Digital analysis of the prostate tumor microenvironment with high-order chromogenic multiplexing.

As our understanding of the tumor microenvironment grows, the pathology field is increasingly utilizing multianalyte diagnostic assays to understand important characteristics of tumor growth. In clinical settings, brightfield chromogenic assays represent the gold-standard and have developed significant trust as the first-line diagnostic method. However, conventional brightfield tests have been limited to low-order assays that are visually interrogated. We have developed a hybrid method of brightfield chromogenic multiplexing that overcomes these limitations and enables high-order multiplex assays. However, how compatible high-order brightfield multiplexed images are with advanced analytical algorithms has not been extensively evaluated. In the present study, we address this gap by developing a novel 6-marker prostate cancer assay that targets diverse aspects of the tumor microenvironment such as prostate-specific biomarkers (PSMA and p504s), immune biomarkers (CD8 and PD-L1), a prognostic biomarker (Ki-67), as well as an adjunctive diagnostic biomarker (basal cell cocktail) and apply the assay to 143 differentially graded adenocarcinoma prostate tissues. The tissues were then imaged on our spectroscopic multiplexing imaging platform and mined for proteomic and spatial features that were correlated with cancer presence and disease grade. Extracted features were used to train a UMAP model that differentiated healthy from cancerous tissue with an accuracy of 89% and identified clusters of cells based on cancer grade. For spatial analysis, cell-to-cell distances were calculated for all biomarkers and differences between healthy and adenocarcinoma tissues were studied. We report that p504s positive cells were at least 2× closer to cells expressing PD-L1, CD8, Ki-67, and basal cell in adenocarcinoma tissues relative to the healthy control tissues. These findings offer a powerful insight to understand the fingerprint of the prostate tumor microenvironment and indicate that high-order chromogenic multiplexing is compatible with digital analysis. Thus, the presented chromogenic multiplexing system combines the clinical applicability of brightfield assays with the emerging diagnostic power of high-order multiplexing in a digital pathology friendly format that is well-suited for translational studies to better understand mechanisms of tumor development and growth.

A Novel Risk Calculator Incorporating Clinical Parameters, Multiparametric Magnetic Resonance Imaging, and Prostate-Specific Membrane Antigen Positron Emission Tomography for Prostate Cancer Risk Stratification Before Transperineal Prostate Biopsy.

Background: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) can detect multiparametric magnetic resonance imaging (mpMRI)-invisible prostate tumours and improve the sensitivity of detection of prostate cancer (PCa) in comparison to mpMRI alone. Numerous risk calculators have been validated as tools for stratification of men at risk of being diagnosed with clinically significant (cs)PCa. Objective: To develop a novel risk calculator using clinical parameters and imaging parameters from mpMRI and PSMA PET/CT in a cohort of patients undergoing mpMRI and PSMA PET/CT before biopsy. Design setting and participants: A total of 291 men from the PRIMARY prospective trial underwent mpMRI and PSMA PET/CT before transperineal prostate biopsy with sampling of systematic and targeted cores. Outcome measurements and statistical analysis: Novel risk calculators were developed using multivariable logistic regression analysis to predict detection of overall PCa (International Society of Urological Pathology grade group [GG] ≥1) and csPCa (GG ≥2). The risk calculators were then compared with the European Randomised Study of Screening for Prostate Cancer risk calculator incorporating mpMRI (ERSPC-MRI). Resampling methods were used to evaluate the discrimination and calibration of the risk calculators and to perform decision curve analysis. Results and limitations: Age, prostate-specific antigen, prostate volume, and mpMRI Prostate Imaging-Reporting and Data System scores were included in the MRI risk calculator, resulting in area under the receiver operating characteristic curve (AUC) values of 0.791 for overall PCa (GG ≥1) and 0.812 for csPCa (GG ≥2). Addition of the maximum standardised uptake value (SUVmax) on PSMA PET/CT for the prostate lesion, and of SUVmax for the mpMRI lesions for the MRI-PSMA risk calculator resulted in AUCs of 0.831 for overall PCa and 0.876 for csPCa (≥ISUP2).The ERSPC-MRI risk calculator had AUCs of 0.758 (p = 0.02) for overall PCa and 0.805 (p = 0.001) for csPCa. Both the MRI and MRI-PSMA risk calculators were superior to the ERSPC-MRI for both overall PCa and csPCa. Conclusions: These novel risk calculators incorporate clinical and radiological parameters for stratification of men at risk of csPCa. The risk calculator including PSMA PET/CT data is superior to a calculator incorporating mpMRI data alone. Patient summary: We evaluated a new risk calculator that uses clinical information and results from two types of scan to predict the risk of clinically significant prostate cancer on prostate biopsy. This risk model can guide patients and clinicians in shared decision-making and may help in avoiding unnecessary prostate biopsies.

US Food and Drug Administration Warning Regarding Finasteride and Suicidal Ideation: What Should Urologists Know?

Finasteride competitively inhibits 5α-reductase (5-AR) isoenzymes, which blocks dihydrotestosterone (DHT) production, thereby reducing DHT. Finasteride is used in the management of benign prostatic hyperplasia (BPH) and androgenic alopecia. Amid patient reports of suicidal ideation (SI), the Post Finasteride Syndrome advocacy group has petitioned for either a stop to selling of the drug or advertisement of stronger warnings. The US Food and Drug Administration recently added SI to the adverse effects listed for finasteride. Here we provide a brief but comprehensive review of the literature on the psychological side effects of 5-AR inhibitors (5-ARIs) to provide an opinion to help in guiding treating urologists. Most of the current evidence, obtained from the literature on dermatology, suggests that 5-ARI users experience a higher rate of depressive symptoms. However, given the lack of comprehensive randomised studies, the causal link between finasteride and SI remains unclear. Urologists prescribing 5-ARIs should be aware of the recent addition of suicide and SI risk to the list of side effects. A mental health screen should be performed and appropriate resources provided to patients commencing treatment. Furthermore, a review should be arranged with the general practitioner to assess new-onset mental health or SI symptoms. Patient summary: We provide recommendations for urologists who prescribe finasteride for the treatment of benign prostate enlargement. Urologists should be aware of the recent addition of suicidal ideation to the list of side effects for this drug. Finasteride prescription should be continued; however, we recommend a detailed medical history to screen for prior mental health and personality disorders, with discontinuation of the medication in patients with new onset of depression or suicidal symptoms. Close liaison with the patient's general practitioner is vital for management of depressive or suicidal symptoms.

A Systematic Review of the Variability in Performing and Reporting Intraprostatic Prostate-specific Membrane Antigen Positron Emission Tomography in Primary Staging Studies.

Context: Prostate cancer (PCa) remains one of the leading causes of cancer-related deaths in men worldwide. Men at risk are typically offered multiparametric magnetic resonance imaging and, if suspicious, a targeted biopsy. However, false-negative rates of magnetic resonance imaging are consistently 18%; therefore, there is growing interest in improving the diagnostic performance of imaging through novel technologies. Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is being utilised for PCa staging and, more recently, for intraprostatic tumour localisation. However, significant variability has been observed in how PSMA PET is performed and reported. Objective: In this review, we aim to evaluate how pervasive this variability is in trials investigating the performance of PSMA PET in primary PCa workup. Evidence acquisition: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, we performed an optimal search in five different databases. After removing duplicates, 65 studies were included in our review. Evidence synthesis: Studies dated back as early as 2016, with numerous different source countries. There was variation in the reference standard for PSMA PET, with some using biopsy specimens or surgical specimens, and in some cases, a combination of the two. Similar inconsistencies were noted when studies selected histological definitions of clinically significant PCa, while some omitted their definition altogether. The most significant variations in performing PSMA PET were the radiotracer type, dose, acquisition time after injection, and the PET camera being utilised. Substantial variation in the reporting of PSMA PET was noted, with no consistency in defining what constitutes a positive intraprostatic lesion. Across 65 studies, four different definitions were used. Conclusions: This systematic review has highlighted considerable variation in obtaining and performing a PSMA PET study in the context of primary PCa diagnosis. Given the discrepancy in how PSMA PET was performed and reported, it questions the homogony of studies from centre to centre. Standardisation of PSMA PET is required for this to become a consistently useful and reproducible modality in the diagnosis of PCa. Patient summary: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is being utilised for staging and localisation of prostate cancer (PCa); however, there is significant variability in performing and reporting PSMA PET. Standardisation of PSMA PET is required for results to be consistently useful and reproducible for the diagnosis of PCa.

A case report of mucinous tubular and spindle cell carcinoma of the kidney.

Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare type of kidney tumor that has only recently been described, with less than eighty cases in the literature. This was only recognized as a specific entity in the World Health Organization 2004 classification of Renal Cell Carcinoma (RCC). MTSCCs are polymorphic renal neoplasms characterized by small, elongated tubules lined by cuboidal cells with cords of spindled cells separated by pale mucinous stroma. We report the case of a 57 year old lady who had an incidental finding of a mass in her right kidney. The radiological features were consistent with a RCC and following a multidisciplinary team discussion she underwent a laparoscopic radical nephrectomy. Macroscopic examination revealed a well circumscribed 6.5 × 6 × 6.5 cm right lower pole mass. Histologically it was composed of elongated tubules, small tubules and papillary structures with a necrotic centre. The cells demonstrated cuboidal and spindle cell morphology. Histological grade was Fuhrman grade 2. The majority of MTSCCs are indolent, and there are only two reports of distant metastases which responded favorably to adjuvant sunitinib. To date there is no international consensus on long term surveillance of these patients. Due of the favorable prognosis with this type of tumor, MTSCC must be differentiated from papillary renal cell carcinoma to avoid administration of excessive adjuvant treatment to patients.

Social determinants of health: does socioeconomic status affect access to staging imaging for men with prostate cancer.

Socioeconomic status (SES), race and geographical factors are known to impact prostate cancer management and outcomes. We aimed to assess these factors with regard to access to novel imaging in prostate cancer. Using the Prostate Cancer Outcomes Registry of Victoria (PCOR-Vic) we identified 5256 men diagnosed with prostate cancer via biopsy. Following the introduction of government rebate, the access to MRI improved with respect to SES. Access to PET imaging remains poor with respect to SES and geographical location in the absence of Federal funding. Further improvements for men with low SES and regional areas to access PET staging.

Recent developments in the diagnosis and management of N1 penile cancer.

PURPOSE OF REVIEW: This article presents a critical review of the current literature to provide a brief update on the contemporary advances in diagnosing and managing N1 penile cancer. RECENT FINDINGS: Penile squamous cell carcinoma (pSCC) has evolved from being an orphan field for cancer innovation. Advances in the understanding tumour biology have enabled sophisticated diagnostics and predictive modelling to better characterize inguinal disease. Minimally invasive inguinal lymph node dissection is emerging as a technique that reduces morbidity while maintaining oncological safety. Furthermore, robust clinical trials are underway ,which will provide level one evidence to guide treatment decisions. Exciting advances in the field of immune-oncology offer promise as adjuvant therapies. International collaboration and centralisation of care will be essential to driving translational research and equitable evidence-based care. SUMMARY: Improving outcomes for men with pSCC remains a global challenge. Radical inguinal lymph node dissection remains the gold standard for diagnosing and curing N1 disease. Although many promising developments are on the horizon, high-level evidence is required to guide therapy.

Combination treatment in metastatic prostate cancer: is the bar too high or have we fallen short?

Androgen deprivation therapy (ADT) alone has been the cornerstone of treatment for patients with newly diagnosed metastatic prostate cancer for the past century. Based on results from landmark trials in the past decade, combination approaches of ADT with chemotherapy or novel hormonal agents have established a new standard of care for these patients. This paradigm shift in treatment has been reflected in the updates to guideline recommendations of major professional associations. However, real-world data from around the world have highlighted the dismal adoption of combination therapy, despite evidence-based recommendations. The disparity between evidence and practice is concerning, especially with emerging evidence of survival benefit with further treatment intensification using triplet combinations (ADT, docetaxel and novel hormonal agents). Thus, a pressing need to raise awareness and call the uro-oncology community to action exists to deliver evidence-based care for these patients.

Distant Nodes Seen on PSMA PET-CT Staging Predicts Post-Treatment Progression in Men with Newly Diagnosed Prostate Cancer-A Prospective Cohort Study.

PSMA PET-CT scans are now recommended in international urological guidelines for primary staging and re-staging of prostate cancer. However, there is little published literature on the clinical outcomes for patients after treatment decisions made using PSMA PET-CT results. This is a multisite, prospective cohort study investigating the clinical outcomes of men who received treatment plans based on PSMA PET-CT results for primary staging. Men with biopsy proven prostate cancer received a PSMA PET-CT scan for primary staging. Treatment plans were recommended by multidisciplinary teams (MDT). After treatment, these men were followed with 6 monthly PSA tests and imaging or biopsies if recommended by MDT. The primary outcome was treatment progression defined as the addition or change of any treatment modalities such as androgen deprivation therapy, radiation therapy or chemotherapy. In total, 80% of men did not have any treatment progression after enactment of treatment based on PSMA PET-CT primary staging results at 29 months of follow up. Men who had distant nodes seen on PSMA PET-CT had a 5 times increased risk of treatment progression. Larger studies with longer follow up are needed to validate our results and optimise the way clinicians use PSMA PET-CT results to guide management.

The impact of health-policy-driven subsidisation of prostate magnetic resonance imaging on transperineal prostate biopsy practice and outcomes.

Background: From 1 July 2018, the Australian Medicare Benefits Schedule (MBS) introduced rebates for multi-parametric magnetic resonance imaging (mpMRI) for the workup for prostate cancer (PCa). We aimed to determine if subsidisation of mpMRI prior to transperineal biopsy altered our institution's prostate biopsy practice patterns and outcomes. Methods: All patients who underwent transperineal prostate biopsy at an Australian tertiary institution from 1 January 2017 to 1 January 2020 were identified. Patients with known PCa were excluded. Patients were stratified into two groups: a pre-subsidisation cohort comprising patients biopsied prior to the introduction of mpMRI subsidisation on 1 July 2018 and a post-subsidisation cohort comprising patients biopsied after 1 July 2018. Histopathological results were compared with further stratification based on mpMRI results. Clinically significant cancer was defined as ISUP Grade Group ≥ 2. Results: Six hundred and fifty men fulfilled the inclusion criteria. Three hundred and sixty-one patients were in the pre-subsidisation cohort and 289 in the post-subsidisation cohort. Of the patients in the pre-subsidisation group, 36.3% underwent a pre-biopsy mpMRI compared with 77.5% in the post-subsidisation group. Of the patients in the pre-subsidisation group, 59.6% had positive biopsies (p = 0.024) compared with 68.2% in the post-subsidisation group. The rate of clinically significant PCa was lower in the pre-subsidisation group (39.1%) compared with the post-subsidisation (49.5%, p = 0.008). The negative predictive value of mpMRI for clinically significant PCa was 86.5%. Conclusion: Our institution experienced a reduction of negative prostate biopsies and an increase in clinically significant PCa within transperineal biopsy specimens after the Australian healthcare system introduced financial subsidisation of mpMRI.

Interrogating the Impassable: A Case Series and Literature Review of Unilateral SPECT-CT Groin Visualization in Men With Penile Cancer.

Penile squamous cell carcinoma (SCC) is a rare malignancy, which is known to invade local inguinal lymph nodes prior to progressing to the pelvis. Dynamic sentinel lymph node biopsy (DSLNB) is a standard for the minimally invasive assessment of lymphadenopathy in patients with subclinical groin metastasis. Hybrid 99mTc Single-Photon Emission Computed Tomography (SPECT-CT) has been shown to increase the accuracy of identifying first draining "sentinel" nodes (SN). Unilateral inguinal visualization on SPECT-CT is a rare presentation, which may increase the likelihood of a false negative SN biopsy. Retrospective analysis from three-penile cancer uro-oncologists in Melbourne, Australia identified 78 groins undergoing DSLNB for intermediate/high risk primary disease. Unilateral SPECT-CT results were observed in four patients suggesting a functional pattern of lymph diversion. Analysis confirmed malignancy (n = 2), sarcoidosis (n = 1), and evidence of local inflammation in SPECT-CT negative groins. Findings re-iterate the role of SPECT-CT a pre-operative adjunct. Experienced multimodal groin assessment using palpation, SPECT-CT, lymphoscintigraphy, and blue dye tracking remains paramount. Unilateral SN on pre-operative SPECT-CT in men with intermediate/high-risk penile SCC should elicit a higher degree of clinical suspicion. We recommend a low threshold for recommending radical inguinal lymph node dissection (ILND) for groins refractory to minimally invasive assessment.

PSMA PET-CT Imaging Predicts Treatment Progression in Men with Biochemically Recurrent Prostate Cancer-A Prospective Study of Men with 3 Year Follow Up.

Prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography (PET-CT) is a novel imaging modality used to stage recurrent prostate cancer. It has the potential to improve prognostication and ultimately guide the timing of treatment for men with recurrent prostate cancer. This study aims to assess the clinical impact of PSMA PET-CT by analyzing its predictive value of treatment progression after 3 years of follow-up. In this prospective cohort study of 100 men, patients received a PSMA PET-CT for restaging of their disease which was used by a multi-disciplinary team to make a treatment decision. The primary endpoint was treatment progression. This was defined as the addition or change of any treatment modalities such as androgen deprivation therapy (ADT), radiation therapy or chemotherapy. The median follow-up time was 36 months (IQR 24-40 months). No treatment progression was found in 72 (75%) men and therefore 24 (25%) patients were found to have treatment progression. In men with a negative PSMA PET-CT result, 5/33 (15.1%) had treatment progression and 28/33 (84.8%) had no treatment progression. In conclusion, clinical decisions made with PSMA PET-CT results led to 75% of men having no treatment progression at 3 years of follow-up. In men with negative PSMA PET-CT results, this increased to 85% of men.

Dynamic Sentinel Lymph Node Biopsy for Penile Cancer: Accuracy is in the Technique.

OBJECTIVES: To demonstrate an operative standard for dynamic sentinel lymph node biopsy (DSLNB). Long-term survival in men with penile squamous cell carcinoma (SCC) depends on accurately staging lymph node metastases. European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) guidelines recognize DSLNB as a standard for staging men with intermediate to high-risk tumors and clinically absent inguinal lymphadenopathy. DSLNB accuracy has been linked with pre-operative planning and surgical technique, yet no peer-reviewed video exists to establish an operative standard. Here we present a narrated video of our technique and discuss the accuracy of this approach using retrospective patient data. METHODS: Ethics approval and patient consent was obtained. Retrospective analysis was performed on patients undergoing DSLNB for inguinal lymph node staging of histologically proven penile SCC. Data was included from 2 experienced uro-oncologists with subspecialty training in penile cancer working in Victoria, Australia between January 2015 and July 2021. Variables collected included Primary tumour histology, DSLNB pathology, progression to radical inguinal lymph node dissection (RILND) and recurrence patterns. DSLNB sensitivity and proportion of groins spared RILND is calculated. RESULTS: DSLNB was performed on 127 groins (64 patients) during the study period. Within the cohort, 44% (n = 28) of patients had a pre-operative lymphoscintigraphy with single-photon emission computed tomography (SPECT/CT). Analysis of primary tumor intervention demonstrates that 82.8% (n = 53) of men underwent penile sparing surgery. Tumor histology in 88% of patients (n = 56) demonstrated pT1-pT2 disease. Overall n = 19 groins undergoing DSLNB were positive for malignancy and n = 108 were negative. 36 groins progressed to RILND during a mean follow up of 29 months. Only 2 groins that previously had a negative DSLNB were positive on RILND, one in the groin and one in the pelvis. We observed a false negative rate of 1.9% and a sensitivity of 90.5%. In our cohort DSLNB allowed 71.7% of groins to proceed for surveillance instead of prophylactic radical ILND. CONCLUSIONS: DSLNB is a safe and accurate method for assessing inguinal lymphadenopathy in men with intermediate to high-risk penile SCC and impalpable groins. This video study establishes an operative standard for DSLNB with oncological outcomes are consistent with international expectations. Standardized use of DSLNB by an experienced team will reduce morbidity while maintaining oncological safety for men with intermediate to high-risk penile cancer and cN0 disease.

Renal cell carcinoma presenting as painless jaundice and unintentional weight loss.

Painless jaundice and unexplained weight loss is an exceedingly rare presentation for renal cell carcinoma (RCC). Such a presentation is more typical of a hepatocellular pathology. Stauffer syndrome is a paraneoplastic syndrome seen in RCC and is characterized by deranged hepatic enzymes and in association with fever, fatigue and weight loss. These symptoms typically resolve following nephrectomy. The predominant picture of this syndrome is that of an anicteric patient. Here we report the case of a 48 year old man who presented with a 3 week history of painless jaundice, malaise, anorexia and unintentional weight loss of 10 kilograms. Imaging revealed a solid right renal mass measuring 11 cm × 11 cm × 14 cm. There were also findings consistent with the presence of an inferior vena cava thrombosis and multiple pulmonary lesions. Biopsy confirmed the pulmonary lesions as metastatic clear cell renal carcinoma. Following multi-disciplinary discussion, cytoreductive nephrectomy was recommended to the patient, however multiple paraneoplastic syndromes subsequently developed and the patient experienced hypertension, severe coagulopathy and hypercalcaemia. Subsequently, the patient opted for supportive and palliative care. The patient died 2 weeks after initial presentation. Paraneoplastic syndromes associated with RCC are often underdiagnosed due to their variety and often non-specific nature. Paraneoplastic syndromes may lead to patient presentation, where they often suggest advanced or metastatic disease, and those caring for such patients should remain vigilant as further syndromes may complicate patient care.