Search

Background It is unknown whether renal pathology lesions in immunoglobulin A nephropathy (IgAN) correlate with renal outcomes over decades of follow-up. Methods In 1130 patients of the original Validation Study of the Oxford Classification for IgA Nephropathy (VALIGA) cohort, we studied the relationship between the MEST score (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T), crescents (C) and other histological lesions with both a combined renal endpoint [50% estimated glomerular filtration rate (eGFR) loss or kidney failure] and the rate of eGFR decline over a follow-up period extending to 35 years [median 7 years (interquartile range 4.1–10.8)]. Results In this extended analysis, M1, S1 and T1–T2 lesions as well as the whole MEST score were independently related with the combined endpoint (P Conclusion Long-term follow-up analyses of the VALIGA cohort showed that the independent relationship between kidney biopsy findings and the risk of progression towards kidney failure in IgAN remains unchanged across all age groups and decades after the renal biopsy.

Contains fulltext : 232930.pdf (Publisher’s version ) (Closed access) BACKGROUND: On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown. METHODS: In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a ≥25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to

Background The VALidation of IGA (VALIGA) study investigated the utility of the Oxford Classification of immunoglobulin A nephropathy (IgAN) in 1147 patients from 13 European countries. Methods. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive (CS/IS) treatments, and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present and central absent, local absent and central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS. Results All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy, while the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity) and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. In contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes when compared with central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent lesions (milder disease) and double present (more severe). Conclusion We conclude that differences in the scoring of MEST-C criteria between local pathologists and a central reviewer have a significant impact on the prognostic value of the Oxford Classification. Since the decision to offer immunosuppressive therapy in this cohort was intimately associated with the MEST-C score, this study indicates a need for a more detailed guidance for pathologists in the scoring of IgAN biopsies.

ImportanceAlthough IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, there is no validated tool to predict disease progression. This limits patient-specific risk stratification and treatment decisions, clinical trial recruitment, and biomarker validation. ObjectiveTo derive and externally validate a prediction model for disease progression in IgAN that can be applied at the time of kidney biopsy in multiple ethnic groups worldwide. Design, Setting, and ParticipantsWe derived and externally validated a prediction model using clinical and histologic risk factors that are readily available in clinical practice. Large, multi-ethnic cohorts of adults with biopsy-proven IgAN were included from Europe, North America, China, and Japan. Main Outcomes and MeasuresCox proportional hazards models were used to analyze the risk of a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, and were evaluated using the R-D(2) measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots. ResultsThe study included 3927 patients; mean age, 35.4 (interquartile range, 28.0-45.4) years; and 2173 (55.3%) were men. The following prediction models were created in a derivation cohort of 2781 patients: a clinical model that included eGFR, blood pressure, and proteinuria at biopsy; and 2 full models that also contained the MEST histologic score, age, medication use, and either racial/ethnic characteristics (white, Japanese, or Chinese) or no racial/ethnic characteristics, to allow application in other ethnic groups. Compared with the clinical model, the full models with and without race/ethnicity had better R-D(2) (26.3% and 25.3%, respectively, vs 20.3%) and AIC (6338 and 6379, respectively, vs 6485), significant increases in C statistic from 0.78 to 0.82 and 0.81, respectively (Delta C, 0.04; 95% CI, 0.03-0.04 and Delta C, 0.03; 95% CI, 0.02-0.03, respectively), and significant improvement in reclassification as assessed by the NRI (0.18; 95% CI, 0.07-0.29 and 0.51; 95% CI, 0.39-0.62, respectively) and IDI (0.07; 95% CI, 0.06-0.08 and 0.06; 95% CI, 0.05-0.06, respectively). External validation was performed in a cohort of 1146 patients. For both full models, the C statistics (0.82; 95% CI, 0.81-0.83 with race/ethnicity; 0.81; 95% CI, 0.80-0.82 without race/ethnicity) and R-D(2) (both 35.3%) were similar or better than in the validation cohort, with excellent calibration. Conclusions and RelevanceIn this study, the 2 full prediction models were shown to be accurate and validated methods for predicting disease progression and patient risk stratification in IgAN in multi-ethnic cohorts, with additional applications to clinical trial design and biomarker research.

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to-0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P

Background: Tonsillectomy has been considered a treatment for IgA nephropathy (IgAN). It is aimed at removing a source of pathogens, reducing mucosa-associated lymphoid tissue and decreasing polymeric IgA synthesis. However, its beneficial effect is still controversial. In Asia, favorable outcomes have been claimed mostly in association with corticosteroids. In Europe, small, single-center uncontrolled studies have failed to show benefits. Methods: The European validation study of the Oxford classification of IgAN (VALIGA) collected data from 1,147 patients with IgAN over a follow-up of 4.7 years. We investigated the outcome of progression to end-stage renal disease (ESRD) and/or 50% loss of estimated glomerular filtration rate (eGFR) and the annual loss of eGFR in 61 patients who had had tonsillectomy. Results: Using the propensity score, which is a logistic regression model, we paired 41 patients with tonsillectomy and 41 without tonsillectomy with similar risk of progression (gender, age, race, mean blood pressure, proteinuria, eGFR at renal biopsy, previous treatments and Oxford MEST scores). No significant difference was found in the outcome. Moreover, we performed an additional propensity score pairing 17 patients who underwent tonsillectomy after the diagnosis of IgAN and 51 without tonsillectomy with similar risk of progression at renal biopsy and subsequent treatments. No significant difference was found in changes in proteinuria, or in the renal end point of 50% reduction in GFR and/or ESRD, or in the annual loss of eGFR. Conclusion: In the large VALIGA cohort of European subjects with IgAN, no significant correlation was found between tonsillectomy and renal function decline.

The authors describe the results of histological, cytomorphological, cytochemical and immunological studies carried out in two cases of follicular lymphoma characterized at onset by an exceptional degree of splenomegaly. Although several different histological types seem to be capable of giving rise to prominent splenic involvement, the authors, on the basis of the reported findings, suggest the possibility that some cases of follicular lymphoma presenting with conspicuous splenomegaly and which at present are classified in the group of the so-called intermediate lymphocytic lymphoma, might be an expression of proliferation of a cell type normally recognizable in the marginal zone of the splenic follicles.

Background Acute coronary syndrome (ACS) is a major cause of morbidity and mortality. Lifestyle and health behavior changes play an important role in the primary and secondary prevention of ACS recurrence. Changes in unhealthy lifestyles after an acute coronary event have been analyzed by considering separate behaviors individually, even though research on the healthy population has demonstrated that unhealthy behaviors tend to co-occur. Purpose The aim of this study was to identify lifestyle profiles of ACS patients and to explore their pathways of change for one year after their first coronary event by adopting a typological approach. Methods Two hundred and twenty-three patients (84% male; mean age = 57.14) completed self-report measures of health-related behaviors at the beginning of cardiac rehabilitation, and six months and twelve months after. At each wave depression, anxiety and heart rate were also evaluated. Cluster analysis was performed to identify lifestyle profiles and to analyze their change over time. Differences in psychological factors and heart rate among clusters were assessed. Results Patients' diet, physical activity, and smoking behavior greatly improved six months after their first coronary event. No further improvements were detected after one year. At each wave specific lifestyle profiles were identified, ranging from more maladaptive to healthier clusters. Patients with multiple unhealthy behaviors experience greater difficulties in maintaining a healthier lifestyle over time. Moreover, the results demonstrated the association between lifestyle profiles at twelve months after the acute coronary event and depression measured six months earlier. Finally, the most maladaptive lifestyle profile had many members with elevated heart rate at twelve months after the cardiac rehabilitation. Conclusions Current findings may have a strong practical impact in the development and implementation of personalized secondary prevention programs targeting lifestyles of ACS patients.

Many studies have focused on Type A and Type D personality types in the context of cardiovascular diseases (CVDs), but nothing is known about how these personality types combine to create new profiles. The present study aimed to develop a typology of Type A and Type D personality in two groups of patients affected by and at risk for coronary disease. The study involved 711 patients: 51.6% with acute coronary syndrome, 48.4% with essential hypertension (mean age = 56.4 years; SD = 9.7 years; 70.7% men). Cluster analysis was applied. External variables, such as socio-demographic, psychological, lifestyle, and clinical parameters, were assessed. Six groups, each with its own unique combined personality profile scores, were identified: Type D, Type A-Negatively Affected, Not Type A-Negatively Affected, Socially Inhibited-Positively Affected, Not Socially Inhibited, and Not Type A-Not Type D. The Type A-Negatively Affected cluster and, to a lesser extent, the Type D cluster, displayed the worst profile: namely higher total cardiovascular risk index, physical inactivity, higher anxiety and depression, and lower self-esteem, optimism, and health status. Identifying combined personality profiles is important in clinical research and practice in cardiovascular diseases. Practical implications are discussed.

Background Research has shown that the provision of pertinent health information to patients with cardiovascular disease is associated with better adherence to medical prescriptions, behavioral changes, and enhanced perception of control over the disease. Yet there is no clear knowledge on how to improve information pertinence. Identifying and meeting the information needs of patients and their preferences for sources of information is pivotal to developing patient-led services. This prospective, observational study was aimed at exploring the information needs and perceived relevance of different information sources for patients during the twenty-four months following an acute coronary syndrome. Methods Two hundred and seventeen newly diagnosed patients with acute coronary syndrome were enrolled in the study. The patients were primarily men (83.41 %) with a mean age of 57.28 years (range 35–75; SD = 7.98). Patients’ needs for information and the perceived relevance of information sources were evaluated between 2 and 8 weeks after hospitalization (baseline) and during three follow-ups at 6, 12 and 24 months after baseline. Repeated measures ANOVA, Bonferroni post hoc tests and Cochran’s Q Test were performed to test differences in variables of interest over time. Results Results showed a reduction in information needs, but this decrease was significant only for topics related to daily activities, behavioral habits, risk and complication. At baseline, the primary sources of information were specialists and general practitioners, followed by family members and information leaflets given by physicians. Relevance of other sources changed differently over time. Conclusion The present longitudinal study is an original contribution to the investigation of changes in information needs and preferences for sources of information among patients who are diagnosed with acute coronary syndrome. One of the main results of this study is that information on self-disease management is perceived as a minor theme for patients even two years after the event. Knowledge on how patients’ information needs and perceived relevance of information sources change over time could enhance the quality of chronic disease management, leading health-care systems to move toward more patient-tailored care. Electronic supplementary material The online version of this article (doi:10.1186/s12875-016-0534-8) contains supplementary material, which is available to authorized users.

Chronic kidney disease (CKD) represents a major public health issue worldwide and entails a high burden of cardiovascular events and mortality. Dyslipidaemia is common in patients with CKD and it is characterized by a highly atherogenic profile with relatively low levels of HDL-cholesterol and high levels of triglyceride and oxidized LDL-cholesterol. Overall, current literature indicates that lowering LDL-cholesterol is beneficial for preventing major atherosclerotic events in patients with CKD and in kidney transplant recipients while the evidence is less clear in patients on dialysis. Lipid lowering treatment is recommended in all patients with stage 3 CKD or worse, independently of baseline LDL-cholesterol levels. Statin and ezetimibe are the cornerstones in the management of dyslipidaemia in patients with CKD, however alternative and emerging lipid-lowering therapies may acquire a central role in near future. This position paper endorsed by the Italian Society of Nephrology aims at providing useful information on the topic of dyslipidaemia in CKD and at assisting decision making in the management of these patients.

Anemia is a well-known consequence of chronic kidney disease (CKD); it is mainly due to a relative insufficiency of erythropoietin synthesis by the failing kidneys. Over the years, the combination of erythropoiesis stimulating agents (ESA) and iron has become the standard of care of anemia. All ESAs effectively increase hemoglobin (Hb) levels in a substantial percentage of patients. However, in the last decade, their use has been surrounded by safety issues in increased cardiovascular risk, especially when used at high doses in inflamed and hyporesponsive patients. This has led to the definition of a more cautious Hb target. Iron deficiency is very frequent in CKD patients, with a higher frequency in non-dialysis patients. Traditionally, iron supplementation is mostly used as supportive therapy for anemia control. However, the concept is growing that intravenous iron therapy per se could be beneficial in the presence of heart failure. A new class of drugs, prolyl hydroxylase domain (PHD) inhibitors (PHD inhibitors) is becoming available for the treatment of anemia in CKD patients. Theoretically, these agents have a number of advantages, the main ones being that of stimulating the synthesis of endogenous erythropoietin and increasing iron availability. The impact of their future use in clinical practice is still to be defined. Another possible strategy could be targeting serum hepcidin and its related pathways. This possibility is fascinating from the scientific point of view, but at present its development phase is still far from clinical application.

Erythropoiesis-stimulating agents (ESAs) have improved the quality of life and reduced the need for transfusions in patients with chronic kidney disease. However, randomized trials showed no benefit but possible safety issues following high doses of ESAs given to reach normal hemoglobin levels. Iron therapy is used together with ESA; when given proactively, it may reduce the risk of mortality and cardiovascular events in hemodialysis patients. Recent trials also showed benefits of intravenous iron therapy in patients with heart failure. New drugs for correcting anemia may retain the present efficacy of ESAs as antianemic drugs and reduce cardiovascular risks.

In recent years, inhibitors of the sodium-glucose co-transporter 2 (SGLT2 inhibitors) have been shown to have significant protective effects on the kidney and the cardiovascular system in patients with diabetes. This effect is also manifested in chronic kidney disease (CKD) patients and is minimally due to improved glycaemic control. Starting from these positive findings, SGLT2 inhibitors have also been tested in patients with non-diabetic CKD or heart failure with reduced ejection fraction. Recently, the DAPA-CKD trial showed a significantly lower risk of CKD progression or death from renal or cardiovascular causes in a mixed population of patients with diabetic and non-diabetic CKD receiving dapagliflozin in comparison with placebo. In patients with heart failure and reduced ejection fraction, two trials (EMPEROR-Reduced and DAPA-HF) also found a significantly lower risk of reaching the secondary renal endpoint in those treated with an SGLT2 inhibitor in comparison with placebo. This also applied to patients with CKD. Apart from their direct mechanism of action, SGLT2 inhibitors have additional effects that could be of particular interest for patients with non-diabetic CKD. Among these, SGLT2 inhibitors reduce blood pressure and serum acid uric levels and can increase hemoglobin levels. Some safety issues should be further explored in the CKD population. SGLT2 inhibitors can minimally increase potassium levels, but this has not been shown by the CREDENCE trial. They also increase magnesium and phosphate reabsorption. These effects could become more significant in patients with advanced CKD and will need monitoring when these agents are used more extensively in the CKD population. Conversely, they do not seem to increase the risk of acute kidney injury.

Background and Aims Idiopathic Focal Segmental Glomerulosclerosis (FSGS) is a rare glomerulonephritis often complicated by a chronic relapsing course frequently characterized by dependency or resistance to immunosuppressive treatment. Moreover, about half of the patients with active disease would develop end-stage renal disease within 10 years from the diagnosis, highlighting the need of novel therapeutic approaches. Rituximab (RTX), a chimeric monoclonal antibody against CD20, showed promising results in pediatric steroid-dependent/frequently relapsing FSGS and in post-transplantation recurrence. However, evidence about its role in the FSGS of the adult is still lacking with small case series suggesting conflicting results. In this study we assess the efficacy of RTX in the largest cohort of adults with FSGS currently available in literature. Methods Adults with biopsy proven idiopathic FSGS treated with RTX were retrospectively identified among several Italian nephrology units. Response to RTX was evaluated at 3, 6, 12 months and, when available, during the long-term follow-up. A positive response (POR) was defined as: (1) proteinuria 50% compared to baseline, (2) stable renal function (3) decreased or stable dose of glucocorticoids and other immunosuppressants. Severe Adverse Events (SAEs) have been recorded. Results 31 patients have been identified: 18 steroid-dependent, 11 steroid-resistant, and 2 patients with major contraindication to steroid therapy. RTX has been administered at a median of 87 months (IQR 54–96) from the diagnoses using heterogeneous schedules of administration. Overall, the POR rate at 6 months was 52% (steroid-dependent=69%; steroid-resistant=22%). At univariate analyses, POR to RTX at 6 months was associated to the steroid-dependent status (p=0.0347) and a proteinuria at RTX Conclusion RTX may be an option in the FSGS of the adult, especially in the steroid-dependent patients and the ones with less severe nephrotic syndrome. In the responders, a RTX based maintenance therapy may be required.

Background: Incomplete re-endothelialization of drug eluting stent (DES) segments has been associated with the occurrence of major adverse cardiac events after DES implantation. It is unknown whether on-clopidogrel platelet reactivity (OPR) and/or circulating endothelial progenitor cells (EPC) levels may predict uncovered strut rate in diabetic patients treated by DES implantation. Methods: One-hundred and five diabetic patients undergoing elective DES implantation were included into the study. EPC levels and OPR were assessed at 24 h (baseline) and 3 months. EPC were evaluated by flow cytometric analysis and defined by the co-expression of the markers CD34 and KDR. OPR was assessed using the impedance aggregometer. The degree of DES re-endothelialization was assessed at 3 months by optical coherence tomography. Results: A direct correlation was observed between the uncovered strut rate and OPR both at baseline (r = 0.47: p < 0.001) and at the 3 months (r = 0.25: p = 0.015). On the contrary, we found no significant correlation between EPC level and uncovered strut rate either at baseline (r = -0.02; p = 0.85) or at 3 months (r = -0.06; p = 0.13). By multivariable regression analysis, independent predictors of uncovered strut rate > 5% were complex lesions (OR = 5.35; 95% confidence interval 1.32-17.57; p = 0.027) and OPR at baseline (OR = 4.73; 95% confidence interval 1.04-8.14; p = 0.039). Conclusions: In diabetic patients treated with DES implantation OPR at baseline and complex lesions are independent predictors of uncovered strut rate at 3 months.

No information is available on the efficacy of ferric carboxymaltose (FCM) in real-world CKD patients outside the hemodialysis setting. We prospectively followed 59 non-hemodialysis CKD patients with iron deficient anemia (IDA: hemoglobin &lt, 12.0/&lt, 13.5 g/dL in women/men and TSAT &lt, 20% and/or ferritin &lt, 100 ng/mL) who were intolerant or non-responders to oral iron. Patients received ferric carboxymaltose (FCM) (single dose of 500 mg) followed by additional doses if iron deficiency persisted. We evaluated efficacy of FCM in terms of increase of hemoglobin, ferritin, and TSAT levels. Direct and indirect costs of FCM were also analyzed in comparison with a hypothetical scenario where same amount of iron as ferric gluconate (FG) was administered intravenously. During the 24 weeks of study, 847 ± 428 mg of FCM per patient were administered. IDA improved after four weeks of FCM and remained stable thereafter. At week-24, mean change (95%CI) from baseline of hemoglobin, ferritin and TSAT were +1.16 g/dL (0.55–1.77), +104 ng/mL (40–168) and +9.5% (5.8–13.2), respectively. These changes were independent from ESA use and clinical setting (non-dialysis CKD, peritoneal dialysis and kidney transplant). Among ESA-treated patients (n = 24), ESA doses significantly decreased by 26% with treatment and stopped either temporarily or persistently in nine patients. FCM, compared to a FG-based scenario, was associated with a cost saving of 288 euros/patient/24 weeks. Saving was the same in ESA users/non-users. Therefore, in non-hemodialysis CKD patients, FCM effectively corrects IDA and allows remarkable cost savings in terms of societal, healthcare and patient perspective.

NTRODUCTION: Circulating tumor cells are thought to play a crucial role in the development of distant metastases. Their detection in the blood of colorectal cancer patients may be linked to poor outcome, but current evidence is controversial. MATERIALS AND METHODS: Pre- and postoperative flow cytometric analysis of blood samples was carried out in 76 colorectal cancer patients undergoing surgical resection. The EpCAM/CD326 epithelial surface antigen was used to identify circulating tumor cells. RESULTS: Fifty-four (71%) patients showed circulating tumor cells preoperatively, and all metastatic patients showed high levels of circulating tumor cells. Surgical resection resulted in a significant decrease in the levels of circulating tumor cells. Among 69 patients undergoing radical surgery, 16 had high postoperative levels of circulating tumor cells, and 12 (75%) experienced tumor recurrence. High postoperative level of circulating tumor cells was the only independent variable related to cancer relapse. In patients without circulating tumor cells, the progression-free survival rate increased from 16 to 86%, with a reduction in the risk of tumor relapse greater than 90%. CONCLUSIONS: High postoperative levels of circulating tumor cells accurately predicted tumor recurrence, suggesting that assessment of circulating tumor cells could optimize tailored management of colorectal cancer patients.

Maternal obesity increases the risk of obesity and/or obesity-related diseases in the offspring of animal models. The aim of this study was to identify metabolic dysfunctions that could represent an enhanced risk for human obesity or obesity-related diseases in newborn or in adult life, similar to what occurs in animal models. To this aim, we studied the proteome of 12 obese (Ob-) and 6 non-obese (Co-) human amniotic mesenchymal stem cells (hA-MSCs) obtained from women at delivery by cesarean section (pre-pregnancy body mass index [mean ± SD]: 42.7 ± 7.7 and 21.3 ± 3.3 kg/m2, respectively). The proteome, investigated by two-dimensional fluorescence difference gel electrophoresis/mass spectrometry, revealed 62 differently expressed proteins in Ob- vs Co-hA-MSCs (P

Background The optimal dosing and the efficacy of rituximab for primary membranous nephropathy (PMN) has not been established. This multicentric prospective study evaluates the efficacy and safety of low-dose rituximab (RTX) therapy in patients with PMN in clinical practice. Methods Thirty-four consecutive patients with PMN and nephrotic syndrome were included and received RTX (375 mg/m 2) once (18 patients) or twice (16 patients). RTX was the first-line therapy for 19 (56%) and the second line for 15 (44%) patients. All patients were followed for 12 months after RTX and 24 for at least 18 months (mean 23.9 ± 18.6 months). Results At 12 months, 5 patients (14.7%) achieved complete response, 10 (29.4%) partial and 19 (55.8%) no response. Response occurred '1/46 months after RTX. At 24 months, the clinical situation was unchanged: two non-responders achieved partial response and two responders relapsed. Responders had significantly higher baseline GFR and lower anti-PLA2R antibodies compared with non-responders. Outcome was similar between one or two doses of RTX (non-responders 55.5 versus 56%, respectively) and between patients who had received previous therapy versus those receiving RTX as first-line therapy (non-responders 40 versus 68%, respectively). In the 15 patients already treated, the response to RTX was comparable to that of previous therapies. Conclusion Low-dose RTX obtains remission in

Presbyphagia represents the physiological aging evolution of the swallowing function. It is related to the natural changes of the anatomical structures involved in the swallowing process. These age-related modifications can be asymptomatic in the early stages of life, but in the late stages, they could lead to dysphagia, aspiration pneumonia, dehydration, or malnutrition, reducing the quality of life. Videofluoromanometry (VFM) is the combined study of videofluoroscopy (VFS) and oropharyngeal manometry that allows simultaneous identification of functional and morphological features of the presbyphagia, also in asymptomatic otherwise healthy elderly adults. This study retrospectively evaluated the effectiveness of the VFM and the role of a multidisciplinary team of specialists in the analysis of a large cohort of old patients with presbyphagia, with the objective of achieving early diagnosis of the disease and the best therapy to delay the development of complications such as aspiration pneumonia, malnutrition, and dehydration. Presbyphagia represents the physiological aging evolution of the swallowing function. It is related to the natural changes of the anatomical structures involved in the swallowing process. These age-related modifications can be asymptomatic in the early stages of life, but in the late stages, they could lead to dysphagia, aspiration pneumonia, dehydration, or malnutrition, reducing the quality of life. Video-fluoromanometry (VFM) is the combined study of videofluoroscopy (VFS) and oropharyngeal manometry that allows simultaneous identification of functional and morphological features of the presbyphagia, also in asymptomatic otherwise healthy elderly adults. This study retrospectively evaluated the effectiveness of the VFM and the role of a multidisciplinary team of specialists in the analysis of a large cohort of old patients with presbyphagia, with the objective of achieving early diagnosis of the disease and the best therapy to delay the development of complications such as aspiration pneumonia, malnutrition, and dehydration. (C) 2016 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.

In recent decades, medical malpractice litigation experienced a large-scale expansion in the United States as well as in Europe, involving both medical and surgical specialties. Previous studies have investigated the reasons why patients decide to sue doctors for malpractice and highlighted that adverse outcome, negative communication with doctors and seeking compensation are among the major reasons for malpractice litigation. In this chapter, patient engagement is discussed as a possible method for reducing the risks of doctors being sued for medical malpractice. The results of a first qualitative study underline how an active role for patients and their engagement in the treatment definition and execution could be a way to limit the occurrence of malpractice litigations. However, a second study noted that in Italy, many patients are still struggling to become involved in the process of their care. The authors discuss the role of professional education in promoting patient engagement in Italy.

We prove that the SH2-containing tyrosine phosphatase 1 (SHP-1) plays a prominent role as resistance determinant of imatinib (IMA) treatment response in chronic myelogenous leukemia cell lines (sensitive/KCL22-S and resistant/KCL22-R). Indeed, SHP-1 expression is significantly lower in resistant than in sensitive cell line, in which coimmunoprecipitation analysis shows the interaction between SHP-1 and a second tyrosine phosphatase SHP-2, a positive regulator of RAS/MAPK pathway. In KCL22-R SHP-1 ectopic expression restores both SHP-1/SHP-2 interaction and IMA responsiveness; it also decreases SHP-2 activity after IMA treatment. Consistently, SHP-2 knocking-down in KCL22-R reduces either STAT3 activation or cell viability after IMA exposure. Therefore, our data suggest that SHP-1 plays an important role in BCR-ABL–independent IMA resistance modulating the activation signals that SHP-2 receives from both BCR/ABL and membrane receptor tyrosine kinases. The role of SHP-1 as a determinant of IMA sensitivity has been further confirmed in 60 consecutive untreated patients with chronic myelogenous leukemia, whose SHP-1 mRNA levels were significantly lower in case of IMA treatment failure (P < .0001). In conclusion, we suggest that SHP-1 could be a new biologic indicator at baseline of IMA sensitivity in patients with chronic myelogenous leukemia.

This study was undertaken to verify the effectiveness of compensatory postures, suggested on the basis of the type of dysphagia identified at videofluoromanometric (VFM) investigation to ensure safe oropharyngeal transit.Eighty-one patients with amyotrophic lateral sclerosis (ALS) underwent speech therapy assessment and VFM investigation of the swallowing process. In the event of altered transit, penetration or aspiration of contrast material into the airways, compensation postures for correction of the swallowing disorder were suggested and verified during VFM examination.In 37 patients, contrast agent transport was preserved and safe; in 19, we observed penetration of the contrast agent into the laryngeal inlet without aspiration; in 24, there was aspiration (four preswallowing, eight intraswallowing, nine postswallowing, three mixed), whereas in one patient no transit was seen. Penetration without aspiration was resolved by coughing or throat clearing; aspiration was resolved in 13 patients by assuming the chin-tuck posture and in six by rotating the head; in five patients, it was not resolved. A hyperextended head posture proved to be effective to resolve lack of transit.By correlating morphological with functional data, VFM enables one not only to precisely characterise the dysphagic disorder but also to identify the most appropriate compensation posture for each patient and verify its effectiveness.

The authors sought to determine the role of video ultrasonography (VUS) in the diagnostic assessment of dysphagia in patients with amyotrophic lateral sclerosis (ALS). Nine patients underwent simultaneous static and dynamic VUS examination and videofluoroscopy (VFS) of swallowing. At the static phase, VUS showed 5/9 patients had lingual atrophy. Abnormal bolus position was observed in 6/9 patients at VUS and 3/9 at VFS. Both techniques identified an inability to keep the bolus in the oral cavity in 4/9 patients. At the dynamic phase, reduced lingual movement was observed in 5/9 patients at VUS and 2/9 at VFS. Disorganised tongue movement was seen in 3/9 patients at VUS and in 2/9 at VFS. Fragmented swallowing was only visualised at VUS. Stagnation of ingested material was never visualised at VUS, whereas it was clearly depicted in 2/9 patients at VFS. VUS can be integrated into the diagnostic protocol for evaluating swallowing in patients with ALS, as it has higher sensitivity than VFS in assessing the dynamic factors that represent the early signs of dysphagia.

Each year, nearly one million people develop colorectal cancer, and 50 % of them are expected to die because of cancer within 5 years of diagnosis. Over the last two decades, significant advances in screening, surgery, adjuvant chemotherapy, and patient monitoring have improved the 5-year survival rate. Colorectal cancer is a molecularly heterogeneous disease, and the analysis of its molecular signatures and the identification of colorectal cancer biomarkers will lead to better screening approaches and personalized therapeutic plans. A biomarker is a substance that can be measured and used as an indicator of a biological and/or pathological state. In cancer pathology, biomarkers can be used to detect the disease, to predict prognosis or response to therapy, and to evaluate the efficacy of therapy thereby improving the patient’s life expectancy and quality of life. The carcinoembryonic antigen (CEA) is the biomarker most frequently used in colorectal cancer. It is effective in the surveillance of colorectal cancer patients and in monitoring the efficacy of therapy, whereas it is less useful in colorectal screening. Recent studies indicate that also CEA-related proteins (CEACAMs) are promising potential colorectal cancer biomarkers. CEA and CEACAM proteins play important roles in cancer pathology, and the analysis of their functions will be useful for the identification of diagnostic and/or prognostic factors and therapeutic targets in colorectal and other cancers. List of Abbreviations CEA Carcinoembyonic Antigen CEACAM Carcinoembryonic Antigen-Family Cell Adhesion Molecule FOBT Fecal Occult Blood Test GPI Glycosylphosphatidylinositol Ig Immunoglobulin IgCAM Ig-like Cell Adhesion Molecule PCR Polymerase Chain Reaction TNM Tumor Nodes Metastases Key Facts of Colorectal Cancer • The intestine is the main site of nutrient absorption; it is subdivided in small and large intestine. The latter comprises the right colon, transverse colon, left colon, sigma, and rectum. • Colorectal cancer develops from uncontrolled growth of colorectal mucosa cells. • Colorectal cancer is an epithelial cancer arising in almost 80 % of cases from nonmalignant lesions that turned into cancer within 5–10 years of their appearance. 686 M. Gemei et al.

Background: Cardiovascular diseases (CVDs) are a major cause of worldwide morbidity and mortality. Nutrition plays an important role in the primary, secondary, and tertiary prevention of CVDs. The present longitudinal study used the Health Action Process Approach (HAPA) to investigate changes in dietary behavior in coronary patients (CPs) affected by acute coronary syndrome and hypertensive patients (HPs) affected by essential arterial hypertension. Methods: CPs (N = 250) and HPs (N = 246) completed a questionnaire during three measurement points (baseline, 6‐month follow‐up, and 12‐month follow‐up). Statistical analyses included a repeated measures ANOVA and a multi‐sample structural equation model. Results: HPs showed no changes in dietary behavior, whereas CPs improved their nutrition at 6 months and then maintained the healthier diet. The multi‐sample analysis indicated equivalence of the HAPA model for both patient populations. Conclusions: These findings provide further evidence for the generalisability of the HAPA model, shedding light on dietary behavior among CVD patients and particularly on hypertensive patients which has received little attention. Moreover, the equivalence of the model suggests that the process of change is almost identical for individuals who are at high risk for a coronary event (i.e. HPs) and individuals who have already had the event (i.e. CPs).

Background and aims The prognostic role of LDL in non-dialysis chronic kidney disease (CKD) is still undefined. We addressed this question in a multicenter prospective study including patients referred to nephrologist for management. Methods and results 1306 patients with CKD stage III–V were studied at basal visit in 79 Italian nephrology clinics in 2004–2006, and then followed for survival analyses. Study endpoints were incident cardiovascular -CV events (fatal and major non-fatal) and renal events (start of renal replacement therapy or eGFR halving). Mean age was 67.6 ± 11.8 years, male 65%, diabetes 25%, CV disease 27%, and eGFR 35.8 ± 12.5 mL/min/1.73 m 2 . LDL was 119 ± 40 mg/dL, with high levels in 50.1% and 82.8% defined on the basis of the individual CV risk profile estimated according to ATPIII 2001 and ESC 2012 guidelines (LDL 100 to 160, and >70 or >100 mg/dL, respectively). Over a median follow up of 2.87 years, 178 CV and 181 renal events occurred. At multivariable Cox analyses, CV risk linearly increased with higher LDL (hazard ratio-HR per 40 mg/dL higher LDL: 1.20, 95% confidence intervals-CI 1.03–1.39); risk doubled when considering high LDL defined according to ESC 2012 (HR 2.37, 95%CI 1.39–4.03) while this association was not significant when considering the higher threshold levels of ATPIII 2001 (HR 1.10, 95%CI 0.82–1.49). No association emerged between LDL and renal risk. Conclusion In non-dialysis CKD patients, CV risk increases linearly with higher LDL and is more than doubled when considering the lower threshold values currently indicated for defining optimal LDL level.

Colorectal cancer (CRC) is one of the most common types of cancer; it is diagnosed in more than one million people each year and causes the death of about half of them. Early detection can help to decrease CRC-related mortality. In fact, the 5-year survival rate exceeds 90 % when the disease is localized and is only 10 % in case of metastases. Consequently, it is imperative to improve methods for the early detection of the disease. In this context, genomic approaches have resulted in new CRC biomarkers and have helped to shed light on the genetic basis of cancer as a whole. However, the proteome provides a more dynamic and faithful image of the genetic program of a cell. Hence, given the importance of proteins as effectors of cellular behavior, proteomic analysis has the potential to identify biomarkers that can help to classify and predict CRC. Several proteomic technique, such as matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), quantitative isotopic protein labeling (SILAC, ICAT, and iTRAQ), and two-dimensional gel electrophoresis (2D-PAGE and 2D-DIGE), are being used in cancer research and can improve the diagnosis of patients; they are also helping to optimize personalized therapy. In this chapter, the main proteomic approaches used in biomarker research will be discussed, together with their impact and potential in the clinical setting. The proteomic biomarkers currently used for CRC diagnosis and/or therapy monitoring will be also described. List of Abbreviations 2D-DIGE Two-Dimensional Differential In-gel Electrophoresis 2D-PAGE Two-Dimensional Polyacrylamide Gel Electrophoresis APC Adenomatous Polyposis Coli CEA Carcinoembryonic Antigen CRC Colorectal Cancer Cy2 Cyanine 2 Fluorescent Dye Cy3 Cyanine 3 Fluorescent Dye Cy5 Cyanine 5 Fluorescent Dye DCBE Double-Contrast Barium Enema ESI Electrospray Ionization FIT Fecal Immunological Test FOBT Fecal Occult Blood Test *Email: salvator@unina.it Biomarkers in Cancer DOI 10.1007/978-94-007-7744-6_16-1 # Springer Science+Business Media Dordrecht 2014

Summary Precise control of the thyroid hormone (T3)-dependent transcriptional program is required by multiple cell systems, including muscle stem cells. Deciphering how this is achieved and how the T3 signal is controlled in stem cell niches is essentially unknown. We report that in response to proliferative stimuli such as acute skeletal muscle injury, type 3 deiodinase (D3), the thyroid hormone-inactivating enzyme, is induced in satellite cells where it reduces intracellular thyroid signaling. Satellite cell-specific genetic ablation of dio3 severely impairs skeletal muscle regeneration. This impairment is due to massive satellite cell apoptosis caused by exposure of activated satellite cells to the circulating TH. The execution of this proapoptotic program requires an intact FoxO3/MyoD axis, both genes positively regulated by intracellular TH. Thus, D3 is dynamically exploited in vivo to chronically attenuate TH signaling under basal conditions while also being available to acutely increase gene programs required for satellite cell lineage progression., Graphical Abstract, Highlights • D3 is induced in proliferating satellite cells thereby reducing thyroid signaling • D3 depletion causes massive cell apoptosis in vitro and in vivo • Apoptosis requires FoxO3, a TH target gene • Satellite cells customize TH signature and adapt it to their functional needs, Deiodinases inactivate thyroid hormone (TH) signaling, allowing a precise control of TH action at the cellular level. Dentice et al. find that type 3 deiodinase acts as a survival factor during skeletal muscle repair, and attenuation of TH signaling is required to prevent muscle stem cell apoptosis and promote lineage progression in vivo.

Background: Dysphagia consists in alteration of the swallowing mechanism, due to different pathological conditions, which can occur at different levels. The exact prevalence of dysphagia is unclear, even if some AA suggest that 15% of the elderly population is affected. Aim of this study is to analyze the main VFMSS findings in elderly dysphagic patients. Materials and methods: The VFMSS of 59 elderly dysphagic patients (32 women, 27 men, ranging in age from 68 to 89 years, mean 81 years) who undergone speech therapy assessment and videofluoromanometric (VFM) investigation of the swallowing process at our institution from January 2011 and December 2012, were retrospectively reviewed. Results: In the oral phase the preparation and the initial stage of swallowing should be explored by videofluoroscopy evaluating the ability to contain food in mouth and to form a bolus and whether there is an inadequate convergence of Passavant’s ridge with preswallowing aspiration. In the pharyngeal phase is necessary to evaluate at videofluoroscopy if there is penetration and/or aspiration and the efficacy of laryngeal closure should be assessed too. The major manometric indicators are: proximal pharyngeal pressure (mmHg), distal pharyngeal pressure (mmHg), relaxation and coordination of upper esophageal sphincter (UES). In the esophageal phase is important to evaluate the esophageal motility and the presence of peristalsis. The manometric parameters used for LES were resting pressure, total length and percentage of post-deglutitive relaxation. Conclusion: The VFSS represents a fundamental examination in the management of the dysphagic patient; this investigation may be associated with manometry providing anatomical and functional informations.

Hypothesis Because of some inconsistencies in the traditional model of human colorectal carcinogenesis, the cancer stem cell (CSC) model was recently proposed, in which tumor results from neoplastic transformation of stem cells, which become CSCs. Identification of CSCs by expression of surface antigens remains a critical issue because no biomarker has been shown to be completely reliable. CD133 and CD44 are commonly used as CSC markers, and correlation of their expression with colorectal cancer (CRC) clinicopathological features and outcomes may be useful. Design Pilot study. Setting University hospital. Patients Thirty-six consecutive patients with CRC.CD133 and CD44 expression (alone or combined) was determined in nontumor cells and in tumor cells by flow cytometry, which identified viable cells only. Main Outcome Measures Correlation of CD133 and CD44 expression with each other, with other prognostic indicators, and with disease-free survival. Results CD133 and CD44 expression was significantly higher in tumor cells than in nontumor cells, and expression of one did not necessarily correlate with expression of the other. CD133 or CD44 expression alone was variable, while combined CD133/CD44 expression identified a small subset of cells positive for CRC. CD133 or CD44 overexpression was not associated with CRC recurrence; only high frequencies of CD133 + /CD44 + cells were a strong indicator of worse disease-free survival and an independent risk factor for CRC recurrence. Conclusion Evaluation of combined CD133/CD44 expression could be useful to identify putative colorectal CSCs and tumors with a poor prognosis.

To investigate the effectiveness of head compensatory postures to ensure safe oropharyngeal transit.A total of 321 dysphagia patients were enrolled and assessed with videofluoromanometry (VFM). The dysphagia patients were classified as follows: safe transit; penetration without aspiration; aspiration before, during or after swallowing; multiple aspirations and no transit. The patients with aspiration or no transit were tested with VFM to determine whether compensatory postures could correct their swallowing disorder.VFM revealed penetration without aspiration in 71 patients (22.1%); aspiration before swallowing in 17 patients (5.3%); aspiration during swallowing in 32 patients (10%); aspiration after swallowing in 21 patients (6.5%); multiple aspirations in six patients (1.9%); no transit in five patients (1.6%); and safe transit in 169 patients (52.6%). Compensatory postures guaranteed a safe transit in 66/75 (88%) patients with aspiration or no transit. A chin-down posture achieved a safe swallow in 42/75 (56%) patients, a head-turned posture in 19/75 (25.3%) and a hyperextended head posture in 5/75 (6.7%). The compensatory postures were not effective in 9/75 (12%) cases.VFM allows the speech-language the-rapist to choose the most effective compensatory posture without a trial-and-error process and check the effectiveness of the posture.

International audience; Transformation to acute myeloid leukemia (AML) is a known complication of myeloproliferative neoplasia (MPN). Recent studies reported the high incidence (53%) of JAK2 negative blasts from transformed JAK2V617F-MPN. We collected, by cell sorting, blast cells and mature cells (GRA) from total bone marrow (BM) of 34 patients newly diagnosed of secondary AML. At MPN diagnosis (PMF n = 18; PV n = 9; ET n = 7), JAK2 was mutated in 22 of 34 patients. Twenty of 22 JAK2V617F-MPN (91%) maintained the mutation in blasts and GRA after leukemic switch, while in 2 of 22 patients the selected compartments lost the mutation. Surprisingly we also found the first case of JAK2V617F-AML from a wild type (WT)-MPN. In contrast to the previous study, we conclude that JAK2V617F-MPN yields rarely (9%) a JAK2WT-AML and any JAK2-status modification/persistence involves always the entire BM during leukemic transformation.

It is well known that MSCs are characterized by a marked heterogeneity, being composed by bonafide stem cells; transit multipotent amplifying cells; osteo- chondro-, and adipoprogenitors; fat, cartilage, and bone precursors. We characterized by flow cytometry, a series of 10 MSC preparations obtained from five human full term placenta specimens and five bone marrow aspirates. hpMSCs were obtained from amniotic membrane and the nature of these cells was demonstrated on the basis of stringent criteria such as high proliferation potential, surface phenotype (CD324/E-Cadherin−, VLA4/CD49d+) adherence to plastic and cell morphology, differentiation potential towards osteogenic, adipogenic an chondrogenic lineage, and fetal origin, determined by sensitive molecular leukocyte antigen typing. We demonstrated that CD56 was consistently expressed on a cell subset of hpMSCs (ranging from 5 to 50% positive cells), whereas it was completely absent on hbmMSCs (p < 0.01, Mann–Whitney U-test). We demonstrated the striking differences as regard the expression of CD10, CD49d, and CD56. To our knowledge, our findings regarding the differential expression of CD10 and CD56 on hpMSC and hbmMSC are absolutely new.

Dysphagia is a symptom of different pathological conditions characterised by alteration of the swallowing mechanism, which may manifest at different levels. We report our experience in the evaluation of the swallowing mechanism with combined videofluoroscopy and manometric recordings.For the combined study, we used a Dyno Compact computerised system (Menfis Biomedical s.r.l., Bologna, Italy) equipped with: (1) graphics card for the management of ultrasonographic or radiological images; (2) A.VI.U.S. dedicated software package, which enables digital-quality recording (PAL/NTSC, composite video or S-Video) of the videofluoroscopy study in AVI format with 320 x 240 resolution and 25 Hz acquisition frequency. The delay introduced by the process of image digitalisation is in the order of 200 ms, so for analysis purposes, the images can be considered synchronised with the manometric recordings. The videomanometry study was performed with the administration of contrast material either in bolus form or diluted. Data were collected on a specifically designed grid for the evaluation of 46 videofluoroscopic items, of which 34 are derived from the laterolateral view (seven in the oral preparatory phase, 15 in the oral transport phase and 12 in the pharyngeal phase) and 12 in the anteroposterior view (six in the oral preparatory phase and six in the oropharyngeal phase). A positive finding for the individual parameters is expressed in a binary fashion. Manometric evaluation was based on 11 items divided into four major and seven minor criteria.Dynamic videofluoroscopy swallow study combined with concurrent manometry enabled the simultaneous recording of anatomical alterations and the functional data of oropharyngeal pressure, thus providing a picture of the anatomical, biomechanical and physiological conditions of swallowing and the manner of bolus propulsion and transit.An early and effective diagnosis of oropharyngeal dysphagia means being able to effectively implement appropriate rehabilitation techniques, improve the patient's quality of life, and minimise the complications associated with swallowing disorders (choking, aspiration pneumonia, malnourishment). Distinction of the anatomical level of dysphagia is not a matter of simple classification; rather, it is essential in that different clinical presentations require different diagnostic strategies, and a precise definition of the anatomical-functional substrate is required to implement the correct therapeutic approach. This study presents the authors' experience with the use of combined videofluoroscopy and manometry with particular emphasis on the examination technique.

Abnormal renal reabsorption of sodium (Na(+)) is likely to play a role in the pathogenesis of salt-sensitivity. In the kidney, chloride channels CLC-Ka (gene CLCNKA) and CLC-Kb (gene CLCNKB) and their subunit Barttin (gene BSND) have important effects on the control of Na(+) and water homeostasis. We investigated if single nucleotide polymorphisms (SNPs) or haplotypes within CLCNKA, CLCNKB and BSND loci affect salt-sensitivity in hypertensive subjects. Associations between blood pressure (BP) change after Na(+)-load and 15 SNPs spanning the length of CLCNKA and CLCNKB and six SNPs spanning the length of BSND were studied in 314 never treated essential hypertensives who underwent an i.v. infusion of saline (300 mm NaCl in 2 l H(2)O in 120 min). Four SNPs were significantly associated with BP change after Na-load. Rs848307 (P = 0.0026) and rs1739843 (P = 0.0023) map upstream the 5' of CLCNKA. Non-coding Rs1010069 (P = 0.0006) and non-synonymous rs1805152 (Thr447Ala; P = 0.0078) map within CLCNKA. Moreover, basal plasma renin activity and heart rate (measured before Na-load) were significantly lower in patients carrying the alleles associated with the larger mean BP increase after Na-load, indicating that such alleles are associated with chronic volume expansion. This study supports the candidacy of CLCNKA as a new susceptibility gene for salt-sensitivity.

BACKGROUND: Chronic kidney disease patients who are resistant to erythropoietin (EPO) treatment may suffer from malnutrition and/or inflammation. METHODS: In a cross-sectional study of haemodialysis patients, we investigated the relationship between the natural logarithm of the weekly EPO dose normalized for post-dialysis body weight and outcome measures of nutrition and/or inflammation [BMI, albumin and C reactive protein (CRP)] by means of multiple linear regression analysis. On the basis of the decile distribution of weekly EPO doses, we also evaluated four groups of patients: untreated, hyper-responders, normo-responders and hypo-responders. RESULTS: Six hundred and seventy-seven adult haemodialysis patients were recruited from five Italian centres. BMI and albumin were lower in the hypo-responders than in the other groups (21.3+/-3.8 vs 24.4+/-4.7 kg/m(2), P

Trilineage extramedullary myeloid tumor (EMT) is an uncommon medical condition mostly diagnosed in patients affected by acute or chronic myeloid leukemia or, more rarely, by a myelodysplastic syndrome, among which the most frequent is refractory anemia with excess of blasts in transformation (RAEB-t). The prognostic significance of EMT is still unclear, although the appearance of trilineage EMT is often considered to affect the outcome adversely. A 70-year-old lady with previous history of intestinal resection for colonic adenocarcinoma in 1995 and subsequently treated with 5-fuorouracyl developed a refractory anemia with excess of blasts (RAEB) in 1998. During the follow-up, a progression to RAEB-t was recorded. During chemotherapy for this condition, slight enlargement of left supraclavicular and right submandibular nodes was noticed. Fine-needle biopsy was performed with ancillary studies. A diagnosis of trilineage extramedullary myeloid tumor was reached. The patient was treated with low doses of chemotherapy with a good response lasting 12 months. The peculiar cytologic picture of this condition when corroborated by ancillary studies (immunocytochemistry and flow cytometry) is diagnostic of this rare condition. Furthermore, the extramedullary myeloid tumor in this case did not significantly affect the response to the chemotherapy of RAEB-t.

In a previous study, we showed the ability of technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) scan to identify active disease in patients with multiple myeloma (Eur J Nucl Med 1998; 25: 714–720). In particular, a semiquantitative score of the extension and in- tensity of bone marrow uptake was derived and correlated with both the clinical status of the disease and plasma cell bone marrow infiltration. In order to estimate quantitatively 99mTc-MIBI bone marrow uptake and to verify the intracellular localization of the tracer, bone marrow samples obtained from 24 multiple myeloma patients, three patients with monoclonal gammopathy of undetermined significance (MGUS) and two healthy donors were studied for in vitro uptake. After centrifugation over Ficoll-Hypaque gradient, cell suspensions were in- cubated with 99mTc-MIBI and the uptake was expressed as the percentage of radioactivity specifically retained within the cells. The cellular localization of the tracer was assessed by micro-autoradiography. Twenty-two out of 27 patients underwent 99mTc-MIBI scan within a week of bone marrow sampling. Whole-body images were ob- tained 10 min after intravenous injection of 555 MBq of the tracer; the extension and intensity of 99mTc-MIBI uptake were graded using the semiquantitative score. A statistically significant correlation was found between in vitro uptake of 99mTc-MIBI and both plasma cell infil- tration (Pearson's coefficient of correlation r=0.69, P

A group of 157 women with primary breast cancer (BC) were typed for HLA antigens, and gene frequencies were compared to those of 327 control healthy individuals. Diagnosis of BC was made for all patients on surgical mastectomy specimens; histologic grading, estrogen (ER) and progesterone (PgR) receptors were determined on all primary tumors. Typed antigens included the majority of the specificities controlled by the HLA-A, -B and -C loci, according to the 8th International Histocompatibility Testing Workshop recommendations. No significant discrepancy in their frequencies was found in the undivided sample as compared to controls. The analysis of HLA gene frequency was extended to subsets of patients identified by the following prognostic features: (a) age at tumor diagnosis (pre-menopause vs. post-menopause); (b) receptor status (presence vs. absence of ER and PgR); (c) mammary gland dysplasia (presence vs. absence); (d) histologic grade (grade 3 vs. grades 1 and 2 combined); (e) time to relapse before or after 24 months following mastectomy). A moderate deviation from normal of some genes was found in several subsets, often affecting only one of the antithetical subgroups (feature present vs. feature absent). In the instance of B5, the increase in frequency of the gene in one of the subset pair (ER + subjects) was balanced by a decrease of the same gene in the counterpart (ER-subjects). Increased frequencies were found for the B7 gene in the following prognostic groups: (a) lack of ER (0.08); (b) lack of PgR (0.09); (c) absence of mammary dysplasia (0.075); (d) histologic grade 3 (0.10); and (e) premenopause (0.12), the last two showing significant divergence from normal. When features (d) and (e) on the one hand and (a), (b), (d) and (e) on the other were combined, B7 reached frequencies of 0.18 (p less than 5 X 10(-4] and of 0.29 (p less than 5 X 10(-6], respectively.

Endoglin (CD105, an accessory component of the TGF-beta receptor complex) expression and distribution on different human tumour cells and its role in cellular proliferation were evaluated. We examined: 1) sixteen human carcinoma cell lines, 2) eight human sarcoma cell lines, 3) five miscellaneous tumour cell lines. HECV (endothelial cells) were employed as a positive control for endoglin expression. Normal Human Dermal Fibroblasts (NHDF) and 293 cells (epithelial kidney cells) were used as normal controls for connective and epithelial tissues, respectively. The results showed that CD105 was poorly expressed in the majority of human carcinoma cells (10/16), whereas it was highly expressed in most human sarcoma cells (7/8), and differently expressed by miscellaneous tumour cell lines. These data reflect endoglin expression by the normal counterparts of tumour cell lines, i.e. NHDF and 293 cells. However, CD105 levels in sarcoma cell lines, even though consistently lower than in NHDF, were significantly higher than those observed in carcinoma cells. Interestingly, CD105 presented a strong expression in the cytoplasm of MDA-MB-453 (breast carcinoma), NPA (papillary thyroid carcinoma), COLO-853 (melanoma) and SaOS-2 (osteosarcoma), but was weakly expressed on their cell membrane. This differential expression in the cytoplasm and on the membrane of some tumour cells, suggests a complex mechanism of translocation for this protein. The analysis of clonal growth in soft agar of some cell lines, characterized by high CD105 expression, showed an increased colony formation potential that was antagonized by the addition of anti-CD105 blocking mAb. The results indicated that endoglin is differentially expressed in human carcinoma and sarcoma cells and its overexpression modulates the proliferative rate of human solid tumour cells. Moreover, these data suggest that CD105 is involved in the regulation of TGF-beta effects in human solid malignancies, and therefore it could play an important role in tumour diagnosis and treatment.