Additional Primary Malignancies in Patients with Gastrointestinal Stromal Tumor (GIST): A Clinicopathologic Study of 260 Patients with Molecular Analysis and Review of the Literature

Annals of Surgical Oncology - The incidence of other primary neoplasms in gastrointestinal stromal tumor (GIST) patients is relatively high. Our aim was to better characterize the clinicopathologic...     

A review of oral food challenges in children presenting to a single tertiary centre with perceived or true food allergies

INTRODUCTION

The prevalence of perceived food allergies exceeds that of true food allergies. Unnecessary food avoidance may increase parental and patient anxiety, reduce quality of life and increase the risk of nutritional deficiency. An oral food challenge (OFC) can provide an objective measure regarding the presence or absence of food allergies in a child. This study reviews the indications for and outcomes of OFCs performed on children.

METHODS

A retrospective review was performed on all children who underwent OFCs at the Allergy Unit of the National University Hospital, Singapore, over a three-year period.

RESULTS

A total of 197 OFCs were performed among 58 patients (34 male, 24 female). Most of the tests were for allergies to tree nuts (n = 107). Among the OFCs, 43.1% were for foods that were avoided and never eaten due to perceived food allergies, 25.9% were for foods that had previously resulted in positive skin prick tests (SPTs) and/or immunoassay results, 16.2% were for foods thought to worsen eczema and 14.7% were for foods thought to have caused a previous reaction. Of all the OFCs, 5% were positive, although adverse reactions were mostly cutaneous. Challenge-positive patients had either positive SPTs (wheal > 3 mm) or raised serum immunoglobulin E levels to specific foods that they reacted to during the challenges. No episodes of anaphylaxis were reported after the challenge. Most of the patients were able to safely introduce the avoided foods into their diets.

CONCLUSION

OFCs provide an objective assessment for suspected food allergies.     

Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis

Bone surfaces attract hematopoietic and nonhematopoietic cells, such as osteoclasts (OCs) and osteoblasts (OBs), and are targeted by bone metastatic cancers. However, the mechanisms guiding cells toward bone surfaces are essentially unknown. Here, we show that the Gαi protein–coupled receptor (GPCR) EBI2 is expressed in mouse monocyte/OC precursors (OCPs) and its oxysterol ligand 7α,25-dihydroxycholesterol (7α,25-OHC) is secreted abundantly by OBs. Using in vitro time-lapse microscopy and intravital two-photon microscopy, we show that EBI2 enhances the development of large OCs by promoting OCP motility, thus facilitating cell–cell interactions and fusion in vitro and in vivo. EBI2 is also necessary and sufficient for guiding OCPs toward bone surfaces. Interestingly, OCPs also secrete 7α,25-OHC, which promotes autocrine EBI2 signaling and reduces OCP migration toward bone surfaces in vivo. Defective EBI2 signaling led to increased bone mass in male mice and protected female mice from age- and estrogen deficiency–induced osteoporosis. This study identifies a novel pathway involved in OCP homing to the bone surface that may have significant therapeutic potential.Osteoclasts (OCs) are multinucleated cells that regulate skeletal development and integrity by actively resorbing excess or damaged bone produced by osteoblasts (OBs) and osteocytes. OBs and osteocytes differentiate from rare mesenchymal stem cells that reside in BM parenchyma (Méndez-Ferrer et al., 2010). In contrast, OCs differentiate from BM-resident and circulatory monocytic precursors that come into close contact with bone surfaces where the essential cytokines ligand for receptor activator of nuclear factor kappa binding (RANKL, encoded by Tnfsf11) and M-CSF (encoded by Csf1) are locally produced by OBs and osteocytes (Teitelbaum, 2000; Nakashima et al., 2011). Cellular interactions between OCs and OBs regulate the activity of both cell types, such that resorbed bone is accurately replaced by newly formed bone. Although the understanding of the molecular signals required for OC differentiation has increased significantly over the past several decades, very little is understood about the mechanisms controlling the migration and positioning of OC precursors (OCPs) near, or in contact with, the bone surface.Monocytes and OCPs are dynamic within BM parenchyma (Ishii et al., 2009). OCPs recirculate between BM and peripheral organs via the action of sphingosine 1-phosphate receptors (S1PRs), which attract multiple hematopoietic cell subsets from BM parenchyma into blood circulation (Walzer et al., 2007; Ishii et al., 2009, 2010; Pereira et al., 2010b). In contrast, the signals promoting cell movement toward bone surfaces remain unknown. However, systemic RANKL administration has been shown to increase OCP homing back to BM and to promote local OC differentiation (Kotani et al., 2013). These studies suggest that OCP movement in and out of BM tissue is highly regulated and that balanced responsiveness to various chemoattractants regulates OCP movement and differentiation. Consistent with this hypothesis, bone resorption produces a milieu that contains potent chemoattractants for monocytes/OCPs (Mundy et al., 1978).Here, we investigated the role played by EBI2, a Gαi protein–coupled receptor (GPCR) involved in dendritic cell and B lymphocyte migration in secondary lymphoid organs (Gatto et al., 2009, 2013; Pereira et al., 2009b; Hannedouche et al., 2011; Kelly et al., 2011; Liu et al., 2011; Yi and Cyster, 2013), in controlling monocyte and OCP movement and positioning within BM. We show that EBI2 is highly expressed in OCPs and mature OCs and promotes OCP motility in vitro and in vivo. Furthermore, we show that OCPs deficient in EBI2 migrate poorly toward bone surfaces, which reduces OC differentiation. In contrast, OCPs that overexpressed EBI2 preferentially localized at the bone surface and fused with preexisting OCs more efficiently than control OCPs. OBs expressed the enzymes CH25H and CYP7B1 that are required for the synthesis of the EBI2-ligand 7α,25-dihydroxycholesterol (7α,25-OHC) and secreted EBI2 ligands in vitro. Interestingly, OCPs also secreted 7α,25-OHC, which results in autocrine EBI2 signaling and tempers EBI2-mediated migration toward bone surfaces. Finally, EBI2 signaling–deficient mice exhibit increased bone mass at young and old ages, and EBI2 signaling deficiency significantly protects female mice from osteoporosis induced by estrogen deficiency.     

Transjugular intrahepatic portosystemic shunt in cirrhosis: An exhaustive critical update

More than five decades after it was originally conceptualized as rescue therapy for patients with intractable variceal bleeding, the transjugular intrahepatic portosystemic shunt(TIPS) procedure continues to remain a focus of intense clinical and biomedical research. By the impressive reduction in portal pressure achieved by this intervention, coupled with its minimally invasive nature, TIPS has gained increasing acceptance in the treatment of complications of portal hypertension. The early years of TIPS were plagued by poor long-term patency of the stents and increased incidence of hepatic encephalopathy. Moreover, the diversion of portal flow after placement of TIPS often resulted in derangement of hepatic functions, which was occasionally severe. While the incidence of shunt dysfunction has markedly reduced with the advent of covered stents, hepatic encephalopathy and instances of early liver failure continue to remain a significant issue after TIPS. It has emerged over the years that careful selection of patients and diligent post-procedural care is of paramount importance to optimize the outcome after TIPS. The past twenty years have seen multiple studies redefining the role of TIPS in the management of variceal bleeding and refractory ascites while exploring its application in other complications of cirrhosis like hepatic hydrothorax, portal hypertensive gastropathy, ectopic varices, hepatorenal and hepatopulmonary syndromes, non-tumoral portal vein thrombosis and chylous ascites. It has also been utilized to good effect before extrahepatic abdominal surgery to reduce perioperative morbidity and mortality. The current article aims to review the updated literature on the status of TIPS in the management of patients with liver cirrhosis.     

Partial compliance with antipsychotics and its impact on patient outcomes

Partial compliance with antipsychotic medications is a common and complex phenomenon that is underestimated by physicians. The consequences of partial compliance include an increased risk of relapse, rehospitalization and suicide attempts. Stigma, negative attitudes towards medications, cognitive impairment and diminished insight negatively impact treatment adherence. Oral atypical antipsychotics may improve both insight and cognitive function, but compliance with these agents is not assured. Depot conventional antipsychotics ensure medication delivery but are associated with side-effects such as EPS and dysphoria that decrease compliance. Long-acting atypicals provide significant symptom improvement, foster adherence and may help achieve improvement in insight and cognition. Addressing issues of partial and non-compliance is a significant consideration in relapse prevention strategies for patients with schizophrenia, given the devastating consequences associated with psychotic relapses.     

Corticosteroid Therapy, Vitamin D Status, and Inflammatory Cytokine Profile in the HIV-Tuberculosis Immune Reconstitution Inflammatory Syndrome

Background.?Tuberculosis-immune reconstitution inflammatory syndrome (TB-IRIS) in patients coinfected with human immunodeficiency virus (HIV) and tuberculosis starting antiretroviral therapy (ART) is associated with hypercytokinemia. As adjunctive corticosteroid therapy and vitamin D have immunomodulatory properties, we investigated the relationship between cytokine/chemokine profiles, corticosteroid use, and vitamin D deficiency in TB-IRIS patients. Methods.?Plasma from 39 TB-IRIS and 42 non-IRIS patients was collected during a prospective study of HIV-associated tuberculosis patients starting ART. In total, 26% of patients received corticosteroid (CTC) therapy pre-ART for severe tuberculosis. Concentrations of total 25-hydroxyvitamin D (25(OH)D) and 14 cytokines/chemokines were determined at ART initiation and 2 weeks later. Results.?Patients prescribed concurrent CTC had lower interferon γ (IFN-γ), IP-10, tumor necrosis factor (TNF), interleukin (IL)-6, IL-8, IL-10, IL-12p40, and IL-18 pre-ART (P?≤?.02). TB-IRIS presented at 12 days (median) of ART, irrespective of CTC use. In patients who developed TB-IRIS (not on CTC) IL-6, IL-8, IL-12p40, IL-18, IP-10, and TNF increased during 2 weeks (P?≤?.04) of ART. Vitamin D deficiency (total 25(OH)D <75?nmol/L) was highly prevalent (89%) at baseline. Although vitamin D deficiency at either baseline or 2 weeks was not associated with TB-IRIS, in those not on CTC the median 25(OH)D decreased during 2 weeks (P?=?.004) of ART. Severe vitamin D deficiency (total 25(OH)D <25?nmol/L) was associated with higher baseline TNF, IL-6, and IL-8 irrespective of IRIS status. Conclusions.?CTC modifies the inflammatory profile of those who develop TB-IRIS. The association between severe vitamin D deficiency and elevated proinflammatory cytokines support a study of vitamin D supplementation in HIV-TB co-infected patients starting ART.