Arginine deprivation, either by nutritional starvation or exposure to ADI-PEG20, induces adaptive transcriptional upregulation of ASS1 and ASL in glioblastoma multiforme ex vivo cultures and cell lines. This adaptive transcriptional upregulation is blocked by neoplasia-specific CpG island methylation in either gene, causing arginine auxotrophy and cell death. In cells with methylated ASS1 or ASL CpG islands, ADI-PEG20 initially induces a protective autophagic response, but abrogation of this by chloroquine accelerates and potentiates cytotoxicity. Concomitant methylation in the CpG islands of both ASS1 and ASL, observed in a subset of cases, confers hypersensitivity to ADI-PEG20. Cancer stem cells positive for CD133 and methylation in the ASL CpG island retain sensitivity to ADI-PEG20. Our results show for the first time that epigenetic changes occur in both of the two key genes of arginine biosynthesis in human cancer and confer sensitivity to therapeutic arginine deprivation. We demonstrate that methylation status of the CpG islands, rather than expression levels per se of the genes, predicts sensitivity to arginine deprivation. Our results suggest a novel therapeutic strategy for this invariably fatal central nervous system neoplasm for which we have identified robust biomarkers and which overcomes the limitations to conventional chemotherapy imposed by the blood/ brain barrier.

Study DesignRetrospective review of an initial cohort of consecutive patients undergoing robot-assisted pedicle screw placement.PurposeWe aimed to evaluate the learning curve, if any, of this new technology over the course of our experience.Overview of LiteraturePercutaneous pedicle screws have specific advantages over open freehand screws. However, they require intraoperative imaging for their placement (e.g., fluoroscopy and navigation) and require increased surgeon training and skill with the learning curve estimated at approximately 20–30 cases. To our knowledge, this is the first study that measures the learning curve of robot-guided purely percutaneous pedicle screw placement with comprehensive objective postoperative computed tomography (CT) scoring, time per screw placement, and fluoroscopy time.MethodsWe included the first 80 consecutive patients undergoing robot-assisted spinal surgery at Melbourne Private Hospital. Data were collected for pedicle screw placement accuracy, placement time, fluoroscopy time, and revision rate. Patient demographic and relevant perioperative and procedural data were also collected. The patients were divided equally into four sub-groups as per their chronological date of surgery to evaluate how the learning curve affected screw placement outcomes.ResultsTotal 80 patients were included; 73 (91%) had complete data and postoperative CT imaging that could help assess that placement of 352 thoracolumbar pedicle screws. The rate of clinically acceptable screw placement was high (96.6%, 95.4%, 95.6%, and 90.7%, in groups 1 to 4, respectively, p=0.314) over time. The median time per screw was 7.0 minutes (6.5, 7.0, 6.0, and 6.0 minutes in groups 1 to 4, respectively, p=0.605). Intraoperative revision occurred in only 1 of the 352 screws (0.3%).Conclusions We found that robot-assisted screw placement had high accuracy, low placement time, low fluoroscopy time, and a low complication rate. However, there were no significant differences in these parameters at the initial experience and the practiced, experience placement (after approximately 1 year), indicating that robot-assisted pedicle screw placement has a very short (almost no) learning curve.

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Hepatocellular carcinoma (HCC) is a major and often therapeutically frustrating oncological problem. A total of 100 patients with unresectable HCC were recruited and randomized to be treated with either transcatheter arterial chemoembolization (TACE) or systemic chemotherapy. Fifty patients were treated with TACE using lipiodol, doxorubicin and cisplatin, while 50 patients were treated with systemic doxorubicin alone. Patients treated with TACE achieved a significantly higher response rate, with partial response achieved in 16 patients (32%) versus five patients (10%) in the chemotherapy arm (P = 0.007). A significantly more favourable tumour response to chemoembolization was found in patients with single lesions (P = 0.02), Child class A (P = 0.007), Okuda stage 1 (P = 0.005) and alpha-feto protein less than 400 ng/mL (P < 0.001). The probability of tumour progression was significantly lower in cases treated with TACE where the median progression free survival was 32 weeks (range, 16-70 weeks) versus 26 weeks (range, 14-54 weeks) for patients treated with systemic chemotherapy (P = 0.03). However, the median overall survival did not differ significantly in cases treated with TACE (38 weeks) compared with those treated with chemotherapy (32 weeks) (P = 0.08), except for patients with serum albumin >3.3 g/dL (60 vs. 36 weeks; P = 0.003). Multivariate Cox regression analysis showed that a rise of serum albumin by 1 g/dL is associated with a decrease in the risk of death by 33% (95% confidence interval: 0.12-0.94, P = 0.038). Mortality in the chemoembolization arm was due to tumour progression in 18 patients (53%), liver failure in 11 patients (32%) and gastro intestinal tract (GIT) bleeding in 5 patients (15%). Mortality in the chemotherapy arm was due to tumour progression in 23 patients (64%), liver failure in 9 patients (25%) and GIT bleeding in 4 patients (11%). Treatment-related mortality was 4% in the TACE arm versus 0% in the chemotherapy arm. In conclusion, the overall survival benefits of TACE and systemic doxorubicin are similar for patients with unresectable HCC amenable to either treatment. It is crucial to optimize the benefit-risk ratio of TACE. In this setting, serum albumin level is a candidate marker for selection of cases who may benefit from this procedure.

We designed this study to assess the effect of storage time and temperature on the international normalized ratio (INR) levels and plasma activities of vitamin K-dependent, clotting factors. A total of 100 subjects, comprising 34 healthy controls, 33 patients with liver cirrhosis and 33 patients on long-term coumarin therapy were enrolled. After centrifugation of collected specimens, aliquots of plasma were stored at room temperature (20 -22 degrees C), refrigerated at 2-6 degrees C and frozen at -40 degrees C. Determinations of INR and plasma activities of clotting factors II, VII, IX and X were performed immediately after sampling (0 time) and after 6, 12 and 24 h. We found no significant change of either INR levels or plasma activity of any of the studied clotting factors up-to 24 h at different studied temperatures (p >0.05). Our data demonstrates that clinical specimens for determination of INR levels and plasma activities of factors II, VII, IX and X are acceptable for testing for up-to 24 h whatever may be the temperature of storage.