Differential effects of arsenic trioxide on chemosensitization in human hepatic tumor and stellate cell lines

ABSTRACT: BACKGROUND: Crosstalk between malignant hepatocytes and the surrounding peritumoral stroma is a key modulator of hepatocarcinogenesis and therapeutic resistance. To examine the chemotherapy resistance of these two cellular compartments in vitro, we evaluated a well-established hepatic tumor cell line, HepG2, and an adult hepatic stellate cell line, LX2. The aim was to compare the chemosensitization potential of arsenic trioxide (ATO) in combination with sorafenib or fluorouracil (5FU), in both hepatic tumor cells and stromal cells. METHODS: Cytotoxicity of ATO, 5-FU, and sorafenib, alone and in combination against HepG2 cells and LX2 cells was measured by an automated high throughput cell-based proliferation assay. Changes in survival and apoptotic signaling pathways were analyzed by flow cytometry and western blot. Gene expression of the 5-FU metabolic enzyme, thymidylate synthase, was analyzed by real time PCR. RESULTS: Both HepG2 and LX2 cell lines were susceptible to single agent sorafenib and ATO at 24 hr (ATO IC50: 5.3 muMu in LX2; 32.7 muMu in HepG2; Sorafenib IC50: 11.8 muMu in LX2; 9.9 muMu in HepG2). In contrast, 5-FU cytotoxicity required higher concentrations and prolonged (48--72 h) drug exposure. Concurrent ATO and 5-FU treatment of HepG2 cells was synergistic leading to increased cytotoxicity due in part to modulation of thymidylate synthase levels by ATO. Concurrent ATO and sorafenib treatment showed a trend towards increased HepG2 cytotoxicity possibly due to a significant decrease in MAPK activation in comparison to treatment with ATO alone. CONCLUSIONS: ATO differentially sensitizes hepatic tumor cells and adult hepatic stellate cells to 5-FU and sorafenib. Given the importance of both of these cell types in hepatocarcinogenesis, these data have implications for the rational development of anti-cancer therapy combinations for the treatment of hepatocellular carcinoma (HCC).     

Otocephaly: report of five new cases and a literature review

Otocephaly, characterized by mandibular hypoplasia or agnathia, ventromedial auricular malposition (melotia) and/or auricular fusion (synotia), and microstomia with oroglossal hypoplasia or aglossia, is an extremely rare anomalad, identified in less than 1 in 70,000 births. The malformation spectrum is essentially lethal, because of ventilatory problems, and represents a developmental field defect of blastogenesis primarily affecting the first branchial arch derivatives. Holoprosencephaly is the most commonly identified association, but skeletal, genitourinary, and cardiovascular anomalies, and situs inversus have been reported. Polyhydramnios may be the presenting feature, but prenatal diagnosis has been uncommon.

We present five new cases of otocephaly, the largest published series to date, with comprehensive review of the literature and an update of research in the etiopathogenesis of this malformation complex. One of our cases had situs inversus, and two presented with unexplained polyhydramnios. Otocephaly, while quite rare, should be considered in the differential diagnosis of this gestational complication.     

Pediatric idiopathic intracranial hypertension

Our understanding of pediatric idiopathic intracranial hypertension has been refined since Dr. Simmons Lessell's review in 1992. The use of rigorous methodologies and standard definitions in recent studies has demonstrated distinct demographic trends. Specifically, the incidence of idiopathic intracranial hypertension seems to be increasing among adolescent children, and among older children its clinical picture is similar to that of adult idiopathic intracranial hypertension (female and obese). Within younger age groups there are more boys and nonobese children who may develop idiopathic intracranial hypertension. The pathogenesis of the disease has yet to be elucidated. Idiopathic intracranial hypertension among young children has been associated with several new etiologies, including recombinant growth hormone and all-trans-retinoic acid. More modern neuroimaging techniques such as MRI and MRI-venograms are being used to exclude intracranial processes. Although most cases of pediatric idiopathic intracranial hypertension improve with medical treatment, those who have had visual progression despite medical treatment have undergone optic nerve sheath fenestration and lumboperitoneal shunting. Because idiopathic intracranial hypertension in young children appears to be a different disorder than in adolescents and adults, separate diagnostic criteria for younger children are warranted. We propose new criteria for pediatric idiopathic intracranial hypertension in which children should have signs or symptoms consistent with elevated intracranial pressure, be prepubertal, have normal sensorium, can have reversible cranial nerve palsies, and have an opening cerebrospinal fluid pressure greater than 180 mm H₂O if less than age 8 and papilledema is present, but greater than 250 mm H₂0 if age 8 or above or less than 8 without papilledema.     

Reduction of fast spin echo cusp artifact using a slice‐tilting gradient

A “featherlike” artifact, termed a cusp artifact, is sometimes seen along the phase‐encoding direction in sagittal or coronal fast spin echo images. This artifact arises from the spins, at a location distant from the magnet isocenter, that are excited and aliased to the field of view because their precession frequency is similar to those at the isocenter. Such a situation is created due to a combination of excessive gradient nonlinearity and rapid change of the main magnetic field near the edge of the magnet where the artifact‐producing spins are located. A novel technique is proposed to reduce this artifact, in which a fast spin echo pulse sequence is modified to slightly tilt the slice selected by the radiofrequency excitation pulse away from the slice selected by the radiofrequency refocusing pulses. At the edge of the field of view, the incomplete overlap between the slices selected by the excitation and refocusing pulses effectively reduces the signals from the artifact‐prone region. In contrast, the slices overlap substantially within the field of view so that the signals are largely retained. This slice‐tilting technique has been implemented on two commercial MRI scanners operating at 3.0 T and 1.5 T, respectively, and evaluated on phantoms and human spine and extremities using clinical protocols. Both phantom and human results showed that the technique decreased the strength of the cusp artifact by at least 65% and substantially limited the spatial extent of the artifact. This technique, which can be further enhanced by a simple postprocessing step, offers significant advantages over a number of other techniques for reducing the fast spin echo cusp artifact. It can be implemented on virtually any scanner without hardware modification, complicated calibration, sophisticated image reconstruction, or patient‐handling alteration. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Sinus histiocytosis with massive lymphadenopathy and malignant lymphoma. An unreported association

Sinus histiocytosis with massive lymphadenopathy is a benign disorder often characterized by spontaneous remission. Although immunologic abnormalities are common and high Epstein Barr virus titers have been reported, to date no case has been associated with malignant lymphoma. The authors report here the first case of this association.