Background/Objectives: Little is known about the synergy between intratumoral immunotherapy and cancer ablation. We conducted a Phase II Trial (Abscopal 5001 trial; NCT04713371) in patients with metastatic solid cancer to assess the safety and efficacy of cryoablation with concurrent injection of RPT-01-5001 (combination of low-dose checkpoint inhibitors and cyclophosphamide), a treatment process referred to as Multiplex Intratumoral Immunotherapy (MITITM). Methods: Twelve patients with metastatic cancer who had failed standard therapy and one with sacral chordoma received at least one intratumoral treatment of MITI preceded by 3-5 days of oral low-dose cyclophosphamide. MITI consisted of CT-guided cryoablation followed by intratumoral injection of RPT-01-5001. GM-CSF was subcutaneously administered daily for four weeks. Treatment was repeated every four weeks if the tumor burden remained stable or reduced, as noted by the iRECIST criteria. These criteria were modified when follow-up biopsies revealed pathology with minimal or no cancer, despite persistent suspicious masses on imaging. Results: Cancers included prostate (four patients), sarcoma (two), and one each of breast, colon, bladder, uterine cervix, tongue, kidney, and sacral chordoma. Eight patients received three cycles of treatment, two received two, and three received one. All patients tolerated the procedure well and were discharged within 2 h. The adverse event rate was 69%, all of which were grade 1 or 2, except for two grade 3 cases with delayed cryosurgical complications (15%). At completion of up to three cycles of treatment, a complete response (iCR) was observed in one patient (7.7%), partial response (iPR) in four patients (30.8%), and stable disease (iSD) in five (38.5%), with a disease control rate (iDCR) of 77%. Disparity between post-treatment imaging and pathologic findings was observed in four patients (positive vs. negative, respectively), requiring modification of the iRECIST criteria in favor of pathology. The best response ranged from 0 to 91%, with a mean for responding patients of 38%. Median progression-free survival (PFS) and 95% confidence intervals (95% CI) were 5.4 months (1.8 to 23.1 months); and median overall survival (OS) was 20.9 months (9.1 to 22.8 months). The injection site cancer response was observed in nine (69%) patients, and the distal abscopal effect was seen in four (31%), including one sarcoma patient with a complete abscopal response of lung metastases and one bladder cancer patient with biopsy-confirmed complete resolution of lung and liver metastases. Conclusions: MITI with RPT-01-5001 is safe and highly feasible, providing 77% disease control and 31% of the abscopal effect in patients with metastatic cancer who have failed standard therapies.

To investigate a novel prostate biopsy device capable of taking specimens between 1.5 and 5.5 cm in length and to determine the distances from apex to base in men undergoing transperineal biopsy. An actuator was developed capable of firing an 18-gauge true-cut biopsy needle with a specimen notch of 5.5 cm adjustable at 1 mm between 1.5 and 5.5 cm. The length of specimens retrieved vs the notch length was determined using fresh porcine kidneys and compared with a Bard device. The distance from prostate apex to base was determined in men undergoing transperineal biopsy using a proprietary software program. The program determined apex to base lengths throughout the gland. The number of needles required to span the prostate between ≤ 2.0 cm to > 5.0 cm was also determined. The variable length device outperformed the Bard device at different lengths collecting an average of 88% vs 82% of the notch length (n = 576, P < .001). The mean biopsy needle length required for an average prostate volume of 48.2 cc was 3.4 cm. 79.6% of the biopsies taken with the Bard device would not have reached that distance. The new needle collected 5.8 mm 3 of tissue vs 3.8 mm 3 (1.5 times more) for the Bard device. The variable length biopsy device can sample the prostate to 5.5 cm in length with an average of 88% of the specimen collected. Eighty percent of men would need a biopsy needle longer than what is typically used in clinical practice.

Prostate adenocarcinoma is a common malignancy associated with a significant morbidity and mortality. In both prostate biopsies and radical prostatectomy specimens Gleason scoring informs both treatment and outcome prediction. The current convention is that in needle biopsies, Gleason patterns 3, 4 and 5 are considered to be malignant. Despite this there is debate as to whether or not Gleason score (GS) 3+3=6 should be diagnosed as cancer due to potential over-treatment and the psychological impact on patients. It is apparent that GS 3+3=6 is indolent disease with a low risk of metastasis. However, it does have the histological features of malignancy and is capable of infiltrating the prostate gland, extraprostatic extension, and metastatic spread. Furthermore GS 3+3=6 carcinoma has immunohistochemical and molecular genetic features similar to those of higher grade prostatic carcinoma. If GS 3+3=6 tumour is considered benign, the question arises should a benign label be given to the Gleason pattern 3 component of tumour that includes Gleason patterns of higher grade? This would seem a logical step as GS 3+3=6 cancers and the pattern 3 component in cancers with multiple patterns are morphologically identical. If pattern 3 is considered to be benign, then Gleason scoring would be limited to 4+4=8, 4+5=9, 5+4=9 and 5+5=10 which is clearly inappropriate. The correct strategy to address potential over-treatment of patients with low-grade cancer is clinician and patient education, not the recalibration of Gleason grading to reclassify malignant tumours as benign.

Appendix S1 Survey monkey question for ISUP membership. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Purpose: To evaluate the efficacy and safety of a novel in situ cancer vaccination method for the treatment of aggressive solid tumors, with an initial focus on metastatic prostate cancer (PCa). Procedure: 27 consecutive patients with metastatic cancers (21 with PCa and 6 with other cancers), were treated by in situ cryosurgical lysis of tumor tissue followed by injection of ipilimumab, pembrolizumab or nivolumab, and sargramostim directly into the zone of lysis. This was followed by 30 daily s.c. injections of sargramostim. Patients received 1 to 3 cycles of the above therapy at intervals of ≥ 1 month. Responses to therapy were assessed by RECIST v.1.1 and for patients with PCa, serum PSA levels. This IRB-approved study, Shulman IRB Protocol #00027107, is a retrospective analysis (with prospective follow-up) of the practice of medicine of two physicians. All patients signed informed consent. Results: 21 patients with progressive metastatic PCa and 6 with other metastatic cancers (2 bladder, 1 pancreatic, 1 colon, 1 melanoma, and 1 unknown) were treated. RECIST responses for 2 patients (both with PCa) could not be evaluated due to a lack of follow-up imaging. Among the remaining 25 patients, CRs were seen in 9 (36%) patients and a PR in 1 (4%), for an ORR of 40%. SD was seen in 8 (32%) patients, and progression was seen in 7 (28%). Among the 19 evaluable PCa patients, there were 9 (47%) CRs and no PRs, for an ORR of 47%. 5 (26%) patients showed SD, and 5 (26%) progressed. 13/21 (62%) of patients had post-therapy PSA reductions of >50%. 12 PCa patients were ADT-naive (11 evaluable by RECIST) and there were 9 with mCRPC (8 evaluable by RECIST), and positive responses were seen in both groups, with ORRs of 55% and 38%, respectively, and PSA reductions of > 50% in 75% and 44% of patients, respectively. These antitumor responses have been durable in many patients, with CRs to date ranging from 1 to over 4.5 years post-treatment. Encouragingly, this durability of response was observed both in ADT-naive patients and in those with mCRPC. Therapy was well tolerated, with AEs in 19/27 (70%) of patients. 24 grade 1-2 AEs were seen in 19 (70%) patients, and 8 grade 3-4 AEs were seen in 5 (19%) patients. Notably, AEs included liver enzyme elevations, hyperthyroidism and hypothyroidism, all of which are associated with autoimmune responses to immunotherapy. One death that was possibly treatment-related, 4 disease-related deaths, and 2 unrelated deaths occurred. Conclusions: This report describes a novel therapeutic modality utilizing local cryosurgical tumor cell lysis and intratumorally-delivered immunotherapy to treat metastatic prostate cancer and other aggressive solid tumor cancers. Its combination of striking efficacy and good tolerability supports additional formal clinical studies. Citation Format: Gary Onik, David Bostwick, David J. Vaughan, Donald L. Trump, Zurizaday Vega, Timothy Murphy, James Miessau, Marlene Wright-Barton, Danielle Hobbs, Charles J. Link, Jon H. Condra. Regression of metastatic cancer and abscopal effects following in situ vaccination by cryosurgical tumor cell lysis and intratumoral immunotherapy: A case series [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6540.

The International Society of Urological Pathology (ISUP) hosts a reference image database supervised by experts with the purpose of establishing an international standard in prostate cancer grading. Here, we aimed to identify areas of grading difficulties and compare the results with those obtained from an artificial intelligence system trained in grading. In a series of 87 needle biopsies of cancers selected to include problematic cases, experts failed to reach a 2/3 consensus in 41.4% (36/87). Among consensus and non-consensus cases, the weighted kappa was 0.77 (range 0.68–0.84) and 0.50 (range 0.40–0.57), respectively. Among the non-consensus cases, four main causes of disagreement were identified: the distinction between Gleason score 3 + 3 with tangential cutting artifacts vs. Gleason score 3 + 4 with poorly formed or fused glands (13 cases), Gleason score 3 + 4 vs. 4 + 3 (7 cases), Gleason score 4 + 3 vs. 4 + 4 (8 cases) and the identification of a small component of Gleason pattern 5 (6 cases). The AI system obtained a weighted kappa value of 0.53 among the non-consensus cases, placing it as the observer with the sixth best reproducibility out of a total of 24. AI may serve as a decision support and decrease inter-observer variability by its ability to make consistent decisions. The grading of these cancer patterns that best predicts outcome and guides treatment warrants further clinical and genetic studies. Results of such investigations should be used to improve calibration of AI systems.

Prostatic stromal proliferations account for the majority of benign tumour-like lesions in the prostate. The most common is nodular hyperplasia, seen in a majority of elderly men. Diagnostic difficulty is encountered with some variants, including stromal hyperplasia with atypia, characterised by degenerative changes of myofibroblasts. In contrast with benign stromal tumours, malignant stromal tumours of the prostate are rare, accounting for less than 0.1% of all prostatic malignancies. The most common are rhabdomyosarcoma (paediatric) and leiomyosarcoma (adults); others include phyllodes tumour and stromal sarcoma. Some authors lump malignant tumours with poor outcome (e.g., phyllodes tumour and stromal sarcoma) with benign stromal tumours (e.g., stromal hyperplasia with atypia, leiomyoma), considering them collectively to be of uncertain malignant potential, but this approach is discouraged. This review presents a contemporary approach to classification and diagnosis of prostatic stromal tumours.

BJU InternationalVolume 127, Issue 2 p. 165-168 Comment Open Access Prostate cancer grading, time to go back to the future Lars Egevad, Corresponding Author lars.egevad@ki.se orcid.org/0000-0001-8531-222X Department of Oncology and Pathology, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorBrett Delahunt, Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New ZealandSearch for more papers by this authorDavid G. Bostwick, Bostwick Laboratories, Orlando, FL, USASearch for more papers by this authorLiang Cheng, orcid.org/0000-0001-6049-5293 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USASearch for more papers by this authorAndrew J. Evans, Laboratory Medicine Program, University Health Network, Toronto, ON, CanadaSearch for more papers by this authorTroy Gianduzzo, Wesley Urology Clinic, Brisbane, Qld, AustraliaSearch for more papers by this authorMarkus Graefen, Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanySearch for more papers by this authorJonas Hugosson, orcid.org/0000-0002-2324-2817 Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Department of Urology, Sahlgrenska University Hospital, Gothenburg, SwedenSearch for more papers by this authorJames G. Kench, orcid.org/0000-0001-8687-4988 Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and Central Clinical School, University of Sydney, Sydney, NSW, AustraliaSearch for more papers by this authorKatia R.M. Leite, Department of Urology, Laboratory of Medical Research, University of Sao Paulo Medical School, Sao Paulo, BrazilSearch for more papers by this authorJon Oxley, orcid.org/0000-0002-4348-0273 Department of Cellular Pathology, Southmead Hospital, Bristol, UKSearch for more papers by this authorGuido Sauter, Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanySearch for more papers by this authorJohn R. Srigley, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, CanadaSearch for more papers by this authorPär Stattin, orcid.org/0000-0002-8306-0687 Department of Surgical Sciences, Uppsala University Hospital, Uppsala, SwedenSearch for more papers by this authorToyonori Tsuzuki, orcid.org/0000-0002-4855-4366 Department of Surgical Pathology, School of Medicine, Aichi Medical University, Nagoya, JapanSearch for more papers by this authorJohn Yaxley, Wesley Urology Clinic, Brisbane, Qld, AustraliaSearch for more papers by this authorHemamali Samaratunga, Aquesta Uropathology, University of Queensland, Brisbane, Qld, AustraliaSearch for more papers by this author Lars Egevad, Corresponding Author lars.egevad@ki.se orcid.org/0000-0001-8531-222X Department of Oncology and Pathology, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorBrett Delahunt, Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New ZealandSearch for more papers by this authorDavid G. Bostwick, Bostwick Laboratories, Orlando, FL, USASearch for more papers by this authorLiang Cheng, orcid.org/0000-0001-6049-5293 Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USASearch for more papers by this authorAndrew J. Evans, Laboratory Medicine Program, University Health Network, Toronto, ON, CanadaSearch for more papers by this authorTroy Gianduzzo, Wesley Urology Clinic, Brisbane, Qld, AustraliaSearch for more papers by this authorMarkus Graefen, Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanySearch for more papers by this authorJonas Hugosson, orcid.org/0000-0002-2324-2817 Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Department of Urology, Sahlgrenska University Hospital, Gothenburg, SwedenSearch for more papers by this authorJames G. Kench, orcid.org/0000-0001-8687-4988 Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and Central Clinical School, University of Sydney, Sydney, NSW, AustraliaSearch for more papers by this authorKatia R.M. Leite, Department of Urology, Laboratory of Medical Research, University of Sao Paulo Medical School, Sao Paulo, BrazilSearch for more papers by this authorJon Oxley, orcid.org/0000-0002-4348-0273 Department of Cellular Pathology, Southmead Hospital, Bristol, UKSearch for more papers by this authorGuido Sauter, Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanySearch for more papers by this authorJohn R. Srigley, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, CanadaSearch for more papers by this authorPär Stattin, orcid.org/0000-0002-8306-0687 Department of Surgical Sciences, Uppsala University Hospital, Uppsala, SwedenSearch for more papers by this authorToyonori Tsuzuki, orcid.org/0000-0002-4855-4366 Department of Surgical Pathology, School of Medicine, Aichi Medical University, Nagoya, JapanSearch for more papers by this authorJohn Yaxley, Wesley Urology Clinic, Brisbane, Qld, AustraliaSearch for more papers by this authorHemamali Samaratunga, Aquesta Uropathology, University of Queensland, Brisbane, Qld, AustraliaSearch for more papers by this author First published: 18 November 2020 https://doi.org/10.1111/bju.15298 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat In November 2014, the International Society of Urological Pathology (ISUP) convened a consensus meeting in Chicago, Illinois, USA to consider grading criteria for prostatic adenocarcinoma [1]. The primary purpose and main outcome of this meeting was a recommendation that, not only should the Gleason score of prostate cancer be reported, but that grading should also incorporate a five-tier grade based on a grouping of Gleason scores. The outcome of the conference has resulted in widespread confusion as to the grading nomenclature. This has weighed heavily on the prostate cancer literature to the extent that the time has now come to question the scientific value of the score grouping. The Chicago conference was held as a stand-alone 1-day meeting and was rushed to enable a consensus decision to be achieved to inform the editorial meeting of the WHO Classification of Tumours of the Urinary System and Male Genital Organs in March 2015. Unfortunately, this consensus was never generated. At the WHO meeting, it was agreed that the WHO Bluebook should not endorse any of the proposed names for the grading scheme and the Bluebook instead adopted the descriptive and provisional term 'grade groups' [2]. An important issue is that while the term 'grade group' is catchy, it is factually incorrect as the system is not a grouping of Gleason grades, but a grouping of Gleason scores. A further major problem is that 'grade groups' are usually abbreviated to GG which has for decades been the acronym for Gleason grade, i.e. Gleason pattern. The issue has been compounded by the plethora of terms and abbreviations that have flooded the literature, with the grading system being referred to as: GG (grade group) [3]; GrG (grade group) [4]; PGG (prognostic grade group [5]; prostate cancer grade group [6]); GGG (Gleason grade group) [7]; ISUP grade [8]; WHO grade group [9]; ISUP grade group [10]; ISUP score [11]; and others. The problems resulting from the use of 'GG' as an acronym are not confined to the confusion as to whether it refers to 'grade group' or Gleason grade (i.e. Gleason pattern) as it is also unclear what is meant by 'grade' in this context. Does this refer to Gleason score, Gleason pattern or 'grade group'? The pathology community has spent considerable energy on this dispute over the last 5 years [12-15]. It has been claimed that the main advantage of grouping of Gleason scores is that it assists clinicians in their discussions with patients over the likely behaviour and outcome of their prostate cancer. Understandably, a diagnosis of a grade 1 cancer may indeed sound more reassuring than that of a Gleason score 6 cancer. However, we question the cost–benefit ratio of the putative pedagogical advantage vs the confusion that has been caused by the plethora of new terms. It has been shown that there is indeed a need to explain the grading information to the patients as fewer than 50% in one study were found to have adequate understanding of the current nomenclature [16]. Yet, an increasing number of patients are well informed as they have access to a wealth of information on the Internet. Even if pathologists did cease to refer to the ISUP 2014 score grouping in the scientific literature, clinicians would still be free to translate a Gleason score 6 to grade 1, if that was more understandable in communications with the patient. There may have been a hope among some pathologists that 'grade groups' would replace Gleason grading entirely, but it is now apparent that this is a very unlikely scenario. Grading of prostate cancer is based on architectural patterns and pathologists need to specify these patterns to describe their findings. The wordy description of the morphology of the ISUP 2014 scheme in the consensus document is clearly insufficient for the discussion of individual architectural patterns [1]. It is clear from this that the so-called groupings and the definitive Gleason scores would always need to be reported simultaneously and thus continue to provide redundant information. Pathology reports tend to become increasingly extensive with an increasing amount of prognostic information. Even if synoptic reporting is used, all this information will risk obscuring the important diagnostic and prognostic elements. Any duplicate information should therefore be avoided. Prostate cancer grading has gone through uninterrupted change over the past two decades. Few other areas of tumour pathology have seen such a landslide of variation in reporting recommendations. Some of this development reflects an increased understanding of the biology of the disease, such as the notion that the presence of invasive cribriform cancer and intraductal carcinoma of the prostate conveys a poor prognosis [17, 18]. While cribriform cancer used to be included in either Gleason pattern 3 or 4, depending on the size and shape of the glands, the ISUP 2014 revision considers all cribriform cancer to be Gleason pattern 4, or even 5 if comedonecrosis is present [19]. The recognition of the prognostic impact of intraductal carcinoma of the prostate has led to the recommendation that this lesion be assigned a Gleason pattern 4 or 5 using the same criteria as for prostatic carcinoma with stromal invasion [18, 20]. Other decisions have been much less well founded and have led to confusion among general pathologists. The first major revision of the Gleason system resulted from the ISUP consensus conference in 2005 [21]. Here a re-definition of the significance of the components of the Gleason scores in needle biopsies was proposed. This has resulted in a significant Gleason inflation, which was confirmed in a registry study of almost 100 000 men with newly diagnosed cancer on needle biopsy in 1998–2011 [22]. A gradual shift towards the upgrading of tumours has been observed over a prolonged period, but this has been particularly evident after 2005. After an adjustment for stage shift, the proportion of tumours diagnosed as Gleason scores 7–10 increased from 59% to 72% when cancers reported before and after 2005 were compared. It has also been shown that, following the publication of the 2005 ISUP revision of the Gleason classification, the grading of general pathologists has become more aggressive than that of uropathology experts [23]. This has had a negative impact on the management of prostate cancer, with the perception that the Gleason score has become fluid rather than finite. This is unfortunate as the development of well-established reporting systems must be based on strong scientific evidence and a high level of consensus in the uropathology community. The correlation between Gleason score in needle biopsies and radical prostatectomy specimens has been claimed to be improved after the ISUP 2005 revision of the Gleason grading system [24]. This conclusion was supported by an often-cited early report [25]; however, that particular study did not take into account the differences in grade distribution when comparing grading undertaken before and after 2005. If the number of grade categories that are actually used is reduced by new recommendations, there will be a spurious improvement of prediction accuracy of prostatectomy grade. In a later registry study of more than 15 000 men, it was found that, when grade distribution and other confounders were taken into account, there was actually a decreased grade concordance after 2005 [26]. When the scores were grouped according to ISUP 2014 the concordance fell even further, suggesting that even the ISUP 2014 revision may have done more harm than good in this respect. The percentage of Gleason pattern 4/5 present in biopsies was introduced as a prognostic marker by Stamey et al. two decades ago [27]. Despite validation of the prognostic value and assessment of the reproducibility of this marker [28, 29], assessment of percentage of Gleason pattern 4/5 present in tumours did not gain widespread traction in clinical practice. More recently the reporting of percentage of pattern 4/5 present in cancers has become more prevalent [8]. An explanation for this increasing interest may be that the Gleason inflation that was fueled by the ISUP 2005 consensus recommendations has pushed a considerable number of cancers from Gleason score 6 to 7 [21]. There is now a need for the identification of additional descriptors that will permit the triaging of Gleason score 7 tumours into categories that will provide guidance in the management of patients. This incremental reporting of percentage of Gleason pattern 4 further reduces interest in the reporting of broad categories of Gleason patterns 3 vs 4 involvement as grades 2, 3 and 4 (1–49%, 50–95% and >95% Gleason pattern 4), especially since pure Gleason score 8 (4 + 4) in radical prostatectomy specimens is apparently rare, contributing to only 0.6–3.9% cases in tumour series [30, 31]. Furthermore, several studies have demonstrated overlapping outcome curves for ISUP grades 3 and 4 [30, 32-34]. This makes it even more questionable whether it is worth assigning a separate grade category to the unusual pure Gleason score 4 + 4 = 8 cancers, while other steps in the continuous scale of percentages of Gleason pattern 4 are ignored. In some active surveillance programmes, 10% is a limit for allowing active surveillance [35]. Stamey et al. emphasized that, if biopsies contained at least 20% Gleason pattern 4/5, the prostatectomy specimen also contained at least 20% of these patterns in 90% of men, indicating that this threshold may be of clinical interest [27]. None of these thresholds is accounted for by 'grade groups' 2–4. Yet another problem with the suggested grouping of grades is the unsettled definition of ISUP grade 4 [36]. At the ISUP consensus conference in 2014, this grade category was defined as Gleason score 8 (4 + 4, 3 + 5 and 5 + 3), while Pierorazio et al. [5] defined prognostic grade group 4 as Gleason score 8 based on investigations of the outcome of Gleason score 4 + 4 cancer alone. Thus, ISUP 2014 grading departs from the Pierorazio et al. grouping, both in the grouping of scores and in the interpretation of morphology. Several studies have indicated a possible heterogeneity in Gleason score 8 tumours. Some have found a higher prostate cancer-specific mortality in Gleason score 5 + 3 than in 3 + 5 and 4 + 4 [37] or in 3 + 5 and 5 + 3 than in 4 + 4 [38], while others have found a lower biochemical [31] or clinical recurrence rate [39] in cancers of Gleason score 3 + 5 than in other Gleason score 8 tumours. A further issue is that 'grade groups' lack the granularity of Gleason scoring. The clearest example of this relates to 'grade group' 4. Here it is unknown if this refers to Gleason score 3 + 5=8, 4 + 4=8 or 5 + 3 = 8. There is increasing evidence that the percentage of pattern 4 tumour present has an impact on outcome and, as such, it seems bizarre that 'grade group' 4 tumours have either 100% pattern 4 or 0% pattern 4 and yet are classified as an identical grade. It has also been suggested that Gleason score 5 + 4 cancers may have a higher risk of lymph node involvement and a worse outcome after radical prostatectomy than Gleason score 4 + 5 tumours [40]. In addition, we may at present be unaware of details that now escape us such as the distinction of very low-grade patterns detected by MRI-targeted biopsies from the anterior prostate, as all low-grade tumours are currently lumped together on needle biopsy. All of these examples illustrate that collapsing the Gleason grading system to five groups simplifies the complexity of prostate cancer morphology, with resulting loss of detail of information. Few revisions of a histopathological grading system have contributed as little as the ISUP grading recommendations of 2014. The notion that this would be a novel grading system is a misconception as it is a mere translation of the Gleason scores into an alternative terminology at the expense of loss of information. It is time to realize that the introduction of this grouping was a mistake and reclaim the universally understood Gleason nomenclature for grading of prostate cancer. The future development of prostate cancer prognostication should rather be based on the integration of novel knowledge of the role of genetics of prostate carcinogenesis [41, 42] and classical morphology, possibly assisted by artificial intelligence [20, 43]. Conflict of Interest None declared. References 1Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PA. 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Infiltration of the prostatic ducts by prostatic adenocarcinoma occurs relatively frequently, being most commonly associated with high grade disease. It is now recognised that intraductal carcinoma of the prostate (IDCP) has an associated poor prognosis and this is reflected in its histological, molecular and immunohistochemical features. The current recommendation of the World Health Organization is that IDCP not be taken into consideration when grading prostate adenocarcinoma. It is apparent that Gleason did not differentiate between IDCP and stromal invasive carcinoma when developing and validating his grading system, and recent studies suggest that the incorporation of IDCP grading into the overall grading of the specimen provides additional prognostic information.

Background: An increasing volume of prostate biopsies and a world-wide shortage of uro-pathologists puts a strain on pathology departments. Additionally, the high intra- and inter-observer variability in grading can result in over- and undertreatment of prostate cancer. Artificial intelligence (AI) methods may alleviate these problems by assisting pathologists to reduce workload and harmonize grading. Methods: We digitized 6,682 needle biopsies from 976 participants in the population based STHLM3 diagnostic study to train deep neural networks for assessing prostate biopsies. The networks were evaluated by predicting the presence, extent, and Gleason grade of malignant tissue for an independent test set comprising 1,631 biopsies from 245 men. We additionally evaluated grading performance on 87 biopsies individually graded by 23 experienced urological pathologists from the International Society of Urological Pathology. We assessed discriminatory performance by receiver operating characteristics (ROC) and tumor extent predictions by correlating predicted millimeter cancer length against measurements by the reporting pathologist. We quantified the concordance between grades assigned by the AI and the expert urological pathologists using Cohen's kappa. Results: The performance of the AI to detect and grade cancer in prostate needle biopsy samples was comparable to that of international experts in prostate pathology. The AI achieved an area under the ROC curve of 0.997 for distinguishing between benign and malignant biopsy cores, and 0.999 for distinguishing between men with or without prostate cancer. The correlation between millimeter cancer predicted by the AI and assigned by the reporting pathologist was 0.96. For assigning Gleason grades, the AI achieved an average pairwise kappa of 0.62. This was within the range of the corresponding values for the expert pathologists (0.60 to 0.73).

Aims Despite efforts to standardise grading of prostate cancer, even among experts there is still a considerable variation in grading practices. In this study we describe the use of Pathology Imagebase, a novel reference image library, for setting an international standard in prostate cancer grading. Methods and results The International Society of Urological Pathology ( ISUP ) recently launched a reference image database supervised by experts. A panel of 24 international experts in prostate pathology reviewed independently microphotographs of 90 cases of prostate needle biopsies with cancer. A linear weighted kappa of 0.67 (95% confidence interval = 0.62–0.72) and consensus was reached in 50 cases. The interobserver weighted kappa varied from 0.48 to 0.89. The highest level of agreement was seen for Gleason score ( GS ) 3 + 3 = 6 ( ISUP grade 1), while higher grades and particularly GS 4 + 3 = 7 ( ISUP grade 3) showed considerable disagreement. Once a two‐thirds majority was reached, images were moved automatically into a public database available for all ISUP members at www.isupweb.org . Non‐members are able to access a limited number of cases. Conclusions It is anticipated that the database will assist pathologists to calibrate their grading and, hence, decrease interobserver variability. It will also help to identify instances where definitions of grades need to be clarified.

186 Background: Ferumoxytol (Feraheme) is a ferromagnetic nanoparticle with lymphotrophic biokinetics, delivered to lymph nodes by normal macrophages. MRI suppresses normal lymph nodes containing Feraheme. Objective is to validate safety and efficacy in finding lymph node positivity in prostate cancer (PCa). Methods: Nonrandomized prospective evaluation of 178 consecutive PCa patients (pts) at high risk for lymph node spread enrolled 2/13-3/15. All received IV Feraheme. 177 received 6/mg/kg over 20 min. One pt received 3 mg/kg infusion. T2 MEDIC and T2* sequence imaging of abdomen and pelvis, given 24 hours later. Images reviewed by 2 board certified radiologists with same interpretations, blinded to clinical and histo-path info (pre-MRI TNM stage/PSA/Gleason). Nodes were deemed abnormal if they did not suppress after Feraheme infusion (group 1, 94 patients). Nodes were deemed suspicious if suppressed and met usual size criteria with high signal intensity on DWI and decreased ADC map values and morphologic features (group 2, 84 pts). 83 group 1 pts had CT biopsies (77 pelvis, 6 retroperitoneum);11 pts had open PLND. 382 lymph nodes sampled. 76 group 2 patients had CT biopsies (73 pelvis, 3 retroperitoneum); 9 pts had open PLND. 340 lymph nodes sampled. Rad-path correlation was performed. Nodes were stained; reviewed by a single pathologist with no knowledge of MRI findings. Histo-path results for each node were cataloged for later MRI comparison. Results: 90 group 1 pts (96%) proved metastatic PCa; 4 pts (4%) were normal. 68 group 1 pts (77%) had malignant lymph nodes not meeting usual imaging criteria. 39 group 2 pts (47%) showed metastatic PCa; 46 pts (53%) were normal. One group 2 pt had an allergic reaction with hives; infusion ceased at 3mg/kg; pt treated to full resolution with 50 mg IV Benadryl. Conclusions: Feraheme can evaluate lymphatic dissemination of metastatic disease in PCa patients, with a lower limit of resolution of focal lymph node metastases of 2-3 mm. Better resolution gives implications for therapeutic radiation planning of newly diagnosed or recurrent/metastatic PCa. Toxicity was very acceptable at 6mg/kg. Feraheme may play a significant role as a lymphatic contrast agent in the early dissemination of lymphatic metastatic disease.

85% of medications prescribed are metabolised by a CYP450 superfamily member. This family contains SNPs linked to medication response. 30,000 participants were evaluated to determine potential differences in ethnic distributions of nucleotide polymorphisms. Next generation sequencing with the Ion Torrent PGM was used to genotype medication response genes. Variations in these key enzymes were common leading to a variety of responses to medication therapy. Our study showed there exists a large range of genetic variation within/between various ethnic groups. With exception of CYP2C9, the wild type genotype is not most common. Each gene showed a unique pattern of distribution that significantly differed within and across ethnic groups. These findings call into question the concept of a 'normal' patient. Our results highlight the need for and applicability of pharmacogenomic testing. Genetic determination of patient response groups can help tailor therapies and increase the likelihood of success.

AimsTo assess the interobserver reproducibility of individual Gleason grade 4 growth patterns.Methods and resultsTwenty-three genitourinary pathologists participated in the evaluation of 60 selected high-magnification photographs. The selection included 10 cases of Gleason grade 3, 40 of Gleason grade 4 (10 per growth pattern), and 10 of Gleason grade 5. Participants were asked to select a single predominant Gleason grade per case (3, 4, or 5), and to indicate the predominant Gleason grade 4 growth pattern, if present. Consensus' was defined as at least 80% agreement, and favoured' as 60-80% agreement. Consensus on Gleason grading was reached in 47 of 60 (78%) cases, 35 of which were assigned to grade 4. In the 13 non-consensus cases, ill-formed (6/13, 46%) and fused (7/13, 54%) patterns were involved in the disagreement. Among the 20 cases where at least one pathologist assigned the ill-formed growth pattern, none (0%, 0/20) reached consensus. Consensus for fused, cribriform and glomeruloid glands was reached in 2%, 23% and 38% of cases, respectively. In nine of 35 (26%) consensus Gleason grade 4 cases, participants disagreed on the growth pattern. Six of these were characterized by large epithelial proliferations with delicate intervening fibrovascular cores, which were alternatively given the designation fused or cribriform growth pattern (complex fused').ConclusionsConsensus on Gleason grade 4 growth pattern was predominantly reached on cribriform and glomeruloid patterns, but rarely on ill-formed and fused glands. The complex fused glands seem to constitute a borderline pattern of unknown prognostic significance on which a consensus could not be reached.

103 Background: Historically, prostate cancer (CAP) is identified through random biopsies. Experts usually recommend 10-12 core transrectal ultrasound guided biopsies (TRUS). This often leads to sampling errors with missed diagnosis, delayed and repeated biopsies, understaging and finding indolent CAP leading to over treatment. Advances in 3DCFPD imaging suggest that selective biopsies may be superior to standard TRUS biopsies. Methods: 192 consecutive patients were biopsied (Feb. 2012 – July 2014) in the dorso-lithotomy position with local anesthesia. Median number of biopsies per patient = 8; total number of cores = 1,520. Only 3 patients had not been previously biopsied (median previous biopsies = 2). We studied tumor detection rate using combined gray scale and 3DCFPD with direct sampling of specific regions using the transperineal brachytherapy template guided method as a simple outpatient procedure. Inclusion criteria were abnormal DRE, PSA kinetics 0.75ng/mg/yr, PSA >10 and % free PSA <17. PSA density 0.27. Cores were stratified into 4 risk groups: 1) hypoechoic lesion (72 patients, 648 cores); 2) hypervascular lesion (26 patients, 182 cores); 3) hypoechogenic with hypervascular pulsatile vessels synchronous and coinciding with normal cardiac pulse (32 patients, 256 cores); and 4) hypoechogenic with hypervascular non-pulsatile vessels suggesting independent vascular flow consistent with neoplasm (62 patients, 434 cores). Isoechoic regions were not biopsied. Subgroups were analyzed using chi-square, student t-test, and logistic regression. Results: The diagnostic yield associated with Group 4 was statistically significantly higher compared to: 1.) 20% biopsy positive (p <0.5); 2.) 19% biopsy positive (p <0.3); 3.) 55% biopsy positive (p <0.1); 4.) 97% biopsy positive (p <0.1). Only Group 4 revealed a greater number of Gleason 7-10 CAP (p <0.1). Conclusions: Transperineal template guided biopsies with gray scale and 3DCFPD are highly effective and cost effective. This may lead to reducing the number of prostate biopsies performed, better staging and allowing for enhanced detection of serious CAP by targeting the most suspicious lesions. Additional research should study the diagnostic gain with 3DCFPD.

Objective. After filtration through glomeruli, β2-microglobulin is reabsorbed in proximal tubules. Increased urinary β2-microglobulin indicates proximal tubule injury and measurement of β2-microglobulin in urine is useful to determine the source of renal injury. Kidney injury molecule-1 (KIM-1) has been characterized as a selective proximal tubule injury marker. This study was designed to evaluate the correlation of urinary β2-microglobulin concentration and KIM-1 expression as evidence of proximal tubule injury. Methods. Between 2009 and 2012, 46 patients with urine β2-microglobulin (RenalVysion) had follow-up kidney biopsy. Diagnoses included glomerular and tubule-interstitial disease. Immunohistochemical staining for KIM-1 was performed and the intensity was graded from 0 to 3+. Linear regression analysis was applied to correlate the values of urinary β2-microglobulin and KIM-1 staining scores. P < 0.05 was considered statistically significant. Results. Thirty patients had elevated urinary β2-microglobulin. KIM-1 staining was positive in 35 kidney biopsies. There was a significant correlation between urinary β2-microglobulin and KIM-1 staining (P < 0.05). Sensitivity was 86.6%, specificity was 43.7%, positive predictive value was 74.2%, and negative predictive value was 63.6%. Conclusion. Increased urinary β2-microglobulin is significantly correlated with KIM-1 staining in injured proximal tubules. Measurement of urine β2-microglobulin is a sensitive assay for proximal tubule injury.

Prostatic intraepithelial neoplasia (PIN) refers to the preinvasive end of the continuum of cellular proliferations within the lining of prostatic ducts, ductules, and acini. High-grade PIN is the earliest identifiable stage in carcinogenesis, possessing most of the phenotypic, biochemical, and genetic changes of cancer without invasion into the fibromuscular stroma. The World Health Organization (WHO) contends that PIN is the only preinvasive lesion for prostate cancer. Other potential but unproven candidates for premalignancy in the prostate include atypical adenomatous hyperplasia, malignancy-associated changes arising in normal-appearing epithelium, and atrophy.