Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial.

Background: The ATLAS trial compared axitinib versus placebo in patients with locoregional renal cell carcinoma (RCC) at risk of recurrence after nephrectomy. Patients and methods: In a phase III, randomized, double-blind trial, patients had >50% clear-cell RCC, had undergone nephrectomy, and had no evidence of macroscopic residual or metastatic disease [independent review committee (IRC) confirmed]. The intent-to-treat population included all randomized patients [≥pT2 and/or N+, any Fuhrman grade (FG), Eastern Cooperative Oncology Group status 0/1]. Patients (stratified by risk group/country) received (1 : 1) oral twice-daily axitinib 5 mg or placebo for ≤3 years, with a 1-year minimum unless recurrence, occurrence of second primary malignancy, significant toxicity, or consent withdrawal. The primary end point was disease-free survival (DFS) per IRC. A prespecified DFS analysis in the highest-risk subpopulation (pT3, FG ≥ 3 or pT4 and/or N+, any T, any FG) was conducted. Results: A total of 724 patients (363 versus 361, axitinib versus placebo) were randomized from 8 May 2012, to 1 July 2016. The trial was stopped due to futility at a preplanned interim analysis at 203 DFS events. There was no significant difference in DFS per IRC [hazard ratio (HR) = 0.870; 95% confidence interval (CI) : 0.660-1.147; P = 0.3211). In the highest-risk subpopulation, a 36% and 27% reduction in risk of a DFS event (HR; 95% CI) was observed per investigator (0.641; 0.468-0.879; P = 0.0051), and by IRC (0.735; 0.525-1.028; P = 0.0704), respectively. Overall survival data were not mature. Similar adverse events (AEs; 99% versus 92%) and serious AEs (19% versus 14%), but more grade 3/4 AEs (61% versus 30%) were reported for axitinib versus placebo. Conclusions: ATLAS did not meet its primary end point; however, improvement in DFS per investigator was seen in the highest-risk subpopulation. No new safety signals were reported. Trial registration number: NCT01599754.

Genetic variants in the CYP24A1 gene are associated with prostate cancer risk and aggressiveness in a Korean study population.

BACKGROUND: Vitamin D-deactivating enzyme CYP24A1 had controversial effects on prostate cancer risk; the genetic study also showed the controversial results. Therefore, we identified the relationships between polymorphisms in CYP24A1 and prostate cancer in a Korean cohort. METHODS: We evaluated the association between 21 single-nucleotide polymorphisms (SNPs) in the CYP24A1 and prostate cancer in Korean men (272 prostate cancers and 173 controls). BPH patients with high PSA or abnormal digital rectal examination who underwent negative prostate biopsy were enrolled in the control group. Twenty-one SNPs in the CYP24A1 were selected from the International HapMap database and the NCBI database with calculation of minor allele frequency and linkage disequilibrium, preferably including the SNPs that were nonsynonymous and located within exons. We also investigated the association between 21 SNPs in the CYP24A1 gene and known clinical characteristics, such as the PSA level, clinical stage, pathological stage and Gleason score. RESULTS: The statistical analysis suggested that five CYP24A1 sequence variants (rs2248461-odds ratio (OR): 0.63, rs2248359-OR: 0.65, rs6022999-OR: 0.65, rs2585428-OR: 0.46, rs4809959-OR: 0.52) had a significant association with prostate cancer risk after multiple comparisons by a method of false discovery rate. Logistic analyses of the CYP24A1 polymorphisms with several prostate cancer-related factors showed that several SNPs were significant: four SNPs to PSA level, three to clinical stage, two to pathological stage and two SNPs to the Gleason score. CONCLUSIONS: The results of this study suggest that some CYP24A1 gene polymorphisms might be associated with the risk of prostate cancer in Korean men. Five CYP24A1 sequence variants showed the significance to predict prostate cancer, and several SNPs of CYP24A1 gene had an important finding to predict prostate cancer-related factors. However, these results should be validated in future large-scale studies.

Characteristic Dynamic Enhancement Pattern of MR Imaging for Malignant Thyroid Tumor. Preliminary Report.

The purpose of this study was to determine the characteristic dynamic enhancement pattern of MR imaging for malignant thyroid tumor. Eight patients were collected, who had pathology confirmed malignant thyroid tumor preoperatively. There were five papillary carcinomas, one medullary carcinoma, one follicular carcinoma and one FNAB proven atypical cell. All images were obtained with a 3.0-T MR imaging system with and without iv contrast administration. Pathologic report and US imaging finding were collected retrospectively. Based on preoperative MR imaging, we compared dynamic MR enhancement pattern relating to pathologic type. All biopsy proven malignant thyroid tumors show hypoechogenicity on previous US imaging, except one follicular carcinoma (isoechogenicity). On T1-weighted images, one papillary carcinoma showed high SI and one medullary carcinoma showed low SI. The other cases were not differentiated with normal parenchyma. On T2-weighted images, three papillary carcinomas and one follicular carcinoma showed high SI and one papillary carcinoma showed low SI. The other case was not differentiated with normal parenchyma. On contrast agent-enhanced dynamic T1WI, five papillary carcinomas and one medullary carcinoma showed delayed enhancement compared to normal parenchyma. One follicular carcinoma showed stronger enhancement than normal parenchyma, one papillary carcinoma showed persistently decreased enhancement than normal parenchyma. Although this study is limited by the small patient population, the data suggest that delayed enhancement on enhanced dynamic T1WI may be a characteristic MR finding of malignant thyroid tumor.

Pictorial review: Unusual tumours involving the prostate: radiological-pathological findings.

The appearance of several unusual tumours in the prostate has resulted in questions being raised concerning their histogenesis; moreover, some of these tumours have prognoses that are quite unlike those of prostatic adenocarcinoma. Unusual neoplasms involving the prostate have been described in recent years, including mucinous cystadenocarcinoma, neuroendocrine cancer, lymphoma, spindle cell neoplasm, squamous cell carcinoma and transitional cell carcinoma. Radiological findings can overlap, and play limited roles in the diagnoses of these entities. However, knowledge of the radiological findings in these conditions can be helpful in making differential diagnoses. Images of prostate lesions using several imaging modalities, including transrectal ultrasound, MRI and CT, as well as available pathological images of such lesions, are presented in this article.

Nocturia in patients with lower urinary tract symptoms: association with diurnal voiding patterns.

OBJECTIVE: To determine whether diurnal voiding patterns predict nocturia in patients with lower urinary tract symptoms (LUTS), as few studies have evaluated the association between diurnal and nocturnal voiding patterns. PATIENTS AND METHODS: We prospectively analysed the frequency-volume charts (FVCs) of consecutive patients with LUTS. At the initial visit patients had a detailed clinical evaluation and subsequently were requested to complete a 72-h FVC. In all, 104 (41 men and 63 women, mean age 63 years, range 50-83) were included in the primary analyses. Associations between daytime variables and nocturia were described using maximum likelihood estimates of the relative risk and by 95% confidence intervals (CIs) based on logistic regression models. RESULTS: When at least one night-time void was used to define nocturia the multivariate logistic model showed a negative association of mean daytime voided volume with nocturia (P = 0.001). The odds ratio for nocturia decreased with this variable to 0.98 (95% CI 0.96-0.99). When 'voiding at least twice per night' was used to define nocturia only the number of daytime voids was positively related to nocturia (odds ratio 1.22; 95% CI 1.01-1.48; P= 0.040). CONCLUSION: Nocturia may be associated with diurnal voiding patterns; these results also suggest that the causes of nocturia of one or of two or more voids may differ. This highlights the role of bladder function in more severe forms of nocturia.

Cell uptake and tissue distribution of radioiodine labelled D-luciferin: implications for luciferase based gene imaging.

Optical luciferase gene imaging is emerging as a method to monitor gene expression in small animals. However, there is concern over how regional availability of exogenously administered substrate may affect photon emission. We thus synthesized [125I]iodo-D-luciferin, which demonstrated substrate characteristics for firefly luciferase, and investigated its cell uptake kinetics and in vivo biodistribution. Luminescence assays of luc gene transduced cells confirmed a linear decline in emitted light units with decreasing luciferin concentration. Both luc gene transduced and control cells demonstrated a low level of cellular uptake and rapid washout of [125I]iodo-D-luciferin, although early uptake was slightly higher for transduced cells (P < 0.005). Biodistribution in ICR mice demonstrated that early uptakes in liver, lung, myocardium and muscle were lower with intraperitoneal compared to intravenous administration. In view of the poor cell uptake, uptake levels (< 3%ID/g) suggest that substrate concentration may limit light emission rates in organs such as bone, muscle, myocardium, and particularly the brain. Thus, substrate availability should be considered as a potential limiting factor for photon emission efficiency in certain organs when attempting quantitative interpretation of optical luc gene imaging.

Use of insulin to improve [18 F]fluorodeoxyglucose labelling and retention for in vivo positron emission tomography imaging of monocyte trafficking.

While 18F-FDG labelling of monocytes would allow in vivo trafficking with positron emission tomography (PET), present methods suffer from poor retention of radioactivity. We investigated the feasibility of utilizing insulin for improved [18F]fluorodeoxyglucose (18F-FDG) labelling. Separated human monocytes and lymphocytes were labelled with 18F-FDG with or without 3 h insulin pre-incubation. Insulin had no effect on lymphocyte labelling (21.4+/-0.8% vs 20.8+/-1.1% efficiency, P=NS). However, for monocytes, insulin pre-incubation led to a 169+/-9% increase in labelling efficiency (19.3+/-4.1 vs 32.5+/-1.8, P<0.05), without significant effects on cell activation or viability. Moreover, while only 57.7+/-4.8% and 40.4+/-5.6% of the 18F-FDG was retained at 1 and 3 h for controls, the retention rate increased to 91.6+/-2.1% (P=0.01) and 86.5+/-1.9% (P<0.01) after insulin pre-incubation. Improved 18F-FDG retention was accompanied by a 70.3+/-7.4% decrease in glucose-6-phosphatase activity (P=0.02). PET imaging of rats showing hepatic ischaemia-reperfusion injury demonstrated higher liver uptake for monocytes labelled after insulin treatment. Thus, insulin improves monocytic 18F-FDG uptake and retention, and may provide a feasible labelling method for PET imaging.