Bettina Borisch

Magnetic resonance imaging of the breast: Recommendations from the EUSOMA working group

The use of breast magnetic resonance imaging (MRI) is rapidly increasing. EUSOMA organised a workshop in Milan on 20-21st October 2008 to evaluate the evidence currently available on clinical value and indications for breast MRI. Twenty-three experts from the disciplines involved in breast disease management - including epidemiologists, geneticists, oncologists, radiologists, radiation oncologists, and surgeons - discussed the evidence for the use of this technology in plenary and focused sessions. This paper presents the consensus reached by this working group. General recommendations, technical requirements, methodology, and interpretation were firstly considered. For the following ten indications, an overview of the evidence, a list of recommendations, and a number of research issues were defined: staging before treatment planning; screening of high-risk women; evaluation of response to neoadjuvant chemotherapy; patients with breast augmentation or reconstruction; occult primary breast cancer; breast cancer recurrence; nipple discharge; characterisation of equivocal findings at conventional imaging; inflammatory breast cancer; and male breast. The working group strongly suggests that all breast cancer specialists cooperate for an optimal clinical use of this emerging technology and for future research, focusing on patient outcome as primary end-point.

Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3.

BACKGROUND/AIMS Patients infected with the hepatitis C virus (HCV) often have liver steatosis, suggesting the possibility of a viral cytopathic effect. The aim of this study was to correlate the occurrence and severity of liver steatosis with HCV RNA type, level and sequence of the core-encoding region. METHODS We scored the liver steatosis in 101 HCV-infected individuals carefully selected to exclude other risk factors of a fatty liver. Results were compared with HCV RNA genotype and level in serum and liver. In selected patients, we assessed the effect of antiviral therapy on steatosis and the relationship between nucleocapsid sequence heterogeneity and fat infiltration. RESULTS Steatosis was found in 41 (40.6%) patients, irrespective of sex, age or route of infection. HCV genotype 3 was associated with higher steatosis scores than other genotypes. A significant correlation between steatosis score and titer of intrahepatic HCV RNA was found in patients infected with genotype 3, but not in those infected with genotype 1. In selected patients, response to alpha-interferon was associated with the disappearance of steatosis. Analysis of the nucleocapsid of 14 HCV isolates failed to identify a sequence specifically associated with the development of steatosis. CONCLUSIONS We provide virological and clinical evidence that the steatosis of the liver is the morphological expression of a viral cytopathic effect in patients infected with HCV genotype 3. At variance with published evidence from experimental models, the HCV nucleocapsid protein does not seem to fully explain the lipid accumulation in these patients.

Prognostic Scoring System for Primary CNS Lymphomas: The International Extranodal Lymphoma Study Group Experience

PURPOSE To identify survival predictors and to design a prognostic score useful for distinguishing risk groups in immunocompetent patients with primary CNS lymphomas (PCNSL). PATIENTS AND METHODS The prognostic role of patient-, lymphoma-, and treatment-related variables was analyzed in a multicenter series of 378 PCNSL patients treated at 23 cancer centers from five different countries. RESULTS Age more than 60 years, performance status (PS) more than 1, elevated lactate dehydrogenase (LDH) serum level, high CSF protein concentration, and involvement of deep regions of the brain (periventricular regions, basal ganglia, brainstem, and/or cerebellum) were significantly and independently associated with a worse survival. These five variables were used to design a prognostic score. Each variable was assigned a value of either 0, if favorable, or 1, if unfavorable. The values were then added together to arrive at a final score, which was tested in 105 assessable patients for which complete data of all five variables were available. The 2-year overall survival (OS) +/- SD was 80% +/- 8%, 48% +/- 7%, and 15% +/- 7% (P =.00001) for patients with zero to one, two to three, and four to five unfavorable features, respectively. The prognostic role of this score was confirmed by limiting analysis to assessable patients treated with high-dose methotrexate-based chemotherapy (2-year OS +/- SD: 85% +/- 8%, 57% +/- 8%, and 24% +/- 11%; P =.0004). CONCLUSION Age, PS, LDH serum level, CSF protein concentration, and involvement of deep structures of the brain were independent predictors of survival. A prognostic score including these five parameters seems advisable in distinguishing different risk groups in PCNSL patients. The proposed score and its relevance in therapeutic decision deserve to be validated in further studies.

Clinical behavior of solitary fibrous tumors of the pleura

BACKGROUND Solitary fibrous tumors of the pleura are rare and present unpredictable clinical behavior. METHODS Between 1981 and 1998, 11 solitary fibrous tumors of the pleura were resected in 10 patients at the University Hospital of Geneva. Their clinical behavior and outcome were reviewed. RESULTS Seven tumors arose from the visceral pleura, and three arose from the parietal pleura. Tumors arising from the parietal pleura were revealed to be more difficult to resect than those from the visceral pleura because of their size and adhesion to the chest wall requiring extrapleural resection. Eight tumors showed benign features, whereas two showed distinct features of malignity. One additional patient presented marked pleomorphism that could represent an intermediate form before frank malignity. Four tumors had been followed expectantly for 2 to 10 years before surgery. Although three enlarged rapidly, no signs of malignity were observed on histological examination. All patients are alive, from 2 months to 14 years after surgery (mean 55 months). In one case, however, a malignant tumor recurred 6 years after resection of a benign variant. CONCLUSIONS Although histologically benign, solitary fibrous tumors of the pleura may enlarge rapidly and occasionally transform into malignant variants after several years. Therefore, complete surgical resection and long-term follow-up is recommended for all patients.

Signaling through sphingolipid microdomains of the plasma membrane: the concept of signaling platform

Transmembrane signaling requires modular interactions between signaling proteins, phosphorylation or dephosphorylation of the interacting protein partners [1] and temporary elaboration of supramolecular structures [2], to convey the molecular information from the cell surface to the nucleus. Such signaling complexes at the plasma membrane are instrumental in translating the extracellular cues into intracellular signals for gene activation. In the most straightforward case, ligand binding promotes homodimerization of the transmembrane receptor which facilitates modular interactions between the receptors cytoplasmic domains and intracellular signaling and adaptor proteins [3]. For example, most growth factor receptors contain a cytoplasmic protein tyrosine kinase (PTK) domain and ligand-mediated receptor dimerization leads to cross phosphorylation of tyrosines in the receptors cytoplasmic domains, an event that initiates the signaling cascade [4]. In other signaling pathways where the receptors have no intrinsic kinase activity, intracellular non-receptor PTKs (i.e. Src family PTKs, JAKs) are recruited to the cytoplasmic domain of the engaged receptor. Execution of these initial phosphorylations and their translation into efficient cellular stimulation requires concomitant activation of diverse signaling pathways. Availability of stable, preassembled matrices at the plasma membrane would facilitate scaffolding of a large array of receptors, coreceptors, tyrosine kinases and other signaling and adapter proteins, as it is the case in signaling via the T cell antigen receptor [5]. The concept of the signaling platform [6] has gained usage to characterize the membrane structure where many different membrane-bound components need to be assembled in a coordinated manner to carry out signaling.The structural basis of the signaling platform lies in preferential assembly of certain classes of lipids into distinct physical and functional compartments within the plasma membrane [7,8]. These membrane microdomains or rafts (Figure 1) serve as privileged sites where receptors and proximal signaling molecules optimally interact [9]. In this review, we shall discuss first how signaling platforms are assembled and how receptors and their signaling machinery could be functionally linked in such structures. The second part of our review will deal with selected examples of raft-based signaling pathways in T lymphocytes and NK cells to illustrate the ways in which rafts may facilitate signaling.

Signal Transduction via CD44: Role of Plasma Membrane Microdomains

CD44 is the principal cell surface receptor for extracellular matrix glycosaminoglycan hyaluronan. CD44-hyaluronan mediated cell adhesion is important in several pathophysiological processes such as inflammation and metastatic spread of cancer cells. It has been recently recognized that CD44 also functions as a signaling receptor in a variety of cell types. Cell stimulation by monoclonal anti-CD44 antibody or natural CD44 ligands activate several signaling pathways that culminate in cell proliferation, cytokine secretion, chemokine gene expression and cytolytic effector functions. One of the earliest signaling events following stimulation via CD44 is tyrosine phosphorylation of intracellular proteins substrates, and CD44 mediated cellular activation could be abolished by protein tyrosine kinase (PTK) inhibitors. The Src-family non-receptor PTKs such as Lck, Fyn, Lyn and Hck were shown to be coupled to CD44 via sphingolipid-rich microdomains (lipid rafts) of the plasma membrane. Studies on T cell receptor and IgE receptor mediated signaling in lymphocytes and mast cells have consolidated the notion that microdomains consist of signaling platforms where components of multiple signaling pathways are assembled. Co-isolation of CD44 with microdomains strongly suggests that CD44 generates cellular activation signals utilizing the signaling machinery of the plasma membrane microdomains.

Management of True Aneurysms of the Splenic Artery

BACKGROUND Splenic artery aneurysms (SAA) are detected with increasing frequency but their management still remains controversial. This paper relates our experience in the outcome and management of ruptured aneurysms of the splenic artery. METHODS Between 1977 and 1996, 8 patients presented to our institution with a ruptured SAA. Their ages ranged from 25 to 72 years (mean 55 ys). RESULTS All patients presented with rupture as the first sign of SAA. One patient was at 32 weeks of gestation and rupture suggested placental abruption. Three patients required cardiopulmonary reanimation prior to surgical procedures. Splenopancreatectomy (n = 4), splenectomy (n = 2), and ligation of the splenic artery (n = 1) were performed. Seven of the 8 patients survived. Size of aneurysms ranged from 2 cm to 3.5 cm (mean 3 cm). CONCLUSIONS SAA may rupture at any age. Diagnosis during pregnancy rests upon a high index of suspicion. The mortality rate remains low if immediate resuscitation is performed and an aggressive surgical approach is taken.

Rapid changes in alcoholic hepatitis histology under steroids: correlation with soluble intercellular adhesion molecule-1 in hepatic venous blood

BACKGROUND/AIMS In alcoholic hepatitis (AH), enhanced expression of intercellular adhesion molecule-1 (ICAM-1) correlates to neutrophil infiltration and histology. In severe AH under steroids, the evolution of the hepatocyte membranous ICAM-1 expression and its soluble form (sICAM-1) is not known. METHODS Twenty-six consecutive patients with biopsy-proven severe AH had liver tissue studies for hepatocyte membranous ICAM-1 expression by immunostaining. Lobular neutrophils (mean per high power field) were counted after chloracetate esterase staining. Histological damage was assessed semiquantitatively. Circulating levels of sICAM-1 and TNFalpha in peripheral and hepatic vein were measured using immunoassays. After 8 days on steroids, 19 patients had repeat biopsy. RESULTS At baseline, hepatocyte membranous ICAM-1 correlated both to histology (r=0.55, P<0.01) and to lobular neutrophils (r=0.56, P<0.01). On steroids, sICAM-1 in hepatic vein and TNFalpha in both vascular beds decreased. Hepatocyte membranous ICAM-1 and hepatocellular damage decreased, but lobular neutrophils increased. Changes in sICAM-1 in hepatic vein correlated to histological changes (r=0.68, P<0.01). CONCLUSIONS In severe AH under steroids, the short term histological improvement was associated with a decrease in circulating TNFalpha, a decrease in ICAM-1 expression, and correlated to hepatic vein sICAM-1 changes.

The Millennium Development Goals: Experiences achievements and what’s next.

The Millennium Development Goals (MDGs) are eight international development goals to be achieved by 2015 addressing poverty, hunger, maternal and child mortality, communicable disease, education, gender inequality, environmental damage and the global partnership. Most activities worldwide have focused on maternal and child health and communicable diseases, while less attention has been paid to environmental sustainability and the development of a global partnership. Up to now, several targets have been at least partially achieved: hunger reduction is on track, poverty has been reduced by half, living conditions of 200 million deprived people enhanced, maternal and child mortality as well as communicable diseases diminished and education improved. Nevertheless, some goals will not be met, particularly in the poorest regions, due to different challenges (e.g. the lack of synergies among the goals, the economic crisis, etc.). The post-2015 agenda is now under discussion. The new targets, whatever they will be called, should reflect todays political situation, health and environmental challenges, and an all-inclusive, intersectoral and accountable approach should be adopted.The Millennium Development Goals (MDGs) are eight international development goals to be achieved by 2015 addressing poverty, hunger, maternal and child mortality, communicable disease, education, gender inequality, environmental damage and the global partnership. Most activities worldwide have focused on maternal and child health and communicable diseases, while less attention has been paid to environmental sustainability and the development of a global partnership. Up to now, several targets have been at least partially achieved: hunger reduction is on track, poverty has been reduced by half, living conditions of 200 million deprived people enhanced, maternal and child mortality as well as communicable diseases diminished and education improved. Nevertheless, some goals will not be met, particularly in the poorest regions, due to different challenges (e.g. the lack of synergies among the goals, the economic crisis, etc.). The post-2015 agenda is now under discussion. The new targets, whatever they will be called, should reflect todays political situation, health and environmental challenges, and an all-inclusive, intersectoral and accountable approach should be adopted.

Effect of population-based screening on breast cancer mortality

Although the wider scientifi c community has long embraced the benefi ts of population-based breast screening, there seems to be an active anti-screening campaign orchestrated in part by members of the Nordic Cochrane Centre. These contrary views are based on erroneous interpretation of data from cancer registries and peerreviewed articles. Their specifi c aim seems to be to support a pre-existing opposition to all forms of screening. These individuals, making claims of poor methods, selectively discount overwhelming scientifi c evidence from numerous randomised trials in diff erent countries that organised screening reduces breast cancer mortality. They claim that the signifi cant decrease in breast cancer mortality achieved by screening is due to improvements in treatment alone, discounting the benefi ts of early detection. If true, this would imply that breast cancer is an exception among adenocarcinomas in that early detection does not improve prog nosis—a claim contrary to the evidence. For women with breast cancer, early detection also results in improved quality of life from less extensive surgical treatment. Women with screen-detected breast cancer in the UK have half the mastectomy rate of women with symptomatic cancers— ie, 27% versus 53%. Organised, high-quality breast screening is an important public health initiative by numerous governments worldwide. These policies are based on robust and extensive analysis of individualised patient data from scientifi c trials, with particular attention paid to the balance of potential benefi ts and harms. To imply that such an international action is mass misrepresentation, or that screening is done for the benefi t of self-interested professionals, is as perverse as it is unjustifi ed. Comprehensive guidelines deal with the entire screening process. Organisations responsible for screening programmes regularly review published evidence on the eff ects of mammographic screening, and also contradictory interpretations. We consider the interpretation by Jorgensen, Keen, and Gotzsche, of the balance of benefi ts and harms to be scientifi cally unsound. Women would be better served by focusing eff orts on how best, and not whether, to provide breast screening. The signatories below, charged with provision and implementation of breast screening in many diff erent countries, remain convinced that the scientifi c foundation for populationbased, quality-assured, organised breast screening is one of the major accomplishments of the translation of clinical cancer research into public health practice. Early detection, in combination with appropriate treatment, signifi cantly lowers breast cancer mortality and improves the life quality of patients with the disease.