Franto Francis

Histologic characteristics of pancreatic intraepithelial neoplasia associated with different pancreatic lesions.

Pancreatic intraepithelial neoplasia (PanIN) has been found in association with pancreatic ductal adenocarcinoma, intraductal papillary-mucinous neoplasm (IPMN), mucinous cystic neoplasm, and other pancreatic lesions, but the characteristics of PanINs associated with these lesions are not well characterized. In this study, 185 partial or total pancreatectomy specimens were collected, and 173 had complete slides for reviewed, which included 74 pancreatic ductal adenocarcinomas, 28 IPMNs, 7 mucinous cystic neoplasms, 44 other nonductal tumors, and 20 nontumorous lesions. Differences in grade, extent, and duct involvement among PanINs associated with different lesions were analyzed. Patients with PanINs were older than those without, regardless of associated tumor or lesions. No sex predilection was noted. PanINs were found in 89%, 96%, 86%, 64%, and 55% pancreata with ductal adenocarcinomas, IPMNs, mucinous cystic neoplasm, other nonductal tumors, and nontumorous lesions, respectively. PanIN 1 and 2 were commonly associated with all types of lesions, but high-grade PanIN 3 was more frequently associated with ductal adenocarcinomas. Ductal involvement of PanINs was more extensive in association with ductal adenocarcinomas than in any other types of pancreatic tumors or lesions. PanINs associated with pancreatic ductal adenocarcinomas affected both the main and branched ducts, whereas PanINs associated with other types of pancreatic tumors or lesions were mainly present in the branch ducts. No statistical differences were observed in distribution, extent, and grade of PanINs among IPMNs, mucinous cystic neoplasms, other nonductal tumors, and nontumorous lesions. Our study demonstrated a high concurrence between PanINs and other precancerous lesions and histologic features of PanINs associated with different pancreatic diseases.

Assessment of Prospectively Assigned Likert Scores for Targeted Magnetic Resonance Imaging-Transrectal Ultrasound Fusion Biopsies in Patients with Suspected Prostate Cancer

PURPOSE We assess the performance of prospectively assigned magnetic resonance imaging based Likert scale scores for the detection of clinically significant prostate cancer, and analyze the pre-biopsy imaging variables associated with increased cancer detection using targeted magnetic resonance imaging-transrectal ultrasound fusion biopsy. MATERIALS AND METHODS In this retrospective review of prospectively generated data including men with abnormal multiparametric prostate magnetic resonance imaging (at least 1 Likert score 3 or greater lesion) who underwent subsequent targeted magnetic resonance imaging-transrectal ultrasound fusion biopsy, we determined the association between different imaging variables (Likert score, lesion size, lesion location, prostate volume, radiologist experience) and targeted biopsy positivity rate. We also compared the detection of clinically significant cancer according to Likert scale scores. Tumors with high volume (50% or more of any core) Gleason score 3+4 or any tumor with greater Gleason score were considered clinically significant. Each lesion served as the elementary unit for analysis. We used logistic regression for univariate and multivariate (stepwise selection) analysis to assess for an association between targeted biopsy positivity rate and each tested variable. The relationship between Likert scale and Gleason score was evaluated using the Spearman correlation coefficient. RESULTS A total of 161 men with 244 lesions met the study eligibility criteria. Targeted biopsies diagnosed cancer in 41% (66 of 161) of the men and 41% (99 of 244) of the lesions. The Likert score was the strongest predictor of targeted biopsy positivity (OR 3.7, p <0.0001). Other imaging findings associated with a higher targeted biopsy positivity rate included smaller prostate volume (OR 0.7, p <0.01), larger lesion size (OR 2.2, p <0.001) and anterior location (OR 2.0, p=0.01). On multiple logistic regression analysis Likert score, lesion size and prostate volume were significant predictors of targeted biopsy positivity. Higher Likert scores were also associated with increased detection of clinically significant tumors (p <0.0001). CONCLUSIONS The Likert scale score used to convey the degree of suspicion on multiparametric magnetic resonance imaging is the strongest predictor of targeted biopsy positivity and of the presence of clinically significant tumor.

Comparison of prostate cancer detection at 3-T MRI with and without an endorectal coil: A prospective, paired-patient study

OBJECTIVES To compare the sensitivity of 2 different non-endorectal coil strategies vs. endorectal coil (ERC) magnetic resonance imaging (MRI) for detection of prostate cancer (PCa). METHODS In this prospective, single-center, paired-patient, paired-reader study, 49 men with a clinical indication for MRI underwent non-ERC (phased-array coil only) T2-weighted imaging and diffusion-weighted imaging followed by the same sequences using both ERC and phased-array coils (ERC Protocol). Patients were randomized into 1 of 2 arms: standard non-ERC protocol and augmented non-ERC protocol. Lesions with Likert score≥3 were defined as suspicious for cancer. Radical prostatectomy specimen or combined systematic plus targeted biopsies served as the standard of reference. Cancers were stratified into risk groups according to the National Comprehensive Cancer Network guidelines. Generalized estimating equations with Bonferroni correction were used for comparisons. The level of reader confidence was inferred by the Likert scores assigned to index lesions. RESULTS The ERC protocol provided sensitivity (78%) superior to MRI without ERC for PCa detection, both with a standard (43%) (P<0.0001) or augmented (60%) (P<0.01) protocol. The ERC MRI missed less-intermediate or high-risk index lesions (4%) than standard non-ERC (42%) (P = 0.02) and augmented non-ERC MRI (25%), although the latter did not reach significance (P = 0.09). The ERC improved radiologist confidence for the detection of PCa (average Likert score = 4.2±1.4) compared to standard (2.3±2.3) and augmented (2.9±2.1) non-ERC (P = 0.001). CONCLUSIONS The use of combined ERC and pelvic phased-array coil for T2-weighted imaging and diffusion-weighted imaging provides superior sensitivity for the detection of PCa compared to an examination performed without the ERC.

Association of overexpression of TIF1γ with colorectal carcinogenesis and advanced colorectal adenocarcinoma

AIM To determine the expression and clinical significance of transcriptional intermediary factor 1 gamma (TIF1γ), Smad4 and transforming growth factor-beta (TGFβR) across a spectrum representing colorectal cancer (CRC) development. METHODS Tissue microarrays were prepared from archival paraffin embedded tissue, including 51 colorectal carcinomas, 25 tubular adenomas (TA) and 26 HPs, each with matched normal colonic epithelium. Immunohistochemistry was performed using antibodies against TIF1γ, Smad4 and TGFβRII. The levels of expression were scored semi-quantitatively (score 0-3 or loss and retention for Smad4). RESULTS Overexpression of TIF1γ was detected in 5/26 (19%) HP; however, it was seen in a significantly higher proportion of neoplasms, 15/25 (60%) TAs and 24/51 (47%) CRCs (P < 0.05). Normal colonic mucosa, HP, and TAs showed strong Smad4 expression, while its expression was absent in 22/51 (43%) CRCs. Overexpression of TGFβRII was more commonly seen in neoplasms, 13/25 (52%) TAs and 29/51 (57%) CRCs compared to 9/26 (35%) HP (P < 0.05). Furthermore, there was a correlation between TIF1γ overexpression and Smad4 loss in CRC (Kendall tau rank correlation value = 0.35, P < 0.05). The levels of TIF1γ overexpression were significantly higher in stage III than in stage I and II CRC (P < 0.05). CONCLUSION The findings suggest that over-expression of TIF1γ occurs in early stages of colorectal carcinogenesis, is inversely related with Smad4 loss, and may be a prognostic indicator for poor outcome.

Improved Magnetic Resonance Imaging-Pathology Correlation With Imaging-Derived, 3D-Printed, Patient-Specific Whole-Mount Molds of the Prostate

Objectives The aim of this study was to compare the anatomical registration of preoperative magnetic resonance imaging (MRI) and prostate whole-mount obtained with 3D-printed, patient-specific, MRI-derived molds (PSM) versus conventional whole-mount sectioning (WMS). Materials and Methods Based on an a priori power analysis, this institutional review board–approved study prospectively included 50 consecutive men who underwent 3 T multiparametric prostate MRI followed by radical prostatectomy. Two blinded and independent readers (R1 and R2) outlined the contours of the prostate, tumor, peripheral, and transition zones in the MRI scans using regions of interest. These were compared with the corresponding regions of interest from the whole-mounted histopathology, the reference standard, using PSM whole-mount results obtained in the study group (n = 25) or conventional WMS in the control group (n = 25). The spatial overlap across the MRI and histology data sets was calculated using the Dice similarity coefficient (DSC) for the prostate overall (DSCprostate), tumor (DSCtumor), peripheral (DSCPZ), and transition (DSCTZ) zone. Results in the study and control groups were compared using Wilcoxon rank sum test. Results The MRI histopathology anatomical registration for the prostate gland overall, tumor, peripheral, and transition zones were significantly superior with the use of PSMs (DSCs for R1: 0.95, 0.86, 0.84, and 0.89; for R2: 0.93, 0.75, 0.78, and 0.85, respectively) than with the use of standard WMS (R1: 0.85, 0.46, 0.66, and 0.69; R2: 0.85, 0.46, 0.66, and 0.69) (P < 0.0001). Conclusions The use of PSMs for prostate specimen whole-mount sectioning provides significantly superior anatomical registration of in vivo multiparametric MRI and ex vivo prostate whole-mounts than conventional WMS.

An initial negative round of targeted biopsies in men with highly suspicious multiparametric magnetic resonance findings does not exclude clinically significant prostate cancer—Preliminary experience

BACKGROUND Targeted prostate biopsies are changing the landscape of prostate cancer (PCa) diagnosis with the degree of suspicion on multiparametric magnetic resonance imaging (mpMRI) being a strong predictor of targeted biopsy outcome. Data regarding the rate and potential causes of false-negative magnetic resonance imaging-transrectal ultrasound (MRI-TRUS) fusion-targeted biopsy in patients with highly suspicious mpMRI findings are lacking. OBJECTIVES To determine the rate of clinically significant PCa detection in repeat targeted biopsy or surgery in patients with highly suspicious mpMRI findings and in an initial negative MRI-TRUS fusion-targeted biopsy. MATERIALS AND METHODS In this single-center, retrospective study of prospectively generated data, men with highly suspicious lesions (Likert 5 score) on mpMRI and an initial negative MRI-TRUS fusion-targeted biopsy were reviewed. The rate of PCa detection in a subsequent MRI-TRUS fusion-targeted biopsy or radical prostatectomy was determined. Tumors in the intermediate- and high-risk groups according to the National Comprehensive Cancer Network criteria were considered clinically significant. RESULTS A total of 32 men with 38 Likert 5 lesions were identified. Repeat targeted biopsy or surgery detected cancer in 42% (16/38) of the Likert 5 lesions with initial negative targeted biopsy. Most of these cancers were intermediate- (69%; 11/16) or high-risk (25%; 4/16) tumors. CONCLUSION A negative round of targeted biopsies does not exclude clinically significant PCa in men with highly suspicious mpMRI findings. Patients with imaging-pathology disagreement should be carefully reviewed and considered for repeat biopsy or for strict surveillance.

Incorporating Oxygen-Enhanced MRI into Multi-Parametric Assessment of Human Prostate Cancer

Hypoxia is associated with prostate tumor aggressiveness, local recurrence, and biochemical failure. Magnetic resonance imaging (MRI) offers insight into tumor pathophysiology and recent reports have related transverse relaxation rate (R2*) and longitudinal relaxation rate (R1) measurements to tumor hypoxia. We have investigated the inclusion of oxygen-enhanced MRI for multi-parametric evaluation of tumor malignancy. Multi-parametric MRI sequences at 3 Tesla were evaluated in 10 patients to investigate hypoxia in prostate cancer prior to radical prostatectomy. Blood oxygen level dependent (BOLD), tissue oxygen level dependent (TOLD), dynamic contrast enhanced (DCE), and diffusion weighted imaging MRI were intercorrelated and compared with the Gleason score. The apparent diffusion coefficient (ADC) was significantly lower in tumor than normal prostate. Baseline R2* (BOLD-contrast) was significantly higher in tumor than normal prostate. Upon the oxygen breathing challenge, R2* decreased significantly in the tumor tissue, suggesting improved vascular oxygenation, however changes in R1 were minimal. R2* of contralateral normal prostate decreased in most cases upon oxygen challenge, although the differences were not significant. Moderate correlation was found between ADC and Gleason score. ADC and R2* were correlated and trends were found between Gleason score and R2*, as well as maximum-intensity-projection and area-under-the-curve calculated from DCE. Tumor ADC and R2* have been associated with tumor hypoxia, and thus the correlations are of particular interest. A multi-parametric approach including oxygen-enhanced MRI is feasible and promises further insights into the pathophysiological information of tumor microenvironment.

Targeting phenotypic heterogeneity in benign prostatic hyperplasia

Benign prostatic hyperplasia and associated lower urinary tract symptoms remain difficult to treat medically, resulting in hundreds of thousands of surgeries performed annually in elderly males. New therapies have not improved clinical outcomes since alpha blockers and 5 alpha reductase inhibitors were introduced in the 1990s. An underappreciated confounder to identifying novel targets is pathological heterogeneity. Individual patients display unique phenotypes, composed of distinct cell types. We have yet to develop a cellular or molecular understanding of these unique phenotypes, which has led to failure in developing targeted therapies for personalized medicine. This review covers the strategic experimental approach to unraveling the cellular pathogenesis of discrete BPH phenotypes and discusses how to incorporate these findings into the clinic to improve outcomes.

Metastatic Melanoma to the Bladder: Case Report and Review of the Literature.

A 49-year-old Caucasian woman presented to the dermatology clinic for follow-up of malignant melanoma with a complaint of painless gross hematuria. Two years prior she was diagnosed with malignant melanoma from a skin lesion on her left flank treated with wide excision, negative axillary sentinel lymph node biopsy, and adjuvant radiotherapy. Subsequently, she had no evidence of disease until urologic evaluation of her hematuria revealed two lesions in her bladder and cytopathology demonstrated findings consistent with malignant melanoma. We review literature on melanoma metastatic to the bladder and discuss the potential role of metastasectomy and other treatment strategies in such rare cases.

Concordance in Biomarker Status Between Bladder Tumors at Time of Transurethral Resection and Subsequent Radical Cystectomy: Results of a 5-year Prospective Study.

Purpose: To assess the concordance rate in alterations of molecular markers at the time of transurethral resection (TUR) and subsequent radical cystectomy (RC) among patients with high-grade urothelial carcinoma of the bladder (UCB). Methods: We prospectively performed immunohistochemical staining p53, p21, p27, Ki-67 and cyclin E1 on TUR and on RC specimens from 102 patients treated with RC and bilateral lymphadenectomy for high-grade UCB. We analyzed the concordance rate of individual markers and of the number of altered markers. Concordant and discordant findings were reported in the overall population and according to clinical stage. Results: Median patient age was 74 years (IQR 67–79) and mostly male (86%). Median time from TUR to RC was 1.5 months (IQR 1.0–2.4). Clinical stage at time of RC was cTa/Tis/T1 in 50% , cT2 in 47% , and cT4 in 1% of patients Nine (9%) patients received neoadjuvant chemotherapy. The concordance of biomarkers between TUR and RC specimens was 92.2% , 77.5% , 80.4% , 77.5% , and 83.3% for cyclin E1, p21, p27, p53 and Ki-67, respectively. The concordance between number of altered biomarkers was 51.0%. Conclusions: The rate of individual marker alterations at time of TUR closely approximates that found at RC specimens. However, the correlation of number of altered markers is lower. Molecular marker status at TUR could help predict the marker status at RC and may help guide multimodal therapeutic planning.