Ultrahypofractionated CyberKnifeTM based stereotactic radiotherapy versus conventional radiotherapy in patients with prostate cancer - acute toxicity evaluation in two phase II prospective studies.

Our purpose was to compare the acute toxicity of ultrahypofractionated CyberKnifeTM based stereotactic radiotherapy (SBRT Arm) and conventional radiotherapy (EBRT Arm) in prostate cancer patients. Two-hundred-sixteen men with prostate cancer were enrolled in our prospective studies. One-hundred and nine were irradiated using CyberKnife to total dose of 36,25 Gy in 5 fractions. One-hundred and seven were irradiated conventionally to total dose of 76 Gy in 38 fractions. Mean age of patients was 69. Acute genitourinary (GU) and gastrointestinal (GI) adverse-events were collected. The maximal acute toxicity EORTC/RTOG score was assumed. A total of 41%, 44%, 12% and 3% of patients presented grade 0, 1, 2 and 3 acute genitourinary toxicity in SBRT arm, respectively. A total of 21%, 33%, 43% and 3% of patients demonstrated acute grade 0, 1, 2 and 3 genitourinary toxicity in EBRT arm. A significant difference between number of patients with grade 2 GU toxicity was observed (p-0.000) and between patients without any toxicity (p-0.0017).A significant difference in frequency of acute GI toxicity between both groups was observed, too. 71% vs. 44% had no toxicity (p-0.0001), and 3% vs. 18% (p-0.0004) presented grade 2 GI toxicity in SBRT and EBRT arms respectively.The acute toxicity rates of fractionated stereotactic radiotherapy is lower compared to conventional irradiation.

Acute toxicity of robotic ultrahypofractionated radiotherapy CyberKnifeTM in prostate cancer patients.

Our purpose was to evaluate the toxicity of CyberKnifeTM based fractionated stereotactic radiotherapy (FSRT) in prostate cancer patients. One-hunred-thirty-two men with low (62) and intermediate (70) prostate cancer were enrolled in our prospective study. Mean age was 69. Total dose of 36,25 Gy in 5 fractions was prescribed. Image guided FSRT was performed on CyberKnife. Minimum follow-up ranged from 3 to 28 months. EORTC/RTOG scale was used to evaluate toxicity. A total of 47%, 10% and 2% of patients presented grade 1, 2 and 3 acute genitourinary toxicity, respectively. In 25% and 3% of patients, respectively, grade 1 and 2 acute gastrointestinal toxicity was observed. No significant association between acute grade ≥ 2 toxicity and clinical factors: age, androgen deprivation therapy or infections were found. Neither CTV nor PTV volumes had significant impact on acute grade ≥ 2 toxicity. Late toxicity was assessed in 104 patients. In 16% and 1% of patients late GU toxicity in grade 1 and 2, respectively, was presented. Late GI toxicity grade 1, 2 and 3 occurred in 8%, 3% and 1% of patients, respectively. The acute toxicity rates of fractionated stereotactic radiotherapy are low. Early data suggest also low late toxicity rates.

Daily image-guidance in prostate cancer radiotherapy - implications for treatment margins.

UNLABELLED: Our purpose was to evaluate interfractional organ and patient movement during radiotherapy of prostate cancer and to calculate the necessary CTV to PTV margins. Fifty patients irradiated between 2009 and 2011were included into the prospective study. The 2D-2D KV system combined with the intraprostatic fiducial marker were used for daily position verification. Based on the 8629 measurements of isocentre displacement an interfractional motion of pelvis and prostate was evaluated. The CTV to PTV margins were calculated. Margins of 0.7 cm (AP), 1 cm (SI) and 0.35 cm (LR) are necessary when only bony based IGRT is performed. Margins of 1.0 cm, 1.8 cm and 0.5 cm in AP, SI and LR directions respectively are necessary in case of no IGRT.There was no clinically relevant changes in patient/target mobility throughout the whole treatment. The IGRT is essential for state of art radiotherapy of prostate cancer. Necessary CTV to PTV margins are much bigger in case of no IGRT performed. Changing of margins size throughout regular treatment is not necessary. KEYWORDS: IGRT, prostate cancer, fiducial marker.

Split-course accelerated hyperfractionated irradiation (CHA-CHA) as a sole treatment for advanced head and neck cancer patients-final results of a randomized clinical trial.

OBJECTIVE: Evaluation of the efficacy and toxicity of split-course accelerated hyperfractionated irradiation (CHA-CHA) as a sole treatment for advanced head and neck (H&N) cancer patients. METHODS: We enrolled 101 patients (39 in CHA-CHA and 37 in conventional (Conv.) arm completed the treatment). The CHA-CHA arm patients were irradiated twice a day, 7 days a week, using a fraction dose (fd) of 1.6 Gy up to 64 Gy with an 8-day gap in midterm. Patients in the control (Conv.) arm group were irradiated with a fd of 2 Gy, five times a week to a total dose of 72-74 Gy in the overall treatment time of 50-53 days. Quality of life (QOL) and acute mucosal reaction were evaluated during radiotherapy (RT). After RT, we followed the effect of treatment, QOL, performance status and adverse effects of radiation. For statistical analysis mainly a hierarchical multilevel modelling was used. RESULTS: QOL was most deteriorated in the CHA-CHA arm; the CHA-CHA scheme also caused a relatively stronger acute injury. There were no significant differences in late adverse effects. In the CHA-CHA arm in 35% and in Conv. arm in 30% of patients, disease was controlled during follow-up. Tumour regression 1 year after the treatment was significantly better in the CHA-CHA arm. However, the overall survival rate analysis did not show significant difference between both arms. CONCLUSION: Despite differences in treatment results, we cannot conclude that split-course accelerated hyperfractionated irradiation is superior to conventionally fractionated RT as a sole treatment for advanced H&N cancer patients. ADVANCES IN KNOWLEDGE: Obtained results in the context of published data support the statement that altered fractionations alone do not give an advantage for advanced H&N cancer patients.

Optimization of circulating cell-free DNA recovery for KRAS mutation and HPV detection in plasma.

BACKGROUND: The precise analysis of tumour markers in blood such as circulating cell-free DNA (cfDNA) could have a significant impact in facilitating monitoring of patients after initial therapy. Although high levels of total cfDNA in plasma of cancer patients are consistently demonstrated, a low sensitivity of DNA alterations is reported. OBJECTIVE: The major question regards the recovery of tumour-specific cfDNA such as KRAS mutated DNA and cancer-associated type 16 of human papillomavirus (HPV16). METHODS: TaqMan technology was used for detection of KRAS mutation, HPV16 and to quantify cfDNA in blood plasma. RESULTS: Comparison of four different column-based commercial kits shows that the cfDNA purification carried out by the Genomic Mini AX Body Fluids kit and the QIAamp Circulating Nucleic Acid kit gave us the possibility to improve the sensitivity of detection of KRAS mutation and HPV16. The optimized method was used to follow the reduction in cancer-specific cfDNA after therapy. We found that large volume extractions with low volume of DNA eluate enabled trace amounts of tumour-specific cfDNA from cancer patients to be effectively identified. CONCLUSIONS: Data presented in this study facilitate detection of tumour-specific cfDNA and improve standards needed for the implementation of cfDNA technology into routine clinical practice.

Sun-protection habits of primary students in a coastal area of Greece.

Aim. The aim of the present study was to record habits and attitudes of primary school students in Greece regarding sun-protection measures. Materials and Methods. 2,163 students with an average age of 9.9 (±1.1) years, studying in 14 schools of a Greek region, constituted our sample. The SPSS 17.0 software was used for the statistical analysis and significance level was set to P ≤ 0.05. Results. Our sample had an equal gender distribution. 16% of the students belonged to the high-risk group, 70.2% of the participants lived 0-5 km away from the sea (urban area), 84.2% of the students were Greek, and 15.8% had non-Greek nationality. Half of the participants said they wear a hat when under the sun and 72% of them said they use sunscreen. 33.1% of the students said they had a sunburn last summer. Greek students as well as those who lived near the sea had better behaviour patterns regarding sun protection. Finally, children who did not use a sunscreen systematically had suffered sunburns more often than the rest. Conclusions. Health education programmes are necessary for students and parents/teachers alike, in order to raise awareness about everyday sun protection.

[Central venous catheters as access for acute and long-term dialysis]. / Zentralvenöse Katheter als Zugang für die Akut- und Dauerdialyse.

Central venous dialysis catheters are indispensible as a rapid large lumen access to the blood compartment. If such a central venous catheter is necessary for longer than 2-3 weeks it is better to implant a tunnelled cuffed catheter initially or to switch early from the non-tunnelled acute catheter to a tunnelled cuffed catheter. Tunnelled cuffed catheters can be used for many weeks or even years and the complication rate is less than that of non-tunnelled acute catheters. The proportion of dialysis patients with long-term dialysis using tunnelled cuffed catheters has increased rapidly in recent years and now stands at approximately 20 % in Germany. These catheters are, however, prone to more infectious complications and more thromboses than native arteriovenous fistulas or prosthetic shunts. The mortality of patients with long-term dialysis catheters is also higher than those with arteriovenous shunts. For these reasons central venous catheters will always be regarded as the third choice dialysis access when arteriovenous fistulas are not possible. Catheters are available in a wide variety of designs but the individual advantages are still unclear. In order to avoid short-term and long-term complications a variety of measures for implantation and use during dialysis treatment have been developed which make the use safer.

Leptin receptor expression in neoplastic and normal ovarian and endometrial tissue.

PURPOSE: The objective of this study was to investigate the expression of leptin receptors in benign and malignant tumors of the ovaries and endometrium and its association with body mass index (BMI). METHODS: Histological uterine and ovarian samples of normal and neoplastic tissue from 35 patients aged 37-72 years were examined for the expression of leptin receptors with the method of RT-PCR. T. RESULTS: A BMI > 30 was correlated with increased expression of leptin receptors. Both Ra and Rb receptors were expressed in normal and neoplastic tissues. A statistically significant difference in leptin receptor expression was detected between normal and neoplastic tissue, with expression being around 5-fold higher in neoplatic tissue. CONCLUSION: Endometrial neoplasms and long leptin isoform receptor expression were associated with an increased BMI. A role of long isoform in endometrial carcinogenesis is proposed.

Retrospective evaluation of radiotherapy in plantar fasciitis.

Plantar fasciitis is a common painful syndrome that is usually treated by irradiation with a fraction dose (fd) of 1 Gy up to a total dose (TD) of 6 Gy according to clinical experience. By analysing our experiences with numerous former patients, we have attempted to find the relationship between dose and effect. To evaluate the effectiveness of radiotherapy and assess the impact of fd and TD in plantar fasciitis radiotherapy, we assessed 1624 irradiations (856 patients) performed using a fd of 1-3 Gy and a TD of 1-45 Gy. Analysis was carried out on the 623 irradiations (327 patients) for which complete follow-up data were available. The mean follow-up period was 74 months. The following parameters were evaluated: pain relief level; period of anaesthetic effect preservation after treatment; presence of pain and the timing of its appearance; and the intake of analgesic drugs at the last follow-up. After treatment, 48% of the patients reported a lack of pain, 21% reported pain relief greater than 50% and 17% reported pain relief less than 50%. The mean pain relief duration was 72 months. The last follow-up found that pain at rest afflicted 25% of the patients, and pain during walking afflicted 32%. A dose-effect relationship was not found. In conclusion, radiotherapy is an effective treatment for plantar fasciitis. A fd of 1.5 Gy and TD of 9 Gy should probably not be exceeded.

[Mechanisms influencing cellular physiology as a concept of treatment for wound healing disturbances]. / Mechanismen zur Beeinflussung der Zellphysiologie als Wundheilungskonzept.

AIM: Recent knowledge about repair mechanisms in different types of tissue is the basic of actual therapeutic efforts. Center of several experimental and clinical approaches is the influencing of angiogenesis with an also distinct meaning concerning wound healing. Therefore, application of growth factors, gene transfer, and employment of genetically manipulated cells often aim at angiogenesis. Nevertheless, manipulation of angiogenesis also leads to secondary problems such as hyperpermeability followed by impairment of local wound milieu. Our study was done to identify mechanisms to protect from disturbances of endothelial barrier function. METHOD: In a first experimental investigation on cultured endothelial cells, the influence of plasma-transglutaminase (Factor XIII) to endothelial barrier function was studied. In a second step, the influence of Factor XIII on wound healing properties was investigated in patients with a chronic venous ulceration. RESULTS: Activated Factor XIII (FXIIIA*) led to a dose-dependent reduction of endothelial cell permeability of 30 % compared to control with a maximum effect using 1 to 5 U/mL. Clinical investigation revealed a nearly complete reduction of wound secretion. CONCLUSION: Experimental studies revealed that activated Factor XIII stabilizes endothelial barrier under basic conditions as well as under conditions of induced hyperpermeability. Clinical study revealed that Factor XIII also distinctly reduces wound secretion. Therefore, plasma-transglutaminase may offer a new therapeutic option to treat the local or generalized leakage-syndrome.

Use of LifeSite port systems for hemodialysis in Germany.

AIM: Studies haveshown lower infection rates of port systems compared to established, transcutaneous cuffed-tunneled dialysis catheters. This was shown in otherwise quite healthy patients starting hemodialysis treatment. It is unclear to what extent these results can be applied to countries such as Germany where, unlike the US, central venous access systems are used mainly for patients with a high comorbidity. We investigated complications in patients with exhausted access sites and a high comorbidity. METHOD: In a retrospective, representative multicenter study, 34 patients with a high rate of comorbidity were assessed. The age was 67.5 +/- 12.5 years, the median number of failed AV fistulas or AV grafts was 4 (0-18). RESULTS: The survival rate was 84.9%, 55.2% and 55.2% after 6, 12 and 24 months, respectively. The rate of local and systemic infections was 2.83 per 1,000 patient days. Thrombotic events occurred at a rate of 2.26 per 1,000 patient days. We did not see a statistically significant effect using 0.2% sodium oxychlorosene (n = 13) or 70% isopropyl alcohol solution (n = 21) as the antimicrobial solution used before opening the valve of the port with the dialysis needle. CONCLUSIONS: We showed that complications of hemodialysis treatment using LifeSite vascular access systems in patients with very high co-morbidity in Germany seem to occur less often than those reported for cuffed-tunneled catheters and were not more frequent than those reported for other patient groups using LifeSites in the US. Technical survival rates were encouraging for up to two years. LifeSite port systems might be a good or even better central venous access than cuffed-tunneled catheters for patients in which an AV fistula or -graft is not possible.

Split-course accelerated hyperfractionation (CHA-CHA) for advanced head and neck cancers -- preliminary results.

The purpose of the study was to evaluate toxicity and effectiveness of the split course, accelerated hyperfractionation with a planned gap (CHA-CHA) on a base of the pilot group treatment results. The material consisted of 27 patients with advanced (T2N2c-3, T3-4N2), oral cavity, oro- hypopharynx and larynx cancers, irradiated with a df 1.6 Gy twice a day, with 6-hour gap, up to TD 64 Gy in 28 days, with 8-day gap in a middle. Mean tumor dimensions were 4.2 and 3.9 cm in X and Y axes, respectively and mean nodes dimensions 3.9 cm in both axes. The course and intensity of the mucositis were evaluated in the Dische scale together with the degree of a tumor and nodes regression. Survival analysis and dependencies evaluation between physical/biological factors and treatment results were performed. The mucositis intensity was high from 2nd to 5th week (the highest mean - 15 Dische points in 4th week), but on acceptable level. 54.5% of CR of the tumor and 57.1% of nodes were noted. Survival analysis showed 44% of a 2-year and 35% of a 4-year OS and 44% of a 2-year and 38% of a 4-year survival excluding deaths from distant metastases. Correlation between the hemoglobin level and the nodal regression two months after the radiotherapy (p=0.01), showed the tumor diameter and TCP (p=0.047), the OS and the nodes diameter (p=0.004), the PS (p=0.02) and the hemoglobin level (p=0.04). CHA-CHA could be a valid method in advanced head and neck cancer treatment but its efficacy should be confirmed in randomized phase of trial.

Intracellular adhesion molecule-1 in patients developing pulmonary insufficiency after cardiopulmonary bypass.

OBJECTIVES: Cardiopulmonary bypass activates adhesion molecules, which are associated with systemic inflammation and organ dysfunction. The intracellular adhesion molecule-1 (ICAM-1) has been evaluated in patients presenting pulmonary dysfunction after cardiac surgery. MATERIALS AND METHODS: Postoperative serum levels of the ICAM-1 were measured in 40 patients who underwent isolated coronary artery bypass grafting, in 28 with uneventful postoperative recovery (70 %) (Group 1), and in 12 (30 %) with postoperative respiratory insufficiency (Group 2), defined by the need for prolonged (> 24 hours) mechanical ventilation using a fractional oxygen concentration of > 40 %. RESULTS: Patients in group 1 were ventilated for 12.21 +/- 4.86 hours and those in group 2 for 92.91 +/- 48.14 hours (p < 0.001). ICAM-1 decreased from 145.98 +/- 73.40 ng/ml to 81.15 +/- 114.82 ng/ml in group 1, while in group 2 ICAM-1 showed a significant higher level and increased to 435.01 +/- 130.02 ng/ml (p < 0.001). The leukocyte count increased in both groups as well as the C-reactive protein (CRP) during the postoperative course. The CRP behaves similar in both groups (p = 0.636) in contrast to the leukocyte count which was significantly higher in group 2 (p < 0.01). While none of the patients in group 1 died the mortality in group 2 was 50 % (p < 0.001). CONCLUSION: Respiratory insufficiency after cardiopulmonary bypass is associated with a distinct increase in the ICAM-1. The reason for the increase of the ICAM-1 in this small subset of patients has not been clarified.

Evaluation of efectiveness of palliative radiotherapy alone or combined with surgery in patients with bone metastases.

Material and methods. The retrospective analysis results of palliative radiotherapy alone or combined with surgery of 200 patients with bone metastases are presented. All patient were irradiatated, 47 of them were operated before or after radiotherapy. General performance status, pain relief, movement efficiency, analgetic drugs and bisphosphonates administration, disease progress and bone reossification were assesed 1, 2, 3, 6, 12 months after the treatment and durning the last examination.
Results. The complete or partial pain relief were observed in 47% of patients 1 month, 56% two months 41% in 3, 38% 6 months after the treatment. 26% reported pain relief 1 year after irradiation and 33% at the last visit
The Kaplan Maier survival analysis shows ststistically significant longer survival for patient treated by combined treatment, women, patients with multiple bone metastases and patients with metastases located in long bones and patients without symptoms of spine compression. Spearman analysis reveals correlation beetween performance status and follow up. There are no correlations between radiation dose, bisphosphonates administration and pain relief, pathology of tumor and follow up.
Conclusions. The obtained results suggests that radiotherapy is effective method of analgetic treatment in bone metastases and that radiotherapy associated with surgery improves survival.

[Factor XIII and endothelial barrier function]. / Faktor XIII und endotheliale Barrierenfunktion.

Activated factor XIII (FXIIIa) crosslinks fibrin monomers to a stable clot. Due to this function, FXIIIa plays a major role in hemostasis and fibrinolysis. Additionally, it is well known that FXIIIa has a special meaning in cell adhesion and migration, in generation of extracellular matrix, in tissue repair and wound healing. New experimental studies revealed a FXIIIa stabilizing endothelial barrier function. In this function, FXIIIa reduces endothelial permeability for macromolecules in cultured endothelial monolayers and prevents impending barrier failure in coronary arteries of isolated hearts. This effect is due to the cross-linking of several proteins within the extracellular matrix, especially in the interendothelial clefts.

[Factor XIII and wound healing]. / Faktor XIII und Wundheilung.

In addition to those wounds with increasing fragility of capillaries during impaired healing, there are especially long lasting diabetic wounds or calf ulcerations due to chronic venous insufficiency or postthrombotic syndrome that show a failure of endothelial barrier function with an increased permeability as an important part of its pathophysiological situation. The possibility of controlling this increased permeability is of great therapeutical interest and may give distinct benefit for wound healing. In the close past, clinical as well as experimental studies revealed the plasma transglutaminase (factor XIIIa) as potential new strategy in treatment of increased vascular permeability.

Liquid to vapor phase transition in excited nuclei.

The thermal component of the 8 GeV/c pi+ Au data of the ISiS Collaboration is shown to follow the scaling predicted by Fisher's model when Coulomb energy is taken into account. Critical exponents tau and sigma, the critical point (p(c),rho(c),T(c)), surface energy coefficient c(0), enthalpy of evaporation DeltaH, and critical compressibility factor C(F)(c) are determined. For the first time, the experimental phase diagrams, (p,T) and (T,rho), describing the liquid vapor coexistence of finite neutral nuclear matter have been constructed.

Protein synthesis of human articular chondrocytes cultured in vitro for autologous transplantation.

Chondrocytes in hyaline cartilage produce typical matrix proteins, the most abundant of them being collagen type II and aggrecan. Chondrocytes in monolayer cell culture dedifferentiate and gain fibroblastic phenotype. The cells gradually start to produce collagen type I while the production of collagen type II and aggrecan decreases. Transplantation of autologous chondrocytes cultured in vitro is used for treatment of aseptic articular cartilage lesions. For this purpose, cartilage biopsy is taken and isolated cells are subsequently proliferated in a monolayer cell culture. When implanted, the cells start to produce specific cartilaginous matrix that fills the defect. Prior to surgical procedure the cells can also be cryopreserved for longer periods of time after reaching appropriate numbers. We tested the influence of cultivation time and number of continuous culture passages as well as the influence of cryopreservation on the matrix protein synthesis of human articular chondrocytes. The ability of dedifferentiated chondrocytes to redifferentiate has been monitored by measuring matrix protein synthesis of the cells, re-seeded in agarose suspension culture. The results obtained show progressive dedifferentiation during monolayer cell culture procedures, facilitated by cryopreservation. Successful redifferentiation of cells re-seeded in suspension cultures was observed regardless of the previous level of chondrocyte dediferentiation.

Determination of optimal transport conditions for biopsies of human articular cartilage as well as for suspensions of cultured chondrocytes used in autologous transplantation.

Autologous transplantation of chondrocytes is currently being promoted as a novel approach for the treatment of deep cartilage lesions. Briefly, the method involves enzyme-mediated release of chondrocytes from cartilage biopsies, the expansion of cells by in vitro cultivation and their re-implantation into the defect. The success of this technique depends on many factors including transport conditions for both, cartilage biopsies from the operating hall to the laboratory and the return transport of final suspension of cultured chondrocytes. To determine the extent of cellular damage in biopsies, chondrocytes were enzymatically isolated following a few days of tissue preservation in different tissue culture media. The proportion of dead cells was assessed by Trypan blue staining and counting. The viability was not dependant of the type of the medium used and remained approximately 50% in all samples, even after 72 h. To develop optimal conditions for transport of final chondrocyte suspension, isolated cells were firstly grown in monolayer cultures. Cell suspensions in media with different additives were injected into special glass containers used for the transport and left at 4 degrees C or 25 degrees C for up to 3 days. During this period every 24 h the samples were taken and viability as well as apoptosis levels were assessed. Viability of cells in suspensions at 25 degrees C decreased significantly and became inadequate already after 48 h. In contrast to that, the proportion of viable cells at 4 degrees C remained above 80% even after 48 h. In the majority of the samples, culture medium containing serum and vitamin C provided the best conditions for long-term preservation of chondrocytes.