Androgen-Induced, ß-Catenin-Activated Hepatocellular Adenomatosis with Spontaneous External Rupture.

Androgens have long been recognized as oncogenic agents. They can induce both benign and malignant hepatocellular neoplasms, including hepatocellular adenoma (HCA) and hepatocellular carcinoma, though the underlying mechanisms remain unclear. Androgen-induced liver tumors are most often solitary and clinically silent. Herein, we reported an androgen-induced HCA complicated by spontaneous rupture. The patient was a 24-year-old male presenting with fatigue, diminished libido, radiology-diagnosed hepatocellular adenomatosis for 3 years, and sudden-onset, severe, sharp, constant abdominal pain for one day. He used Aveed (testosterone undecanoate injection) from age 17 and completely stopped one year before his presentation. A physical exam showed touch pain and voluntary guarding in the right upper quadrant of the abdomen. An abdominal CT angiogram demonstrated multiple probable HCAs, with active hemorrhage of the largest one (6.6 × 6.2 × 5.1 cm) accompanied by large-volume hemoperitoneum. After being stabilized by a massive transfusion protocol and interventional embolization, he underwent a percutaneous liver core biopsy. The biopsy specimen displayed atypical hepatocytes forming dense cords and pseudoglands. The lesional cells diffusely stained ß-catenin in nuclei and glutamine synthetase in cytoplasm. Compared to normal hepatocytes from control tissue, the tumor cells were positive for nuclear AR (androgen receptor) expression but had no increased EZH2 (Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit) protein expression. The case indicated that androgen-induced hepatocellular neoplasms should be included in the differential diagnosis of acute abdomen.

Endoscopic molecular imaging of cancer.

White light endoscopy has proven to be a very powerful tool in oncology. There is still, however, a need for better endoscopic techniques to overcome the current limitations of white light optics. New technologies that allow higher sensitivity, improved microanatomy and molecular characterization have been available for in vitro microscopy and are now being translated into in vivo endoscopy. Endoscopic molecular imaging is still in its infancy but holds the promise for enhancing sensitivity for early lesions, thus allowing earlier diagnosis and enabling early image-guided endoscopic intervention. A key feature of endoscopic molecular imaging is its increased sensitivity and specificity, which will be illustrated in this article, as well as describing perspectives on its future use in oncologic surgery.

Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia.

GABA signaling molecules are critical for both human brain development and the pathophysiology of schizophrenia. We examined the expression of transcripts derived from three genes related to GABA signaling [GAD1 (GAD67 and GAD25), SLC12A2 (NKCC1), and SLC12A5 (KCC2)] in the prefrontal cortex (PFC) and hippocampal formation of a large cohort of nonpsychiatric control human brains (n = 240) across the lifespan (from fetal week 14 to 80 years) and in patients with schizophrenia (n = 30-31), using quantitative RT-PCR. We also examined whether a schizophrenia risk-associated promoter SNP in GAD1 (rs3749034) is related to expression of these transcripts. Our studies revealed that development and maturation of both the PFC and hippocampal formation are characterized by progressive switches in expression from GAD25 to GAD67 and from NKCC1 to KCC2. Previous studies have demonstrated that the former leads to GABA synthesis, and the latter leads to switching from excitatory to inhibitory neurotransmission. In the hippocampal formation, GAD25/GAD67 and NKCC1/KCC2 ratios are increased in patients with schizophrenia, reflecting a potentially immature GABA physiology. Remarkably, GAD25/GAD67 and NKCC1/KCC2 expression ratios are associated with rs3749034 genotype, with risk alleles again predicting a relatively less mature pattern. These findings suggest that abnormalities in GABA signaling critical to brain development contribute to genetic risk for schizophrenia.

Dynamic fluorescent imaging with indocyanine green for monitoring the therapeutic effects of photoimmunotherapy.

A new type of monoclonal antibody (mAb)-based, highly specific phototherapy (photoimmunotherapy; PIT) that uses a near-infrared (NIR) phthalocyanine dye, IRDye700DX (IR700) conjugated with an mAb, has recently been described. NIR light exposure leads to immediate, target-selective necrotic cell death. However, tumor shrinkage takes several days to occur, making it difficult to detect earlier changes in the tumor. In this study, Panitumumab targeting the epidermal growth factor receptor (EGFR1) conjugated to IR700 was used to treat EGFR-expressing A431 tumor cells and in vivo xenografts. PIT was performed at varying doses of NIR light (10, 30, 50 and 100 J cm(-2)) in xenograft tumors in mice. Indocyanine green (ICG) dynamic imaging was evaluated for monitoring cytotoxic effects for the first hour after PIT. Our results demonstrated a statistical difference (p < 0.05) in ICG intensity between control and PIT treated tumors in the higher light exposure groups (50 J cm(-2): 2.94 ± 0.35 vs 5.22 ± 0.92, p = 0.02; and 100 J cm(-2) : 3.56 ± 0.96 vs 5.71 ± 1.43, p = 0.008) as early as 20 min post ICG injection. However, no significant difference (p > 0.05) in ICG intensity between control and PIT treated tumors was evident in the lower light exposure group at any time points up to 60 min (10 J cm(-2) : 1.92 ± 0.49 vs 1.71 ± 0.3, p = 0.44; and 30 J cm(-2): 1.57 ± 0.35 vs 2.75 ± 0.59, p = 0.07). Similarly, the retention index (background to corrected uptake ratio of ICG) varied with light exposure. In conclusion, ICG may serve as a potential indicator of acute cytotoxic effects of mAb-IR700-induced PIT even before morphological changes can be seen in targeted tumors.

Detection of obstructive coronary artery disease using regadenoson stress and 82Rb PET/CT myocardial perfusion imaging.

UNLABELLED: Our objective was to study the diagnostic performance of regadenoson (82)Rb myocardial perfusion PET imaging to detect obstructive coronary artery disease (CAD). METHODS: We studied 134 patients (mean age, 63 ± 12 y; mean body mass index, 31 ± 9 kg/m(2)) without known CAD (96 with coronary angiography and 38 with low pretest likelihood of CAD). Stress left ventricular ejection fraction (LVEF) minus rest LVEF defined LVEF reserve. The Duke score was used to estimate the anatomic extent of jeopardized myocardium. RESULTS: Regadenoson PET had a high sensitivity, 92% (95% confidence interval [CI], 83%-97%), in detecting obstructive CAD, with a normalcy rate of 97% (95% CI, 86%-99%), specificity of 77% (54/70 patients; 95% CI, 66%-86%), and area under the receiver-operator-characteristic curve of 0.847 (95% CI, 0.774-0.903; P < 0.001). Regadenoson PET demonstrated high sensitivity to detect CAD in patients with single-vessel CAD (89%; 95% CI, 70%-98%). The mean LVEF reserve was significantly higher in patients with normal myocardial perfusion imaging results (6.5% ± 5.4%) than in those with mild (4.3 ± 5.1, P = 0.03) and moderate to severe reversible defects (-0.2% ± 8.4%, P = 0.001). Also, mean LVEF reserve was significantly higher in patients with a low likelihood of CAD (7.2% ± 4.5%, P < 0.0001) and mild or moderate jeopardized myocardium than in those with significant jeopardized myocardium (score ≥ 6), -2.8% ± 8.3%. CONCLUSION: Regadenoson (82)Rb myocardial perfusion imaging is accurate for the detection of obstructive CAD. LVEF reserve is high in patients without significant ischemia or significant angiographic jeopardized myocardium.

Activatable fluorescent cys-diabody conjugated with indocyanine green derivative: consideration of fluorescent catabolite kinetics on molecular imaging.

Antibody fragments including diabodies have more desirable pharmacokinetic characteristics than whole antibodies. An activatable optical imaging probe based on a cys-diabody targeting prostate-specific membrane antigen conjugated with the near-infrared fluorophore, indocyanine green (ICG), was designed such that it can only be activated when bound to the tumor, leading to high signal-to-background ratios. We employed short polyethylene glycol (PEG) linkers between the ICG and the reactive functional group (Sulfo-OSu group), resulting in covalent conjugation of ICG to the cys-diabody, which led to lower dissociation of ICG from cys-diabody early after injection, reducing hepatic uptake. However, unexpectedly, high and long-term fluorescence was observed in the kidneys, liver, and blood pool more than 1 h after injection of the cys-diabody PEG-ICG conjugate. A biodistribution study using I125-labeled cys-diabody-ICG showed immediate uptake in the kidneys followed by a rapid decrease, while gastric activity increased due to released radioiodine during rapid cys-diabody-ICG catabolism in the kidneys. To avoid this catabolic pathway, it would be preferable to use antibody fragments large enough not to be filtered through glomerulus or to conjugate the fragments with fluorescent dyes that are readily excreted into urine when cleaved from the cys-diabody to achieve high tumor-specific detection.