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Purpose: Surgery and radiotherapy as part of breast cancer treatment can lead to lymphoedema of the upper extremities (breast cancer-related lymphoedema = BCRL) and reduce the quality of life (health-related quality of life = HRQoL). The aim of the present study was to investigate the influence of paddling in a dragon boat (PP) on HRQoL and BCRL in breast cancer survivors (BCS)., Methods: Between April and October 2017, a prospective case-control study evaluated the effects of PP compared to a control group. In the paddle group (n = 28), weekly arm circumference measurements were taken at four defined anatomic areas of the arm before and after training; in the control group (n = 70), the measurements were taken once a month. At the beginning and end of the study, questionnaires from both groups (SF 36, EORTC QLQ C30) were evaluated to understand the differences in HRQoL., Results: The paddle group started with a higher HRQoL compared to the control group. Most interesting, whether the affected or unaffected arm, whether before or after training-the arm circumference decreased over time in the paddling group. A pre-existing lymphoedema was not negatively influenced by paddling. In the paddle group, the physical health was constant over the season, while the physical health of the control group decreased significantly over time., Conclusion: PP in a dragon boat does not lead to the development or worsening of pre-existing lymphoedema due to breast cancer therapy, and seems to have a positive effect on the quality of life., (© 2022. The Author(s).)

Background: Heparins are usually produced from animal tissues. It is now possible to synthesize heparins. This provides the abilities to overcome shortages of heparin, to optimize biological effects, and to reduce adverse drug effects. Heparins interact with platelet factor 4 (PF4), which can induce an immune response causing thrombocytopenia. This side effect is called heparin-induced thrombocytopenia (HIT). We characterized the interaction of PF4 and HIT antibodies with oligosaccharides of 6-, 8-, 10-, and 12-mer size and a hypersulfated 12-mer (S12-mer)., Methods: We utilized multiple methodologies including isothermal calorimetry, circular dichroism spectroscopy, single molecule force spectroscopy (SMFS), enzyme immunosorbent assay (EIA), and platelet aggregation test to characterize the interaction of synthetic heparin analogs with PF4 and anti-PF4/heparin antibodies., Results: The synthetic heparin-like compounds display stronger binding characteristics to PF4 than animal-derived heparins of corresponding lengths. Upon complexation with PF4, 6-mer and S12-mer heparins showed much lower enthalpy, induced less conformational changes in PF4, and interacted with weaker forces than 8-, 10-, and 12-mer heparins. Anti-PF4/heparin antibodies bind more weakly to complexes formed between PF4 and heparins ≤ 8-mer than with complexes formed between PF4 and heparins ≥ 10-mer. Addition of one sulfate group to the 12-mer resulted in a S12-mer, which showed substantial changes in its binding characteristics to PF4., Conclusions: We provide a template for characterizing interactions of newly developed heparin-based anticoagulant drugs with proteins, especially PF4 and the resulting potential antigenicity., (© 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Essentials At low pH and low salt concentrations: Maximal conformational change of PF4 upon complexation with heparin occurs. Changing physicochemical conditions may become an approach to better discriminate the signal of platelet-activating- and nonactivating PF4/H Abs in antigen tests., Background: Enzyme immunosorbent assays (EIA) are widely used to detect human antiplatelet factor 4/heparin antibodies (aPF4/H Abs) to rule out heparin-induced thrombocytopenia. EIAs cannot differentiate between clinically relevant, platelet-activating, and nonrelevant, nonplatelet-activating Abs and only ~50% of patients' sera testing positive by EIA contain antibodies that activate platelets. Recently, we have shown platelet-activating aPF4/H Abs bind more strongly to PF4/H complexes than nonplatelet-activating antibodies. Antigen-antibody interactions are known to depend on electrostatic interactions governed by pH, heat, and ionic strength. We tested whether changes in pH and ionic strength can improve the specificity of EIAs detecting aPF4/H Abs., Methods: We investigated first the conformational change of PF4 when binding to heparin under various pH and salt conditions using circular dichroism spectroscopy, and then the binding of aPF4/H Abs to PF4/H complexes by EIA., Results: Maximal conformational change of PF4 on complexation with heparin was identified at low pH and low salt concentrations. EIA tested with a large number of sera at 50 mmol/L NaCl, pH 6.0 shows a potential to increase the specificity for the detection of platelet-activating aPF4/H Abs., Conclusion: Changing physicochemical conditions may become an approach to better discriminate the signal of platelet-activating and nonactivating PF4/H Abs in antigen tests., (© 2019 International Society on Thrombosis and Haemostasis.)

Background: Drug-induced immune thrombocytopenia (DITP) is an adverse drug reaction associated with platelet (PLT) destruction by drug-dependent antibodies. Demonstration of drug-dependent PLT antibodies is often difficult and can only be rendered by extensive laboratory testing. In this report, we present the first serologically confirmed case of DITP caused by the antibiotic flucloxacillin., Case Report: A 68-year-old man developed severe thrombocytopenia that was first suspected to be related to heparin-induced thrombocytopenia. The absence of PLT-activating heparin-dependent antibodies and the abrupt decrease in PLT count to fewer than 20 × 10(9) /L raised the suspicion of DITP., Discussion: Flucloxacillin-dependent antibodies were detected in patient serum using whole PLT enzyme immunoassay and flow cytometry. The glycoprotein (GP) specificity was identified to be against GP IIb/IIIa complexes using the monoclonal antibody immobilization of PLT antigens assay. Interestingly, antibody binding was abolished when EDTA plasma was used and restored after adding calcium., Conclusion: In summary, DITP should be considered in cases of acute thrombocytopenia during treatment with flucloxacillin., (© 2015 AABB.)

Purpose: The aim of this study was to review the outcome of transscaphoid perilunate fracture dislocations by MRI to use the advantages of MRI to show the post-traumatic degenerative changes, the examination of cartilage, the integrity of the ligaments and the vascularisation of the carpal bones. A second aim of this study is to interpret the findings in correlation to the functional results and the individual perception of hand functionality (PRWE)., Patients and Methods: In this retrospective study, 20 patients (1 woman and 19 men), who were treated with open reduction and internal fixation at our institution, were reviewed at a mean of 67 (25-145) months postoperative. The mean age was 30 (12-73) years. The functional results were measured by range of motion (ROM), grip and pinch strength. The Mayo and Krimmer wrist scores were calculated and the SF-36 and the patient-rated wrist evaluation (PRWE) questionnaires were performed. Radiological findings included consolidation of the fracture and the radiological measures (revised carpal height, SL gap, SL and RL angle). An MRI, performed without a contrasting agent, was used to assess the degenerative changes of the joints, the vascularisation of the carpalia and the integrity of the SL ligament. Statistical data was calculated with SPSS., Results: Range of motion and strength were reduced by 10-20% compared to the uninjured opposite side. Although the majority of the patients (85%) achieved good to very good results in the Mayo and Krimmer wrist scores, the MRI showed osteoarthritis in 95% of the cases in at least in 1 out of 5 patients evaluated intracarpal joints. MRI showed signs of complete SL ligament tears in 5 patients and a partial tear in 2 patients. The same group also showed the strongest degenerative changes. However, there was no correlation between patient satisfaction and imaging results., Conclusion: MRI findings, as well as X-ray findings, do not correlate with the subjective and objective functional outcomes after surgical treatment of transscaphoid perilunate fracture dislocations. It can be assumed that SL ligament lesions seen in MRI play a major role over the long term course., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies that recognize platelet factor 4/heparin (PF4/hep) complexes. The in vitro demonstration of PF4/hep antibodies using functional and immunological methods is essential for optimal management of patients suspected to have HIT. Since functional assays are technically challenging and limited to specialized laboratories, antigen-binding assays are commonly used in routine laboratories., Study Design: Blood samples from 448 consecutive patients in whom HIT was suspected were investigated using a latex agglutination test HemosIL® HIT-Ab(PF4-H) (HemosIL-Ab), two chemiluminescence tests HemosIL AcuStar HIT-Ab(PF4-H) (HemosIL AcuStar-Ab) and AcuStar HIT-IgG(PF4-H) (HemosIL AcuStar-IgG), an in-house PF4/hep IgG enzyme immunoassay (EIA) and the heparin induced platelet aggregation (HIPA) test., Results: Antibodies against PF4/hep were detectable in 44 out of 119 samples using HemosIL-Ab among which 20 samples were also reactive in the HIPA; and in 122, 64 and 108 out of 448 sera using HemosIL AcuStar-Ab, HemosIL AcuStar-IgG and in-house PF4/hep IgG-EIA, respectively, among which 52 sera were also reactive in the HIPA. All assays had high sensitivities of >95% for platelet activating antibodies; however, they differed in their specificities. The highest specificity and positive predictive value was observed by HemosIL AcuStar-IgG (96% and 78%, respectively)., Conclusion: Automated immunoassays are useful in the laboratory investigations of HIT and present a potential improvement toward standardization of laboratory investigations of HIT. The high positive predictive capability may justify treating the patient with alternative anticoagulants without waiting for the results of a functional assay., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: The vacuum biopsy of the breast under sonographic guidance (VB) was introduced in Germany in the year 2000 and the first consensus recommendations were published by Krainick-Strobel et al. in 2005. Since then, many clinical studies on this technique have been published. The purpose of this publication is to update the consensus recommendations from 2005 regarding the latest literature., Materials and Methods: The consensus statements were the result of two preliminary meetings after the review of the latest literature by members of the Minimally Invasive Breast Intervention Study Group from the German Society of Senology. The final consensus text was review by all members of the working group. The statements listed under results obtained complete acceptance (consensus 100 %)., Results: The consensus recommendations describe the indications, investigator qualifications, technical requirements, documentation, quality assurance and follow-up intervals regarding the latest literature., Conclusion: The VB is a safe method for extracting breast tissue for histological workup. The technique allows the resection of breast tissue up to 8 cm3. Besides the diagnostic indications, the method qualifies for a therapeutic resection of symptomatic benign lesions (e. g. fibroadenomas). The technique should be used in specialized breast centers working in a multidisciplinary setup. This paper is an expert's recommendation for the use of VB under sonographic guidance. It is not formulated as a nationwide guideline., (© Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: The purpose of the study was to analyze sonographic criteria for the differentiation of benign and malignant breast lesions using real-time spatial compound imaging (CT) in combination with adaptive image processing (XRES)., Materials and Methods: In a retrospective analysis of 460 patients, the sonographic criteria: shape, orientation, margin, echo pattern and posterior acoustic features were determined using CT and XRES. All investigations were performed using a 12 MHz linear transducer. The findings were classified according to the DEGUM criteria analogous to BIRADS and were histologically confirmed by core needle or vacuum biopsy. Statistical analysis was performed using a Chi-square test, logistic uni- and multivariate regression analysis and an ROC-curve analysis to detect the false-positive rate., Results: All investigated diagnostic criteria were significant in the descriptive analysis (Chi-squared). The multivariate analysis showed that the criteria of irregular shape versus round, and not circumscribed margin versus circumscribed margin as well as the posterior acoustic features of enhanced versus reduced have a significant influence on the prediction of a malignant finding. The univariate analysis also showed a statistical significance using the indifferent and not parallel orientation versus parallel. To attain a detection rate of > 95 %, a false-positive rate of 60 % must be expected., Conclusion: This study shows that when using CT in combination with XRES, the analyzed sonographic criteria for the differentiation of benign and malignant breast lesions are still of diagnostic value. In particular, the shape, margin and posterior sonographic features are important., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: IgG-specific anti-PF4/heparin enzyme-immunoassays (EIAs) are sensitive but not specific for platelet-activating antibodies, the cause of heparin-induced thrombocytopenia (HIT). Two features of EIA reactivity predict for presence of HIT antibodies - the magnitude of a positive result (in optical density [OD] units) and the inhibition of reactivity at high heparin concentrations - but their combined utility remains uncertain., Objective: To determine for an IgG-specific EIA how the OD values of a positive reaction and its inhibition by high heparin can be optimally combined., Methods: We screened 1,000 consecutive patients with suspected HIT using an IgG-specific PF4/heparin in-house EIA with and without high heparin (100 IU/mL); and by the heparin-induced platelet activation test., Results: Platelet-activating antibodies were rarely detected (<0.2%) when the IgG-specific EIA was negative at the conventional cut-off (OD, 0.5). However, an OD cut-off of 1.0 resulted in an unacceptable loss of sensitivity (14/83=17%) for detecting platelet-activating antibodies. The high heparin step increased specificity for platelet-activating antibodies from 72% to 89% without loss of sensitivity when applied to weak-positive sera (OD≤1.0). However, decreased sensitivity was observed with strong-positive sera (OD>1.0): 11/69 such sera (16%) that did not show >40% inhibition by high heparin nevertheless contained platelet-activating antibodies., Conclusion: Specificity of an IgG-specific EIA for detecting platelet-activating antibodies can be optimized by applying the high heparin inhibition step to weak-positive reactions (0.5-≤1.0 OD). However, applying the high heparin inhibition step to strong-positive reactions (>1.0 OD) in our in-house assay risks falsely classifying a serum as negative for platelet-activating antibodies., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We have identified the ATP-binding cassette (ABC) transporter ABCC4 as an active constituent of mediator-storing granules in human platelets. In addition to multidrug resistance protein 4, other ABC-type transport proteins may contribute to platelet secretory function as well as determine intended or adverse effects of drugs. Here, we provide a comprehensive expression profiling of ABC transporters in human platelets based on a novel screening approach by combining the TaqMan low-density array RNA screening platform with a recently developed liquid chromatography/mass spectrometry (MS)/MS method for the simultaneous detection of membrane proteins. Transcripts of 25 ABC transporters were detected and showed differential expression compared with megakaryocytic progenitor cells. On the protein level ABCA7, ABCB4, ABCC1, ABCC3 and ABCC4 were identified by liquid chromatography/MS/MS and localized by immunofluorescence microscopy. Their functions may be related to glutathione and lipid homeostasis, secretion of lipid mediators, cell protection as well as drug transport.

Purpose: The study evaluates the differences between the Mammotome (MT) and ATEC (A) vacuum biopsy (VB) of the breast in terms of diagnostic reliability, biopsy duration and complications., Methods: In a prospective randomized study, 62 ultrasound-guided VBs of the breast were performed. MT and A were compared using Mann-Whitney U test., Results: The mean lesion size and the BI-RADS distribution were equal in both groups. Representative tissue was extracted in all 62 biopsies; thus no repeat biopsies were necessary. A sonographically guided complete excision was possible in 46 cases. More imaging-guided complete excisions were achieved with the MT than with A (87 vs. 63%). Technical complications occurred twice with A and once with MT. No medical complications occurred in either group., Conclusions: Both systems are suitable for the diagnostic clarification of unclear breast lesions as well as complete excision of benign lesions under sonographic imaging. Sonographically guided complete resection was achieved more often with the MT.

The immune response in heparin-induced thrombocytopenia (HIT) is puzzling: heparin-naive patients can develop IgG antibodies and clinical HIT as early as day 5, and evidence for an anamnestic response on heparin reexposure is lacking. We assessed daily serum samples by anti-PF4/heparin enzyme-immunoassay (EIA) in patients receiving heparin thromboprophylaxis. Of 435 patients, 56.1% showed an increase in EIA optical density (OD) of more than or equal to 15%, with more than 90% starting between days 4 and 14. After reaching maximum reactivity by days 10 to 12, ODs declined despite heparin continuation, including in 2 patients with clinical HIT. Individual IgG/A/M classes showed identical time of onset (median, day 6). Most (58.7%) antibody-positive patients developed all 3 Ig classes; only 11.3% lacked IgG response. IgG/A/M increase usually occurred simultaneously (+/- 1 day) with no general tendency for IgM precedence. Consistent with the transient immune response, none of the IgG-EIA-positive (OD > 0.5) patients at discharge developed clinically evident thrombosis during extended low-molecular-weight heparin thromboprophylaxis. The rapid onset of the anti-PF4/heparin immune response, its transience, and the simultaneous appearance of antibodies of different classes with no IgM precedence suggest short-term activation of B cells that have previously undergone Ig-class switching even without previous pharmacologic heparin exposure.

Statins are widely used to treat dyslipidemia. Effects of statins in addition to low-density lipoprotein lowering include altered platelet aggregation, requiring drug uptake into platelets. Possible candidates for mediating intraplatelet accumulation of statins include members of the organic anion-transporting polypeptide family such as OATP2B1 (SLCO2B1), a high-affinity uptake transporter for atorvastatin. Therefore, we analyzed OATP expression, localization, and function in human platelets. OATP2B1, but not OATP1B1, was detected in platelets and megakaryocytes on transcript and protein levels. Protein localization was almost exclusively confined to the plasma membrane. Moreover, we could demonstrate significant inhibition of estrone sulfate uptake into platelets by atorvastatin as well as direct transport of atorvastatin into platelets using a liquid chromatography-tandem mass spectrometry method. As a consequence of OATP2B1-mediated uptake of atorvastatin, we observed significant atorvastatin-mediated reduction of thrombin-induced Ca(2+) mobilization in platelets (37.3 +/- 6.7% of control at 15 microM atorvastatin), mechanistically explainable by reduced lipid modification of signal proteins. This effect was reversed by addition of mevalonate. Finally, we demonstrated expression of HMG-CoA reductase, the primary target of atorvastatin, in platelet cytosol. In conclusion, OATP2B1 is an uptake transporter expressed in platelets and is involved in statin-mediated alteration of platelet aggregation.

Aim: In comparison to round breast implants, anatomically formed implants have a broader indication spectrum in augmentation surgery for the formation of a natural breast shape. In order to achieve a long-term result, it is necessary for anatomically formed breast implants to remain secured in the position desired and planned initially. In the case of textured implants of a certain pore size and depth, this can be aided by the development of a stabilising implant-capsule-interaction (interface). The aim of this study was to investigate whether there are sonographic criteria for verifying the position of anatomically formed breast implants and the development of a stable interface., Material and Methods: 628 patients underwent breast implant surgery and were followed up clinically as well as sonographically at the Frauenklinik und Institut für Asthetische Chirugie am St. Josefs-Hospital, Wiesbaden. 228 implants (Style 410 Inamed McGhain) were evaluated after a mean of 27 months postoperatively. Only cosmetic augmentations were included in the results. Verification of the implant position was conducted by palpation as well as by sonography. Statistical analysis was performed using the McNemar-Test (Chi-squared test)., Results: Two marker points on the anterior side of the implant capsule in the lower hemisphere, which are designed for intraoperative position monitoring by palpation, could be reproduced sonographically in all cases and the position of the breast implant could thereby by determined. Two cases of clinically apparent implant rotation of more than 90 degrees around the vertical axis were discovered in this way. The sonographical identification of the development of a stable interface between the implant and the periprosthetic capsule is possible when sonographic criteria of the "parasternal movement layer" are met. The sonographic outcome is significantly superior to palpation., Conclusion: Breast sonography used for the clinical follow-up of patients with anatomically formed breast implants represents an efficient diagnostic supplement with clinical relevance.

Background: Minimal invasive breast biopsy is standard care for the diagnosis of suspicious breast lesions. There are different vacuum biopsy (VB) systems in use. The aim of the study was to determine the differences between the 8-gauge and the 11-gauge needle with respect to a) diagnostic reliability, b) complication rate and c) subjective perception of pain when used for vacuum-assisted breast biopsy., Methods: Between 01/2000 and 09/2004, 923 patients at St. Josefs-Hospital Wiesbaden underwent VB using the Mammotome (Ethicon Endosurgery, Hamburg). Depending on preoperative detection, the procedure was performed under sonographic or mammographic guidance under local anaesthesia. All patients included in the study were followed up both clinically and using imaging techniques one week after the VB and a second time after a median of 41 months. Excisional biopsy on the ipsilateral breast was an exclusion criteria. Subjective pain scores were recorded on a scale of 0 - 10 (0 = no pain, 10 = unbearable pain). The mean age of the patients was 53 years (30 - 88)., Results: 123 patients were included in the study in total. 48 patients were biopsied with the 8-gauge needle and 75 with the 11-gauge needle. The use of the 8-gauge needle did not show any significant differences to the 11-gauge needle with regard to diagnostic reliability, complication rate and subjective perception of pain., Conclusion: Our data show that there are no relevant differences between the 8-gauge and 11-gauge needle when used for VB. Under sonographic guidance, the use of the 8-gauge needle is recommended for firm breast tissue due to its sharp scalpel point and especially for complete removal of benign lesions. We did not find any advantages in the use of the larger 8-gauge needle compared to the 11-gauge needle in the mammography setting. The utilisation costs of the 8-gauge needle are somewhat higher.

Functional analysis of intracellular structures requires isolation and purification of these cellular compartments. With regard to platelet function both delta and alpha granules are relevant target structures. However, the availability of sufficient purification protocols for these structures is rather limited and restricted to density gradient centrifugation. Because this method is time-consuming and the resulting products are often of limited purity, we designed a new purification method based on immunolabeling followed by magnetic sorting. We directly compared this new method with the conventional method of ultracentrifugation. We were able to get highly purified subcellular fractions of human platelets using several antibodies against specific markers for dense granules (LAMP2), alpha granules (P-selectin) and the plasma membrane (GPIIb/IIIa) in combination with antibody-coated magnetic beads. In the respective fractions the marker proteins used for isolation as well as further independent, structure specific markers (for example MRP4 for dense granules, von Willebrand factor (vWF) for alpha granules and protein disulfide isomerase, PDI and GPIb beta, for plasma membrane) could be detected by Western blotting. The method describes purification of membranal structures of human platelets such as the plasma membrane and both types of granules. Therefore, studies requiring highly purified material (e.g. identification of specific transporters and receptors) will benefit from these results.

Cystosarcoma phyllodes (CP), otherwise known as phyllodes tumour (PT) of the breast, is a very rare but locally aggressive fibroepithelial tumour in its malignant form, and accounts for 0.3-1% of all breast neoplasias. Using 4 cases reports with different histological classifications as examples (benign-borderline-malignant), we describe the (differential) diagnosis and treatment options of this tumour entity and give an additional review of the available literature.

Background: Inappropriate therapy delivery is an important concern in the management of patients with implantable cardioverter defibrillators (ICDs). Recently, a morphology-based algorithm (wavelet feature) has been introduced for differentiation of ventricular and supraventricular tachycardia. In this study, we evaluated the performance of the wavelet algorithm using various electrogram (EGM) configurations during different body positions., Methods: Patients with a single-chamber Medtronic model 7230 ICD (Minneapolis, MN, USA) and a double-coil lead were included. EGM templates were collected during baseline rhythm in supine position for different EGM sources (right ventricular [RV] coil-can, RV coil-superior vena cava [SVC] coil, tip-ring, SVC coil-can). For each EGM configuration, morphologic similarity (match percentage) of EGMs obtained during different body positions (supine, left and right lateral, sitting, standing, walking) were compared with the templates., Results: Twenty-eight patients (24 males; age 58 +/- 17 years) were studied. A total of 9,775 intracardiac EGMs were analyzed. Median match percentage (interquartile range) was 88% (85-94), 88% (82-94), 82% (76-88), and 73 (58-85) for the RV coil-can, RV coil-SVC coil, tip-ring, and SVC coil-can configurations, respectively. Correct classification rates, as defined by match percentage of 70% or higher, were significantly higher with the RV coil-can, RV coil-SVC coil, and tip-ring EGM configurations, as compared to the SVC coil-can configuration (95, 91, and 91 vs 58% > or =70% match percent, P < 0.001)., Conclusion: Wavelet-based morphology scores in ICDs may change with various body positions. These variations are relatively minor using the nominal configuration (RV coil-can), as well as by using RV coil-SVC coil and tip-ring. However, morphology scores can vary considerably when SVC coil-can is used; therefore, this configuration should be avoided while using the wavelet algorithm.

Objective: Heparin-induced thrombocytopenia (HIT) is a prothrombotic drug reaction caused by antibodies that recognize positively charged platelet factor 4 (PF4), bound to the polyanion, heparin. The resulting immune complexes activate platelets. Unfractionated heparin (UFH) causes HIT more frequently than low-molecular-weight heparin (LMWH), whereas the smallest heparin-like molecule (the pentasaccharide, fondaparinux), induces anti-PF4/heparin antibodies as frequently as LMWH, but without exhibiting cross-reactivity with these antibodies. To better understand these findings, we analyzed the molecular structure of the complexes formed between PF4 and UFH, LMWH, or fondaparinux., Methods and Results: By atomic force microscopy and photon correlation spectroscopy, we show that with any of the 3 polyanions, but in the order, UFH>LMWH>>fondaparinux--PF4 forms clusters in which PF4 tetramers become closely apposed, and to which anti-PF4/heparin antibodies bind. By immunoassay, HIT antibodies bind strongly to PF4/H/PF4 complexes, but only weakly to single PF4/heparin molecules., Conclusions: HIT antigens are formed when charge neutralization by polyanion allows positively charged PF4 tetramers to undergo close approximation. Whereas such a model could explain why all 3 polyanions form antibodies with similar specificities, the striking differences in the relative size and amount of complexes formed likely correspond to the observed differences in immunogenicity (UFH>LMWH approximately fondaparinux) and clinically relevant cross-reactivity (UFH>LMWH>>fondaparinux).

In combination with high-resolution ultrasound (US), vacuum-assisted biopsy (VB) techniques can be used for accurate diagnosis confirmation and therapeutic minimally invasive removal of benign breast lesions. We developed a gel-simulation model to imitate the removal of benign breast lesions (e.g., fibroadenoma) with VB from a turkey breast-phantom. Bilobular US-sensitive models in the form of a fibroadenoma were manufactured from flexible, cuttable synthetic material (longitudinal diameters of 4-20 mm). They were implanted in turkey meat and vacuum biopsied under 2-D and 3-D imaging with 11G and 8 G needles. The minimum number of cylinders removed per tumour volume, the maximum complete excision tumour size and the optimum needle gauge were determined. Lesions with a longitudinal diameter of up to 10 to 12 mm could be removed with the 11G needle, those up to 20 mm with the 8G needle. The values for the correct needle size, number of cylinders per tumour size to be removed produced with the gel turkey phantoms provide a reference for clinicians performing VB with total excision intent. VB is suitable for the removal of benign lesions with a diameter of up to 20 mm.

Lymphangiomas are benign lesions but are associated with high morbidity when they become very large, occur in critical locations, or when surgically removed, develop secondary wound infections. Almost all lesions require surgical treatment. Complete excision is curative; however, relapses must be anticipated with incomplete excision. We report the case of a patient with a long history of massive cavernous lymphangioma of the breast and thoracic wall extending into the axilla in whom complete excision was not possible.

Background: Heparin-induced thrombocytopenia (HIT) is usually caused by anti-platelet factor 4 (PF4)/heparin antibodies, leading to intravascular platelet activation. These antibodies can be detected by PF4/polyanion antigen assays or platelet activation assays. While antigen assays are very sensitive and recognize immunoglobulin (Ig)G, IgA, and IgM antibodies, the role of IgM and IgA HIT-antibodies is debated. Platelet activation assays recognize IgG and are more specific for clinical HIT., Methods: We analyzed sera from 755 consecutive patients referred for diagnostic testing for HIT using a PF4/heparin enzyme-linked immunosorbent assay (ELISA) for IgG, IgA, and IgM and by the heparin-induced platelet activation (HIPA) test. Clinical information was provided by the treating physicians., Results: A total of 108 of 755 (14.3%) patients tested positive, 105 (13.9%) in the PF4/heparin IgG/A/M ELISA [28 (26.7%) only for IgM/A]; 53 (7.0%) sera were positive in the HIPA, of those 50 tested also positive in the ELISA. In 77 patients sufficient clinical information was provided. Available clinical information for 17 of the 28 patients who had only IgM and/or IgA detected showed plausible alternative (non-HIT) explanations in four of seven who had thromboembolic complications and in nine of 10 who had isolated HIT., Conclusion: Detection of IgG, IgM and IgA class antibodies by PF4/heparin ELISA yields a positive test result about twice as often as does a platelet activation assay, with only a minority of the additional patients detected likely having HIT. Thus, there is a potential for considerable over-diagnosis of HIT by laboratories that utilize only an ELISA for diagnostic testing.

Objectives: We sought to investigate the potential value of magnetic resonance (MR) elastography to improve the differentiation between benign and malignant tumors., Material and Methods: Measurements of 5 patients with 6 malignant lesions, 11 patients with benign lesions, and 4 patients with no lesions at all were performed at 1.5 Tesla. After breast MR imaging, MR elastography was performed as a targeted measurement. Low-frequency mechanical waves (65 Hz) were transmitted into the breast tissue using an oscillator and were displayed by means of a MR sequence within the phase of the MR image. After reconstruction, the viscoelastic information was correlated with the signal intensity and morphology data., Results: All examinations were technically successful realized in approximately 25 minutes. Malignant tumors documented higher values of elasticity than benign corresponding with signal intensity and morphologic data., Conclusion: A good separation exists between benign and malignant lesions in elasticity, corresponding with specific signal intensity and morphologic data. Further clinical studies with a larger number of patients are needed for extended validation.

Objectives: The objectives of this study were to assess practicability, outcome, and possible advantages of magnetic resonance imaging (MRI)-guided localizations with modified embolization coils for exclusively MRI-detected suspicious breast lesions., Materials and Methods: We performed 131 MRI-guided preoperative localizations in 105 patients with exclusively MRI-detected breast lesions. Contrast-enhanced, T1-weighted, 3-dimensional gradient echo sequences were used for imaging. Breast fixation and needle guidance were achieved by a perforated plate. Lesion localization was performed with a modified embolization coil. The distance between coil and lesion was measured. Results of specimen radiography and histopathology were analyzed., Results: Thirty-four of 131 lesions (26%) were malignant. Lesion localization and excision was successful in all patients. The mean distance between the coil and the lesion was 0.5 mm (+/-1.7 mm standard deviation)., Conclusions: Exact MRI-guided preoperative localization of exclusively MRI-detected breast lesions by using a modified embolization coil is feasible with excellent precision. Advantages over wire localization procedures are the possibility of specimen x-ray and the independence from time and place of operation.

Neoadjuvant chemotherapy has been employed increasingly in operable breast cancer during recent years. Several randomized trials showed that the chances of breast conserving therapy are being enhanced, and that survival was not compromised by primary systemic therapy compared to adjuvant treatment. Apart from the surgical advantages of tumor downstaging and breast conservation, therapy upfront might offer the chance to predict subsequent response of an individual patient to a given agent in the adjuvant setting. Furthermore, by investigating pre- and posttreatment tumor specimens, the neaodjuvant setting might help to evaluate new predictive biological markers, assess biologic effects of new treatments, and gain insight into molecular mechanisms. For postmenopausal patients with receptor-positive disease who cannot tolerate the toxicities of chemotherapy regimens or are not eligible for immediate surgery, endocrine treatment is emerging as an attractive alternative in the neoadjuvant setting. The new third-generation aromatase inhibitors letrozole and anastrozole have been compared to tamoxifen in 3 well-designed randomized neoadjuvant phase III trials (PO24, IMPACT, and PROACT). These studies showed significantly higher response rates for letrozole than for tamoxifen, and comparable ones for anastrozole. Thus, the primary use of an aromatase inhibitor seems a feasible and safe treatment option for postmenopausal women with early-stage breast cancer who do not wish to or are unable to undergo immediate surgery or preoperative chemotherapy. Further neoadjuvant endocrine trials should help us to elucidate the cross-talk between the different signal transduction pathways and their role in endocrine resistance.

Bivalirudin is a synthetic antithrombin sharing a sequence of 11 amino acids with the recombinant hirudin lepirudin. We investigated whether antilepirudin antibodies recognize epitopes on bivalirudin. Antilepirudin antibody-positive sera of 43 patients, treated with lepirudin for heparin-induced thrombocytopenia, were analyzed. Lepirudin- and bivalirudin-coated microtiter plates were used for antibody testing in an enzyme-linked immunosorbent assay (ELISA) system. Of the 43 sera-containing antibodies binding to lepirudin, 22 (51.2%) contained antibodies that also recognized bivalirudin. Binding of these antibodies to bivalirudin was inhibited by more than 70% by preincubation with high doses of bivalirudin. However, if lepirudin-coated microtiter plates were used, high concentrations of bivalirudin inhibited only 2 of the 43 positive sera by more than 30%. Therefore antihirudin antibodies must be polyspecific. The clinical consequences of this cross-reactivity are unknown but bivalirudin, targeted by antibodies of patients treated with lepirudin previously, could potentially boost antibody titers in such patients or even trigger an immune response by itself. Clinically significant antibody formation in response to bivalirudin monotherapy has not been observed, however. Yet, as lepirudin and antilepirudin antibodies have recently been implicated in severe anaphylactic reactions, caution is warranted when using bivalirudin in patients previously treated with lepirudin.

Recombinant hirudin has been found to be immunogenic in patients treated with lepirudin following heparin-induced thrombocytopenia (HIT). We assessed the incidence of immunoglobulin G (IgG) antihirudin antibodies by enzyme-linked immunosorbent assay in 112 patients enrolled in a dose-finding study with desirudin. Patients received desirudin subcutaneously following orthopedic hip surgery at 10 mg twice a day (n = 17), 15 mg twice a day (n = 75), and 20 mg twice a day (n = 20). Of 112 patients, 11 (9.8%) developed antihirudin antibodies independently of the dose. The rate of immunization did not differ from that observed in HIT patients treated with lepirudin (P =.113). Plasma concentrations of desirudin did not differ between antihirudin antibody-positive and -negative patients. Antihirudin antibodies had no impact on incidences of deep vein thrombosis and/or pulmonary embolism, allergic reactions, and hemorrhage. However, the total number of immunized patients observed was low and so infrequent (but severe) effects of antihirudin antibodies cannot be excluded.

Previous studies showed that transthoracic impedance minute ventilation (IMV), as measured by a pacemaker sensor, is closely correlated to actual minute ventilation (VE) determined by standard methods. The aim of this study was to analyze the changes in the calibration between IMV and VE at rest and during exercise over time. Fifteen patients (age 60 +/- 13 years) with Medtronic Kappa 400 pacemakers completed a baseline visit followed by two visits separated by 1 month and 1 week, respectively. In each patient, VE (L/min) was monitored at rest in the supine and sitting positions and during graded bicycle ergometer exercise using a standard cardiopulmonary metabolic gas analysis system with simultaneous recording of IMV (omega/min) using DR-180 extended telemetry monitors. Calibration at rest was defined as the ratio of IMV to VE, calculated from 1-minute average values in the supine and sitting positions. Calibration during bicycle exercise was defined as intercept (IMV value at VE = 10 L/min-typical VE value at beginning of exercise), and slope of the IMV/VE regression line. The calibration of IMV showed individual variability over time. The magnitude (absolute value) of observed fractional changes in calibration at 1 month was 0.23 +/- 0.20 (rest-supine), 0.20 +/- 0.15 (rest-sitting), 0.18 +/- 0.19 (exercise-intercept), 0.28 +/- 0.35 (exercise-slope), and 0.18 +/- 0.15, 0.15 +/- 0.09, 0.28 +/- 0.39, and 0.27 +/- 0.15, respectively, at 1 week. The magnitude of change at 1 month was not statistically different from the magnitude of change at 1 week. In conclusion, the calibration of IMV, as measured by a pacemaker sensor, versus actual VE may demonstrate variability. However, this study also suggests that the observed changes are not cumulative over time. These results have implications for patient monitoring applications using these sensors and for development of future pacemaker rate response algorithms.

The present experiments were designed to assess the renal functional response to alterations in nitric oxide formation in animals with different forms of nephropathy. To address this issue, the effects of Nomega-nitro-L-arginine methyl ester (L-NAME) or L-arginine were assessed in animal models exhibiting arterial hypertension due to chronic nitric oxide inhibition (L-NAME, 50 mg/l in drinking water for 12 weeks) or diabetes mellitus (streptozotocin, 60 mg/kg IP). Vehicle-treated, age-matched animals served as controls. Following 12 weeks of pretreatment, mean arterial pressure (MAP), renal hemodynamics, urinary albumin, and electrolyte excretion were determined in standard clearance experiments prior to and following infusion of L-NAME (50 microg/kg/min), l-arginine (5 mg/kg/min), or saline vehicle. In control animals, L-NAME resulted in an increase in MAP and renal vascular resistance and a decline in glomerular filtration rate and renal plasma flow, as expected. L-arginine had no effect on renal hemodynamics. In nitric oxide-depleted hypertensive animals, L-NAME had no additional effect on MAP or renal hemodynamics. Infusion of L-arginine reduced elevated MAP but did not reverse changes in renal hemodynamics. Diabetic rats demonstrated glomerular hyperfiltration and proteinuria. No significant changes in MAP or renal hemodynamics were observed following infusion of L-NAME or L-arginine, respectively. However, L-NAME increased urinary albumin excretion in the absence of hemodynamic changes. The effects of nitric oxide on vascular tone were shown to be dependent on the vascular bed and the underlying disease. Variations in local nitric oxide formation and susceptibility may account for the differential response of the systemic and renal vasculature and contribute to the degree of renal functional impairment observed in different systemic diseases.

Previous studies have shown a high correlation between transthoracic impedance minute ventilation (IMV) determined by a pacemaker sensor and actual minute ventilation (VE) measured by standard methods. We hypothesized that several factors (e.g., posture, breathing pattern, and exercise type) could potentially affect the calibration between IMV and VE. In patients with Medtronic Kappa 400 pacemakers, VE (L/min) was monitored using a standard cardiopulmonary metabolic gas analysis system with simultaneous recording of IMV (ohms/min) using DR-180 extended telemetry monitors. Effects of posture and of breathing pattern at rest (19 patients; age 60 +/- 13 years) were evaluated by monitoring each patient under three conditions: (a) slow breathing, supine, (b) slow breathing, sitting, and (c) shallow breathing, supine. Calibration at rest was defined as the ratio of IMV to VE. Effect of type of exercise on calibration compared treadmill versus graded bicycle ergometer exercise (18 patients; age 62 +/- 14 years). Calibration during exercise was defined as: (a) "Begin" (the IMV to VE ratio at VE = 10 L/min, the typical VE value at beginning of exercise), and (b) slope of the IMV/VE regression line. Calibration of IMV/VE was significantly smaller for sitting versus supine position (0.7130.177, P < 0.001) and for shallow versus slow breathing (0.7210.373, P < 0.001), and larger for treadmill versus bicycle exercise (Begin: 1.240.43, P = 0.018; Slope: 1.260.42, P = 0.013). In conclusion, posture, breathing pattern, and type of exercise affect the IMV estimation of the actual VE, possibly by altering the static or dynamic geometry (thus, the impedance) of the intrathoracic viscera.

Different antihypertensive treatment regimes were studied in rats during long-term inhibition of nitric oxide synthesis. Male Munich Wistar rats (weight 150-200 g) were put on oral L-nitro-arginine methyl ester (L-NAME, 50 mg/l drinking water) for 12 weeks. The control group (n = 16) received only tap water. Six weeks after starting L-NAME administration rats were divided into 7 groups (n = 13 in each group: group 1, no treatment; group 2, l-arginine 1 g/l drinking water; group 3, doxazosin 30 mg/kg/day; group 4, felodipine 25-30 mg/kg/day; group 5, losartan 40 mg/kg/day; group 6, metoprolol 300-350 mg/kg/day, and group 7, ramipril 1 mg/kg/day. Systolic blood pressure (sBP) was measured in the conscious rat 1, 6, and 12 weeks after study begin. After a treatment period of 6 weeks albuminuria, glomerular filtration rate (GFR) and renal plasma flow (RPF; inulin and p-aminohippuric acid clearance) were analyzed. All rats showed a significant increase in sBP under 6 weeks of L-NAME administration. Control rats remained normotensive during the whole study period. Rats receiving L-NAME without antihypertensive treatment showed a further increase in sBP after 12 weeks. Blood pressure was lowered in all treated animals, except in rats receiving l-arginine. Values for GFR were lowest in the placebo group, the l-arginine group and in rats receiving felodipine (p < 0.05 compared to the control group). RPF was lowest in the placebo group, the l-arginine group, the felodipine group and the ramipril group (p < 0.05 compared to the control group).(ABSTRACT TRUNCATED AT 250 WORDS)