Differential effects of biocompatible peritoneal dialysis fluids on human mesothelial and endothelial cells in 2D and 3D phenotypes.

INTRODUCTION: Peritoneal dialysis (PD) is a life maintaining treatment in patients with end-stage renal disease. Its chronic application leads to peritoneal mesothelial layer denudation and fibrotic transformation along with vascular activation of inflammatory pathways. The impact of different PD fluids (PDF) on mesothelial and endothelial cell function and repair mechanisms are not comprehensively described. MATERIALS AND METHODS: Mesothelial (MeT-5A) and endothelial cells (EA.hy926) were cultured in 1:1 ratio with cell medium and different PDF (icodextrin-based, amino acid-based, and glucose-based). Cell adhesion, cell migration, and cell proliferation in 2D and spheroid formation and collagen gel contraction assays in 3D cell cultures were performed. RESULTS: Cell proliferation and cell-mediated gel contraction were both significantly decreased in all conditions. 3D spheroid formation was significantly reduced with icodextrin and amino acid PDF, but unchanged with glucose PDF. Adhesion was significantly increased by amino acid PDF in mesothelial cells and decreased by icodextrin and amino acid PDF in endothelial cells. Migration capacity was significantly decreased in mesothelial cells by all three PDF, while endothelial cells remained unaffected. CONCLUSIONS: In 3D phenotypes the effects of PDF are more uniform in both mesothelial and endothelial cells, mitigating spheroid formation and gel contraction. On the contrary, effects on 2D phenotypes are more uniform in the icodextrin and amino acid PDF as opposed to glucose ones and affect mesothelial cells more variably. 2D and 3D comparative assessments of PDF effects on the main peritoneal membrane cell barriers, the mesothelial and endothelial, could provide useful translational information for PD studies.

Remission as an Emerging Therapeutic Target in Type 2 Diabetes in the Era of New Glucose-Lowering Agents: Benefits, Challenges, and Treatment Approaches.

Type 2 diabetes mellitus (T2DM) is a progressive disease with a growing prevalence, associated with an increased risk of complications. The introduction of new classes of antidiabetic drugs into clinical practice has dramatically changed the landscape of diabetes therapy. However, despite the progress made in the pharmacotherapy of T2DM, mitigating the burden of the disease on individuals, societies and health care systems remains a challenge. Remission has recently emerged as a therapeutic target in T2DM, achievable through a wide range of interventions. Recent studies have shown that extensive lifestyle changes, such as weight reduction, bariatric surgery, and intensive glucose lowering therapy, can prompt the remission of diabetes, but some unanswered questions remain regarding its long-term effects on diabetic complications. Metabolic surgery and novel classes of glucose-lowering medications are currently the most effective interventions to induce weight loss and by extension remission in patients with diabetes; however, the ideal strategy to achieve the long-term maintenance of remission remains doubtful. In this narrative review, we discuss the available therapeutic approaches to target the remission of diabetes through personalized multimodal care, based on the latest evidence.

From Skepticism to Hope: The Evolving Concept of the Initiation and Use of Sodium-Glucose Cotransporter 2 Inhibitors in Hospitalized Patients.

The management of hyperglycemia in patients admitted to hospital is mainly based on insulin therapy. However, the positive and rapid effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiorenal outcomes raises the possibility that they might confer benefits to hospitalized patients. In recent, well designed, randomized trials (SOLOIST-WHF and EMPULSE) recruiting inpatients with heart failure (HF), SGLT2i demonstrated the potential to improve survival and quality of life and reduce the number of HF events, time to first HF event, hospitalizations, and urgent visits for HF compared with placebo. They were also well tolerated, whereas incidence of diabetic ketoacidosis was low. In EMBODY, empagliflozin was shown to be protective against the deleterious effects of cardiac injury in patients with acute myocardial infarction. In DARE-19, the administration of dapagliflozin to inpatients with cardiometabolic risk factors and COVID-19 was based on the hypothesis that the anti-inflammatory properties of SGLT2i could alleviate organ damage. Although the findings did not reach statistical significance, the efficacy and safety profiles of the drug were encouraging. These promising findings in the field of cardiometabolic medicine set the stage for future research to explore whether the benefits of gliflozins can expand to inpatients with non-cardiometabolic disorders, including sepsis, cirrhotic ascites, and malignancies. The concept of inpatient use of SGLT2i has evolved greatly over the past few years. The latest evidence suggests that SGLT2i may be effective and safe in the hospital setting, provided patients are carefully selected and closely monitored. Real-world data will prove whether present hope about inpatient use of gliflozins will transform into future confidence.

Multisite Tumor Sampling Reveals Extensive Heterogeneity of Tumor and Host Immune Response in Ovarian Cancer.

BACKGROUND/AIM: Ovarian cancer (OVCA) is characterized by genomic/molecular intra-patient heterogeneity (IPH). Tissue histology and morphological features are surrogates of the underlying genomic/molecular contexture. We assessed the morphological IPH of OVCA tumor compartments and of lymphocytic infiltrates in multiple matched samples per patient. MATERIALS AND METHODS: We examined 294 hematoxylin & eosin (H&E) OVCA tumor whole sections from 70 treatment-naïve patients who had undergone cytoreductive surgery. We assessed morphological subtypes as immunoreactive (IR), solid - proliferative (SD), papilloglandular (PG), and mesenchymal transition (MT); subtype load per patient; stromal tumor-infiltrating lymphocyte (sTIL) density as average per sample; and, as maximal sTIL values (max-TILs) among all samples per patient, ovaries and implants. RESULTS: Among all 294 tumor sections, the most frequent primary morphological subtype was PG (n=150, 51.0%), followed by MT (71, 24.1%), SD (48, 16.3%) and IR (15, 5.1%). Subtype combinations were observed in 67/294 sections (22.8%) and IPH in 48/70 patients (68.6%). PG prevailed in ovaries (p<0.001), SD and MT in implants (p=0.023 and p<0.001, respectively). sTILs were higher in SD compared to non-SD (p=0.019) and lower in PG, respectively (p<0.001). sTIL density was higher in implants than in ovaries (p<0.001). Higher max-TILs were associated with stage IV disease (p=0.043), upper abdominal dissemination (p=0.024), endometrioid histology (p=0.013), and grade 3 tumors (p=0.021). Favorable prognosticators were higher max-TILs per patient (PFS, OS) and higher SD-load (PFS). CONCLUSION: Clinically relevant morphological and host immune-response IPH appear to be the norm in OVCA. This may complicate efforts to decipher sensitivity of the tumor to certain treatment modalities from a single pre-operative biopsy.

10-year-long survival in a PD patient with severe calcifying encapsulating peritoneal sclerosis treated with tamoxifen: a case-report.

BACKGROUND: Encapsulating-peritoneal-sclerosis (EPS) is a rare, but serious and life-threatening complication of peritoneal dialysis (PD). Treatment of EPS consists of discontinuation of PD and maintenance of nutritional status, whereas the role of corticosteroids, tamoxifen and other immunosuppresive agents is not yet fully elucidated. CASE-PRESENTATION: We report the case of a 28-year-old patient, who developed a severe form of calcifying EPS after a 6-year-long therapy with automated PD. The clinical presentation was severe with repeated episodes of total bowel obstruction, weight loss and malnutrition that mandated his prolonged hospitalization. Initial treatment included corticosteroids and tamoxifen (20 mg/day) with a clinically meaningful improvement in gastrointestinal function and nutritional status over the first 6-12 months. Corticosteroids were discontinued at 18 months, but owing to persistence of calcifying lesions and peritoneal thickening in repeated computed-tomography (CT) scans, tamoxifen remained unmodified at a low-dose of 20 mg/day for a 10-year-long period. During follow-up, the patient remained symptoms-free in an excellent clinical condition and the CT findings were unchanged. CONCLUSIONS: Long-term administration of tamoxifen was not accompanied by any drug-related adverse effects and potentially exerted a beneficial action on down-regulation of inflammatory and fibrotic processes and improvement of gastrointestinal function, nutritional status and overall health-related quality of life.

Acute Interstitial Nephritis in a Patient with Non-Small Cell Lung Cancer under Immunotherapy with Nivolumab.

Immune-checkpoint-inhibitors (ICPIs) represent a novel class of immunotherapy against several malignancies. These agents are associated with several "immune-mediated" adverse effects, but the reported renal toxicity of ICPIs is less well defined. We present the case of a 60-year-old man with a history of non-small cell lung cancer, who developed acute kidney injury (AKI) approximately 3.5 months after initiation of immunotherapy with nivolumab. Urinalysis revealed sterile pyuria, without microscopic hematuria or proteinuria. Immunological examination was negative. A renal biopsy showed severe interstitial inflammatory infiltration of T-cells, monocytes, and eosinophils without interstitial granulomas and normal appearance of glomeruli, indicating acute interstitial nephritis (AIN) as the cause of AKI. After a short-term course of corticosteroids and permanent nivolumab discontinuation, partial recovery of renal function was noted. AIN is a rare adverse effect of ICPIs that mandates the close monitoring of renal function in patients under immunotherapy with these agents.

Hypercalcitoninaemia in pseudohypo-parathyroidism type 1A and type 1B.

Pseudohypoparathyroidism (PHP) is a heterogeneous group of rare endocrine disorders characterised by normal renal function and renal resistance to the action of the parathyroid hormone. Type 1A (PHP1A), which is the most common variant, also include developmental and skeletal defects named as Albright hereditary osteodystrophy (AHO). We present two cases, a 54- and a 33-year-old male diagnosed with PHP who were referred to us for persistently high levels of serum calcitonin. AHO and multinodular goitre were present in the 54-year-old male, while the second patient was free of skeletal deformities and his thyroid gland was of normal size and without nodular appearance. We performed GNAS molecular analysis (methylation status and copy number analysis by MS-MLPA) in genomic DNA samples for both patients. The analysis revealed a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1, in the patient with the clinical diagnosis of PHP1A. This amino acid change appears to be in accordance with the clinical diagnosis of the patient. The genomic DNA analysis of the second patient revealed the presence of the recurrent 3-kb deletion affecting the imprinting control region localised in the STX16 region associated with the loss of methylation (LOM) at the GNAS A/B differentially methylated region and consistent with the diagnosis of an autosomal dominant form of PHP type 1B (PHP1B). In conclusion, hypercalcitoninaemia may be encountered in PHP1A and PHP1B even in the absence of thyroid pathology. Learning points: We describe a novel missense variant c.131T>G p.(Leu44Pro) affecting GNAS exon 1 as the cause of PHP1A. Hypercalcitoninaemia in PHP1A is considered an associated resistance to calcitonin, as suggested by the generalised impairment of Gsα-mediated hormone signalling. GNAS methylation defects, as in type PHP1B, without thyroid pathology can also present with hypercalcitoninaemia.

Should the last be first? Questions and dilemmas regarding early short-term insulin treatment in Type 2 Diabetes Mellitus.

INTRODUCTION: Early short-term insulin treatment (STIT), defined as insulin administration shortly after diabetes diagnosis for only a brief period of time, is an alternative concept, aiming to entirely revise the perspective of type 2 diabetes (T2DM) management. AREAS COVERED: The present review intends to summarize what is already known regarding early STIT in T2DM and highlight questions and dilemmas from the clinician's point of view, with a discourse on future research agenda. EXPERT OPINION: STIT has the potential to modify the natural history of T2DM, resulting in improved drug-free remission rates by favorably affecting the underlying pathophysiology of the disease. Existing data in the field manifest significant weaknesses, mainly being the small number of trials and patients included, the lack of control groups in most studies and the wide heterogeneity between study designs and explored outcomes, which limit definitive conclusions. Therefore, before such a therapeutic strategy is incorporated into daily practice, important issues require further clarification by future trials. These issues include the optimal time point for the intervention, the ideal insulin type, the identification of patients being most likely to benefit, the STIT effects on cardiovascular and other clinical outcomes and the cost-effectiveness evaluation of this therapeutic strategy. ABBREVIATIONS: T2DM: Type 2 Diabetes Mellitus; HbA1C: Hemoglobin A1c; OHA: Oral Hypoglycemic Agents; STIT: Short-term Insulin Treatment; CSII: Continuous Subcutaneous Insulin Infusion; MDI: Multiple Daily Injections; PPG: Postprandial Plasma Glucose; FPG: Fasting Plasma Glucose; HOMA-b: Homeostasis Model Assessment of beta-cell function; TDD: Total Daily Insulin Dose; DI: Disposition Index; HOMA-IR: Homeostasis Model Assessment of Insulin Resistance; ROS: Reactive Oxygen Species; TNF: Tumor Necrosis Factor; GLP-1: Glucagon-like peptide-1; GIP: Glucose-dependent Insulinotropic Polypeptide; BMI: Body Mass Index; CV: Cardiovascular; DR: Diabetic Retinopathy; SU: Sulfonylurea; IGI: Insulinogenic Index.

Distant lung metastases caused by a histologically benign phosphaturic mesenchymal tumor.

Tumor-induced osteomalacia (TIO) is a rare form of hypophosphatemia usually caused by phosphaturic mesenchymal tumors (PMTs); the biologic behavior of PMTs is under investigation. Herein we present a case of TIO with a protracted course over 12 years leading to a fatal outcome. A 39-year-old man presented with weakness in 2004 and was found to have decreased serum phosphorus, phosphaturia and low levels of 1,25-dihydroxyvitamin D3. Four years later he developed a painful left calf mass. The lesion was resected, but recurred causing extreme pain and dysfunction. Radiological examination showed a large cluster of soft tissue tumors affecting all the muscle compartments of the calf and a smaller lesion inside the metaphysis of the tibia. Above-knee amputation was performed. Histological examination of all lesions showed a cellular spindle cell neoplasm with variously sized vessels, wide vessel-like spaces and scattered deposits of calcified extracellular material. The tumor infiltrated skeletal muscles, subcutaneous fat and the proximal end of the fibula. The tibial lesion had identical histology. Three years after the amputation the patient presented with cough and dyspnea. Radiological examination, followed by an open biopsy, showed that there were multiple metastatic nodules of PMTs in both lungs. Shortly after the diagnosis the patient died. This case illustrates that even benign cases of PMTs may lead to a fatal outcome and the classification of PMTs into benign and malignant should be reassessed in order to correspond to its biological behavior. LEARNING POINTS: PMTs, aside from having locally aggressive behavior, may metastasize and cause deathPMTs may behave aggressively despite 'benign' histological findings Accurate diagnosis of tumor-induced osteomalacia and patient management require a multidisciplinary approach.

Serum Fas Ligand, Serum Myostatin and Urine TGF-ß1 Are Elevated in Autosomal Dominant Polycystic Kidney Disease Patients with Impaired and Preserved Renal Function.

BACKGROUND/AIMS: The pathophysiology of renal disease progression in autosomal dominant polycystic disease (ADPKD) is largely unknown. Recent evidence suggests microvascular dysfunction leading to renal ischemia, as an additional pathway for renal function decline. This study examined the levels of serum Fas ligand (FasL), serum myostatin and urine transforming growth factor-beta 1 (TGF-ß1) and their association with markers of endothelial dysfunction, in ADPKD patients with preserved or impaired renal function. METHODS: Seventy-eight participants were enrolled in the study, divided in three groups: Group A consisted of 26 ADPKD patients with impaired renal function (eGFR 45-70 ml/min/1.73m2), Group B of 26 ADPKD patients with preserved renal function (eGFR > 70 ml/min/1.73m2), and Group C of 26 age- and sex- matched controls with no history of renal disease. Serum FasL, myostatin and urine levels of TGF-ß1 were measured as biomarkers of vascular dysfunction, apoptosis and fibrosis with ELISA techniques. RESULTS: Group A patients had significantly higher levels of FasL (13.12±1.69 ng/mL), myostatin (4.62±0.59 ng/mL) and urine logTGF-ß1 (3.56±0.49 ng/24h) compared to Group B (9.6±1.28 ng/mL, 3.06±0.35, and 2.09±0.37, respectively, p< 0.001 for all comparisons) or controls (6.59±1.17 ng/mL, 2.18±0.45 ng/ml, and 1.58±0.21, respectively, p< 0.001 for all comparisons). Patients in Group B had also higher levels of all markers compared to controls (p< 0.001), despite having similar renal function. In ADKPD patients negative associations of eGFR with FasL (r=-0.799, p< 0.001), myostatin (r=-0.856, p< 0.001) and TGF-ß1 (r=-0.476, p< 0.001) but positive correlations of these markers with asymmetric dimethylarginine (ADMA) (r=0.825; r=0.749; and r=0.599, respectively p< 0.001) were noted. Multivariate analysis demonstrated that FasL was independently associated with high urine TGF-ß1 (OR 3.774, 95%CI 1.180-12.072, p=0.025). CONCLUSIONS: ADPKD patients with moderately preserved renal function have higher levels of FasL, myostatin and urine TGF-ß1 than controls. These results indicate that an interplay between endothelial dysfunction and renal ischemia with mechanisms linked to apoptosis and fibrosis may be present even in early stages of ADPKD.

The Relationship between Primary Hyperparathyroidism and Thrombotic Events: Report of Three Cases and a Review of Potential Mechanisms.

We have described three uncommon cases of patients who presented with clinical thrombotic events (stroke, pulmonary embolism and deep venous thrombosis) during the course of a hypercalcemia-induced hypercoagulable state. After thorough investigation, the diagnosis of primary hyperparathyroidism - due to a parathyroid adenoma - was established in all cases. The association between hypercalcemia and venous or arterial thrombosis has been previously described; however, relevant data are still insufficient. The existing evidence in the field was reviewed and the interesting underlying pathophysiologic mechanisms were also discussed. Further studies are required to shed more light on the unusual, still intriguing relationship between calcium and thrombosis.

A Role for Circular Non-Coding RNAs in the Pathogenesis of Sporadic Parathyroid Adenomas and the Impact of Gender-Specific Epigenetic Regulation.

Epigenetic changes, including altered small non-coding RNAs, appear to be implicated in the pathogenesis of sporadic parathyroid adenomas (PAs). In this study, we investigated the circular RNAs (circRNAs) expression profile in sporadic PAs. Sixteen tissue samples of sporadic PAs, and four samples of normal parathyroid tissue (NPT) were investigated. Sample preparation and microarray hybridization were performed based on the Arraystar's standard protocols, and circRNAs sequences were predicted by bioinformatics tools. We identified 35 circRNAs that were differentially expressed in sporadic PAs compared to NPT; 22 were upregulated, and 13 were downregulated, according to the pre-defined thresholds of fold-change > 2.0 and p< 0.05. In the subgroup analysis of PAs from male patients (n = 7) compared to PAs from female patients (n = 9), we also find a different expression profile. In particular, 19 circRNAs were significantly upregulated, and four circRNAs were significantly downregulated in male patients, compared to female counterparts. We show here for the first time a differential circRNA expression pattern in sporadic PAs compared to NPT, and a different expression profile in PA samples from male compared to female patients, suggesting an epigenetic role in the PA pathogenesis, and also an effect of gender in the epigenetic regulation of PAs.

Pyoderma gangrenosum in a patient with chronic granulomatous disease: A case report.

RATIONALE: The simultaneous occurrence of pyoderma gangrenosum (PG) and chronic granulomatous disease (CGD) is uncommon and few cases have been reported worldwide. PATIENT CONCERNS: PG is a rare, chronic, ulcerative, neutrophilic skin disease of unknown etiology that requires immunosuppressive treatment. CGD belongs to Primary Immune Deficiencies in which the main defect lies in an inability of the phagocytic cells to generate superoxide making patients susceptible to serious, potentially life-threatening bacterial and fungal infections. DIAGNOSES: In this manuscript, we present a case of ulcerative pyoderma gangrenosum in a 28-year-old man with recent diagnosis of chronic granulomatous disease during hospitalization for resistant pulmonary tuberculosis complicated with Aspergillus infection. INTERVENTIONS: Second-line therapy with dapsone and intravenous immunoglobulin was initially administered but eventually corticosteroids were added to treatment because of disease progression and further ulceration. OUTCOMES: Patient's ulcers were gradually healed with no side effects. LESSONS: Corticosteroids could be used under close monitoring for the treatment of PG in a patient with CGD, despite the increased risk for infections.

Mineralocorticoid Antagonists in ESRD: An Overview of Clinical Trial Evidence.

BACKGROUND: Add-on therapy with the Mineralocorticoid-Receptor-Antagonists (MRAs) spironolactone and eplerenone was shown to enhance the cardioprotective action of angiotensinconverting- enzyme-inhibitors (ACEIs), angiotensin-receptor-blockers (ARBs) and/or ß-blockers in nondialysis patients with congestive heart failure (CHF) and reduced left ventricular (LV) ejection fraction. The risk/benefit ratio of MRAs in dialysis patients is less well defined, owing to concerns that their cardioprotective actions may be counteracted by excess risk of hyperkalemia. METHODS: We performed a systematic literature search of MEDLINE/PubMed database (inception to September 15, 2016) to identify randomized controlled studies evaluating the effects of spironolactone and eplerenone on surrogate cardiovascular risk factors and clinical outcomes in patients receiving hemodialysis or peritoneal dialysis. RESULTS: A growing body of evidence derived from small randomized studies suggests that MRA therapy improves a number of surrogate cardiovascular risk factors (i.e. blood pressure, LV mass index, LV ejection fraction, carotid intima-media-thickness) in long-term dialysis patients. Two larger studies evaluating "hard" cardiovascular endpoints showed that these cardioprotective actions of MRAs are translated into a clinically relevant (up to 60%) reduction in the risk of all-cause and cardiovascular mortality. On the other hand, MRA use was shown to be accompanied by a parallel increase in the risk of hyperkalemia and gynecomastia. CONCLUSION: Small, hypothesis-generating randomized trials support a cardioprotective role of MRA therapy in patients receiving hemodialysis or peritoneal dialysis. These promising results call for larger, properly-designed studies aiming to fully elucidate the potential harms and benefits of MRAs in this high-risk population. In anticipation of the results of ongoing outcome trials, the wide use of MRAs in dialysis patients should be avoided.

The controversial impact of B cells subsets on immune response to pneumococcal vaccine in HIV-1 patients.

BACKGROUND: Chronic HIV infection leads to severe perturbations of the B cell populations and hypo-responsiveness to vaccines. The associations between circulating B cell subpopulations and the antibody response to pneumococcal polysaccharide vaccine in antiretroviral-naïve and treated patients were studied. METHODS: Sixty-six HIV-infected adults were grouped according to antiretroviral therapy (ART) and CD4+ cell count; 31 were ART-naïve and 35 were ART-treated, and they were matched for age, CD4 cell count, and duration of HIV infection. All subjects were immunized with the 23-valent polysaccharide vaccine against Streptococcus pneumoniae. Pre- and post-vaccination B cell subpopulations were assessed by flow cytometry. Serum IgG concentrations for vaccine serotypes were quantified by ELISA at baseline and at 4 and 48 weeks post-vaccination. RESULTS: Patients under highly active antiretroviral therapy (HAART) had significantly higher antibody levels against pneumococcal vaccine antigens, while an adequate number of patients responded to vaccination. Memory B cells were diminished over time, although treated patients maintained higher levels of all subsets studied, with the exception of activated memory and isotype-switched memory B cells. CONCLUSIONS: Low concentrations of total B cells and exhausted memory B cells was the strongest independent predictor of poor pneumococcal vaccine responsiveness, emphasizing that B cell subset disturbances are associated with a poor vaccine response among HIV-infected patients.

Postprandial response of bone turnover markers in patients with Crohn's disease.

AIM: To investigate the postprandial response of bone turnover markers in patients with Crohn's disease (CD). METHODS: Fifty nine patients with CD aged 38 ± 14 years, and 45 healthy individuals matched for age and body mass index were included in the study. All participants underwent an oral glucose tolerance test (OGTT) after an overnight fast and serum levels of the bone resorption marker C-terminal crosslinking telopeptide of type I collagen (CTX-I) and the bone formation marker procollagen type I N propeptide were measured. Activity of the disease was assessed by calculation of the Crohn's disease activity index (CDAI). RESULTS: Serum CTX-I was significantly higher in patients compared to controls (CTX-I: 453 ± 21 pg/mL vs 365 ± 25 pg/mL, P = 0.008), and values were significantly correlated with the activity of the disease (r = 0.435, P = 0.001). Results from OGTT-induced suppression of CTX-I showed two different trends. Patients with more active disease (assessed as CDAI > 150) had a more excessive suppression of CTX-I compared to controls (55% vs 43% P < 0.001), while patients on remission (assessed as CDAI < 150) demonstrated an attenuated CTX-I suppression (30% vs 43% P < 0.001). In line with this, CTX-I suppression after oral glucose load was significantly correlated with the activity of the disease (r = 0.913, P < 0.001). CONCLUSION: The physiological skeletal response of postprandial suppression of bone resorption is maintained in patients with CD and is strongly dependent to the activity of the disease.

Differential expression of the insulin-like growth factor receptor among early breast cancer subtypes.

INTRODUCTION: We sought to determine the level of protein expression of the critical components of the insulin-like growth factor receptor (IGFR) pathway and to evaluate their prognostic significance across the different early breast cancer subtypes. PATIENTS AND METHODS: Archival tumor tissue from 1,021 women with early, node positive breast cancer, who were prospectively evaluated within two randomized clinical trials, was used to construct tissue microarrays that were stained for hormone receptors (HR), Ki67, HER2, epidermal growth factor receptor (EGFR) and cytokeratins 5/6, to classify tumors into five immunophenotypical subgroups. Immunohistochemical (IHC) expression of IGF1R-alpha and beta subunits, IGF2R and IGF-binding protein 2 (IGFBP2) was assessed using the immunoreactive score (IRS). Repeated internal cross-validation was performed to examine the statistical validity of the cut off points for all biomarkers. RESULTS: After a median follow-up time of 105.4 months, overall 370 women (36.2%) had relapsed and 270 (26.4%) had died. Tumors expressing IGF1R-alpha above the median IRS were significantly more frequently HR positive (luminal A+B+HER2), as compared to HER2-enriched and triple negative ones (p<0.001 for both comparisons). IGF2R was overexpressed significantly more frequently in HR negative tumors (p = 0.001) and had an inverse correlation with all other biomarkers. Patients with luminal A and B tumors with high IGF1R-alpha and negative EGFR expression (N = 190) had significantly higher 4-year survival rates, as compared to the rest (log-rank p = 0.046), as did patients with luminal A and B tumors with high IGF1R-alpha and low IGF2R expression, as compared to the rest (N = 91), (log-rank p = 0.035). After adjustment for significant variables, patients in the latter group had a relative 45% reduction in the risk of death, as compared to the rest (p = 0.035). CONCLUSION: Aberrant expression of components of the IGF1R pathway is associated with better clinical outcomes in women with luminal A and B, node positive, early breast cancer.

Complicated hepatic hydatid cyst with simultaneous biliary tree and intraperitoneal rupture: can we treat it in a minimally invasive way?

We report a case of complicated liver hydatid cyst with biliary system communication, cholangitis, and having at the same time simultaneous free intraperitoneal rupture. This very rare case was treated successfully by a minimally invasive method, namely ERCP, large sphincterotomy and bile duct decompression by cysts and membranes, percutaneous radiologic subdiaphragmatic drainage and prolonged medical treatment with albendazole. Our patient, an 87-year-old lady, was considered unfit for open or laparoscopic surgery because of her poor general condition, although surgery represents the common practice in such cases.

Obesity is associated with increased arterial stiffness from adolescence until old age.

OBJECTIVE: To our knowledge, only two previous studies have investigated the age dependence of the relationship between the characteristics of large arteries and excessive body weight. We therefore investigated whether the relationship between arterial stiffness and body mass index (BMI) was consistent across an age range from 10 to 86 years. METHODS: Using a cross-sectional population-based design, we randomly recruited 1306 individuals (median age 43.9 years; 50.5% women). Using a wall-tracking ultrasound system, we measured the properties of the carotid, femoral and brachial arteries and carotid-femoral pulse wave velocity. We analysed men and women separately while adjusting for significant covariates, including age, mean arterial pressure, heart rate, current smoking, alcohol intake and use of antihypertensive drugs. RESULTS: Before and after adjustment, arterial diameter increased with BMI in all territories, with an opposite trend for arterial distensibility. In men and women, the relationships of brachial and femoral properties with BMI were consistent across the whole age range. In men and women, carotid distensibility decreased more with BMI at young than old age. In middle-aged and older women, but not in men of any age, pulse wave velocity increased with higher BMI. CONCLUSIONS: Across a wide age range, the diameter and stiffness of muscular arteries increased with higher BMI. In elastic arteries, the relationship between arterial stiffness and BMI was more complex and varied with sex and age. The mechanisms underlying the influence of adiposity on the properties of muscular and elastic arteries and the reversibility of these associations by weight reduction at young age need further clarification.