The gene(s) whose expression is regulated by allergy risk variants is unknown for many loci identified through genome-wide association studies. Addressing this knowledge gap might point to new therapeutic targets for allergic disease. The aim of this study was to identify the target gene(s) and the functional variant(s) underlying the association between rs7009110 on chromosome 8q21 and allergies. Eight genes are located within 1 Mb of rs7009110. Multivariate association analysis of publicly available exon expression levels from lymphoblastoid cell lines (LCLs) identified a significant association between rs7009110 and the expression of a single gene: PAG1 (P=0.0017), 732 kb away. Analysis of histone modifications and DNase I hypersensitive sites in LCLs identified four putative regulatory elements (PREs) in the region. Chromosome conformation capture confirmed that two PREs interacted with the PAG1 promoter, one in allele-specific fashion. To determine if these PREs were functional, LCLs were transfected with PAG1 promoter-driven luciferase reporter constructs. PRE3 acted as a transcriptional enhancer for PAG1 exclusively when it carried the rs2370615:C allergy predisposing allele, a variant in complete linkage disequilibrium with rs7009110. As such, rs2370615, which overlaps RelA transcription factor (TF) binding in LCLs and was found to disrupt Foxo3a binding to PRE3, represents the putative functional variant in this locus. Our studies suggest that the risk-associated allele of rs2370615 predisposes to allergic disease by increasing PAG1 expression which may promote B-cell activation and have a pro-inflammatory effect. Inhibition of PAG1 expression or function may have therapeutic potential for allergic diseases.
Allergic disease; PAG1 expression; chromosome 8q21; target gene; functional variant
Patient preferences for radiation therapy (rt) access were investigated.
Patients completing a course of rt at 6 centres received a 17-item survey that rated preferences for time of day; day of week; actual, ideal, and reasonable travel times for rt; and actual, ideal, and reasonable times between referral and first oncologic consultation. Patients receiving single-fraction rt or brachytherapy alone were excluded.
Of the respondents who returned surveys (n = 1053), 54% were women, and 74% had received more than 15 rt fractions. With respect to appointment times, 88% agreed or strongly agreed that rt between 08h00 and 16h30 was preferred; 14%–15% preferred 07h30–08h00 or 16h30–17h00; 10% preferred 17h00–18h00; and 6% or fewer preferred times before 07h30 or after 18h00. A preference not to receive rt before 07h30 or after 18h00 was expressed by 30% or more of the respondents. When days of the week were considered, 18% and 11% would have preferred to receive rt on a Saturday or Sunday respectively; 52% and 55% would have preferred not to receive rt on those days. A travel time of 1 hour or less for rt was reported by 82%, but 61% felt that a travel time of 1 hour or more was reasonable. A first consultation within 2 weeks of referral was felt to be ideal or reasonable by 88% and 73% of patients respectively.
An rt service designed to meet patient preferences would make most capacity available between 08h00 and 16h30 on weekdays and provide 10%–20% of rt capacity on weekends and during 07h30–08h00 and 16h30–18h00 on weekdays. Approximately 80%, but not all, of the responding patients preferred a 2-week or shorter interval between referral and first oncologic consultation.
Radiation therapy; health service capacity; patient-centred care; preferences
We present a case of spontaneous regression of a neuroendocrine tumor following pregnancy in the absence of chemotherapy, radiotherapy, or alternative medicine (including herbal medicine). The diagnosis of a nonsecretory carcinoid tumor was confirmed using CT imaging, octreotide scan, and histology. Furthermore, serial imaging has demonstrated spontaneous regression of the carcinoid suggesting that pregnancy did not worsen the course of the disease but instead may have contributed to tumour regression. We discuss mechanisms underlying tumour regression and the possible effect of pregnancy on these processes.
Background. Laparoscopic liver resection (LLR) has emerged as an alternative procedure to open liver resection in selected patients. The purpose of this study was to describe our initial experience of 100 patients undergoing LLR.
Methods. We analysed a prospectively maintained hepatobiliary database of 100 patients who underwent LLR between August 2007 and August 2012. Clinicopathological data were reviewed to evaluate surgical outcomes following LLR. Results. The median age was 64 and median BMI 27. Patients had a liver resection for either malignant lesions (n = 74) or benign lesions (n = 26). Commonly performed procedures were segmentectomy/metastectomy (n = 55), left lateral sectionectomy (LLS) (n = 26), or major hepatectomy (n = 19). Complete LLR was performed in 84 patients, 9 were converted to open and 7 hand-assisted. The most common indications were CRLM (n = 62), followed by hepatic adenoma (n = 9) or hepatocellular carcinoma (n = 7). The median operating time was 240 minutes and median blood loss was 250 mL. Major postoperative complications occurred in 9 patients. The median length of stay (LOS) was 5 days. One patient died within 30 days of liver resection. Conclusions. LLR is a safe and oncologically feasible procedure with comparable short-term perioperative outcomes to the open approach. However, further studies are necessary to determine long-term oncological outcomes.
A modeling framework relating exposure, biomarkers (vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor (sVEGFR)-2, -3, soluble stem cell factor receptor (sKIT)), and tumor growth to overall survival (OS) was extended to include adverse effects (myelosuppression, hypertension, fatigue, and hand–foot syndrome (HFS)). Longitudinal pharmacokinetic–pharmacodynamic models of sunitinib were developed based on data from 303 patients with gastrointestinal stromal tumor. Myelosuppression was characterized by a semiphysiological model and hypertension with an indirect response model. Proportional odds models with a first-order Markov model described the incidence and severity of fatigue and HFS. Relative change in sVEGFR-3 was the most effective predictor of the occurrence and severity of myelosuppression, fatigue, and HFS. Hypertension was correlated best with sunitinib exposure. Baseline tumor size, time courses of neutropenia, and relative increase of diastolic blood pressure were identified as predictors of OS. The framework has potential to be used for early monitoring of adverse effects and clinical response, thereby facilitating dose individualization to maximize OS.
Radioembolisation is a way of providing targeted radiotherapy to colorectal liver metastases. Results are encouraging but there is still no standard method of assessing the response to treatment. This paper aims to review the current experience assessing response following radioembolisation. A literature review was undertaken detailing radioembolisation in the treatment of colorectal liver metastases comparing staging methods, criteria, and response. A search was performed of electronic databases from 1980 to November 2011. Information acquired included year published, patient numbers, resection status, chemotherapy regimen, criteria used to stage disease and assess response to radioembolisation, tumour markers, and overall/progression free survival. Nineteen studies were analysed including randomised controlled trials, clinical trials, meta-analyses, and case series. There is no validated modality as the method of choice when assessing response to radioembolisation. CT at 3 months following radioembolisation is the most frequently modality used to assess response to treatment. PET-CT is increasingly being used as it measures functional and radiological aspects. RECIST is the most frequently used criteria. Conclusion. A validated modality to assess response to radioembolisation is needed. We suggest PET-CT and CEA pre- and postradioembolisation at 3 months using RECIST 1.1 criteria released in 2009, which includes criteria for PET-CT, cystic changes, and necrosis.
The predictive value of longitudinal biomarker data (vascular endothelial growth factor
(VEGF), soluble VEGF receptor (sVEGFR)-2, sVEGFR-3, and soluble stem cell factor receptor
(sKIT)) for tumor response and survival was assessed based on data from 303 patients with
imatinib-resistant gastrointestinal stromal tumors (GIST) receiving sunitinib and/or
placebo treatment. The longitudinal tumor size data were well characterized by a tumor
growth inhibition model, which included, as significant descriptors of tumor size change,
the model-predicted relative changes from baseline over time for sKIT (most significant)
and sVEGFR-3, in addition to sunitinib exposure. Survival time was best described by a
parametric time-to-event model with baseline tumor size and relative change in sVEGFR-3
over time as predictive factors. Based on the proposed modeling framework to link
longitudinal biomarker data with overall survival using
pharmacokinetic–pharmacodynamic models, sVEGFR-3 demonstrated the greatest
predictive potential for overall survival following sunitinib treatment in GIST.
To develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS.
The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions.
Results and Recommendations:
AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of ∼50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of ∼50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme-inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors, as pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C).
Minimally invasive interventional cancer therapy of drug-carrying lipid nanoparticles (liposomes) via convection enhanced delivery generally applied by the use of an infusion pump can increase intratumoral drug concentration and retention while facilitating broad distribution throughout solid tumors. We investigated the utility of liposome-carrying β-emitting radionuclides to treat head and neck cancer in nude rats by direct intratumoral infusion.
Four groups of nude rats were subcutaneously inoculated with human tongue cancer cells. After tumors reached an average size of 1.6 cm3, the treatment group received an intratumoral infusion of liposomal rhenium-186 (186Re) (185 MBq (5 mCi)/cm3 tumor). Three control groups were intratumorally infused with either, 1) unlabeled liposomes, 2) unencapsulated 186Re-perrhenate, or 3) unencapsulated intermediate 186Re-compound (186Re-BMEDA). In vivo distribution of 186Re-activity was measured by planar gamma camera imaging. Tumor therapy and toxicity were assessed by measurements of tumor size, body weight, and hematology.
Average tumor volume of the 186Re-liposome group on post-treatment day-14 decreased to 87.7±20.1%, while tumor volumes increased to 395.0% - 514.4% on average in other three groups (P<0.001 vs 186Re-liposome group). 186Re-liposomes provided much higher intratumoral retention of 186Re-activity, resulting in an average tumor radiation absorbed dose of 526.3±93.3 Gy, whereas 186Re-perrhenate and 186Re-BMEDA groups had only 3.3±1.2 and 13.4±9.2 Gy tumor doses respectively. No systemic toxicity was observed.
Liposomal 186Re effectively treated the head and neck cancer with minimal side effects after convection enhanced interventional delivery. These results suggest the potential of liposomal 186Re for clinical application in interventional therapy of cancer.
This report presents the case of a 70-year-old woman with a previous history of a left nephrectomy for renal cell carcinoma (RCC), who developed general malaise and fatigue. Abdominal computed tomography demonstrated an enhancing 6 × 7 cm necrotic lesion in the lower pole of the spleen suggestive of a metastasis. Given the highly suspicious nature of the lesion we proceeded to splenectomy. The tumour did not breach the splenic capsule, and there was no local diaphragmatic involvement. The mass was concluded to be a true metastasis of the original RCC rather than local recurrence of the disease. The causes of isolated solid splenic lesions are wide and varied, however a past or present history of malignancy should lead to a high index of suspicion for a splenic metastasis. We report an extremely unusual case of spread from a RCC.
Spleen; Metastasis; Renal cell carcinoma
Surgical resection for colorectal liver metastases may only be considered when an adequate functional residual volume can be preserved. Selective portal venous embolisation may be used to increase this volume, whilst chemotherapy and radiofrequency ablation (RFA) can be used to treat inoperable lesions. A 73-year-old man with liver metastasis proceeded to surgery, with the intention to perform a right hemi-hepatectomy. Unexpectedly at laparotomy, despite adequate pre-operative imaging, both the right and middle hepatic veins were involved. At that time extended right hemi-hepatectomy was contraindicated by insufficient residual volume and RFA was performed. Follow-up imaging revealed atrophy of the lesion. Significantly, there was also left lateral lobe hypertrophy sufficient to permit resection, which was performed without complication. Thrombosis of intra-hepatic portal veins is a recognised complication of RFA but here it appears to have been beneficial. The case highlights the need for regular review of unresectable hepatic disease by a liver surgeon and could suggest new modalities of portal embolisation.
Radiofrequency ablation; Liver metastasis; Resectability
Meningiomas are slow-growing intracranial/intraspinal tumours, with a wide range of histopathological variants. The more aggressive atypical and malignant types can disseminate via the venous system, lymphatics or cerebrospinal fluid, with the lungs and pleura being the most common site of extracranial metastasis. We look at a 68-year-old woman presenting with abdominal pain, who had previously been treated for an intracranial meningioma with a ventriculo-peritoneal shunt in situ. Investigation revealed a lesion in segment 4 of the liver with the shunt tip being in close proximity. Biopsy was consistent with metastatic meningioma. A liver resection was subsequently performed. We postulate that this is the first reported case of dissemination of an intracranial meningioma via cerebrospinal fluid by means of a ventriculo-peritoneal shunt.
Hepatic metastasis; Meningioma; Ventriculo-peritoneal shunt
Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid use, prenatal vitamin K use, risk of hemorrhagic disease of the newborn, clinical implications of placental and breast milk transfer of antiepileptic drugs (AEDs), risks of breastfeeding, and change in AED levels during pregnancy.
Methods: A 20-member committee evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and October 2007.
Results: Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in amounts that may be clinically important. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative.
Recommendations: Supplementing women with epilepsy with at least 0.4 mg of folic acid before they become pregnant may be considered (Level C). Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered (Level B) and monitoring of levetiracetam and oxcarbazepine (as monohydroxy derivative) levels may be considered (Level C). A paucity of evidence limited the strength of many recommendations.
Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy.
Methods: Systematic review of relevant articles published between January 1985 and June 2007.
Results: It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine and possible compared to phenytoin or lamotrigine. Compared to untreated WWE, it is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. It is probable that antiepileptic drug (AED) polytherapy as compared to monotherapy regimens contributes to the development of MCMs and to reduced cognitive outcomes. For monotherapy, intrauterine exposure to VPA probably reduces cognitive outcomes. Further, monotherapy exposure to phenytoin or phenobarbital possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of <7.
Recommendations: If possible, avoidance of valproate (VPA) and antiepileptic drug (AED) polytherapy during the first trimester of pregnancy should be considered to decrease the risk of major congenital malformations (Level B). If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered to prevent reduced cognitive outcomes (Level B). If possible, avoidance of phenytoin and phenobarbital during pregnancy may be considered to prevent reduced cognitive outcomes (Level C). Pregnancy risk stratification should reflect that the offspring of women with epilepsy taking AEDs are probably at increased risk for being small for gestational age (Level B) and possibly at increased risk of 1-minute Apgar scores of <7 (Level C).
Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including the risk of pregnancy complications or other medical problems during pregnancy in WWE compared to other women, change in seizure frequency, the risk of status epilepticus, and the rate of remaining seizure-free during pregnancy.
Methods: A 20-member committee including general neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review and classification of relevant articles published between 1985 and February 2008.
Results: For WWE taking antiepileptic drugs, there is probably no substantially increased risk (greater than two times expected) of cesarean delivery or late pregnancy bleeding, and probably no moderately increased risk (greater than 1.5 times expected) of premature contractions or premature labor and delivery. There is possibly a substantially increased risk of premature contractions and premature labor and delivery during pregnancy for WWE who smoke. Seizure freedom for at least 9 months prior to pregnancy is probably associated with a high likelihood (84%–92%) of remaining seizure-free during pregnancy.
Recommendations: Women with epilepsy (WWE) should be counseled that seizure freedom for at least 9 months prior to pregnancy is probably associated with a high rate (84%–92%) of remaining seizure-free during pregnancy (Level B). However, WWE who smoke should be counseled that they possibly have a substantially increased risk of premature contractions and premature labor and delivery during pregnancy (Level C).
In selecting and defining composite end points in clinical trials, are we trading off clinical significance for statistical significance?
clinical trials; coronary heart disease; end points
Background/Aims. At present, there is no simple test for predicting severity in acute pancreatitis. We investigated the use of an assay of soluble E-cadherin (sE-cadherin). Methods. Concentrations of sE-cadherin, from 19 patients with mild acute pancreatitis, 7 patients with severe acute pancreatitis, 11 patients with other acute gastrointestinal pathologies, and 12 healthy subjects were measured using a commercially available sandwich ELISA kit based on two monoclonal antibodies specific to the extracellular fragment of human E-cadherin. Measurements were made at 12 hours or less from onset of pain and also at 24 and 48 hours after onset of pain. Results. Mean (standard deviation) concentration of sE-cadherin in patients with severe acute pancreatitis at <12 hours was 17780 ng/mL (7853), significantly higher than that of healthy volunteers 5180 ng/mL (1350), P = .0039, patients with other gastrointestinal pathologies 7358 ng/mL (6655), P = .0073, and also significantly higher than that of patients with mild pancreatitis, 7332 ng/mL (2843), P = .0019. Discussion. Serum sE-cadherin could be an early (within 12 hours) objective marker of severity in acute pancreatitis. This molecule warrants further investigation in the form of a large multicentre trial.
Cholinergic neurons of the striatum play a crucial role in controlling output from this region. Their firing is under the control of a relatively limited glutamatergic input, deriving principally from the thalamus. Glutamate transmission is effected via three major subtypes of receptors, including those with affinity for N-methyl-d-aspartate (NMDA) and the properties of individual receptors reflect their precise subunit composition. We examined the distribution of NMDA2C and NMDA2D subunits in the rat striatum using immunocytochemistry and show that a population of large neurons is strongly immunoreactive for NMDA2D subunits. From their morphology and ultrastructure, these neurons were presumed to be cholinergic and this was confirmed with double immunofluorescence. We also show that NMDA2C is present in a small number of septal and olfactory cortical neurons but absent from the striatum.
Receptors that include NMDA2D subunits are relatively insensitive to magnesium ion block making neurons more likely to fire at more negative membrane potentials. Their localization to cholinergic neurons may enable very precise regulation of firing of these neurons by relatively small glutamatergic inputs.
interneuron; ultrastructure; synapse; endoplasmic reticulum