Superior detection of significant prostate cancer by transperineal prostate biopsy using MRI-transrectal ultrasound fusion image guidance over cognitive registration.

BACKGROUND: The BioJet system allows the fusion of magnetic resonance imaging (MRI) images with real-time transrectal ultrasonography to accurately direct biopsy needles to the target lesions. To date, the superiority of targeted biopsy using the BioJet system over cognitive registration remains unknown. METHODS: This retrospective study included 171 biopsy-naïve men with elevated prostate-specific antigen (2.5-20 ng/mL) and MRI-positive lesions; 74 and 97 men underwent a four-core targeted biopsy per MRI-positive target lesion and a 14-core systematic biopsy transperineally using the BioJet system and cognitive registration, respectively. Detection rates of significant cancer, defined as grade group ≥ 2 or maximum cancer length ≥ 5 mm, were compared between the BioJet system and cognitive registration using propensity score matching and a multivariate logistic regression model. RESULTS: After propensity score matching (67 men for each group), the detection rates of significant cancer were significantly higher in the BioJet group than in the cognitive group for both targeted (76% vs. 46%, P = 0.002) and systematic (70% vs. 46%, P = 0.018) biopsy. Multivariate analysis of the entire cohort also showed that the BioJet system was independently associated with significant cancer detection by targeted and systematic biopsy (P < 0.01), along with a higher prostate-specific antigen density and a higher prostate imaging reporting and data system score. CONCLUSIONS: Transperineal prostate biopsy using the BioJet system is superior to cognitive registration in detecting significant cancer for targeted and systematic biopsies.

Who Can Avoid Biopsy of Magnetic Resonance Imaging-Negative Lobes without Compromising Significant Cancer Detection among Men with Unilateral Magnetic Resonance Imaging-Positive Lobes?

OBJECTIVES: To assess whether biopsy of multiparametric magnetic resonance imaging (MRI)-negative lobes can be avoided without compromising significant cancer (SC) detection among men with unilateral MRI-positive lobes. METHODS: From April 2013 to April 2019, 322 men with elevated prostate-specific antigen (PSA <20 ng/mL) and unilateral MRI-positive lobes underwent targeted 4-core and systematic 14-core biopsy. MRI findings were prospectively collected and evaluated according to the Prostate Imaging-Reporting and Data System (PI-RADS) version 2, and scores ≥3 were considered positive. SC was defined as Gleason score ≥3 + 4 or maximal cancer length ≥5 mm. We developed predictive models of overall cancer and SC in MRI-negative lobes and evaluated the performance of these models. RESULTS: Detection rates of overall cancer/SC were 69%/61% for the overall cohort, 58%/48% for MRI-positive lobes, and 36%/20% for MRI-negative lobes. Age ≥75 years, PSA density ≥0.3, and PI-RADS ≥4 were independently predictive of both overall cancer and SC in MRI-negative lobes; 1 point was assigned for each risk factor, and the predictive score was defined as the sum of points (0-3) for both overall cancer and SC. Areas under the curve of the model for overall cancer/SC were 0.67/0.71. In the decision curve analysis, the model was of value above the threshold probability of 13%/6% for detecting overall cancer/SC in MRI-negative lobes. Of 40 men with score 0, overall cancer/SC was detected in the MRI-negative lobe in 4 (10%)/1 (2.5%). CONCLUSION: Biopsies of MRI-negative lobes may be avoided without compromising SC detection using our predictive model.

Renal Angiomyolipoma Mimicking a Well-Differentiated Retroperitoneal Liposarcoma.

A 37-year-old Burmese woman presented with an incidentally found retroperitoneal fat-containing tumor. The tumor was 9 cm in the longest diameter, surrounding the right kidney, and composed of homogenous adipose tissue with thickened septum-like structures and spotty nonadipose structures, which were enhanced on contrast-enhanced computed tomography and magnetic resonance imaging. The tumor did not show either a beak sign or synchronous angiomyolipoma-like lesion in the kidneys. The tumor had irregular septa, thin blood vessels, and spotty small soft-tissue nodules. The tumor did not contain any heterogeneously enhanced solid lesions suspicious for dedifferentiated liposarcomas. Based on these imaging findings, a clinical diagnosis of a well-differentiated liposarcoma was made. Under the consensus of a multidisciplinary cancer board, she was recommended to undergo core-needle biopsy to confirm the clinical diagnosis. However, she declined to undergo biopsy for financial reasons. She underwent kidney-sparing retroperitoneal tumor resection. Histopathologically, the tumor was an angiomyolipoma with positive immunostaining for HMB45 and Melan A. The present case suggests the importance of core-needle biopsy prior to surgical intervention for retroperitoneal fat-containing tumors.

Who Can Avoid Systematic Biopsy Without Missing Clinically Significant Prostate Cancer in Men Who Undergo Magnetic Resonance Imaging-Targeted Biopsy?

BACKGROUND: The objective of the study was to identify a subset of men who can avoid systematic multisite biopsy (SyB) among those undergoing magnetic resonance imaging (MRI)-targeted transperineal 4-core biopsy (TgB) without missing clinically significant cancer (SC). PATIENTS AND METHODS: From April 2013 to December 2017, 304 men with elevated prostate-specific antigen levels (< 20 ng/mL) or abnormal digital rectal examination and positive MRI findings underwent transrecta ultrasound and MRI-targeted transperineal 4-core with 14-core systematic biopsy. MRI findings were prospectively collected and evaluated using Prostate Imaging-Reporting and Data System version 2 (PI-RADS), and scores ≥3 were considered positive. SC was defined as Gleason score ≥3 + 4 or maximum cancer length ≥5 mm. We evaluated the diagnostic performance of TgB and SyB to detect SC and characterized men who could avoid SyB without missing SC. RESULTS: Detection rates of any cancer and SC for TgB/SyB/their combination were 59%/63%/68% and 51%/52%/61%, respectively. TgB alone missed 14% (29/207) of any cancer and 16% (29/184) of SC detected using TgB with SyB. In uni- and multivariable analyses, PI-RADS scores of 3 to 4 were independent predictors for missing SC using TgB alone. When restricted to 81 men with PI-RADS scores of 5 (27%), SC was missed using TgB alone only in 3 (4.6% vs. 22% for the remaining 223 men; P = .007). CONCLUSION: SC was missed using TgB alone in a non-negligible proportion of men who underwent TgB and SyB. SyB might be safely avoided in men with PI-RADS score 5 lesions with reduced risks of missing SC.

Crucial role of phospholipase Cepsilon in induction of local skin inflammatory reactions in the elicitation stage of allergic contact hypersensitivity.

Phospholipase Cepsilon (PLCepsilon) is an effector of Ras/Rap small GTPases. We previously demonstrated that PLCepsilon plays a crucial role in development of phorbor ester-induced skin inflammation, which is intimately involved in the promotion of skin carcinogenesis. In this study, we have examined its role in local skin inflammatory reactions during development of contact hypersensitivity toward a hapten 2,4-dinitrofluorobenzene (DNFB). PLCepsilon(+/+) and PLCepsilon(-/-) mice were sensitized with DNFB, followed by a DNFB challenge on the ears. PLCepsilon(-/-) mice exhibited substantially attenuated inflammatory reactions compared with PLCepsilon(+/+) mice as shown by suppression of ear swelling, neutrophil infiltration, and proinflammatory cytokine production. In contrast, the extent and kinetics of CD4+ T cell infiltration showed no difference depending on the PLCepsilon background. Adoptive transfer of CD4+ T cells from the sensitized mice to naive mice between PLCepsilon(+/+) and PLCepsilon(-/-) backgrounds indicated that PLCepsilon exerts its function in cells other than CD4+ T cells, presumably fibroblasts or keratinocytes of the skin, to augment inflammatory reactions during the elicitation stage of contact hypersensitivity. Moreover, dermal fibroblasts and epidermal keratinocytes cultured from the skin expressed proinflammatory cytokines in a PLCepsilon-dependent manner on stimulation with T cell-derived cytokines such as IL-17, IFN-gamma, TNF-alpha, and IL-4. These results indicate that PLCepsilon plays a crucial role in induction of proinflammatory cytokine expression in fibroblasts and keratinocytes at the challenged sites, where infiltrated CD4+ T cells produce their intrinsic cytokines, thereby augmenting the local inflammatory reactions.

Crucial role of phospholipase C epsilon in skin inflammation induced by tumor-promoting phorbol ester.

In two-stage skin chemical carcinogenesis, phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) acts as a promoter essential for clonal expansion of the initiated cells carrying the activated ras oncogenes. Although protein kinase C (PKC) isozymes are the main targets of TPA, their role in tumor promotion remains controversial. We previously reported that mice lacking a Ras/Rap effector phospholipase C epsilon (PLC epsilon(-/-) mice) exhibited marked resistance to tumor formation in the two-stage skin carcinogenesis. PLC epsilon(-/-) mice also failed to exhibit basal layer cell proliferation and epidermal hyperplasia induced by TPA, suggesting a role of PLC epsilon in tumor promotion. Here, we show that PLC epsilon(-/-) mice exhibit resistance to TPA-induced skin inflammation as assessed by reduction in edema, granulocyte infiltration, and expression of a proinflammatory cytokine, interleukin-1 alpha (IL-1 alpha). On the other hand, the proliferative potentials of keratinocytes or dermal fibroblasts in culture remain unaffected by the PLC epsilon background, suggesting that the PLC epsilon's role in tumor promotion may be ascribed to augmentation of inflammatory responses. In dermal fibroblast primary culture, TPA can induce activation of the PLC epsilon lipase activity, which leads to the induction of IL-1 alpha expression. Experiments using small interfering RNA-mediated knockdown indicate that this activation is mediated by Rap1, which is activated by a TPA-responsive guanine nucleotide exchange factor RasGRP3. Moreover, TPA-induced activation of Rap1 and PLC epsilon is inhibited by a PKC inhibitor GF109203X, indicating a crucial role of PKC in signaling from TPA to PLC epsilon. These results imply that two TPA targets, RasGRP3 and PKC, are involved in TPA-induced inflammation through PLC epsilon activation, leading to tumor promotion.

Mouse epidermal keratinocytes in three-dimensional organotypic coculture with dermal fibroblasts form a stratified sheet resembling skin.

We describe an organotypic model of mouse skin consisting of a stratified sheet of epidermal keratinocytes and dermal fibroblasts within a contracted collagen gel. The model was designed to maintain the polarity of stratified keratinocytes and permit their long-term culture at an air-liquid interface. After air exposure, the thickness of the keratinocyte sheet transiently increased and then decreased to two cell layers at 2 weeks. The two-cell-layer structure is similar to that of the adult mouse epidermis. Cytokeratin 5 was localized in the lowest cell layer in the epithelial sheet, but cytokeratin 1 and loricrin were localized in the outer cell layers, resembling mouse skin. The expressions of interleukin 1alpha and 1beta in the keratinocytes and of keratinocyte growth factor 1 and 2 in the fibroblasts correlated with keratinocyte stratification. The mouse organotypic coculture is useful in studying epithelial cell-mesenchymal cell interactions in vitro.