Integrative multi-region molecular profiling of primary prostate cancer in men with synchronous lymph node metastasis.

Localized prostate cancer is frequently composed of multiple spatially distinct tumors with significant inter- and intra-tumoral molecular heterogeneity. This genomic diversity gives rise to many competing clones that may drive the biological trajectory of the disease. Previous large-scale sequencing efforts have focused on the evolutionary process in metastatic prostate cancer, revealing a potential clonal progression to castration resistance. However, the clonal origin of synchronous lymph node (LN) metastases in primary disease is still unknown. Here, we perform multi-region, targeted next generation sequencing and construct phylogenetic trees in men with prostate cancer with synchronous LN metastasis to better define the pathologic and molecular features of primary disease most likely to spread to the LNs. Collectively, we demonstrate that a combination of histopathologic and molecular factors, including tumor grade, presence of extra-prostatic extension, cellular morphology, and oncogenic genomic alterations are associated with synchronous LN metastasis.

PML restrains p53 activity and cellular senescence in clear cell renal cell carcinoma.

Clear-cell renal cell carcinoma (ccRCC), the major subtype of RCC, is frequently diagnosed at late/metastatic stage with 13% 5-year disease-free survival. Functional inactivation of the wild-type p53 protein is implicated in ccRCC therapy resistance, but the detailed mechanisms of p53 malfunction are still poorly characterized. Thus, a better understanding of the mechanisms of disease progression and therapy resistance is required. Here, we report a novel ccRCC dependence on the promyelocytic leukemia (PML) protein. We show that PML is overexpressed in ccRCC and that PML depletion inhibits cell proliferation and relieves pathologic features of anaplastic disease in vivo. Mechanistically, PML loss unleashed p53-dependent cellular senescence thus depicting a novel regulatory axis to limit p53 activity and senescence in ccRCC. Treatment with the FDA-approved PML inhibitor arsenic trioxide induced PML degradation and p53 accumulation and inhibited ccRCC expansion in vitro and in vivo. Therefore, by defining non-oncogene addiction to the PML gene, our work uncovers a novel ccRCC vulnerability and lays the foundation for repurposing an available pharmacological intervention to restore p53 function and chemosensitivity.

Pulmonary lesion after surgery for renal cancer: progression or new primary?

PURPOSE: To investigate clinical and radiological differences between kidney metastases to the lung (RCCM +) and metachronous lung cancer (LC) detected during follow-up in patients surgically treated for Renal Cell Carcinoma (RCC). METHODS: cM0 surgically-treated RCC who harbored a pulmonary mass during follow-up were retrospectively scrutinized. Univariate logistic regression assessed predictive features for differentiating between LC and RCCM + . Multivariable analyses (MVA) were fitted to predict factors that could influence time between detection and histological diagnosis of the pulmonary mass, and how this interval could impact on survivals. RESULTS: 87% had RCCM + and 13% had LC. LC were more likely to have smoking history (75% vs. 29%, p < 0.001) and less aggressive RCC features (cT1-2: 94% vs. 65%, p = 0.01; pT1-2: 88% vs. 41%, p = 0.02; G1-2: 88% vs. 37%, p < 0.001). The median interval between RCC surgery and lung mass detection was longer between LC (55 months [32.8-107.2] vs. 20 months [9.0-45.0], p = 0.01). RCCM + had a higher likelihood of multiple (3[1-4] vs. 1[1-1], p < 0.001) and bilateral (51% vs. 6%, p = 0.002) pulmonary nodules, whereas LC usually presented with a solitary pulmonary nodule, less than 20 mm. Univariate analyses revealed that smoking history (OR:0.79; 95% CI 0.70-0.89; p < 0.001) and interval between RCC surgery and lung mass detection (OR:0.99; 95% CI 0.97-1.00; p = 0.002) predicted a higher risk of LC. Conversely, size (OR:1.02; 95% CI 1.01-1.04; p = 0.003), clinical stage (OR:1.14; 95% CI 1.06-1.23; p < 0.001), pathological stage (OR:1.14; 95% CI 1.07-1.22; p < 0.001), grade (OR:1.15; 95% CI 1.07-1.23; p < 0.001), presence of necrosis (OR:1.17; 95% CI 1.04-1.32; p = 0.01), and lymphovascular invasion (OR:1.18; 95% CI 1.01-1.37; p = 0.03) of primary RCC predicted a higher risk of RCCM + . Furthermore, number (OR:1.08; 95% CI 1.04-1.12; p < 0.001) and bilaterality (OR:1.23; 95% CI 1.09-1.38; p < 0.001) of pulmonary lesions predicted a higher risk of RCCM + . Survival analysis showed a median second PFS of 10.9 years (95% CI 3.3-not reached) for LC and a 3.8 years (95% CI 3.2-8.4) for RCCM + . The median OS time was 6.5 years (95% CI 4.4-not reached) for LC and 6 years (95% CI 4.3-11.6) for RCCM + . CONCLUSIONS: Smoking history, primary grade and stage of RCC, interval between RCC surgery and lung mass detection, and number of pulmonary lesions appear to be the most valuable predictors for differentiating new primary lung cancer from RCC progression.

Progressive alteration of murine bladder elasticity in actinic cystitis detected by Brillouin microscopy.

Bladder mechanical properties are critical for organ function and tissue homeostasis. Therefore, alterations of tissue mechanics are linked to disease onset and progression. This study aims to characterize the tissue elasticity of the murine bladder wall considering its different anatomical components, both in healthy conditions and in actinic cystitis, a state characterized by tissue fibrosis. Here, we exploit Brillouin microscopy, an emerging technique in the mechanobiology field that allows mapping tissue mechanics at the microscale, in non-contact mode and free of labeling. We show that Brillouin imaging of bladder tissues is able to recognize the different anatomical components of the bladder wall, confirmed by histopathological analysis, showing different tissue mechanical properties of the physiological bladder, as well as a significant alteration in the presence of tissue fibrosis. Our results point out the potential use of Brillouin imaging on clinically relevant samples as a complementary technique to histopathological analysis, deciphering complex mechanical alteration of each tissue layer of an organ that strongly relies on mechanical properties to perform its function.

Stool Microbiome Signature Associated with Response to Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Cancer.

Neoadjuvant pembrolizumab has been shown to be a valid treatment for patients affected by muscle-invasive bladder cancer (MIBC), as demonstrated in the PURE-01 clinical trial (NCT02736266). Among the tumor-extrinsic factors influencing immunotherapy efficacy, extensive data highlighted that the microbiome is a central player in immune-mediated anticancer activity. This report aimed to investigate the composition and role of stool microbiome in patients enrolled in the PURE-01 clinical trial. An orthotopic animal model of bladder cancer (MB49-Luc) was used to support some of the findings from human data. An analysis of stool microbiome before pembrolizumab was conducted for 42 patients, of whom 23 showed a pathologic response. The information in the preclinical model of orthotopic bladder cancer treated with anti-PD-1 antibody or control isotype was validated. Linear discriminant analysis effect size and linear models were used to identify the bacterial taxa enriched in either responders or nonresponders. The identified taxa were also tested for their association with event-free survival (EFS). Survival at 31 d after tumor instillation was used as the study endpoint in the preclinical model. Responders and nonresponders emerged to differ in terms of enrichment for 16 bacterial taxa. Of these, the genus Sutterella was enriched in responders, while the species Ruminococcus bromii was enriched in nonresponders. The negative impact of R. bromii on anti-PD-1 antibody activity was also observed in the preclinical model. EFS and survival of the preclinical model showed a negative role of R. bromii. We found different stool bacterial taxa associated with the response or lack of response to neoadjuvant pembrolizumab. Moreover, we provided experimental data about the negative role of R. bromii on immunotherapy response. Further studies are needed to externally validate our findings and provide mechanistic insights about the host-pathogen interactions in MIBC. PATIENT SUMMARY: Using prepembrolizumab stool samples collected from patients enrolled in the PURE-01 clinical trials, we identified some bacterial taxa that were enriched in patients who either responded or did not respond to immunotherapy. Using an animal model of bladder cancer, we gathered further evidence of the negative impact of the Ruminococcus bromii on immunotherapy efficacy. Further studies are needed to confirm the current findings and test the utility of these bacteria as predictive markers of immunotherapy response.

Aberrant expression of GATA3 in metastatic adenocarcinoma of the prostate: an important pitfall.

AIMS: The distinction of high-grade prostate cancer (PCa) from poorly differentiated urothelial carcinoma (UC) can be somewhat challenging on clinical and morphological grounds alone, yet it is of great importance for prognostication and choice of treatment. GATA3 is a useful immunohistochemical marker to confirm urothelial origin. However, recent works report strong GATA3 immunoexpression in primary high-grade PCa. The aim of this study was to explore GATA3 expression specifically in metastatic PCa. METHODS AND RESULTS: The pathology databases of four tertiary institutions were queried for cases of metastatic PCa. Available slides and clinical records were reviewed by experienced genitourinary pathologists. Prostatic markers (PSA, PSAP, NKX3.1) and GATA3 immunohistochemistry were performed. A total of 163 metastatic PCa cases were included. At least one prostate marker was positive in each case of non-regional distant metastasis, confirming prostatic origin. GATA3 strong staining was found in four (2.5%) cases: two liver, one bone and one non-regional lymph-node metastases. All four patients had Grade Group 5 PCa at the initial diagnosis. The metastatic prostatic adenocarcinomas were solid, either with no gland formation (n = 3) or with only focal cribriforming (n = 1). CONCLUSIONS: To our knowledge, this is the first study exploring GATA3 expression specifically in metastatic PCa. Despite being infrequent, GATA3 positivity in high-grade PCa may lead to misdiagnosis, with clinical implications. We recommend a panel of immunohistochemical markers, both prostatic and urothelial, for ruling out UC, either in primary tumour samples or in the event of metastases of unknown primary, when a genitourinary origin is suspected.

SIUrO best practice recommendations to optimize BRCA 1/2 gene testing from DNA extracted from bone biopsy in mCRPC patients (BRCA Optimal Bone Biopsy Procedure: BOP).

The main guidelines and recommendations for the implementation of the BRCA1/2 somatic test do not focus on the clinical application of predictive testing on bone metastases, a frequent condition in metastatic prostate cancer, by analyzing the critical issues encountered by laboratory practice. Our goal is to produce a document (protocol) deriving from a multidisciplinary team approach to obtain high quality nucleic acids from biopsy of bone metastases. This document aims to compose an operational check-list of three phases: the pre-analytical phase concerns tumor cellularity, tissue processing, sample preservation (blood/FFPE), fixation and staining, but above all the decalcification process, the most critical phase because of its key role in allowing the extraction of somatic DNA with a good yield and high quality. The analytical phase involves the preparation of the libraries that can be analyzed in various NGS genetic sequencing platforms and with various bioinformatics software for the interpretation of sequence variants. Finally, the post-analytical phase that allows to report the variants of the BRCA1/2 genes in a clear and usable way to the clinician who will use these data to manage cancer therapy with PARP Inhibitors.

A simple and robust nanosystem for photoacoustic imaging of bladder cancer based on α5ß1-targeted gold nanorods.

BACKGROUND: Early detection and removal of bladder cancer in patients is crucial to prevent tumor recurrence and progression. Because current imaging techniques may fail to detect small lesions of in situ carcinomas, patients with bladder cancer often relapse after initial diagnosis, thereby requiring frequent follow-up and treatments. RESULTS: In an attempt to obtain a sensitive and high-resolution imaging modality for bladder cancer, we have developed a photoacoustic imaging approach based on the use of PEGylated gold nanorods (GNRs) as a contrast agent, functionalized with the peptide cyclic [CphgisoDGRG] (Iso4), a selective ligand of α5ß1 integrin expressed by bladder cancer cells. This product (called GNRs@PEG-Iso4) was produced by a simple two-step procedure based on GNRs activation with lipoic acid-polyethyleneglycol(PEG-5KDa)-maleimide and functionalization with peptide Iso4. Biochemical and biological studies showed that GNRs@PEG-Iso4 can efficiently recognize purified integrin α5ß1 and α5ß1-positive bladder cancer cells. GNRs@PEG-Iso4 was stable and did not aggregate in urine or in 5% sodium chloride, or after freeze/thaw cycles or prolonged exposure to 55 °C, and, even more importantly, do not settle after instillation into the bladder. Intravesical instillation of GNRs@PEG-Iso4 into mice bearing orthotopic MB49-Luc bladder tumors, followed by photoacoustic imaging, efficiently detected small cancer lesions. The binding to tumor lesions was competed by a neutralizing anti-α5ß1 integrin antibody; furthermore, no binding was observed to healthy bladders (α5ß1-negative), pointing to a specific targeting mechanism. CONCLUSION: GNRs@PEG-Iso4 represents a simple and robust contrast agent for photoacoustic imaging and diagnosis of small bladder cancer lesions.

Cystic Clear Cell Renal Cell Carcinoma: A Morphological and Molecular Reappraisal.

A wide variety of renal neoplasms can have cystic areas. These can occur for different reasons: some tumors have an intrinsic cystic architecture, while others exhibit pseudocystic degeneration of necrotic foci or they have cystically dilated renal tubules constrained by stromal neoplastic cells. Clear cell renal cell carcinoma (CCRCC), either solid or cystic, is the most frequent type of renal cancer. While pseudocysts are found in high-grade aggressive CCRCC, cystic growth is associated with low-grade indolent cases. The latter also form through a cyst-dependent molecular pathway, and they are more frequent in patients suffering from VHL disease. The differential diagnosis of multilocular cystic renal neoplasm of low malignant potential and clear cell papillary renal cell tumor can be especially hard and requires a focused macroscopical and microscopical pathological analysis. As every class of renal tumor includes cystic forms, knowledge of the criteria required for a differential diagnosis is mandatory.

Anti-Müllerian hormone predicts positive sperm retrieval in men with idiopathic non-obstructive azoospermia-findings from a multi-centric cross-sectional study.

STUDY QUESTION: Is it possible to identify a reliable marker of successful sperm retrieval (+SR) in men with idiopathic non-obstructive azoospermia (iNOA) undergoing microdissection testicular sperm extraction (mTESE)? SUMMARY ANSWER: A higher likelihood of +SR during mTESE is observed in men with iNOA and lower preoperative serum anti-Müllerian hormone (AMH) levels, with good predictive accuracy achieved using an AMH threshold of <4 ng/ml. WHAT IS KNOWN ALREADY: AMH has been previously linked to +SR in men with iNOA undergoing mTESE prior to ART. STUDY DESIGN, SIZE, DURATION: A multi-centre cross-sectional study was carried out with a cohort of 117 men with iNOA undergoing mTESE at three tertiary-referral centres. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data from 117 consecutive white-European men with iNOA presenting for primary couple's infertility associated with a pure male factor at three centres were analysed. Descriptive statistics was applied to compare patients with negative (-SR) versus +SR at mTESE. Multivariate logistic regression models were fitted to predict +SR at mTESE, after adjusting for possible confounders. Diagnostic accuracy of the factors associated with +SR was assessed. Decision curve analyses were used to display the clinical benefit. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 60 (51.3%) men had an -SR and 57 (48.7%) had a +SR at mTESE. Patients with +SR had lower levels of baseline AMH (P = 0.005) and higher levels of estradiol (E2) (P = 0.01). At multivariate logistic regression analysis, lower levels of AMH (odds ratio: 0.79; 95% CI: 0.64-0.93, P = 0.03) were associated with +SR at mTESE, after adjusting for possible confounders (e.g. age, mean testicular volume, FSH, and E2). A threshold of AMH <4 ng/ml achieved the highest accuracy for +SR at mTESE, with an AUC of 70.3% (95% CI: 59.8-80.7). Decision curve analysis displayed the net clinical benefit of using an AMH <4 ng/ml threshold. LIMITATIONS, REASONS FOR CAUTION: There is a need for external validation in even larger cohorts, across different centres and ethnicities. Systematic reviews and meta-analysis to provide high level of evidence are lacking in the context of AMH and SR rates in men with iNOA. WIDER IMPLICATIONS OF THE FINDINGS: Current findings suggest that slightly more than one in two men with iNOA had -SR at mTESE. Overall, men with iNOA with lower levels of AMH had a significantly higher percentage of successful SR at surgery. A threshold of <4 ng/ml for circulating AMH ensured satisfactory sensitivity, specificity, and positive predictive values in the context of +SR at mTESE. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by voluntary donations from the Urological Research Institute (URI). All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

The Learning Curve for Radical Nephrectomy for Kidney Cancer: Implications for Surgical Training.

Although radical nephrectomy (RN) is the most common treatment for kidney cancer, no data on the learning curve for RN are available. In this study we investigated the effect of surgical experience (EXP) on RN outcomes using data for 1184 patients treated with RN for a cT1-3a cN0 cM0 renal mass. EXP was defined as the total number of RNs performed by each surgeon before the patient's operation. The primary study outcomes were all-cause mortality, clinical progression, Clavien-Dindo grade ≥2 postoperative complications (CD ≥2), and the estimated glomerular filtration rate (eGFR). Secondary outcomes were operative time, estimated blood loss, and length of stay. Multivariable analyses adjusted for case mix revealed no evidence of association between EXP and all-cause mortality (p = 0.7), clinical progression (p = 0.2), CD ≥2 (p = 0.6), or 12-mo eGFR (p = 0.9). Conversely, EXP was associated with shorter operative time (estimate -0.9; p < 0.01). Mortality, cancer control, morbidity, and renal function might not be affected by EXP. The very large cohort examined and the extensive follow-up support the validity of these negative findings. Patient summary: For patients with kidney cancer undergoing surgical removal of a kidney, those treated by novice surgeons have similar clinical outcomes to those treated by experienced surgeons. Thus, this procedure represents a convenient scenario for surgical training if longer operating theatre time can be planned.

Effectiveness and Safety of Thulium Fiber Laser in the Conservative Management of Patients with Upper Tract Urothelial Carcinoma.

Background: Few clinical data are available on thulium fiber laser (TFL) and conservative treatment of upper urinary tract urothelial carcinoma (UTUC). Objective: To assess the effectiveness and safety of TFL in the conservative treatment of UTUC in terms of both tumor ablation and complication rates in a short-term follow-up. Design setting and participants: Retrospective data were collected from all patients who underwent endoscopic management of UTUC between January 2021 and April 2022. All patients with nonmetastatic UTUC who were deemed suitable candidates (low- and high-grade disease) for conservative treatment were reviewed. Intervention: All patients underwent ureteroscopy with biopsy and at 2, 6, and 12 mo after the first surgery. UTUC ablation was achieved using TFL. Outcome measurements and statistical analysis: Clinical data were collected in a dedicated database. Intra- and postoperative outcomes were assessed. A descriptive statistical analysis was performed. Results and limitations: In total, 28 patients were evaluated. Thirteen patients (46.4%) were included in the low-risk UTUC treatment group and 15 (53.6%) in the high-risk group. The mean tumor size was 15.3 ± 5.7 mm. Biopsy showed low- and high-grade UTUCs in 19 and eight patients, respectively. Only one biopsy was inconclusive for achieving a diagnosis. At the second procedure biopsy, no tumor was found in 19 cases (70.4%), whereas seven had tumors confirmed (25.9%). To date, 23 and 17 out of 26 patients completed the 6- and 12-mo follow-up, respectively. UTUC recurrence was detected in five of 23 patients (21.7%) and in three of 17 patients (17.7%) at 6 and 12 mo, respectively. A total of 95 procedures were performed. No intraoperative complications were observed. In ten of the 95 procedures (10.5%), Clavien-Dindo grade I-II postoperative complications were experienced. Only one grade IIIB postoperative complication was noted. Conclusions: TFL is a safe and effective technique for conservative treatment of UTUC in a short-term follow-up. Optimal tumor ablation and fine hemostatic control were achieved without major complications. Patient summary: In this study, we looked at the outcomes of upper urinary tract tumors conservatively treated with the new thulium fiber laser (TFL). We conclude that TFL represents a safe and effective technique for the treatment of this kind of tumors in a short-term follow-up.

Early diagnosis of bladder cancer by photoacoustic imaging of tumor-targeted gold nanorods.

Detection and removal of bladder cancer lesions at an early stage is crucial for preventing tumor relapse and progression. This study aimed to develop a new technological platform for the visualization of small and flat urothelial lesions of high-grade bladder carcinoma in situ (CIS). We found that the integrin α5ß1, overexpressed in bladder cancer cell lines, murine orthotopic bladder cancer and human bladder CIS, can be exploited as a receptor for targeted delivery of GNRs functionalized with the cyclic CphgisoDGRG peptide (Iso4). The GNRs@Chit-Iso4 was stable in urine and selectively recognized α5ß1 positive neoplastic urothelium, while low frequency ultrasound-assisted shaking of intravesically instilled GNRs@Chit-Iso4 allowed the distribution of nanoparticles across the entire volume of the bladder. Photoacoustic imaging of GNRs@Chit-Iso4 bound to tumor cells allowed for the detection of neoplastic lesions smaller than 0.5 mm that were undetectable by ultrasound imaging and bioluminescence.

Neoadjuvant Pembrolizumab and Radical Cystectomy in Patients with Muscle-Invasive Urothelial Bladder Cancer: 3-Year Median Follow-Up Update of PURE-01 Trial.

PURPOSE: The PURE-01 study (NCT02736266) pioneered the neoadjuvant immune-checkpoint inhibitor (ICI) therapy before radical cystectomy (RC) in patients with muscle-invasive urothelial bladder carcinoma (MIBC). We herein present the survival outcomes after a median follow-up of three years. PATIENTS AND METHODS: The intention-to-treat (ITT) population included 155 patients. Event-free survival (EFS) was defined as the time from pembrolizumab initiation until radiographic disease progression precluding RC, initiation of neoadjuvant chemotherapy, recurrence after RC, or death. Further outcomes were recurrence-free survival (RFS) post-RC and overall survival (OS). Multivariable Cox regression analyses for EFS were performed. Kaplan-Meier analyses compared EFS outcomes according with baseline programmed cell-death-ligand-1 (PD-L1) combined positive score (CPS) and according to the molecular subtypes. RESULTS: After a median (interquartile range, IQR) follow-up of 39 (30-47) months, 36-month EFS and OS were 74.4% [95% confidence interval (CI), 67.8-81.7] and 83.8% (95% CI, 77.8-90.2) in the ITT population, respectively. Overall, 143 (92.3%) patients underwent RC. Within the cohort of patients who did not receive additional chemotherapy (N = 125), 36-month RFS was 96.3% (95% CI, 91.6-100) for patients achieving a ypT0N0, 96.1% (95% CI, 89-100) for ypT1/a/isN0, 74.9% (95% CI, 60.2-93) for ypT2-4N0, and 58.3% (95% CI, 36.2-94.1) for ypTanyN1-3 response. EFS was significantly stratified among PD-L1 tertiles (lower tertile: 59.7% vs. medium tertile: 76.7% vs. higher tertile: 89.8%, P = 0.0013). The claudin-low and basal/squamous subtypes displayed the lowest rates of events. CONCLUSIONS: At a median follow-up of three years, PURE-01 results further confirm the sustained efficacy of neoadjuvant pembrolizumab before RC. PD-L1 expression was the strongest predictor of sustained response post-RC.

Pancreatic metastases after surgery for renal cell carcinoma: survival and pathways of progression.

PURPOSE: Metastatic ccRCC has peculiar tropism in the pancreas. We describe the characteristics and pathways of progression of patients with PM in a large multi-institutional consortium and compare them to patients with metastases from ccRCC at other sites. METHODS: Detailed clinical and histopathological data were collected. To account for differences in baseline characteristics between the two groups, IPTW was used to compare the two groups in terms of PFS and OS. RESULTS: Of the 182 patients, 33 (18%) had pancreatic, 94 (52%) pulmonary, 30 (16%) bone, 13 (7%) hepatic, and 12 (7%) brain metastases. Patients with PM had less aggressive ccRCC at baseline compared to those with progression at other sites in terms of tumour stage and grade. Median time from ccRCC surgery to PM was 8 (95%CI 5-10) vs. 1 year (95%CI 1-2) for progression to other sites (p < 0.001). Median IPTW-weighted time to second progression was 4.3 years (95%CI 2.4-not reached) for patients with PM vs 1.1 year (95%CI 0.8-2.3) for those with progression in other sites (p < 0.001). The most frequent second progression sites were pancreas (24%) and liver (15%) in patients with PM, while progression to the pancreas was rare (4%) in those with a different first progression site. Surgery alone (55%) or in combination with medical therapy (30%) was more frequent in the PM group than in other sites (p < 0.001). Median IPTW-OS time was longer for patients with PM [8.8 years (95%CI 6.5-not reached)] compared to those with first progression in other sites [2.8 years (95%CI 1.9-4.3), p < 0.001]. CONCLUSION: Pancreatic tropism is typical of ccRCC tumours with more indolent behaviour than those progressing to other sites. A long follow-up period is necessary to distinguish PM from ccRCC.

Testicular Germ-Cell Tumors with Spermatic Cord Involvement: A Retrospective International Multi-Institutional Experience.

The 8th Edition of the American Joint Committee on Cancer (AJCC) Staging Manual designates discontinuous involvement of spermatic cord soft tissue by testicular germ cell tumors as a metastatic deposit. We conducted a retrospective international multi-institutional study to validate the current recommendations. Thirty-three (72%) nonseminomatous and 13 (28%) seminomatous testicular germ cell tumors were collected from 15 institutions in America, Europe, and Asia. Testicular tumor size ranged from 1.3 to 18.0 cm (mean: 6.1). Cases were classified as discontinuous involvement of spermatic cord soft tissue (n = 26), continuous cord involvement (n = 17), or cord lymphovascular invasion (n = 3). The mean follow-up was 39 months. Clinical stage for discontinuous involvement of spermatic cord soft-tissue patients was I (local disease) in 2/24 (8%), II (regional disease) in 6/24 (25%), and III (distant disease) in 16/24 (67%) cases; 16 (67%) patients presented with distant metastasis. Clinical stage for continuous cord involvement patients was I in 9/17 (53%), II in 4/17 (23%), and III in 4/17 (23%); 4 (23%) patients presented with distant metastasis. Disease progression was seen in 4 patients with discontinuous involvement of spermatic cord soft tissue and 5 with continuous cord-involvement (p = 0.699). When comparing discontinuous and continuous cord involvement, a significant difference was found in cord margin status (p = 0.044), spermatic cord tumor size (p = 0.016), lymph-node involvement (p = 0.037), distant metastasis (p = 0.010), individual clinical stage (p = 0.003), and nonadvanced vs. advanced disease (p = 0.003) at presentation. In multivariate analysis, after adjusting for age, histology, testicular tumor size, percent of embryonal carcinoma, lymphovascular invasion, and cord margin status, discontinuous involvement of spermatic cord soft tissue was significantly associated (p = 0.011) with advanced clinical stage at presentation. Our findings support the designation of metastatic disease for discontinuous involvement of spermatic cord soft tissue, as introduced by the 8th edition of the AJCC staging.

Leiomyoadenomatoid tumours of the epididymis: A new case report and review of the literature.

Benign tumours of the epididymis are rare, and the most common tumour types include adenomatoid tumours, representing more than half of all cases, and leiomyomas. Here, we reported a case of leiomyoadenomatoid tumours of the epididymis, a very rare, benign histological entity with only few cases described in the English literature, which have been reviewed and summarised. Clinically, the lesion presented as a solitary mass growing at the level of the tail of the right epididymis. After the intraoperative frozen section analysis revealed a benign adenomatoid lesion, the mass was enucleated with a conservative surgery sparing the testis. This case highlights the importance for both pathologists and urologists to be aware of these rare, but benign, tumours, to avoid misdiagnosis, especially in the setting of frozen intraoperative consultation, or primary radical surgical procedures, as radical orchiepididymectomy without frozen section consultation.

Prostate cancer testicular metastasis: Are they underestimated? Case report and analysis of the literature.

INTRODUCTION: We aim to present a rare case of a patient who developed a late testicular metastasis of PCa after radical prostatectomy. CASE DESCRIPTION: A 78 years old man presenting for left testicular swelling slowly increasing of size over the last 2 months. He underwent a retropubic radical prostatectomy and extended bilateral lymphadenectomy in 2007 for prostatic adenocarcinoma. At the time of the presentation the last PSA was 0.91 ng/mL. The patient underwent a standard left orchifunicolectomy in April 2019 without intra- or perioperative complications. The pathological analysis showed a testicular metastasis of acinar adenocarcinoma. CONCLUSIONS: In conclusion, testicular metastasis from PCa are uncommon conditions. PSA evaluation and physical examination of all sites of metastasis and accurate evaluation of all signs/symptoms during the clinical visit remains crucial to the diagnosis of recurrence.

A feasibility study of preoperative pembrolizumab before radical nephroureterectomy in patients with high-risk, upper tract urothelial carcinoma: PURE-02.

INTRODUCTION: Advances in neoadjuvant therapy for patients with localized, nonmetastatic, upper tract urothelial carcinoma (UTUC) is needed. PATIENTS AND METHODS: PURE-02 was a feasibility study enrolling individuals with UTUC, at clinical stage N0M0, with high-risk features according to the modified European Association of Urology definition, based on the presence of either: high-grade disease, multifocality, tumor size ≥2 cm, and/or hydronephrosis. The treatment consisted of 3 courses of 200 mg pembrolizumab, intravenously, every 3 weeks, followed by radical nephroureterectomy (RNU). The endpoints were to assess the safety, pathological responses, and biomarkers. RESULTS: Ten patients were enrolled between August 2018 and November 2020, 9 (90%) completed the neoadjuvant course. One treatment-related death occurred as a complication of severe myocarditis, myasthenia gravis, hepatitis and myositis. One (14.3%) patient achieved a clinical complete response and refused to undergo RNU. Two (20%) had disease progression and received subsequent chemotherapy, prior to RNU. Overall, 7 patients underwent RNU: one (14.3%) achieved an ypT1N0 response, although this patient was reported to have a cT1 tumor at baseline imaging. The remaining patients were nonresponders. Circulating tumor DNA assay did not identify patients likely to achieve a complete pathologic response. CONCLUSION: Single-agent neoadjuvant pembrolizumab did not appear to be a promising treatment strategy for patients with biomarker-unselected, high-risk localized UTUC.