Feasibility of Hepatology-Directed Microwave Ablation in Management of Hepatocellular Carcinoma in North America: A Pilot Project.

In North America, the role of Hepatologists in treatment of hepatocellular carcinoma is limited. We conducted a pilot project wherein a Hepatologist participated directly in microwave ablation of HCC at an academic center in the United States (n = 14). The pilot project shows promising outcomes, with complete remission rate of 93%.

Relationship between in vivo receptor occupancy and efficacy of metabotropic glutamate receptor subtype 5 allosteric modulators with different in vitro binding profiles.

Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu5) have exciting potential as therapeutic agents for multiple brain disorders. Translational studies with mGlu5 modulators have relied on mGlu5 allosteric site positron emission tomography (PET) radioligands to assess receptor occupancy in the brain. However, recent structural and modeling studies suggest that closely related mGlu5 allosteric modulators can bind to overlapping but not identical sites, which could complicate interpretation of in vivo occupancy data, even when PET ligands and drug leads are developed from the same chemical scaffold. We now report that systemic administration of the novel mGlu5 positive allosteric modulator VU0092273 displaced the structurally related mGlu5 PET ligand, [(18)F]FPEB, with measures of in vivo occupancy that closely aligned with its in vivo efficacy. In contrast, a close analog of VU0092273 and [(18)F]FPEB, VU0360172, provided robust efficacy in rodent models in the absence of detectable occupancy. Furthermore, a structurally unrelated mGlu5 negative allosteric modulator, VU0409106, displayed measures of in vivo occupancy that correlated well with behavioral effects, despite the fact that VU0409106 is structurally unrelated to [(18)F]FPEB. Interestingly, all three compounds inhibit radioligand binding to the prototypical MPEP/FPEB allosteric site in vitro. However, VU0092273 and VU0409106 bind to this site in a fully competitive manner, whereas the interaction of VU0360172 is noncompetitive. Thus, while close structural similarity between PET ligands and drug leads does not circumvent issues associated with differential binding to a given target, detailed molecular pharmacology analysis accurately predicts utility of ligand pairs for in vivo occupancy studies.

Percutaneous management of renal caliceal diverticular stones: Ten-year experience of a tertiary care center with different techniques to deal with diverticula after stone extraction.

INTRODUCTION: Caliceal diverticulae are a frequent surgical problem. We present our experience with caliceal diverticular stones (CDS) managed with percutaneous nephrolithotomy (PCNL) and describe the two different techniques to deal with diverticula after stone retrieval. MATERIALS AND METHODS: We retrospectively analyzed 10-year data of 44 consecutive patients who underwent PCNL for CDS. During PCNL, if the guide wire could be negoted through the neck of the diverticula, we dilated and stented it. If we couldnot find the neck, we fulgurated the diverticular walls. Follow-up included intravenous urogram at 3 months and annual plain films thereafter. We analyzed the outcome, complications, and recurrence rate. RESULTS: Total stone clearance was obtained in 40 (90.90%) patients. We dilated and stented the diverticula in 35 (79.5%) patients and fulgurated the walls in nine (20.5%) patients. Complications occurred in three patients. The postoperative intravenous urogram showed obliteration of diverticula in seven patients and the improved drainage in 37 patients. At the average follow-up of 2 years, 41 (93.18%) patients were asymptomatic and two (4.5%) patients showed the recurrence of stone. CONCLUSIONS: PCNL can clear calculi from caliceal diverticula in most cases with minimal morbidity. After stone retrieval, the diverticula may be drained into the pyelocaliceal system, if the neck is negotiable and fulgurated if the neck cannot be dilated.

An unusual cause of toe necrosis.

Peripheral vascular disease is a rare feature of pheochromocytoma. This potentially catastrophic but curable tumor should be suspected in combination of distal necrosis with hypertension and palpable pulses. We report such an unusual case of pheochromocytoma presenting as toe necrosis.

Relationship of dopamine type 2 receptor binding potential with fasting neuroendocrine hormones and insulin sensitivity in human obesity.

OBJECTIVE: Midbrain dopamine (DA) neurons, which are involved with reward and motivation, are modulated by hormones that regulate food intake (insulin, leptin, and acyl ghrelin [AG]). We hypothesized that these hormones are associated with deficits in DA signaling in obesity. RESEARCH DESIGN AND METHODS: We assessed the relationships between fasting levels of insulin and leptin, and AG, BMI, and insulin sensitivity index (S(I)) with the availability of central DA type 2 receptor (D2R). We measured D2R availability using positron emission tomography and [(18)F]fallypride (radioligand that competes with endogenous DA) in lean (n = 8) and obese (n = 14) females. Fasting hormones were collected prior to scanning and S(I) was determined by modified oral glucose tolerance test. RESULTS: Parametric image analyses revealed associations between each metabolic measure and D2R. The most extensive findings were negative associations of AG with clusters involving the striatum and inferior temporal cortices. Regional regression analyses also found extensive negative relationships between AG and D2R in the caudate, putamen, ventral striatum (VS), amygdala, and temporal lobes. S(I) was negatively associated with D2R in the VS, while insulin was not. In the caudate, BMI and leptin were positively associated with D2R availability. The direction of associations of leptin and AG with D2R availability are consistent with their opposite effects on DA levels (decreasing and increasing, respectively). After adjusting for BMI, AG maintained a significant relationship in the VS. We hypothesize that the increased D2R availability in obese subjects reflects relatively reduced DA levels competing with the radioligand. CONCLUSIONS: Our findings provide evidence for an association between the neuroendocrine hormones and DA brain signaling in obese females.

Isolated renal zygomycosis: novel diagnostic and prognostic criteria with experience of a tertiary care center.

BACKGROUND: Isolated renal zygomycosis is a life-threatening infection and difficult to diagnose ante mortem due to varied presentations. Most reports in the literature are case reports. We are presenting our experience of 10 patients. MATERIALS AND METHODS: Retrospective data of 10 consecutive patients with primary renal zygomycosis, including 2 post-transplant patients, in our tertiary care center was analyzed. Epidemiological characteristics, predisposing conditions, clinical presentation, diagnostic findings and treatment outcomes were recorded. Characteristic radiological findings were recorded. Localized disease was managed by supportive treatment or percutaneous drainage and extensive disease with unilateral or bilateral nephrectomy. Renal involvement was confirmed in all patients by histopathology. RESULTS: The mean age of presentation was 35 years. Five patients who had bilateral renal involvement presented with oliguric acute renal failure, hematuria and abdominal pain. Three had unilateral renal disease and presented with flank pain and fever. The two post-transplant patients presented with fever and graft dysfunction. Even after aggressive treatment 5 patients died, accounting for a mortality rate of 50%. CONCLUSION: Isolated renal zygomycosis can be diagnosed with typical radiological findings, combined with clinical, laboratory and histopathological features. This study describes the newer ante mortem radiological diagnostic criteria and prognostic predictors of the disease.

Multimodal image coregistration and inducible selective cell ablation to evaluate imaging ligands.

We combined multimodal imaging (bioluminescence, X-ray computed tomography, and PET), tomographic reconstruction of bioluminescent sources, and two unique, complementary models to evaluate three previously synthesized PET radiotracers thought to target pancreatic beta cells. The three radiotracers {[(18)F]fluoropropyl-(+)-dihydrotetrabenazine ([(18)F]FP-DTBZ), [(18)F](+)-2-oxiranyl-3-isobutyl-9-(3-fluoropropoxy)-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline ((18)F-AV-266), and (2S,3R,11bR)-9-(3-fluoropropoxy)-2-(hydroxymethyl)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol ((18)F-AV-300)} bind vesicular monoamine transporter 2. Tomographic reconstruction of the bioluminescent signal in mice expressing luciferase only in pancreatic beta cells was used to delineate the pancreas and was coregistered with PET and X-ray computed tomography images. This strategy enabled unambiguous identification of the pancreas on PET images, permitting accurate quantification of the pancreatic PET signal. We show here that, after conditional, specific, and rapid mouse beta-cell ablation, beta-cell loss was detected by bioluminescence imaging but not by PET imaging, given that the pancreatic signal provided by three PET radiotracers was not altered. To determine whether these ligands bound human beta cells in vivo, we imaged mice transplanted with luciferase-expressing human islets. The human islets were imaged by bioluminescence but not with the PET ligands, indicating that these vesicular monoamine transporter 2-directed ligands did not specifically bind beta cells. These data demonstrate the utility of coregistered multimodal imaging as a platform for evaluation and validation of candidate ligands for imaging islets.

Estimation of baseline dopamine D2 receptor occupancy in striatum and extrastriatal regions in humans with positron emission tomography with [18F] fallypride.

BACKGROUND: This study examined whether positron emission tomography (PET) studies with [18F] fallypride performed before and after alpha-methyl-para-tyrosine (AMPT) administration can be used to estimate baseline dopamine (DA) D2 receptor occupancy in striatal and extrastriatal regions. METHODS: Six normal subjects underwent PET with [18 F] fallypride before and after administration of AMPT. The DA D2 receptor binding potentials (bp) were calculated with the reference region method. Percent changes in bp in striatal and extrastriatal regions were calculated with both region-of-interest analysis and on a voxel by voxel basis with parametric images of DA D2 receptor levels. RESULTS: The results of the current study indicate that AMPT treatment significantly increased the bp in the caudate, putamen, ventral striatum, and substantia nigra. A trend level increase was seen in the medial thalamus. CONCLUSIONS: This study demonstrates that PET with [18F] fallypride can be used to estimate baseline DA D2 receptor occupancy in striatal and extrastriatal regions.