Gallbladder metastasis: spectrum of imaging findings

The objective of this study is to report the diagnostic features of hematogenous gallbladder metastasis using various imaging modalities. We carried out a single-center retrospective analysis of 13 patients with gallbladder metastasis. The primary malignancy was cutaneous melanoma (11 cases), hepatocellular carcinoma (1 case), and non-Hodgkin lymphoma (1 case). All patients underwent sonography (US), with color-power-Doppler assessment in 11 cases. Contrast-enhanced US (CEUS) was performed in 8 patients, MDCT in 8, and MR imaging in 1. Four subjects studied by whole-body PET. The gallbladder lesions were first detected with US in 9 cases and with MDCT in 3 cases. The remaining patient was investigated because of hepatic fluorodeoxyglucose uptake at PET; CEUS failed to detect any liver metastasis in this subject but identified a gallbladder lesion. Typical findings included multiplicity of gallbladder vegetations, broad base, limited mural thickening, presence of contrast enhancement, absence of gallstones and gallbladder bed infiltration, presence of combined lesions within other organs. Only two patients presented an isolated location in the gallbladder and were successfully treated with surgery. Gallbladder metastasis is a rare but possible occurrence. Knowledge of the typical imaging features and careful evaluation of the gallbladder may avoid an incorrect or false negative diagnosis.     

Phosphatidylinositol 3'-kinase is a critical mediator of interferon-gamma-induced increases in enteric epithelial permeability

The epithelial lining of mucosal surfaces acts as a barrier to regulate the entry of antigen and pathogens. Nowhere is this function of the contiguous epithelium more important than in the gut, which is continually exposed to a huge antigenic load and, in the colon, an immense commensal microbiota. We assessed the intracellular signaling events that underlie interferon (IFN) gamma-induced increases in epithelial permeability using monolayers of the human colonic T84 epithelial cell line. Confluent epithelial monolayers on semipermeable supports were treated with IFNgamma (20 ng/ml), and barrier function was assessed 48 h later by measuring transepithelial electrical resistance (TER: reflects passive ion flux), fluxes of (51)Cr-EDTA and horseradish peroxidase (HRP), and transcytosis of noninvasive, nonpathogenic Escherichia coli (strain HB101). Exposure to IFNgamma decreased barrier function as assessed by all four markers. The phosphatidylinositol 3'-kinase (PI-3K) inhibitors, LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride] and wortmannin, did not affect baseline permeability characteristics but completely blocked the drop in TER, increased fluxes of (51)Cr-EDTA and HRP, and significantly reduced E. coli transcytosis evoked by IFNgamma. In addition, use of the pan-protein kinase C (PKC) inhibitor, bisindolylmaleimide I (5 muM), but not rottlerin (blocks PKCdelta), partially ameliorated the drop in TER and inhibited increased E. coli transcytosis. Addition of the PI-3K and PKC inhibitors to epithelia 6 h after IFNgamma exposure still prevented the increase in paracellular permeability but not E. coli transcytosis. Thus, IFNgamma-induced increases in epithelial paracellular and transcellular permeability are critically dependent on PI-3K activity, which may represent an epithelial-specific target to treat immune-mediated loss of barrier function.     

Small bowel exploration by wireless capsule endoscopy: results from 314 procedures

Objectives

To assess the diagnostic efficiency of capsule endoscopy in a large group of patients with different indications, to weigh the reliability of the procedure for excluding small bowel lesions, and to identify factors associated with the likelihood of obtaining a definitive diagnosis.

Methods

Three hundred four consecutive patients (141 female, mean age 55 years, range 12-91 years) underwent capsule endoscopy in two different Gastroenterology Units, for a total of 314 procedures, and were followed-up for a median period of 15 months. Referrals were obscure occult/overt gastrointestinal bleeding (203 patients), suspected small bowel disease (74), gastrointestinal polyposis (18), suspected/previous intestinal or endocrine malignancies (13), previously diagnosed intestinal lymphangectasia (3), and vascular abnormalities (3).

Results

Adequate visualization of the small bowel was obtained in 96% of patients, although the capsule did not visualize cecum in 20% of cases. Non-natural excretion of the capsule was observed in 4 patients, all of whom underwent laparotomy for intestinal stenosis. Diagnostic yields were 58% for obscure gastrointestinal bleeding and 31% for patients with suspected small bowel disease. Capsule endoscopy was able to rule out small bowel disease in 14% of patients, and a definitive diagnosis was achieved in 65% of patients. The only parameter associated with the likelihood of reaching a conclusive diagnosis was the indication to the procedure (overall chi-square 13.5, P = .004).

Conclusions

Capsule endoscopy represents a reliable tool for verifying the state of the small bowel. Accurate selection of indications and critical evaluation of the results are essential to fully exploit this procedure.     

Palonosetron (Aloxi®) and dexamethasone for the prevention of acute and delayed nausea and vomiting in patients receiving multiple-day chemotherapy

OBJECTIVE: The objective of this study was to determine the efficacy of palonosetron combined with dexamethasone in prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving multiple-day chemotherapy and the efficacy of a second dose of palonosetron in treating breakthrough emesis. MATERIALS AND METHODS: Forty-six patients treated with multiple-day chemotherapy for hematologic malignancies received palonosetron as prophylaxis for CINV on the first day of chemotherapy and dexamethasone throughout the entire period of chemotherapy. If breakthrough emesis occurred, a second dose of palonosetron was administered after 72 h following the first administration. The results were retrospectively compared to group of patients with similar clinical characteristics undergoing similar multiple-day chemotherapy. This group had received single-dose ondansetron as CINV prophylaxis on the first day of chemotherapy plus dexamethasone throughout the entire period of chemotherapy and metoclopramide for breakthrough emesis. RESULTS: One hundred eighty and 173 chemotherapy cycles were administered in the palonosetron and ondansetron groups, respectively. Nausea and vomiting were absent in 80% of patients of the palonosetron group and 60% of the control group (p < 0.05). In the palonosetron group, 67% of patients who experienced CINV were successfully rescued by a second dose of palonosetron, while in the ondansetron group, only 22% showed a no CINV after metoclopramide treatment (p = 0.04). CONCLUSIONS: The present results appear to be encouraging in terms of complete prophylaxis of CINV and treatment of breakthrough emesis in the setting of multiple-day chemotherapy.     

Bapineuzumab: anti-β-amyloid monoclonal antibodies for the treatment of Alzheimer's disease

In the last decade, new therapeutic approaches targeting β-amyloid (Aβ) have been discovered and developed with the hope of modifying the natural history of Alzheimer's disease (AD). The most revolutionary of these approaches consists in the removal of brain Aβ via anti-Aβ antibodies. After an active vaccine (AN1792) was discontinued in 2002 due to occurrence of meningoencephalitis in approximately 6% of patients, several other second-generation active Aβ vaccines and passive Aβ immunotherapies have been developed and are under clinical investigation with the aim of accelerating Aβ clearance from the brain of AD patients. The most advanced of these immunological approaches is bapineuzumab, which is composed of humanized anti-Aβ monoclonal antibodies that has been tested in two Phase II trials. Bapineuzumab has been shown to reduce Aβ burden in the brain of AD patients. However, its preliminary cognitive efficacy appears uncertain, particularly in ApoE ε4 carriers, and vasogenic edema may limit its clinical use. The results of four ongoing large Phase III trials on bapineuzumab will provide answers regarding whether passive anti-Aβ immunization is able to alter the course of this devastating disease.     

Pituitary adenylate cyclase-activating polypeptide, vasoactive intestinal polypeptide and their receptors: distribution and involvement in the secretion of Podarcis sicula adrenal gland

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are regulatory neuropeptides of the hypothalamus-hypophyseal-adrenal axis, acting via the common receptors VPAC(1) and VPAC(2) and the selective PACAP receptor PAC(1). In the adrenal glands of the Italian wall lizard, Podarcis sicula, the presence of VIP in chromaffin cells, and the VIP-stimulated release of catecholamine and aldosterone in vivo, was previously shown. To examine the localization of both peptides and receptors and their mRNAs in the adrenal gland of P. sicula, immunohistochemistry and in situ hybridization were performed: PACAP and its mRNA were detected in chromaffin cells, VPAC(1) was found associated with steroidogenic tissue, VPAC(2) and PAC(1) with chromaffin tissue. Using 'far western blot' technique, we showed the presence of specific binding sites for VIP/PACAP in the adrenal glands of the lizard. The effects of both VIP and PACAP on the adrenal cells of the lizard were examined in vitro in adrenal cell co-cultures: both VIP and PACAP enhanced catecholamine, corticosterone and aldosterone release from adrenal cell co-culture in a time- and dose-dependent manner. The catecholamine release was inhibited by PAC(1) antagonist and in VPAC(2) immunoneutralized adrenal cells. The effects of VIP and PACAP on aldosterone secretion were counteracted by VPAC(1) antagonist administration in vitro. Corticosterone secretion elicited by VIP was not blocked by VPAC(1) antagonist, while the PACAP-induced release of corticosterone was blocked by the antagonist. Overall, our investigations indicate that these neuropeptides of the secretin superfamily can act not only as neurotransmitters but also as autocrine and paracrine regulators on chromaffin and cortical cells, being important mediators of the non-cholinergic system in the lizard adrenal gland.     

Methods of investigation for cardiac autonomic dysfunction in human research studies

This consensus document provides evidence‐based guidelines regarding the evaluation of diabetic cardiovascular autonomic neuropathy (CAN) for human research studies; the guidelines are the result of the work of the CAN Subcommittee of the Toronto Diabetic Neuropathy Expert Group. The subcommittee critically reviewed the limitations and strengths of the available diagnostic approaches for CAN and the need for developing new tests for autonomic function. It was concluded that the most sensitive and specific approaches currently available to evaluate CAN in clinical research are: (1) heart rate variability, (2) baroreflex sensitivity, (3) muscle sympathetic nerve activity, (4) plasma catecholamines, and (5) heart sympathetic imaging. It was also recommended that efforts should be undertaken to develop new non‐invasive and safe CAN tests to be used in clinical research, with higher sensitivity and specificity, for studying the pathophysiology of CAN and evaluating new therapeutic approaches. Copyright © 2011 John Wiley & Sons, Ltd.     

Angiotensin-converting enzyme inhibitors and incidence of mild cognitive impairment. The Italian Longitudinal Study on Aging

Midlife elevated blood pressure and hypertension contribute to the development of Alzheimer's disease (AD) and overall dementia. We sought to estimate whether angiotensin-converting enzyme inhibitors (ACE-Is) reduced the risk of developing mild cognitive impairment (MCI) in cognitively normal individuals. In the Italian Longitudinal Study on Aging, we evaluated 1,445 cognitively normal individuals treated for hypertension but without congestive heart failure from a population-based sample from eight Italian municipalities with a 3.5-year follow-up. MCI was diagnosed with current clinical criteria. Dementia, AD, and vascular dementia were diagnosed based on DSM-IIIR criteria, NINCDS–ADRDA criteria, and ICD-10 codes. Among 873 hypertension-treated cognitively normal subjects, there was no significant association between continuous exposure to all ACE-Is and risk of incident MCI compared with other antihypertensive drugs [hazard ratio (HR), 0.45, 95% confidence interval (CI), 0.16–1.28]. Captopril exposure alone did not significantly modify the risk of incident MCI (HR, 1.80, 95% CI, 0.39–8.37). However, the enalapril sub-group alone (HR, 0.17, 95% CI, 0.04 –0.84) or combined with the lisinopril sub-group (HR, 0.27, 95% CI, 0.08–0.96), another ACE-I structurally related to enalapril and with similar potency, were associated with a reduced risk of incident MCI. Study duration exposure to ACE-Is as a “class” was not associated with incident MCI in older hypertensive adults. However, within-class differences linked to different chemical structures and/or drug potencies may exist, with a possible effect of the enalapril and lisinopril sub-groups in reducing the risk of incident MCI.     

Fibrosis Evaluation by Transient Elastography in Patients With Long-Term Sustained HCV Clearance

Background

Reversibility of advanced fibrosis after HCV-clearance is an important goal of therapy.

Objectives

Measuring liver stiffness (LS) by transient elastography (TE) might be helpful in this setting.

Patients and Methods

We evaluated 104 patients with biopsy-proven chronic hepatitis C (CHC) and sustained virological response (SVR) after Peg-Interferon (IFN) plus ribavirin since at least 18 months. HCV-eradication was confirmed searching for serum HCV-RNA (TMA® sensitivity > 5-10 IU/ml). Data from literature reported the best LS cut-off values for different stages of liver fibrosis were 7.1 kPa for Metavir stage 2 (F2), 9.5 kPa for F3 and 12.5 for cirrhosis (F4).

Results

TE was not reliable in four SVR obese patients. Metavir-stage of biopsy was F0-1 in 28, F2 in 47, F3 in 17 and F4 in eight patients. The median interval elapsed since achieving SVR was 36 months (range: 18-77, SD¬¬:18). Stratifying patients according to the histological stage assessed before treatment, a clear-cut gradient of LS values was observed from F0-1: median: 3.8 kPa (range: 3.5-4.9) to F2: 4.6 kPa (3.8-6.0), F3: 6.2 kPa (4.8-8.6) and F4: 8.4 kPa (6.2-9.2) (P = 0.001). Overall, 86 patients had lower values of LS than the expected LS values according to Metavir-stage. At multivariate logistic analysis γ-GT and histological steatosis were independently associated with persistence of higher values of LS.

Conclusion

Long term responders to IFN-based therapies have lower LS values than those who are untreated and still viraemic. High levels of γ-GT and liver steatosis, all markers of insulin resistance, may hamper reduction of liver stiffness after HCV-clearance.