A Comparison of Cancer Detection Rates Between Template Systematic Biopsies Obtained Using Magnetic Resonance Imaging-Ultrasound Fusion Machine and Freehand Transrectal Ultrasound-Guided Systematic Biopsies.

Introduction: There are reports that the 12-core template systematic biopsies (SBx) obtained by using software registration machines (e.g., Artemis) have higher cancer detection rates (CDRs) of prostate cancer (PCa) than the standard, freehand 12-core transrectal ultrasound (TRUS)-guided biopsies. The goal of our study is to compare the clinically significant (CS) CDRs of SBx in two independent cohorts who underwent freehand TRUS-SBx alone (Cohort A) or machine-guided SBx as part of a combined MRI-ultrasound (MRI-US) fusion biopsy (FBx) (Cohort B). Materials and Methods: A retrospective review of all patients undergoing prostate biopsies over a 4-year period at the University of Cincinnati Medical Center was performed. CS cancer was defined as having a Gleason score ≥7. MRI-US FBx were obtained by using an Artemis software registration device (ARTEMIS™, Eigen, Inc., Grass Valley, CA). Statistical significance was considered at p < 0.05. Results: Nine hundred and thirty men underwent SBx (Cohort A: 474, Cohort B: 456). There were no statistical differences between cohort A and B in CS CDRs in the overall population (39.3% vs 33.8%; p = 0.093), biopsy naive patients (40.4% vs 39.8%; p = 0.951), or patients with a prior negative biopsy (22.7% vs 25.0%; p = 0.910). Multivariate logistic regression controlling for age, race, prostate-specific antigen level, prostate volume, abnormal digital rectal exam, and family history of PCa demonstrated comparable CS CDRs, which was maintained when further stratified by prior biopsy history (all patients: odds ratio [OR] 0.99, 95% confidence interval [CI] 0.71-1.38, p = 0.958; biopsy naive: OR 0.79, 95% CI 0.51-1.22, p = 0.291; prior negative biopsy: OR 0.64, 95% CI 0.21-1.75, p = 0.403). Conclusions: Our study did not find a significant difference in the CS CDRs of machine-guided SBx compared with the freehand TRUS-SBx. Unless the SBx is done at the time of FBx, the use of these machines for obtaining SBx only is unlikely to result in any increase of CS CDRs.

Anti-Tumor Potential of IMP Dehydrogenase Inhibitors: A Century-Long Story.

The purine nucleotides ATP and GTP are essential precursors to DNA and RNA synthesis and fundamental for energy metabolism. Although de novo purine nucleotide biosynthesis is increased in highly proliferating cells, such as malignant tumors, it is not clear if this is merely a secondary manifestation of increased cell proliferation. Suggestive of a direct causative effect includes evidence that, in some cancer types, the rate-limiting enzyme in de novo GTP biosynthesis, inosine monophosphate dehydrogenase (IMPDH), is upregulated and that the IMPDH inhibitor, mycophenolic acid (MPA), possesses anti-tumor activity. However, historically, enthusiasm for employing IMPDH inhibitors in cancer treatment has been mitigated by their adverse effects at high treatment doses and variable response. Recent advances in our understanding of the mechanistic role of IMPDH in tumorigenesis and cancer progression, as well as the development of IMPDH inhibitors with selective actions on GTP synthesis, have prompted a reappraisal of targeting this enzyme for anti-cancer treatment. In this review, we summarize the history of IMPDH inhibitors, the development of new inhibitors as anti-cancer drugs, and future directions and strategies to overcome existing challenges.

Validation and Enhancement of the Clinicopathological Melanoma Nomogram via Incorporation of a Molecular Marker in the Primary Tumor.

BACKGROUND/AIM: To validate the melanoma nomogram and improve its function in prediction of nodal dissemination by incorporating a molecular marker in the model. Microphthalmia transcription factor (MITF) is an important regulator of melanocyte homeostasis and differentiation. We have shown that the grade of MITF expression in primary melanoma cells can serve as a predictor of nodal status. Many efforts to identify the nodal spread in cutaneous melanoma using non-invasive means have been recently undertaken. A nomogram was developed by Memorial Sloan Kettering Cancer Center (MSKCC) based on clinicopathological features of the primary melanoma to predict the nodal status. In this study, we applied the same nomogram for external validation. Then, we added MITF as an independent predictive factor, and assessed its impact on the nomogram's accuracy in prediction of the nodal spread. MATERIALS AND METHODS: We included 171 patients with melanoma with available tumor specimens, and used MITF staining grade of ≥50% as a pathological characteristic of the primary tumor in addition to age, location, thickness, Clark level, and ulceration, as reported by MSKCC. RESULTS: Upon comparison of receiver operating curves, we confirmed the external validation of the melanoma nomogram, in accordance with the MSKCC curves [area under the curve (AUC) 0.742 vs. 0.650]. Addition of MITF ≥50% as an independent factor in the analysis improved the model fit significantly (AUC=0.825 vs. 0.742; p<0.0001). CONCLUSION: The nomogram described by MSKCC is a valuable tool in predicting sentinel lymph node involvement in primary cutaneous melanoma. Addition of MITF≥50% into the logistic regression analysis significantly improves the accuracy of the melanoma nomogram in prediction of regional nodal spread.

Microphthalmia transcription factor in malignant melanoma predicts occult sentinel lymph node metastases and survival.

Microphthalmia transcription factor (Mitf) is involved in melanocyte development and differentiation. We previously reported that Mitf expression, as detected by immunohistochemical analysis, is an independent prognostic marker in patients with intermediate-thickness melanoma. However, the clinical significance of Mitf expression in melanoma is not well delineated. In this prospective study, we attempted to demonstrate the correlation between Mitf expression in primary melanoma and the sentinel lymph node status and prognosis. We prospectively examined primary cutaneous melanomas from 94 patients undergoing nodal staging by sentinel lymph node biopsy. We quantified the percentage of tumor cells whose nuclei stained with the Mitf antibody visually. Survival curves were generated using the Kaplan-Meier method. The correlation between Mitf expression and nodal status was evaluated using the Mann-Whitney U-test. Here we demonstrate that Mitf expression is directly correlated with both disease-free survival (DFS) and overall survival (OS) over a median follow-up of 28.5 months. The mean DFS and OS in the eight patients whose melanomas did not stain positive for Mitf were 15.75±3.36 months (median, 12 months) and 38.17±5.18 months (median, 29 months), respectively. These results are significantly lower than those for patients who showed evidence of Mitf expression, in whom the mean DFS and OS were 66.1±4.03 months (median, not reached, P=0.0001) and 66.75±38.17 months (median, not reached, P=0.0001), respectively. The mean DFS and OS with greater than 25% (67 patients) of the melanoma cells staining positive for Mitf expression were 78.37±2.78 and 82.38±1.6 months, respectively, compared with 26.37±3.2 months (P=0.0001) and 44.53±4.5 months (P=0.0001), respectively, with up to 25% (27 patients) of cells stained positive for Mitf expression. In addition, there was a significant relationship between Mitf expression and nodal status, as evaluated by sentinel node biopsy. For example, none of the melanomas with greater than 50% Mitf expression had a positive sentinel node biopsy. Our study shows that expression of the molecular marker Mitf in primary cutaneous melanomas is a useful tool in assessing lymph node status. Mitf immunostaining in the primary tumor serves as a reliable predictor of occult lymph node metastases, as well as a favorable prognosticator of DFS and OS in melanoma patients.