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Background and Objective: The majority of small testicular masses (STMs) are benign and therefore radical orchidectomy (RO) may represent overtreatment. In appropriately selected patients, surveillance or testis-sparing surgery (TSS) is an alternative option to preserve testicular function. Since there are no clear guidelines, we aimed to develop consensus recommendations on the management of STMs., Methods: A four-round Delphi study was conducted by 24 experts representing multiple subspecialties to reach consensus. Consensus was defined as ≥75% of the participants scoring within the same 3-point grouping (1-3, disagree; 4-6, uncertain; 7-9, agree.). The first two rounds were survey based, the third round was an online meeting to discuss uncertainties from the first two rounds, and the fourth round was a review of the final consensus statements from rounds 1-3., Key Findings and Limitations: The initial survey consisted of 126 statements. Following the four rounds of assessment, a list of 96 statements were produced, which focused on clinical and biochemical assessment, colour Doppler ultrasound (CDUS) characteristics, and management options including surveillance, RO, and TSS. Management should be personalised according to risk factors for testicular cancer, fertility status, uni- or bilateral tumours, status of the contralateral testis, and CDUS characteristics, with solid lesions displaying vascularity and hypoechogenicity being more suspicious for malignancy. The consensus statements are prone to a bias, and some may not reflect robust, randomised evidence., Conclusions and Clinical Implications: The expert panel has produced consensus recommendations on the management of STMs, and TSS should be considered in patients with an STM. The recommendations could aid in the dissemination of best practice., Patient Summary: There are no clear guidelines on the management of small testicular masses. Excising the whole testicle (radical orchidectomy) with a small or an indeterminate mass may affect fertility and hormonal function. A panel of experts was formed, and consensus recommendations were developed on how to deal with small and indeterminate testicular masses, which include surveillance or testis-sparing surgery., (Copyright © 2024 European Association of Urology. All rights reserved.)

Background: Penile squamous cell carcinoma (PSCC) is characterised by stepwise lymphatic dissemination. Skip metastases (SkMs) are rare metastases in the corpus cavernosum or spongiosum without continuity to the primary tumour or its resection site., Objective: To assess the distinct pattern of spread in SkM + patients and the effect of SkM on prognosis., Design, Setting, and Participants: We conducted a retrospective analysis of patients with SkM + PSCC at ten high-volume international referral centres between January 2006 and May 2022., Outcome Measurements and Statistical Analysis: We evaluated histopathological data, primary lymph node (LN) staging, and metastatic spread. We included a cohort of patients matched for pT stage, LN status, and grade who did not have SkM (SkM - ) to compare the SkM prognosis and predictive value for cancer-specific mortality (CSM)., Results and Limitations: Among the 63 SkM + patients who met our inclusion criteria, the SkM diagnosis was synchronous in 54.0% and metastases were mostly located in the corpus cavernosum. SkM was symptomatic in 14% of cases, was detected on imaging in 32%, and was found incidentally on pathological examination in 27%. Fifty-one patients (81%) presented with positive LNs and 28 (44%) developed distant metastases. Seven patients (11%) presented with or developed distant metastasis without displaying any LN involvement. The 2-yr cancer-specific survival estimates were 36% (95% confidence interval [CI] 25-52%) for SkM + and 66% (95% CI 55-80%) for matched SkM - patients (p < 0.001). On multivariable Cox regression analysis, SkM presence was an independent predictor for higher CSM (hazard ratio 2.05, 95% CI 1.06-4,12; p = 0.03)., Conclusions: PSCC-related SkM is associated with aggressive disease behaviour and poor survival outcomes. Palpation of the entire penile shaft is essential, and distant staging is recommended in patients suspected of having SkM owing to the tendency for distant metastatic spread., Patient Summary: We investigated outcomes for patients with cancer of the penis who had metastases in the tissues responsible for erection. We found that metastases in this location were associated with poor prognosis, even in the absence of more typical spread of cancer via the lymph nodes., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate penile squamous cell carcinoma (PSCC) incidence and centralisation trends in the Netherlands over the past three decades, as well as the effect of centralisation of PSCC care on survival., Patients and Methods: In the Netherlands PSCC care is largely centralised in one national centre of expertise (Netherlands Cancer Institute [NCI], Amsterdam). For this study, the Netherlands Cancer Registry, an independent nationwide cancer registry, provided per-patient data on age, clinical and pathological tumour staging, follow-up, and vital status. Patients with treatment at the NCI were identified and compared to patients who were treated at all other centres. The age-standardised incidence rate was calculated with the European Standard Population. The probability of death due to PSCC was estimated using the relative survival. Multivariable Cox regression analysis was performed to evaluate predictors of survival., Results: A total of 3160 patients were diagnosed with PSCC between 1990 and 2020, showing a rising incidence (P < 0.001). Annual caseload increased at the NCI (1% in 1990, 65% in 2020) and decreased at other (regional) centres (99% to 35%). Despite a relatively high percentage of patients with T2-4 (64%) and N+ (33%) at the NCI, the 5-year relative survival was higher (86%, 95% confidence interval [CI] 82-91%) compared to regional centres (76%, 95% CI 73-80%, P < 0.001). Patients with a pathological T2 tumour were treated with glans-sparing treatment more often at the reference centre than at the regional centres (16% vs 5.0%, P < 0.001). After adjusting for age, histological grading, T-stage, presence of lymph node involvement and year of diagnosis, treatment at regional centres remained a predictor for worse survival (hazard ratio 1.22, 95% CI 1.05-1.39; P = 0.006)., Conclusion: The incidence of PSCC in the Netherlands has been gradually increasing over the past three decades, with a noticeable trend towards centralisation of PSCC care and improved relative survival rate., (© 2024 BJU International.)

Purpose: Patients with advanced penile squamous cell carcinoma have a poor prognosis (21% 2-year overall survival [OS] from diagnosis). We assessed the activity of atezolizumab (anti-PD-L1) in patients with advanced penile cancer, with or without radiotherapy (RT)., Patients and Methods: A single-center, nonrandomized phase II study with two treatment arms was conducted in 32 patients with histologically confirmed advanced penile cancer. All patients received atezolizumab (1,200 mg) once every 3 weeks. Twenty patients, who were expected to benefit from RT for locoregional disease control, received additional irradiation. The primary end point was 1-year progression-free survival (PFS) for the complete cohort and was reached if the actual 1-year PFS was at least 35%. Secondary end points included OS, objective response rate (ORR), and tolerability. Exploratory biomarker analyses were conducted in pretreatment specimens., Results: Median follow-up was 29.1 months (IQR, 18.1-33.5). Grade 3-4 adverse events related to atezolizumab or RT were observed in 3/32 (9.4%) and 13/20 (65%) patients, respectively. One-year PFS was 12.5% (95% CI, 5.0 to 31.3), which did not meet the study's primary end point. Median OS was 11.3 months (95% CI, 5.5 to 18.7). In the objective response-evaluable population (n = 30; 93.8%), the ORR was 16.7% (95% CI, 6 to 35), including 2 (6.7%) complete responders and 3 (10%) partial responders. Improved PFS was observed in patients with high-risk human papillomavirus (hrHPV)-positive tumors ( P = .003) and those with high infiltration of intratumoral CD3 + CD8 + T cells ( P = .037)., Conclusion: Although the primary end point of 1-year PFS was not met, durable antitumor activity to atezolizumab was observed in a subset of patients. Biomarkers, such as hrHPV and intratumoral CD3 + CD8 + T-cell infiltration, may help to better select responders.

Purpose: Neoadjuvant chemotherapy followed by surgery for locoregionally advanced penile carcinoma (LAPSCC) is associated with severe toxicity and a 1-year survival probability of ∼50%. We aimed to evaluate the safety and efficacy of chemoradiotherapy (CRT) as the primary treatment for LAPSCC and the association of high-risk human papillomavirus (hrHPV) with the outcome., Methods and Materials: This was a prospective, single-center, single-arm study of CRT in LAPSCC, defined as a large/inoperable primary tumor, large palpable nodes, suspicion of extranodal extension or pelvic nodal involvement, and no distant metastases. CRT consisted of 49.5 Gy (33 × 1.5 Gy) on affected inguinal and pelvic areas combined with intravenous mitomycin C on day 1 and capecitabine on radiation days. Primary tumors and positron emission tomography/computed tomography-positive deposits received a boost of 59.4 Gy (33 × 1.8 Gy). The response was evaluated by 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. If feasible, patients with residual/recurrent disease underwent salvage surgery. The primary endpoint was 1-year progression-free survival (PFS), reached when 1-year PFS was ≥50%. Other endpoints were 2-year PFS, overall survival, and toxicity rates. Kaplan-Meier survival curves were compared using the log-rank test., Results: Thirty-three patients were included: 29 (88%) with stage IV disease (T4 any-N M0 and/or any-T N3 M0) and 8 (24%) with hrHPV-positive disease. Median follow-up was 41 months. Thirty-two completed CRT. Eleven (33%) experienced ≥1 grade 3 treatment-related adverse event. There were no grade 4 or 5 treatment-related events. Twenty-four patients (73%) responded, including 13 (39%) complete responses. Nine patients (27%) underwent salvage surgery, and an additional 8 patients underwent later surgery (together 52%). One- and 2-year PFS were 34% and 31%, respectively. One- and 2-year overall survival were 73% and 46%, respectively. No significant difference between patients with hrHPV-positive and -negative tumors was observed., Conclusions: CRT is a viable treatment option for LAPSCC with acceptable toxicity. CRT can result in an enduring response. If patients have residual tumor, salvage surgery is feasible. HrHPV status was not associated with outcomes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: To evaluate clinical characteristics associated with survival in patients with metastases to the penis., Methods: After approval by the IRB, records of collaborating centres in Leuven, London, Rostock, Amsterdam and Tampa were screened for men presenting with metastatic disease to penis. Multivariate logistic regression analyses were used to identify covariables associated with survival. We analysed clinical data on 34 patients., Results: Primary sites were most frequently prostate ( n  = 14, 41%) and bladder ( n  = 9, 26%). Twenty-eight of 34 (82%) presented with metachronous penile metastases, and 11 (32%) patients had penile metastases as the sole metastatic site. Penile metastatic locations were most frequently in the corpora ( n  = 18; 53%). Seven (21%) patients with penile metastases had priapism on presentation. Systemic therapy was frequent and variable (chemotherapy n  = 12; immunotherapy n  = 5; hormones n  = 3). Local management included either surgery ( n  = 10) or RT ( n  = 8). Twelve- and 24-month overall survival rate were 67% and 35%, respectively. No clinical parameter including primary histology, synchronous or metachronous metastases or priapism showed statistical survival benefit or detriment., Conclusion: Metastasis to penis arises most frequently from pelvic primaries. Priapism does not appear to correlate with survival in this large, well-defined series., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Background: Penile cancer (PeCa) is rare, and the survival of patients with advanced disease remains poor. A better understanding of where treatment fails could aid the development of new treatment strategies., Objective: To describe the disease course after pelvic lymph node (LN) treatment for PeCa., Design Setting and Participants: We retrospectively analysed 228 patients who underwent pelvic LN treatment with curative intent from 1969 to 2016. The main treatment modalities were neoadjuvant chemotherapy, chemoradiation, and pelvic LN dissection., Outcome Measurements and Statistical Analysis: In the case of multiple recurrence locations, the most distant location was taken and recorded as follows: local (penis), regional (inguinal and pelvic LN), and distant (any other location). A competing risk analysis was used to calculate the time to recurrence per location, and a Kaplan-Meier analysis was used for overall survival (OS)., Results and Limitations: The median follow-up of the surviving patients was 79 mo. The reason for pelvic treatment was pelvic involvement on imaging (29%), two or more tumour-positive inguinal LNs (61%), or inguinal extranodal extension (52%). More than half of the patients (61%) developed a recurrence. The median recurrence-free survival was 11 mo. The distribution was local in 9%, regional in 27%, and distant in 64% of patients. The infield control rate of nonsystemically treated patients was 61% (113/184). From the start of pelvic treatment, the median OS was 17 mo (95% confidence interval 12-22). After regional or distant recurrence, all but one patient died of PeCa with median OS after a recurrence of 4.4 (regional) and 3.1 (distant) mo. This study is limited by its retrospective nature., Conclusions: The prognosis of PeCa patients treated on their pelvis who recur despite locoregional treatment is poor. The tendency for systemic spread emphasises the need for more effective systemic treatment strategies., Patient Summary: In this report, we looked at the outcomes of penile cancer patients in an expert centre undergoing various treatments on their pelvis. We found that survival is poor after recurrence despite locoregional treatment. Therefore, better systemic treatments are necessary., (© 2022 The Author(s).)

Objective: To determine the incidence and types of complications after dynamic sentinel node biopsy (DSNB) in patients with penile cancer (PeCa) and identify risk factors for the occurrence of postoperative complications., Patients and Methods: We evaluated 644 patients with PeCa (1284 DSNB procedures) with at least one clinically node negative (cN0) groin who underwent DSNB between 2011 and 2020 at a single high-volume centre. The 30- and 30-90-day postoperative complications were collected according to the modified Clavien-Dindo classification and the standardised methodology proposed by the European Association of Urology panel. Uni- and multivariable generalised linear mixed models were used to identify risk factors for the occurrence of complications per groin., Results: A 30-day postoperative complication occurred in 14% of groins (n = 186), of which 94% were mild to moderate. Wound infection and lymphocele formation were most common. A 30-90-day postoperative complication occurred in 3.4% of the groins, all of which were mild or moderate (Grade I-II). The number of removed lymph nodes (LNs) per groin was the main independent predictor for any 30-day complications and Grade ≥II complications (odds ratio 1.40; P < 0.001). There was an increase in the probability of postoperative complications with the number of LNs removed after accounting for all confounders., Conclusions: Despite being less morbid than (modified) inguinal LN dissection, DSNB is still associated with a considerable risk of postoperative mild-to-moderate complications. This risk increases with increasing number of LNs removed. Further procedural refinement aimed at removing the true sentinel node(s) only, may help further reduce the morbidity of surgical staging in PeCa., (© 2022 The Authors BJU International © 2022 BJU International.)

Purpose: To analyse the risk of inguinal lymph node (ILN) metastases in T1G2 penile cancer stratified by lymphovascular invasion (LVI), perineural invasion (PNI) and tumour size., Methods: Retrospective study of men with localised T1G2 penile cancer with non-palpable lymph nodes and no local recurrence during follow-up at six European institutional high-volume centres was performed. ILN involvement was defined as cancer detected during ultrasound-guided fine-needle aspiration cytology, core needle biopsy, dynamic sentinel lymph node biopsy, ILN dissection or inguinal recurrence during follow-up. Uni- and multivariable logistic regression analyses were performed., Results: In the cohort of 554 men with T1G2 penile cancer, from 6 European institutions, ILN metastases were observed in 46/554 men (8%, 95% confidence interval (CI) 6-11%). Men with both, LVI- and PNI- primary cancers had the lowest risk of ILN involvement (6%) whereas men with LVI + or PNI + showed ILN metastases in 22% and 30%. In multivariable regression, men with LVI + or PNI + had higher odds for ILN metastases compared to men with LVI- and PNI- (OR 3.9, 95% CI 1.6-9.0, p value < 0.01) Tumour size was not associated with ILN risk (OR 1.01 95% CI 0.99-1.04, p = 0.17)., Conclusion: Approximately, one out of ten men with T1G2 overall and one out of four men with either LVI + or PNI + still have ILN metastases despite being clinically node negative. Therefore, invasive ILN staging should strongly be recommended in T1G2 with LVI + or PNI + but importantly, must be discussed in patients with T1G2 with LVI- or PNI-., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To develop a predictive model for additional inguinal lymph node metastases (LNM) at inguinal lymph node dissection (ILND) after positive dynamic sentinel node biopsy (DSNB) using DSNB characteristics to identify a patient group in which ILND might be omitted., Patients and Methods: We conducted a retrospective study of 407 inguinal basins with a positive DSNB in penile cancer patients who underwent subsequent ILND from seven European centres. From the histopathology reports, the number of positive and negative lymph nodes, presence of extranodal extension and size of the metastasis were recorded. Using bootstrapped logistic regression, variables were selected for the clinical prediction model based on the optimization of Akaike's information criterion. The area under the curve (AUC) of the receiver-operating characteristic curve was calculated for the resulting model. Decision curve analysis (DCA) was used to evaluate the clinical utility of the model., Results: Of the positive DSNBs, 64 (16%) harboured additional LNM at ILND. Number of positive nodes at positive DSNB (odds ratio [OR] 2.19, 95% confidence interval (CI) 1.17-4.00; P = 0.01) and largest metastasis size in mm (OR 1.06, 95% CI 1.03-1.10; P = 0.001) were selected for the clinical prediction model. The AUC was 0.67 (95% CI 0.60-0.74). The DCA showed no clinical benefit of using the clinical prediction model., Conclusion: A small but clinically important group of basins harbour additional LNM at completion ILND after positive DSNB. While DSNB characteristics were associated with additional LNM, they did not improve the selection of basins in which ILND could be omitted. Thus, completion ILND remains necessary in all basins with a positive DSNB., (© 2021 The Authors BJU International © 2021 BJU International.)

The presence of lymph node metastasis is the most important prognostic factor in penile cancer (PeCa). Due to limited sensitivity of currently available imaging modalities, invasive staging approaches remain indispensable for adequate nodal staging. As an alternative to radical inguinal lymphadenectomy and with the aim to reduce morbidity, staging strategies such as modified lymphadenectomy and dynamic sentinel node biopsy (DSNB) have been introduced. Over the years, DSNB evolved into a safe and reliable staging technique when performed in high volume centers. Recent enhancements of the procedure such as Single-photon emission computed tomography/computed tomography (SPECT/CT) and the introduction of hybrid tracers have improved pre- and intraoperative sentinel node (SN) visualization. Other technologies such as superparamagnetic iron oxide nanoparticles could have a potential future role to further refine DSNB. Future efforts should be aimed at optimizing diagnostic accuracy whilst minimizing perioperative morbidity., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The increasing availability of new imaging technologies and tracers has enhanced the application of nuclear molecular imaging in urogenital interventions. In this context, preoperative nuclear imaging and radioactivity-based intraoperative surgical guidance have become important tools for the identification and anatomical allocation of tumor lesions and/or suspected lymph nodes. Fluorescence guidance can provide visual identification of the preoperatively defined lesions during surgery. However, the added value of fluorescence guidance is still mostly unknown. This review provides an overview of the role of fluorescence imaging in radioguided surgery in urogenital malignancies. The sentinel node (SN) biopsy procedure using hybrid tracers (radioactive and fluorescent component) serves as a prominent example for in-depth evaluation of the complementary value of radio- and fluorescence guidance. The first large patient cohort and long-term follow-up studies show: 1) improvement in the SN identification rate compared to blue dye; 2) improved detection of cancer-positive SNs; and 3) hints towards a positive effect on (biochemical) recurrence rates compared to extended lymph node dissection. The hybrid tracer approach also highlights the necessity of a preoperative roadmap in preventing incomplete resection. Recent developments focus on receptor-targeted approaches that allow intraoperative identification of tumor tissue. Here radioguidance is still leading, but fluorescent and hybrid tracers are also finding their way into the clinic. Emerging multiwavelength approaches that allow concomitant visualization of different anatomical features within the surgical field may provide the next step towards even more refined procedures.

Objective: A lack of demonstrated clinical benefit precludes radiotherapy (RT) from being recommended for pN1/pN2 penile cancer (PeCa) lesions; but it may be recommended in case of extranodal (pN3) disease or for positive resection margins. Perineal urethrostomy (PU) is a technique of urinary diversion in patients with PeCa requiring total or subtotal penectomy as primary therapy. Prior studies suggest PU failure rates of up to 30%, without specific mention of the potential role of RT. When RT is delivered for PeCa it is usually to the pre-pubic fat, groin and lateral pelvis, and not to the region of the PU. Here we describe the role of perioperative RT in a large, multi-institutional registry of PU for PeCa., Methods: In our cohort, 299 patients from seven international, high-volume centers in Belgium, Brazil, China, Netherlands, United Kingdom and the United States underwent PU as urinary diversion for PeCa between 2000 and 2020. Demographic and clinicopathologic characteristics were reviewed., Results: Median patient age was 67 years and median follow-up was 19 months. Seven patients (2.3%) received pre-operative RT; six of them with chemotherapy. 37 received RT post-operatively, 21 (57%) with chemotherapy. Stenosis of the PU occurred in 35 (12%) of the total population. The majority of these patients (74%) required surgical revision at a median of 6.1 months post-operatively. RT delivery was neither significantly related to PU stenosis (p = 0.16) or to subsequent revision ( p  = 0.75)., Conclusion: Receipt of RT was not significantly associated with increased stenosis risk in PeCa patients who underwent PU., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Purpose: Perineal urethrostomy (PU) is often the definitive form of urinary diversion in patients with locally-advanced or anatomically unfavorable penile cancer (PC) requiring total penectomy. Here, we report post-operative PU-related complications and PU stenosis rates after total penectomy with PU in a large multicenter cohort of PC patients., Methods: We retrospectively reviewed the medical records of 299 patients who underwent PU as a means of urinary diversion for primary PC across seven international centers from 2000 to 2020. The Clavien-Dindo grading system was used to record 30-day post-operative complications. Cumulative incidence of stenosis was evaluated using the Kaplan-Meier method., Results: Median patient age was 67 years (interquartile range (IQR) 58-74), and median follow-up was 19 months (IQR 7.2-57). A total of 58 patients (19%) developed a 30-day post-operative complication, of which 45 (79%) were deemed minor (CD Grade I and II). Wound infection (11%; CD grade I-III) and dehiscence (4.0%; CD grade I-III) were the more common complications. The overall incidence of stenosis was 12% (35/299 patients), of which 26 (74%) needed surgical revision (probability of stenosis revision at one year of 9.3%, median time until the revision: 6.1 months (IQR 3.0-13)). Only two stenoses were seen after two years of follow-up., Conclusion: We present the most extensive series of PU in the management of PC to date. Wound infections of the primary surgical site were the most common complication. Stenosis occurred mostly within one and a half years after treatment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Comprehensive analysis of tumor infiltrating myeloid cells in the tumor microenvironment of penile squamous cell carcinoma (PSCC) is lacking. In this retrospective study, for the first time, PSCC resection specimens (N = 103) were annotated into the following compartments: intratumoral tumor (IT Tumor), intratumoral stroma (IT Stroma), peritumoral tumor (PT Tumor) and peritumoral stroma (PT Stroma) compartments. We then quantified CD14+, CD68+ and CD163+ myeloid cells within these compartments using an image analysis software and assessed their association with various clinical parameters, including high-risk human papillomavirus (hrHPV) status. In the total cohort, hrHPV status, grade of differentiation, age and tumor size were associated with myeloid cell densities. hrHPV + tumors had higher infiltration rates of CD14+, CD68+ and CD163+ myeloid cells in the IT tumor compartment (p < 0.001, for all) compared to hrHPV - tumors. Furthermore, when examining the association between compartment-specific infiltration and differentiation grade, increased myeloid cell densities in the IT tumor compartment were associated with a more advanced histological grade (p < 0.001, for all). This association remained significant when the hrHPV - cohort (N = 60) was analyzed (CD14+ p = 0.001; CD68+ p < 0.001; CD163+ p = 0.004). Subgroup analysis in the hrHPV + group (N = 43) showed that high infiltration rates of CD68+ and CD163+ cells in the PT tumor compartment were associated with lymph node (LN) metastasis (p = 0.031 and p = 0.026, respectively). Regarding the association between myeloid cell densities and disease-specific survival, the risk of death was found to decrease slightly as the number of myeloid cells in the IT tumor compartment increased (CD14+ p = 0.04; CD68+ p = 0.05; CD163+ p = 0.02). However, after adjusting for hrHPV, no independent association between myeloid densities and disease-specific survival were found. Altogether, these findings demonstrate the importance of assessing myeloid cell densities within the spatial context of the tumor. Further studies are needed to unravel the specific phenotype of myeloid cells residing in the different compartments, their effect on clinical parameters and the impact of hrHPV on the recruitment of myeloid cell populations in PSCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rafael, de Vries, Ottenhof, Hofland, Broeks, de Jong, Bekers, Horenblas, de Menezes, Jordanova and Brouwer.)

Background: Sentinel node (SN) biopsy in penile cancer (PeCa) is typically performed using 99m Tc-nanocolloid and blue dye. Recent reports suggested that the hybrid (radioactive and fluorescent) tracer indocyanine green (ICG)- 99m Tc-nanocolloid may improve intraoperative optical SN identification., Objective: The current study aimed to confirm the reliability of ICG- 99m Tc-nanocolloid and to assess whether blue dye is still of added value., Design, Setting, and Participants: A total of 400 ≥T1G2N0 PeCa patients were staged with SN biopsy at a single European centre. SNs were preoperatively identified with lymphoscintigraphy and single-photon emission computed tomography. Intraoperatively, SNs were detected via gamma tracing, blue staining, and fluorescence imaging., Outcome Measurements and Statistical Analysis: All patients (n=400, 740 groins) received ICG- 99m Tc-nanocolloid. Intraoperative SN identification rates were retrospectively evaluated. In those patients who received ICG- 99m Tc-nanocolloid and blue dye (n=266, 492 groins), SN visualisation rates were compared using the McNemar test., Results and Limitations: In total, 740 groins were assessed. No tracer-related (allergic) reactions were reported. All preoperatively defined SNs (n=1163) were localised intraoperatively. Of all excised SNs, 98% were detectable with gamma probe and 96% were visible with fluorescence imaging. In the analysis of the patients who received ICG- 99m Tc-nanocolloid and blue dye, fluorescence imaging yielded a 39% higher SN detection rate than blue dye (95% confidence interval 36-43%, p<0.001). Of the SNs that were tumour positive, 100% were intraoperatively visualised by fluorescence imaging, whereas merely 84% of the positive nodes stained blue., Conclusions: This study confirms that ICG- 99m Tc-nanocolloid is a reliable SN tracer for PeCa that significantly improves optical SN detection over blue dye., Patient Summary: Hybrid indocyanine green (ICG)- 99m Tc-nanocolloid is a safe and reliable sentinel node (SN) tracer, as established in this large series of 400 penile cancer patients (740 groins). It enables accurate pre- and intraoperative SN identification and significantly improves SN detection rate compared with blue dye, without staining the surgical field or the need for an additional injection., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objectives: To develop and externally validate a risk calculator for prediction of any cancer recurrence in patients with penile squamous cell carcinoma (pSCC) and inguinal lymph node metastases (ILNM), as to date no validated prognostic tool is available for patients with pSCC and ILNM., Patients and Methods: The development cohort included 234 patients from seven referral centres. The external validation cohort included 273 patients from two additional referral centres. Cox regression identified predictors of any recurrence, which were used to develop a risk calculator. The risk-calculator grouped the development and the validation cohorts according to the individual risk of any recurrence at 24 months (24m-R). Adjuvant treatment effects were tested on overall survival (OS) according to the derived tertiles, within the development and validation cohorts., Results: Positive surgical margins, pN 3 , and ILNM ratio were associated with higher recurrence rate. The 2-year OS rates were lower for patients with high (>37%) and intermediate (19-37%) compared to low (<19%) 24m-R risk of recurrence, for both the development (43% and 58% vs 83%, P < 0.001) and validation cohort (44% and 50% vs 85%, P < 0.001). Results were confirmed in the subgroup of patients who did not receive adjuvant treatment (P < 0.001), but not in patients who did receive adjuvant treatments in both the development and validation cohorts (P > 0.1)., Conclusion: Adjuvant treatment planning is crucial in patients with pSCC with ILNM, where only weak evidence is available. The current tool proved to successfully stratify patients according to their individual risk, potentially allowing better tailoring of adjuvant treatments., (© 2020 The Authors BJU International © 2020 BJU International Published by John Wiley & Sons Ltd.)

Purpose of Review: The level of evidence for current (adjuvant) treatment strategies after node positive inguinal lymphadenectomy is relatively low because of a paucity of prospective studies and controversy exist between the two major guidelines. The present review aims to provide a review of current literature on the available treatment options of patients after a tumor positive inguinal lymph node dissection., Recent Findings: Patients without inguinal extranodal extension or less than two tumor positive inguinal nodes are at low risk of ipsilateral pelvic nodal disease. Patients with pN1 disease are unlikely to benefit from adjuvant treatment, whereas patients with pN2 disease might benefit from adjuvant radiotherapy. For patients with high risk of pelvic nodal disease, prophylactic pelvic lymph node dissection (PLND) is advised by current guidelines. The InPACT study investigates whether adjuvant chemoradiotherapy could be used instead of prophylactic PLND. Subgroup analyses of retrospective cohorts suggest that patients with pN3 disease based on tumor positive pelvic nodes may benefit from adjuvant radiotherapy or chemotherapy. Given the weak level of evidence and substantial toxicity associated with current regimens, adjuvant chemotherapy cannot be generally recommended., Summary: Despite current treatment strategies, patients with pN2-pN3 disease still have a poor prognosis. Prospective international multicenter studies are necessary to identify the best treatment options for patients with advanced node positive penile squamous cell carcinoma.

Current chemotherapeutic treatment for advanced penile squamous cell carcinoma has substantial side effects and no randomized data to support an overall survival benefit. Immunotherapy with checkpoint blockade is currently being tested in penile cancer patients in clinical trials. The high PD-L1 expression and CD8 + T-cell infiltration in penile cancer represent a promising prospect for immunotherapy response in the treatment of locally advanced disease. For efficacious immunotherapy treatment, a better understanding of the tumor microenvironment (TME) is critical. Here we use the structure revealed by cancer immunograms to define current knowledge of the penile cancer TME as a backbone for future research. PATIENT SUMMARY: Advanced penile cancer has a poor prognosis with a need for more effective therapy. In this manuscript we describe the potential of immunotherapy as a new treatment modality in penile cancer., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: This review discusses new findings in penile cancer imaging in relation to the European Association of Urology and National Comprehensive Cancer Network guidelines., Recent Findings: For imaging in penile cancer patients who are candidates for organ-sparing primary treatment, ultrasound with Doppler seems to be the method of choice in addition to physical examination. The sentinel node biopsy (SNB) procedure is used to detect small nodal metastases in clinically node-negative patients. In recent years, this procedure has been enhanced by 3D imaging using single photon emission computed tomography (SPECT) with computed tomography (CT) to improve preoperative localization and interpretation of sentinel nodes, as well as hybrid fluorescent and radioactive tracers to increase intraoperative localization of sentinel nodes. 18F-fluorodeoxyglucose PET (FDG-PET) with CT appears to be mainly useful for pelvic and distant staging in clinically node-positive patients. Other modalities with a potential future role in penile cancer are ultrasound with shear wave elastography, FDG-PET with MRI and ultrasmall paramagnetic iron oxide-enhanced MRI., Summary: Imaging modalities in penile cancer have advanced throughout the years, assisting in treatment decision-making and during invasive procedures.

Purpose: Despite the availability of different lactate clearance (LC) metrics for clinical use, it remains unknown which metric is superior as a clinical predictor for outcome, particularly in trauma patients. This retrospective study compared four previously described metrics of LC and examined the association between LC and outcome in trauma patients., Methods: Lactate values of trauma patients admitted to a level I trauma center between 2010 and 2013 were retrieved from patient records. LC was calculated according to Huckabee, Regnier et al., Billeter et al. and Zhang et al. Patients were categorized as isolated traumatic brain injury (TBI), trauma with TBI, and trauma without TBI. The primary study outcome was in-hospital mortality., Results: 367 trauma patients were eligible for LC calculation. Only LC by Zhang et al. [area under the curve (AUC) > 0.622, p < 0.01], and Billeter et al. (AUC > 0.616, p < 0.05) were predictive for mortality in trauma patients with and without TBI. However, both were equally prognostic as the initial lactate value for in-hospital mortality. The prognostic value of initial lactate and lactate clearance for in-hospital mortality were not found to differ between isolated TBI, polytrauma with TBI, and trauma without TBI., Conclusions: LC metrics based on the methods of Zhang et al. and Billeter et al. predicted mortality in trauma patients, and their prognostic value did not differ between patients with and without TBI. However, initial lactate value was equally prognostic as these LC metrics. Our findings suggest that a single initial lactate measurement may be a more clinically useful tool to predict mortality than the calculation of lactate clearance.

Background: Traumatic brain injury (TBI)-related coagulopathy appears to be most prevalent in patients with tissue hypoperfusion, but evidence for this association is scarce. This study investigated the relationship between tissue perfusion and hemostatic derangements in TBI patients., Materials and Methods: Coagulation parameters were measured on emergency department admission in patients with TBI (head abbreviated injury scale ≥ 3). The level of hypoperfusion was simultaneously assessed by near-infrared spectroscopy (NIRS) at the forehead and arm, and by base excess and lactate. Coagulopathy was defined as an international normalized ratio > 1.2 and/or activated partial thromboplastin time > 40 s and/or thrombocytopenia (<120 × 10(9)/L)., Results: TBI patients with coagulopathy (42%) had more signs of tissue hypoperfusion as indicated by increased lactate levels (2.1 [1.1-3.2] mmol/L versus 1.2 [1.0-1.7] mmol/L; P = 0.017) and a larger base deficit (-3.0 [-4.6 to -2.0] mmol/L versus -0.1 [-2.5 to 1.8] mmol/L; P < 0.001). There was no difference in the cerebral or somatic tissue oxygenation index. However, there was a distinct trend toward a moderate inverse association between the cerebral tissue oxygenation index and D-dimer levels (r=-0.40; P = 0.051) as marker of fibrinolysis. The presence of coagulopathy was associated with an increased inhospital mortality rate (45.5% versus 6.7%; P = 0.002)., Conclusions: This is the first study to investigate the relationship between hemostatic derangements and tissue oxygenation using NIRS in TBI patients. This study showed that TBI-related coagulopathy is more profound in patients with metabolic acidosis and increased lactate levels. Although there was no direct relationship between tissue oxygenation and coagulopathy, we observed an inverse relationship between NIRS tissue oxygenation levels and fibrinolysis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Phosphorus contents of epidermal vacuoles and mesophyll cells of Lupinus lutens leaflets were measured by electron probe x-ray microanalysis of fully hydrated, bulk frozen samples. Quantitation was achieved using standard solutions containing colloidal graphite to simulate cell contents and the derived nonlinear relationship between peak over background ratio and concentration improved the accuracy of the analytical procedure. Inorganic phosphate contents of mesophyll cells were shown to be highly dependent on phosphate nutrition. Comparison with data obtained from conventional analysis leads to the suggestion that in heterogeneous tissues the inorganic phosphate concentrations of the cytoplasm may show greater variation than observed in the cytoplasm of simple plant systems such as cell suspension and root tips.