Current Management of Neuroendocrine Tumour Liver Metastases.

PURPOSE OF REVIEW: This article aims to illustrate the current state of investigations and management of liver metastases in patients with Neuroendocrine Neoplasms. Neuroendocrine tumours (NETs) are rising in incidence globally and have become the second most prevalent gastrointestinal malignancy in UK and USA. Frequently, patients have metastatic disease at time of presentation. The liver is the most common site of metastases for gastro-enteropancreatic NETs. Characterisation of liver metastases with imaging is important to ensure disease is not under-staged. RECENT FINDINGS: Magnetic resonance imaging and positron emission tomography are now becoming standard of care for imaging liver metastases. There is an increasing armamentarium of therapies available for management of NETs and loco-regional therapy for liver metastases. The data supporting surgical and loco-regional therapy is reviewed with focus on role of liver transplantation. It is important to use appropriate imaging and classification of NET liver metastases. It is key that decisions regarding approach to treatment is undertaken in a multidisciplinary team and that individualised approaches are considered for management of patients with metastatic NETs.

Outcomes of Renal Tumors Treated by Image-Guided Percutaneous Cryoablation: Immediate and 3- and 5-Year Outcomes at a Regional Center.

OBJECTIVE. The purpose of this study was to evaluate the immediate and 3- and 5-year outcomes of patients with clinical stage T1 (cT1) biopsy-proven renal cell carcinoma (RCC) treated by image-guided percutaneous cryoablation at a regional interventional oncology center. MATERIALS AND METHODS. A prospectively maintained local interventional radiology database identified patients with cT1 RCC lesions that were treated by percutaneous cryoablation. Technical success, procedural complications (graded using the Clavien-Dindo classification system), and the residual unablated tumor rate were collated. Local tumor progression-free survival was estimated using Kaplan-Meier estimates. RESULTS. A total of 180 patients with 185 separate cT1 RCC lesions were identified. Mean patient age was 68.4 years (range, 34.1-88.9 years) and 52 patients (28.9%) were women. There were 168 (90.8%) and 17 (9.2%) cT1a and cT1b lesions, respectively, with a mean lesion size of 28.5 mm (range, 11-58 mm). Technical success was achieved in 183 of 185 (98.9%) patients. The major complication rate (Clavien-Dindo classification ≥ grade III) was 2.2% (four out of 185). Residual unablated tumor on the first follow-up scan was identified in four of 183 tumors (2.2%). Estimated local tumor progression-free survival at 3 and 5 years was 98.3% and 94.9%, respectively. No distant metastases or deaths attributable to RCC occurred. Mean estimated glomerular filtration rate (eGFR) before the procedure was 72.4 ± 18.5 (SD) mL/min/1.73 m2 and this was not statistically significantly different after the procedure (69.7 ± 18.8 mL/min/1.73 m2), at 1 year (70.7 ± 16.4 mL/min/1.73 m2), or at 2 years (69.8 ± 18.9 mL/min/1.73 m2) (p > 0.05). CONCLUSION. These data add to the accumulating evidence that image-guided cryoablation is an efficacious treatment for selected cT1 RCC with a low complication rate and ro bust 3- and 5-year outcomes.

Triazolopyridine ethers as potent, orally active mGlu2 positive allosteric modulators for treating schizophrenia.

Triazolopyridine ethers with mGlu2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2 PAMs for the treatment of schizophrenia and merit further preclinical investigation.

Corticosteroids for the treatment of Kawasaki disease in children.

BACKGROUND: Kawasaki disease (KD), or mucocutaneous syndrome, is the leading cause of childhood-acquired heart disease in the developed world. There is much controversy on how best to treat children with KD and in particular who may benefit from additional treatment beyond the standard intravenous immunoglobulin (IVIG) and aspirin, such as the addition of corticosteroids. OBJECTIVES: To assess the impact of corticosteroid use on the incidence of coronary artery abnormalities in KD as either first-line or second-line treatment. Corticosteroids may be given alone or in conjunction with other accepted KD treatments. Secondary objectives include the effect of steroids on mortality, the time taken for laboratory parameters to normalise, the duration of acute symptoms (such as fever), the long-term impact of steroid use and evaluating their safety in KD and their efficacy in relevant population subgroups. SEARCH METHODS: The Cochrane Vascular Information Specialist searched Cochrane Vascular's Specialised Register (25 November 2016) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10) in the Cochrane Library (searched 25 November 2016). Trial registries were also searched for details of ongoing or unpublished studies. SELECTION CRITERIA: We selected randomised trials involving children with all severities of KD who were treated with corticosteroids, including different types of corticosteroid and different durations of treatment. DATA COLLECTION AND ANALYSIS: MJS and GMC independently selected studies, assessed evidence quality and extracted data. This process was overseen by AJW. MAIN RESULTS: Seven trials consisting of 922 participants were included in this analysis. Trials ranged from 32 to 242 participants. On pooled analysis, corticosteroids reduced the subsequent occurrence of coronary artery abnormalities (odds ratio (OR) 0.29, 95% confidence interval (CI) 0.18 to 0.46; 907 participants; 7 studies; I² = 55%) without resultant serious adverse events (no events, 737 participants) and mortality (no events, 915 participants). In addition, corticosteroids reduced the duration of fever (mean difference (MD) -1.65 days, 95% CI -3.31 to 0.00; 210 participants; 2 studies; I² = 88%), time for laboratory parameters (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) to normalise (MD -2.80 days, 95% CI -4.38 to -1.22; 178 participants; 1 study) and length of hospital stay (MD -1.41 days, 95% CI -2.36 to -0.46; 39 participants; 1 study). No studies detailed outcomes beyond 24 weeks. Subgroup analysis showed some potential groups that may benefit more than others; however, further randomised controlled trials are required before this can be the basis for clinical action.Evidence quality was graded according to the GRADE system. Evidence was considered high quality for the incidence of serious adverse events, mortality and time for laboratory parameters to normalise. Evidence was considered moderate for the incidence of coronary artery abnormalities due to potential inconsistencies in data geography and patient benefits according to grouping. Evidence was moderate for duration of clinical symptoms (fever, rash) due to potential subjectivity in measurement. Evidence was moderate for length of hospital stay as only one study recorded this outcome. This means that we are reasonably confident that the true effect is close to that estimated in this work. AUTHORS' CONCLUSIONS: Moderate-quality evidence shows that use of steroids in the acute phase of KD can be associated with improved coronary artery abnormalities, shorter duration of hospital stay and a decreased duration of clinical symptoms. High-quality evidence shows reduced inflammatory marker levels. There were insufficient data available regarding incidence of adverse effects attributable to steroids, mortality and long-term (> 1 year) coronary morbidity. Certain groups, including those based in Asia, those with higher risk scores, and those receiving longer steroid treatment may have greater benefit from steroid use, especially with decreasing rates of heart problems, but more tests are needed to answer these questions. Evidence presented in this study suggests that treatment with a long course of steroids should be considered for all children diagnosed with KD until further studies are performed.

The Diagnostic Utility and Clinical Impact of After-Hours CT Scans of the Abdomen and Pelvis Investigating Abdominal Pain.

INTRODUCTION: The aim of this study was to evaluate the diagnostic utility and impact on clinical management of after-hours CT scans investigating abdominal pain in surgical patients. METHODS: After-hours CT A/P reports investigating the acute surgical abdomen were compared with clinical outcomes and histopathological findings to assess sensitivity and specificity of CT reporting. Comparisons between CT reports and clinical notes were made. CT scans were categorised as having direct effects on clinical management, ruling out a serious pathology, ruling out a nonserious pathology, or having no effect. Discrepancies between information in case-notes and information provided to radiologists were also analysed. RESULTS: 79 clinical notes were located. After-hours CT demonstrated 91% sensitivity and 82% reporting specificity using clinical outcomes as the standard. In the 26 patients with histopathological findings, CT reports demonstrated 91% sensitivity. In 79.7% of cases, CT scanning had an impact on management. In 35.4% of cases, an indication for scanning was not documented with variation in clinical information in 8.9% of cases. DISCUSSION: This study demonstrates after-hours CT A/P reports result in significant impacts on clinical management of surgical patients with acute abdominal pain. Improvements in providing information when requesting scans are however needed to facilitate accurate reporting.

Guanylate cyclase stimulators for pulmonary hypertension.

BACKGROUND: Pulmonary hypertension is a condition of complex aetiology that culminates in right heart failure and early death. Soluble guanylate cyclase (sGC) stimulators are a promising class of agents that have recently gained approval for use. OBJECTIVES: To evaluate the efficacy of sGC stimulators in pulmonary hypertension. SEARCH METHODS: We searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE and the reference lists of articles. Searches are current as of 12 February 2016. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) involving participants with pulmonary hypertension of all ages, severities and durations of treatment. DATA COLLECTION AND ANALYSIS: AW, MS and RW independently selected studies, assessed evidence quality and extracted data. This process was overseen by RT and SG. All included studies were sponsored by the drug manufacturer. MAIN RESULTS: Five trials involving 962 participants are included in this review. All trials were of relatively short duration (< 16 weeks). Due to the heterogenous aetiology of pulmonary hypertension in participants, results are best considered according to each pulmonary hypertension subtype.Pooled analysis shows a mean difference (MD) increase in six-minute walking distance (6MWD) of 30.13 metres (95% CI 5.29 to 54.96; participants = 659; studies = 3). On subgroup analysis, for pulmonary arterial hypertension (PAH) there was no effect noted (6MWD; MD 11.91 metres, 95% CI -44.92 to 68.75; participants = 398; studies = 2), and in chronic thromboembolic pulmonary hypertension (CTEPH) sGC stimulators improved 6MWD by an MD of 45 metres (95% CI 23.87 to 66.13; participants = 261; studies = 1). Data for left heart disease-associated PH was not available for pooling. Importantly, when participants receiving phosphodiesterase inhibitors were excluded, sGC stimulators increased 6MWD by a MD of 36 metres in PAH. The second primary outcome, mortality, showed no change on pooled analysis against placebo (Peto odds ratio (OR) 0.57, 95% CI 0.18 to 1.80).Pooled secondary outcomes include an increase in World Health Organization (WHO) functional class (OR 1.53, 95% CI 0.87 to 2.72; participants = 858; studies = 4), no effect on clinical worsening (OR 0.45, 95% CI 0.17 to 1.14; participants = 842; studies = 3), and a reduction in mean pulmonary artery pressure (MD -2.77 mmHg, 95% CI -4.96 to -0.58; participants = 744; studies = 5). There was no significant difference in serious adverse events on pooled analysis (OR 1.12, 95% CI 0.66 to 1.90; participants = 818; studies = 5) or when analysed at PAH (MD -3.50, 95% CI -5.54 to -1.46; participants = 344; studies = 1), left heart disease associated subgroups (OR 1.56, 95% CI 0.78 to 3.13; participants = 159; studies = 2) or CTEPH subgroups (OR 1.29, 95% CI 0.65 to 2.56; participants = 261; studies = 1).It is important to consider the results for PAH in the context of a person who is not also receiving a phosphodiesterase-V inhibitor, a contra-indication to sGC stimulator use. It should also be noted that CTEPH results are applicable to inoperable or recurrent CTEPH only.Evidence was rated according to the GRADE scoring system. One outcome was considered high quality, two were moderate, and eight were of low or very low quality, meaning that for many of the outcomes the true effect could differ substantially from our estimate. There were only minor concerns regarding the risk of bias in these trials, all being RCTs largely following the original protocol. Most trials employed an intention-to-treat analysis. AUTHORS' CONCLUSIONS: sGC stimulators improve pulmonary artery pressures in people with PAH (who are treatment naive or receiving a prostanoid or endothelin antagonist) or those with recurrent or inoperable CTEPH. In these settings this can be achieved without notable complication. However, sGC stimulators should not be taken by people also receiving phosphodiestase-V inhibitors or nitrates due to the risks of hypotension, and there is currently no evidence supporting their use in pulmonary hypertension associated with left heart disease. There is no evidence supporting their use in children. These conclusions are based on data with limitations, including unavailable data from two of the trials.

The use of functional imaging in the diagnosis of carotid patch infection.

Carotid patch infection following carotid patch angioplasty is a rare but serious complication. Accurate diagnosis is vital yet currently ill-defined. We present the use of computed tomography positron emission tomography and leucocyte radioisotope scintigraphy and highlight their potential role in the diagnosis of equivocal carotid patch infection.

Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation.

The forebrain cholinergic system promotes higher brain function in part by signaling through the M(1) muscarinic acetylcholine receptor (mAChR). During Alzheimer's disease (AD), these cholinergic neurons degenerate, therefore selectively activating M(1) receptors could improve cognitive function in these patients while avoiding unwanted peripheral responses associated with non-selective muscarinic agonists. We describe here benzyl quinolone carboxylic acid (BQCA), a highly selective allosteric potentiator of the M(1) mAChR. BQCA reduces the concentration of ACh required to activate M(1) up to 129-fold with an inflection point value of 845 nM. No potentiation, agonism, or antagonism activity on other mAChRs is observed up to 100 microM. Furthermore studies in M(1)(-/-) mice demonstrates that BQCA requires M(1) to promote inositol phosphate turnover in primary neurons and to increase c-fos and arc RNA expression and ERK phosphorylation in the brain. Radioligand-binding assays, molecular modeling, and site-directed mutagenesis experiments indicate that BQCA acts at an allosteric site involving residues Y179 and W400. BQCA reverses scopolamine-induced memory deficits in contextual fear conditioning, increases blood flow to the cerebral cortex, and increases wakefulness while reducing delta sleep. In contrast to M(1) allosteric agonists, which do not improve memory in scopolamine-challenged mice in contextual fear conditioning, BQCA induces beta-arrestin recruitment to M(1), suggesting a role for this signal transduction mechanism in the cholinergic modulation of memory. In summary, BQCA exploits an allosteric potentiation mechanism to provide selectivity for the M(1) receptor and represents a promising therapeutic strategy for cognitive disorders.

Inhibition of calcineurin-mediated endocytosis and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors prevents amyloid beta oligomer-induced synaptic disruption.

Synaptic degeneration, including impairment of synaptic plasticity and loss of synapses, is an important feature of Alzheimer disease pathogenesis. Increasing evidence suggests that these degenerative synaptic changes are associated with an accumulation of soluble oligomeric assemblies of amyloid beta (Abeta) known as ADDLs. In primary hippocampal cultures ADDLs bind to a subpopulation of neurons. However the molecular basis of this cell type-selective interaction is not understood. Here, using siRNA screening technology, we identified alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits and calcineurin as candidate genes potentially involved in ADDL-neuron interactions. Immunocolocalization experiments confirmed that ADDL binding occurs in dendritic spines that express surface AMPA receptors, particularly the calcium-impermeable type II AMPA receptor subunit (GluR2). Pharmacological removal of the surface AMPA receptors or inhibition of AMPA receptors with antagonists reduces ADDL binding. Furthermore, using co-immunoprecipitation and photoreactive amino acid cross-linking, we found that ADDLs interact preferentially with GluR2-containing complexes. We demonstrate that calcineurin mediates an endocytotic process that is responsible for the rapid internalization of bound ADDLs along with surface AMPA receptor subunits, which then both colocalize with cpg2, a molecule localized specifically at the postsynaptic endocytic zone of excitatory synapses that plays an important role in activity-dependent glutamate receptor endocytosis. Both AMPA receptor and calcineurin inhibitors prevent oligomer-induced surface AMPAR and spine loss. These results support a model of disease pathogenesis in which Abeta oligomers interact selectively with neurotransmission pathways at excitatory synapses, resulting in synaptic loss via facilitated endocytosis. Validation of this model in human disease would identify therapeutic targets for Alzheimer disease.

Quinolizidinone carboxylic acid selective M1 allosteric modulators: SAR in the piperidine series.

SAR study of the piperidine moiety in a series of quinolizidinone carboxylic acid M(1) positive allosteric modulators was examined. While the SAR was generally flat, compounds were identified with high CNS exposure to warrant additional in vivo evaluation.

Fused heterocyclic M1 positive allosteric modulators.

Fused aromatics such as naphthalene were identified as highly potent and CNS penetrant M(1) positive allosteric modulators during an SAR study to replace the phenyl B-ring linkage.

Combination of ablation and embolization for intermediate-sized liver metastases from colorectal cancer: what can we learn from treating primary liver cancer?

Colorectal cancer liver metastases (CRLMs) are common. Treating CRLMs with thermal ablation can prolong survival, but compared to lesions smaller than 3 cm, local control rates and overall survival are relatively worse with larger, intermediate (3-5 cm) lesions. Local recurrence rates range between 1.7%-20.2% and 6.7%-68.9% for CRLMs less than 3 cm and greater than 3 cm, respectively. Worse outcomes are also present when ablating intermediate size hepatocellular carcinoma (HCC) and there are some pathological similarities with CRLMs, namely the presence of micrometastatic disease. Combining ablation with transarterial chemoembolization is more effective in treating intermediate-size HCC than ablation alone. A meta-analysis of robust randomized controlled trials demonstrated long-term improved survival with combination therapy compared to ablation alone (odds ratio at 1, 3 and 5 years of 2.74, 2.77 and 5.23, respectively). There is, however, minimal evidence for combination therapy in CRLMs, limited to a handful of studies that are predominantly retrospective and have heterogeneous inclusion criteria. Given the difficulty in successfully treating intermediate CRLMs, the strong evidence for combination therapy in intermediate HCC and potential pathological similarities, formal evaluation of combination treatment in CRLM is merited. This review highlights existing evidence for treatment of intermediate-size liver lesions and highlights where trials in CRLMs should focus.

Renal cryoablation - a practical guide for interventional radiologists.

Renal cryoablation is a treatment option for early stage renal cell carcinomas with excellent oncological outcomes and low morbidity. This review outlines the technique of renal cryoablation and provides a guide for interventional radiologists on setting up an integrated service within a renal cancer network multidisciplinary setting. Patient selection and preparation, together with the technical aspects which ensure optimal oncological outcomes and avoid collateral damage to adjacent organs are highlighted.

Pyridine containing M(1) positive allosteric modulators with reduced plasma protein binding.

Incorporation of pyridines and diazines into the biphenyl region of quinolone carboxylic acid derived M(1) positive allosteric modulators was investigated as a means of lowering plasma protein binding to enhance CNS exposure.

Heterocyclic fused pyridone carboxylic acid M(1) positive allosteric modulators.

The phenyl ring in a series of quinolone carboxylic acid M(1) positive allosteric modulators was replaced with a variety of heterocycles in order to reduce protein plasma binding and enhance CNS exposure.

Hydroxy cycloalkyl fused pyridone carboxylic acid M(1) positive allosteric modulators.

Incorporation of hydroxycycloalkyl fused pyridone carboxylic acids in lieu of quinolone carboxylic acids enhance free fraction without increased susceptibility to P-glycoprotein transport.

N-heterocyclic derived M1 positive allosteric modulators.

Replacement of a phenyl ring with N-linked heterocycles in a series of quinolone carboxylic acid M1 positive allosteric modulators was investigated. In particular, a pyrazole derivative exhibited improvements in potency, free fraction, and CNS exposure.

Parallel synthesis of N-biaryl quinolone carboxylic acids as selective M(1) positive allosteric modulators.

An iterative analog library synthesis approach was employed in the exploration of a quinolone carboxylic acid series of selective M(1) positive allosteric modulators, and strategies for improving potency and plasma free fraction were identified.

Splenogonadal fusion: A rare paratesticular lesion and how to recognise it on ultrasound.

INTRODUCTION: Splenogonadal fusion is a rare developmental disorder that results in a gonadal or paragonadal mass due to the close proximity of the developing spleen and gonad. CASE REPORT: We describe a case of splenogonadal fusion presenting as a paratesticular mass in a 25-year-old male. This was ultimately diagnosed on surgical biopsy. DISCUSSION: Splenogonadal fusion is a rare abnormality but can be managed conservatively. The sonographic features and the differential diagnosis are highlighted. CONCLUSION: Through this case, we highlight the clinical and sonographic features of splenogonadal fusion. Awareness amongst ultrasound practitioners is important, given that it can be managed conservatively, and means of a non-invasive diagnosis are highlighted.

Evaluation of 5-HT7 receptor antagonism for the treatment of anxiety, depression, and schizophrenia through the use of receptor-deficient mice.

The 5-HT7 receptor is the most recently identified receptor subtype within a family of 5-HT receptors activated by the neurotransmitter serotonin. There has been significant interest in investigating the potential role of this receptor in psychiatric disorders including depression, anxiety, and schizophrenia. Behaviors of 5-HT7 +/+ (wild-type or WT) and 5-HT7 -/- (receptor knockout or KO) mice were compared across 10 different assays (7 for anxiety, 1 for depression, 2 for psychosis) to identify differences that could indicate clinical potential for 5-HT7 receptor antagonism. Evaluation of KO vs. WT mice demonstrated significant differences between the genotypes in the fear conditioning, shock-probe burying, novelty-suppressed feeding, punishment memory, forced swim test, and d-amphetamine hyperactivity assays. There was not consistency in either the direction of behavioral effects across genotypes or across assays. Thus, data from these behavioral assays did not uniformly support the idea that 5-HT7 receptors constitute an important drug target for these psychiatric disorders. The present findings are generally congruent with the mixed results in the literature on the behaviors of 5-HT7 -/-mice and with the data on effects of 5-HT7 receptor antagonists in rodent models that detect activity of anxiolytic, antidepressant, and antipsychotic effects.