Decipher correlation patterns post prostatectomy: initial experience from 2 342 prospective patients.

BACKGROUND: Currently, there are multiple commercially available RNA-based biomarkers that are Medicare approved and suggested for use by the National Comprehensive Cancer Network guidelines. There is uncertainty as to which patients benefit from genomic testing and for whom these tests should be ordered. Here, we examined the correlation patterns of Decipher assay to understand the relationship between the Decipher and patient tumor characteristics. METHODS: De-identified Decipher test results (including Decipher risk scores and clinicopathologic data) from 2 342 consecutive radical prostatectomy (RP) patients tested between January and September 2015 were analyzed. For clinical testing, tumor specimen from the highest Gleason grade was sampled using a 1.5 mm tissue punch. Decipher scores were calculated based on a previously locked model. Correlations between Decipher score and clinicopathologic variables were computed using Spearman's rank correlation. Mixed-effect linear models were used to study the association of practice type and Decipher score. The significance level was 0.05 for all tests. RESULTS: Decipher score had a positive correlation with pathologic Gleason score (PGS; r=0.37, 95% confidence interval (CI) 0.34-0.41), pathologic T-stage (r=0.31, 95% CI 0.28-0.35), CAPRA-S (r=0.32, 95% CI 0.28-0.37) and patient age (r=0.09, 95% CI 0.05-0.13). Decipher reclassified 52%, 76% and 40% of patients in CAPRA-S low-, intermediate- and high-risk groups, respectively. We detected a 28% incidence of high-risk disease through the Decipher score in pT2 patients and 7% low risk in pT3b/pT4, PGS 8-10 patients. There was no significant difference in the Decipher score between patients from community centers and those from academic centers (P=0.82). CONCLUSIONS: Although Decipher correlated with baseline tumor characteristics for over 2 000 patients, there was significant reclassification of tumor aggressiveness as compared to clinical parameters alone. Utilization of the Decipher genomic classifier can have major implications in assessment of postoperative risk that may impact physician-patient decision making and ultimately patient management.

Direct Oral Anticoagulants in Cirrhosis Patients Pose Similar Risks of Bleeding When Compared to Traditional Anticoagulation.

BACKGROUND AND AIMS: Direct oral anticoagulants (DOAC) are important new anticoagulant therapies that are not well studied in patients with chronic liver disease. The aim of this study was to compare rates of bleeding in cirrhosis patients treated with DOAC (factor Xa inhibitors: rivaroxaban and apixaban) to those in cirrhosis patients treated with traditional anticoagulation (warfarin and low molecular weight heparin). METHODS: We identified a total of 39 patients with cirrhosis who received anticoagulation therapy over a 3-year period (20 DOAC and 19 traditional anticoagulation) from a research database. Medical records were reviewed to obtain clinical data to compare between the groups. RESULTS: Clinical characteristics between the two groups were similar. There were three documented bleeding events in the traditional anticoagulation group and four bleeding events in the DOAC group (p = 0.9). There were two major bleeding events in the traditional anticoagulation group and one major bleeding event in the DOAC group. There were no documented reports of drug-induced liver injury during this study period. Among all patients, no significant predictors of bleeding were identified using univariate regression and Cox proportional hazard modeling. CONCLUSIONS: This is the first clinical study evaluating the use of DOAC in patients with cirrhosis. DOAC display similar safety characteristics when compared to traditional anticoagulation in patients with cirrhosis and are potentially attractive agents for anticoagulation therapy. Larger studies are now needed to better understand the safety and efficacy of these agents in cirrhosis.

In vivo chromosome aberration test for hydroxyapetite in mice.

This study evaluates the cytotoxic and mutagenic effect of synthetic hydroxyapatite granules (source: School of Material and Mineral Resources Engineering, Universiti Sains Malaysia) in the bone marrow cells of mice. Mice are exposed to synthetic hydroxyapatite granules, the bone marrow cells are collected and observed for chromosome aberrations. No chromosome aberrations were noticed in the animals exposed to distilled water (negative control) and to the test substance, synthetic hydroxyapatite granules (treatment) groups. Chromosome aberrations were observed in the animals exposed to Mitomycin C (positive control group). There was no indication of cytotoxicity due to synthetic hydroxyapatite granules in the animals as revealed by the mitotic index. Hence, synthetic hydroxyapatite granules are considered non-mutagenic under the prevailing test conditions.

Chromosome aberration test for hydroxyapatite in sheep.

The present study is aimed at finding the mutagenicity and cytotoxicity of dense form of synthetic hydroxyapatite (Source: School of Materials and Mineral Resources Engineering, Universiti Sains Malaysia) in the blood of sheep. The biomaterial was implanted in the tibia of Malin, an indigenous sheep breed of Malaysia. Blood was collected from the sheep before implantation of the biomaterial, cultured and a karyological study was made. Six weeks after implantation, blood was collected from the same animal, cultured and screened for chromosome aberrations. The mitotic indices and karyological analysis indicated that the implantation of synthetic hydroxyapatite (dense form) did not produce any cytotoxicity or chromosome aberrations in the blood of sheep.

Functional p53 mutation as a molecular determinant of paclitaxel and gemcitabine susceptibility in human bladder cancer.

PURPOSE: Paclitaxel and gemcitabine are promising new agents for treatment of human bladder cancer. We determine how the presence or absence of p53 function impacts the cytotoxic effects of these chemotherapeutic agents in human bladder cancer. MATERIALS AND METHODS: The J82 human bladder cancer (TCC) cell line was transfected with a temperature sensitive p53 (tsp53) mutant that functions as mutated p53 at 37C but functions as wild-type (normal) p53 at 32C. Susceptibility of these inducible p53 TCC cells to paclitaxel and gemcitabine induced cytotoxicity was evaluated and kill significance determined between sub-lethal and lethal doses. RESULTS: Significant paclitaxel dose dependent cytotoxicity was observed in J82 TCC cells lacking normal p53 and tsp53 transfected cells at 37C, which was the mutant p53 temperature in transfectants between maximal and minimal kill concentrations for either (p <0.001). Likewise, significant cytotoxicity was observed in parental J82 TCC at 32C (p <0.001), while restoration of p53 function in tsp53 transfected cells on shift to 32C abrogated significant dose dependent cytotoxicity. Gemcitabine caused significant cell death in the cell lines incubated at either temperature and, thus, was equally effective regardless of cellular p53 function (p <0.001, respectively). CONCLUSIONS: Paclitaxel requires functionally mutated p53 to induce cell death in human bladder cells, indicating that it may be more effective against TCC with p53 mutations than against TCC, which lacks p53 abnormalities, while gemcitabine is effective regardless of p53 function. These findings provide a rationale for selecting chemotherapy based on the p53 status of individual bladder cancers.

"Bull's-eye" sign on gadolinium-enhanced magnetic resonance venography determines thrombus presence and age: a preliminary study.

PURPOSE: Venous thrombosis is associated with a significant inflammatory response, which can be visualized by gadolinium magnetic resonance venography (MRV). Gadolinium extravasates into tissue during inflammation, producing perithrombus enhancement on magnetic resonance scanning. This study determines (1) whether gadolinium enhancement occurs during deep venous thrombosis (DVT); and (2) whether this enhancement changes with time and can therefore establish the age of thrombus. METHODS: Patients with a diagnosis of iliofemoral DVT by duplex ultrasound who were referred for MRV to document central thrombus extent were studied. T1 weighted images were obtained before and after gadolinium injection (0.1 mmol/kg); repeat scans were obtained up to 3 months thereafter. At the level of maximum thrombus, measurements of signal intensity were made at the periphery (rim), and the center of the thrombosed vein, as well as the contralateral normal vein, on images after gadolinium enhancement. Rim-center vein signal intensity ratios were then calculated and followed. RESULTS: A total of 39 scans were obtained in 14 patients (eight men, six women). The thrombosed veins were enlarged, with a peripheral rim of enhancement ("bull's-eye" sign). The rim-center ratio for thrombosed veins (2.16 +/- 0.18) was different from that of normal veins (0.66 +/- 0.10; n = 39; p < 0.001). For all acute studies (< or = 14 days) the rim-center ratio was 2.38 +/- 0.17 (n = 31), whereas for all chronic studies (> 14 days) the rim-center ratio was 1.29 +/- 0.44 (n = 8; p = 0.001). Among patients who underwent both early and late studies, the rim-center ratio dropped significantly, from 2.33 +/- 0.20 acutely to 1.29 +/- 0.44 in chronic studies (n = 8; p = 0.03). One patient with active malignancy had a paradoxic increase in rim-center ratio over time and a clinical recurrence of symptoms, suggesting active thrombosis. CONCLUSIONS: We conclude that (1) a pattern of peripheral gadolinium enhancement (bull's-eye sign) is seen around acutely thrombosed veins on gadolinium-enhanced MRV, facilitating DVT diagnosis; and (2) the ratio of signal intensity at the rim versus the center of the thrombosed vein may be a good discriminator of acute compared with chronic DVT, which may help direct therapy.

Effect of independent changes in mixed-venous PCO2 or PO2 on cardiac output in anesthetized sheep.

To determine whether changes mixed-venous PCO2 or PO2 affect cardiac output independent of changes in arterial blood gases, we used extracorporeal gas exchange to increase mixed-venous PCO2 or decrease mixed-venous PO2 in adult sheep. Sheep were anesthetized, mechanically ventilated, and connected to a veno-venous extracorporeal circuit. The circuit included a gas exchanger which was used to increase mixed-venous PCO2 or decrease mixed-venous PO2; the native lungs were ventilated to maintain arterial PCO2 and PO2 at control levels. When mixed-venous PCO2 was increased by 32% above control levels for a period of 60 min, cardiac output increased significantly to 28% above control levels. Cervical vagotomy abolished this response. In contrast, decreasing mixed-venous PO2 by 29% did not increase cardiac output. These results demonstrate that increasing mixed-venous PCO2 can increase cardiac output independent of changes in arterial blood gases and that intact vagus nerves are necessary for this response to occur.

Primary unifocalization for the absence of intrapericardial pulmonary arteries in the neonate.

The management of the neonate with absence of intrapericardial pulmonary arteries in association with complex intracardiac anomalies presents a challenging surgical problem. The more traditional approach of palliation with unilateral or bilateral systemic-pulmonary artery shunts may result in peripheral pulmonary artery stenoses and uneven distribution of pulmonary blood flow. In addition, this approach may lead to complicated reconstructive procedures necessitating reconstruction of the branch pulmonary artery with prosthetic material, which restricts pulmonary artery growth and often complicates reoperation. To avoid these potential limitations, we have performed primary unifocalization for absence of intrapericardial pulmonary arteries in eight consecutive neonates (median age 9 days) between May 1990 and December 1991. Absence of intrapericardial pulmonary arteries occurred in association with tetralogy of Fallot (n = 4), truncus arteriosus (n = 2), and transposition of the great arteries with pulmonary atresia (n = 2). Four patients had unilateral absence of the right (n = 1) or left (n = 3) intrapericardial pulmonary artery. In the remaining four patients, there was complete absence of both intrapericardial pulmonary arteries. Wide mobilization and excision of all ductal tissue before anastomosis was performed from a midline approach in seven patients. In one patient, a preliminary right thoracotomy was required. Primary unifocalization was performed simultaneously with complete repair in five patients. In the remaining three patients, unifocalization was part of a staged repair and included insertion of a systemic-pulmonary artery shunt to the reconstructed central pulmonary artery confluence. No operative or late cardiac deaths occurred, although one death occurred during subsequent repair of a tracheoesophageal fistula. Three patients underwent reoperation, and only one patient required revision of an anastomotic pulmonary artery stenosis. All survivors were growing normally at 2 to 22 months after operation (mean follow-up 10 months). Our experience suggests that primary reconstruction for the absence of intrapericardial pulmonary arteries can be successfully accomplished in the neonate. This approach provides uniform bilateral pulmonary blood flow, avoids prosthetic material in the branch pulmonary arteries, and may eliminate, or at least simplify, future reconstructive procedures.

Prolonged extracorporeal circulation without heparin. Evaluation of the Medtronic Minimax oxygenator.

Bleeding remains the most common complication of prolonged extracorporeal life support (ECLS). This study evaluated the Medtronic Minimax (Annaheim, CA) microporous oxygenator with the Carmeda Bio Active (heparin bonded) Surface (Stockholm, Sweden) for use in prolonged neonatal ECLS. Eight adult sheep were maintained on venovenous extracorporeal circulation (ECC) for a period of 4 days without systemic heparin. After 4 days of venovenous ECC without anticoagulation, there was no evidence of significant bleeding, circuit thrombosis, or systemic embolism. Gas exchange, hydrodynamic performance, coagulation, and biocompatibility studies suggest that the Minimax is safe and reliable for short-term or long-term ECLS in neonates.