Pressure-standardised mammography does not affect visibility, contrast and sharpness of stable lesions.

INTRODUCTION: A recent technological development allows pressure-standardised mammography by personalizing the compression force to the breast size and firmness. The technique has been shown to reduce pain and compression variability between consecutive exams, but also results in a slightly thicker compressed breast during exposure. This raises the question whether visibility, contrast and sharpness of lesions are affected? METHODS: Four experienced radiologists compared 188 stable lesions and structures including (clusters of) calcifications, (oil) cysts and lymph nodes that were visible in mammograms obtained in 2009 with a pain-tolerance limited 18 daN target force compression protocol, and in 2014/2015 obtained with a 10kPa (75mmHg) pressure-standardised compression protocol. Observers were blinded for all DICOM metadata and rated which of the randomly ordered, side by side presented images had better lesion visibility, contrast and sharpness, or whether they saw no difference. They also indicated which overall image they preferred, if any, and whether the non-preferred image was still adequate. Statistical non-inferiority is concluded when the lower limit of the 95% confidence interval of the 4-rater averaged 'new protocol better' proportions exceed the non-inferiority limit of 0.463. RESULTS: In 2014/2015, the compressions were significantly milder, with on average 17% (mediolateral oblique) to 29% (craniocaudal) lower forces. Breasts remained on average 2.4% (1.4mm) thicker. Dose was significantly lower (6.5%), which is explained by glandular atrophy. The 95% confidence interval lower limits are 0.479 for visibility, 0.473 for contrast, 0.488 for sharpness and 0.486 for preference, all exceeding the non-inferiority limit. Of the 60 non-preferred mammograms, multiple observers found only five to be inadequate: 4 obtained with the force protocol and 1 with the pressure protocol. CONCLUSION: Pain-reduced mammography with 10kPa pressure-standardised compression has non-inferior visibility, contrast and sharpness for stable lesions compared to pain-tolerance limited 18daN target force compression.

Force balancing in mammographic compression.

PURPOSE: In mammography, the height of the image receptor is adjusted to the patient before compressing the breast. An inadequate height setting can result in an imbalance between the forces applied by the image receptor and the paddle, causing the clamped breast to be pushed up or down relative to the body during compression. This leads to unnecessary stretching of the skin and other tissues around the breast, which can make the imaging procedure more painful for the patient. The goal of this study was to implement a method to measure and minimize the force imbalance, and to assess its feasibility as an objective and reproducible method of setting the image receptor height. METHODS: A trial was conducted consisting of 13 craniocaudal mammographic compressions on a silicone breast phantom, each with the image receptor positioned at a different height. The image receptor height was varied over a range of 12 cm. In each compression, the force exerted by the compression paddle was increased up to 140 N in steps of 10 N. In addition to the paddle force, the authors measured the force exerted by the image receptor and the reaction force exerted on the patient body by the ground. The trial was repeated 8 times, with the phantom remounted at a slightly different orientation and position between the trials. RESULTS: For a given paddle force, the obtained results showed that there is always exactly one image receptor height that leads to a balance of the forces on the breast. For the breast phantom, deviating from this specific height increased the force imbalance by 9.4 ± 1.9 N/cm (6.7%) for 140 N paddle force, and by 7.1 ± 1.6 N/cm (17.8%) for 40 N paddle force. The results also show that in situations where the force exerted by the image receptor is not measured, the craniocaudal force imbalance can still be determined by positioning the patient on a weighing scale and observing the changes in displayed weight during the procedure. CONCLUSIONS: In mammographic breast compression, even small changes in the image receptor height can lead to a severe imbalance of the applied forces. This may make the procedure more painful than necessary and, in case the image receptor is set too low, may lead to image quality issues and increased radiation dose due to undercompression. In practice, these effects can be reduced by monitoring the force imbalance and actively adjusting the position of the image receptor throughout the compression.

Influence of segmented vessel size due to limited imaging resolution on coronary hyperemic flow prediction from arterial crown volume.

Computational predictions of the functional stenosis severity from coronary imaging data use an allometric scaling law to derive hyperemic blood flow (Q) from coronary arterial volume (V), Q = αV(ß) Reliable estimates of α and ß are essential for meaningful flow estimations. We hypothesize that the relation between Q and V depends on imaging resolution. In five canine hearts, fluorescent microspheres were injected into the left anterior descending coronary artery during maximal hyperemia. The coronary arteries of the excised heart were filled with fluorescent cast material, frozen, and processed with an imaging cryomicrotome to yield a three-dimensional representation of the coronary arterial network. The effect of limited image resolution was simulated by assessing scaling law parameters from the virtual arterial network at 11 truncation levels ranging from 50 to 1,000 µm segment radius. Mapped microsphere locations were used to derive the corresponding relative Q using a reference truncation level of 200 µm. The scaling law factor α did not change with truncation level, despite considerable intersubject variability. In contrast, the scaling law exponent ß decreased from 0.79 to 0.55 with increasing truncation radius and was significantly lower for truncation radii above 500 µm vs. 50 µm (P< 0.05). Hyperemic Q was underestimated for vessel truncation above the reference level. In conclusion, flow-crown volume relations confirmed overall power law behavior; however, this relation depends on the terminal vessel radius that can be visualized. The scaling law exponent ß should therefore be adapted to the resolution of the imaging modality.

High cumulative risk of intussusception in patients with Peutz-Jeghers syndrome: time to update surveillance guidelines?

OBJECTIVES: Peutz-Jeghers syndrome (PJS) is characterized by gastrointestinal hamartomas. The hamartomas are located predominantly in the small intestine and may cause intussusceptions. We aimed to assess the characteristics, risk, and onset of intussusception in a large cohort of PJS patients to determine whether enteroscopy with polypectomy should be incorporated into surveillance recommendations. METHODS: All PJS patients from two academic hospitals were included in this cohort study (prospective follow-up between 1995 and July 2009). We obtained clinical data by interview and chart review. Deceased family members with PJS were included retrospectively. Cumulative intussusception risks were calculated by Kaplan­Meier analysis. RESULTS: We included 110 PJS patients (46% males) from 50 families. In all, 76 patients (69%) experienced at least one intussusception (range 1-6), at a median age of 16 (3-50) years at first occurrence. The intussusception risk was 50% at the age of 20 years (95% confidence interval 17-23 years) and the risk was independent of sex, family history, and mutation status. The intussusceptions occurred in the small intestine in 95% of events, and 80% of all intussusceptions (n=128) presented as an acute abdomen. Therapy was surgical in 92.5% of events. Based on 37 histology reports, the intussusceptions were caused by polyps with a median size of 35 mm (range 15-60 mm). CONCLUSIONS: PJS patients carry a high cumulative intussusception risk at young age. Intussusceptions are generally caused by polyps >15 mm and treatment is mostly surgical. These results support the approach of enteroscopic surveillance, with removal of small-intestinal polyps >10-15 mm to prevent intussusceptions. The effect of such an approach on the incidence of intussusception remains to be established in prospective trials.

Quality of life and psychological distress in patients with Peutz-Jeghers syndrome.

Little is known about psychological distress and quality of life (QoL) in patients with Peutz-Jeghers syndrome (PJS), a rare hereditary disorder. We aimed to assess QoL and psychological distress in PJS patients compared to the general population, and to evaluate determinants of QoL and psychological distress in a cross-sectional study. PJS patients completed a questionnaire on QoL, psychological distress, and illness perceptions. The questionnaire was returned by 52 patients (85% response rate, 56% females, median age 44.5 years). PJS patients reported similar anxiety (p = 0.57) and depression (p = 0.61) scores as the general population. They reported a lower general health perception (p = 0.003), more limitations due to emotional problems (p = 0.045) and a lower mental well-being (p = 0.036). Strong beliefs in negative consequences of PJS on daily life, a relapsing course of the disease, strong emotional reactions to PJS, and female gender were major determinants for a lower QoL. PJS patients experience a similar level of psychological distress as the general population, but a poorer general health perception, more limitations due to emotional problems, and a poorer mental QoL. Illness perceptions and female gender were major predictors for this lower QoL. These results may help to recognize PJS patients who might benefit from psychological support.

High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations.

OBJECTIVES: Peutz-Jeghers syndrome (PJS) is an autosomal dominant inherited disorder associated with increased cancer risk. Surveillance and patient management are, however, hampered by a wide range in cancer risk estimates. We therefore performed a systematic review to assess cancer risks in PJS patients and used these data to develop a surveillance recommendation. METHODS: A systematic PubMed search was performed up to February 2009, and all original articles dealing with PJS patients with confirmed cancer diagnoses were included. Data involving cancer frequencies, mean ages at cancer diagnosis, relative risks (RRs), and cumulative risks were collected. RESULTS: Twenty-one original articles, 20 cohort studies, and one meta-analysis fulfilled the inclusion criteria. The cohort studies showed some overlap in the patient population and included a total of 1,644 patients; 349 of them developed 384 malignancies at an average age of 42 years. The most common malignancy was colorectal cancer, followed by breast, small bowel, gastric, and pancreatic cancers. The reported lifetime risk for any cancer varied between 37 and 93%, with RRs ranging from 9.9 to 18 in comparison with the general population. Age-related cumulative risks were given for any cancer and gastrointestinal, gynecological, colorectal, pancreatic, and lung cancers. CONCLUSIONS: PJS patients are markedly at risk for several malignancies, in particular gastrointestinal cancers and breast cancer. On the basis of these elevated risks, a surveillance recommendation is developed to detect malignancies in an early phase and to remove polyps that may be premalignant and may cause complications, so as to improve the outcome.

Adhesive surface determines raft composition in platelets adhered under flow.

Adhesion to von Willebrand factor (VWF) induces platelet spreading, whereas adhesion to collagen induces aggregation. Here we report that cholesterol-rich domains (CRDs) or rafts play a critical role in clustering of receptors that control these responses. Platelets adhered to VWF and collagen show CRDs concentrated in filopodia which contain both the VWF receptor glycoprotein (GP) Ibalpha and the collagen receptor GPVI. Biochemical analysis of CRDs shows a threefold enrichment of GPIbalpha (but not GPVI) in VWF-adhered platelets and a fourfold enrichment of GPVI (but not GPIbalpha) in collagen-adhered platelets. Depletion of cholesterol (i) leaves the initial adhesion unchanged, (ii) inhibits spreading on VWF and aggregate formation on collagen, (iii) leaves filopodia formation intact, and (iv) reduces the localization in filopodia of GPIbalpha but not of GPVI. These data show that the adhesive substrate determines the composition of CRDs, and that cholesterol is crucial for redistribution of GPIbalpha but not of GPVI.

Cytokeratin phenotyping does not help in distinguishing oesophageal adenocarcinoma from cancer of the gastric cardia.

BACKGROUND: It is sometimes difficult to distinguish between cardia cancer and oesophageal cancer. AIMS: To evaluate whether cytokeratin (CK) expression of the tumour can be of value in differentiating between the two tumour types. METHODS: Consecutive patients with a malignant tumour in the oesophagus or stomach were recruited. Biopsy specimens were taken for routine haematoxylin and eosin staining. One tissue block with representative tissue was selected for immunohistochemical staining (CK7 and CK20). RESULTS: Endoscopically located adenocarcinoma of the oesophagus was present in 84 patients (64 men, 20 women; mean age, 68 years; range, 44-91). Cancer located primarily in the gastric cardia was present in 63 patients (42 men, 21 women; mean age, 68 years; range, 42-88). The histological diagnosis was metastasis from a primary tumour outside the oesophagus or stomach in 19 patients. The patients were divided into three groups for the immunohistochemical analysis. Patients in group A had definite oesophageal cancer, group B patients had a definite carcinoma located in the gastric cardia, and group C patients had an obstructing tumour distal in the oesophagus at the level of the diaphragm, which could not be passed with the endoscope. Paraffin wax embedded material was available from 122 patients for immunostaining and CK analysis. There was no significant difference in expression or distribution of CK7 or CK20 in the three groups of patients. CONCLUSION: CK phenotyping cannot distinguish between cancer arising from a Barrett's oesophagus and carcinoma originating in the gastric cardia.

A tripeptide mimetic of von Willebrand factor residues 981-983 enhances platelet adhesion to fibrinogen by signaling through integrin alpha(IIb)beta3.

BACKGROUND: RGD is a major recognition sequence for ligands of platelet alpha(IIb)beta3. OBJECTIVE AND METHODS: To identify potential binding sites for alpha(IIb)beta3 apart from RGD, we screened phage display libraries by blocking the enrichment of RGD-containing phages with a GRGDS peptide and identified a novel integrin recognition tripeptide sequence, VPW. RESULTS: Platelets adhered to an immobilized cyclic VPW containing peptide in a alpha(IIb)beta3-dependent manner; platelets and alpha(IIb)beta3-expressing CHO cells adhered faster to immobilized alpha(IIb)beta3-ligands in the presence of soluble VPW. In platelets adhering to fibrinogen, VPW accelerated the activation of the tyrosine kinase Syk which controls cytoskeletal rearrangements. In alpha(IIb)beta3-expressing CHO cells, VPW induced a faster formation of stress fibers. Sequence alignment positioned VPW to V980-P981-W982 in the von Willebrand factor (vWf) A-3 domain. In blood from a vWf-deficient individual, VPW increased platelet adhesion to fibrinogen but not to collagen under flow and rescued the impaired adhesion to vWf deficient in A-3. CONCLUSION: These data reveal a VPW sequence that contributes to alpha(IIb)beta3 activation in in vitro experiments. Whether the V980-P981-W982 sequence in vWf shows similar properties under in vivo conditions remains to be established.

Concentration of rafts in platelet filopodia correlates with recruitment of c-Src and CD63 to these domains.

The molecular mechanism that causes non-adhesive, discoid platelets to transform into sticky dendritic bodies that form blood clumps is a complex series of events. Recently it has become clear that lipid microdomains--also known as rafts--play a crucial role in this process. We have used a non-cytolytic derivative of perfringolysin-O, a cholesterol binding cytolysin, that binds selectively to cholesterol-rich membrane domains, combined with confocal- and immunoelectron microscopy to visualize cholesterol-raft dynamics during platelet adhesion. In resting platelets cholesterol was uniformly distributed on the cell surface and confined to distinct intracellular compartments (i.e. multivesicular bodies, dense granules, and the internal membranes of alpha-granules). Upon interaction with fibrinogen, cholesterol accumulated at the tips of filopodia and at the leading edge of spreading cells. Stimulation with thrombin receptor activating peptide (TRAP) resulted in a similar redistribution of cholesterol towards filopodia. The adhesion-dependent raft aggregation was accompanied by concentration of the tyrosine kinase c-Src and the tetraspanin CD63 in these domains, whereas glycoprotein Ib (GPIb) was not selectively targeted to the raft clusters. c-Src, the tetraspanin CD63, and GPIb were recovered in biochemically isolated low-density membrane fractions. Disruption of rafts by depleting membrane cholesterol had no effect on platelet shape change but inhibited platelet spreading on fibrinogen and TRAP-induced aggregation. Our results demonstrate that cholesterol rafts in platelets are dynamic entities in the membrane that co-cluster with the tyrosine kinase c-Src and the costimulatory molecule CD63 in specialized domains at the cell surface, thereby providing a possible mechanism in functioning as signaling centres.