High-performance liquid chromatography of the renal blood flow marker p-aminohippuric acid (PAH) and its metabolite N-acetyl PAH improves PAH clearance measurements.

PAH (N-(4-aminobenzoyl)glycin) clearance measurements have been used for 50 years in clinical research for the determination of renal plasma flow. The quantitation of PAH in plasma or urine is generally performed by colorimetric method after diazotation reaction but the measurements must be corrected for the unspecific residual response observed in blank plasma. We have developed a HPLC method to specifically determine PAH and its metabolite NAc-PAH using a gradient elution ion-pair reversed-phase chromatography with UV detection at 273 and 265 nm, respectively. The separations were performed at room temperature on a ChromCart (125 mmx4 mm I.D.) Nucleosil 100-5 microm C18AB cartridge column, using a gradient elution of MeOH-buffer pH 3.9 1:99-->15:85 over 15 min. The pH 3.9 buffered aqueous solution consisted in a mixture of 375 ml sodium citrate-citric acid solution (21.01 g citric acid and 8.0 g NaOH per liter), added up with 2.7 ml H3PO4 85%, 1.0 g of sodium heptanesulfonate and completed ad 1000 ml with ultrapure water. The N-acetyltransferase activity does not seem to notably affect PAH clearances, although NAc-PAH represents 10.2+/-2.7% of PAH excreted unchanged in 12 healthy subjects. The performance of the HPLC and the colorimetric method have been compared using urine and plasma samples collected from healthy volunteers. Good correlations (r=0.94 and 0.97, for plasma and urine, respectively) are found between the results obtained with both techniques. However, the colorimetric method gives higher concentrations of PAH in urine and lower concentrations in plasma than those determined by HPLC. Hence, both renal (ClR) and systemic (Cls) clearances are systematically higher (35.1 and 17.8%, respectively) with the colorimetric method. The fraction of PAH excreted by the kidney ClR/ClS calculated from HPLC data (n=143) is, as expected, always <1 (mean=0.73+/-0.11), whereas the colorimetric method gives a mean extraction ratio of 0.87+/-0.13 implying some unphysiological values (>1). In conclusion, HPLC not only enables the simultaneous quantitation of PAH and NAc-PAH, but may also provide more accurate and precise PAH clearance measurements.

Diagnostic accuracy of body mass index, body fat and waist in defining low aerobic fitness in adolescents

Objective: to assess the diagnostic accuracy of different anthropometric markers in defining low aerobic fitness among adolescents. Methods: cross-sectional study on 2,331 boys and 2,366 girls aged 10 - 18 years. Body mass index (BMI) was measured using standardized methods; body fat (BF) was assessed by bioelectrical impedance. Low aerobic fitness was assessed by the 20-meter shuttle run using the FITNESSGRAMR criteria. Waist was measured in a subsample of 1,933 boys and 1,897 girls. Overweight, obesity and excess fat were defined according to the International Obesity Task Force (IOTF) or FITNESSGRAMR criteria. Results: 38.5% of boys and 46.5% of girls were considered as unfit according to the FITNESSGRAMR criteria. In boys, the area under the ROC curve (AUC) and 95% confidence interval were 66.7 (64.1 - 69.3), 67.1 (64.5 - 69.6) and 64.6 (61.9 - 67.2) for BMI, BF and waist, respectively (P<0.02). In girls, the values were 68.3 (65.9 - 70.8), 63.8 (61.3 - 66.3) and 65.9 (63.4 - 68.4), respectively (P<0.001). In boys, the sensitivity and specificity to diagnose low fitness were 13% and 99% for obesity (IOTF); 38% and 86% for overweight + obesity (IOTF); 28% and 94% for obesity (FITNESSGRAMR) and 42% and 81% for excess fat (FITNESSGRAMR). For girls, the values were 9% and 99% for obesity (IOTF); 33% and 82% for overweight + obesity (IOTF); 22% and 94% for obesity (FITNESSGRAMR) and 26% and 90% for excess fat (FITNESSGRAMR). Conclusions: BMI, not body fat or waist, should be used to define low aerobic fitness. The IOTF BMI cut-points to define obesity have a very low screening capacity and should not be used.

PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification.

PURPOSE: To improve the risk stratification of patients with rhabdomyosarcoma (RMS) through the use of clinical and molecular biologic data. PATIENTS AND METHODS: Two independent data sets of gene-expression profiling for 124 and 101 patients with RMS were used to derive prognostic gene signatures by using a meta-analysis. These and a previously published metagene signature were evaluated by using cross validation analyses. A combined clinical and molecular risk-stratification scheme that incorporated the PAX3/FOXO1 fusion gene status was derived from 287 patients with RMS and evaluated. RESULTS: We showed that our prognostic gene-expression signature and the one previously published performed well with reproducible and significant effects. However, their effect was reduced when cross validated or tested in independent data and did not add new prognostic information over the fusion gene status, which is simpler to assay. Among nonmetastatic patients, patients who were PAX3/FOXO1 positive had a significantly poorer outcome compared with both alveolar-negative and PAX7/FOXO1-positive patients. Furthermore, a new clinicomolecular risk score that incorporated fusion gene status (negative and PAX3/FOXO1 and PAX7/FOXO1 positive), Intergroup Rhabdomyosarcoma Study TNM stage, and age showed a significant increase in performance over the current risk-stratification scheme. CONCLUSION: Gene signatures can improve current stratification of patients with RMS but will require complex assays to be developed and extensive validation before clinical application. A significant majority of their prognostic value was encapsulated by the fusion gene status. A continuous risk score derived from the combination of clinical parameters with the presence or absence of PAX3/FOXO1 represents a robust approach to improving current risk-adapted therapy for RMS.

Clinical features for diagnosis of pneumonia in children younger than 5 years: a systematic review and meta-analysis.

BACKGROUND: Pneumonia is the biggest cause of deaths in young children in developing countries, but early diagnosis and intervention can effectively reduce mortality. We aimed to assess the diagnostic value of clinical signs and symptoms to identify radiological pneumonia in children younger than 5 years and to review the accuracy of WHO criteria for diagnosis of clinical pneumonia. METHODS: We searched Medline (PubMed), Embase (Ovid), the Cochrane Database of Systematic Reviews, and reference lists of relevant studies, without date restrictions, to identify articles assessing clinical predictors of radiological pneumonia in children. Selection was based on: design (diagnostic accuracy studies), target disease (pneumonia), participants (children aged <5 years), setting (ambulatory or hospital care), index test (clinical features), and reference standard (chest radiography). Quality assessment was based on the 2011 Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria. For each index test, we calculated sensitivity and specificity and, when the tests were assessed in four or more studies, calculated pooled estimates with use of bivariate model and hierarchical summary receiver operation characteristics plots for meta-analysis. FINDINGS: We included 18 articles in our analysis. WHO-approved signs age-related fast breathing (six studies; pooled sensitivity 0·62, 95% CI 0·26-0·89; specificity 0·59, 0·29-0·84) and lower chest wall indrawing (four studies; 0·48, 0·16-0·82; 0·72, 0·47-0·89) showed poor diagnostic performance in the meta-analysis. Features with the highest pooled positive likelihood ratios were respiratory rate higher than 50 breaths per min (1·90, 1·45-2·48), grunting (1·78, 1·10-2·88), chest indrawing (1·76, 0·86-3·58), and nasal flaring (1·75, 1·20-2·56). Features with the lowest pooled negative likelihood ratio were cough (0·30, 0·09-0·96), history of fever (0·53, 0·41-0·69), and respiratory rate higher than 40 breaths per min (0·43, 0·23-0·83). INTERPRETATION: Not one clinical feature was sufficient to diagnose pneumonia definitively. Combination of clinical features in a decision tree might improve diagnostic performance, but the addition of new point-of-care tests for diagnosis of bacterial pneumonia would help to attain an acceptable level of accuracy. FUNDING: Swiss National Science Foundation.

The potential use of microcalorimetry in rapid differentiation between septic arthritis and other causes of arthritis.

Current diagnostic methods in differentiating septic from non-septic arthritis are time-consuming (culture) or have limited sensitivity (Gram stain). Microcalorimetry is a novel method that can rapidly detect microorganisms by their heat production. We investigated the accuracy and time to detection of septic arthritis by using microcalorimetry. Patients older than 18 years of age with acute arthritis of native joints were prospectively included. Synovial fluid was aspirated and investigated by Gram stain, culture and microcalorimetry. The diagnosis of septic arthritis and non-septic arthritis were made by experienced rheumatologists or orthopaedic surgeons. Septic arthritis was diagnosed by considering the finding of acute arthritis together with findings such as positive Gram stain or positive culture of synovial fluid or positive blood culture. The sensitivity and specificity for diagnosing septic arthritis and the time to positivity of microcalorimetry were determined. Of 90 patients (mean age 64 years), nine had septic arthritis, of whom four (44 %) had positive Gram stain, six (67 %) positive synovial fluid culture and four (44 %) had positive blood culture. The sensitivity of microcalorimetry was 89 %, the specificity was 99 % and the mean detection time was 5.0 h (range, 2.2-8.0 h). Microcalorimetry is an accurate and rapid method for the diagnosis of septic arthritis. It has potential to be used in clinical practice in diagnosing septic arthritis.

Genes outside The Hla Region affecting Susceptibility to Type 1 Diabetes - The Role of Iddm2 and Iddm9 in the Finnish Population

Tyypin 1 diabeteksen perinnöllinen alttius Suomessa - HLA-alueen ulkopuolisten alttiuslokusten IDDM2 ja IDDM9 rooli taudin periytymisessä HLA-alue, joka sijaitsee kromosomissa 6p21.3, vastaa noin puolesta perinnöllisestä alttiudesta sairastua tyypin 1 diabetekseen. Myös HLA-alueen ulkopuolisten lokusten on todettu liittyvän sairausalttiuteen. Näistä kolmen lokuksen on varmistettu olevan todellisia alttiuslokuksia ja lisäksi useiden muiden, vielä varmistamattomien lokusten, on todettu liittyvän sairausalttiuteen. Tässä tutkimuksessa 12:n HLA-alueen ulkopuolisen alttiuslokuksen kytkentä tyypin 1 diabetekseen tutkittiin käyttäen 107:aa suomalaista multiplex-perhettä. Jatkotutkimuksessa analysoitiin IDDM9-alueen kytkentä ja assosiaatio sairauteen laajennetuissa perhemateriaaleissa sekä IDDM2-alueen mahdollinen interaktio HLA-alueen kanssa sairauden muodostumisessa. Lisäksi suoritettiin IDDM2-alueen suojaavien haplotyyppien alatyypitys tarkoituksena tutkia eri haplotyyppien käyttökelpoisuutta sairastumisriskin tarkempaa ennustamista varten. Ensimmäisessä kytkentätutkimuksessa ei löytynyt koko genomin tasolla merkitsevää tai viitteellistä kytkentää tutkituista HLA-alueen ulkopuolisista lokuksista. Voimakkain havaittu nimellisen merkitsevyyden tavoittava kytkentä nähtiin IDDM9-alueen markkerilla D3S3576 (MLS=1.05). Tutkimuksessa ei kyetty varmistamaan tai sulkemaan pois aiempia kytkentähavaintoja tutkituilla lokuksilla, mutta IDDM9-alueen jatkotutkimuksessa havaittu voimakas kytkentä (MLS=3.4) ja merkitsevä assosiaatio (TDT p=0.0002) viittaa vahvasti siihen, että 3q21-alueella sijaitsee todellinen tyypin 1 diabeteksen alttiusgeeni, jolloin alueen kattava assosiaatiotutkimus olisi perusteltu jatkotoimenpide. Sairauteen altistava IDDM2-alueen MspI-2221 genotyyppi CC oli nimellisesti yleisempi matalan tai kohtalaisen HLA-sairastumisriskin diabeetikoilla, verrattuna korkean HLA-riskin potilaisiin (p=0.05). Myös genotyyppijakauman vertailu osoitti merkitsevää eroa ryhmien välillä (p=0.01). VNTR-haplotyyppitutkimus osoitti, että IIIA/IIIA-homotsygootin sairaudelta suojaava vaikutus on merkitsevästi voimakkaampi kuin muiden luokka III:n genotyypeillä. Nämä tulokset viittaavat IDDM2-HLA -vuorovaikutukseen sekä siihen että IDDM2-alueen haplotyyppien välillä esiintyy etiologista heterogeniaa. Tämän johdosta IDDM2-alueen haplotyyppien tarkempi määrittäminen voisi tehostaa tyypin 1 diabeteksen riskiarviointia.

Use of the dried blood spot sampling process coupled with fast gas chromatography and negative-ion chemical ionization tandem mass spectrometry: application to fluoxetine, norfluoxetine, reboxetine, and paroxetine analysis.

The objective of this work was to combine the advantages of the dried blood spot (DBS) sampling process with the highly sensitive and selective negative-ion chemical ionization tandem mass spectrometry (NICI-MS-MS) to analyze for recent antidepressants including fluoxetine, norfluoxetine, reboxetine, and paroxetine from micro whole blood samples (i.e., 10 microL). Before analysis, DBS samples were punched out, and antidepressants were simultaneously extracted and derivatized in a single step by use of pentafluoropropionic acid anhydride and 0.02% triethylamine in butyl chloride for 30 min at 60 degrees C under ultrasonication. Derivatives were then separated on a gas chromatograph coupled with a triple-quadrupole mass spectrometer operating in negative selected reaction monitoring mode for a total run time of 5 min. To establish the validity of the method, trueness, precision, and selectivity were determined on the basis of the guidelines of the "Société Française des Sciences et des Techniques Pharmaceutiques" (SFSTP). The assay was found to be linear in the concentration ranges 1 to 500 ng mL(-1) for fluoxetine and norfluoxetine and 20 to 500 ng mL(-1) for reboxetine and paroxetine. Despite the small sampling volume, the limit of detection was estimated at 20 pg mL(-1) for all the analytes. The stability of DBS was also evaluated at -20 degrees C, 4 degrees C, 25 degrees C, and 40 degrees C for up to 30 days. Furthermore, the method was successfully applied to a pharmacokinetic investigation performed on a healthy volunteer after oral administration of a single 40-mg dose of fluoxetine. Thus, this validated DBS method combines an extractive-derivative single step with a fast and sensitive GC-NICI-MS-MS technique. Using microliter blood samples, this procedure offers a patient-friendly tool in many biomedical fields such as checking treatment adherence, therapeutic drug monitoring, toxicological analyses, or pharmacokinetic studies.

Combined T2 -preparation and two-dimensional pencil-beam inner volume selection.

PURPOSE: To improve coronary magnetic resonance angiography (MRA) by combining a two-dimensional (2D) spatially selective radiofrequency (RF) pulse with a T2 -preparation module ("2D-T2 -Prep"). METHODS: An adiabatic T2 -Prep was modified so that the first and last pulses were of differing spatial selectivity. The first RF pulse was replaced by a 2D pulse, such that a pencil-beam volume is excited. The last RF pulse remains nonselective, thus restoring the T2 -prepared pencil-beam, while tipping the (formerly longitudinal) magnetization outside of the pencil-beam into the transverse plane, where it is then spoiled. Thus, only a cylinder of T2 -prepared tissue remains for imaging. Numerical simulations were followed by phantom validation and in vivo coronary MRA, where the technique was quantitatively evaluated. Reduced field-of-view (rFoV) images were similarly studied. RESULTS: In vivo, full field-of-view 2D-T2 -Prep significantly improved vessel sharpness as compared to conventional T2 -Prep, without adversely affecting signal-to-noise (SNR) or contrast-to-noise ratios (CNR). It also reduced respiratory motion artifacts. In rFoV images, the SNR, CNR, and vessel sharpness decreased, although scan time reduction was 60%. CONCLUSION: When compared with conventional T2 -Prep, the 2D-T2 -Prep improves vessel sharpness and decreases respiratory ghosting while preserving both SNR and CNR. It may also acquire rFoV images for accelerated data acquisition.

Connectivity and tissue microstructural alterations in right and left temporal lobe epilepsy revealed by diffusion spectrum imaging.

Focal epilepsy is increasingly recognized as the result of an altered brain network, both on the structural and functional levels and the characterization of these widespread brain alterations is crucial for our understanding of the clinical manifestation of seizure and cognitive deficits as well as for the management of candidates to epilepsy surgery. Tractography based on Diffusion Tensor Imaging allows non-invasive mapping of white matter tracts in vivo. Recently, diffusion spectrum imaging (DSI), based on an increased number of diffusion directions and intensities, has improved the sensitivity of tractography, notably with respect to the problem of fiber crossing and recent developments allow acquisition times compatible with clinical application. We used DSI and parcellation of the gray matter in regions of interest to build whole-brain connectivity matrices describing the mutual connections between cortical and subcortical regions in patients with focal epilepsy and healthy controls. In addition, the high angular and radial resolution of DSI allowed us to evaluate also some of the biophysical compartment models, to better understand the cause of the changes in diffusion anisotropy. Global connectivity, hub architecture and regional connectivity patterns were altered in TLE patients and showed different characteristics in RTLE vs LTLE with stronger abnormalities in RTLE. The microstructural analysis suggested that disturbed axonal density contributed more than fiber orientation to the connectivity changes affecting the temporal lobes whereas fiber orientation changes were more involved in extratemporal lobe changes. Our study provides further structural evidence that RTLE and LTLE are not symmetrical entities and DSI-based imaging could help investigate the microstructural correlate of these imaging abnormalities.

Screening of breast lesions: a comparative study between mammography, B-mode ultrasonography, sonoelastography and histological results

Objective To compare the capacity of mammography, sonoelastography, B-mode ultrasonography and histological analysis to differentiate benign from malignant breast lesions. Materials and Methods A total of 12 histopathologically confirmed breast lesions were documented. The lesions were assessed by means of mammography, B-mode ultrasonography and sonoelastography, and histopathological analysis was utilized as a gold standard. Sensitivity and specificity were calculated. A receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic performance of the mentioned techniques. Results Sensitivity and specificity in the differentiation between benign and malignant lesions were respectively 100% and 50% for mammography, 100% and 71% for B-mode ultrasonography, and 67% and 83% for sonoelastography. The area under the ROC curve was calculated for the three imaging modalities and corresponded to 0.792 for mammography, 0.847 for B-mode ultrasonography, and 0.806 for sonoelastography. Conclusion Sonoelastography demonstrated higher specificity and lower sensitivity as compared with mammography and B-mode ultrasonography. On the other hand, B-mode ultrasonography had the largest area under the ROC curve. Sonoelastography has demonstrated to be a promising technique to detect and evaluate breast lesions, and could potentially reduce the number of unnecessary biopsies.

Prediction of preeclampsia by means of Doppler flowmetry of uterine artery and flow-mediated dilation of brachial artery

Objective To evaluate the association of Doppler of uterine artery and flow-mediated dilation of brachial artery (FMD) in the assessment of placental perfusion and endothelial function to predict preeclampsia. Materials and Methods A total of 91 patients considered as at risk for developing preeclampsia were recruited at the prenatal unit of the authors' institution. All the patients underwent FMD and Doppler of uterine arteries between their 24th and 28th gestational weeks. Calculations of sensitivity and specificity for both isolated and associated methods were performed. Results Nineteen out of the 91 patients developed preeclampsia, while the rest remained normotensive. Doppler flowmetry of uterine arteries with presence of bilateral protodiastolic notch had sensitivity of 63.1% and specificity of 87.5% for the prediction of preeclampsia. Considering a cutoff value of 6.5%, FMD showed sensitivity of 84.2% and specificity of 73.6%. In a parallel analysis, as the two methods were associated, sensitivity was 94.2% and specificity, 64.4%. Conclusion The association of Doppler study of uterine arteries and FMD has proved to be an interesting clinical strategy for the prediction of preeclampsia, which may represent a positive impact on prenatal care of patients considered as at high-risk for developing such a condition.

Verbal learning in mild cognitive impairment and alzheimer's disease : behavioural and neural approaches

The main focus of the present thesis was at verbal episodic memory processes that are particularly vulnerable to preclinical and clinical Alzheimer’s disease (AD). Here these processes were studied by a word learning paradigm, cutting across the domains of memory and language learning studies. Moreover, the differentiation between normal aging, mild cognitive impairment (MCI) and AD was studied by the cognitive screening test CERAD. In study I, the aim was to examine how patients with amnestic MCI differ from healthy controls in the different CERAD subtests. Also, the sensitivity and specificity of the CERAD screening test to MCI and AD was examined, as previous studies on the sensitivity and specificity of the CERAD have not included MCI patients. The results indicated that MCI is characterized by an encoding deficit, as shown by the overall worse performance on the CERAD Wordlist learning test compared with controls. As a screening test, CERAD was not very sensitive to MCI. In study II, verbal learning and forgetting in amnestic MCI, AD and healthy elderly controls was investigated with an experimental word learning paradigm, where names of 40 unfamiliar objects (mainly archaic tools) were trained with or without semantic support. The object names were trained during a 4-day long period and a follow-up was conducted one week, 4 weeks and 8 weeks after the training period. Manipulation of semantic support was included in the paradigm because it was hypothesized that semantic support might have some beneficial effects in the present learning task especially for the MCI group, as semantic memory is quite well preserved in MCI in contrast to episodic memory. We found that word learning was significantly impaired in MCI and AD patients, whereas forgetting patterns were similar across groups. Semantic support showed a beneficial effect on object name retrieval in the MCI group 8 weeks after training, indicating that the MCI patients’ preserved semantic memory abilities compensated for their impaired episodic memory. The MCI group performed equally well as the controls in the tasks tapping incidental learning and recognition memory, whereas the AD group showed impairment. Both the MCI and the AD group benefited less from phonological cueing than the controls. Our findings indicate that acquisition is compromised in both MCI and AD, whereas long13 term retention is not affected to the same extent. Incidental learning and recognition memory seem to be well preserved in MCI. In studies III and IV, the neural correlates of naming newly learned objects were examined in healthy elderly subjects and in amnestic MCI patients by means of positron emission tomography (PET) right after the training period. The naming of newly learned objects by healthy elderly subjects recruited a left-lateralized network, including frontotemporal regions and the cerebellum, which was more extensive than the one related to the naming of familiar objects (study III). Semantic support showed no effects on the PET results for the healthy subjects. The observed activation increases may reflect lexicalsemantic and lexical-phonological retrieval, as well as more general associative memory mechanisms. In study IV, compared to the controls, the MCI patients showed increased anterior cingulate activation when naming newly learned objects that had been learned without semantic support. This suggests a recruitment of additional executive and attentional resources in the MCI group.

First-Line Chemotherapy with Anthracycline and Taxane Combination in Metastatic Breast Cancer. Detection of bone metastases with TRACP 5b

Background: In Finland, breast cancer (BC) is the most common cancer among women, and prostate cancer (PC) that among men. At the metastatic stage both cancers remain essentially incurable. The goals of therapy include palliation of symptoms, improvement or maintenance of quality of life (QoL), delay of disease progression, and prolongation of survival. Balancing between efficacy and toxicity is the major challenge. With increasing costs of new treatments, appropriate use of resources is paramount. When new treatment regimes are introduced into clinical practice a comprehensive assessment of clinical benefit, adverse effects and cost is necessary. Both BC and PC show a predilection to metastasize to bone. Bone metastases cause significant morbidity impairing the patients´ QoL. Diagnosis of bone metastases relies mainly on radiological methods, which however lack optimal sensitivity and specificity. New tools are needed for detection and follow-up of bone metastases. Aims: Anthracyclines and taxanes are effective chemotherapeutic agents in the treatment of metastatic breast cancer (MBC) with different mechanisms of action. Therefore, evaluation of the combination of anthracyclines with taxanes was a justifiable approach in the treatment of MBC patients. We assessed the efficacy, toxicity, cost of treatment and QoL of BC patients treated with first-line chemotherapy for metastatic disease with the combination epirubicin and docetaxel. We also evaluated the diagnostic potential of tartrate-resistant acid phosphatase 5b (TRACP 5b) and carboxyterminal telopeptides of type I collagen (ICTP) in the diagnosis of bone metastases in BC and TRACP 5b in PC patients. Results: The combination of epirubicin and docetaxel was effective in this phase II study, but required individual dose adjustment to avoid neutropenic infections, and the use of growth factors to maintain a feasible dose level. The response rate was 54 % (95 % CI 37-71) and the median overall survival (OS) was 26 months. Of the patients, 87 % were treated for infections. The treatment of adverse events required additional use of health resources mainly due to neutropenic infections, thereby raising direct treatment costs by 20 %. Despite adverse events, the global QoL was not significantly compromised during the treatment. Clinically evident acute cardiac toxicity was not observed. The combination of serum TRACP 5b and ICTP was at least equally sensitive and specific in detection of of bone metastases as commonly used total alkaline phosphatise (tALP) in BC patients. In contrast, TRACP 5b was less specific and sensitive than tALP as a marker of skeletal changes in PC patients. Conclusions: Treatment with epirubicin and docetaxel showed high efficacy in first-line chemotherapy of MBC. The relatively high incidence of neutropenic infections requiring hospitalization increased the treatment costs. Despite adverse events, the global QoL of the patients was not significantly compromised. The combination of TRACP 5b and ICTP showed similar activity as tALP in detecting bone metastases in MBC. In contrast, TRACP 5b was less specific and sensitive than tALP as a marker of skeletal changes in PC.

Application of morphometry, static DNA ploidy analysis, and steroid receptor expression in diagnosis and prognosis of Libyan breast cancer

The aim of this study was to describe the demographic, clinicopathological, biological and morphometric features of Libyan breast cancer patients. The supporting value of nuclear morphometry and static image cytometry in the sensitivity for detecting breast cancer in conventional fine-needle aspiration biopsies were estimated. The findings were compared with findings in breast cancer in Finland and Nigeria. In addation, the value of ER and PR were evaluated. There were 131 histological samples, 41 cytological samples, and demographic and clinicopathological data from 234 Libyan patients. The Libyan breast cancer is dominantly premenopausal and in this feature it is similar to breast cancer in sub-Saharan Africans, but clearly different from breast cancer in Europeans, whose cancers are dominantly postmenopausal in character. At presention most Libyan patients have locally advanced disease, which is associated with poor survival rates. Nuclear morphometry and image DNA cytometry agree with earlier published data in the Finnish population and indicate that nuclear size and DNA analysis of nuclear content can be used to increase the cytological sensitivity and specificity in doubtful breast lesions, particularly when free cell sampling method is used. Combination of the morphometric data with earlier free cell data gave the following diagnostic guidelines: Range of overlap in free cell samples: 55 μm2 -71 μm2. Cut-off values for diagnostic purposes: Mean nuclear area (MNA) >54 μm2 for 100% detection of malignant cases (specificity 84 %), MNA < 72 μm2 for 100% detection of benign cases (sensitivity 91%). Histomorphometry showed a significant correlation between the MNA and most clinicopathological features, with the strongest association observed for histological grade (p <0.0001). MNA seems to be a prognosticator in Libyan breast cancer (Pearson’s test r = - 0.29, p = 0.019), but at lower level of significance than in the European material. A corresponding relationship was not found in shape-related morphometric features. ER and PR staining scores were in correlation with the clinical stage (p= 0.017, and 0.015, respectively), and also associated with lymph node negative patients (p=0.03, p=0.05, respectively). Receptor-positive (HR+) patients had a better survival. The fraction of HR+ cases among Libyan breast cancers is about the same as the fraction of positive cases in European breast cancer. The study suggests that also weak staining (corresponding to as few as 1% positive cells) has prognostic value. The prognostic significance may be associated with the practice to use antihormonal therapy in HR+ cases. The low survival and advanced presentation is associated with active cell proliferation, atypical nuclear morphology and aneuploid nuclear DNA content in Libyan breast cancer patients. The findings support the idea that breast cancer is not one type of disease, but should probably be classified into premenopausal and post menopausal types.