Accuracy of conventional plus transoral carotid ultrasonography in distinguishing pseudo-occlusion from total occlusion of the internal carotid artery

BACKGROUND: To investigate the accuracy of conventional carotid ultrasonography (CCU) combined with transoral carotid ultrasonography (TOCU) for distinguishing pseudo-occlusion from total occlusion of the internal carotid artery (ICA). METHODS: This study included 95 patients who were suspected of having an occlusion of the ICA on magnetic resonance angiography (MRA) and underwent both CCU and conventional digital subtraction angiography (DSA) in order to confirm the diagnosis. TOCU was also performed to observe the cervical portion of the ICA distal to the stenosis. We compared the ultrasonographic findings with the DSA findings. RESULTS: Twelve of the 95 patients were defined as having an ICA pseudo-occlusion on DSA. On B-mode images with CCU color Doppler, slight residual flow signals in the ICA lumen were shown in 20 patients. Among them, 2 patients had a pulsed Doppler waveform of the distal ICA occlusion pattern. Among the remaining 18 patients, 4 had a pulsed Doppler waveform of the to and fro flow pattern, and 14 had a weak antegrade flow pattern in the ICA lumen. The conventional ultrasonographic method showed 100% sensitivity with 93% specificity for diagnosing an ICA pseudo-occlusion. The addition of TOCU findings increased the specificity to 98%. In 2 patients, who were overdiagnosed as having an ICA pseudo-occlusion even using TOCU, DSA revealed an occlusion of the ICA distal to the ophthalmic artery with a severe stenosis of the proximal ICA. CONCLUSIONS: Using conventional and transoral carotid ultrasonography, an ICA pseudo-occlusion can be diagnosed with higher accuracy.     

Neural differentiation potential of peripheral blood- and bone-marrow-derived precursor cells

Transplantation of mesenchymal stem cells (MSCs) prepared from adult bone marrow (BMSCs) has been reported to ameliorate functional deficits in several CNS diseases in experimental animal models. Bone marrow was enriched in MSCs by selecting for plastic-adherent cells that were grown to confluency in appropriate culture conditions as flattened fibroblast-like cells. Despite the fact that the stem/precursor cells in peripheral blood are widely used for reconstruction in the hematopoietic system, it is not fully understood whether peripheral blood-derived plastic-adherent precursor/stem cells (PMSCs) can differentiate into a neural lineage. To compare the potential of PMSCs and BMSCs for neural differentiation in vitro, BMSCs and PMSCs were prepared from the adult rat and expanded in culture. Although the growth rate of PMSCs was less than BMSCs, immunocytochemical and RT-PCR analyses indicated that both MSC types were successfully induced to nestin-positive neurospheres in the presence of EGF and bFGF. After withdrawal of the mitogens, these cells could differentiate into neurofilament-positive neurons or GFAP-positive glia. Thus, our findings suggest the potential use of PMSCs for a cell therapy in CNS diseases.     

Cochlin-tomoprotein (CTP) detection test identified perilymph leakage preoperatively in revision stapes surgery

Perilymphatic fistula (PLF) is defined as an abnormal leakage between perilymph from the labyrinth to the middle ear. Symptoms include hearing loss, tinnitus, and vertigo. The standard mode of PLF detection is intraoperative visualization of perilymph leakage and fistula, which ostensibly confirms the existence of PLF. Other possible methods of diagnosis include confirmation of pneumolabyrinth via diagnostic imaging. Recently, a cochlin-tomoprotein (CTP) detection test has been developed that allows definitive diagnosis of PLF-related hearing loss.     

Partial splenic embolisation using n-butyl cyanoacrylate: intraprocedural evaluation by magnetic resonance imaging

Objectives

To evaluate the use of diffusion-weighted imaging (DWI) for estimating infarcted splenic volume during partial splenic embolisation (PSE) using n-butyl cyanoacrylate (NBCA).

Methods

Twenty consecutive patients (57.2?±?11.7 years) with hypersplenism underwent PSE. Intrasplenic branches were embolised using NBCA via a 2.1-French microcatheter aiming at infarction of 50 to 80 % of total splenic volume. Immediately after PSE, signal intensities (SI) of embolised and non-embolised splenic parenchyma were measured on DWI. Semi-automated volumetry (SAV) on DWI was compared with conventional manual volumetry (MV) on contrast-enhanced CT 1 week after PSE. Platelet counts were recorded before and after PSE.

Results

The SI on DWI in the embolised parenchyma decreased significantly (P?<?0.01) to 24.7?±?8.1 % as compared to non-embolised parenchyma. SAV and MV showed a strong correlation (r?=?0.913 before PSE, r?=?0.935 after PSE, P?<?0.01) and significant (P?<?0.01) reduction of normal splenic volume was demonstrated on both SAV (71.9?±?12.4 %) and MV (73.6?±?9.3 %) after PSE. Based on the initial SAV, three patients (15 %) underwent additional branch embolisation to reach sufficient infarction volume. Platelet counts elevated significantly (522.8?±?209.1 %, P?<?0.01) by 2 weeks after PSE. No serious complication was observed.

Conclusion

Immediate SI changes on DWI after PSE allowed semi-automated splenic volumetry on site.

Key Points

? Partial splenic embolisation (PSE) is an important interventional technique for hypersplenism ? Diffusion-weighted MR reveals an immediate decrease in signal in the embolised parenchyma ? Such signal reduction permits semi-automated splenic volumetry on site. ? This allows precise quantification of the amount of parenchyma infarcted, avoiding additional PSE.     

A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin®) in cancer patients

Background

A growing number of preclinical studies have demonstrated that curcumin could be a promising anticancer drug; however, poor bioavailability has been the major obstacle for its clinical application. To overcome this problem, we developed a new form of curcumin (Theracurmin^®) and reported high plasma curcumin levels could be safely achieved after a single administration of Theracurmin^® in healthy volunteers. In this study, we aimed to evaluate the safety of repetitive administration of Theracurmin^® in cancer patients.

Methods

Pancreatic or biliary tract cancer patients who failed standard chemotherapy were eligible for this study. Based on our previous pharmacokinetic study, we selected Theracurmin^® containing 200 mg of curcumin (Level 1) as a starting dose, and the dose was safely escalated to Level 2, which contained 400 mg of curcumin. Theracurmin^® was orally administered every day with standard gemcitabine-based chemotherapy. In addition to safety and pharmacokinetics data, NF-κB activity, cytokine levels, efficacy, and quality-of-life score were evaluated.

Results

Ten patients were assigned to level 1 and six were to level 2. Peak plasma curcumin levels (median) after Theracurmin^® administration were 324 ng/mL (range, 47–1,029 ng/mL) at Level 1 and 440 ng/mL (range, 179–1,380 ng/mL) at Level 2. No unexpected adverse events were observed and 3 patients safely continued Theracurmin^® administration for >9 months.

Conclusions

Repetitive systemic exposure to high concentrations of curcumin achieved by Theracurmin^® did not increase the incidence of adverse events in cancer patients receiving gemcitabine-based chemotherapy.     

Phase I study of oral gemcitabine prodrug (LY2334737) in Japanese patients with advanced solid tumors

Purpose

LY2334737 is an oral gemcitabine prodrug. This Phase I study assessed the safety and tolerability of LY2334737 in Japanese patients with solid tumors and evaluated pharmacokinetics (PK), pharmacodynamics, and antitumor activity.

Methods

Patients with advanced/metastatic solid tumors received escalating doses of LY2334737 once daily for 14 days, followed by a 7-day drug-free period. Cycles were repeated until discontinuation criteria were met.

Results

Of 13 patients treated, 3 received 20 mg/day, 6 received 30 mg/day, 4 received 40 mg/day. On the 40 mg dose, 3 patients experienced dose-limiting toxicities (DLTs): hepatic toxicities (e.g., Grade [G]3/4 transaminase and G1–3 bilirubin elevation) and G4 thrombocytopenia; all 3 showed features of disseminated intravascular coagulation. One additional DLT occurred on the 30 mg dose (G3 transaminase elevation). Exploratory pharmacogenetic analyses identified a genetic variation in the CES2 gene potentially associated with these DLTs. PK data showed no clear relationship between the AUC of gemcitabine and its incorporation into leukocyte DNA; 2 of the 3 DLT patients had high incorporation. Two patients (30 mg/day) achieved stable disease with progression-free survival lasting 135 and 155 days.

Conclusions

LY2334737 was tolerated by Japanese patients up to 30 mg/day. The toxicities observed at the 40 mg dose may require the development of alternative dosing schedules.     

Conditionally replicative adenoviral vectors for imaging the effect of chemotherapy on pancreatic cancer cells

Pancreatic cancer has a poor prognosis after complete macroscopic resection combined with chemotherapy. Even after neoadjuvant chemotherapy, R0 resection is often not possible. Moreover, current imaging techniques cannot reliably distinguish viable cancer cells from scar tissue at the resectional margin. We investigated the use of a conditionally replicative adenovirus (CRAd), Ad5/3Cox2CRAd‐ΔE3ADP‐Luc, for imaging the effects of chemotherapy. The CRAd infectivity of pancreatic cancer cells was enhanced by a chimeric Ad5/3 fiber, E1A expression was under the control of the Cox2 promoter, and the luciferase gene was inserted adjacent to the adenovirus death protein (ADP) gene. Subcutaneous xenografts of the pancreatic cancer cell line MiaPaCa‐2 were established in 24 BALB/c nu/nu mice. When xenografts reached a diameter of 4–6 mm (day 1), the mice were injected i.p. with either PBS (group A; n = 12) or 1000 mg/kg gemcitabine (group B; n = 12), weekly. On days 19, 26, 33, and 40, CRAd were injected intratumorally into three mice in groups A and B. Bioluminescence was imaged 72 h after CRAd injection, and gross tumor volumes were measured then tumors were removed for ex vivo histopathology using H&E and Ki‐67 staining. Correlations between gross tumor volume, pathological evaluation of the percentage of viable tumor area, and CRAd bioluminescence were analyzed. Bioluminescence correlated closely with the percentage of viable tumor area (R = 0.96), but not with gross tumor volume (R = 0.31). Therefore, CRAds might be reliable imaging tools for monitoring chemotherapy in pancreatic cancer, and could improve our ability to distinguish viable tumor cells from scar tissue.     

Exposure parameters in sens-a-ray direct digital radiography and their effects on diagnostic accuracy of carious lesions

We studied the effects of tube potentials and exposures on the accuracy of carious diagnosis using Sens-A-Ray direct digital radiography with two types of CCD detectors, one without and one with a scintillator layer. Our second objective was to determine the optimum exposure factors. Radiographs of 75 extracted premolars with and without clinically observed discolorations or cavities were obtained at exposure settings of 70 kVp and 90 kVp. The observers diagnosed dental caries in radiographs exposed with the two types of detectors. The results were analyzed with Receiver Operating Curve (ROC) technique. The averaged areas under the ROC curves were plotted as functions of exposure to obtain Diagnostic Accuracy (DA) curves. No statistically significant difference was found in diagnostic accuracy for the two tube potentials. However, there was a statistically significant difference in diagnostic accuracy for the two lesion types, discolorations and cavities. There was also a significant effect on diagnostic accuracy related to exposure: the exposure providing the optimum diagnostic accuracy corresponds to a gray level of about 31 when SVGA graphics are employed, i.e., in the middle of the available range. To acquire optimum radiographs for diagnosing carious lesions with the Sens-A-Ray system, the operator must select the appropriate exposure parameters.     

Cytokine production by keratinocytes and mononuclear infiltrates in oral lichen planus

Cytokine generation by tissue-infiltrating mononuclear cells (TIMC) and by keratinocytes (KC) was investigated in material obtained from the oral mucosal tissues of patients with oral lichen planus (OLP). Peripheral blood mononuclear cells (PBMC) and chronically inflamed and noninflamed gingival KC (CIG-KC, NOR-KC, respectively) were used as the controls. Compared to NOR-KC and CIG-KC, KC from OLP patients (OLP-KC) produced much more interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The OLP-KC superiority in the production of these cytokines was more prominent when the KC were cultured in the presence of interleukin-l beta (IL-1β), lipopolysaccharide and phorbol myristate acetate. OLP-KC also produced more monocyte-chemotactic factor(s) which were not inactivated by the antibodies against GM-CSF, macrophage colony-stimulating factor and monocyte chemoattractant protein-1. TIMC in OLP tissues (OLP-TIMC) were superior to PBMC in the generation of IL-6 and GM-CSF. OLP-TIMC were stimulated to produce more TNF-a by IL-1β, IL-6 and GM-CSF, more IL-6 by IL-1β and GM-CSF, and more GM-CSF by IL-1β and IL-6 than PBMC. When compared to cytokine generation in TIMC from the chronically inflamed gingivae, more interferon-gamma, IL-6 and TNF-α were generated by OLP-TIMC. These results indicate that KC play a critical role in OLP, producing cytokines including monocyte-chemotactic factor(s), and that the cytokines produced by TIMC and OLP-KC through autocrine and paracrine processes enhance the local inflammatory response.