Requirements for dose calculation on an active scanned proton beamline for small, shallow fields.

INTRODUCTION: A growing interest in using proton pencil beam scanning in combination with collimators for the treatment of small, shallow targets, such as ocular melanoma or pre-clinical research emerged recently. This study aims at demonstrating that the dose of a synchrotron-based PBS system with a dedicated small, shallow field nozzle can be accurately predicted by a commercial treatment planning system (TPS) following appropriate tuning of both, nozzle and TPS. MATERIALS: A removable extension to the clinical nozzle was developed to modify the beam shape passively. Five circular apertures with diameters between 5 to 34mm, mounted 72cm downstream of a range shifter were used. For each collimator treatment plans with spread-out Bragg peaks (SOBP) with a modulation of 3 to 30mm were measured and calculated with GATE/Geant4 and the research TPS RayStation (RS11B-R). The dose grid, multiple coulomb scattering and block discretization resolution were varied to find the optimal balance between accuracy and performance. RESULTS: For SOBPs deeper than 10mm, the dose in the target agreed within 1% between RS11B-R, GATE/Geant4 and measurements for aperture diameters between 8 to 34mm, but deviated up to 5% for smaller apertures. A plastic taper was introduced reducing scatter contributions to the patient (from the pipe) and improving the dose calculation accuracy of the TPS to a 5% level in the entrance region for large apertures. CONCLUSION: The commercial TPS and GATE/Geant4 can accurately calculate the dose for shallow, small proton fields using a collimator and pencil beam scanning.

Investigation of the Bragg peak degradation caused by homogeneous and heterogeneous lung tissue substitutes: proton beam experiments and comparison to current clinical dose calculation.

Submillimetre structures of lung tissue are not represented in computed tomography images used for radiotherapeutic dose calculation. In order to study the effect experimentally, lung substitutes with properties similar to lung tissue were chosen, namely two types of commercial lung tissue equivalent plates (LTEPs) (CIRS, USA), two types of cork, balsawood, floral foam and konjac sponge. Laterally integrated dose profiles were measured as a function of depth for proton pencil beams (PBs) with an initial nominal energy of 97.4 and 148.2 MeV, respectively. The obtained dose profiles were investigated for their shifting and degradation of the Bragg peak (BP) caused by the materials, expressed as water equivalent thickness (WET) and full width half maximum. The set-up was simulated in the treatment planning system (TPS) RayStation using the Monte Carlo (MC) dose calculation algorithm. While the WET between experiment and dose calculation agreed within 0.5 mm, except for floral foam, the full width half maximum was underestimated in the TPS by up to 2.3 mm. Normalisation to the same mass thickness of the lung substitutes allowed to classify LTEPs and balsawood as homogeneous and cork, floral foam and konjac sponge as heterogeneous materials. The material specific BP degradation was up to 3.4 times higher for the heterogeneous samples. The modulation power as a measure for the heterogeneity was compared to the spectrum of Hounsfield units (HU) of the materials. A clear correlation was not found, but with further improvements the HU spectrum may serve as an indicator for the material heterogeneity. Further, MC simulations of binary voxel models using GATE/Geant4 were performed to investigate the influence of grain size and mass density. For mass densities similar to lung tissue the BP degradation had a maximum at 3 and 7 mm grain size.

Quantification of the uncertainties of a biological model and their impact on variable RBE proton treatment plan optimization.

PURPOSE: In proton radiation therapy, a relative biological effectiveness (RBE) equal to 1.1 is currently assumed, although biological experiments show that it is not constant. The purpose of this study was to quantify the uncertainties of a published biological model and explore their impact on variable RBE treatment plan (TP) optimization. METHODS: Two patient cases with a high and a low (α/ß)x tumor were investigated. Firstly, intensity modulated proton therapy TPs assuming constant RBE were derived, and subsequently the variable RBE weighted dose (RWD), including the uncertainty originating in the fit to the experimental data and the uncertainty of the (α/ß)x, were calculated. Secondly, TPs optimized for uniform biological effect assuming a variable RBE were created using the worst case tissue specific (α/ß)x. RESULTS: For the nasopharyngeal cancer patient, the uncertainty of (α/ß)x corresponded to a CTV D98 confidence interval (CI) of (-2, +4)% while for the fit parameter CI was (-2,+1)%. For the standard fractionation prostate case the (α/ß)x CI was (-7,+5)% and the fit parameter CI was (-3,+3)%. For the hypofractionated case both CIs were (-1,+1)%. In both patient cases, the RBE in most organs at risk (OARs) was significantly underestimated by the constant RBE approximation, whereas the situation was not as definite in the target volumes. Overdosage of OARs was reduced by using the biological effect optimization. CONCLUSION: For the two patient cases, the RWD uncertainty from the fit parameter in the biological model contributed non-negligibly to the total uncertainty, depending on the patient case and the organ. The presented optimization strategy is a basic method for robust biological effect optimization to reduce potential consequences caused by the (α/ß)x uncertainty.

Recent developments and current concepts in medulloblastoma.

Medulloblastoma is the most common malignant brain tumor of childhood. While prognosis has significantly improved in the last decades with multimodal therapy including surgery, radiotherapy, and chemotherapy, one third of patients still succumb to their disease. Further research is needed to find more efficient treatment strategies for prognostically unfavorable patient groups and to minimize long-term sequelae of tumor treatment. This review gives a summary of the current state of treatment concepts including an outlook on the near future. We describe recent advances in the understanding of molecular mechanisms, their potential impact on risk stratification in upcoming clinical trials, and perspectives for the clinical implementation of targeted therapies.

Burden of pulmonary arterial hypertension in Germany.

This study aimed to describe health care provision, resource consumption and related costs, as well as treatment patterns and quality of life in adult patients with pulmonary arterial hypertension (PAH) in Germany. Data for this retrospective and prospective cost-of-illness-study were derived from hospitals, general practitioners and patients. Costs were evaluated from the perspective of third party payer and patient. Quality of life data were collected by using three validated instruments. A total of 167 patients were enrolled at 10 hospitals. Time period from first occurrence of symptoms to confirmed diagnosis of PAH was 2.3 years on average. Mean number of GP visits was 1.5 per patient per month, and within 15 months, inpatient stays were reported for 50% of patients. The ratio of combination therapy to single-drug therapy for endothelin receptor antagonists, phosphodiesterase-5-inhibitor and prostacyclin analogues increased significantly during 15 months. Treatment costs were, on average, euro47,400 per patient per year, arising mainly from drugs. Compared to the general population, quality of life of PAH patients was considerably impaired. This is the first study which evaluated aspects of the medical and economic consequences of PAH based on a large cohort of PAH patients in Germany.

Cost-effectiveness of linezolid vs vancomycin in suspected methicillin-resistant Staphylococcus aureus nosocomial pneumonia in Germany.

BACKGROUND: The oxazolidinone antibiotic linezolid has demonstrated efficacy in treating infections caused by methicillin-resistant Staphylococcus aureus (MRSA). In a retrospective analysis of two prospective randomized clinical trials in patients with nosocomial pneumonia (NP), initial therapy with linezolid produced significantly better clinical cure and survival rates than vancomycin in the subset of patients with documented MRSA infection. This study was designed to evaluate the economic impact of these clinical outcomes from the perspective of the German health care system to determine the use of these regimens in the light of limited resources and rising costs. METHODS: A decision-analytic model using clinical trial data was developed to examine the costs and outcomes of treatment with linezolid or vancomycin in hospitalized patients with NP caused by suspected MRSA. The model followed an average patient from initiation of empiric treatment until treatment success, death, or second-line treatment failure. Local treatment patterns and resource use were obtained from a Delphi panel. Costs were taken from published sources. Outcomes included total cost per patient, cost per additional cure, cost per death avoided, and cost per life-year gained. RESULTS: The model calculated that linezolid was associated with an 8.7% higher cure rate compared with vancomycin (73.6% vs 64.9%, respectively). Average total costs per episode for linezolid- and vancomycin-treated patients were 12,829 and 12,409, respectively. Death rates were 13.2% lower with linezolid than with vancomycin (20.7% vs 33.9%), resulting in an average of 2.3 life-years gained per linezolid-treated patient in a 65-year-old cohort (14.0 life-years vs 11.7 life-years). With linezolid, incremental costs per death avoided and per patient cured were 3,171 and 4,813, respectively. The base case estimated a similar mean length of stay for both drugs (11.2 vs 10.8 days). One-way sensitivity analyses did not change the overall results. CONCLUSION: The model estimated a higher clinical cure (+8.7%) and survival (+13.2%) for linezolid compared with vancomycin at an incremental cost of 420 per treatment episode. The cost-benefit profile suggests that linezolid could be considered a cost-effective alternative to vancomycin in the treatment of patients with NP caused by suspected MRSA in Germany.

Atopic disease and its determinants -- a focus on the potential role of childhood infection.

BACKGROUND: Atopic diseases develop on a genetic background and are modulated by environmental factors among which some infectious diseases are thought to have a protective influence. OBJECTIVE: The aim of this study was to determine the influence of infectious diseases in younger ages, bacterial and viral, on atopic diseases and sensitization to aero- and food-allergens in adults. METHODS: A population-based sample of 4262 subjects aged 25-74 years were interviewed concerning their history of infectious disease within the first 18 years of life. Information about allergic disease, including atopic eczema, allergic rhinitis (AR), and asthma was obtained. A blood sample was drawn and analysed for allergen-specific IgE antibodies against food- and aero-allergens. RESULTS: Multiple logistic regression analyses identified viral infection to be associated with AR (adjusted odds ratio (OR) = 1.39; 95% confidence interval (95% CI): 1.13-1.72) and sensitization to aeroallergens (OR = 1.21; 95% CI: 1.05-1.41). Bacterial disease was a negative predictor for atopy development in the subgroup of patients sensitized to nutritional allergens with concomitant atopic eczema (OR = 0.34; 95% CI: 0.11-0.99), AR (OR = 0.67; 95% CI: 0.42-1.07), or asthma (OR = 0.41; 95% CI: 0.19-0.87). Influences of viral and bacterial infection on AR differed with regard to family history of atopic disease. CONCLUSION: In our study population, history of viral infection was consistently positively associated with AR. Our data suggests that bacterial infections might be preventive for specific subgroups of atopy.

Selenoprotein synthesis in archaea.

The availability of the genome sequences from several archaea has facilitated the identification of the encoded selenoproteins and also of most of the components of the machinery for selenocysteine biosynthesis and insertion. Until now, selenoproteins have been identified solely in species of the genera Methanococcus (M.) and Methanopyrus. Apart from selenophosphate synthetase, they include only enzymes with a function in energy metabolism. Like in bacteria and eukarya, selenocysteine insertion is directed by a UGA codon in the mRNA and involves the action of a specific tRNA and of selenophosphate as the selenium donor. Major differences to the bacterial system, however, are that no homolog for the bacterial selenocysteine synthase was found and, especially, that the SECIS element of the mRNA is positioned in the 3' nontranslated region. The characterisation of a homolog for the bacterial SelB protein showed that it does not bind to the SECIS element necessitating the activity of at least a second protein. The use of the genetic system of M. maripaludis allowed the heterologous expression of a selenoprotein gene from M. jannaschii and will facilitate the elucidation of the mechanism of the selenocysteine insertion process in the future.

Genome-wide detection of alternative splicing in expressed sequences of human genes.

We have identified 6201 alternative splice relationships in human genes, through a genome-wide analysis of expressed sequence tags (ESTs). Starting with approximately 2.1 million human mRNA and EST sequences, we mapped expressed sequences onto the draft human genome sequence and only accepted splices that obeyed the standard splice site consensus. A large fraction (47%) of these were observed multiple times, indicating that they comprise a substantial fraction of the mRNA species. The vast majority of the detected alternative forms appear to be novel, and produce highly specific, biologically meaningful control of function in both known and novel human genes, e.g. specific removal of the lysosomal targeting signal from HLA-DM beta chain, replacement of the C-terminal transmembrane domain and cytoplasmic tail in an FC receptor beta chain homolog with a different transmembrane domain and cytoplasmic tail, likely modulating its signal transduction activity. Our data indicate that a large proportion of human genes, probably 42% or more, are alternatively spliced, but that this appears to be observed mainly in certain types of molecules (e.g. cell surface receptors) and systemic functions, particularly the immune system and nervous system. These results provide a comprehensive dataset for understanding the role of alternative splicing in the human genome, accessible at http://www.bioinformatics.ucla.edu/HASDB.

Heterologous expression of archaeal selenoprotein genes directed by the SECIS element located in the 3' non-translated region.

Previous in silico analysis of selenoprotein genes in Archaea revealed that the selenocysteine insertion (SECIS) motif necessary to recode UGA with selenocysteine was not adjacent to the UGA codon as is found in Bacteria. Rather, paralogous stem-loop structures are located in the 3' untranslated region (3' UTR), reminiscent of the situation in Eukarya. To assess the function of such putative SECIS elements, the Methanococcus jannaschii MJ0029 (fruA, which encodes the A subunit of the coenzyme F420-reducing hydrogenase) mRNA was mapped in vivo and probed enzymatically in vitro. It was shown that the SECIS element is indeed transcribed as part of the respective mRNA and that its secondary structure corresponds to that predicted by RNA folding programs. Its ability to direct selenocysteine insertion in vivo was demonstrated by the heterologous expression of MJ0029 in Methanococcus maripaludis, resulting in the synthesis of an additional selenoprotein, as analysed by 75Se labelling. The selective advantage of moving the SECIS element in the untranslated region may confer the ability to insert more than one selenocysteine into a single polypeptide. Evidence for this assumption was provided by the finding that the M. maripaludis genome contains an open reading frame with two in frame TGA codons, followed by a stem-loop structure in the 3' UTR of the mRNA that corresponds to the archaeal SECIS element.

[Mediastinal Hodgkin lymphomas in computerized tomography. Comparison of exact CT-assisted volumetry and volume assessment using simple geometric models]. / Mediastinale Hodgkin-Lymphome in der Computertomographie. Vergleich von exakter CT-gestützter Volumetrie und Volumenabschätzung mit Hilfe einfacher geometrischer Modelle.

BACKGROUND: The importance of the size of the primary tumor in lymphomas and its size after treatment is still uncertain. Assuming a prognostic relevance, an assessment of tumor volume before and after induction of chemotherapy has been performed in the pediatric Hodgkin's disease study (HD-90). Since an exact CT-scan-based volumetric tumor assessment is time-consuming and in some centers not possible, the tumor volume is often estimated based on simple geometric approximations. Aim of this study was the development of an easy to apply and nearly exact model of volume estimation compared to CT-scan-based tumor volume measurements. MATERIAL AND METHODS: Thirty computed tomographies (CT) of mediastinal Hodgkin lymphomas of children aged 5 to 16 years have been examined. The CT scans were digitalized using a CCD camera combined with a frame grabber. Applying the Global Lab image software, the true tumor volume was determined excluding local organs, which did not belong to the lymphoma. Subsequently, volumes were assessed using simple geometric models (block, ellipsoid, octaeder) by using the maximum diameters of the tumor. The differences between the volume of the geometric models and the true volume, based on the CT scan evaluation, were compared. RESULTS: The maximum diameters of a tumor can be used to calculate its volume based on simple geometric models. The model "block" overestimates the volume by 89 to 268%. The model "ellipsoid" overestimates the volume on average by 29%. The model "octaeder" underestimates the volume on average by 18%. A division of the block volume by 2.3 approximated the geometric closest to the true volume: the average volume was overestimated by 2% in tumors with a volume larger than 20 ml. No model was sufficient to approximate tumors with a volume of less than 20 ml. CONCLUSIONS: For the estimation of tumor volumes in mediastinal Hodgkin lymphomas exceeding 20 ml, the formula "block/2.3" results in the closest approximation compared to the true volume. In the course of clinical studies it might be helpful to apply this formula to determine the prognostic relevance of the tumor size and its development under therapy.

Escherichia coli O157 infections and unpasteurised milk.

We report on two children with Escherichia coli O157 infection, one of whom developed haemolytic uraemic syndrome (HUS). Both had drunk raw cows or goats milk in the week before their illness. Molecular subtyping identified a sorbitol fermenting Escherichia coli O157:H isolate from a dairy cow. This isolate differed from Shiga toxin producing O157:H strains isolated from the 6 year old boy with HUS. This result underlines the need to search for other causes of infection, despite documented consumption of unpasteurised milk. In the second patient, human sorbitol non-fermenting O157:H isolates and animal isolates from goats were indistinguishable. The isolation of indistinguishable sorbitol non-fermenting Escherichia coli O157:H from contact animals supports the association between HUS and consumption of raw goats milk, and re-emphasises the importance of pasteurising milk.

Ultrasound and X-ray-based bone densitometry in patients with anorexia nervosa.

In 20 patients (mean age 23+/-5 years) with anorexia nervosa (AN), bone mass was evaluated by broadband ultrasound attenuation (BUA) of the calcaneus, peripheral quantitative computed tomography (pQCT) of the distal radius, and dual X-ray absorptiometry (DXA) of the lumbar spine and the hip. Compared with 20 age- and sex- matched healthy controls, patients with AN showed marked osteopenia at all measuring sites. Values of BUA (33.0+/-9 dB/MHz vs. 51.0+/-5.7 dB/MHz; P<0.0001) and of BMD of all regions of the hip (e.g., femoral neck: 0.71+/-0.13 g/cm(2) versus 0.89+/-0.07 g/cm(2); P<0.001), lumbar spine (0.82+/-0.15 g/cm(2) versus 1.24+/-0.06 g/cm(2); P<0.003) and total BMD of the peripheral radius (303.2+/-75 g/cm(3) versus 369.4+/-53.2 g/cm(3), P<0.001) were significantly reduced. Calculating a Z-score we found the most prominent differences between AN and controls by BUA of the calcaneus (-3.2+/-1.6), followed by DXA at the lumbar spine (-2.9+/-2.2) and the hip (femoral neck -2.1+/-1.7) and by pQCT at the distal radius (total BMD -1.2+/-2.0). There were highly significant correlations between BUA of the calcaneus and BMD of the femoral neck (r = 0.78, P<0.0001) and lumbar spine (r = 0.75, P<0.0001) as well as between BMD values of the femoral neck and lumbar spine (r = 0.95; P<0.0001). In addition, there were significant correlations (P<0.001) between body mass index (BMI) and the three different measuring sites and between the duration of the disease and BUA (r = 0.5, P<0.05). Our data suggest that BUA of the calcaneus is a valuable tool in the management of osteoporosis. Being a fast, radiation-free investigation method of good acceptance, it may be well suited for an assessment of the skeletal status in patients with AN.

Effect of distortions and asymmetry in MR images on radiotherapeutic treatment planning.

Before using MR-images for radiotherapeutic treatment planning, it is necessary to check whether geometrical distortions influence the calculated dose distribution. In this study, 27 MRI units from different manufacturers and with different magnetic field strengths were investigated. First, all geometrical distortions and asymmetry were determined by specially defined parameters. Virtual planning target volume and organ of risk were drawn into MR images from different units and optimized dose distributions were calculated. The resulting field parameters were then transferred to the reference geometry. Geometric distortions caused small variations of the dose maximum (+/-0.5%). Twenty-five percent of the investigated calculated dose distributions showed an increase of the 95% isodose volume, 60% a decrease. The dose deviations in the organ of risk were comparable with the dose deviations in the planning target volume (PTV). This study has shown that measurements of geometrical distortions and asymmetry are necessary for MR-assisted treatment planning. For evaluation, we recommend dose calculations with hypothetical PTV's and organs of risk. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 46-50 (2000).

[Contour defects after breast preserving therapy of breast carcinoma. Primary and secondary possibilities of correction]. / Konturdefekte bei brusterhaltender Therapie des Mammakarzinoms. Primäre und sekundäre Möglichkeiten der Korrektur.

BACKGROUND: Breast conserving treatment is increasing for primary treatment of breast carcinoma because of the importance of the cosmetic outcome. PATIENTS AND METHOD: We examined 195 patients after breast conserving therapy which was performed between 1983 and 1992. For evaluation of the cosmetic result symmetry, contour of the breast and location of the areola were examined. Radiation effect on breast tissue was evaluated by the Lent score. 72% of the patients had been treated with quadrantectomy and 28% with lumpectomy. RESULTS: Deformities of the contour were visible in 59% of the patients depending on the primary location of the tumor. Lumpectomy from medial quadrants caused poor results. Dislocation of the areola of more than 2 cm was detected in 32% of the patients. The dislocation depended on the primary kind of incision and resulted in 89% of the patients after a radial incision and only in 11% after curvilinear incisions. Telangiectasias were absent in 84% of the patients, the others showed telangiectasias Grade 1 to 3. In 48% of the patients no signs of fibrosis could be detected, in 49% fibrosis Grade 1 to 2 was found. 68% of the patients estimated the cosmetic result as very good or good. Only 10% of the patients estimated the result as fair or bad. The examiner estimated the results as good or very good in 28%. Examples of operative procedures for primary and secondary correction are demonstrated. CONCLUSIONS: Our results showed an adverse effect of long radial incisions. For lumpectomy and axillary node dissection separate incisions should be used. Correction of contour deformities should be done primarily in breast conserving procedures. This is possible by using modified reduction mammaplasties, local flaps of the breast tissue or switching a latissimus dorsi muscle flap. For secondary correction of defects after breast conserving treatment a latissimus dorsi muscle can be used as well as z-plasty for scar contracture.

Antithrombogenic coating of stents using a biodegradable drug delivery technology.

To reduce the thrombogenic properties of coronary artery stents, a biodegradable polylactic acid (PLA) stent coating with an incorporated thrombin inhibitor and a platelet aggregation inhibitor has been developed. In an ex vivo human stasis model, its effect on platelets, plasmatic coagulation and its release characteristics were studied using whole blood. Bare steel and bare gold-surface stents were compared to steel and gold-surface stents coated with PLA (30 kDa) containing 5% polyethyleneglycol (PEG)-hirudin and 1% iloprost, with an empty tube as control. Markers of activated coagulation (prothrombin fragment F1-2 and thrombin-antithrombin III complex, TAT), were assayed and the release of drugs from the coating was assessed by aPTT and collagen-induced platelet aggregation. Bare steel and gold stents were completely covered by a blood clot, and high levels of coagulation markers (F1-2 fragment and TAT) were detected. No differences in the thrombogenic properties were found between bare gold or steel stents. Coated stents were free of blood clots and only minor elevations of markers were detected. Release data from in-vitro studies over 90 days showed a gradual release of the drugs with an initial exponential release characteristic for PEG-hirudin, slow release of iloprost and a 10% degradation of the PLA carrier. This drug releasing biodegradable coating effectively reduced thrombus formation independent of the metallic surface.

Translation initiation factor 3 antagonizes authentic start codon selection on leaderless mRNAs.

In this study, we have examined the influence of initiation factors on translation initiation of leaderless mRNAs whose 5'-terminal residues are the A of the AUG initiating codon. A 1:1 ratio of initiation factors to ribosomes abolished ternary complex formation at the authentic start codon of different leaderless mRNAs. Supporting this observation, in vitro translation assays using limiting ribosome concentrations with competing leaderless lambda cl and Escherichia coli ompA mRNAs, the latter containing a canonical ribosome binding site, revealed reduced cl synthesis relative to OmpA in the presence of added initiation factors. Using in vitro toeprinting and in vitro translation assays, we show that this effect can be attributed to IF3. Moreover, in vivo studies revealed that the translational efficiency of a leaderless reporter gene is decreased with increased IF3 levels. These studies are corroborated by the observed increased translational efficiency of a leaderless reporter construct in an infC mutant strain unable to discriminate against non-standard start codons. These results suggest that, in the absence of a leader or a Shine-Dalgarno sequence, the function(s) of IF3 limits stable 30S ternary complex formation.

Discrimination of 5'-terminal start codons by translation initiation factor 3 is mediated by ribosomal protein S1.

The interrelation between ribosomal protein S1 and IF3 in recognition/discrimination of 5'-terminal start codons by 30S ribosomes has been studied using in vitro toeprinting. The study has been performed with two naturally occurring leaderless mRNAs, lambda cI and phage r1t rro mRNA, as well as with an artificial leaderless mRNA derived from the E. coli ompA gene. We show that in the absence of S1, IF3 does not discriminate against the authentic 5'-terminal start codon of both cI and rro mRNA. Since IF3 was able to exert its proofreading function for initiator tRNA(fMet) on 30S ribosomes lacking S1, this observation cannot be attributed to a lack of binding to or action of IF3 on 30S(-S1) ribosomes. In contrast to leaderless mRNAs, ternary complex formation occurs in the presence of IF3 with 30S ribosomes when the start codon is preceded by a short 20-nucleotide 5'-untranslated region containing a canonical Shine and Dalgarno sequence. This suggests that 5'-terminal start codons are recognised by IF3 as non-standard because of the lack of 16S rRNA-mRNA contacts.

Evidence that tamoxifen preserves bone density in late postmenopausal women with breast cancer.

Tamoxifen, which is used for treating breast cancer, exhibits estrogenic and antiestrogenic characteristics, depending on the tissue. In the human breast it acts as an antiestrogen, whereas estrogenic effects have been reported on endometrium and bone. The purpose of this study was to determine whether tamoxifen (TAM) prevents bone loss in elderly, postmenopausal women. Bone mineral density of the lumbar spine (SBD) was measured in elderly women (at least 10 years after menopause) 5 years after stage I or II breast cancer (n = 111). The results showed that SBD in untreated patients (n = 74) was significantly lower (p < 0.05) than SBD in patients (n = 37) treated with TAM over 5 years. In a subgroup of patients (n = 24) with positive estrogen receptor status, changes in SBD 12 months after discontinuation of 5-year TAM therapy were measured and compared with the changes of extended TAM treatment over a sixth year. Twelve months after withdrawal of 5-year TAM medication (n = 11) bone density decreased significantly (- 4.8+/-2.5%; p > 0.05), whereas in the group of women (n = 13) receiving extended TAM medication (20 mg) for an additional 12 months, SBD ( + 1.9+/-3.5 %) was maintained during the observation period, and was significantly higher when compared with the group of untreated patients (p <0.05). We conclude that tamoxifen has a preventive effect on trabecular bone loss at the lumbar spine, when compared to age-matched data and to untreated women with breast cancer in the late menopause. Our data give evidence of benefits to bone density provided by prolonged administration in patients after breast cancer and at risk of osteoporosis.