Automated Ki-67 labeling index assessment in prostate cancer using artificial intelligence and multiplex fluorescence immunohistochemistry.

The Ki-67 labeling index (Ki-67 LI) is a strong prognostic marker in prostate cancer, although its analysis requires cumbersome manual quantification of Ki-67 immunostaining in 200-500 tumor cells. To enable automated Ki-67 LI assessment in routine clinical practice, a framework for automated Ki-67 LI quantification, which comprises three different artificial intelligence analysis steps and an algorithm for cell-distance analysis of multiplex fluorescence immunohistochemistry (mfIHC) staining, was developed and validated in a cohort of 12,475 prostate cancers. The prognostic impact of the Ki-67 LI was tested on a tissue microarray (TMA) containing one 0.6 mm sample per patient. A 'heterogeneity TMA' containing three to six samples from different tumor areas in each patient was used to model Ki-67 analysis of multiple different biopsies, and 30 prostate biopsies were analyzed to compare a 'classical' bright field-based Ki-67 analysis with the mfIHC-based framework. The Ki-67 LI provided strong and independent prognostic information in 11,845 analyzed prostate cancers (p < 0.001 each), and excellent agreement was found between the framework for automated Ki-67 LI assessment and the manual quantification in prostate biopsies from routine clinical practice (intraclass correlation coefficient: 0.94 [95% confidence interval: 0.87-0.97]). The analysis of the heterogeneity TMA revealed that the Ki-67 LI of the sample with the highest Gleason score (area under the curve [AUC]: 0.68) was as prognostic as the mean Ki-67 LI of all six foci (AUC: 0.71 [p = 0.24]). The combined analysis of the Ki-67 LI and Gleason score obtained on identical tissue spots showed that the Ki-67 LI added significant additional prognostic information in case of classical International Society of Urological Pathology grades (AUC: 0.82 [p = 0.002]) and quantitative Gleason score (AUC: 0.83 [p = 0.018]). The Ki-67 LI is a powerful prognostic parameter in prostate cancer that is now applicable in routine clinical practice. In the case of multiple cancer-positive biopsies, the sole automated analysis of the worst biopsy was sufficient. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Prediction of Response to Cisplatin-Based Neoadjuvant Chemotherapy of Muscle-Invasive Bladder Cancer Patients by Molecular Subtyping including KRT and FGFR Target Gene Assessment.

Patients with muscle-invasive urothelial carcinoma achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NAC) have improved prognosis. Molecular subtypes of bladder cancer differ markedly regarding sensitivity to cisplatin-based chemotherapy and harbor FGFR treatment targets to various content. The objective of the present study was to evaluate whether preoperative assessment of molecular subtype as well as FGFR target gene expression is predictive for therapeutic outcome­rate of ypT0 status­to justify subsequent prospective validation within the "BladderBRIDGister". Formalin-fixed paraffin-embedded (FFPE) tissue specimens from transurethral bladder tumor resections (TUR) prior to neoadjuvant chemotherapy and corresponding radical cystectomy samples after chemotherapy of 36 patients were retrospectively collected. RNA from FFPE tissues were extracted by commercial kits, Relative gene expression of subtyping markers (e.g., KRT5, KRT20) and target genes (FGFR1, FGFR3) was analyzed by standardized RT-qPCR systems (STRATIFYER Molecular Pathology GmbH, Cologne). Spearman correlation, Kruskal−Wallis, Mann−Whitney and sensitivity/specificity tests were performed by JMP 9.0.0 (SAS software). The neoadjuvant cohort consisted of 36 patients (median age: 69, male 83% vs. female 17%) with 92% of patients being node-negative during radical cystectomy after 1 to 4 cycles of NAC. When comparing pretreatment with post-treatment samples, the median expression of KRT20 dropped most significantly from DCT 37.38 to 30.65, which compares with a 128-fold decrease. The reduction in gene expression was modest for other luminal marker genes (GATA3 6.8-fold, ERBB2 6.3-fold). In contrast, FGFR1 mRNA expression increased from 33.28 to 35.88 (~6.8-fold increase). Spearman correlation revealed positive association of pretreatment KRT20 mRNA levels with achieving pCR (r = 0.3072: p = 0.0684), whereas pretreatment FGFR1 mRNA was associated with resistance to chemotherapy (r = −0.6418: p < 0.0001). Hierarchical clustering identified luminal tumors of high KRT20 mRNA expression being associated with high pCR rate (10/16; 63%), while the double-negative subgroup with high FGFR1 expression did not respond with pCR (0/9; 0%). Molecular subtyping distinguishes patients with high probability of response from tumors as resistant to neoadjuvant chemotherapy. Targeting FGFR1 in less-differentiated bladder cancer subgroups may sensitize tumors for adopted treatments or subsequent chemotherapy.

Solid organ transplantation programs facing lack of empiric evidence in the COVID-19 pandemic: A By-proxy Society Recommendation Consensus approach.

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has a drastic impact on national health care systems. Given the overwhelming demand on facility capacity, the impact on all health care sectors has to be addressed. Solid organ transplantation represents a field with a high demand on staff, intensive care units, and follow-up facilities. The great therapeutic value of organ transplantation has to be weighed against mandatory constraints of health care capacities. In addition, the management of immunosuppressed recipients has to be reassessed during the ongoing coronavirus disease 2019 (COVID-19) pandemic. In addressing these crucial questions, transplant physicians are facing a total lack of scientific evidence. Therefore, the aim of this study was to offer an approach of consensus-based guidance, derived from individual information of 22 transplant societies. Key recommendations were extracted and the degree of consensus among different organizations was calculated. A high degree of consensus was found for temporarily suspending nonurgent transplant procedures and living donation programs. Systematic polymerase chain reaction-based testing of donors and recipients was broadly recommended. Additionally, more specific aspects (eg, screening of surgical explant teams and restricted use of marginal donor organs) were included in our analysis. This study offers a novel approach to informed guidance for health care management when a priori no scientific evidence is available.

Incidence, Risk Factors, Management, and Complications of Rectal Injuries During Radical Prostatectomy.

Rectal injury (RI) during radical prostatectomy (RP) is a severe complication. So far, only limited data describing the incidence, risk factors, management, and complications of RI are available. In an analysis of data for 24178 patients, we identified 113/24076 patients (0.47%) undergoing open or robotic RP and 7/102 patients (6.86%) after salvage RP who experienced an RI. Besides salvage RP, local tumor stage, Gleason grade, lymph node status, and surgical experience, but not surgical approach (robotic vs open), could be identified as risk factors for RI in univariate and multivariate analysis. Intraoperative management of RI comprised closure with two to three layers. In 13/109 patients (11.9%), a diverting colostomy/ileostomy was carried out. Some 12% of men with closure of an RI developed a recto-anastomosis fistula, and 57% of those who had an additional diverting enterostomy. Thus, the overall incidence of recto-anastomosis fistula after RP was <0.1%. The extent of rectal laceration, prior radiation, and intraoperative signs of rectal infiltration were associated with the development of a subsequent recto-anastomosis fistula. Some 83% of patients with a recto-anastomosis fistula needed further intervention. PATIENT SUMMARY: We analyzed the incidence, risk factors, management, and complications of rectal injury during radical prostatectomy. Overall, the incidence of rectal injury and subsequent development of recto-anastomosis fistulas is low unless the patient has significant risk factors.

A comparative assessment of active surveillance for localized prostate cancer in the community versus tertiary care referral center.

OBJECTIVES: To date, evidence on active surveillance (AS) is restricted to protocol-based studies. Conversely, practice patterns outside of such protocols are unknown. The aim of this study was to capture the current AS treatment patterns for localized prostate cancer in patients managed by office-based urologists compared to patients treated at a tertiary care center. METHODS AND MATERIALS: Two prospective cohorts were investigated: 361 AS arm patients of the German Hormonal treatment, Active surveillance, Radiation therapy, OP, Watchful waiting (HAROW) study, an observational health service study and 387 protocol-based AS patients treated at the Department of Urology of the Kantonsspital Aarau, Switzerland were included. Observational non-protocol HAROW versus on-protocol Kantonsspital Aarau (KSA) was compared, and active-treatment-free survival represented the primary outcome. RESULTS: Study population of the observational HAROW versus tertiary care protocol-based KSA cohorts differed statistically significantly regarding age (p < 0.001) and proportion of patients meeting the Chism criteria (p < 0.001). In stratified analyses, AFTS at 1 and 2 years was, respectively, 87.7 % (95 % CI 84.0-91.7) and 75.0 % (95 % CI 69.7-80.8) in HAROW patients compared to 90.8 % (95 % CI 87.8-93.9) and 75.3 % (95 % CI 70.7-80.1) for patients in the KSA cohort (p = 0.97). CONCLUSION: We demonstrate significant differences in terms of AS inclusion, surveillance and discontinuation criteria between patients managed by office-based urologists compared to their tertiary care counterparts. Interestingly, the risk of deferred active therapy was equally moderate for both groups in the short-term follow-up.

Assessment of rates of lymph nodes and lymph node metastases in periprostatic fat pads in a consecutive cohort treated with retropubic radical prostatectomy.

OBJECTIVE: To determine the rates of lymph nodes and lymph node metastases in periprostatic fat pads yielded during exposure of the anterior surface of the dorsal vein complex, puboprostatic ligaments, and endopelvic fascia during radical prostatectomy. METHODS: Histopathologic examination was performed in 356 patients who underwent radical prostatectomy between July 2010 and September 2010 at a single institution. Separate histologic work-up of the periprostatic fat pads addressed the presence of lymph nodes and possible metastatic invasion of lymph nodes within this area. Descriptive analyses and multivariable analyses to predict the presence of lymph node metastases within these fat pads were performed. RESULTS: Lymph nodes within periprostatic fat pads were detected in 19 (5.5%) patients. Among these patients, tumor infiltration was found in 4 (1.2%). Three of these 4 patients harbored lymph node metastases without any other lymph node metastasis during standard lymphadenectomy. No relationship was detected between the total number of lymph nodes removed and the detection of lymph nodes within periprostatic fat pads (P = .6). CONCLUSION: Our analysis demonstrates that periprostatic fat pads harbor lymph nodes. No relationship between the presence of lymph node metastases in periprostatic fat pads and the presence of lymph node metastases in other areas was found. Similarly, no relationship exists between the presence of lymph nodes in this area and the total number of lymph nodes yielded in other lymphatic fields. Therefore, for guaranteeing precise lymph node staging, implementing routinely pathologic work-up of periprostatic fat pads yielded during radical prostatectomy should be considered.

Risk assessment of metastatic recurrence in patients with prostate cancer by using the Cancer of the Prostate Risk Assessment score: results from 2937 European patients.

UNLABELLED: Study Type--Prognosis (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Different tools allow the individual estimation of the various endpoints in patients with prostate cancer. The Cancer of the Prostate Risk Assessment (CAPRA) score is an easy to calculate prediction tool, based on a large population based database. However, little is known about the performance of this prediction tool in European patients. The data obtained in the present study demonstrate differences in tumour characteristics between European patients and the initial development cohort from the USA. However, the concordance index of the CAPRA scores for predicting biochemical recurrence and metastatic recurrence was 76.2 and 78.5, respectively, in European patients. Therefore, the CAPRA score also allows reliable prediction of the examined endpoints in European patients. OBJECTIVES: • To assess the ability of the Cancer of the Prostate Risk Assessment Score (CAPRA) score for predicting biochemical recurrence (BCR) and metastatic recurrence (MR) by using a large cohort of European patients with prostate cancer. • The CAPRA score was initially developed using patients treated in community-based hospitals in the USA and allows a prediction of the risk of different clinical endpoints, without incorporating the surgical margin status. PATIENTS AND METHODS: • BCR and metastatic recurrence rates were studied in 2937 patients who underwent radical prostatectomy in a tertiary referral centre after a mean (median, range) follow-up of 49 (56, 12-220) months. • The association between the examined endpoints, individual CAPRA scores and pathological features was analyzed by using Kaplan-Meier, proportional hazard and logistic regressions analyses. • Graphical representation assessed the calibration of the CAPRA score for predicting both endpoints. RESULTS: • Compared to the initial development cohort, worse tumour characteristics and a lower overall positive surgical margin rate (17.2% vs 32.4%) were detected in the European cohort. • Overall, 530 (18.4%) and 58 (1.9%) of patients developed BCR and MR. Increasing CAPRA scores were related to less favourable pathological characteristics and higher BCR and metastatic recurrence rates. • For example, the 5-year BCR and metastatic recurrence rates were markedly different at the extremes of 0-1 vs ≥ 8 (9.2% vs 70.8% and 0.7% vs 16.4%, respectively). • The concordance index for the prediction of BCR and metastatic recurrence was 76.2 and 78.5, respectively. CONCLUSIONS: • Despite differences between the present cohort and the initial development cohort with respect to clinical features and the outcomes achieved, the data obtained in the present study shows the generalizability of the CAPRA score. • Specifically, the data allow the precise identification of those European patients who are at high risk for BCR and MR.

Importance of baseline potency rate assessment of men diagnosed with clinically localized prostate cancer prior to radical prostatectomy.

INTRODUCTION: Erectile dysfunction (ED) is a common, and multifactorial medical problem with significant impact on quality of life. Knowledge about baseline potency is highly important in men undergoing treatment for prostate cancer (PCa) as it might influence judgments about impact of treatment and thereby treatment decisions. AIMS: To analyze the baseline potency rate of men with clinically localized PCa prior to radical prostatectomy (RP). Furthermore, it was of interest to identify comorbid factors of preoperative ED. MAIN OUTCOME MEASURE: Prevalence of preoperative ED and association between comorbidities and ED in men prior to RP in bi- and multivariable logistic regression analyses. METHODS: Retrospective analysis of a large single center cohort of 1,330 evaluable PCa patients who were preoperatively assessed with the abridged 5-item version of the International Index of Erectile Function (IIEF) also described as Sexual Health Inventory for Men. Baseline potency and comorbidity rates, and their distribution were described. The risk of baseline ED associated with age, body mass index (BMI), the presence of hyperlipoproteinemia (HLP), non-insulin-dependent diabetes mellitus (NIDDM), hypertension, and depression were analyzed in bi- and multivariable logistic regression analyses. RESULTS: Using the IIEF-5 cutoff value of 21, 48% demonstrated some degree of ED. Severe, moderate, mild to moderate, mild, and no ED was observed in 9.2, 4.0, 10.2, 24.7, and 52% respectively. In univariable analyses, ED significantly increased according to increasing age, BMI, presence of HLP, hypertension, NIDDM, and depression (P

Assessment of biochemical recurrence rate in patients with pathologically confirmed insignificant prostate cancer.

OBJECTIVES: To examine the rate of biochemical recurrence (BCR) in patients with pathologically confirmed insignificant prostate cancer (PIPCa). METHODS: A total of 1358 patients underwent open retropubic radical prostatectomy at the University Medical Center Eppendorf in Hamburg, Germany, and their specimens were whole-mounted, step-sectioned, and subjected to computer-based three-dimensional reconstruction. We identified patients who fulfilled the Epstein criteria for definition of PIPCa (tumor volume

Health-insurance status is a determinant of the stage at presentation and of cancer control in European men treated with radical prostatectomy for clinically localized prostate cancer.

OBJECTIVE: To determine whether health-insurance status might result in more localized stage at presentation, more favourable stage at surgery and in a lower rate of biochemical recurrence (BCR), in patients diagnosed with prostate cancer and treated with radical prostatectomy (RP), as despite uninhibited access to healthcare, private and public health insurance are available in most European countries. PATIENTS AND METHODS: In all, 4442 consecutive men had RP in two large European centres, of whom 2372 had public and 2070 had private health insurance. The groups were compared for several variables according to insurance status (private vs public). Means and proportions tests were complemented with logistic regression or Kaplan-Meier analyses. RESULTS: Serum prostate-specific antigen level (P < 0.001), clinical stage (P < 0.001), pathological Gleason sum (P = 0.02), positive surgical margin rate (18.4% vs 25.4%, P < 0.001), extracapsular extension rate (17.7% vs 20.0%, P = 0.047) and seminal vesicle invasion rate (9.6% vs 11.6%, P = 0.04) were more favourable in privately insured patients. Conversely, the rate of lymph-node involvement was higher in those with private than public insurance (4.4% vs 3.3%, P = 0.045). In univariate analyses addressing pathological variables, private insurance was invariably protective (all P < 0.05). The Kaplan-Meier analyses showed that privately insured patients had a lower rate of BCR after RP (log-rank P = 0.017). CONCLUSION: Despite uninhibited access to healthcare, insurance status represents a rate-limiting variable, which affects stage at presentation and the outcome of cancer control.