Imaging Tumour ATB0,+ Transport Activity by PET with the Cationic Amino Acid O-2((2-[18F]fluoroethyl)methyl-amino)ethyltyrosine

Purpose

The concentrative amino acid transporter ATB^0,+ (SLC6A14) is under evaluation as a target for anticancer therapy. An ATB^0,+-selective positron emission tomography (PET) probe could advance preclinical drug development. We characterised the cationic tyrosine analogue O-2((2-[¹⁸F]fluoroethyl)methyl-amino)ethyltyrosine ([¹⁸F]FEMAET) as a PET probe for ATB^0,+ activity.

Procedures

Cell uptake was studied in vitro. ATB^0,+ expression was quantified by real-time PCR. [¹⁸F]FEMAET accumulation in xenografts was investigated by small animal PET with mice.

Results

[¹⁸F]FEMAET accumulated in PC-3 and NCI-H69 cancer cells in vitro. As expected for ATB^0,+ transport, uptake was inhibited by LAT/ATB^0,+ inhibitors and dibasic amino acids, and [¹⁸F]FEMAET efflux was only moderately stimulated by extracellular amino acids. ATB^0,+ was expressed in PC-3 and NCI-H69 but not MDA-MB-231 xenografts. PET revealed accumulation in PC-3 and NCI-H69 xenografts and significant reduction by ATB^0,+ inhibition. Uptake was negligible in MDA-MB-231 xenografts.

Conclusion

ATB^0,+ activity can be imaged in vivo by PET with [¹⁸F]FEMAET.     

KISS1 expression in colorectal cancer

Kisspeptins, the products of the KISS1 gene, are involved in cancer invasion, migration, metastasis and angiogenesis, while they induce apoptosis in various cancers. Herein, we studied KISS1 expression in colorectal cancer. We analyzed KISS1 expression using immunohistochemistry and image analysis in normal and malignant tissue samples from 60 patients with colorectal adenocarcinoma. The results correlated with various clinicopathological parameters. The expression of KISS1 was much higher in normal than in malignant colonic mucosa. However, among malignant tissues, KISS1 expression was higher in larger tumors (>4 cm) than in smaller ones (≤4 cm) and in stages III and IV than in stages I and II. In addition, it was higher in patients with lymph node metastases. Moreover, KISS1 levels in the normal mucosa and their difference from those in the malignant mucosa were higher in the right part of the large intestine than in the left one. KISS1 expression is reduced during the malignant transformation of the colonic mucosa and there is a difference in the expression pattern between the right and the left part of the large intestine. However, larger and advanced colorectal tumors express higher KISS1 levels than smaller and localized ones.     

Modified deep sclerectomy combined with Ex-PRESS filtration device versus trabeculectomy for primary open angle glaucoma

AIM: To compare the efficacy of modified deep sclerectomy combined with Ex-PRESS shunt versus trabeculectomy in primary open angle glaucoma. METHODS: This is a prospective cohort comparative single-center study. Forty-nine eyes of 49 patients were enrolled in the study. Patients were randomly divided into two groups. Group A (22 patients) underwent classic trabeculectomy and group B (27 patients) underwent modified deep sclerectomy combined with insertion of Ex-PRESS model P50 drainage device. RESULTS: Mean age was 69±7y in group A and 64±8y in group B (P=0.03). The mean reduction was 11.1±5.7 mm Hg in group A compared to 15.8±5.7 mm Hg in group B at 6mo (P=0.006), and 9.8±4.9 mm Hg and 15.4±4.7 mm Hg respectively at 1y (P=0.0001). Regarding the postoperative glaucoma medication, significant difference was observed between the two groups (in favour of group B) only at 6mo (P=0.017). At the end of the follow-up period complete success rate in group A was 68.2% compared to 92.6% in group B (χ2 test, P=0.07) and qualified success rate was 100% in both groups. CONCLUSION: Modified deep sclerectomy combined with Ex-PRESS shunt may provide comparable IOP reduction with fewer complications in management of primary open angle glaucoma.     

Automated detection of rare fetal cells in maternal blood: eliminating the false-positive XY signals in XX pregnancies

OBJECTIVE: The purpose of this study was to develop a new method to help differentiate XX from XY signals in maternal blood from women carrying XY fetuses. STUDY DESIGN: We have developed a system to scan automatically for cells that bear X and Y fluorescence in situ hybridization signals. These XY target cells are identified by scans at low (x20) magnification, and all identified targets are revisited and verified at high (x100) magnification. The viewer software component of the system displays x20 images of all cells and intracellular fluorescence in situ hybridization signals that are present in each of the 4000 optical fields per slide, along with x100 images of automatically detected target cells. RESULTS: We initially examined 36,000 fields from 18 slides in 12 pregnancies (6 male and 6 female) using our system that is based on fluorescence in situ hybridization with a single probe for the X-chromosome and a single probe for the Y-chromosome and found XY nuclei in all samples, regardless of fetal gender. In the second phase of the study, a refinement of the approach that incorporated 2 independent probes for the Y-chromosome resulted in a false-positive rate for detection of XY nuclei in XX cases <0.00005%. CONCLUSION: Our data suggest that this system may allow for excellent "signal to noise" separation, which is required absolutely for fetal cell methods to differentiate aneuploid from normal pregnancies. Quantitation of fetal cells in the maternal circulation and standardization of processes that have been developed for their enrichment are crucial to moving fetal cell assessment from esoteric basic science to applied new technology.     

Treatment of resistant/relapsing chronic lymphocytic leukemia with a combination regimen containing deoxycoformycin and rituximab

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) are sometimes resistant to treatment or relapse soon after the administration of the currently available frontline therapy including chlorambucil-prednisolone CHOP and fludarabine. We report the beneficial effect of an alternative chemotherapeutic regimen containing 2'-deoxycoformycin (pentostatin) and the monoclonal antibody anti-CD20 (rituximab) in 5 patients with resistant/relapsing CLL. PATIENTS: Five patients (4 men and 1 woman) with CLL at stage C, according to Binet's classification, were included in the therapeutic protocol. The median age of the patients was 76 years (range 57-84 years). Previous treatment consisted of chlorambucil-prednisolone, fludarabine, and CHOP. The current regimen comprised six 2-week cycles of pentostatin, 4 mg/m(2) i.v., combined with four cycles of rituximab, in a dose of 375 mg/m(2), every other week. RESULTS: Three patients responded to therapy, 2 achieved complete remission and 1 a partial response. Two patients did not respond to treatment. Toxicity was mild and well tolerated. The median survival duration of the responders was 19 months. These promising results suggest that salvage therapy with a combination regimen including pentostatin and rituximab may have a beneficial effect in patients with resistant/relapsing CLL.