Incidental Intrahepatic Hepatocellular Cholangiocarcinoma Detected on 68Ga-PSMA PET/CT.

ABSTRACT: A 69-year-old man with intermediate-risk prostate cancer and a mildly elevated prostate-specific antigen of 8.2 µg/L was referred for 68Ga-prostate-specific membrane antigen (68Ga-PSMA) PET/CT for primary staging. An incidental intensely 68Ga-PSMA-avid hepatic focus was seen on PSMA PET and subsequent FDG PET/CT and MRI cholangiogram. This was confirmed to be hepatocellular cholangiocarcinoma on subsequent histopathological examination.

68Ga-Prostate-Specific Membrane Antigen Uptake in Cerebral Tuberculosis.

A 71-year-old man with a history of high-risk prostate adenocarcinoma (Gleason score 4 + 5 = 9) treated with brachytherapy in 2016 was referred for a Ga-prostate-specific membrane antigen (PSMA)-HBED-CC PET/CT scan for suspected cancer recurrence on a background of slowly rising serum prostate-specific antigen (0.95 ng/mL; reference, <0.2 ng/mL). This revealed PSMA-avid dura-based hyperdense lesions in the brain, suggestive of cerebral metastases. Biopsy demonstrated the presence of acid-fast bacilli, and with further clinical and microbiological testing, a diagnosis of PSMA-avid cerebral tuberculous mycobacterium infection was made.

Granulomatous Lymphangitis Masquerading as Relapsed Hodgkin Disease on FDG PET/CT.

A 38-year-old woman with Hodgkin lymphoma was referred for staging fludeoxyglucose (18F) positron emission tomography/computed tomography (FDG PET/CT) that showed widespread intensely FDG-avid disease in multiple nodal stations above the diaphragm and spleen and extranodal involvement in the lungs and vertebral bodies. She underwent chemotherapy and radiotherapy. Progress FDG PET/CT 5 months later showed significant metabolic and anatomic response. Repeat FDG PET/CT 1 month later was highly suspicious of recurrent disseminated FDG-avid lymphoma in multiple nodal stations above and below the diaphragm, spleen, multiple bones, and lungs. Subsequent bone marrow biopsy showed sarcoid-like granulomatous inflammation with no evidence of lymphoma. The patient was clinically well and no active treatment was instituted. Subsequent FDG PET/CT 2 months later showed complete resolution of metabolic activity.

Kcnj6(GIRK2) trisomy is not sufficient for conferring the susceptibility to infantile spasms seen in the Ts65Dn mouse model of down syndrome.

OBJECTIVE: Infantile spasms (IS) is a catastrophic childhood seizure disorder that is characterized by extensor and/or flexor spasms, cognitive deterioration and a characteristic EEG abnormality. The latter consists of a pattern of a spike-wave followed by an electrodecremental response (EDR), which is a flattening of the EEG waveform amplitude. The mechanism/circuitry that underpins IS is unknown. Children with Down Syndrome (DS) are particularly vulnerable to IS. The standard mouse model of DS is the Ts65Dn mutant mouse (Ts). Using the Ts mouse, we have created an animal model of IS in DS. This model entails the treatment of Ts mice with a GABABR agonist with a resultant recapitulation of the semiological, electrographic, and pharmacological phenotype of IS. One of the genes triplicated in Ts mice is the kcnj6 gene which codes for the G-protein inwardly rectifying potassium channel 2 (GIRK2) protein. We have shown that over expression of GIRK2 in Ts brain is necessary for the production of the GABABR agonist induced IS phenotype in the Ts mouse. Here, we ask the question whether the excess GIRK2 is sufficient for the production of the GABABR agonist induced IS phenotype. METHODS: To address this question, we used kcnj6 triploid mice, and compared the number of spasms via video analysis and EDR events via EEG to that of the WT mice. RESULTS: We now show that GABARR agonist-treated kcnj6 triploid mice failed to show susceptibility to the IS phenotype. Therefore, over expression of GIRK2 in the brain is necessary, but not sufficient to confer susceptibility to the GABABR agonist-induced IS phenotype in the Ts model of DS. SIGNIFICANCE: It is therefore likely that GIRK2 is working in concert with another factor or factors that are altered in the Ts brain in the production of the GABABR agonist-induced IS phenotype.

68Ga-DOTATATE Uptake in Solitary Pancreatic Metastasis From Clear Cell Renal Cancer.

A 64-year-old man with a lesion of the pancreatic tail was referred for Ga-DOTATATE PET/CT imaging. His medical history included previous metastatic clear cell renal cell cancer. Ga-DOTATATE PET/CT demonstrated increased DOTATATE uptake (SUVmax 10.5) in a pancreatic tail lesion. Histopathology of the resected lesion confirmed clear renal cell cancer metastasis. This case illustrates that clear cell renal cancer metastasis can demonstrate Ga-DOTATATE accumulation.

Incidental Prostate-Specific Membrane Antigen Uptake in a Peripheral Nerve Sheath Tumor.

A 66-year-old man with recently diagnosed prostate cancer (Gleason score 9) was referred for Ga-prostate-specific membrane antigen (PSMA) PET/CT with prostate-specific antigen level of 7.5 µg/L. PET/CT demonstrated increased PSMA uptake (SUVmax 4.7) in a soft tissue density in the left adductor compartment. MRI and cytopathology of the biopsied soft tissue density was compatible with a peripheral nerve sheath tumor. This case illustrates that PSMA uptake can occur in a peripheral nerve sheath tumor and should be taken into consideration as a benign cause of PSMA uptake.

Infantile spasms in down syndrome: Rescue by knockdown of the GIRK2 channel.

OBJECTIVE: The Ts65Dn (Ts) mouse model of Down syndrome (DS) is exquisitely sensitive to an infantile spasms phenotype induced by γ-aminobutyric acidB receptor (GABAB R) agonists. The Ts mouse contains the core genomic triplication of the DS critical region, which includes 3 copies of the Kcnj6 gene that encodes the GABAB R-coupled G protein-coupled inward rectifying potassium channel subunit 2 (GIRK2) channel. We test the hypothesis that GIRK2 is necessary for the GABAB R agonist-induced infantile spasms phenotype in Ts. METHODS: We assessed the result of either genetic or pharmacological knockdown of the GIRK2 channel in Ts brain upon the GABAB R agonist-induced infantile spasms phenotype in the Ts mouse model of DS. As well, we examined GABAB R currents in hippocampal neurons prepared from GIRK2-trisomic Ts control mice and GIRK2-disomic Ts mice in which Kcnj6 had been genetically knocked down from 3 to 2 copies. RESULTS: The reduction of the copy number of Kcnj6 in Ts mice rescued the GABAB R agonist-induced infantile spasms phenotype. There was an increase in GABAB R-mediated GIRK2 currents in GIRK2-trisomic Ts mouse hippocampal neurons, which were normalized in the GIRK2-disomic Ts mice. Similarly, pharmacological knockdown of the GIRK2 channel in Ts brain using the GIRK antagonist tertiapin-Q also rescued the GABAB R agonist-induced infantile spasms phenotype in Ts mutants. INTERPRETATION: The GABAB R-coupled GIRK2 channel is necessary for the GABAB R agonist-induced infantile spasms phenotype in the Ts mouse and may represent a novel therapeutic target for the treatment of infantile spasms in DS. Ann Neurol 2016;80:511-521.

Extrapulmonary Small Cell Carcinoma of the Seminal Vesicles and Prostate Demonstrated on 18F-FDG Positron Emission Tomography/Computed Tomography.

Extrapulmonary primary small cell carcinomas arising from the urogenital tract is infrequent. It can rarely arise from the prostate and even more rarely from the seminal vesicles. We present a 79-year-old male who was admitted due to acute renal failure with a history of radical radiotherapy for prostate adenocarcinoma 13 years ago. The prostate specific antigen level was not elevated. An abdominopelvic computed tomography (CT) scan showed markedly enlarged seminal vesicles causing bilateral ureteral obstruction and a mildly enlarged prostate. Further evaluation with fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/CT demonstrated extensive 18F-FDG uptake in the pelvis with diffuse involvement of both seminal vesicles and the prostate without pathologic uptake in the lungs or elsewhere in the body. Core biopsies of the prostate and both seminal vesicles revealed diffuse involvement by small cell carcinoma. Therapy could not be instituted due to a rapid deterioration in the patient's clinical condition.

Riedel's Thyroiditis with Intense FDG Uptake Demonstrated on FDG PET/CT.

A 39 year old female presented with rapidly enlarging goitre, minimal obstructive symptoms and no constitutional symptoms. Clinical examination revealed diffusely enlarged, firm, non-tender thyroid gland. Biochemical investigations showed subclinical hypothyroidism, positive thyroid antibodies and unremarkable inflammatory markers. Ultrasound examination and CT scan of the neck were suspicious of Riedels thyroiditis. The patient was referred for a FDG PET scan to evaluate for systemic fibro-inflammatory process or lymphoma. Subsequent core biopsy of the thyroid gland demonstrated a chronic inflammatory process with fibrosis consistent with Riedels thyroiditis. A FDG PET/CT study showed diffuse FDG uptake in the thyroid gland and no abnormal retroperitoneal FDG uptake elsewhere to suggest active retroperitoneal fibrosis. The goitre reduced in size with thyroid hormone replacement and steroids, however the patient was lost to follow up.

A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a heritable disorder of GABA degradation characterized by ataxia, psychomotor retardation and seizures. To date, there is no effective treatment for SSADH deficiency. We tested the hypothesis that a ketogenic diet (KD) would improve outcome in an animal model of SSADH deficiency, the SSADH knockout mouse (Aldh5a1-/-). Using a 4:1 ratio of fat to combined carbohydrate and protein KD we set out to compare the general phenotype, in vivo and in vitro electrophysiology and [35S]TBPS binding in both Aldh5a1-/- mice and control (Aldh5a1+/+) mice. We found that the KD prolonged the lifespan of mutant mice by >300% with normalization of ataxia, weight gain and EEG compared to mutants fed a control diet. Aldh5a1-/- mice showed significantly reduced mIPSC frequency in CA1 hippocampal neurons as well as significantly decreased [35S]TBPS binding in all brain areas examined. In KD fed mutants, mIPSC activity normalized and [35S]TBPS binding was restored in the cortex and hippocampus. The KD appears to reverse toward normal the perturbations seen in Aldh5a1-/- mice. Our data suggest that the KD may work in this model by restoring GABAergic inhibition. These data demonstrate a successful experimental treatment for murine SSADH deficiency using a KD, giving promise to the idea that the KD may be successful in the clinical treatment of SSADH deficiency.

Parathyroid hormone inhibits renal phosphate transport by phosphorylation of serine 77 of sodium-hydrogen exchanger regulatory factor-1.

Parathyroid hormone (PTH), via activation of PKC and/or protein kinase A, inhibits renal proximal tubular phosphate reabsorption by facilitating the internalization of the major sodium-dependent phosphate transporter, Npt2a. Herein, we explore the hypothesis that the effect of PTH is mediated by phosphorylation of serine 77 (S77) of the first PDZ domain of the Npt2a-binding protein sodium-hydrogen exchanger regulatory factor-1 (NHERF-1). Using recombinant polypeptides representing PDZ I, S77 of NHERF-1 is phosphorylated by PKC but not PKA. When expressed in primate kidney epithelial cells (BSC-1 cells), however, activation of either protein kinase phosphorylates S77, suggesting that the phosphorylation of PDZ I by PKC and PKA proceeds by different biochemical pathways. PTH and other activators of PKC and PKA dissociate NHERF-1/Npt2a complexes, as assayed using quantitative coimmunoprecipitation, confocal microscopy, and sucrose density gradient ultracentrifugation in mice. Murine NHERF-1-/- renal proximal tubule cells infected with adenovirus-GFP-NHERF-1 containing an S77A mutation showed significantly increased phosphate transport compared with a phosphomimetic S77D mutation and were resistant to the inhibitory effect of PTH compared with cells infected with wild-type NHERF-1. These results indicate that PTH-mediated inhibition of renal phosphate transport involves phosphorylation of S77 of the NHERF-1 PDZ I domain and the dissociation of NHERF-1/Npt2a complexes.

Thyroid dysfunction during interferon alpha therapy for chronic hepatitis C.

Interferon-alpha therapy is well known to induce a wide range of thyroid dysfunction. A 22-year-old woman with chronic hepatitis C developed overt hyperthyroidism while on interferon-alpha and ribavirin therapy. Tc-99m thyroid scintigraphy demonstrated virtually absent tracer uptake consistent with subacute thyroiditis. Ten months after starting antiviral therapy, overt hyperthyroidism recurred. Repeat thyroid scintigraphy revealed diffusely increased tracer uptake throughout the thyroid gland consistent with Graves disease. This is an unusual case of 2 forms of hyperthyroidism-confirmed scintigraphically and occurring in the same patient over time while on interferon-alpha therapy.

Stress granule assembly is mediated by prion-like aggregation of TIA-1.

TIA-1 is an RNA binding protein that promotes the assembly of stress granules (SGs), discrete cytoplasmic inclusions into which stalled translation initiation complexes are dynamically recruited in cells subjected to environmental stress. The RNA recognition motifs of TIA-1 are linked to a glutamine-rich prion-related domain (PRD). Truncation mutants lacking the PRD domain do not induce spontaneous SGs and are not recruited to arsenite-induced SGs, whereas the PRD forms aggregates that are recruited to SGs in low-level-expressing cells but prevent SG assembly in high-level-expressing cells. The PRD of TIA-1 exhibits many characteristics of prions: concentration-dependent aggregation that is inhibited by the molecular chaperone heat shock protein (HSP)70; resistance to protease digestion; sequestration of HSP27, HSP40, and HSP70; and induction of HSP70, a feedback regulator of PRD disaggregation. Substitution of the PRD with the aggregation domain of a yeast prion, SUP35-NM, reconstitutes SG assembly, confirming that a prion domain can mediate the assembly of SGs. Mouse embryomic fibroblasts (MEFs) lacking TIA-1 exhibit impaired ability to form SGs, although they exhibit normal phosphorylation of eukaryotic initiation factor (eIF)2alpha in response to arsenite. Our results reveal that prion-like aggregation of TIA-1 regulates SG formation downstream of eIF2alpha phosphorylation in response to stress.

Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor alpha, cyclooxygenase 2, and inflammatory arthritis.

TIA-1 and TTP are AU-rich element-binding proteins that prevent the pathological overexpression of tumor necrosis factor alpha (TNF-alpha). TIA-1 inhibits the translation of TNF-alpha transcripts, whereas TTP promotes the degradation of TNF-alpha transcripts. Here we show that TIA-1 and TTP function as arthritis suppressor genes: TIA-1(-/-) mice develop mild arthritis, TTP(-/-) mice develop severe arthritis, and TIA-1(-/-)TTP(-/-) mice develop very severe arthritis. Peritoneal macrophages derived from all three genotypes overexpress cyclooxygenase 2 and TNF-alpha. Surprisingly, lipopolysaccharide-activated TIA-1(-/-)TTP(-/-) macrophages secrete less TNF-alpha protein than either TIA-1(-/-) or TTP(-/-) macrophages. In these mice, arthritogenic cytokine may be produced by neutrophils that accumulate in the bone marrow and peripheral blood. Our results suggest that TIA-1 and TTP are genetic modifiers of inflammatory arthritis that can alter the spectrum of cells that produce arthritogenic cytokines.