Identification of putative genetic modifying factors that influence the development of Papillon-Lefévre or Haim-Munk syndrome phenotypes.

BACKGROUND: Papillon-Lefévre syndrome (PLS; OMIM 245000) and Haim-Munk syndrome (HMS; OMIM 245010), which are both characterized by palmoplantar hyperkeratosis and periodontitis, are phenotypic variants of the same disease caused by mutations of the cathepsin C (CTSC) gene. AIM: To identify putative genetic modifying factors responsible for the differential development of the PLS or HMS phenotypes, we investigated two Hungarian patients with different phenotypic variants (PLS and HMS) but carrying the same homozygous nonsense CTSC mutation (c.748C/T; p.Arg250X). METHODS: To gain insights into phenotype-modifying associations, whole exome sequencing (WES) was performed for both patients, and the results were compared to identify potentially relevant genetic modifying factors. RESULTS: WES revealed two putative phenotype-modifying variants: (i) a missense mutation (rs34608771) of the SH2 domain containing 4A (SH2D4A) gene encoding an adaptor protein involved in intracellular signalling of cystatin F, a known inhibitor of the cathepsin protein, and (ii) a missense variant (rs55695858) of the odorant binding protein 2A (OBP2A) gene, influencing the function of the cathepsin protein through the glycosyltransferase 6 domain containing 1 (GLT6D1) protein. CONCLUSION: Our study contributes to the accumulating evidence supporting the clinical importance of phenotype-modifying genetic factors, which have high potential to aid the elucidation of genotype-phenotype correlations and disease prognosis.

Developing FGFR4 inhibitors as potential anti-cancer agents via in silico design, supported by in vitro and cell-based testing.

Fibroblast growth factor receptor-4 (FGFR4) is a tyrosine kinase with a range of important physiological functions. However, it is also frequently mutated in various cancers and is now generating significant interest as a potential therapeutic target. Unfortunately, biochemical characterization of its role in disease, and further evaluation as a drug target is hampered by lack of a specific inhibitor. We aimed to discover new inhibitors for FGFR4 ab initio using a strategy combining in silico, in vitro and cell-based assays. We used the homologous FGFR1 to calculate docking scores of a chemically-diverse library of approximately 2000 potential kinase inhibitors. Nineteen potential inhibitors and ten randomly- selected negative controls were taken forward for in vitro FGFR4 kinase assays. All compounds with good docking scores significantly inhibited FGFR4 kinase activity, some with sub-micromolar (most potent being V4-015 with an IC(50) of 0.04 µM). Four of these compounds also demonstrated substantial activity in cellular assays using the FGFR4- overexpressing breast carcinoma cell line, MDA-MB453. Through immunoblot assays, these compounds were shown to block the phosphorylation of the FGFR4 adaptor protein, FGFR substrate protein-2α (FRS2α). The most potent compound to date, V4-015, suppressed proliferation of MDA-MB453 cells at sub-micromolar concentrations, activated the pro-apoptotic caspases 3/7 and inhibited cellular migration. While achieving complete selectivity of this compound for FGFR4 will require further lead optimization, this study has successfully identified new chemical scaffolds with unprecedented FGFR4 inhibition capacities that will support mechanism of action studies and future anti-cancer drug design.

Three-dimensional movements of the lumbar spine facet joints and segmental movements: in vivo examinations of normal subjects with a new non-invasive method.

INTRODUCTION: Examination with CT and image registration is a new technique that we have previously used to assess 3D segmental motions in the lumbar spine in a phantom. Current multi-slice computed tomography (CT) offers highly accurate spatial volume resolution without significant distortion and modern CT scanners makes it possible to reduce the radiation dose to the patients. Our aim was to assess segmental movement in the lumbar spine with the aforementioned method in healthy subjects and also to determine rotation accuracy on phantom vertebrae. MATERIAL AND METHOD: The subjects were examined in flexion-extension using low dose CT. Eleven healthy, asymptomatic subjects participated in the current study. The subjects were placed on a custom made jig which could provoke the lumbar spine into flexion or extension. CT examination in flexion and extension was performed. The image analysis was performed using a 3D volume fusion tool, registering one of the vertebrae, and then measuring Euler angles and distances in the registered volumes. RESULTS: The mean 3D facet joint translation at L4-L5 was in the right facet joint 6.1 mm (3.1-8.3), left facet joint 6.9 mm (4.9-9.9), at L5-S1: right facet joint 4.5 mm (1.4-6.9), and for the left facet joint 4.8 mm (2.0-7.7). In subjects the mean angles at the L4-L5 level were: in the sagittal plane 14.3°, coronal plane 0.9° (-0.6 to 2.8), and in the transverse plane 0.6° (-0.4 to 1.5), in the L5-S1 level the rotation was in sagittal plane 10.2° (2.4-16.1), coronal plane 0° (-1.2 to 1.2), and in the transverse plane 0.2° (-0.7 to 0.3). Repeated analysis for 3D facet joint movement was on average 5 mm with a standard error of mean of 0.6 mm and repeatability of 1.8 mm (CI 95%). For segmental rotation in the sagittal plane the mean rotation was 11.5° and standard error of mean 1°. The repeatability for rotation was 2.8° (CI 95%). The accuracy for rotation in the phantom was in the sagittal plane 0.7°, coronal plane 1°, and 0.7 in the transverse plane. CONCLUSION: This method to assess movement in the lumbar spine is a truly 3D method with a high precision giving both visual and numerical output. We believe that this method for measuring spine movement is useful both in research and in clinical settings.

Novel, selective CDK9 inhibitors for the treatment of HIV infection.

Cyclin Dependent Kinases (CDKs) are important regulators of cell cycle and gene expression. Since an up-to-date review about the pharmacological inhibitors of CDK family (CDK1-10) is not available; therefore in the present paper we briefly summarize the most relevant inhibitors and point out the low number of selective inhibitors. Among CDKs, CDK9 is a validated pathological target in HIV infection, inflammation and cardiac hypertrophy; however selective CDK9 inhibitors are still not available. We present a selective inhibitor family of CDK9 based on the 4-phenylamino-6- phenylpyrimidine nucleus. We show a convenient synthetic method to prepare a useful intermediate and its derivatisation resulting in novel compounds. The CDK9 inhibitory activity of the derivatives was measured in specific kinase assay and the CDK inhibitory profile of the best ones (IC(50) < 100 nM) was determined. The most selective compounds had high selectivity over CDK1, 2, 3, 5, 6, 7 and showed at least one order of magnitude higher inhibitory activity over CDK4 inhibition. The most selective molecules were examined in cytotoxicity assays and their ability to inhibit HIV-1 replication was determined in cellular assays.

Health-related quality of life (EQ-5D) before and one year after surgery for lumbar spinal stenosis.

We investigated the pre-operative and one-year post-operative health-related quality of life (HRQoL) outcome by using a Euroqol (EQ-5D) questionnaire in 230 patients who underwent surgery for lumbar spinal stenosis. Data were obtained from the National Swedish Registry for operations on the lumbar spine between 2001 and 2002. We analysed the pre- and postoperative quality of life data, age, gender, smoking habits, pain and walking ability. The relative differences were compared to a Swedish EQ-5D population survey. The mean age of the patients was 66 years, and there were 123 females (53%). Before the operation 62 (27%) of the patients could walk more than 500 m. One year after the operation 150 (65%) were able to walk 500 m or more. The mean EQ-5D score improved from 0.36 to 0.64, and the HRQoL improved in 184 (80%) of the patients. However, they did not reach the level reported by a matched population sample (mean difference 0.18). Women had lower pre- and post-operative EQ-5D scores than men. Severe low back pain was a predictor for a poor outcome.

Signalling inhibitors against Mycobacterium tuberculosis--early days of a new therapeutic concept in tuberculosis.

Tuberculosis causes nearly two million deaths per year world-wide. In addition multidrug-resistant mycobacterial strains rapidly emerge so novel therapeutic approaches are needed. Recently, several promising mycobacterial target molecules were identified, which are involved in bacterial or host cell signalling e.g. the serine/threonine protein kinases, PknB and PknG, NAD kinase and the NAD synthetase. Here we describe some early efforts in the development of novel signal transduction inhibitory anti-mycobacterial drugs using a multiple target approach, with special emphasis on the kinase inhibitory field. Initially, we are using the Nested Chemical Library (NCL) technology and pharmacophore modelling. A hit-finding library, consisting of approximately 19000 small molecules with a bias for prototypic kinase inhibitors from our NCL library and commercial sources was virtually screened against these validated target molecules. Protein structures for the virtual screening were taken from the published three dimensional crystal structures of the enzymes. The hits from the virtual screening were subsequently tested in enzymatic assay systems. Potent hits were then tested for biological activity in macrophages, infected with mycobacteria. The final goal of this exercise is not only to identify potent anti-mycobacterial substances, but also a common pharmacophore for the mycobacterial target PknG in combination with PknB, NAD kinase and/or NAD synthetase. This common pharmacophore still needs to be a unique pharmacophore for the mycobacterial target proteins over human off-targets. Such a pharmacophore might then drive the optimization of a completely new profile of an antibiotic agent with activity against latent mycobacteria and resistance mycobacterial strains.

Model studies on segmental movement in lumbar spine using a semi-automated program for volume fusion.

OBJECTIVE: To validate a new non-invasive CT method for measuring segmental translations in lumbar spine in a phantom using plastic vertebrae with tantalum markers and human vertebrae. MATERIAL AND METHODS: One hundred and four CT volumes were acquired of a phantom incorporating three lumbar vertebrae. Lumbar segmental translation was simulated by altering the position of one vertebra in all three cardinal axes between acquisitions. The CT volumes were combined into 64 case pairs, simulating lumbar segmental movement of up to 3 mm between acquisitions. The relative movement between the vertebrae was evaluated visually and numerically using a volume fusion image post-processing tool. Results were correlated to direct measurements of the phantom. RESULTS: On visual inspection, translation of at least 1 mm or more could be safely detected and correlated with separation between the vertebrae in three dimensions. There were no significant differences between plastic and human vertebrae. Numerically, the accuracy limit for all the CT measurements of the 3D segmental translations was 0.56 mm (median: 0.12; range: -0.76 to +0.49 mm). The accuracy for the sagittal axis was 0.45 mm (median: 0.10; range: -0.46 to +0.62 mm); the accuracy for the coronal axis was 0.46 mm (median: 0.09; range: -0.66 to +0.69 mm); and the accuracy for the axial axis was 0.45 mm (median: 0.05; range: -0.72 to + 0.62 mm). The repeatability, calculated over 10 cases, was 0.35 mm (median: 0.16; range: -0.26 to +0.30 mm). CONCLUSION: The accuracy of this non-invasive method is better than that of current routine methods for detecting segmental movements. The method allows both visual and numerical evaluation of such movements. Further studies are needed to validate this method in patients.

A comparison of accommodation amplitudes in pseudophakic eyes measured with three different methods.

PURPOSE: To compare the accommodative amplitudes with three different methods in pseudophakic eyes with different types of intraocular lenses (IOLs). METHODS: Fifty-one pseudophakic eyes of 44 patients (age: 72.02+/-8.53 years) were studied. One of two different types of IOL were implanted (N=30, three-piece Alcon Acrysof MA60AC and N=21, one-piece Alcon Acrysof SA60AT) in-the-bag after standard phacoemulsification. The time of the examinations was 13.85+/-7.35 months postoperatively. We measured the amplitude of accommodation with three different methods: (1) subjective minus-lenses-to-blur method; (2) a new optical device (ACMaster, Carl Zeiss, Jena, Germany) using partial coherence interference (PCI) technique under physiological stimulus; and (3) objective anterior chamber depth measuring with a standard A-scan ultrasonic device (Ultrascan Imaging System, Alcon Laboratories, Forth Worth, TX, USA) before and after pharmacological relaxation of ciliary muscle. RESULTS: We measured -0.83+/-0.63 D amplitude of accommodation with subjective minus-lenses-to-blur method. The IOL position did not change significantly during physiological accommodation effort measured with PCI method (-0.026+/-0.134 mm). The change in the IOLs position between near fixating and after ciliary muscle relaxation was -0.18+/-0.28 mm measured with ultrasound. There were no significant differences between values of one-piece and three-piece IOL groups. CONCLUSION: The amplitude of accommodation measured by subjective and objective methods are different and are not comparable with each other. We did not observe any difference between values of examined two types of IOLs.

Comparison of divide and conquer and phaco-chop techniques during fluid-based phaco-emulsification.

PURPOSE: To determine whether, similar to ultrasound phaco-emulsification, applied energy and surgery time decrease using phaco-chop nucleus fragmentation method compared to divide and conquer technique using the fluid-based system. METHODS: This prospective, comparative, randomized clinical study included patients with cataract who were randomly assigned to use either standard divide and conquer technique (25 eyes of 25 patients, Group 1) or Nagahara phaco-chop maneuver (25 eyes of 25 patients, Group 2) during fluid-based phaco-emulsification. Surgical parameters were recorded and patients were examined 1 day, 10 days, and 1 month after surgery. Statistical analyses were performed using the paired test of Wilcoxon. RESULTS: Fluid-based time, mean fluid-based magnitude, effective fluid-based time, and the number of pulses were significantly less using phaco-chop technique compared to divide and conquer method (p<0.001). Surgery time was similar using the two nucleofractis techniques (p=0.97). Visual acuities showed no statistical differences between the two groups (p>0.05). CONCLUSIONS: Nuclear fragmentation can be performed with Nagahara phaco-chop technique using the fluid-based system as well. The applied fluid-based energy decreases compared to divide and conquer method. However, surgery time is not reduced due to the difficulties reaching the full occlusion necessary to hold the nucleus during the chop maneuver.

Corneal endothelial function after phacoemulsification using the fluid-based system compared to conventional ultrasound technique.

AIM: To quantitatively assess corneal endothelial changes after phacoemulsification with the fluid-based system compared to conventional ultrasound technique. METHODS: This prospective, randomized clinical study included patients with cataract who were randomly assigned either to have phacoemulsification with the fluid-based system (30 eyes of 30 patients--Group 1) or with traditional ultrasound (30 eyes of 30 patients--Group 2). Patients who were available at each follow-up visit (25 eyes in both groups) were enrolled in the statistical analysis. Endothelial function was evaluated by measuring central corneal thickness, central endothelial cell density (ECD), mean cell size, and coefficient of variation in cell size preoperatively, 10 days, 1 and 3 months, and 1 year after surgery. Statistical analyses were performed using two-way repeated measure ANOVA. RESULTS: An acute, reversible increase of central corneal thickness (CCT) was found 10 days after surgery, which was similar in both groups (P=0.35). ECD decreased, whereas mean cell size increased significantly immediately after surgery. However, the impairments were finished after 1 month. The alterations were similar in both groups (ECD: P=0.99; mean cell size: P=0.85). The coefficient of variation in cell size remained stable after surgery (P=0.08), and significant difference was not found between groups (P=0.99). The endothelial cell loss (ECL) was 6.5+/-8.4% in Group 1 and 6.5+/-11.7% in Group 2 (P=0.69). CONCLUSIONS: Corneal endothelial changes were similar using the fluid-based system compared to the traditional ultrasound technique. The fluid-based method proved to be as safe as conventional ultrasound in cataract surgery.

An illustrative case and a review on the dosing of recombinant factor VIIa in congenital factor XI deficiency.

Recombinant activated factor VII (rFVIIa) has been used in a very limited number of patients with severe factor XI (FXI) deficiency. The dose and duration of treatment has varied greatly between these case reports. In a few of these cases there was also evidence of thrombotic complications. We present here a report on one additional patient with congenital FXI deficiency. For two major orthopaedic procedures in this patient we used rFVIIa as a single bolus dose followed by continuous infusion at a low rate. The data from these treatment episodes, together with those from a review of the published cases, lend support to the concept of using much lower doses than in haemophilia with inhibitors. A bolus dose of 20 microg kg(-1) and thereafter maintenance of the FVII activity at approximately 3 IU mL(-1) appears effective and safe.

Health-related quality of life in patients before and after surgery for a herniated lumbar disc.

We investigated the pre-operative and one-year post-operative health-related quality of life (HRQOL) outcome by using a Euroqol (EQ-5D) questionnaire in 263 patients who had undergone surgery for herniation of a lumbar disc. Data from the National Swedish Register for lumbar spinal surgery between 2001 and 2002 were used and, in addition, a comparison between our cohort and a Swedish EQ-5D population survey was performed. We analysed the pre- and post-operative quality of life data, age, gender, smoking habits, pain and walking capacity. The mean age of the patients was 42 years (20 to 66); 155 (59%) were men and 69 (26%) smoked. Pre-operatively, 72 (17%) could walk at least 1 km compared with 200 (76%) postoperatively. The mean EQ-5D score improved from 0.29 to 0.70, and the HRQOL improved in 195 (74%) of the patients. The pre-operative score did not influence the post-operative score. In most patients, all five EQ-5D dimensions improved, but did not reach the level reported by an age- and gender-matched population sample (mean difference 0.17). Predictors for poor outcome were smoking, a short pre-operative walking distance, and a long history of back pain.

Surgery for herniation of a lumbar disc in Sweden between 1987 and 1999. An analysis of 27,576 operations.

The National Inpatient Register and the Swedish Death Register were linked to determine the incidence of surgical intervention, the trends and characteristics of the patients, the death rate and the pre- and post-operative admissions for herniation of a lumbar disc based on comprehensive national data between 1987 and 1999. There were 27,576 operations which were followed cumulatively for 155,249 years, with a median of 6.0 years. The mean annual rate of operation was 24 per 100,000 inhabitants, the median age of the patients was 42 years. The 30-day death rate was 0.5 per 1000 operations. The rates of re-operation at one and ten years were 5% and 10%, respectively, decreasing significantly (40%) with time. The mean length of stay decreased from nine to five days. Patients who had been in hospital because of a previous spinal disorder had a significantly higher risk of readmission.

Brachytherapy of vestibular schwannomas: report of three cases.

OBJECTIVE: Gamma knife and multileaf collimator LINAC have recently gained notoriety in the treatment of vestibular schwannomas. Without the use of gamma knife or LINAC, we have successfully pursued the 125-iodine interstitial irradiation of three vestibular schwannomas. CASE REPORT: Up to March 2004, there was a 57 and 45 month follow-up period in two cases. One patient died of heart insufficiency 15 months after the brachytherapy. At the end of the follow-up period audiometric examinations revealed slight improvements of hearing in patients 1 and 2. In patient 1, the tumor volume measured was 4.06 mL on the control CT indicating a 40 % shrinkage in comparison to the 6.74 mL target volume at the brachytherapy. In patient 2, the tumor volume measured on the control MRI was 6.64 mL, indicating a 42 % shrinkage of the 11.45 mL target volume at the time of brachytherapy. Eleven months after the brachytherapy in patient 3 we found 10 % tumor shrinkage, a post-irradiation cyst developed inside the tumor and reached up to 35 % of the tumor volume. INTERVENTION: In the treatment of three vestibular schwannomas we have used CT and image-fusion guided 125-iodine stereotactic brachytherapy. CONCLUSION: Due to financial considerations, gamma knife and LINAC are not available for many countries and neurosurgical institutes. In the absence of the above-mentioned radiosurgical methods, we have shown brachytherapy as a new alternative and solution in the treatment of the three patients studied with vestibular schwannoma.

Methodological concerns using intra-cortical pins to measure tibiofemoral kinematics.

The complexity of human tibiofemoral joint motion is now better understood with the advancement of new methodologies to measure tibiofemoral kinematics in vivo. Marker clusters anchored to stainless steel bone pins inserted directly into the femur and tibia provide the most sensitive and accurate means for directly measuring skeletal tibiofemoral joint motion. Despite its invasiveness, this technique has been successful, although complications have been reported with the femoral pin and its insertion site. The purpose of this technical report is twofold: to review the difficulties with the femoral pin and its insertion site from a historical perspective, and to identify the load force required from biological tissue to permanently deform the pin. In addition, proposals in the advancement of this method are discussed in the context of reducing impingement with the femoral pin and the Iliotibial band. Because stainless steel exhibits plastic behaviour with no sharp yield point, Apex self-drilling/self-tapping bone pins underwent incremental loading on an Instron materials testing machine. Loads were transmitted perpendicular to the pin with the threads partially exposed and fully secured in vice. Since the accuracy of our combined stereophotogrammetry and Optoelectric motion analysis was less than 0.4 mm, it was decided that plastic deformation occurred after deflections of 0.4 mm. With exposed threads, deflections larger than 0.4 mm were observed at 150 N and 100 N when loads were applied at 15 mm and 20 mm from the vice (representative of where the tissue came in contact with the pin). Loads greater than 200 N produced deflections less than 0.2 mm when threads were fully inserted. The 90 Hz resonant frequency for the marker cluster-bone pin complex is beyond the spectrum of human movement and can be lowpass filtered. To reduce impingement and pin bending, one solution may be to implant pins with a shorter threaded section. By completely penetrating the bone, only the smooth surface of the pin is exposed which is more resistant to bending. Otherwise pins with larger diameters and longer longitudinal incisions about the femoral insertion site are an alternative. Lengthening the longitudinal incisions about the insertion site, and correctly aligning and inserting the femoral pin between the Iliotibial band and quadriceps tendon may diminish impingement. Performing dynamic open chain flexion and extension movements while on the operating table may aid in aligning the pin at the incision site. This may stretch the IT band and quadriceps tendon and may guide the femoral pin into a more optimal position prior to it being inserted into the cortex of the bone.

Spinal stenosis surgery in Sweden 1987-1999.

Despite being recognised for many years as a clinical diagnosis, no exact definition of spinal stenosis has yet been agreed, leading to difficulties in interpreting and comparing studies of the incidence, prevalence and treatment. This study presents the first analysis of national data to be reported. It is a retrospective population-based national register study, aimed at analyzing surgical interventions in patients with lumbar spinal stenosis, patient characteristics, subsequent development, and case fatality rate, based on Swedish national data for 1987-1999. Complete follow-up data were obtained of incidence and type of spinal stenosis surgery, rate of multiple operations, mortality, underlying causes of death, length of hospital stay, and case fatality rate by linkage of the National Inpatient Register and Swedish Death Register. The study cohort consisted of 10,494 patients. Laminectomy was performed in 89%, and additional fusion in 11%. The mean annual rate of operations was 9.7 per 100,000 inhabitants, the annual number of operations performed increased from 4.7 to 13.2 per 100,000 inhabitants per year. The case fatality rate within 30 days after surgery was 3.5 per 1000 operations. Cardiovascular disease was the most common cause of death (46%). Relative risk of dying within 30 days of admission was doubled in men, and for fusion surgery, and increased four fold in patients older than 80 years. The relative risk of dying decreased during the study period. The results show that spinal stenosis surgery in Sweden has increased, and is associated with a low risk. Within an ageing group of patients, mortality has declined.

Giant clusters in random ad hoc networks.

The present paper introduces ad hoc communication networks as examples of large scale real networks that can be prospected by statistical means. A description of giant cluster formation based on a single parameter of node neighbor numbers is given along with the discussion of some asymptotic aspects of giant cluster sizes.

CT densitometry of the brain: a novel method for early detection and assessment of irradiation induced brain edema.

The purpose of the study was to examine if the CT densitometric analysis during radiotherapy (RT) of brain tumors is suitable for the early detection of RT induced brain edema (BE), predicting related neurological progress, and assessing the effects of different edema therapies. Planimetric CT-densitograms were constructed by modifying the "High-Lighting" method. Three theoretical density regions were defined and color-coded on the images of the brain. These were defined as edema (10-20 HU), mild edema, and normal brain (29-38 HU). Corresponding axial CT slices were created at the mid-level of the lesion and that of the periventricular white matter to verify the changes in perifocal and diffuse BE. The monitoring was performed on 50 solitary brain tumor patients treated with RT. During RT courses weekly CT-densitometric examinations were carried out. We experienced that changes in densitograms coincided with clinical symptoms, furthermore, preceded the latter. With the use of preventive edema medication based on diuretics and along with adjunctive edema medication adopted to densitograms, the 5-7 week irradiation was completed without ultimate worsening in performance state in 49 of 50 cases and besides we succeeded in avoiding the routine usage of steroids. Based on our findings the CT-densitometry is suitable for early detection and continuous assessment of BE and preventing patient distress during RT. This simple, reproducible and non-invasive procedure could provide an additional clinical tool for new treatment strategies.

The time-course of metastases from breast cancer after mastectomy and breast-conserving surgery with and without isolated local-regional recurrence.

We have examined time intervals between events in 390 metastatic breast cancer (MBC) patients whose distant failure developed within 10 years from initial surgery of Stage I/II disease. All of the patients underwent axillary dissection and mastectomy (n=295) or breast-conserving surgery (BCS, n=95), between 1983 and 1987. Distinctions have been made between distant failure with (n=79) and without (n=311) isolated local-regional recurrence (LRR). The median survival time after first relapse was significantly longer with intrabreast (30 months) and chest wall (24 months) than with distant relapse (15 months), but with axillary (17 months) or with supraclavicular (17 months) relapse survival was similar. The delay between LRR and distant metastasis was shorter with axillary (7 months) and supraclavicular (9 months) than with breast (20 months) and chest wall (12 months) recurrences. The median postmetastatic survival time by site of first relapse was significantly shorter with supraclavicular (6 months) and axillary (9 months) than with distant site relapse (15 months) but with intrabreast (12 months) or with chest wall (11 months) recurrence survival was similar. In MBC, regional recurrences are associated with a shorter interval between events than with local recurrences. The shortened intervals for patients with regional recurrence suggest that metastases existed at the time of initial surgery. The question of whether prevention of local or regional recurrence or both improves cause-specific survival after mastectomy or BCS needs to be answered in randomized studies.

Postoperative radiotherapy of childhood medulloblastomas.

The purpose of this work is to review the result of radiotherapy in the treatment of medulloblastoma in pediatric patients. Between 1986 and 1998, 66 children (45 boys and 21 girls) received postoperative irradiation in our institute. Their mean age was 8.29 years. Irradiation was performed by linear accelerator, 36 Gy were applied in the high risk group (partial tumor resection, tumor cell positivity in the liquor, metastases within the central nervous system) and 30 Gy in the low risk group (total tumor resection, negative liquor cytology, no metastases within the central nervous system) on the entire cerebrum and spinal cord. This was followed in both groups by the application of 20-20 Gy boost irradiation on the posterior scala. Studying the survival it has been found that the surgical radicality did not significantly influence the survival chances of patients, however, with the increase in the tumor size the survival chance significantly decreases (p = 0.03). When predicting life expectancy, however, the stage of tumor, the age of patients, the risk group and the M stage yielded essential information. At the age of 8 years and less, the rate of survivors is 67.6%, for those over 8 years is 75.9% (p = 0.21), however the younger age was not significant. The appearance of metastases considerably deteriorates the chances of survival (from 81.5% to 66.7%, p = 0.02). In the low risk group of patients the 5-year survival is 80%, while in the high risk group it is significantly lower, 67.4% (p = 0.04).