective study was to analyze the association of selected tumor markers (TMs) including serum carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), thymidine kinase, and tissue polypeptide specific antigen with outcomes in patients with metastatic colorectal cancer (mCRC) treated with bevacizumab. There is an increasing body of evidence from retrospective/observational studies that some serum TMs may be predictive of effect of targeted therapies in mCRC. In our study, the cohort included 152 patients treated with bevacizumab-based therapy between years 2005 and 2014 at Department of Oncology and Radiotherapy, Medical School and Teaching Hospital Pilsen. Serum samples for measurement of TMs were collected within 1 month before the initiation of bevacizumab-based treatment. In multivariate Cox analysis that included serum tumor markers and clinical baseline parameters, the number of metastatic sites (hazard ratio [HR] = 2.00, p = 0.001) and CEA levels (HR = 2.80, p < 0.001) were significantly associated with progression-free survival, whereas CA 19-9 levels (HR = 2.25, p = 0.008) were the only studied parameter associated with overall survival. Quantification of serum CEA and CA 19-9 is simple and readily available, and their candidate prognostic importance in the setting of antiangiogenesis therapy deserves to be studied in prospective trials.

Erlotinib is a low molecular weight tyrosine kinase inhibitor (TKI) directed at epidermal growth factor receptor (EGFR), widely used in the treatment of locally advanced or metastatic-stage non-small cell lung cancer (NSCLC). Although introduction of EGFR-TKIs have significantly extended survival of advanced-stage NSCLC patients, their efficacy in the entire patient population is relatively low. Aside from activating EGFR mutations, no reliable biochemical or molecular predictors of response to erlotinib have been established. The aim of our retrospective study was to evaluate the association of baseline serum levels of C-reactive protein (CRP) with outcomes in patients with advanced-stage NSCLC treated with erlotinib. We retrospectively analyzed clinical data of 595 patients with advanced-stage NSCLC (IIIB or IV) treated with erlotinib. Serum CRP was measured using an immunoturbidimetric method. High baseline levels of CRP (≥10 mg/l) were measured in 387 (65 %) patients, and normal levels (<10 mg/l) were measured in 208 (35 %) patients. The median progression-free survival (PFS) and overall survival (OS) for patients with high CRP was 1.8 and 7.7 compared to 2.8 and 14.4 months for patients with low CRP (p < 0.001 and p < 0.001). The multivariable Cox proportional hazards model revealed that CRP was significantly associated with PFS and also with OS (hazard ratio (HR) = 1.57, p < 0.001, and HR = 1.63, p < 0.001, respectively). In conclusion, the results of the conducted retrospective study suggest that high baseline level of CRP was independently associated with worse outcome of patients with advanced-stage NSCLC treated with erlotinib. CRP is a commonly used biomarker which is simple and easy to detect, and thus, it is feasible for the use in the routine clinical practice.

Objective: To evaluate the spectral power of the cortical bands in patients with first episode schizophrenia and schizoaffective disorder at rest and during the performance of a mental arithmetic task., Methods: We analyzed EEG spectral power (SP) in the resting state and subsequently while counting down from 200 in steps of 7, in 32 first episode schizophrenia patients (SZ), 32 patients with first episode schizoaffective disorder (SA) and healthy controls (HC, n=40). Behavioral parameters such as accuracy and counting speed were also evaluated., Results: Both SZ and SA patients were slower in counting than HC, no difference was obtained in the accuracy and counting speed in the patient groups. In the resting state patients showed elevated midline theta power, off-midline anterior beta 2 power and decreased central/posterior alpha power. The SA group occupied an intermediate position between the schizophrenia patients and controls. In task performance patients lacked a typical increase of midline theta, left anterior beta 2, and anterior gamma power; however, schizoaffective patients demonstrated a growing trend of power in the gamma band in left anterior off-midline sites similar to HC. Moreover, alpha power was less inhibited in schizoaffective patients and more pronounced in schizophrenia patients indicating distinct inhibitory mechanisms in these psychotic disorders., Conclusions: Patients with SA demonstrate less alteration in the spectral power of bands at rest than SZ, and present spectral power changes during cognitive task performance close to the controls., Significance: Our study contributes to the present evidence on the neurophysiological distinction between schizophrenia and schizoaffective disorder., (Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) represent novel effective agents approved for the treatment of patients with advanced-stage NSCLC. KRAS mutations have been reported as a negative prognostic and predictive factor in patients with NSCLC treated with EGFR-TKIs. Several studies have recently shown that statins can block tumour cell growth, invasion and metastatic potential. We analysed clinical data of 67 patients with locally advanced (IIIB) or metastatic stage (IV) NSCLC harbouring Kirsten rat sarcoma viral oncogene (KRAS) mutation treated with erlotinib or gefitinib. Twelve patients were treated with combination of EGFR-TKI and statin and 55 patients were treated with EGFR-TKI alone. Comparison of patients' survival (progression-free survival (PFS) and overall survival (OS)) according to the treatment used was performed using the Gehan-Wilcoxon test. The median of PFS and OS for patients treated with EGFR-TKI alone was 1.0 and 5.4 months compared to 2.0 and 14.0 months for patients treated with combination of EGFR-TKI and statin (p = 0.025, p = 0.130). In conclusion, the study results suggest significant improvement of PFS for patients treated with combination of statin and EGFR-TKI, and the difference in OS was not significant.

Aim: The aim of this retrospective, registry-based study was to analyse treatment outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib and renal insufficiency (RI)., Methods: The cohort included 790 patients treated with sunitinib between 2006 and 2013. At the start of sunitinib therapy 22, 234, and 534 patients had severe (glomerular filtration rate [GFR] <30ml/min/1.73m(2)), moderate (GFR 30-60 ml/min/1.73m(2)) or mild RI/normal renal function (GFR >60ml/min/1.73m(2)), respectively., Results: For the three groups defined above, median progression-free survival (PFS) (95% confidence interval [CI]) was 5.3 months (0.1-18.5), 8.1 months (6.2-9.9) and 11.3 months (9.4-13.2) (p=0.244), and median overall survival (OS) was 26.3 months (1.2-51.4), 21.2 months (13.2-29.1) and 26.3 months (22.6-29.9) (p=0.443), respectively. The disease control rates were 45.5%, 56.4% and 59.2%, respectively (p=0.374). No unexpected toxicity was reported in the patients with RI, but the treatment was more frequently discontinued because of adverse events and the duration of therapy was significantly shorter in these patients (p=0.007)., Conclusions: Duration of first-line targeted treatment for mRCC was significantly shorter for patients with RI, and may have translated into a trend to shorter PFS. These results highlight the need for optimal management of side-effects in patients with mRCC and RI., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Hyponatremia is a well-known phenomenon in cancer patients. The aim of our retrospective study was to assess the relationship of natremia levels to predict treatment with erlotinib and also to assess the prognosis of patients with hyponatremia., Patients and Metods: We analyzed data of 544 patients with advanced-stage non-small cell lung cancer (NSCLC) treated with erlotinib., Results: Hyponatremia was measured in 21.5 % of patients before treatment with erlotinib. We found a significant increase in the effectiveness of treatment with erlotinib in patients with normal levels of sodium to hyponatremic patients. Progression-free survival (PFS) and overall survival (OS) were also significantly higher in patients with normal natremia. Multivariate Cox model analysis demonstrated that natremia was an independent factor for PFS and OS., Conslusion: We reported hyponatremia not only as a prognostic marker in NSCLC patients but also as predictive marker of erlotinib treatment efficacy, being an independent factor at the present large retrospective study. Its possible effect in clinical practice is bigger thanks the simple possibility of testing of hyponatremia and the low cost of this biomarker., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Objective: The aim of the study is to determine the frequency of parkin allelic variants in Czech early-onset Parkinson's disease patients and healthy controls., Methods: A total of 70 early-onset Parkinson's disease patients (age at onset ≤40 years) and 75 controls were screened for the sequence variants and exon rearrangements in the parkin gene., Results: Parkin mutations were identified in five patients (7.1%): the p.R334C point mutation was present in one patient, four patients had exon deletions. The detected mutations were observed in the heterozygous state except one homozygous deletion of the exon 4. No mutations were obtained in control subjects. A novel sequence variant p.V380I (c.1138G>A) was identified in one control. Non-pathogenic polymorphisms p.S167N and p.D394N were seen in similar percentage in patients and controls, polymorphism p.V380L was almost twice as frequent in controls as in patients., Conclusions: Our study contributes to the growing body of evidence on the low frequency of the parkin mutations in the early-onset Parkinson's disease suggesting the potential role of other genes in the pathogenesis of the disease.

Background/aim: Tumor biomarkers are used for diagnostics and follow-up monitoring of patients with non-small cell lung cancer (NSCLC). We focused on the predictive role of neuron-specific enolase (NSE) and thymidine [corrected] kinase (TK) in patients with advanced-stage NSCLC treated with epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs)., Patients and Methods: In a total of 163 patients with advanced-stage (IIIB or IV) NSCLC treated with EGFR-TKIs (erlotinib or gefitinib), pre-treatment levels of NSE and TK were measured., Results: We observed significantly shorter progression-free (PFS) and overall survival (OS) in patients with high NSE levels (p=0.002; p=0.003) and also in those with high TK levels (p=0.026; p=0.020). The multivariate Cox proportional hazards model confirmed that high NSE is a strong independent predictive factor for short PFS (hazard ratio; HR=2.36; p=0.003)., Conclusion: High pre-treatment serum levels of NSE is an independent biomarker predicting poor outcome of patients with NSCLC treated with EGFR-TKIs., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Patients with ephedrone parkinsonism (EP) show a complex, rapidly progressive, irreversible, and levodopa non-responsive parkinsonian and dystonic syndrome due to manganese intoxication. Eye movements may help to differentiate parkinsonian syndromes providing insights into which brain networks are affected in the underlying disease, but they have never been systematically studied in EP. Horizontal and vertical eye movements were recorded in 28 EP and compared to 21 Parkinson's disease (PD) patients, and 27 age- and gender-matched healthy subjects using standardized oculomotor tasks with infrared videooculography. EP patients showed slow and hypometric horizontal saccades, an increased occurrence of square wave jerks, long latencies of vertical antisaccades, a high error rate in the horizontal antisaccade task, and made more errors than controls when pro- and antisaccades were mixed. Based on oculomotor performance, a direct differentiation between EP and PD was possible only by the velocity of horizontal saccades. All remaining metrics were similar between both patient groups. EP patients present extensive oculomotor disturbances probably due to manganese-induced damage to the basal ganglia, reflecting their role in oculomotor system.

Objectives: The aim of the present study was to describe the efficacy and safety of everolimus in the treatment of metastatic renal cell carcinoma (mRCC) after administration of 1 vs. 2 prior tyrosine kinase inhibitors (TKIs)., Patients and Methods: A national renal information system database was used as the data source for the retrospective study. There were 483 patients who received everolimus as the second (n = 350) or the third (n = 112) targeted agent following TKIs., Results: Median progression-free survival (PFS) from the start of everolimus in the second or the third line of targeted therapy was 6.1 months for both subgroups (P = 0.863). Median total PFS from the start of the first targeted agent to progression on the third targeted agent for patients receiving 3 lines of therapy with TKI-TKI-everolimus (n = 112) and TKI-everolimus-TKI (n = 27) sequences was 28.3 months vs. 31.3 months, respectively (P = 0.16), and there was no significant difference in overall survival. PFS on everolimus was associated with PFS on previous TKIs in patients receiving 1 but not 2 previous TKIs. Only 13% of 352 patients starting targeted therapy for mRCC in 2010 had received 3 sequential targeted agents by the data cutoff in March 2013., Conclusion: PFS on everolimus correlated with PFS on TKIs in patients pretreated with 1 but not 2 TKIs. Everolimus can be deferred to the third line without loss of efficacy or increased toxicity. However, only a minority of patients with mRCC starting targeted treatment can be expected to receive third-line therapy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Tumor biomarkers are used for predicting therapy effect and prognosis of patients with non-small cell lung cancer (NSCLC). We focused on their potential role in prediction of the efficacy of erlotinib., Patients and Methods: In a total of 144 patients with advanced-stage (IIIB or IV) NSCLC treated with erlotinib, pre-treatment levels of soluble carcinoembryonic antigen (CEA) and cytokeratin markers in serum were measured., Results: The median progression-free and overall survival for patients with a high level of carcinoembryonic antigen (CEA) was 1.9 and 8.6 vs. 2.9 and 16.1 months for patients with low CEA (p=0.046 and p=0.116). The respective medians for patients with a high level of cytokeratin-19 fragment were 1.9 and 6.1 vs. 3.4 and 23.8 months for patients with the low cytokeratin-19 fragment (p<0.001 and p<0.001)., Conclusion: High pre-treatment serum levels of one or both biomarkers are associated with poor outcome of patients with NSCLC treated with erlotinib., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor used for the treatment of advanced stage non-small cell lung cancer (NSCLC). Clinical trials have shown high efficacy of erlotinib, particularly in patients harboring activating mutations in the EGFR gene. Here we describe the case of a 42-year-old female light smoker diagnosed with EGFR mutation-positive adenocarcinoma of the left lung with pleural metastases, pleural effusion and metastases to the thoracic vertebrae (stage IV, T4NXM1). Although the patient developed resistance to erlotinib in the first line, she achieved disease stabilization lasting for 13 months as a response to erlotinib retreatment after 6 cycles of second-line chemotherapy. In conclusion, retreatment with erlotinib in our patient was effective. Therefore it should be considered as a good treatment option for patients with NSCLC harboring EGFR mutation.

Suppression of tau protein expression has been shown to improve behavioral deficits in mouse models of tauopathies, offering an attractive therapeutic approach. Experimentally this had been achieved by switching off the promoters controlling the transgenic human tau gene (MAPT), which is not possible in human patients. The aim of the present study was therefore to evaluate the effectiveness of small interfering RNAs (siRNAs) and their cerebral delivery to suppress human tau expression in vivo, which might be a therapeutic option for human tauopathies. We used primary cortical neurons of transgenic mice expressing P301S-mutated human tau and Lund human mesencephalic (LUHMES) cells to validate the suppressive effect of siRNA in vitro. For measuring the effect in vivo, we stereotactically injected siRNA into the brains of P301S mice to reveal the suppression of tau by immunochemistry (AT180, MC1, and CP13 antibodies). We found that the Accell™ SMART pool siRNA against MAPT can effectively suppress tau expression in vitro and in vivo without a specific delivery agent. The siRNA showed a moderate distribution in the hippocampus of mice after single injection. NeuN, GFAP, Iba-1, MHC II immunoreactivities and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed neither signs of neurotoxicity or neuroinflammation nor apoptosis when MAPT siRNA is present in the hippocampus. Our data suggest that siRNA against MAPT can serve as a potential tool for gene therapy in tauopathies.

Background: Pemetrexed and erlotinib represent novel agents for the treatment of non-small cell lung cancer (NSCLC). The role of sequential treatment in NSCLC has not been elucidated yet. We compared the efficacy of second-line pemetrexed followed by third-line erlotinib (P-E) to treatment with the reverse sequence (E-P)., Patients and Methods: We analyzed data of 57 patients with advanced-stage (IIIB/IV) lung adenocarcinoma harboring wild-type epidermal growth factor receptor (EGFR) gene; 31 patients were treated with P-E and 26 patients with the E-P sequence., Results: The median progression-free survival (PFS) for patients treated with P-E was 3.6 months vs. 7.8 months for patients treated with E-P (p=0.029). The median overall survival (OS) for patients treated with P-E was 7.9 months vs. 26.3 months for patients treated with E-P (p=0.006)., Conclusion: The results proved a significant improvement of both PFS and OS for patients treated with the E-P sequence as compared to the P-E sequence.

Background: Epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene (KRAS) and phosphatidylinositide-3-kinase catalytic subunit-alpha (PIK3CA) mutations are biomarkers used for the prediction of efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small cell lung cancer (NSCLC)., Patients and Methods: In total, 223 patients with advanced-stage squamous cell NSCLC were tested; 179 patients were treated with EGFR-TKIs. Genetic testing was performed using a combination of denaturing capillary electrophoresis and direct Sanger sequencing., Results: EGFR mutations were detected in 7.2%; KRAS mutations in 7.4% and PIK3CA mutations in 3.8% of patients. No correlation of EGFR or PIK3CA mutation status with progression-free survival (PFS) (p=0.425; p=0.197), nor overall survival (OS) (p=0.673; p=0.687), was observed. KRAS mutations correlated with shorter OS (p=0.039), but not with PFS (p=0.120)., Conclusion: We did not observe any role of EGFR, KRAS, PIK3CA mutations in prediction of EGFR-TKIs efficacy in patients with advanced-stage squamous cell NSCLC.

The role of KRAS mutations in molecular targeted therapy by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) has not been fully understood. The present investigation is aimed at an elucidation of the role of specific KRAS mutation types in predicting outcomes of patients with advanced NSCLC receiving EGFR-TKI therapy. Initially, 448 NSCLC patients were tested for the presence of KRAS mutations, to obtain frequencies of specific KRAS mutation types. Subsequently, the clinical outcome of treatment was evaluated in a subgroup of 38 KRAS-positive patients receiving EGFR-TKI therapy. KRAS mutations were detected in 69 of 448 patients (15.4%), mostly in smokers (17.86% vs. 5.8%, P = 0.0048), and appeared more frequently in adenocarcinomas than in squamous cell NSCLC or NSCLC that is not otherwise specified (21% vs. 6.99% vs. 4.4%, P = 0.0004). The most frequent type of KRAS mutation was G12C. The progression-free survival (PFS) was doubled in a group of non-G12C patients compared with that of the G12C group (9.0 wk vs. 4.3 wk, P = 0.009). The overall survival (OS) was not significantly different between non-G12C and G12C groups (12.1 wk vs. 9.3 wk, P = 0.068). The G12C KRAS mutation is a strong negative predictor for EGFR-TKI treatment, whereas other KRAS mutation types have not negatively predicted treatment efficacy compared with that for the wild-type KRAS genotype., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Erlotinib is an epidermal growth factor receptor tyrosine-kinase inhibitor. Clinical trials have shown its efficacy in advanced non-small cell lung cancer (NSCLC). We conducted a large retrospective study based on clinical experience aiming to prove erlotinib's efficacy and safety in patients with advanced-stage squamous cell NSCLC. Totally 375 patients with advanced-stage (IIIB, IV) squamous cell NSCLC were treated with erlotinib. Erlotinib was continued until disease progression or intolerable toxicity. 1 (0.3%) complete response (CR), 28 (7.5%) partial responses (PR) and 198 (52.8%) stable diseases (SD) were achieved. Overall response rate (ORR) and disease control rate (DCR) were 7.8% and 60.5%, respectively. Median progression-free survival (PFS) was 3.0 months and median overall survival (OS) was 7.6 months. PFS of patients with CR/PR, SD and PD were 7.6, 3.9 and 1.0 months, respectively (P<0.001). OS of patients with CR/PR, SD and PD were 13.3, 10.9 and 3.8 months, respectively (P<0.001).The most common adverse effects were rash and diarrhoea. In conclusion ertlotinib is effective and well-tolerated in patients with advanced-stage squamous cell NSCLC.

Background: Chylous ascites is a rare complication of the gastrointestinal neuroendocrine tumor. There are two mechanisms of its origin: mechanical obstruction by the tumor mass and fibrosis of the surrounding tissue due to overproduction of serotonin. Its presence restricts treatment options., Case: We report a case of 66year old man suffering from recurrent diarrhoea and ascites. We found elevated tumor marker Chromogranin A and elevation of hydroxyindoleacetic acid (5- HIAA) in the urine. A subsequent whole body scintigraphy scan by octreoscan confirmed multinodal process with increased somatostatin receptors activity in the wall of the ileum, rectosigmoideum, lymph nodes of the retroperitoneum and mesenterium and left supraclavicular area. We performed bio-psy from the lymph node of supraclavicular area, and there was metastasis of the neuroendocrine tumor. Start of cytostatic therapy was repeatedly complicated by recurrent massive chylous ascites. The patient underwent only one series of palliative chemotherapy. Another procedure was again complicated by chylous ascites that caused hospitalization at the internal department, and the patient died four months after dia-gnosis., Conclusion: Chylous ascites is a very rare complication of gastrointestinal neuroendocrine tumor. It is not only a marker of poor prognosis, but also a complication that makes systemic treatment very difficult.

Background: Tapentadol is a µ -opioid receptors agonist as well as an inhibitor of noradrenaline reuptake. This pharmacologic profile of tapentadol makes it a suitable drug of choice in nociceptive and neuropathic pain control., Case Report: This clinical report pressents a 65year old man with poorly differentiated prostate cancer -  Gleason score 8 (4 + 4) with metastatic bone disease. Besides the initial application of bisphosphonates, the patient had been treated with androgen deprivation therapy (cyproterone acetate + leuprolide acetate) for the period of 18 months. This therapy was terminated due to an increase of PSA levels. Subsequently, the patient underwent palliative docetaxelbased chemotherapy. There were eight cycles applied with positive clinical and laboratory effect. However, the further application was limited by the averse effects, namely the peripheral neuropathy manifested by pain in arms and legs. The peripheral neuropathy had progressive tendency even after the end of chemotherapy, and supportive treatment with gabapentin and amitryptiline failed to succeed. Four months after zoledronic acid monotherapy, the patient was started on tapentadol in 50-mg dose b.i.d., consequently escalated to 100 mg b.i.d. (to this point, 25 µg of transdermal fentanyl were used for pain management). Significant relief from neuropathic discomfort was observed three weeks from the onset of tapentadol therapy. Patients state of health normalized within three months after the initiation of therapy. Consequently, the patient was able to receive docetaxel chemotherapy again, without any neuropathic pain exacerbation on the maintenance dose of tapentadol 50 mg b.i.d., Conclusion: Tapentadol administration resulted in stable and longtime relief from neuropathic pain which is a frequent side effect in the course of castrate-resistant prostate cancer therapy with taxanes.

Molecular targeted therapy based on tyrosine kinase inhibitors, directed at the epidermal growth factor receptor (EGFR) is one of novel options for management of NSCLC. Erlotinib is EGFR tyrosine kinase inhibitor used for treatment of the advanced NSCLC. This presented study is focused on comparison of erlotinib and chemotherapy efficacy in the second line treatment of the advanced NSCLC. DCR and PFS became the primary endpoints.Total number of patients was 290. A group treated with chemotherapy in the second line consisted of 150 patients and a group treated with erlotinib in the second line consisted of 140 patients. Comparison of DCR was performed using Fisher's exact test, visualization of PFS was performed using Kaplan-Meier survival curves and differences were tested using the log-rank test. Genetic testing was performed using PCR direct sequencing. In the group treated with chemotherapy 2 CR, 23 PR and 51 SD were achieved vs. 5 CR, 10 PR and 55 SD in the group treated with erlotinib in the second line. DCR in patients treated with chemotherapy was 54.0% vs. 51.3% in patients without EGFR mutation treated with erlotinib (p=0.707); in patients harboring EGFR mutation, treated with erlotinib (n=9) outstanding results were achieved: 4 CR, 2 PR and 3 SD (not tested). Median of PFS in patients treated with chemotherapy was 2.1 months vs. 1.9 months in patients without EGFR mutation (p=0.879) vs. 8.4 months in patients harboring EGFR mutation treated with erlotinib (p=0.017). Results of analysis show that even patients without EGFR mutation are able to benefit from erlotinib treatment in the second line. The efficacy (DCR, PFS) of erlotinib in patients without EGFR mutation was comparable with chemotherapy. The treatment efficacy in a subgroup of patients harbouring EGFR mutation treated with erlotinib was significantly better than in patients without EGFR mutation.

Erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor used in treatment of advanced NSCLC. Patients harboring EGFR or KRAS mutations represent minority of all patients in caucasian population and there is no available predictor for a predominant group of patients harboring the wild-type EGFR and wild-type KRAS genes. Skin rash is the most frequent manifestation of cutaneous toxicity of erlotinib. Rash is associated with a good therapeutic response. We aimed at the evaluation of rash as a predictor of therapeutic effect of erlotinib in patients harboring the wild-type EGFR and KRAS wild-type genes and to assess its possible usage in a clinical practice.Totally 184 patients with advanced stage NSCLC (IIIB, IV) harboring the wild-type EGFR and wild-type KRAS genes were analysed. Comparison of ORR, PFS and OS according to the occurrence of rash was performed. In order to assess the impact of rash in clinical practice it was conducted landmark analysis of the group of patients whose rash was observed during first month of treatment (n=124). Patients in whom progression was observed during the first month of treatment were excluded from the landmark analysis. The comparison of ORR was performed using Fisher's exact test, visualization of survival was performed using Kaplan-Meier survival curves and the differences in survival were tested using the log-rank test. Median PFS in patients who were observed with rash during the treatment was 3.0 vs. 1.2 months in patients with no rash (p<0.001), median of OS in patients who were observed with rash during the treatment was 13.9 vs. 5.8 months in patients with no rash (p<0.001). ORR in patients who were observed with rash during the treatment was 17.4% vs. 3.3% in patients with no rash (p=0.001). Median of PFS after 1 month of treatment in patients who were observed with rash during the first month was 2.9 vs. 1.1 months in patients with no rash (p=0.027). Median of OS after 1 month of treatment in patients who were observed with rash during the first month was 13.8 vs. 9.9 months in patients with no rash (p=0.082). Rash is strongly associated with better survival and ORR in patients harboring wild-type EGFR and wild-type KRAS genes. Occurrence of rash during the first month of treatment is a useful predictor of better effect of erlotinib after one month of treatment. Patients who were not observed with rash during the first month of treatment are in high risk of progression. Optimization of the treatment of these patients can contribute restaging after two months of treatment, assessment of plasma levels of erlotinib and eventually attempt to dose escalation.

Unlabelled: Chemotherapy is an important modality of treatment for non-small cell lung cancer (NSCLC). Recent studies have shown that assessment of predictive molecular markers could be helpful for estimation of the response rate to chemotherapy. The aim of our study was to assess the relation of mRNA levels of DNA repair genes excision repair cross-complementary group 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1) and breast cancer 1 (BRCA1), in surgically-resected tumor tissues from patients who underwent adjuvant chemotherapy, to the disease-free interval (DFI) and overall survival (OS). We investigated if potential residual tumor cells after resection reflect properties of the primary tumor and response to chemotherapy according to the level of predictive markers with respect to current knowledge., Patients and Methods: We studied a group of 90 patients with NSCLC who had undergone curative lung resection; 59 of them were subsequently treated with adjuvant chemotherapy, DFI and OS were evaluated only in this subgroup. Quantitative estimation of mRNA of selected genes in paired (tumor and control)-lung tissue samples was performed by real-time reverse transcription-polymerase chain reaction (RT-PCR)., Results: We found a significantly lower mRNA expression of ERCC1 (p<0.001) and RRM1 (p=0.023) in NSCLC tumor tissues compared to normal lung tissues. Comparing expression in histological subtypes, we recorded higher mRNA expression of ERCC1 (p=0.021), RRM1 (p=0.011) and BRCA1 (p=0.011) in adenocarcinoma than in squamous cell carcinoma (SCC). Differences in DFI and OS were found only in specific subgroups according to tumor type and stage. We found longer OS for patients with adenocarcinoma with higher expression of the RRM1 mRNA (p=0.002), and for patients with SCC with higher expression of the BRCA1 mRNA (p=0.041). In patients with NSCLC of stage III, we found longer DFI in those with higher expression of RRM1 (p=0.004) and ERCC1 (p=0.038)., Conclusion: Patients who had been treated with adjuvant chemotherapy and had shown lower expression of repair genes had adverse prognosis. We observed that the assessment of DNA repair gene level in primary tumors treated by surgical resection had prognostic significance and did not predict response to adjuvant chemotherapy.

Targeted biological therapy is becoming a standard in personalized medicine for patients with advanced stages of cancer. Treatment with cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody, represents an example of personalized anticancer therapy for patients with metastatic colorectal cancer and wild (non-mutated) type of the Kirsten rat sarcoma viral oncogene (KRAS). Here the role of cetuximab in treating metastatic colorectal cancer is discussed with a focus on the treatment of hepatic metastases.

Background/aims: Portal vein ligation (PVL) could multiply the future liver remnant volume (FLRV). Tumor necrosis factor- alpha (TNF-α) is a pleiotropic cytokine that is connected with initial phase of liver regeneration. The aim of this basic pilot study was to accelerate regeneration of liver parenchyma after PVL. The experimental porcine model was developed to be as much compatible as possible with portal vein embolization (PVE) in human medicine., Methodology: After ligation of portal branches of caudate and right lateral and right medial liver lobes recombinant porcine TNF-α (TNF-α group) or physiological solution (control group) were applied into non-occluded portal vein branches. The biochemical and immunoanalytical parameters were assessed. The compensatory hypertrophy was evaluated by periodic ultrasonography. The histological examination of liver was performed., Results: The acceleration of growth of hypertrophic liver lobes was maximal at the 7th postoperative day in comparison with the control group (p<0.05); nevertheless this stimulating effect was lost at the end of experiment. The important differences in biochemical or histological studied parametres between study groups were not proved., Conclusions: The achieved acceleration of growth of hypertrophic liver lobes after application of TNF-α confirms the role of studied cytokine in priming of liver regeneration.

Background: Molecular targeted therapy based on tyrosine kinase inhibitors, directed at the epidermal growth factor receptor (EGFR) is one of novel options for management of NSCLC. EGFR gene mutations, exon 19 deletions and exon 21 point mutations (L858R) are good predictors of response to EGFR-TKI treatment. The aim of this study was to assess the incidence of EGFR mutations in a large cohort of Europeans with advanced NSCLC and subsequently to evaluate their impact on the effect of EGFR-TKI treatment., Patients and Methods: In total, 613 patients with advanced stage NSCLC (IIIB, IV) were genetically tested. The effect of treatment was evaluated in 410 patients treated with EGFR-TKI. Survival was evaluated using Kaplan-Meier method, and statistical comparison was performed using log-rank test., Results: EGFR mutations were detected in 73 (11.9%) patients. Exon 19 deletions were detected in 49 patients, exon 21 point mutations (L858R) were detected in 22 patients, and both mutation types were detected in 2 patients. An increased incidence of EGFR mutations among patients with adenocarcinoma (14.9% vs 7.8%, p = 0.008), women (20.2% vs 7.1%, p < 0.001) and nonsmokers (29.9% vs 7.0%, p < 0.001) was demonstrated. Sixty patients with EGFR mutation and 350 patients with wild-type EGFR were treated with EGFR-TKI. Median PFS in patients harboring EGFR mutation was 7.2 vs 2.0 months in patients harboring wild-type EGFR (p < 0.001), median OS in patients harboring EGFR mutation was 14.5 vs 7.5 months in patients harboring wild-type EGFR (p = 0.019)., Conclusion: The incidence of EGFR mutations in the studied population, their increased incidence among patients with adenocarcinoma, women and non-smokers correlated with data previously published. Results of survival analysis in patients treated with EGFR-TKI confirmed high potential of EGFR mutations to predict good effect of the EGFR-TKI treatment. Genetic testing in patients with NSCLC should be a standard part of diagnostic procedures

Objectives: Mutations in several genes such as parkin can be detected in up to 20% of patients with early-onset Parkinson's disease (EOPD). The aim of our study was to determine the frequency of parkin alterations and phenotypic characteristics in Czech EOPD patients., Methods: A total of 45 EOPD individuals (age at onset <45 years) were phenotyped and screened for parkin mutations., Results: In total, 19 patients (42.2%) were carriers of previously described heterozygous genetic alterations. Parkin mutations (Ex2del, R402C) were identified in two (4.4%) cases, non-pathogenic variant A82E plus polymorphism D394N occurred in one (2.2%) patient and parkin polymorphisms (3x S167N, 1x R334C, 7x V380L, 4x D394N) were found in 15 (34.9%) individuals. Furthermore, the G2019S mutation in the LRRK2 gene was found in one (2.2%) subject., Conclusion: The clinical characteristics of our patients correspond to previous descriptions of EOPD phenotype. This is the first report on EOPD-associated genetic alterations among Czech patients. Our results support the hypothesis that single heterozygous parkin variants may act as risk factors for EOPD.

Background: Portal vein ligation (PVL) could multiply the future liver remnant volume (FLRV). Interuleukin-6 (IL-6) is a pleiotropic cytokine that is associated with an initial phase of liver regeneration. The aim of this study was to accelerate the regeneration of liver parenchyma after PVL by intraportal cytokine application., Materials and Methods: After ligation of portal branches of caudate and right lateral and right medial liver lobes, recombinant porcine IL-6 (IL-6 group) or physiological solution (control group) were applied into non-occluded portal vein branches. The biochemical and immunoanalytical parameters were assessed. The compensatory hypertrophy was evaluated by periodic ultrasonography. The histological examination of liver was performed., Results: The acceleration of growth of hypertrophic liver lobes was maximal at the 7th postoperative day in comparison with the control group (p<0.05), nevertheless, this stimulating effect was lost at the end of the experiment. Important differences in biochemical or histological studied parametres were not proved., Conclusion: The presented study describes the use of IL-6 for stimulation of the first phase of liver regeneration. The achieved acceleration of growth of hypertrophic liver lobes after application of IL-6 confirmed the key role of the studied cytokine in priming regenerating liver parenchyma after portal vein ligation.

The Aim of Study: The limits of liver surgery are restricted today by the functional reserves of remnant parenchyma. The aim of this article was to acquaint the general surgical and medical public with the results of experimental liver regeneration stimulated by cytokines and thus to enhance their effort to carry on with implementing the research results in clinical practice., Methods: Authors present their experimental model of liver regeneration after ligation of portal branches for caudate and right lateral, and right medial liver lobes. The regeneration was induced by application of TNF-alpha and IL-6 into the non-occluded portal branches, and compared with the results of other experimental teams., Results and Conclusion: The absolute volume of hypertrophic lobes increases after application of TNF-alpha more rapidly, whereas in the control group, practically no changes were recorded in hypertrophic liver lobes volumes in first three days. The achieved acceleration of growth of hypertrophic liver lobes after application of TNF-alpha and IL-6 confirmed the key role of studied pleiotropic cytokines in the priming of liver parenchyma regeneration after portal vein ligation (Fig. 3, Ref. 26).

A total of 58 children is referred to with fractured growth plates of the distal forearm, proximal humerus, radial condyle of humerus, ulnar epicondyle of humerus, distal tibia, proximal tibia and the distal femur. The related injuries are divided in accord with Salter-Harris classification. The treatment of epiphyseolyses is concerned together with summarizing its results and the appropriate experience. In addition, the indications for both conservative and surgical approaches are delimitated in treating these injuries.

Authors present the initial experience with the closed locked intramedullary fixation of long bones (mainly the tibial bone) in conditions of the Teaching Hospital. Possible improvisation is reported on when lacking the foreign osteosynthetical material.

Stressory reactions in surgical patients are studied as the main adaptative reaction occurring in loads both in physiological limits and graded measure, where the reaction itself appears to action as a pathological nuisance. The human stressors are reviewed as well as up-to-date data on the pathophysiology, diagnostics and prevention of stressory reaction including the therapeutical measures in order to prevent the development of organ damages with graded anxious reaction. Of special attention are interrelations of neurohumoral and immune reactions in syndromes of the so-called acute phase holoorganic reaction in the response of the organism on the graded aggression. In addition, the multifactorial stress is scrutinised in detail as the patient goes through the diagnosis and treatment with both its objectivation and minimalization. In conclusion, the modifications are mentioned of the course of stressory reaction in endocrynopathies as well as risks and measures on how to prevent such surprising and harmful interactions.

The experience is summarized in using the method of external fixation (Stuhler-Heise from Aesculap, Poldi 7, Ilizarov's compressory distractive devices) in the traumatology of extremities within 5-year lasting period. Starting from june 1985 to July 1990, the amount of 90 open fractures of long bones has been managed (10.2% of all fractures admitted). Open fractures related to III. grade by Gustilo's classification were 20 in number, i.e. 22.0% of all open fractures admitted with anatomical distribution as follows: 50% crural, 25% humeral, 15% forearm and 10% femoral locations. The EF device was applied in 11 cases, i.e. 55%. Primary amputations were done in 4 cases, i.e. 20%. The EF application period averaged for 64 days. One case showed primary healing of EF treated fractures. The remaining cases attributed an exchange of the type of osteosynthesis or were supplemented with plastic surgery on the soft tissues and bone. Another group of 36 pseudoarthroses of long bones were operated on within the mentioned period, from them 9 cases as infected ones were treated with EF method. Once the infection has been healed, the authors proceeded with surgery and EF exchange in all cases when treating pseudoarthroses. Third--the group of 18 nonstabile intraarticular fractures of distal radius treated by means of EF is presented. The advantages of individual EF methods are discussed, and the comprehensive care approaches are presented in documental groups of injuries as illustrated with the short case-reports.

Possible replacements in vascular reconstructive surgery are studied. The indicatory measures to vascular operations are delimited altogether summarizing the main criteria of successful grafting. The review is presented of both biological and artificial vascular replacements and their benefits and disadvantages are mentioned as well.