Comparison of Multiparametric MRI-targeted and Systematic Biopsies for Detection of Cribriform and Intraductal Carcinoma Prostate Cancer.

Background Intraductal carcinoma (IDC) and invasive cribriform (Cr) subtypes of prostate cancer (PCa) are an indication of aggressiveness, but the evidence regarding whether MRI can be used to detect Cr/IDC-pattern PCa is contradictory. Purpose To compare the detection of Cr/IDC-pattern PCa at multiparametric MRI (mpMRI)-targeted biopsy versus systematic biopsy in biopsy-naive men at risk for PCa. Materials and Methods This study was a secondary analysis of a prospective randomized controlled trial that recruited participants with a clinical suspicion of PCa between April 2017 and November 2019 at five centers. Participants were randomized 1:1 to either the MRI arm or the systematic biopsy arm. Targeted biopsy was performed in participants with a Prostate Imaging Reporting and Data System score of at least 3. MRI features were recorded, and biopsy slides and prostatectomy specimens were reviewed for the presence or absence of Cr/IDC histologic patterns. Comparison of Cr/IDC patterns was performed using generalized linear mixed modeling. Results A total of 453 participants were enrolled, with 226 in the systematic biopsy arm (median age, 65 years [IQR, 59-70 years]; 196 biopsies available for assessment) and 227 in the mpMRI-targeted biopsy arm (median age, 67 years [IQR, 60-72 years]; 132 biopsies available for assessment). Identification of Cr/IDC PCa was lower in the systematic biopsy arm compared with the mpMRI arm (31 of 196 biopsies [16%] vs 33 of 132 biopsies [25%]; P = .01). No evidence of a difference in mean cancer core length (CCL) (11.3 mm ± 4.4 vs 9.7 mm ± 4.5; P = .09), apparent diffusion coefficient (685 µm2/sec ± 178 vs 746 µm2/sec ± 245; P = .52), or dynamic contrast-enhanced positivity (27 [82%] vs 37 [90%]; P = .33) for clinically significant PCa (csPCa) was observed between participants with or without Cr/IDC disease in the MRI arm. Cr/IDC-positive histologic patterns overall had a higher mean CCL compared with Cr/IDC-negative csPCa (11.1 mm ± 4.4 vs 9.2 mm ± 4.1; P = .009). Conclusion MRI-targeted biopsy showed increased detection of Cr/IDC histologic patterns compared with systematic biopsy. Clinical trial registration no. NCT02936258 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Scialpi and Martorana in this issue.

Evaluating the Effects of Kidney Preservation at 10 °C with Hemopure and Sodium Thiosulfate in a Rat Model of Syngeneic Orthotopic Kidney Transplantation.

Kidney transplantation is preferred for end-stage renal disease. The current gold standard for kidney preservation is static cold storage (SCS) at 4 °C. However, SCS contributes to renal graft damage through ischemia-reperfusion injury (IRI). We previously reported renal graft protection after SCS with a hydrogen sulfide donor, sodium thiosulfate (STS), at 4 °C. Therefore, this study aims to investigate whether SCS at 10 °C with STS and Hemopure (blood substitute), will provide similar protection. Using in vitro model of IRI, we subjected rat renal proximal tubular epithelial cells to hypoxia-reoxygenation for 24 h at 10 °C with or without STS and measured cell viability. In vivo, we preserved 36 donor kidneys of Lewis rats for 24 h in a preservation solution at 10 °C supplemented with STS, Hemopure, or both followed by transplantation. Tissue damage and recipient graft function parameters, including serum creatinine, blood urea nitrogen, urine osmolality, and glomerular filtration rate (GFR), were evaluated. STS-treated proximal tubular epithelial cells exhibited enhanced viability at 10 °C compared with untreated control cells (p < 0.05). Also, STS and Hemopure improved renal graft function compared with control grafts (p < 0.05) in the early time period after the transplant, but long-term function did not reach significance. Overall, renal graft preservation at 10 °C with STS and Hemopure supplementation has the potential to enhance graft function and reduce kidney damage, suggesting a novel approach to reducing IRI and post-transplant complications.

The use of Lutetium-177 PSMA radioligand therapy with high dose rate brachytherapy for locally recurrent prostate cancer after previous definitive radiation therapy: a randomized, single-institution, phase I/II study (ROADSTER).

BACKGROUND: Isolated local failure (ILF) can occur in patients who initially receive definitive radiation therapy for prostate cancer. Salvage therapy for ILF includes high dose rate (HDR) brachytherapy. Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) can accurately detect ILF and can exclude extraprostatic disease. Lutetium-177 PSMA Radioligand Therapy (RLT) is a novel treatment for prostate cancer that can target prostate cancer accurately, while sparing radiation dose to normal tissues. METHODS: ROADSTER is a phase I/II randomized, single-institution study. Patients with an ILF of prostate cancer after definitive initial radiation therapy are eligible. The ILF will be confirmed with biopsy, magnetic resonance imaging (MRI) and PSMA PET. Patients will be randomized between HDR brachytherapy in two fractions (a standard of care salvage treatment at our institution) (cohort 1) or one treatment of intravenous Lutetium-177 PSMA RLT, followed by one fraction of HDR brachytherapy (cohort 2). The primary endpoints for the phase I portion of the study (n = 12) will be feasibility, defined as 10 or more patients completing the study protocol within 24 months of study activation; and safety, defined as zero or one patients in cohort 2 experiencing grade 3 or higher toxicity in the first 6 months post-treatment. If feasibility and safety are achieved, the study will expand to a phase II study (n = 30 total) where preliminary efficacy data will be evaluated. Secondary endpoints include changes in prostate specific antigen levels, acute toxicity, changes in quality of life, and changes in translational biomarkers. Translational endpoints will include interrogation of blood, urine, and tissue for markers of DNA damage and immune activation with each treatment. DISCUSSION: ROADSTER explores a novel salvage therapy for ILF after primary radiotherapy with combined Lutetium-177 PSMA RLT and HDR brachytherapy. The randomized phase I/II design will provide a contemporaneous patient population treated with HDR alone to facilitate assessment of feasibility, tolerability, and biologic effects of this novel therapy. TRIAL REGISTRATION: NCT05230251 (ClinicalTrials.gov).

A three-gene DNA methylation biomarker accurately classifies early stage prostate cancer.

BACKGROUND: We identify and validate accurate diagnostic biomarkers for prostate cancer through a systematic evaluation of DNA methylation alterations. MATERIALS AND METHODS: We assembled three early prostate cancer cohorts (total patients = 699) from which we collected and processed over 1300 prostatectomy tissue samples for DNA extraction. Using real-time methylation-specific PCR, we measured normalized methylation levels at 15 frequently methylated loci. After partitioning sample sets into independent training and validation cohorts, classifiers were developed using logistic regression, analyzed, and validated. RESULTS: In the training dataset, DNA methylation levels at 7 of 15 genomic loci (glutathione S-transferase Pi 1 [GSTP1], CCDC181, hyaluronan, and proteoglycan link protein 3 [HAPLN3], GSTM2, growth arrest-specific 6 [GAS6], RASSF1, and APC) showed large differences between cancer and benign samples. The best binary classifier was the GAS6/GSTP1/HAPLN3 logistic regression model, with an area under these curves of 0.97, which showed a sensitivity of 94%, and a specificity of 93% after external validation. CONCLUSION: We created and validated a multigene model for the classification of benign and malignant prostate tissue. With false positive and negative rates below 7%, this three-gene biomarker represents a promising basis for more accurate prostate cancer diagnosis.

Characterization of clinical human prostate cancer lesions using 3.0-T sodium MRI registered to Gleason-graded whole-mount histopathology.

BACKGROUND: Overtreatment of prostate cancer (PCa) is a healthcare issue. Development of noninvasive imaging tools for improved characterization of prostate lesions might reduce overtreatment. PURPOSE: To measure the distribution of tissue sodium concentration (TSC), proton T2 -weighted signal, and apparent diffusion coefficient (ADC) values in human PCa and to test the presence of a correlation between regional differences in imaging metrics and the Gleason grade of lesions determined from histopathology. STUDY TYPE: Cross-sectional. SUBJECTS: Ten men with biopsy-proven PCa. SEQUENCES/FIELD STRENGTH: Sodium, proton T2 -weighted, and diffusion-weighted MRI data were acquired using Broad-Band 3D-Fast-Gradient-Recalled, 3D Cube (Isotropic 3D-Fast-Turbo-Spin-Echo acquisition) and 2D Spin-Echo sequences, respectively, with a 3.0T MR scanner. ASSESSMENT: All imaging data were coregistered to Gleason-graded postprostatectomy histology, as the standard for prostate cancer lesion characterization. Regional TSC and T2 data were assessed using percent changes from healthy tissue of the same patient (denoted ΔTSC, ΔT2 ). STATISTICS: Differences in ΔTSC, ADC, and ΔT2 as a function of Gleason score were analyzed for each imaging contrast using a one-way analysis of variance or a nonparametric t-test. Correlations between imaging data measures and Gleason score were assessed using a Spearman's ranked correlation. RESULTS: Evaluation of the correlation of ΔTSC, ADC, and ΔT2 datasets with Gleason scoring revealed that only the correlation between ΔTSC and Gleason score was statistically significant (rs = 0.791, p < 0.01), whereas the correlations of ADC and ΔT2 with Gleason score were not (rs = -0.306, p = 0.079 and r s = -0.069, p = 0.699, respectively). In addition, all individual patients showed monotonically increasing ΔTSC with Gleason score. DATA CONCLUSION: The results of this preliminary study suggest that changes in TSC, assessed by sodium MRI, has utility as a noninvasive imaging assay to accurately characterize PCa lesions. Sodium MRI may provide useful complementary information on mpMRI, which may assist the decision-making of men choosing either active surveillance or treatment. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1409-1419.

SKA1 over-expression promotes centriole over-duplication, centrosome amplification and prostate tumourigenesis.

Although spindle- and kinetochore-associated protein 1 (Ska1) has previously been identified as essential for proper chromosome segregation, it is unknown whether it plays a role in tumour development. Here, we report that Ska1 over-expression promotes prostate tumourigenesis. Immunohistochemistry and quantitative RT-PCR analysis revealed that Ska1 was over-expressed in human prostatic intra-epithelial neoplasia (PIN), the most likely prostate cancer precursor, and adenocarcinomas. Up-regulation of Ska1 protein was also found to be tumour-specific in breast, lung and other common human cancers. Importantly, prostate-specific up-regulation of Ska1 in a transgenic mouse model resulted in spontaneous tumourigenesis. Furthermore, in addition to its abundance in spindle microtubules and the outer kinetochore interface during mitosis, Ska1 was enriched at centrosomes in cultured cells. Depletion of Ska1 caused a failure of centrosome duplication, whilst Ska1 over-expression led to centrosome amplification in human prostate epithelial cells via the induction of centriole over-duplication. These epithelial cells harbouring extra centrosomes switched from a non-tumourigenic to a tumourigenic state in nude mice. Taken together, these data indicate that Ska1 over-expression promotes tumourigenesis.

Neoadjuvant Cabazitaxel plus Abiraterone/Leuprolide Acetate in Patients with High-Risk Prostate Cancer: ACDC-RP Phase II Trial.

PURPOSE: Early treatment intensification with neoadjuvant therapy may improve outcomes in patients with high-risk, localized prostate cancer treated with radical prostatectomy. Our objective was to compare pathologic, oncologic, and safety outcomes of neoadjuvant abiraterone acetate plus leuprolide acetate with or without cabazitaxel prior to radical prostatectomy in patients with localized, high-risk prostate cancer. PATIENTS AND METHODS: This open-label, multicenter, phase II trial randomized men with clinically localized, D'Amico high-risk prostate cancer to neoadjuvant abiraterone acetate (1,000 mg/day) and leuprolide acetate (22.5 mg every 3 months) with or without cabazitaxel (25 mg/m2) prior to radical prostatectomy. The primary outcome was pathologic complete response (pCR) or minimal residual disease (MRD). Secondary outcomes included surgical margins, lymph node involvement, pathologic stage, 12-month biochemical relapse-free survival (BRFS) rates, and safety profile. RESULTS: The per-protocol population consisted of 70 patients [cabazitaxel arm (Arm A): 37, no cabazitaxel arm (Arm B): 33]. Median patient age and prostate-specific antigen levels were 63.5 years [interquartile range (IQR), 58.0-68.0] and 21.9 ng/mL (IQR, 14.6-42.8), respectively. pCR/MRD occurred in 16 (43.2%) versus 15 patients (45.5%) in arms A and B, respectively (P = 0.85). pCR occurred in two (5.4%) versus three patients (9.1%) in arms A and B, respectively (P = 0.66). Patients with ≤ 25% total biopsy cores positive had increased odds of pCR/MRD (P = 0.04). Patients with pCR/MRD had superior 12-month BRFS rates (96.0% vs. 62.0%, P = 0.03). Grade 3+ adverse events occurred in 42.5% and 23.7% of patients in arms A and B, respectively (P = 0.078). CONCLUSIONS: Neoadjuvant cabazitaxel addition to abiraterone acetate/leuprolide acetate prior to radical prostatectomy did not improve pCR/MRD in clinically localized, high-risk prostate cancer.

Prostate: registration of digital histopathologic images to in vivo MR images acquired by using endorectal receive coil.

PURPOSE: To develop and evaluate a technique for the registration of in vivo prostate magnetic resonance (MR) images to digital histopathologic images by using image-guided specimen slicing based on strand-shaped fiducial markers relating specimen imaging to histopathologic examination. MATERIALS AND METHODS: The study was approved by the institutional review board (the University of Western Ontario Health Sciences Research Ethics Board, London, Ontario, Canada), and written informed consent was obtained from all patients. This work proposed and evaluated a technique utilizing developed fiducial markers and real-time three-dimensional visualization in support of image guidance for ex vivo prostate specimen slicing parallel to the MR imaging planes prior to digitization, simplifying the registration process. Means, standard deviations, root-mean-square errors, and 95% confidence intervals are reported for all evaluated measurements. RESULTS: The slicing error was within the 2.2 mm thickness of the diagnostic-quality MR imaging sections, with a tissue block thickness standard deviation of 0.2 mm. Rigid registration provided negligible postregistration overlap of the smallest clinically important tumors (0.2 cm(3)) at histologic examination and MR imaging, whereas the tested nonrigid registration method yielded a mean target registration error of 1.1 mm and provided useful coregistration of such tumors. CONCLUSION: This method for the registration of prostate digital histopathologic images to in vivo MR images acquired by using an endorectal receive coil was sufficiently accurate for coregistering the smallest clinically important lesions with 95% confidence.

Registration of prostate histology images to ex vivo MR images via strand-shaped fiducials.

PURPOSE: To present and evaluate a method for registration of whole-mount prostate digital histology images to ex vivo magnetic resonance (MR) images. MATERIALS AND METHODS: Nine radical prostatectomy specimens were marked with 10 strand-shaped fiducial markers per specimen, imaged with T1- and T2-weighted 3T MRI protocols, sliced at 4.4-mm intervals, processed for whole-mount histology, and the resulting histological sections (3-5 per specimen, 34 in total) were digitized. The correspondence between fiducial markers on histology and MR images yielded an initial registration, which was refined by a local optimization technique, yielding the least-squares best-fit affine transformation between corresponding fiducial points on histology and MR images. Accuracy was quantified as the postregistration 3D distance between landmarks (3-7 per section, 184 in total) on histology and MR images, and compared to a previous state-of-the-art registration method. RESULTS: The proposed method and previous method had mean (SD) target registration errors of 0.71 (0.38) mm and 1.21 (0.74) mm, respectively, requiring 3 and 11 hours of processing time, respectively. CONCLUSION: The proposed method registers digital histology to prostate MR images, yielding 70% reduced processing time and mean accuracy sufficient to achieve 85% overlap on histology and ex vivo MR images for a 0.2 cc spherical tumor.

Prostate cancer classification using radiomics and machine learning on mp-MRI validated using co-registered histology.

BACKGROUND: Multi-parametric magnetic resonance imaging (mp-MRI) is emerging as a useful tool for prostate cancer (PCa) detection but currently has unaddressed limitations. Computer aided diagnosis (CAD) systems have been developed to address these needs, but many approaches used to generate and validate the models have inherent biases. METHOD: All clinically significant PCa on histology was mapped to mp-MRI using a previously validated registration algorithm. Shape and size matched non-PCa regions were selected using a proposed sampling algorithm to eliminate biases towards shape and size. Further analysis was performed to assess biases regarding inter-zonal variability. RESULTS: A 5-feature Naïve-Bayes classifier produced an area under the receiver operating characteristic curve (AUC) of 0.80 validated using leave-one-patient-out cross-validation. As mean inter-class area mismatch increased, median AUC trended towards positively biasing classifiers to producing higher AUCs. Classifiers were invariant to differences in shape between PCa and non-PCa lesions (AUC: 0.82 vs 0.82). Performance for models trained and tested only in the peripheral zone was found to be lower than in the central gland (AUC: 0.75 vs 0.95). CONCLUSION: We developed a radiomics based machine learning system to classify PCa vs non-PCa tissue on mp-MRI validated on accurately co-registered mid-gland histology with a measured target registration error. Potential biases involved in model development were interrogated to provide considerations for future work in this area.

Targeting prostate lesions on multiparametric MRI with HDR brachytherapy: Optimal planning margins determined using whole-mount digital histology.

PURPOSE: Multiparametric magnetic resonance imaging (mpMRI) has demonstrated the ability to localize intraprostatic lesions. It is our goal to determine how to optimally target the underlying histopathological cancer within the setting of high-dose-rate brachytherapy (HDR-BT). METHODS AND MATERIALS: Ten prostatectomy patients had pathologist-annotated mid-gland histology registered to pre-procedural mpMRI, which were interpreted by four different observers. Simulated HDR-BT plans with realistic catheter placements were generated by registering the mpMRI lesions and corresponding histology annotations to previously performed clinical HDR-BT implants. Inverse treatment planning was used to generate treatment plans that treated the entire gland to a single dose of 15 Gy, as well as focally targeted plans that aimed to escalate dose to the mpMRI lesions to 20.25 Gy. Three margins to the lesion were explored: 0 mm, 1 mm, and 2 mm. The analysis compared the dose that would have been delivered to the corresponding histologically-defined cancer with the different treatment planning techniques. RESULTS: mpMRI-targeted plans delivered a significantly higher dose to the histologically-defined cancer (p < 0.001), in comparison to the standard treatment plans. Additionally, adding a 1 mm margin resulted in significantly higher D98, and D90 to the histologically-defined cancer in comparison to the 0 mm margin targeted plans (p = 0.019 & p = 0.0026). There was no significant difference between plans using 1 mm and 2 mm margins. CONCLUSIONS: Adding a 1 mm margin to intraprostatic mpMRI lesions significantly increased the dose to histologically-defined cancer, in comparison applying no margin. No significant effect was observed by further expanding the margins.

Kinetic analysis of dominant intraprostatic lesion of prostate cancer using quantitative dynamic [18F]DCFPyL-PET: comparison to [18F]fluorocholine-PET.

PURPOSE: Identification of the dominant intraprostatic lesion(s) (DILs) can facilitate diagnosis and treatment by targeting biologically significant intra-prostatic foci. A PSMA ligand, [18F]DCFPyL (2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid), is better than choline-based [18F]FCH (fluorocholine) in detecting and localizing DIL because of higher tumour contrast, particularly when imaging is delayed to 1 h post-injection. The goal of this study was to investigate whether the different imaging performance of [18F]FCH and [18F]DCFPyL can be explained by their kinetic behaviour in prostate cancer (PCa) and to evaluate whether DIL can be accurately detected and localized using a short duration dynamic positron emission tomography (PET). METHODS: 19 and 23 PCa patients were evaluated with dynamic [18F]DCFPyL and [18F]FCH PET, respectively. The dynamic imaging protocol with each tracer had a total imaging time of 22 min and consisted of multiple frames with acquisition times from 10 to 180 s. Tumour and benign tissue regions identified by sextant biopsy were compared using standardized uptake value (SUV) and tracer kinetic parameters from kinetic analysis of time-activity curves. RESULTS: For [18F]DCFPyL, logistic regression identified Ki and k4 as the optimal model to discriminate tumour from benign tissue (84.2% sensitivity and 94.7% specificity), while only SUV was predictive for [18F]FCH (82.6% sensitivity and 87.0% specificity). The higher k3 (binding) of [18F]FCH than [18F]DCFPyL explains why [18F]FCH SUV can differentiate tumour from benign tissue within minutes of injection. Superior [18F]DCFPyL tumour contrast was due to the higher k4/k3 (more rapid washout) in benign tissue compared to tumour tissue. CONCLUSIONS: DIL was detected with good sensitivity and specificity using 22-min dynamic [18F]DCFPyL PET and avoids the need for delayed post-injection imaging timepoints. The dissimilar in vivo kinetic behaviour of [18F]DCFPyL and [18F]FCH could explain their different SUV images. Clinical Trial Registration NCT04009174 (ClinicalTrials.gov).

Short-duration dynamic [18F]DCFPyL PET and CT perfusion imaging to localize dominant intraprostatic lesions in prostate cancer: validation against digital histopathology and comparison to [18F]DCFPyL PET/MR at 120 minutes.

PURPOSE: Localized prostate cancer (PCa) in patients is characterized by a dominant focus in the gland (dominant intraprostatic lesion, DIL). Accurate DIL identification may enable more accurate diagnosis and therapy through more precise targeting of biopsy, radiotherapy and focal ablative therapies. The goal of this study is to validate the performance of [18F]DCFPyL PET and CT perfusion (CTP) for detecting and localizing DIL against digital histopathological images. METHODS: Multi-modality image sets: in vivo T2-weighted (T2w)-MRI, 22-min dynamic [18F]DCFPyL PET/CT, CTP, and 2-h post-injection PET/MR were acquired in patients prior to radical prostatectomy. The explanted gland with implanted fiducial markers was imaged with T2w-MRI. All images were co-registered to the pathologist-annotated digital images of whole-mount mid-gland histology sections using fiducial markers and anatomical landmarks. Regions of interest encompassing DIL and non-DIL tissue were drawn on the digital histopathological images and superimposed on PET and CTP parametric maps. Logistic regression with backward elimination of parameters was used to select the most sensitive parameter set to distinguish DIL from non-DIL voxels. Leave-one-patient-out cross-validation was performed to determine diagnostic performance. RESULTS: [18F]DCFPyL PET and CTP parametric maps of 15 patients were analyzed. SUVLate and a model combining Ki and k4 of [18F]DCFPyL achieved the most accurate performance distinguishing DIL from non-DIL voxels. Both detection models achieved an AUC of 0.90 and an error rate of < 10%. Compared to digital histopathology, the detected DILs had a mean dice similarity coefficient of 0.8 for the Ki and k4 model and 0.7 for SUVLate. CONCLUSIONS: We have validated using co-registered digital histopathological images that parameters from kinetic analysis of 22-min dynamic [18F]DCFPyL PET can accurately localize DILs in PCa for targeting of biopsy, radiotherapy, and focal ablative therapies. Short-duration dynamic [18F]DCFPyL PET was not inferior to SUVLate in this diagnostic task. CLINICAL TRIAL REGISTRATION NUMBER: NCT04009174 (ClinicalTrials.gov).

Clinical Significance of Isolated V1 Arteritis in Renal Transplantation.

BACKGROUND: The presence of intimal arteritis (v) in renal allograft biopsy specimens establishes the presence of acute T-cell mediated rejection (TCMR), Grade IIa-III, according to the Banff classification of rejection. The clinical significance of isolated v1 lesions (v1), characterized by arteritis alone, compared with lesions of arteritis with tubulointerstitial inflammation (i-t-v) has been controversial. METHODS: We performed a retrospective review of 280 patients undergoing renal transplantation between 2005 and 2015 who received a "for cause" transplant biopsy using the Banff 2013 classification. Patients with TCMR grade IIa (n = 83) were subdivided into groups with isolated v1 arteritis and i-t-v. Pre- and postoperative renal function, graft survival, and overall survival were evaluated in all patients. RESULTS: Donor and recipient demographics were similar between groups. One month following treatment of rejection, patients with v1 disease had superior recovery of glomerular filtration rate vs patients with i-t-v (P < .002). At a median follow-up of 41 months from transplant, death-censored graft survival was 92% vs 79% (P = .04), and overall survival was 98% vs 79% (P < .004) in the isolated v1 and i-t-v groups, respectively. CONCLUSION: Despite having identical Banff classification of TCMR IIa, our results indicate that graft survival in patients with isolated v1 rejection is superior to those with i-t-v. Following corroboration with data from other centers, modification of the Banff classification scheme should be considered.

A multiobserver study investigating the effectiveness of prostatic multiparametric magnetic resonance imaging to dose escalate corresponding histologic lesions using high-dose-rate brachytherapy.

PURPOSE: Using multiparametric MRI data and the pathologic data from radical prostatectomy specimens, we simulated the treatment planning of dose-escalated high-dose-rate brachytherapy (HDR-BT) to the Multiparametric MRI dominant intraprostatic lesion (mpMRI-DIL) to compare the dose potentially delivered to the pathologically confirmed locations of the high-grade component of the cancer. METHODS AND MATERIALS: Pathologist-annotated prostatectomy midgland histology sections from 12 patients were registered to preprostatectomy mpMRI scans that were interpreted by four radiologists. To simulate realistic HDR-BT, we registered each observer's mpMRI-DILs and corresponding histology to two transrectal ultrasound images of other HDR-BT patients with a 15-Gy whole-gland prescription. We used clinical inverse planning to escalate the mpMRI-DILs to 20.25 Gy. We compared the dose that the histopathology would have received if treated with standard treatment plans to the dose mpMRI-targeting would have achieved. The histopathology was grouped as high-grade cancer (any Gleason Grade 4 or 5) and low-grade cancer (only Gleason Grade 3). RESULTS: 212 mpMRI-targeted HDR-BT plans were analyzed. For high-grade histology, the mpMRI-targeted plans achieved significantly higher median [IQR] D98 and D90 values of 18.2 [16.7-19.5] Gy and 19.4 [17.8-20.9] Gy, respectively, in comparison with the standard plans (p = 0.01 and p = 0.003). For low-grade histology, the targeted treatment plans would have resulted in a significantly higher median D90 of 17.0 [16.1-18.4] Gy in comparison with standard plans (p = 0.015); the median D98 was not significantly higher (p = 0.2). CONCLUSIONS: In this retrospective pilot study of 12 patients, mpMRI-based dose escalation led to increased dose to high-grade, but not low-grade, cancer. In our data set, different observers and mpMRI sequences had no substantial effect on dose to histologic cancer.

Stochastic Sequential Modeling: Toward Improved Prostate Cancer Diagnosis Through Temporal-Ultrasound.

Prostate cancer (PCa) is a common, serious form of cancer in men that is still prevalent despite ongoing developments in diagnostic oncology. Current detection methods lead to high rates of inaccurate diagnosis. We present a method to directly model and exploit temporal aspects of temporal enhanced ultrasound (TeUS) for tissue characterization, which improves malignancy prediction. We employ a probabilistic-temporal framework, namely, hidden Markov models (HMMs), for modeling TeUS data obtained from PCa patients. We distinguish malignant from benign tissue by comparing the respective log-likelihood estimates generated by the HMMs. We analyze 1100 TeUS signals acquired from 12 patients. Our results show improved malignancy identification compared to previous results, demonstrating over 85% accuracy and AUC of 0.95. Incorporating temporal information directly into the models leads to improved tissue differentiation in PCa. We expect our method to generalize and be applied to other types of cancer in which temporal-ultrasound can be recorded.

Prostate specific membrane antigen positron emission tomography for lesion-directed high-dose-rate brachytherapy dose escalation.

BACKGROUND AND PURPOSE: Prostate specific membrane antigen positron emission tomography imaging (PSMA-PET) has demonstrated potential for intra-prostatic lesion localization. We leveraged our existing database of co-registered PSMA-PET imaging with cross sectional digitized pathology to model dose coverage of histologically-defined prostate cancer when tailoring brachytherapy dose escalation based on PSMA-PET imaging. MATERIALS AND METHODS: Using a previously-developed automated approach, we created segmentation volumes delineating underlying dominant intraprostatic lesions for ten men with co-registered pathology-imaging datasets. To simulate realistic high-dose-rate brachytherapy (HDR-BT) treatments, we registered the PSMA-PET-defined segmentation volumes and underlying cancer to 3D trans-rectal ultrasound images of HDR-BT cases where 15 Gray (Gy) was delivered. We applied dose/volume optimization to focally target the dominant intraprostatic lesion identified on PSMA-PET. We then compared histopathology dose for all high-grade cancer within whole-gland treatment plans versus PSMA-PET-targeted plans. Histopathology dose was analyzed for all clinically significant cancer with a Gleason score of 7or greater. RESULTS: The standard whole-gland plans achieved a median [interquartile range] D98 of 15.2 [13.8-16.4] Gy to the histologically-defined cancer, while the targeted plans achieved a significantly higher D98 of 16.5 [15.0-19.0] Gy (p = 0.007). CONCLUSION: This study is the first to use digital histology to confirm the effectiveness of PSMA-PET HDR-BT dose escalation using automatically generated contours. Based on the findings of this study, PSMA-PET lesion dose escalation can lead to increased dose to the ground truth histologically defined cancer.

Immunohistochemical analysis of kallikrein-related peptidases in the normal kidney and renal tumors: potential clinical implications.

Kallikrein-related peptidases (KLKs) have been shown to be differentially expressed in various malignancies and shown to be useful tumor markers. Previous immunohistochemistry (IHC) analysis demonstrated that KLKs 5, 6, 10, and 11 have a potential prognostic significance in renal cell carcinoma (RCC). To further explore the significance of KLKs, we examined KLKs 1, 6, 7, and 15 in different subtypes of renal tumors. KLK1 has stronger expression in high grade compared to low grade clear cell RCC. However, KLK6 and KLK7 show strong expression in low grade in contrast to high grade clear cell RCC. Furthermore, the expression of KLK7 can distinguish between oncocytoma and chromophobe RCC. Oncocytoma showed diffuse, strong granular cytoplasmic staining, but chromophobe RCC showed focal weak homogeneous cytoplasmic stain. The pattern of staining of different KLKs can also be helpful in differentiating some of the subtypes of renal tumors. Our results show the potential ability of KLKs to serve as diagnostic markers and expand previous data about the prognostic significance of KLKs in kidney cancer. In addition, our study is the first to show the ability of KLK staining to distinguish various types of kidney cancers when morphology is similar.

Salvage open radical prostatectomy for recurrent prostate cancer following MRI-guided transurethral ultrasound ablation (TULSA) of the prostate: feasibility and efficacy.

Introduction: MRI-guided transurethral ultrasound ablation (TULSA) is a novel modality for minimally invasive ablation in patients with localised prostate cancer (PCa). A multi-national Phase 1 (30 patients) and subsequent Phase 2 (115 patients) study showed TULSA to be feasible, safe and well tolerated. However, technical viability and safety of salvage prostatectomy for those who failed TULSA is unclear. Herein, we report the feasibility and morbidity of salvage radical prostatectomy (sRP) post-TULSA.Methods: Four patients with biopsy-proven residual cancer following TULSA underwent open retropubic sRP within 39 months of TULSA. Peri-and post-operative morbidity were reported. Detailed histopathologic assessment is reported.Results: Median follow-up was 43 months after sRP. Mean operating times, blood loss, and length of stay were 210 min, 866 ml, and 3.5 days, respectively. Intraoperative finding of some fibrotic reaction of endopelvic and Denonvilliers fascia was characteristic. There were no perioperative complications. Whole-mount pathology sections showed one pT2b and three pT3a, suggesting under-staging pre-TULSA. Location of disease was compatible with persistent cancer mostly in the untreated peripheral safety region. One man received an artificial urinary sphincter. All men experienced erectile dysfunction responsive to treatment. Two patients with positive surgical margins had PSA progression requiring salvage radiation, with one requiring long-term androgen deprivation therapy.Conclusions: RP is a viable and safe salvage option if TULSA fails. Technical difficulty and perioperative morbidity were negligible and attributable to minimal peri-prostatic reaction from TULSA.