Influence of different spectra of NOTCH3 variants on the clinical phenotype of CADASIL - experience from Slovakia.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary vascular disorder causing ischaemic attacks and strokes in middle-aged adults. Though the clinical spectrum includes some typical symptoms, recognition of the disease, especially at an earlier stage, is very difficult because of the highly variable manifestation and incomplete clinical picture. Characteristic brain MRI findings and the presence of pathogenic variants in the NOTCH3 gene are fundamental for CADASIL diagnosis. In this paper, we provide the first comprehensive report on CADASIL patients from Slovakia. Altogether, we identified 23 different pathogenic variants in 35 unrelated families. In our cohort of patients with clinical suspicion of CADASIL, we found a causal genetic defect and confirmed the diagnosis in 10.2% of cases. We present the case reports with up-to-date unpublished NOTCH3 variants and describe their phenotype-genotype correlation: p.(Cys65Phe), p.(Pro86Leu/Ser502Phe), p.(Arg156*), p.(Cys408Arg), p.(Tyr423Cys), p.(Asp1720His), and p.(Asp1893Thrfs*13). The most frequently described location for pathogenic variants was in exon 4, whereas the most common single variant was p.Arg1076Cys in exon 20. Based on the results of our study, we propose a re-evaluation of the criteria for the selection of patients suitable for NOTCH3 gene analysis. We hereby state that the currently used protocol of a high score requirement is not ideal for assessing molecular analysis, and it will be desirable to be less strict in criteria for genetic testing.

Stereotactic radiosurgery and radiotherapy for resected brain metastases: current pattern of care in the Radiosurgery and Stereotactic Radiotherapy Working Group of the German Association for Radiation Oncology (DEGRO).

PURPOSE: Preoperative stereotactic radiosurgery (SRS) of brain metastases may achieve similar local control and better leptomeningeal control rates than postoperative fractionated stereotactic radiotherapy (FSRT) in patients treated with elective metastasectomy. To plan a multicentre trial of preoperative SRS compared with postoperative FSRT, a survey of experts was conducted to determine current practice. METHODS: A survey with 15 questions was distributed to the DEGRO Radiosurgery and Stereotactic Radiotherapy Working Group. Participants were asked under what circumstances they offered SRS, FSRT, partial and/or whole brain radiotherapy before or after resection of a brain metastasis, as well as the feasibility of preoperative stereotactic radiosurgery and neurosurgical resection within 6 days. RESULTS: Of 25 participants from 24 centres, 22 completed 100% of the questions. 24 respondents were radiation oncologists and 1 was a neurosurgeon. All 24 centres have one or more dedicated radiosurgery platform and all offer postoperative FSRT. Preoperative SRS is offered by 4/24 (16.7%) centres, and 9/24 (37.5%) sometimes recommend single-fraction postoperative SRS. Partial brain irradiation is offered by 8/24 (33.3%) centres and 12/24 (50%) occasionally recommend whole-brain irradiation. Two centres are participating in clinical trials of preoperative SRS. SRS techniques and fractionation varied between centres. CONCLUSION: All responding centres currently offer postoperative FSRT after brain metastasectomy. Approximately one third offer single-fraction postoperative SRS and four already perform preoperative SRS. With regard to potential co-investigators, 18 were identified for the PREOP­2 multicentre trial, which will randomise between preoperative SRS and postoperative FSRT.

PTEN mutations as predictive marker for the high-grade endometrial cancer development in slovak women.

Endometrial carcinoma (ECa) is one of the most common neoplasia of the female genital tract. The phosphatase and tensin (PTEN) homolog is the most frequently mutated tumor suppressor gene in endometrial carcinoma. PTEN encodes a phosphatase, a key regulatory enzyme involved in a signal transduction pathway that regulates cell growth, migration and apoptosis. The study evaluates an association between the morphological appearance of endometrial hyperplasia and ECa, and the presence of PTEN variations, PTEN protein´s level and intracellular localization. A total of 67 archived formalin-fixed and paraffin-embedded human biopsy tissue specimens with normal proliferative and secretory endometrium, endometrial hyperplasia without atypia and endometrial atypical hyperplasia, endometrioid the grade G1 and G3 and serous subtype of ECa were evaluated by sequencing for the presence of mutations in coding regions of PTEN gene of endometrial epithelial cells. The PTEN gene expression and intercellular localization of PTEN protein were evaluated immunohistochemically by immunoreactive score (IRS). PTEN mutation spectrum in endometrial carcinoma was identified for Slovak population. 28 non-silent mutations were identified in PTEN, twelve of them were novel, not annotated in Catalogue of Somatic Mutations in Cancer. Higher frequency of PTEN mutations was observed in serous carcinoma compared to global average. No correlation was observed between samples´ IRS, PTEN cellular localization and identified mutations. PTEN sequencing can be beneficial for patients considering prognosis of disease and sensitivity to treatment.

[Bullous pemphigoid on a healed herpes zoster : A rare example of an isotopic response]. / Bullöses Pemphigoid auf einem ausgeheilten Zoster thoracalis : Ein seltenes Fallbeispiel für eine isotope Reaktion.

Wolf's isotopic response describes the eruption of a secondary, pathogenically independent skin disease within the borders of a primary, already healed skin disease. The exact mechanism is unknown, but the restriction to diseases with a known T­cell component in the pathogenesis suggests an involvement of persistent local immune activation. We report the case of an 87-year-old woman who developed bullous pemphigoid lesions within the boundaries of a previous, already healed herpes zoster C7-C8, which had been diagnosed clinically and treated 2 months previously. Histopathological examination revealed subepidermal blisters, and indirect immunofluorescence showed IgG antibodies against the basal membrane zone. Both BP 180 and BP 230 enzyme-linked immunoassays (ELISAs) were positive. Based on these findings, we diagnosed a bullous pemphigoid arising on the site of the already healed herpes zoster, linked by an isotopic response.

Single umbilical artery and reproduction losses in Slovak population: relation to karyotype and fetal anomalies.

AIM: The purpose of this study was to monitor the association between single umbilical artery (SUA), chromosomal abnormalities and associated anomalies during the routine examination of spontaneous or induced miscarriages and premature births. METHODS: During 1992-2015 we morphologically and cytogenetically examined a series of 4098 samples. For 1330 cases the number of umbilical cord vessels could be reported. RESULTS: The presence of single umbilical artery was identified in 67 fetuses of 1330 pregnancies (5.04 %); 36 of the 67 fetuses (53.7 %) had additional congenital malformations. The cultures were unsuccessful in 29 of 67 cases (43.3 %). 38 cases (56.7 %) were successfully karyotyped; 20 out of them had a normal karyotype and 18 had chromosomal anomalies including trisomy 18 (n = 4), trisomy 13 (n = 3), trisomy 21 (n = 2), trisomy 11 (n = 1), triploidy (n = 3), monosomy X (n = 3) and structural chromosomal aberrations (n = 2). CONCLUSION: Isolated SUA is not at increased risk of chromosomal abnormalities and generally does not endanger pregnancy. All chromosomally abnormal embryos and fetuses had associated congenital anomalies. The most frequently associated congenital anomalies were in the musculoskeletal system, central nervous system and genitourinary tract (Tab. 4, Ref. 44).

Distribution of the most common polymorphisms in TYMS gene in Slavic population of central Europe.

Thymidylate synthetase (TS) plays a critical role in the de novo synthesis of dTMP inside the cell. Therefore, TS is a suitable target for cytotoxic drugs such as fluoropyrimidines. Drug efficacy and toxicity depend on the intracellular level of TS, which is significantly influenced by the polymorphisms in the 5'UTR (TSER - rs45445694, TSER*3G>C - rs2853542) and 3'UTR (1494del TTAAAG - rs151264360) of TYMS gene. Polymorphic variants of TYMS gene affect TS activity via gene expression and transcript stability. Patients who undergo fluoropyrimidine therapy may benefit from genetic testing prior to the administration of chemotherapy. At the 5' terminus of TYMS, there is a polymorphic region represented by a variable number of 28bp long tandem repeats (2-9 tandems) with the G or C nucleotide variant (SNP G>C). The 3'end of TYMS gene may decrease the stability of mRNA in the case of 6 base deletion (1494del6, D). In our study, we have focused on testing of TYMS gene polymorphisms, determination of TYMS variant frequencies in Western Slavic population and comparison of Slovak population with other populations.We performed identification of 5'UTR (rs45445694 - TSER*2 or TSER*3; rs2853542 - TSER*3G>C; TSER*3+ins6) and 3'UTR (rs151264360/1494del6/D) polymorphic regions of TYMS gene among 96 volunteers by PCR-RFLP and fragment analysis. Slovak frequencies of selected polymorphisms were established as follows: the frequency of TSER*2, TSER*3, TSER*3G>C, 1494del6/D and I to be 41%, 59%, 34%, 37.5% and 62.5% respectively. The high resolution of the capillary electrophoresis technique allowed among TSER*3 group identification of a subgroup of four individuals with rare 6bp insertion in 3R allele, id est 2.1% TSER*3+ins6 allele frequency. In our study, we have revealed individuals with rare G>C substitution in the first 28bp tandem repeat of TSER*2 promoter enhancer region (rs183205964) as well, the overall frequency of this polymorphic allele in Slovak population was 2.1%. Our results proved that Slovak population is in Hardy-Weinberg equilibrium and proportion of TYMS polymorphisms is in accordance with other published data.

The first imported human infestation with Furuncular myiasis in man in the Slovakia and current knowledge of myiasis.

INTRODUCTION: Furuncular myiasis is caused by the genus of botfly Dermatobia hominis. It belongs to the family Cuterebridae and is indigenous to Central and South America. OBJECTIVE: to present a case report of the first case of this disease in Slovakia. CURRENT STATE OF PROBLEM SOLUTION: The term myiasis refers to infestation of the host (animal, man) by botfly larvae. Its larvae burrow under the skin. They feed on the host's living tissues and fluids. MateriAl and methods: Patient's history analysis, parasitological examination. RESULTS: A 58-year-old woman after returning from Central America found in the skin above her m. gluteus mayor 2 indurations, which contained three botfly larvae. DISCUSSION: Infestation with botfly larvae Dermatobia hominis is for man annoying and from a health point of view dangerous. CONCLUSION: With proper diagnosis, it is possible to remove the larvae safely from furuncles. The authors point to the first case of imported infestation with Furuncular myiasis caused by botfly Dermatobia hominis in man introduced to Slovakia. They note that increasing tourism spread to the countries with the endemic occurrence of Furuncular myiasis will cause its higher prevalence also in Central European countries (Fig. 5, Ref. 45).

ERVW-1 gene polymorphisms related to preeclampsia.

OBJECTIVES: Identification of genetic association between the gene ERVW-1 and preeclampsia. BACKGROUND: Preeclampsia is a multifactorial disease affecting women during pregnancy and it is one of the main causes of perinatal and maternal morbidity and mortality. The pathophysiology of preeclampsia is very complex and several aspects of the disease have not been elucidated yet. Abnormal placentation frequently occurs during severe preeclampsia. Protein syncytin 1, a product of the ERVW-1 gene, plays a crucial role in the syncytiotrophoblast differentiation and optimal placentation. The syncytin 1 expression is disturbed during preeclampsia. The main focus of this study was the analysis of the ERVW-1 regulatory regions and identification of DNA polymorphisms associated with preeclamptic cases in Slovak population. METHODS: Regulatory region of gene ERVW-1 was analyzed by sequencing to identify genetic variants. RESULTS: We identified four DNA variants, namely rs4727276, rs148592540, rs569899772 and rs555416193, in samples of Slovak population. CONCLUSION: No relation between polymorphisms and preeclampsia was observed, indicating that further investigations with a larger sampling are still required. However, our work represents new original approach in genetic differential diagnosis of preeclampsia with possible useful findings in the future (Tab. 3, Fig. 1, Ref. 34).

Can we predict orofacial cleft in future pregnancy?

AIM: The aim of this thesis was not only to define the frequency of all orofacial clefts and their particular types, but also to determine the sex of an embryo or fetus and detect associated developmental and chromosomal abnormalities. Approximately one third of orofacial clefts are a part of chromosomal syndromes. MATERIALS AND METHODS: Retrospective morphological and cytogenetic study of 43 cases of different types of orofacial clefts between 1992-2014 from miscarriages (spontaneous abortions) and premature births. RESULTS: Associated abnormalities were found in 34 cases. Most of the anomalies were skeletal anomalies (29), NTD (24) and anomalies of the abdominal wall (9). Most associated anomalies were found in the R III group (93.3 %). Eleven of the successfully cultivated cases (26 %) had a normal karyotype and in 14 of the cases (32 %), numerical or unbalanced structural chromosomal aberrations were found. CONCLUSION: Our data did not show that isolated clefts were not associated with a higher risk of chromosomal aberrations. Higher percentage of chromosomal aberrations found in isolated clefts in our pool can be explained by the age of the embryos and fetuses - usually between day 43 and week 12. It is nearly impossible to diagnose some associated congenital defects at such an early age. Thanks to the morphological and cytogenetic analysis of embryos and fetuses with orofacial cleft, it is possible to estimate if not determine the etiologic factor which influenced the miscarriage. Additionally, in the case of birth defects, the prognosis for future pregnancy can be offered, which is important information for gynecologist and clinical geneticist (Tab. 5, Fig. 5, Ref. 31).

[Multimodal therapy of locally advanced prostate cancer]. / Multimodale Therapie des lokal fortgeschrittenen Prostatakarzinoms.

Locally advanced prostate cancer (LAPCA) comprises about 5-10 % of all newly diagnosed prostate cancers and is associated with the highest prostate cancer specific mortality (approximately 8-20 %). LAPCA is defined by the presence of extraprostatic extension, seminal vesicle invasion, and bladder neck infiltration of pelvic lymph node metastases. It is evident that prognosis can only be improved by interdisciplinary multimodality treatment strategies. Adequate local staging by multiparametric MRI is one of the cornerstones for an individualized, risk-adapted treatment approach. This might consist of extended radical prostatectomy with an extended pelvic lymphadenectomy or intensity-modulated radiation therapy with androgen deprivation as the primary local therapeutic approach. Both treatment strategies may be combined with neoadjuvant or adjuvant radiation therapy or salvage surgery. Combination with neoadjuvant or adjuvant chemotherapy and new androgen receptor pathway inhibitors might also be possible. This article summarizes the current treatment strategies for LAPCA.

Molecular diagnosis of spinal and bulbar muscular atrophy in Slovakia.

OBJECTIVES: Molecular-genetic analysis is a determining step in setting the diagnosis of spinal and bulbar muscular atrophy (SBMA). We present the first nation-wide study and experience with this disease and its diagnosis in Slovakia. The study is enriched by comparison of genetic findings from Slovak patients to patients from other countries. METHODS: Molecular-genetic analysis was performed for patients suspected of SBMA. Data of patients with confirmed diagnosis were statistically evaluated. In addition, the detection rate and the prevalence of the disease for Slovakia were estimated. RESULTS: In 40 patients with confirmed diagnosis of SBMA, average values were observed at 44.7 CAG repeats and 52.5 years at the time of molecular-genetic diagnosis. The detection rate represents approximately 23% and an estimated prevalence is of 1 : 41,700. CONCLUSION: Concerning the population of Slovakia with 5,420,000 inhabitants, we document a relatively large cohort of SBMA patients. This is obvious when comparing similar studies from other countries, while this is the only study representing the Central Europe. Our findings prove that molecular-genetic analyses for the detection of this neuromuscular disorder show high efficiency. This fact underlines the necessity of such testing and may serve as a guide for clinicians from other countries in setting the right diagnosis for these patients (Tab. 1, Fig. 2, Ref. 29).

Biomarkers for determination prostate cancer: implication for diagnosis and prognosis.

Prostate cancer (PCa) belongs to most common cancers and it is the second leading cause of cancer death in men. A genetic predisposition or acquired genetic and epigenetic changes with effect of other factors, such as advanced age, race and environmental factors contribute to PCa development. PCa is a very heterogeneous disease that is characterized by different clinical behavior, from indolent, slow-growing tumors to aggressive, fast-growing tumors with lethal progression. Early diagnostics and identification of PCa type are crucial prerequisites for efficient treatment of patients. Recently, the diagnostics of early stages of PCa is based mostly on evaluation of prostate-specific antigen (PSA) in serum of patients. Men with high levels of PSA undergo biopsy in order to determine histopatological grading of PCa - Gleason scoring which classifies tumors from most to least differentiated as well as staging - determination of the status of their primary tumors, with or without lymph node involvement. The results from this screening diagnosis lead into conventional treatment, including radical prostatectomy and brachytherapy. In case of advanced PCa, conventional treatment continues with androgen deprivation therapy. However, in many cases the cancer recurs. Therefore, the clinicians and researchers are forced to find more precise and sensitive biomarker suitable for PCa diagnostics as well as prognostics and therapy. This paper provides review of current most promising molecular and immunohistochemical biomarkers in PCa diagnosis, prognosis and clinical behavior.

PTEN sequence analysis in endometrial hyperplasia and endometrial carcinoma in Slovak women.

Phosphatase and tensin homolog (PTEN) is a protein that acts as a tumor suppressor by dephosphorylating the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate. Loss of PTEN function has been implicated in the pathogenesis of a number of different tumors, particularly endometrial carcinoma (ECa). ECa is the most common neoplasia of the female genital tract. Our study evaluates an association between the morphological appearance of endometrial hyperplasia and endometrial carcinoma and the degree of PTEN alterations. A total of 45 endometrial biopsies from Slovak women were included in present study. Formalin-fixed and paraffin-embedded tissue samples with simple hyperplasia (3), complex hyperplasia (5), atypical complex hyperplasia (7), endometrioid carcinomas G1 (20) and G3 (5), and serous carcinoma (5) were evaluated for the presence of mutations in coding regions of PTEN gene, the most frequently mutated tumor suppressor gene in endometrial carcinoma. 75% of the detected mutations were clustered in exons 5 and 8. Out of the 39 mutations detected in 24 cases, 20 were frameshifts and 19 were nonsense, missense, or silent mutations. Some specimens harboured more than one mutation. The results of current study on Slovak women were compared to a previous study performed on Polish population. The two sets of results were similar.

Peroxisomal D-bifunctional protein deficiency: First case reports from Slovakia.

D-bifunctional protein deficiency (#OMIM 261515) is a rare autosomal recessive hereditary metabolic disorder causing severe clinical and biochemical abnormalities that are usually fatal in the course of the first years of life. This disease is classified as single enzyme peroxisomal disorder affecting the ß-oxidation pathway in this compartment. In this paper we present a full overview of the clinical presentation, magnetic resonance imaging, biochemical and molecular data of two Slovak D-bifunctional protein deficient patients. In the clinical presentation of both patients severe generalized hypotonia, depression of neonatal reflexes, craniofacial dysmorphism and seizures dominated starting from the second day of life. In both patients, who died up to two years of life, we found elevated plasma levels of very long chain fatty acids and we identified the presence of causative mutations in the HSD17B4 gene. In the first case, we found the homozygous mutation c.46G>A, which is responsible for a defect in the dehydrogenase domain. In the second patient, the heterozygous mutations c.1369A>G and c.1516C>T were present and functionally they are related to the hydratase domain of the protein. This combination of mutations in the second patient is very rare and has not been reported until now. The presence of mutations was examined in all family members, and the resulting data were successfully utilized for prenatal diagnosis.

Molecular analysis of EGFR gene in different types of tumor material from NSCLC patients.

Lung carcinoma is the most frequently occurring cancer worldwide and the Non-small Cell Lung Cancer (NSCLC) subtype represents 80% of all diagnosed cases. Epidermal growth factor receptor (EGFR) has an important dual role in NSCLC patients. On one hand, EGFR is frequently mutated in many types of tumors, which leads to deregulation of important downstream pathways including those affecting cell proliferation, differentiation and migration. On the other hand, presence of certain activating mutation leads to increased sensitivity of EGFR to tyrosine kinase inhibitors (TKIs) treatment. Detection of these mutations is essential for identification of NSCLC patients who would profit from such therapy. However, due to the nature of available tumor material and the relatively high number of mutation hot spots, such DNA analysis may be challenging and time consuming. Here we present an approach combining direct sequencing and SNaPshot assay for identification of EGFR mutations in FFPE tissues as well as in rarely analyzed cytological smears. Using this strategy on the set of 450 tested NSCLC samples; we have identified 29 activating mutations and 14 variants, which might be interesting in predicting the efficiency of TKI therapy.

Protection of quality and innovation in radiation oncology: the prospective multicenter trial the German Society of Radiation Oncology (DEGRO-QUIRO study). Evaluation of time, attendance of medical staff, and resources during radiotherapy with IMRT.

BACKGROUND: A number of national and international societies published recommendations regarding the required equipment and manpower assumed to be necessary to treat a number of patients with radiotherapy. None of these recommendations were based on actual time measurements needed for specific radiotherapy procedures. The German Society of Radiation Oncology (DEGRO) was interested in substantiating these recommendations by prospective evaluations of all important core procedures of radiotherapy in the most frequent cancers treated by radiotherapy. The results of the examinations of radiotherapy with intensity-modulated radiation therapy (IMRT) in patients with different tumor entities are presented in this manuscript. PATIENTS, MATERIAL, AND METHODS: Four radiation therapy centers [University Hospital of Marburg, University Hospital of Giessen, University Hospital of Berlin (Charité), Klinikum rechts der Isar der Technischen Universität München] participated in this prospective study. The workload of the different occupational groups and room occupancies for the core procedures of radiotherapy were prospectively documented during a 2-month period per center and subsequently statistically analyzed. RESULTS: The time needed per patient varied considerably between individual patients and between centers for all the evaluated procedures. The technical preparation (contouring of target volume and organs at risk, treatment planning, and approval of treatment plan) was the most time-consuming process taking 3 h 54 min on average. The time taken by the medical physicists for this procedure amounted to about 57%. The training part of the preparation time was 87% of the measured time for the senior physician and resident. The total workload for all involved personnel comprised 74.9 min of manpower for the first treatment, 39.7 min for a routine treatment with image guidance, and 22.8 min without image guidance. The mean room occupancy varied between 10.6 min (routine treatment without image guidance) and 23.7 min (first treatment with image guidance). CONCLUSION: The prospective data presented here allow for an estimate of the required machine time and manpower needed for the core procedures of radiotherapy in an average radiation treatment with IMRT. However, one should be aware that a number of necessary and time-consuming activities were not evaluated in the present study.

[Radiotherapy in the treatment of advanced and recurrent prostate cancer]. / Strahlentherapie des fortgeschrittenen und rezidivierenden Prostatakarzinoms.

The incidence of advanced prostate cancer has decreased since the introduction of prostate-specific antigen (PSA) measurements. The treatment of these patients remains a challenge due to the bad prognosis and continues to be controversially discussed. The article discusses the questions concerning radiotherapy including pelvic lymph nodes as well as an additional androgen deprivation therapy. The risk of recurrent cancer has increased since the introduction of radical prostatectomy for patients with high risk factors or locally advanced tumors. In these cases adjuvant and salvage radiotherapy represent a mainstay of therapy. Low-dose rate (LDR) and high-dose rate (HDR) brachytherapy are primary treatment options for patients with low and high risk factors and localized disease. An elaborate management of treatment-related toxicities is mandatory and may provide persistent symptom relief. A comprehensive assessment of radiation side effects and treatment concepts is provided. The development of secondary cancers after radiotherapy represents a most severe side effect for which an assessment of available data is presented.

[External beam radiotherapy in the treatment of prostate cancer]. / Perkutane Strahlentherapie in der Behandlung des Prostatakarzinoms.

Prostate cancer represents the most frequently diagnosed malignant tumor in Germany. Primary radiotherapy is one of the two recommended curative treatment options for this disease. There are two types of radiotherapy: external beam radiotherapy and interstitial brachytherapy. Technical developments during the last two decades have made it possible to achieve improved chances of being cured of tumors and improved relief from disease-related symptoms for patients at all tumor stages. Moreover, treatment can be administered with a reduced rate of side effects. Results of classical 3D conformal radiotherapy as well as modern radiation therapy techniques are comprehensively presented including the concept of hypofractionation with results from available randomized trials. After comprehensive assessment of all relevant risk factors, recommendations for the type of treatment must be based on a multidisciplinary approach.

[Radiation therapy for prostate cancer in the new S3 guideline. Part 1: localized and locally advanced prostate cancer]. / Strahlentherapie des Prostatakarzinoms in der neuen S3-Leitlinie. Teil 1: Lokal begrenztes und lokal fortgeschrittenes Prostatakarzinom.

Radiation therapy is a treatment option for curative management of localized and locally advanced prostate cancer. Depending on tumor stage and constellation of risk factors (PSA level, findings on digital rectal examination, and Gleason score), various forms of radiotherapy are applied. In addition to the sole use of external beam radiotherapy, brachytherapy with radioactive seeds is also employed as stand-alone treatment in patients with low risk factors and in early clinical stages. Increasing risk of recurrence requires more intensive therapies which can be accomplished by adding hormone deprivation therapy and/or intensifying radiation therapy (dose escalation). Combined approaches using brachytherapy and percutaneous radiotherapy are also initiated in these cases. If hormone ablation therapy is administered, this should occur over a course of 3-36 months as neoadjuvant, concommitant and/or adjuvant treatment, depending on the risk of recurrence.