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+There have been few studies reported with conflicting results in the use of neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), redcell-distribution-width (RDW), etc. for predicting prognosis and differential diagnosis of adrenal tumors. The aim of this study is to investigate the role of inflammatory markers through a complete blood count, which is an easy access low-cost method, for the differential diagnosis of adrenocortical adenoma (ACA), adrenocortical carcinoma (ACC), and pheochromocytoma. The data of patients who underwent adrenalectomy between the years of 2010–2020 were retrospectively analyzed. Systemic hematologic inflammatory markers based on a complete blood count such as neutrophil ratio (NR), lymphocyte ratio (LR), NLR, PLR, RDW, mean platelet volume (MPV), and maximum tumor diameter (MTD) were compared between the groups. A statistically significant difference was found between the three groups in terms of PLR, RDW, and MTD. With post-hoc tests, a statistically significant difference was found in PLR and MTD between the ACA and ACC groups. A statistically significant difference was found between the ACA and pheochromocytoma groups in PLR and RDW values. In conclusion, it could be possible to plan a more accurate medical and surgical approach using PLR and RDW, which are easily calculated through an easy access low-cost method such as a complete blood count, together with MTD in the differential diagnosis of ACC, ACA, and pheochromocytoma.Adrenal tumors are seen 3–10% in the general population and the majority are made up of benign adrenocortical adenomas (ACA) [1]. Although most ACAs are non-functional, approximately 15% have been reported to produce hormone secretion [2]. On the other hand, adrenocortical carcinomas (ACC) are very rarely seen in 1–2 patients per million in a year, and approximately 40–60% show hormonal hypersecretion (Cushing’s syndrome, hyperaldosteronism, etc.) [3]. In addition, pheochromocytomas are other rare adrenal tumors originating from the adrenal medulla that secrete catecholamines [4]. All three tumors are generally asymptomatic, although some may exhibit clinical findings associated with endocrinopathies due to excessive hormone secretion, abdominal pain may be a symptom depending on the size of the mass, as well [1]. Diagnosis is based on adrenal imaging as well as clinical and laboratory (hormonal) evaluation [5]. Differential diagnosis of functional ACA and ACC may be difficult due to hormonal hypersecretion [6,7]. Even though new imaging techniques have been progressively developing in recent years, they have been reported to be insufficient [5]. In addition to fine-needle aspiration biopsy being an invasive procedure, it has been seen to have a low effect in differentiating primary benign and malignant tumors of the adrenal gland [8]. All of these factors highlight the importance of using new methods for differential diagnosis.Interest in the relationship between inflammation and cancer has been increasing throughout recent years. Cancer-inflammation-related processes in tumors are associated with the production of cytokines (IL-6 and TNF-α), growth factors, and granulocyte colony-stimulating factors in oncology patients [3]. The systemic inflammatory responses are associated with thyroid, pancreas, and many endocrine organ malignancies, as well as in urogenital malignancies such as prostate and testis [9,10,11,12]. Furthermore, the association of inflammatory response with hypertension, diabetes mellitus, and many systemic diseases has also been demonstrated [13]. Cushing disease and hyperaldosteronism, which cause excessive secretion of adrenal hormones, lead to an increase in inflammation by affecting the immune system [14,15]. However, immunohistochemically, it has been reported that inflammation around the tumors’ microenvironment is seen at a lower level in ACC rather than ACA and pheochromocytoma [16].Hematological parameters such as neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), red cell distribution width (RDW), which are used as indicators of acute and chronic inflammation, are effective in the diagnosis and prediction of inflammatory disease and some malignancies [3,11,17,18]. There have been few studies reported with conflicting results in the use of NLR, PLR, RDW, etc. for predicting prognosis and differential diagnosis of adrenal tumors. Hence, the aim of this study is to investigate the role of inflammatory markers through a complete blood count, which is an easy access low-cost method, for the differential diagnosis of ACA, ACC, and pheochromocytoma.The data of patients who underwent adrenalectomy between the years of 2010–2020 were retrospectively analyzed from the hospital electronic system in the Urology Clinic. Analyzed data contain the patients’ basic demographic characteristics (age, gender, etc.) as well as blood test results that include routine biochemical and radiological parameters. Informed consent forms were obtained from the patients and the study was approved by the university’s scientific research ethics committee.The including criteria consist of patients whose pathological evaluation of adrenalectomy material resulted in ACC, ACA, and pheochromocytoma. Patients who underwent adrenalectomy during radical nephrectomy, who underwent adrenalectomy due to adrenal metastasis, who had an active infection, an inflammatory (ankylosing spondylitis, FMF), and a hematological disease affecting their hemogram parameters were excluded from the study. Systemic hematologic inflammatory markers based on a complete blood count such as neutrophil ratio (NR), lymphocyte ratio (LR), NLR, PLR, RDW, MPV were compared between the groups. NLR was found by dividing the neutrophil count to the lymphocyte count, whereas PLR was found by dividing the platelet count to the lymphocyte count. In addition, the maximum tumor diameter (MTD) was measured by computed tomography and the groups were compared.Data analysis was performed using IBM SPSS v 23.0.0 (IBM Corp., Armonk, NY, USA). Numbers, percentages, arithmetic mean, and median values were evaluated as descriptive statistics. A p-value < 0.05 was set for statistical significance. The data were divided into three groups as ACC, ACA, and pheochromocytoma. The chi-square test was used for the comparison of categorical variables (gender). The variables were tested for normal distribution with the Shapiro-Wilk test. The variables within a normal distribution were compared using the ANOVA test, and non-normally distributed variables were compared with the Kruskal-Wallis test. A post-hoc test using Dunn’s test with Bonferroni correction was used to determine the statistically significant difference between the groups and the significance value was adjusted the as p < 0.05.After the inclusion and exclusion criteria were taken into evaluation, 52 adrenalectomy patients remained. Patients were divided into three groups, 32 out of 52 patients were in ACA, 12 were in ACC, and eight were in the pheochromocytoma group. Age, MTD, NR, LR, NLR, PLR, RDW, and MPV values were compared. According to the distribution of the groups, the mean ages of the patients were 53.34 ± 11.28 years in the ACA group, 55.83 ± 16.05 years in the ACC group, 54.5 ± 12.24 years in the pheochromocytoma group. Descriptive statistics and their distribution by groups are summarized in Table 1.A statistically significant difference was found between the three groups in terms of PLR, RDW, and MTD (p = 0.001, p = 0.031, p = 0.031, respectively) (Table 1). With post-hoc tests, a statistically significant difference was found in PLR and MTD between the ACA and ACC groups (p = 0.015, p = 0.035, respectively). A statistically significant difference was found between the ACA and pheochromocytoma groups in PLR and RDW values (p = 0.005, p = 0.047, respectively) (Table 2).Our study showed that PLR and MTD values were significantly higher in ACC than ACA, whereas RDW and PLR values were significantly higher in pheochromocytomas than ACA. These findings demonstrate that MTD, PLR, and RDW values can be used in the differentiation of ACA-ACC-pheochromocytoma. Thus far, two studies have investigated hematological markers in the differential diagnosis of ACA and ACC [19,20].In the most recent study by Şişman et al. [20] which was conducted with the participation of 39 patients, PLR was found statistically significant between adenoma and carcinoma groups as well as our study. Recent studies show that the platelets’ concentration in the tumor microenvironment could play a significant role in stimulating tumor development [21]. Thrombocytosis seen in many patients with solid tumors is associated with tumor infiltration and metastasis [21]. This information supports the statistically significant difference of PLR value between ACA-ACC groups in our study.Şişman et al. [20] found a statistically significant difference in NLR values between ACA and ACC groups. Another study by Mochizuki et al. [19], consisting of 59 patients performed in 2017, also found that NLR was effective in distinguishing ACC from non-malignant adrenal tumors. However, in our study, NLR was found to be statistically insignificant in the differential diagnosis. This contradiction in NLR values between our study and the literature may be caused due to the sample size. Since adrenocortical tumors are rare, gathering a homogenous sample size with a greater number of patients is challenging. Therefore, in all of the studies, including ours, the population size may not be enough to reflect the real-world data. Further studies with a greater sample size and diverse patient populations are needed to investigate the role of NLR in adrenocortical tumors. It has been reported in the literature that some functional adrenocortical tumors increase the neutrophil count and decrease lymphocytes [14]. Unlike the two studies above, all of our patients in the ACA group have functional adenomas and although the NLR values are not as high as ACC, the increase in the ACA group, due to the functionality of the tumors, may play a role in the difference between our study and the literature.In recent years, developments in cancer immunology show the crucial role of cells in the tumor microenvironment. Utilization of this information can have prominent effects on establishing patients’ prognostic criteria. Guadagno et al. [16] demonstrated how lymphocytes surrounding ACA were higher compared to ACC, which was supported by the possible immunosuppressive role of malignant tumor cells. These results were also associated with a better prognosis [16]. Supporting these results, studies investigating prognostic markers of ACC show how PLR values are higher in patients with poor prognosis [3,16,22]. Due to the retrospective nature of our study, we could not analyze the prognosis of our patients. However, higher PLR values detected in the ACC group, in addition to imaging modalities and other laboratory tests, may help with the benign and malignant behavior of adrenal tumors.In addition, it was shown in the study by Guadagno et al. [16] that the immune response in pheochromocytoma, a tumor originating from the adrenal medulla, is not different from other adrenal tumors. Our study differs from this study by the statistical difference in PLR and RDW values between ACA and pheochromocytoma groups. The immunohistochemical study by Guadagno et al. [16] provides information about the local immune reaction and found no difference between ACA and pheochromocytoma. A systemic response was at the forefront in our study, and the fact that catecholamines trigger the systemic immune response may significantly make the difference between these two studies. It has been shown that excessive catecholamine secretion in pheochromocytoma triggers systemic inflammation and increases acute phase reactants, as well as increases active platelet counts more than the lymphocyte count [4]. This may explain the higher detection of PLR levels in pheochromocytoma compared to ACA. On the other hand, many carcinomas and systemic inflammatory diseases have also been shown to increase RDW levels in parallel with inflammatory markers [18]. The increase in RDW in parallel with the increased acute phase reactants in excess catecholamine secretion supports the difference in the pheochromocytoma and ACA groups in our study. Although RDW is a complex marker that can be affected by factors such as age and diet, to our knowledge for the first time in the literature, we argue that RDW may be a new supportive marker in addition to the tests used to differentiate ACA from pheochromocytoma [18].In the studies that investigate the malignancy and prognostic values of the tumor size in adrenal incidentalomas, it has been seen that when the tumor size increases (especially masses of 4–6 cm and above), the transformation into malignancy also increases, and the prognosis worsens [5,19]. In our study, the median MTD in the ACC group was found as 7.8 cm, almost twice as the ACA group, which is consistent with the literature [5,19]. Therefore, our findings demonstrate that the combination of hematological parameters and tumor size could be effective in the diagnosis and follow-up of patients with adrenal tumors.The main limitation of our study was its retrospective nature and limited patient population. Another limitation was the inadequate homogenous distribution between the groups due to the rarity of ACC in general. Further multicentered randomized control studies are needed to investigate the use of new markers in the differential diagnosis of ACC that could later on be included in future guidelines.In conclusion, PLR and RDW may be two new markers which can be easily calculated based on an easy-access low-cost method, such as a complete blood count, that can help in the differentiation of ACC, ACA, and pheochromocytoma with a comprehensive and detailed approach.Conceptualization, E.A. and M.G.A.; methodology, N.G.İ. and M.G.A.; software, G.A.Ö.; validation, N.G.İ., M.G.A., and G.A.Ö.; formal analysis, N.S.; investigation, M.G.A.; resources, G.A.Ö. and N.G.İ.; data curation, N.G.İ.; writing—original draft preparation, M.G.A.; writing—review and editing, İ.Y., E.A., and N.S.; visualization, N.S. and İ.Y.; supervision, İ.Y. and E.A.; project administration, M.G.A. and G.A.İ.; funding acquisition, none. All authors have read and agreed to the published version of the manuscript.This research received no external funding.The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Trakya University, School of Medicine (TUTF-BAEK 2021/204 and 15.03.2021).Informed consent was obtained from all subjects involved in the study.The data presented in this study are available on request from the corresponding author. The data are not publicly available due to restrictions of privacy.The authors declare no conflict of interest.Statistics of patients’ demographic data, hematological parameters, and maximum tumor diameter.ACA: Adrenocortical adenoma; ACC: Adrenocortical carcinoma; NR: Neutrophil ratio; LR: Lymphocyte ratio; NLR: Neutrophil-lymphocyte ratio; PLR: Platelet-lymphocyte ratio; MPV: Mean platelet volume; RDW: Red cell distribution width; MTD: Maximum tumor diameter. * on-normally distributed variables were given as median (interquartile range).Post-hoc test results of patients.PLR: Platelet-lymphocyte ratio; RDW: Red cell distribution width; MTD: Maximum tumor diameter.Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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+The relationship between prostatic chronic inflammation (PCI) and prostate cancer (PCa) is unclear and controversial. Some authors reported that a history of chronic prostatitis may be correlated with PCa induction, while others associate chronic inflammation with less aggressive disease or consider inflammation as a possible protective factor against PCa. Four different types of prostatitis are known: bacterial acute prostatic inflammation, bacterial chronic prostatic inflammation, abacterial prostatitis/chronic pelvic pain syndrome, and asymptomatic prostatic chronic inflammation. Prostatic inflammation is underestimated during daily clinical practice, and its presence and degree often go unmentioned in the pathology report of prostate biopsies. The goal of this report is to further our understanding of how PCI influences the biology of PCa. We investigated the main pathogenetic mechanisms responsible for prostatic inflammation, including the cellular response and inflammatory mediators to describe how inflammation modifies the prostatic environment and can lead to benign or malignant prostatic diseases. We found that prostatic inflammation might have a pivotal role in the pathogenesis of prostatic diseases. Details about PCI in all prostate biopsy reports should be mandatory. This will help us better understand the prostatic microenvironment pathways involved in PCa biology, and it will allow the development of specific risk stratification and a patient-tailored therapeutic approach to prostatic diseases.Chronic inflammation has been suspected of playing a major role in the pathogenesis of several neoplasms. However, in the pathogenesis of prostate cancer (PCa), its role is unclear and controversial.The National Institutes of Health (NIH) has classified prostatitis into four categories [1].Type I (bacterial acute prostatic inflammation): microscopic appearance is characterized by groups of neutrophils within glandular acini and throughout the stroma, intra-ductal desquamated cellular debris, stromal edema, and hyperemia.Type II (bacterial chronic prostatic inflammation): presence of lympho-plasma cellular infiltrate in a peri-acinar distribution and sometimes a few lymphocytes between the epithelial acinar cells.Type III (chronic abacterial prostatitis/chronic pelvic pain syndrome): distinguished by dilated ducts and acini filled with neutrophils, histocytes, and desquamated epithelial cells. Additionally, granulomas secondary to inflammation may be present due to ruptured and dilated ducts or acini. In such cases, further granulomatosis sub-classification by the pathologist should be reported as either infectious or non-specific granulomatous prostatitis, post-biopsy resection granulomatitis, or systemic granulomatous prostatitis. Among these, the most common are non-specific granulomatous prostatitis and post-biopsy granulomatitis. These conditions may also mimic PCa in digital rectal examination, prostate ultrasound, increased PSA levels, and histologic appearance [2].Type IV (asymptomatic prostatic chronic inflammation): detected after biopsy in patients who have no history and symptoms of prostatic diseases. Clinical presentation includes increased levels of PSA and/or an abnormal digital rectal examination [1].Prostatitis Types I to III and prostatitis-like symptoms can seriously impact men’s health and quality of life and represent a common cause of medical consultations, accounting for around 8% of urologist visits. Still, the real prostatitis prevalence remains uncertain [3,4].Prostatitis might result from different mechanisms. Frequently, it is caused by specific Gram-positive or -negative bacterial subspecies according to prostatitis type, but uropathogenic organisms can be detected in fewer than 10% of symptomatic men, and they remain hidden in most cases [5]. If not properly treated, 10% of the acute bacterial prostatitis will transition to chronic bacterial prostatitis/chronic pelvic pain syndrome [6]. The prostatic reflux of contaminated urine through prostatic ducts can prompt and perpetuate acute and chronic prostatitis when bladder outlet obstruction (BOO) secondary to benign prostatic hyperplasia (BPH) is present. Additionally, sexually transmitted pathogens can be involved in prostatitis pathogenesis due to their ability to retrogradely reach the prostate [5]. Moreover, transrectal biopsy or urethral instrumentation are frequent etiologies of prostate infection due to a direct introduction of bacteria while performing the maneuvers [5]. Uncommonly the source of the infection originates in distant organs and microorganisms reach the prostate gland through hematogenous seeding [5]. Animal model studies report how sex hormone levels can alter the regulation of prostate inflammation. Different estrogen and androgen concentrations are related to different kinds of inflammatory response, each with its specific interleukin expression within the prostatic microenvironment [7]. It is also known that dietary variations such as fatty acid composition result in different metabolic phenotypes and impact prostate size, epithelial volume, inflammation, and gene expression [8,9].The presence of prostatic inflammation is underestimated during daily clinical practice. Too often, details about inflammation are not mentioned in the pathological report, despite international guidelines that recommend specifying the presence or absence of inflammation and if present whether it is active or granulomatous inflammation [10]. Various authors have reported that a personal history of chronic prostatitis, as well as a history of sexually transmitted disease, may be causally related to PCa induction. Cheng et al. found STDs were not associated with overall PCa risk. A sub analysis showed Latinos reporting any STDs had a greater risk of disease than those with no STDs. Interestingly, foreign-born Latinos displayed a larger risk associated with STDs [11]. Gurel et al. demonstrated that the presence of chronic prostatic inflammation is associated with a 30% increase in the risk of PCa [12]. Recently, Sanguedolce et al. demonstrated that low-grade prostatic inflammation classified according to the Irani system [13], was associated with adverse pathology, (ISUP III and/or extra-prostatic disease) in patients with pre-operative ISUP I or II undergoing radical prostatectomy [14]. PCa induction appears to be influenced by a combination of factors associated with the prostatic tissue milieu or micro-environment. Here, inflammatory cells and mediators, such as chemokines, interleukins (IL), and cytokines, correlate with either favorable or unfavorable conditions for cancer development and progression [15].On the other hand, a lower risk of PCa development has been reported in the context of prostatic inflammation [16]. Porcaro et al., in patients undergoing baseline random biopsies, found that prostatic chronic inflammation lowered the risk of a high PCa tumor burden, and was also associated with less aggressive PCa biology [17,18].It is known that the prostate is an immunocompetent organ that harbors many immune cell types [19,20]. These components can be activated by different inflammatory triggers and produce different mediators, activating intra-prostatic pathways that can be involved in the pathogenesis of all major prostate diseases [21].Prostatic microenvironment alterations that occur when PCI is present, and other systemic conditions and external factors such as androgen hormone levels, age-related changes, and metabolic syndromes could influence prostatic immune cells to modify the cellular infiltrate and their cytokine secretions [21].Different stimuli activate different inflammation-related pathways, resulting in several pathological modifications such as proliferative inflammatory atrophy, PCa, or BPH. Each of these might be related to various interleukins and cytokines, but even the same soluble mediator can have different effects, conditioned by the presence of immune cell populations, their membrane antigens, and the signaling that arises from their binding. For instance, benign prostatic enlargement has been associated with high levels of IL-2, IL-4, IL-13, IL-17, IL-23, TGF-β, and FGF-2 produced by lymphocytes subtypes TH1 and TH17, as well as macrophages and infiltrating dendritic cells. On the contrary, other pathological conditions may elicit secretion of IL-6-8-10 or TGF-α which contributes to cellular proliferation and PCa induction [22].Immune responses against the tumors are dependent on the subset of T cells recruited to the tumor site, which is determined by the chemokines’ and cytokines’ local and systemic gradient. The presence of CD3+ tumor-infiltrating lymphocytes was significantly associated with shortened PSA recurrence-free survival in PCa patients [22]. Furthermore, the number of CD3+ cells in tumor areas and stromal areas was significantly higher in metastatic than in non-metastatic PCa [22]. High expression of epithelial CD4+ Tregs in normal prostatic tissue was associated with a four-fold increased risk of PCa in comparison with low expression of epithelial CD4+ Tregs [23]. Additionally, a greater number of epithelial CD4+ Tregs in normal prostatic tissue was positively associated with a higher Gleason score and pT-stage. An explanation for this association may relate to the high expressions of CD25 and FOXP3 that are found in this population of T cells, both being able to actively suppress antitumor immune response [22]. Also, tumor-associated macrophages (TAM) play a role in cancer progression. Increased density of TAM was correlated with increased Gleason score and conferred a poor prognosis. Together these findings strengthen the likelihood that in PCa patients, specific subtypes of immune cells, such as tumor-associated macrophages and CD3+ T cells, are associated with an unfavorable prognosis [22].In this complex scenario, interleukins and cytokines may play a main role. IL-6 has been related to cancer initiation and progression. IL-6 and its receptor are released by cancer cells, and IL-6 circulating levels are elevated in patients with metastatic disease and hormone-refractory disease [22]. Chemokines like CCR5, CXCR3, and CXCR4 on the CD4+ Th1 surface and cytokines like IL-2 are accountable for the attraction of immune system elements. An increase in inflammatory cell infiltrates leads to a higher PCa risk and poorer survival outcomes [22]. Chronic inflammation and ties to the immune system are involved in prostate carcinogenesis. In the prostatic microenvironment, chronic inflammation leads to oxidative stress via the generation of reactive oxygen species (ROS) and reactive nitrogen species released by immune cells as a consequence of chronic inflammation. Consequently, this results in DNA breaks and recruitment of epigenetic machinery which in turn favors DNA methylation, transcriptional silencing of genes, and gene fusion [22]. Oxidative stress might also underlie the relationship between fat intake and prostate cancer. Indeed, polyunsaturated fatty acids were found to be related to an increased risk of a high-grade Gleason score of 8–10. Specifically, omega-6 fatty acids involve the metabolism of linoleic acid that is metabolized into arachidonic acid, which is a precursor of proinflammatory factors such as eicosanoids, prostaglandin E2, and leukotriene B4 [22]. Immunosurveillance is a primary function of the human immune system, and the inflammatory response can prevent carcinogenesis by recognizing and eliminating tumor-specific antigens. Penetration of CD8+ T cells, or cytotoxic T lymphocytes, within the PCa microenvironmental niche confers a better prognosis. This is correlated to the expression of CCR5 on the CD8+ surface, where activation recruits cells having antitumor activity [15]. Cells expressing CD8 antigen have also been linked to BPH. In the condition of low androgen levels, CD8+ T cells infiltrate glandular epithelium and cause cell proliferation [24]. There is growing evidence that chronic inflammation is a main factor in BPH and lower urinary tract symptoms (LUTS). Data from the Medical Therapy of Prostate Symptoms (MTOPS) trial suggested that around 40% of baseline biopsy specimens had chronic inflammatory infiltrates. These patients showed higher PSA levels and larger prostate volumes suggesting a cause–effect relationship between chronic inflammation and BPH/LUTS [25]. A summary of the different cytokines and interleukins linked to PCa can be find by the reader in Table 1.A meta-analysis on this subject was conducted by Vasavada et al., including 25 studies and a total of 20,585 patients, of which 6641 had prostate cancer. The presence of any type of inflammation (acute and chronic) was significantly associated with a lower PCa risk. When subanalysis by inflammation type was performed, acute inflammation in four studies and chronic inflammation in 15 were each associated with a lower prostate cancer risk [16].Recently, Moreira et al. found a protective role of inflammation against PCa, based on data coming from the REDUCE trial. They showed how men with baseline PCI had significantly fewer high-grade tumors compared to those without PCI in a cohort of 889 men aged 50 to 75 years who had baseline prostate biopsies negative for PCa, but who, on 2-year follow-up biopsy, demonstrated PCa. The authors concluded that chronic inflammation in a negative biopsy was associated with lower prostate cancer grade among men detected with PCa in a 2-year follow-up biopsy [26].An interesting pilot study by Barkin et al. analyzed natural killer (NK) cell activity (NKA) and used its measurement as a surrogate of PCa detection risk. Detection of lower NKA levels in whole blood samples was more likely correlated with a positive result at prostate biopsy. They were also able to propose an NKA cut-off value of 200 pg/mL, below which the relative risk of PCa was 2.76 (OR 13.33) [27]. Likewise, Gannon et al. examined the immune cell infiltration during androgen deprivation therapy for PCa. Higher counts of CD56+ NK cells were strongly related to less disease progression and protection from biochemical recurrence in patients undergoing androgen deprivation therapy [28]. These findings are consistent with a possible protective role for NK cells in patients with PCa. They also confirm the influence of sex hormone status in inflammatory response modulation as shown in animal model studies [7,29].New findings of the relationship between prostatic inflammation and PCa present the possibility of targeting these specific pathways with immunotherapy. An understanding of cancer cell–immune system interactions is needed to develop new effective immunotherapy. There has been great interest in programmed cell death protein (PCDP-1), specifically PD-1, and its ligand PD-ligand-1. T lymphocytes express PD-1 as part of an immunosuppressive mechanism, which favors cancer growth and progression [30]. Additionally, PCa vaccines that activate T-cell populations against tumor cells have been developed. Sipuleucel-T was the first vaccine approved by the FDA for men with asymptomatic or minimally symptomatic metastatic castration-resistant PCa [31]. Prostatic inflammation has a pivotal role in the pathogenesis of prostatic diseases. Its identification and molecular characterization are mandatory if we are to better understand the influence of inflammation on PCa biology and develop a specific risk stratification and patient-tailored therapeutic approach [31].A.T., A.P., F.D., A.G.: project development, manuscript writing. A.A., M.A.C., V.V., A.B.P.: critical revision. All authors have read and agreed to the published version of the manuscript.This research received no external funding.Not applicable.Not applicable.Not applicable.The authors declare no conflict of interest.Summary of cell types, cytokines, and interleukins involved in the prostate microenvironment during PCI and their link with PCa.T cells Th1T cells Th17Tumor-associated macrophagestumor-infiltrating T cells CD3+Tregs CD4+IL-2IL-4IL-6IL-13IL-17CD25Natural Killer cellsCD8+ T cellsCCL5CCR5CD56Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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+(1) Introduction and Objective: Upper tract urothelial carcinoma (UTUC) is an uncommon disease, only accounting for 5–10% of all urothelial carcinomas. Current clinical practice guidelines encourage a risk-adapted approach to UTUC management, including lymph node dissection (LND) in patients with muscle-invasive or high-risk tumors. If pathological characteristics could be more accurately predicted from preoperative data, we could optimize perioperative management strategies and outcomes. The aim of this article is to present a detailed revision of preoperative predictors for muscle-invasive UTUC, locally advanced or advanced UTUC, as well as current indications, technique variations, and the reasons as to why LND should be offered to these patients. (2) Methods: We included any kind of studies related to information concerning UTUC, nephroureterectomy, LND, risk factors for recurrence, prediction tools and models for risk stratification. A literature search was conducted following medical subject headings (MeSh), Emtree language, Decs, and text words related. We searched through MEDLINE (OVID), EMBASE (Scopus), LILACS, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to May 2021. Evidence acquisition was presented according to the PRISMA diagram. (3) Results: Preoperative risk factors for either muscle-invasive UTUC (≥pT2), extra urothelial recurrence (EUR), locally advanced disease, or high-risk UTUC can either be derived from ureteroscopic (URS) findings, urine cytology, URS biopsy, or from preoperative radiologic findings. It seems reasonable that LND may provide not only staging and prognostic information but also play a therapeutic role in selected UTUC patients. The patients who benefit the most from LND appear to be those with ≥ pT2 disease, because patients with tumors ≤ pT1 rarely metastasized to LNs. UTUC has characteristic patterns of lymphatic spread that are dependent on tumor laterality and anatomical location. Choosing the right patients for LND, designing and standardizing LND templates based on tumor location and laterality is critical to improve LN yield, survival outcomes, and to avoid under-staging or overtreatment. (4) Conclusions: Patients with muscle-invasive or non-organ-confined UTUC have an extremely high risk for disease recurrence and cancer-specific mortality (CSM). Preoperative factors and prediction models must be included in the UTUC management pathway in our clinical practice to improve the accurate determination of high-risk groups that would benefit from LND. We recommend offering LND to patients with ipsilateral hydronephrosis, cHG, cT1 at URS biopsy and renal sinus fat or periureteric fat invasion. The role of lymphadenectomy in conjunction with radical nephroureterectomy (RNU) is still controversial, given that it may result in overtreatment of patients with pTa-pT1 tumors. However, a clear benefit in terms of recurrence-free survival (RFS) and cancer-specific survival (CSS) has been reported in patients with ≥pT2. We try to avoid LND in patients with cLG, cTa, and no ipsilateral hydronephrosis if the patient is expected to be compliant with the follow up schedule. There is still plenty of work to do in this area, and new molecular and non-invasive tests are necessary to improve risk stratification.Upper tract urothelial carcinoma (UTUC) is an uncommon disease, only accounting for 5–10% of all urothelial carcinomas [1,2,3]. The current standard of care for non-metastatic UTUC is radical nephroureterectomy (RNU) with the excision of a bladder cuff. Unfortunately, UTUC is a biologically aggressive tumor with a high potential for disease recurrence, metastasis, and cancer-specific mortality (CSM) [4,5]. Trying to overcome this issue, current clinical practice guidelines encourage a risk-adapted approach to UTUC management. Including a detailed preoperative tumor invasiveness assessment, and recommending either neoadjuvant chemotherapy (NAC) or lymph node dissection (LND) in patients with muscle-invasive or high-risk tumors, which includes patients with clinical high grade (cHG) when the diagnosis is made by means of cytology or ureteroscopic biopsy and pathological high grade (pHG) when the diagnosis has been made by radical or nephron-sparing surgery [6]. Due to the low incidence of UTUC, the majority of studies mainly consist of single-institution studies, resulting in low-level evidence for most recommendations [1,2,6,7,8,9].If pathological characteristics could be more accurately predicted from preoperative data, we could optimize perioperative management strategies and outcomes. Beyond the established prognostic factors such as clinical stage (cT), high grade ureteroscopic (URS) biopsy, and positive urine cytology, another subset of factors may play an important role in predicting the need for LND, such as lymphovascular invasion (LVI), hydronephrosis, length of the ureteral tumor, tumor location, glomerular filtration rate (GFR), and neutrophil counts [1,2,6,7,8,9]. Recent efforts to combine imaging and ureteroscopic variables to accurately identify ≥ pT2 disease have been made. The integration of these factors in predictive tools or models is gaining acceptance to guide decision-making for personalized care delivery [2].Because of the difficulty in accurately choosing patients for LND in clinically node-negative UTUC, it has been recommended that a LND should be performed in all patients [10]. We are convinced that there is a subset of patients with UTUC that will benefit from this staging procedure and another subset of patients for whom LND can be safely omitted, avoiding surgery-related complications. The aim of this article is to present a detailed revision on preoperative predictors for muscle-invasive or locally advanced UTUC, as well as analyzing current indications, technique variations, and the reasons why a LND should be offered to these patients.We included any kind of study related to information concerning UTUC, nephroureterectomy, LND, risk factors for recurrence, prediction tools, and prediction models for risk stratification. We included reviews, systematic reviews, and primary studies. The literature search was conducted in accordance with the use of medical subject headings (MeSh), Emtree language, Decs, and text words related. We searched through MEDLINE (OVID), EMBASE (Scopus), LILACS, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to May 2021. To ensure literature saturation, we scanned references from relevant articles identified through the search, conferences, thesis databases, Open Grey, Google scholar, and clinicaltrials.gov. We contacted authors by e-mail when there was missing information.A grey literature search was also performed on the pages of The National Technical Information Service (NTIS) and the European Association for Grey Literature Exploitation (EAGLE); however, no additional relevant information was found.The search criteria were established in the form of free text and indexed terms. To characterize UTUC, we used the free terms: “upper tract urothelial carcinoma”, “renal pelvis”, “transitional cell carcinoma”, “ureteral carcinoma”, “prediction tools”, “prediction models”, “retroperitoneal lymph node dissection”, “muscle invasive”, “UTUC muscle-invasive”, and we used the following MeSH terms “Lymph node dissection”, “Transitional cell carcinoma”, “Ureteral neoplasm”, “Renal pelvis”, “Local neoplasm recurrence”. The search was limited to publications in the last 10 years, and we used the following search strategy: “Lymph Node Excision” [Mesh] AND “Carcinoma, Transitional Cell” [Mesh] AND “Ureteral Neoplasms” [Mesh] AND “Kidney Pelvis” [Mesh].Four researchers reviewed each reference by title and abstract. Then, we scanned full texts of relevant studies. We included papers reporting data on predictive factors or models for muscle-invasive UTUC, and studies reporting on LND limited to UTUC. We excluded studies that did not fulfill the abovementioned criteria and that were written in a language different from English. Duplicate studies were removed. Evidence acquisition is presented according to the PRISMA diagram (Figure 1).Preoperative risk factors for either muscle-invasive UTUC (≥pT2), extra urothelial recurrence (EUR), locally advanced disease, or high-risk UTUC have been described [1,2,3,5,8,9]. These factors can either be derived from URS findings, cytology, URS biopsy, or from preoperative radiographic findings. Most of these tests are included in routine preoperative evaluation for suspected UTUC.Discordance between URS biopsy and final surgical pathology is high, and the major challenge is that the use of small caliber biopsy forceps or baskets normally yields small fragments of tissue, which increase the difficulty of accurately establishing tumor clinical grade and stage. Clinical staging by radiographic characteristics has its limitations; it can be difficult to predict tumor stage in UTUC, mainly because of different tumor locations and characteristics. Prior research showed that cross-sectional imaging has an accuracy of only 52%, tending to overstage most patients, especially when hydronephrosis was present, which was found in 80% of overstaged cases [11].Margolin et al. [12] evaluated 314 patients with UTUC who had undergone URS biopsy and subsequently RNU to determine pathology discordance. They reported that on URS biopsy, 61% had cHG tumors and 21% had subepithelial connective tissue invasion (cT1+). As expected in RNU pathology, 79% had pHG tumors and 45% had stage ≥pT2. Urine cytology was collected and analyzed in 230 cases, and it was positive only in 37% of the cases. The probability of missing invasion (cT1+) when URS was performed was significantly increased when biopsy fragments were ≤1 mm, and using forceps was associated with a higher likelihood of identifying smaller fragments. Only three preoperative factors for ≥pT2 UTUC were statistically significant in multivariate analysis: cHG (OR 2.4, 95% CI 1.1–5.2, p = 0.04), cT1+ (OR 9.0, 95% CI 3.2–25.6, p < 0.001), and advanced age (OR 1.0, 95% CI 1.0–1.1, p = 0.02). cHG combined with cT1+ reached a positive predictive value (PPV) of 86% [12].Few studies have assessed predictors of recurrence in ureteral carcinoma [5]. Ito et al. conducted a retrospective study including 70 patients, and they found that 30% developed EUR, and 66% in regional lymph nodes [5]. EUR-free survival was significantly worse in patients with ≥pT3 disease (HR 7.69), length of ureteral cancer along the ureter ≥ 3 cm (HR 3.90), positive cytology (HR 4.90), eGFR < 60 mL/min/1.73 m2 (HR 6.57), maximal diameter of ureteral cancer ≥ 1.6 cm, and neurophil-to-lymphocyte ratio (NLR) > 3.0. They stratified patients into three risk groups, according to the number of risk factors present (0, 1–2, and ≥3), a 3-year EUR-free survival of 100%, 81.4%, and 25.1% was found according to the aforementioned risk groups, respectively. One of the main limitations of this study was that not all patients underwent LND, they did not use a template-based LND, and adjuvant chemotherapy was administered to patients with ≥pT2 disease, which could have altered the rate of EUR [5].Optimal preoperative radiographic staging is required to appropriately tailor surgical treatment for individual patients. Hydronephrosis on preoperative axial computed tomography (CT) has been associated with features of high-risk UTUC and is a good predictor of advanced stage (≥pT2) for both, renal pelvis and ureteral tumors [8].Messer J. et al., in a study of 469 patients, evaluated whether ipsilateral hydronephrosis was a reliable predictor of advanced pathological stage—55% had preoperative ipsilateral hydronephrosis. At final pathology revision, 47% had ≥pT2 disease, 36% non-organ-confined disease (≥pT3 and/or pathological positive nodes (pN+)) and 73% had high grade UTUC. Hydronephrosis was a statistically significant predictor of ≥pT2 disease (HR 7.4, p < 0.001), ≥pT3, pN+ (HR 5.5, p < 0.001), and pHG (HR 1.6, p < 0.03) [8]. The conclusion was that the simplest radiographic predictive factor to determine muscle-invasive, non-organ confined disease or pHG was hydronephrosis [8]. These findings are in contrast to a previous study, in which hydronephrosis tended to overstage 80% of the tumors [11]. This study was conducted between 1984 and 1995 and included 31 patients. The technological improvements in the cross-sectional imaging techniques in the upcoming years, as well as the limited number of patients, might explain the contradictory findings regarding Messer’s et al. study.Attempts at combining radiographic characteristics with URS biopsy and urine cytology have been made in order to improve prediction of ≥pT2 stage UTUC. Brien et al. reported a study of 172 patients, 54% with ipsilateral hydronephrosis, 43% with cHG on URS biopsy, and 80% with a positive cytology. On multivariate analysis, ipsilateral hydronephrosis was a significant predictor of pT2 (HR 12.0, p < 0.001), non-organ confined (HR 5.2, p < 0.001), and high grade (HR 2.3, p = 0.04). Positive cytology was a predictor of non-organ confined UTUC (HR 3.1, p = 0.035) instead of pT2 or pHG. URS biopsy grade was associated with pT2 (HR 4.5, p < 0.001), non-organ confined (HR 3.9, p < 0.001), and pHG (HR 25.9, p < 0.001) [9]. When combining all three variables into a single model (hydronephrosis, cHG, and positive cytology), they found 89% PPV for pT2 stage and 73% for non-organ confined UTUC. A negative predictive value (NPV) of 100% was reported when all three variables were normal [9].Chen XP et al. analyzed data of 729 patients. They found in multivariate analysis that male gender (hazard ratio (HR 1.898, p = 0.001), sessile architecture (HR 3.249, p < 0.001), cHG (HR 5.007, p < 0.001), ipsilateral hydronephrosis (HR 4.768, p < 0.001), renal pelvis UTUC (HR 2.620, p < 0.001), and no multifocality (HR 1.639, p = 0.028) were significant predictors for muscle-invasive UTUC [1]. The reported accuracy was 79% for both pT2 stage and non-organ confined UTUC.Favaretto et al. aimed to create a preoperative model to identify patients at risk of ≥pT2 stage and non-organ confined UTUC. They retrospectively analyzed data from 274 patients treated with RNU. Overall, 49% had ≥pT2 stage and 30% had non-organ confined UTUC at final pathology. In the univariate analysis, local invasion in imaging (defined as renal sinus fat or periureteric fat) (p < 0.001), hydronephrosis (p = 0.011), and URS biopsy cHG tumors were all significantly associated with increased risk of ≥pT2 stage, and all variables, with the exception of hydronephrosis, were also significantly associated with non-organ confined UTUC. Tumor location and hydronephrosis were not significant predictors of ≥pT2 stage or non-organ confined UTUC at the multivariable models (p = 0.6 and p = 0.7), (p = 0.065 and p = 0.4), respectively. However, cHG (p = 0,04 and p = 0,005) and local invasion on imaging (p = 0.017 and p = 0.001) were both significantly associated with ≥pT2 stage and non-organ confined UTUC. The accuracy to predict ≥pT2 and non-organ confined UTUC was 71% and 70%, respectively [2].LN metastases in UTUC are common, with a reported incidence of up to 30–40% [13,14,15,16,17]. LN dissemination typically precedes the identification of visceral metastases [13,14,15,18]. It seems reasonable that LND may provide not only staging and prognostic information, but also plays a therapeutic role in selected UTUC patients [14,16,17]. It is clear that pN+ patients have a significantly worse prognosis when compared to pN0 patients [13,14,15,16,17]. Therefore, control of nodal metastases is an important milestone in the treatment of this disease.Nodal status has been thought to be a significant predictor of CSS in UTUC. Roscigno et al. examined data of 1130 patients treated with RNU and LND. Overall, they found that 5-year CSS was lower in patients with pN+ compared with pNX (35% vs. 69%, p < 0.001), and in pNx vs. pN0 (69% vs. 77%, p = 0.024). In a sub-analysis of patients with pT2-4 disease, CSS rates were lowest in pN+ followed by pNx and pN0 (33% vs. 58% vs. 70%, p < 0.017). These findings suggest that pNx was significantly associated with worse prognosis than pN0 in pT2-4 UTUC, which corroborates the suggestion that patients expected to have pT2-4 disease should undergo LND [17].In a recent meta-analysis, LND failed to show a statistically significant effect on CSS (HR 1.17, 95% CI: 0.93–1.48, p = 0.18). Patients with pN0 did not have a better CSS compared with those with pNx (HR 0.99, 95% CI: 0.81–1.22, p = 0.95); as expected, significant heterogeneity (I2 = 94%, Chi2 = 35.97, p < 0.00001) was found. LND had no association with better recurrence free survival (RFS), the pooled HR for RFS was 1.33 (95% CI: 0.87–2.06, p = 0.19) [16]. These findings are in contrast with a systematic review by the European Association of Urology Guidelines Panel on non–muscle-invasive bladder cancer, evaluating the potential benefit of LND during RNU for UTUC [15]. Dominguez-Escrig et al. demonstrated a survival benefit with LND in ≥pT2 disease of the renal pelvis [15].A recent population-based analysis of trends in LND for UTUC, using the surveillance epidemiology and end results (SEER) database, showed a significant increase in LND rates at the time of RNU from 20% in 2004 to 33% in 2012, and a tendency towards improved 5-year CSS was observed in the highest quartile of LNs harvested [19]. One of the main concerns of LND in UTUC is that there is huge variation in surgical practices, even at the same institutions. Strategies for standardizing the procedure, selecting the appropriate candidates, and adopting surgical adequacy parameters are required in order to improve oncological outcomes.As previously reported, the patients who benefit the most from LND appear to be those with ≥pT2 disease. Abe et al. suggested that the incidence of LN involvement is 1.9%, 4.5%, 8.9%, 28.7% and 70.1% for pTa, pT1, pT2, pT3, and pT4, respectively [20]. Miyao et al. reported slightly higher rates of LN metastasis in cT1 (13.3%) [20].In patients with node-negative disease (cN0), Kondo et al. reported that 42.5% of tumors ≤cT1 are upstaged to a clinical stage ≥pT2 and would lose the benefit of LND, if LND is omitted at the time of RNU. The latter makes it difficult to trust conventional staging to select candidates for LND based only on clinical stage [20]. Therefore, many experts in the field, as well as EAU clinical practice guidelines recommended LND in all patients who undergo RNU, except for those with severe comorbidities.Lughezzani et al. performed a population-based analysis using the SEER database, including 2824 patients treated with RNU between 1988 and 2004. They reported a 5-year CSS of 81.2% for pN0 and 77.8% for pNx. No association was found between pNx and pN0 status with CSS using univariable and multivariate analysis [13]. These findings suggest that there is no survival benefit related to the performance of LND in UTUC [13]. However, Brausi et al., in a retrospective study including 82 patients with ≥pT2 UTUC, compared patients who underwent LND versus those who did not, in terms of oncological outcomes. A total of 40 patients (48.8%) underwent LND. Of the patients who underwent LND, 40% were pN+ and 60% were pN0. The group of patients that did not undergo LND were classified as pNX and 54% of these patients developed recurrences or progressed. RFS and CSS rates were 64.3% and 81.6% in patients treated with LND, respectively, and alarmingly, in the group of patients in which LND was not performed, RFS and CSS rates were 46.3% and 44.8%, showing a significant benefit of LND in ≥pT2 disease (RFS, p = 0.03; CSS, p = 0.007) [21].The major pitfall of LND decision-making is that it remains difficult to reliably identify patients with ≥pT2 disease before RNU. Many experts continue to recommend performing LND in all patients treated with RNU if accurate staging is desired. However, this approach could lead to overtreating some patients [11,12,13,14,15,16]. We believe that all patients with suspicion of ≥pT2 disease must undergo LND at the same time of RNU, regardless of the surgical approach (laparoscopic, robotic or open). For patients with no clear landmarks of muscle-invasive or locally advanced disease, we recommend using the following predictive models or predictive variables that have shown significant predictive capabilities for ≥pT2 disease:-Ipsilateral hydronephrosis + cHG + positive urine cytology (The three variables combined have 89% PPV and 100% NPV) [9] (Figure 2)-cHG + cT1 at URS biopsy (PPV 86%) [12]-Sessile architecture, cHG, ipsilateral hydronephrosis, renal pelvis UTUC, and no multifocality (79% accuracy) [1] (Figure 2)-Local invasion on imaging (renal sinus fat or periureteric invasion), ipsilateral hydronephrosis, and cHG (71% accuracy) [2] (Figure 2)Ipsilateral hydronephrosis + cHG + positive urine cytology (The three variables combined have 89% PPV and 100% NPV) [9] (Figure 2)cHG + cT1 at URS biopsy (PPV 86%) [12]Sessile architecture, cHG, ipsilateral hydronephrosis, renal pelvis UTUC, and no multifocality (79% accuracy) [1] (Figure 2)Local invasion on imaging (renal sinus fat or periureteric invasion), ipsilateral hydronephrosis, and cHG (71% accuracy) [2] (Figure 2)We recommend performing LND at the time of RNU if a patient has muscle-invasive disease or in a patient with any of the following characteristics: ipsilateral hydronephrosis, cHG, cT1 at URS biopsy or radiographic signs of renal sinus fat or periureteric fat invasion. If any of the variables are present at preoperative evaluation, the risk of losing the potential benefit of LND is too high; therefore, all these patients should undergo LND.UTUC has characteristic patterns of lymphatic spread that are dependent on tumor laterality and anatomical location. Adopting LND templates based on tumor location and laterality is critical to improve LN yield, survival outcomes, and to avoid under staging or overtreatment. Kondo et al. reported a detailed anatomical mapping study of regional LNs in patients with pN+ UTUC. This study showed that right-sided renal pelvis, proximal and mid ureteral tumors encompassed a wider area for nodal dissemination than previously thought, including the renal hilum, paracaval, retrocaval, and interaortocaval regions. Left-sided renal pelvis, proximal, and mid ureteral tumors always metastasized to para-aortic and left renal hilum nodes and distal ureteral tumors, regardless of the laterality metastasized to intrapelvic LNs [10] (Figure 3).Matin et al. conducted a retrospective multicentric study including 73 patients with non-metastatic pN+ UTUC to determine the patterns of lymphatic metastases and aiming to propose consolidated templates for LND. They reported that right-sided renal pelvis tumors had LN metastases to the hilum, paracaval, retrocaval and interaortocaval regions in 22.1%, 44.1%, 10.3%, and 20.6% of cases, respectively. Left-sided renal pelvis tumors metastasized to the hilum in 53% of the cases, with paraaortic, interaortocaval, common iliac, and aortic bifurcation in 31%, 4%, 1%, and 1%, respectively. The right-sided proximal ureteral tumors had lymph node metastases to the hilum in 46.2% of cases, and to paracaval and retrocaval regions in 46.2% and 7.7%, respectively. In a similar fashion, in the left-sided proximal ureteral tumors, LN metastases were found in 36.4% of hilar nodes and 63.6% of paraaortic nodes. The four patients with distal ureter tumors had LN metastases to the para-aortic, common iliac, external iliac, and internal iliac stations in 33.3%, 33.3%, 16.7%, and 16.7% of cases, respectively [18] (Figure 3).Template-based regional LND plays an important role in reducing locoregional recurrence in patients with cN0 UTUC, as shown by Matsumoto et al. [22]. They evaluated 105 patients with cTa-3N0M0 UTUC who were treated with regional LND during laparoscopic RNU, using the anatomical-based templates proposed by Abe et al. [22]. In renal pelvis or proximal ureteral tumors (considered above as the crossing of the common iliac artery), renal hilar, paracaval, retrocaval, and interaortocaval LNs were removed if the tumor was located on the right side, and if it was a left-sided tumor, renal hilar and para-aortic lymph nodes were harvested. In patients with tumors of the distal ureter, ipsilateral obturator and common, external, and internal iliac nodes were harvested. The median number of LN harvested was 12, and seven patients (6.7%) had LN metastases on hematoxylin-eosin. Immunohistochemistry (IHC) revealed micrometastases in five additional patients. One of the highlights of this paper is that of the seven pN+ patients, 71% developed distant organ or nodal metastases, and of the five pN+ micrometastatic patients, only one (20%) developed distant metastases, suggesting that regional LND could promote local disease control by eliminating micrometastasis in patients previously thought to be cN(−). Five-year CSS was 95% for pN0, 53.3% for pN+ (Detected with IHC), and 23.8% for pN+ [22]. These data support the use of an anatomical template-based LND for UTUC and confirms that CSS is determined by nodal status and that LND could play an important role improving survival [22].Kondo et al. also suggested a potential benefit of template-based LND, and they demonstrated that UTUC patients in which LND was performed had better CSS than those who did not undergo LND or had a suboptimal LND (p = 0.06). This benefit was even better in patients with ≥pT3 disease (p = 0.01). CSS was likely to improve when the number of lymph nodes removed increased, especially when seven or more nodes were harvested [23].Rao et al. proposed a modified LND template. In patients with right-sided UTUC, the template included hilar, paracaval, and right pelvic LNs. In patients with left-sided UTUC, the template included perihilar, para-aortic, and left pelvic LNs. The mean LNY was seven. None of the patients died, 85% of them were disease free, and 10% had evidence of metastatic disease. The morbidity of the LND was acceptable, mostly with minor complications (Clavien grades I and II) [24].We recommend performing anatomical template-based LND according to tumor laterality and location. It certainly has been shown not only to improve the LNY but also avoids over-dissecting areas in which lymphatic spread does not occur. We used the anatomical-based templates proposed by Abe et al. (Figure 3). We believe with these templates, all the regions in which LN metastasis could be found are dissected and the nodes are removed. One question that remains unanswered is: should we offer LND after RNU when LND was not performed initially? We consider this to be a difficult question that may have more than one correct answer. If we are trying to improve CSS in patients with ≥pT2 UTUC, we should offer LND after RNU, a thorough discussion of the potential risks and side effects with the patient is mandatory, before making the decision. On the other hand, some experts could argue that with the results of the POUT trial, all patients staged as pT2–T4 pN0 may benefit from cisplatin or carboplatin-based adjuvant chemotherapy, and that LND at a second stage could be avoided [24].The number of lymph nodes removed has significant prognostic value for many malignancies, including UTUC [25]. A higher lymph node yield (LNY) is significantly associated not only with finding positive nodes but also increasing the probability of finding multiple positive nodes. Surgeon volume is the most important factor to account for LNY, and open surgery has been proposed as another factor increasing LNY. Thompson et al. in a study of 124 patients treated with RPLND for testicular cancer, reported a mean total node count of 51, and mean node counts for the paracaval, interaortocaval, and paraaortic regions of 8, 17, and 26 nodes, respectively. They concluded that these results should provide a benchmark for surgical adequacy, even in UTUC. For example, if a paracaval LND is performed, at least eight lymph nodes on average should be counted, and if a paraaortic LND is performed for a left tumor, 26 lymph nodes on average should be harvested [25]. These findings are important, although it is quite difficult to extrapolate parameters for surgical adequacy from testicular cancer to UTUC, given that the two are very different diseases, with different landing pathways and zones in the retroperitoneal LNs.Roscigno et al. in a multicentric study including 551 patients with UTUC, examined the minimal number of LNs that needed to be harvested to certainly detect LN involvement. They reported that a total of 13 LNs needed to be harvested in order to achieve a 90% probability of detecting metastases, and the removal of eight or more LNs was associated with a 75% probability of detecting one or more positive node [17]. The same author found that the LNY was not associated with CSM in univariable (HR 0.99; p = 0.16) or in multivariable (HR 0.97; p = 0.12) analyses. However, in the subgroup of pN0 patients, LNY achieved the independent predictor status of CSM (HR 0.93; p = 0.02). They concluded that a LNY of eight or more was the best variable predicting CSM (HR: 0.42; p = 0.004) [26]. With the small amount of evidence on this specific topic, and the very well conducted and designed studies by Roscigno et al. [17,26], we used the LNY of eight or more LNs as a parameter of surgical adequacy in our clinical practice, until novel and better evidence become available. Despite the importance of this parameter, for now, we cannot use them to make any clinical decisions.Abe et al. found no significant correlation between the LNY and CSS, in a retrospective study including 166 patients that underwent LND for UTUC. The median LNY was six nodes, and when specifically comparing between the 72 patients with <6 LNs removed and the 78 with ≥6 nodes, no significant difference in CSS were found p = 0.216. These findings were maintained even after re-categorizing as 6–10 harvested nodes and ≥11 nodes. A limitation of this study is that they did not use a standardized template for LND [27].A LNY of at least eight LNs has been shown to predict cancer specific mortality and to increase the probability of detecting LN metastases, therefore, arbitrarily in our clinical practice, we have established a threshold of eight or more nodes, as a surrogate of surgical adequacy in LND for UTUC. However, because of the different lymphatic landing pathways, according to tumor location or laterality, and because the templates may vary according to these factors, it is not prudent to set a definitive threshold for this disease.A useful parameter to predict the risk of recurrence and CSM that has been assessed in many tumors is lymph node density. Defined as the total of positive nodes, divided by the total of harvested nodes, expressed in a percentage. Bolenz et al. suggested that LN density could aid in risk stratification of patients with pN+ UTUC. They conducted a multicentric study including a total of 135 patients with an alarming 4-year recurrence rate of 68% and CSM of 58%. The best LN density threshold to predict recurrence or CSM was ≥30%, with 5-year recurrence and mortality rates of 38% and 48%, respectively. Compared to 25% and 30% when LN density was <30% [28].Lymph node density for UTUC has only been reported in the MSKCC study, with a proposed threshold of ≥30%, to accurately predict RFS and CSM. At the moment, the only clinical application of using this parameter is to counsel patients. With the recently published POUT trial, all patients staged as pT2–T4 pN0N3 M0 or pTany N1–3 M0, regardless of their LNY or lymph node density, should be offered cisplatin-based chemotherapy or carboplatin in patients unfit for cisplatin within 90 days of surgery [29]. Additionally, the same applies to the most recent study Checkmate 274, in which all patients with urothelial carcinoma (including renal pelvis and ureter) staged as pT3-4, R0, and/or pN+ not eligible for or declined adjuvant chemotherapy, should be offered nivolumab within 120 days of surgery, every 2 weeks for up to 1 year, with a 30% absolute improvement in disease free survival or death [30].Patients with muscle-invasive or non-organ-confined UTUC have an extremely high risk for disease recurrence and CSM. Preoperative factors and prediction models must be included in the UTUC management pathway to improve accurate determination of ≥pT2 patients that would benefit from LND. In our own practice, we perform LND in patients with ipsilateral hydronephrosis, cHG, cT1 at URS biopsy, and renal sinus fat or periureteric fat invasion. The role of lymphadenectomy in conjunction with RNU is still controversial, given that it may result in overtreatment of patients with pTa-pT1 tumors. However, a clear benefit in terms of RFS and CSS has been shown in patients with ≥pT2. Experts’ opinions and clinical practice guidelines recommend that all patients undergoing RNU should be offer regional LND at the same time, which optimally should be carried out following template-based anatomical dissections, aiming to harvest the highest possible amount of LNs. Despite the aforementioned recommendation, we still try to avoid LND in patients with cLG, cTa, no ipsilateral hydronephrosis, and no other URS or radiographic signs of non-organ confined disease or muscle-invasive disease, if the patient is expected to be compliant with the follow up schedule. There is still plenty of work to do in this area, and new molecular and non-invasive tests are necessary to improve risk stratification and avoid undertreatment or overtreatment.Conceptualization, J.C. and J.E.; methodology, J.S., J.C. and C.M.; software, L.M.; validation, G.R., C.M., J.C. and J.E. formal analysis, J.C. and C.M.; investigation, J.C. and C.M.; resources, J.E.; data curation, J.C., G.R. and J.S.; writing—original draft preparation, J.C.; writing—review and editing, C.M.; visualization, G.R., C.M., J.C., J.E., J.S. and L.M.; supervision, C.M. and J.C.; project ad-ministration, J.C.; All authors have read and agreed to the published version of the manuscript.This research received no external funding.Not applicable.Written informed consent has been obtained from the patients to publish this paper.The authors declare no conflict of interest.Evidence acquisition according to the PRISMA diagram.Predictive factors for ≥pT2 UTUC. (A) Hematoxylin-eosin 20× cHG transitional cell carcinoma, diagnosed with URS biopsy of a renal pelvis tumor. (B) Positive urinary cytology (in this case HG). (C) Local invasion of UTUC (periureteric fat extension). (D) Right hydronephrosis secondary to proximal ureteral transitional cell carcinoma.Regional LND templates for anatomical LND in UTUC. (A) Blue template for a renal pelvis or proximal or mid ureteral right-sided UTUC. Green template for distal or mid ureteral right-sided UTUC. (B) Yellow template for a renal pelvis or proximal or mid ureteral left-sided UTUC. Purple template for distal or mid ureteral left-sided UTUC.Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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+Dear esteemed researchers and colleagues,It is a great pleasure for me to announce a new journal in the field of urology: Uro, published by the MDPI group.Staying up to date is a necessity in the era of rapid technical innovation, as novel concepts are being constantly introduced into clinical practice from bench research. It is important to stay competitive and to offer patients the best and most innovative clinical approaches. At the same time, all physicians are required to keep in mind the concept of patient-centered medicine.We are, therefore, moving between the impressive acceleration of technical and pharmaceutical innovations and the patients’ desire for a tailored approach and personalized medicine.On the basis of these considerations, an easily accessible source of information is urgently required. From this perspective, Uro makes its first appearance in the world of urological and andrological journals. With great enthusiasm, the Uro editorial board is currently forming to take care of the real needs of researchers and clinically based physicians. We are working with the aim of giving readers a new, easily accessible journal that provides information on the real necessities of everyday clinical practice. In the coming months, a new modality of keeping up to date will be available in Uro.Keep up to date or perish! That’s our motto!Uro is taking its first steps, keeping in mind that translational medicine is the bridge between the pre-clinical “world” and everyday clinical practice. The final “core” aspect of Uro is the multidisciplinary approach to “border diseases”. Gynecologists, endocrinologists, surgeons, and infectious diseases specialists are some of the most common physicians involved in the management of urological patients. The multidisciplinary approach is a key component in everyday clinical practice and, moreover, in the improvement of our knowledge. In line with this aim, and to fully cover any aspect of the modern multidisciplinary approach to urological and andrological diseases, a large group of experts from many different backgrounds is enrolling for the Uro mission. Together and with the pivotal help of authors and reviewers, we aim to make the Uro a high-quality and easily accessible tool for all physicians and researchers involved in the management of patients affected by urological diseases. We hope that you will consider Uro as your privileged partner in everyday clinical practice and a source of up-to-date information and news. The author declares no conflict of interest.

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+This study was undertaken to compare Fuhrman grading with World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading and stereologically measured nuclear area in patients with Clear Cell Renal Cell Carcinoma (ccRCC) or Papillary Renal Cell Carcinoma (PRCC) and to evaluate the independent predictive value of Fuhrman, WHO/ISUP and stereologically measured nuclear area combined with necrosis in a series of patients with ccRCC in relation to cancer-specific survival. In all, 124 cases of ccRCC and PRCC were included. All slides were blindly scored by two trained pathologists according to the Fuhrman and WHO/ISUP grading systems. Nuclear measurements were performed on digitally scanned slides in Visiopharm® and correlated to survival. Analysis of ccRCC and PRCC cases showed that application of WHO/ISUP grading resulted in a significant downgrading of cases from G2 to G1, when comparing with Fuhrman grading. Neither of these patients experienced progression. Cancer specific survival estimates in 101 ccRCC patients showed that WHO/ISUP grading was slightly superior in predicting cancer-specific survival. Novel models included WHO/ISUP grading and mean nuclear area (MNA) each of which combined with necrosis. Both demonstrated an increased ability to predict cancer-specific survival. The study demonstrates that WHO/ISUP grading provides superior prognostic information compared to Fuhrman grading and stereologically measured nuclear area. Necrosis in combination with either WHO/ISUP grading or MNA adds additional prognostic information.Renal cell carcinoma (RCC) is a neoplasm with widely varying prognosis, from an aggressive neoplasm, with metastasis at presentation, to a slowly growing neoplasm that can be observed safely for years [1]. The overall 5-year progression-free survival rate is 70% and the cancer-specific mortality rate is 24% [2]. Numerous different prognostic markers have been investigated. However, only morphological features such as tumor size, vascular invasion, necrosis, stage and grade are routinely utilized in an effort to predict outcome [3,4].A variety of grading systems have been proposed that focuses on nuclear morphology. Of these, that of Fuhrman et al. [5], published in 1982, has achieved widespread use throughout the world in clinical routine pathology. It is a 4-tiered grading system, which is based primarily on the simultaneous assessment of nucleolar prominence, nuclear size, and nuclear irregularity. The first three grades are defined on nuclear features and the fourth grade is defined by the presence of nuclear pleomorphism, Table 1. Despite widespread usage of the Fuhrman grading system, it has become apparent that the system has a number of inherent problems, in particular those related to poor reproducibility [6,7]. At the ISUP consensus conference, a novel grading system was proposed, based on nucleolar prominence [8], Table 1. The ISUP grading system was later endorsed by the World Health Organization (WHO) and renamed as the WHO/ISUP grading system [9] with few modifications, but that the staining quality of the nucleolus should also be encompassed. The WHO/ISUP grading system should be applied to Clear Cell RCC (ccRCC) and Papillary RCC (PRCC). However, Chromophobe RCC (ChRCC) should not be graded, since neither Fuhrman or WHO/ISUP are appropriate for grading of this tumor subtype [10]. The WHO/ISUP grading system has achieved widespread usage and has now replaced the Fuhrman grading system worldwide [11].Tumor necrosis is another factor that has shown prognostic significance in several studies [4,12,13]. It occurs frequently in RCC and appears to be dependent on the histological subtype, with the highest occurrence in PRCC (32%–40%) and ccRCC (27%–32%) [4,14,15]. Delahunt et al. [4] recently proposed a modification of the current WHO/ISUP grading system incorporating tumor necrosis, Table 1. In this study, a significant difference in survival between each grade for ccRCC was demonstrated, in addition to a superior concordance index compared to ISUP grading. The ISUP Vancouver Consensus Conference on Renal Cell Carcinoma recommended to routinely include the presence or absence of tumor necrosis [8]. However, necrosis has not yet been implemented in any of the grading systems. The ability to study nuclear morphometry quantitatively is made possible by advances in computer imaging technology. Issues with lack of reproducibility, different grading systems and the subjectivity that always belongs to histological grading systems might be avoided by using a more reproducible method to assess nuclear features and thereby predicting prognosis [16,17]. Hence, it is important to acknowledge the necessity of validation of the novel grading systems in different populations, and to the best of our knowledge, only few validation studies have been performed until now [18,19]. Furthermore, with the introduction of digital pathology in many countries, it seems relevant to investigate, how stereologically assessed nuclear morphometry correlates to the different grading systems.The objectives of our study were twofold: 1) to assess interobserver reliability and agreement using the Fuhrman nuclear grading system and the WHO/ISUP grading system for ccRCC and PRCC and to correlate gradings with nuclear morphometry; 2) To evaluate the independent predictive value of Fuhrman, WHO/ISUP and stereologically measured nuclear area in relation to cancer-specific survival in patients with ccRCC and to validate novel proposed models for grading incorporating tumor necrosis.Patients nephrectomized at our institution between 2001 and 2012, who gave written informed consent and were diagnosed with PRCC or ccRCC, were included in the study. None of the patients received neo-adjuvant therapy. Files of all patients were reviewed and data regarding pathological parameters, sex, age at diagnosis and data regarding follow-up and death were obtained retrospectively. Date and cause of death were obtained from the Cause of Death Register, Denmark. The Danish Ethics Committee (permit No. S-VF.20010035, notification No. 29573) approved the experimental protocol and the study was reported to the Danish Data Protection Agency (permit No. 2008-58-0035). Paraffin-embedded tumors were sectioned and stained with hematoxylin-eosin (HE). Two pathologists reviewed independently and were blinded to all tumor slides with regard to the assessment of Fuhrman grade, WHO/ISUP grade, microscopic necrosis and subtype. Grading followed criteria listed in Table 1. Necrosis was reported, when well-demarcated foci of necrosis within tumor was observed.All slides were scanned for evaluation using a digital slide scanner, NanoZoomer 2.0-HT (Hamamatsu, Japan). Visiopharm newCAST Whole Slide Sterology software (Visiopharm, Hørsholm, Denmark) was used for calculation of nuclear area. Tumor areas were manually drawn as region-of-interest (ROI) and sample images from these were collected randomly using meander fraction-based sampling at 20 times magnification. In these images, nuclei area was calculated using the nucleator function (Figure S1).Mean nuclear area (MNA) in all sampled nuclei and mean nuclear area in the 10 largest measured nuclei (MNA-10) was calculated for each patient together with standard deviation and the number of measured nuclei in each sample. Comparisons of nuclear area across patients and pathological characteristics were performed using Student’s t-test or one-way ANOVA followed by Bonferroni’s multiple comparisons test. Correlation analysis was performed with Spearman’s rank correlation.Cancer specific survival was calculated from the date of diagnosis by imaging to the date of death from RCC or to last follow-up contact. Patients alive at the end of the follow-up, who did not experience progression during the study period, where censored at the date of last follow-up. A receiver-operating-characteristic (ROC) curve was generated for MNA and the optimal cutoff point was selected according to the point of the ROC curve closest to the top-left corner of the ROC plot. Cancer-specific survival was estimated using the Kaplan-Meier method and differences in survival among groups were calculated using log rank tests. Two novel grading systems were evaluated, one based on the 4-tiered grading classification proposed by Delahunt et al. [4], incorporating tumor necrosis in the existing WHO/ISUP grading system, the other based on dichotomization of MNA incorporating tumor necrosis.The ability of the prognostic models to predict death from RCC was evaluated by the area under a ROC curve and the c-index (Harell´s C) [20,21].The κ statistics, a measurement of reliability between observers that corrects for chance agreement, was used to evaluate the interobserver reproducibility in grading of ccRCC and PRCC between two pathologists. The maximum value for κ is 1.00, which indicates perfect agreement and 0 indicates the level of agreement expected by chance alone. Negative values indicate less than chance agreement. Agreement measures for categorical data according to Landis et al. [22] are as follows: Slight, 0.00–0.20; Fair, 0.21–0.40; Moderate, 0.41–0.60; Substantial, 0.61–0.80 and Almost Perfect, 0.81–1.00. Absolute agreement was assessed with proportions of agreement [23]. Two-sided p-values < 0.05 were considered significant. All analyses were done with STATA/SE 16.0 (StataCorp, College Station, TX, USA). The study comprised 124 patients with RCC, with either the papillary subtype 1 (n = 14), papillary subtype 2 (n = 9) or the clear cell subtype (n = 101). Table 2 presents clinicopathological data for all 124 patients included in the study and summarizes the statistical analysis for nuclear morphometry. The median follow-up was 40.6 months (range 0.9 to 136.3), during which a total of 52 (42%) patients died and 33 (27%) patients died from RCC. Forty patients (32%) experienced recurrence within follow-up with a median time to recurrence of 9.4 months. Of the 101 ccRCC patients, 35 patients (34.6%) experienced recurrence with a median time to recurrence of 9.4 months. Mean nuclei area (MNA) and mean nuclei area in the 10 largest nuclei (MNA-10) are listed in Table 2. The mean number of measured nuclei per tumor was 133 (range 13–287). Microscopic necrosis correlated with MNA (p < 0.0001) and MNA-10 (p < 0.0001), with a higher MNA and MNA-10 in patients with microscopic tumor necrosis. Neither pT stage, subtype, nor sex correlated with MNA or MNA-10. All patients were assigned a Fuhrman grade and a WHO/ISUP grade by two pathologists, blinded to clinical data. Detailed relationship between WHO/ISUP grading and Fuhrman grading is shown in Table 3 and Figure 1A. MNA and MNA-10 both correlated with Fuhrman grade and WHO/ISUP grade with a proportional increase in MNA and MNA-10 with higher grades of both Fuhrman and WHO/ISUP, Figure 1B,C. Correlation analysis revealed a significant correlation between MNA and Fuhrman as well as MNA and WHO/ISUP grade (p < 0.0001, r = 0.53 and p < 0.0001, r = 0.57, respectively).Comparison of WHO/ISUP and Fuhrman grades demonstrated a significant downgrading upon WHO/ISUP grading (p < 0.0001). In particular, only five patients were given the grade G1 (4%) according to Fuhrman grading, whereas 26 patients were graded G1 according to WHO/ISUP (21%). No significant difference in MNA was seen between the grades of Fuhrman and WHO/ISUP (Figure 1D). Interobserver κ-value for Fuhrman was 0.34, SE = 0.059 (Fair) and for WHO/ISUP 0.48, SE = 0.055 (Moderate). Interobserver κ-value for microscopic necrosis was 0.60, SE = 0.09 (Moderate). The proportion of agreement for Fuhrman grade and WHO/ISUP grade was 72.6% (95% CI: 63.8%–80.2%).Figure 2A depicts the receiver operating characteristic (ROC) curve characterizing the ability of MNA to predict death from RCC (Cancer Specific Survival), which was used to generate the optimal cut-point, as shown by the dashed vertical line in Figure 2B. The cut-off value of 35.75 μm2, as determined by the ROC curve, had a sensitivity of 93.9% and a specificity of 47.3% in predicting death from RCC.Kaplan–Meier survival curves for 101 cases with ccRCC morphology according to Fuhrman grading, WHO/ISUP grading and MNA are shown in Figure 3, Figure 4 and Figure 5. None of the patients with grade 1 tumors developed tumor recurrence or metastatic disease during the follow-up period, Figure 3 and Figure 4. The division of MNA into a two-tiered grading system could significantly separate patients with good or poor prognosis, Figure 5. However, in the good prognosis group, five patients experienced progression in disease.As demonstrated by the c-indexes, the WHO/ISUP grading system contained greater predictive ability compared with the Fuhrman grading system and the stereologically measured MNA (c- indexes of 0.74 versus 0.68 and 0.70, respectively), Table 4. Proposed novel grading models, incorporating necrosis with either MNA or WHO/ISUP, resulted in slightly greater predictive ability (c-indexes of 0.76 and 0.75, respectively). In this study, we investigated the prognostic significance of the Fuhrman grading system, the WHO/ISUP grading system, and the correlation of nuclear morphometry to clinical outcome together with two novel, modified grading systems in ccRCC. We demonstrated that the WHO/ISUP grading system is superior in predicting cancer-specific survival. Modified groups, combining either WHO/ISUP or MNA with necrosis, were only slightly superior to WHO/ISUP grading alone. Interobserver reliability calculated with kappa statistics was moderate for the WHO/ISUP grading system and fair for the Fuhrman grading system.The Fuhrman grading system was published in 1982 and the study behind has later been criticized for having major limitations, such as small number of patients, limited follow-up time, and no distinction between the different morphological subtypes of RCC. Yet, the Fuhrman grading system has achieved great popularity and is still used by many pathologists today [7]. Over the years, other issues have arisen when validation has been pursued, including poorly defined criteria for nuclear pleomorphism and difficulties in assessing nuclear diameter objectively. There is no recommendation of the relative importance of each of the parameters (nuclear diameter, nuclear shape, and nucleolar prominence) and no guidance on how to stratify between them, when contradictory results are obtained. Furthermore, lack of reproducibility within studies with reporting of significant variation in the distribution of the Fuhrman grades and variation in association to outcome are other important issues. Some studies suggest limited prognostic significance unless grades are combined for statistical analysis [24,25]. This has led pathologists to attempt to grade only on the basis of nucleolar prominence, which does not conform to the grading criteria of the Fuhrman system [6]. The WHO/ISUP system has now, to some extent, replaced the Fuhrman grading system. Only a few studies have validated the novel WHO/ISUP system in comparison to Fuhrman grading [13,18,19,26]. These studies demonstrated a superior predictive ability of the WHO/ISUP compared to the Fuhrman grading system. In our series, we showed that grade 1 tumors according to both the WHO/ISUP grading system and the Fuhrman grading system were associated with an excellent prognosis, with no cases showing cancer progression. There was a significant separation in outcome between grades 1 and 3 according to both grading systems. However, grade 2 showed overlap of survival curves and we could not demonstrate a clear separation by WHO/ISUP grading. This could indeed be due to a smaller case number and not reflect a true problem of the grading system, since other larger studies did not report this [18]. Dagher et al. demonstrated that grading according to the WHO/ISUP resulted in a relative downgrading of cases as compared with Fuhrman grading. This was explained by the criteria of the WHO/ISUP, which bases the first three grades on nucleolar features. We could demonstrate a similar downgrading of cases when applying the WHO/ISUP grading system. Since WHO/ISUP grading demonstrated a significant downgrading of cases from G2 to G1, of which none of these experienced recurrence or metastatic disease, it seems that this grading system is slightly better at separating the group with excellent prognosis from the intermediate group.In the present study, Fuhrman nuclear grading and WHO/ISUP grading was carried out by two observers. There was a fair agreement between them with a kappa value of 0.34 for Fuhrman nuclear grading and a moderate agreement with a kappa value of 0.48 for WHO/ISUP grading. Clearly, there is a subjectivity in nuclear grading, using either the Fuhrman grading system or the WHO/ISUP grading system, that might be avoided when replaced by quantitative morphometric approaches which evaluate nuclear features. There has been significant research investigating the usefulness of nuclear morphometry to provide information regarding prognosis in patients with RCC [16,27]. MNA has been considered to be one of the most valuable prognostic factors among several morphometric parameters. In the literature, the proposed cut point for dichotomization of patients with good and poor prognosis differs within a range of 32 to 39 µm, which could reflect a true difference, but could also be explained by differences in fixation times or preparation methods. Nevertheless, the identified cut point of MNA in our study is within this range. An isolated assessment of only one quantitative feature, such as nuclear area, may not suffice to describe nuclear abnormalities and the combination of several features may be required in order to give an accurate prediction of prognosis, as concluded by Montironi et al. [28]. Other suggested morphometric parameters are, among others, nuclear area index (NAI), nuclear perimeter, nuclear roundness factor, major and minor diameter, and nuclear form factor [17,27,29]. Stereological measurements of nuclear size are time- and labor-consuming when they, as in this case, are performed by applying the Nucleator function in Visiopharm. Whether the introduction of worldwide digital pathology makes such quantitation quicker and easier is not yet possible to establish. Our work has shown that both Fuhrman and WHO/ISUP grading correspond with increasing mean nuclear size (MNA). The objective, quantitative, and reproducible measurement of nuclear morphometry might be useful as a supplement to the histopathological grading, but the WHO/ISUP grading is significantly easier to applicate, less time-consuming, and provides a reasonable reliability. Another important issue is the prognostic significance of tumor-related necrosis, which has also been emphasized in many other studies [4,13,30]. However, there seems to be conflicting terminology to describe necrosis. Delahunt et al. describe RCC tumor necrosis as either thrombo-embolic infarction, resulting in tumor coagulative necrosis or as a specific form of necrosis or tumor-related necrosis [31]. Dagher et al., define tumor-associated necrosis as well-demarcated foci of necrosis within the tumor [12]. The ISUP Vancouver Consensus Conference on Renal Cell Carcinoma recommend that the presence or absence of macroscopic and microscopic necrosis should be routinely reported in pathology reports [8]. However, since tumors may be associated with two separate forms of necrosis and thereby two different pathogenic pathways leading to necrosis, confusion relating to how to report necrosis could arise. Unfortunately, none of the two reference groups recommend a methodology for interpreting the prognostic significance of these two types of necrosis [8,9] In this study, microscopic necrosis was reported in accordance with Dagher et al. [12]. Foci of hemorrhage, fibrosis, or hyalinization should not be encountered as tumor necrosis. The prognostic significance of tumor necrosis applies only to ccRCC and has not been demonstrated for the papillary RCC [9].It is important to acknowledge the limitations of this study. First, the results are based on a single-center retrospective study and must be verified in larger, prospective multi-center studies. Second, only the mean nuclear area was reported, and other nuclear features could be relevant to investigate. However, the strengths of our study include separation of renal cell carcinomas into subtypes, subjecting only ccRCC to prognostic evaluation, and inclusion of necrosis as a prognostic factor. In conclusion, our study did not demonstrate a clear separation of cancer-free survival curves between the four groups of either the WHO/ISUP system or Fuhrman grading. The WHO/ISUP grading system was slightly superior in predicting cancer-specific survival than the Fuhrman grading system and Mean Nuclear Area. Furthermore, a downgrading of cases from G2 to G1 according to WHO/ISUP in comparison with Fuhrman grading resulted in a separation of patients with an excellent prognosis. Combining necrosis with either the WHO/ISUP grading system or MNA enhanced the predictive ability. The following are available online at https://www.mdpi.com/2673-4397/1/1/2/s1, Figure S1: Illustration of the Nucleator function in Visiopharm, measuring the area of the nucleus in ccRCC.Conceptualization, N.M and M.R.; methodology, N.M. and M.R.; formal analysis, M.R. and O.G.; investigation, N.M, M.R., O.G., and B.E.; resources, N.M.; writing—original draft preparation, M.R.; visualization, M.R.; supervision, N.M., O.G., and B.E. All authors have read and agreed to the published version of the manuscript. This research received no external funding.The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of The Danish Ethics Comittee (permit No. S-VF.20010035, notification No. 29573, date of approval: 03.05.2011).Informed consent was obtained from all subjects involved in the study.The data presented in this study are available on request from the corresponding author. The data are not publicly available due to restrictions of privacy.The authors declare no conflict of interest.(A). Comparison of Fuhrman and WHO/ISUP grading systems in 124 patients with clear cell or papillary renal cell carcinoma. (B–D). Comparison of Fuhrman grade and WHO/ISUP grade with Mean Nuclear Area (MNA) and Mean Nuclear Area in the 10 largest nuclei (y-axis).(A) Receiver operating characteristics (ROC) curve characterizing the ability of the Mean Nuclei Area (MNA) to detect patients who die from RCC (CSS). The cut-off value of 35.75 μm2 had a sensitivity of 93.9% and a specificity of 47.3% in predicting death from RCC. (B) Histogram depicting Mean Nuclei Area and the selected cut-off value.Cancer specific survival by the four-tiered Fuhrman grading system for 101 patients with ccRCC (p = 0.008).Cancer specific survival by the WHO/ISUP four-tiered grading system for 101 patients with ccRCC (p = 0.002).Cancer specific survival in ccRCC patients with tumors with an MNA of >35.75 μm2 (represented by the red line) vs. others (p = 0.0006).Overview of different grading systems.Correlation of nuclear area with patient characteristics.* Students t-test. ** One-way ANOVA followed by Bonferroni’s multiple comparisons test. Abbreviations: MNA; mean nuclear area, MNA-10; mean nuclear area in the 10 largest nuclei, SD; standard deviation. RCC; Renal cell carcinoma, ccRCC; Clear Cell RCC.Relationship between Fuhrman grading and WHO/ISUP grading.Abbreviations: WHO/ISUP; World Health Organization/International Society of Urological Pathology.Comparison of AUC-ROC and C-indexes between different prognostic models.Abbreviations: MNA; mean nuclear area, WHO/ISUP; World Health Organization/International Society of Urological Pathology, AUC-ROC; Area Under the ROC-Curve. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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+The quality of life (QoL) concept now includes new aspects related to patients’ well-being because QoL has become more of a personal perception than an an objective and measurable entity. Here, we discuss the principal aspects of QoL-related aspects in urology and andrology by using a narrative review. Some aspects concerning the QoL are essential when managing uro-andrological patients. The aim of treatments should not only include the absence of disease or symptoms relief but also the improvement of a patient’s QoL with regard to his/her internal status and relationship with others. In this sense, any therapeutic approach should be based on the patient’s perspectives and not only on the instrumental and laboratory findings. Finally, we discussed the role of a patient’s sexual partner adding an extra dimension to the patient-centerd approach as part of the QoL concept in andrology.Due to the improvements in medical care such as technical innovations, new drugs and new insights into the pathophysiology of urological diseases, the average life expectancy of patients has increased considerably in the last few decades [1]. However, improvement in life expectancy is not always linked with an improvement in quality of life (QoL). For this reason, all health-care practitioners are advised to pay attention to the QoL of urological patients [2]. In an editorial in the Annals of Internal Medicine, Elkington states, “What every physician wants for every one of his patients old or young, is not just the absence of death but life with a vibrant quality that we associate with a vigorous youth. This is nothing less than a humanistic biology that is concerned, not with material mechanisms alone, but with the wholeness of human life, with the spiritual quality of life that is unique to man” [2,3]. In this sense, all urologists and andrologists should improve their knowledge about QoL and the tools for QoL measurement. In doing so, urologists and andrologists can pioneer these ethical and professional perspectives in their respective medical fields. In everyday clinical practice, patient-centered medicine and patient engagement has a key role in improving the patient-doctor alliance and patients’ adherence to the treatment. The aim of the present paper is to give a narrative review of QoL-related aspects in urology and andrology in order to provide the reader with some simple tools to use in everyday clinical practice.This narrative review aims to update QoL aspects in the urological and andrological settings, focusing on attitudes towards the concept of QoL and its implementation in everyday clinical practice.A search was performed in PubMed, Cochrane CENTRAL, and Scopus databases for relevant publications by using the following terms "quality of life" AND “urology" OR "andrology". Two authors (TC and PV) independently reviewed the selected articles. Any disagreements among reviewers were resolved through discussion and consensus. All references cited in relevant articles were also reviewed and analyzed. The filters used included the English language. Even if this search was planned as a narrative review, our search was performed in line with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) and the recommendations of the European Association of Urology guidelines (EAU) for conducting systematic reviews and meta-analyses [4,5]. Our research identified 2403 articles of potential interest. After the first screening round, 196 articles were considered eligible for inclusion in our narrative review. Most articles (185) were published during the last 20 years. Only 5 articles were published between 1990 and 1995. In 1947, the World Health Organization (WHO) defined QoL as a “state of complete physical, mental, and social well-being, and not merely the absence of disease and infirmity” [6]. In 1995, the WHO definition evolved as follows: “Individuals’ perceptions of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards, and concerns. It is a broad ranging concept incorporating in a complex way the persons’ physical health, psychological state, level of independence, social relationships, personal beliefs, and their relationships to salient features of the environment" [7].For long, this definition has been the most important and influential definition, but the concept of QoL has changed during recent years. Successively, the concept of health-related quality of life (HR-QoL) was introduced and defined as “how well a person functions in their life and his or her perceived wellbeing in physical, mental, and social domains of health” [5,6,8,9]. In other words, HR-QoL could be defined as: “Quality of life is an all-inclusive concept incorporating all factors that impact upon an individual’s life. Health-related quality of life includes only those factors that are part of an individual’s health” (Torrance [8]). Nowadays, the QoL concept includes other aspects related to a patient’s well-being. Many authors placed a greater emphasis on people’s subjective perceptions of the most important features of their lives, considering the QoL more of a personal perception and not only an objective and measurable entity. In this sense, Wenger et al. in 1984 defined QoL as “an individual’s perceptions of his or her functioning and well-being in different domains of life” [10]. This new definition of QoL takes into account what a patient thinks about his/her internal state, as well as their relationship with other people. QoL should be considered as a rich interplay and balance between how people see their internal state and how people see their relationships with other people (e.g., partner, friend, etc.). This new concept of QoL has important consequences for the management of patients affected by urological and andrological diseases. Any therapeutic approach should be considered in the light of this new and extended definition [11]. In this sense, the aim of treatment was not only to promote the absence of the disease or symptoms relief, but to improve patients’ QoL both in terms of his/her internal status and the relationship with other people [2,11]. The QoL then becomes a two-dimensional entity: an internal dimension (patients’ feel good about her/himself) and an external dimension (patients’ feel good about others) [2].Figure 1 shows the interaction between internal and external dimensions when determining patients’ QoL.On the other hand, some authors described four broad health dimensions that summarize the specific QoL components (Figure 2) [2,12]:Physical health (somatic sensations, disease symptoms)Mental health (positive sense of well-being, nonpathological forms of psychological distress or diagnosable psychiatric disorders)Social health (aspects of social contacts and interactions)Functional health (self-care, mobility, physical activity level and social role functioning in relation to family and work).Physical health (somatic sensations, disease symptoms)Mental health (positive sense of well-being, nonpathological forms of psychological distress or diagnosable psychiatric disorders)Social health (aspects of social contacts and interactions)Functional health (self-care, mobility, physical activity level and social role functioning in relation to family and work).The Dijkers’s model is one of the most important examples of this concept because it summarizes all patient-related aspects that impact QoL [2,13].Figure 3 shows a simplified representation of the Dijkers’s model.We argue that the Dijkers’s model should also be adopted in the urological and andrological settings [13]. Indeed, uro-andrological diseases have a two-dimensional feature:The objective dimension (outsider)The subjective dimensions (insider)The objective dimension (outsider)The subjective dimensions (insider)In the objective dimension (outsider), we found that all observable life conditions were measurable and influenced by the relationship with other people (e.g., partners, friends) [14]. In this dimension, we found all physical functioning conditions. In the subjective dimension, we found all aspects referring to the patient’s perceptions, such as previous personal experience and perspectives.This new concept of QoL perfectly describes patients’ expectations to any given treatment. Urological treatments are not only asked to resolve the clinical problem but improve or maintain patients’ QoL, where possible. For instance, the maintenance of urinary continence and erectile function are, together with cancer free-survival, the most important goals in the management of patients affected by prostate cancer [15]. Even if this concept seems easy to understand and consider in everyday clinical practice, the patient perspective is not always taken adequately into account [11]. This especially may occur in the management of non-oncological disease. Recently, Cai et al. demonstrated that, during management patients, affected by lower urinary tracts symptoms (LUTS), the sexual function, and sexual quality of life should be analyzed in depth because sometimes patients report LUTS instead of sexual symptoms because they feel embarrassed [16]. In this paper, Cai et al. demonstrated that an appropriate and useful therapeutic approach should be based on the patient’s perspectives and not only on the instrumental and laboratory findings. The extended definition of QoL has recently increased interest in everyday clinical practice and, for it, QoL is one of the most important endpoints included in the guidelines and recommendations of many medical societies.The recent evolution of the concept of QoL has positively changed the doctor–patient relationship. An increasing number of published papers demonstrates increasing interest in the concept of QoL. Over the last 5 years, about 50% of published articles on QoL (1032 out of 2403) were in the field of urology, thus demonstrating a particular interest of the scientific urological community. Schmick et al. reported, in a large survey among German urologists, that their attitude towards QoL was mainly positive, and most urologists considered QoL as a necessary part of their everyday clinical practice, even if urologists’ knowledge concerning QoL assessment, analysis, and interpretation was limited [17]. Moreover, they highlighted an important aspect that we discuss in the next section: the use of patient-reported outcome measures (PROMS) in QoL measurement [17]. Stewart considered QoL as a core element in the doctor–patient relationship [18]. She underlined that important aspects of the doctor–patient relationship are “the integration of these concepts of disease and illness with an understanding of the whole person in context, that is, an awareness of the multiple aspects of the patient’s life such as personality, developmental history, life cycle issues, the proximal context, such as family, and the distal context, such as community and physical environment” [18]. According to Stewart, the following components are essential in a patient-centered clinical approach:-Exploring both disease and the patients’ illness experience-Understanding the whole person-Finding common ground-Incorporating prevention and health promotion-Enhancing the patient-doctor relationship-Being realistic [18].Exploring both disease and the patients’ illness experienceUnderstanding the whole personFinding common groundIncorporating prevention and health promotionEnhancing the patient-doctor relationshipBeing realistic [18].The concept of a patient-centered approach was recently introduced in urology with special focus on improving patients’ adherence to treatment and patients’ QoL. In 2018, De Nunzio demonstrated a dramatically low drug adherence and satisfaction with medical treatment among LUTS patients [19]. He highlighted the need for a patient-centered approach that aimed to improve drug adherence and other unmet needs in this area, such as adverse effects on sexual function management and the risk of disease progression [19]. No other substantial contributions in the urological or andrological field have been reported so far, even though a patient-centered approach is likely to benefit many patients in these fields. In particular, there is room for improvement in the andrological setting by increasing involvement of the patient’s sexual partner. The patient’s sexual partner adds an extra dimension to the patient-centered approach as part of the QoL concept in andrology.Figure 4 shows this new concept of andrological patient aspects influencing QoL: the interaction between “insider and outsider view of the patient” and “insider and outsider view of the partner”, as well as their interaction with the outsider view of the “couple”.The partners’ sexual interest is important for a patient to recover the sexual function both in non-oncological and oncological diseases [20]. In a review article, Guercio et al. showed that mental health, physical health, quality of interpersonal communication, and patient-perceived partner support are the most important predictors of sexual satisfaction both for patients and partners in the post-prostatectomy period, demonstrating the need for further research on this topic [21].On the other hand, cultural or religious schemata could limit the usefulness of treating patients as ’couples.’ In this sense, Asian, African, or Middle Eastern origin patients may withhold such information for cultural reasons, and lesbian, gay, bisexual, and transgender (LGBT) partners may not be so forthcoming in their disclosures for fear of stigmatization [22]. All urologists and andrologists are asked to pay particular attention to patients’ sexual orientation in order to improve adherence to the therapeutic approach. Future research in this area is needed. The definition and assessment of QoL should be conducted considering various cross-cultural and religious dimensions. Several factors affecting the QoL definition are mainly determined by cultural or religious schemata, as is apparent in folk illnesses [23,24]. In urological and andrological setting, these aspects should be considered due to the fact that some diseases affect the sexual function or genitalia.Due to the expansion of the concept of QoL and the raising interest for QoL in everyday clinical practice and research, there is a need for reproducible and accurate tools for its measurement. In the world of business management, there is a mantra that guides all decisions: What is not measured cannot be improved. In the last century, Lord Kelvin said that “What is not defined cannot be measured. What is not measured cannot be improved. What is not improved is always degraded” [25]. In healthcare, this principle is of crucial importance. Health professionals rely on empirical evidence to develop new treatments, optimize decision-making, save more lives. and improve patients’ quality of life [26]. Measuring a patient’s well-being after a treatment is fundamental to understand the effectiveness of that intervention [27]. QoL is not directly measurable and needs to be translated to indicators of its constituents and domains to be quantified [27]. General health perception, psychological well-being, and functioning are essential dimensions of QoL while symptoms and vitality are important causative variables [28]. Today, we have hundreds of QoL measures, many of which have been developed in recent years using generic measures that are applicable to most people, as well as specific tools for QoL measurement in people with specific clinical conditions [28]. Examples of QoL measures include the Beck Depression Inventory (BDI), the Sickness Impact Profile (SIP), and the 36-item Short Form Health Survey (SF-36) [28] (Table 1). These measures cover a wide range of aspects of life that can be adversely affected by ill health, such as physical functioning, emotional well-being, and ability to undertake work and social activities [29,30]. In a review article about the role of QoL in urological non-oncological and oncological diseases, Heldwein et al. underlined that QoL outcome measurements have become an important endpoint in urology, allowing urologists to better understand how each disease differs in different individuals [11]. Moreover, they reported that major urology society guidelines now recommend using self-report questionnaires for the most commonly used QoL measurement tools in clinical settings.PROMs has become a valuable tool for use in everyday clinical practice as well as in research [11]. PROMs is a fundamental instrument to learn and understand the before and after condition of patients, and to put patients’ needs and preferences at the center of their care [31]. Several studies have used PROMs in a variety of generic measures of QoL to evaluate the efficacy of a treatment. PROMs is different than PRO (patient reported outcomes), which is a generic term that refers to the perspective of the patient themselves [31]. In an urological setting, the use of PROMs is common, especially when evaluating the outcome of oncological disease management. Several reviews have evaluated the scientific or psychometric properties of existing PRO questionnaires being used for patients diagnosed with prostate cancer [32]. However, even if there are many published studies that use PROMs to evaluate the QoL in prostate cancer patients, these instruments strongly focus on urinary, sexual, and bowel symptoms/function. All questionnaires include some items with a more subjective element to determine the extent to which men are concerned or bothered by a particular symptom [30]. However, no instrument includes the full range of items necessary to assess HRQL in terms of the subjective impact of physical, mental, and social aspects of prostate cancer [32].In andrological and urological setting, no specific assessment tools for QoL of the patients’ sexual partner have been developed and validated. The Female Sexual Function Index (FSFI) was created only to assess female sexual function. A specific tool for assessing QoL of the sexual partner, independently from the partner sexual orientation, is urgently required [33].  The QoL concept now includes new aspects related to a patient’s well-being, particularly people’s subjective perceptions of the most important parts of their lives. QoL has become more of a personal perception and not only an objective and measurable entity. The aim of treatments is not only the absence of the disease or symptom relief but also to improve a patient’s QoL for his/her internal status and relationships with other people.Any therapeutic approach should be based on patients’ perspectives rather than instrumental and laboratory findings. A patient’s sexual partner adds an extra dimension to the patient-centered approach as part of the QoL concept in andrology.Measuring a patient’s well-being after treatment is fundamental to understanding the effectiveness of that intervention. QoL is not directly measurable and needs to be translated to indicators of its constituents and domains to be quantified.Presently, among the many extant QoL measures, PROMs constitute a significant advance as a tool for use in the routine clinical management of individual patients and in clinical research.Conceptualization, T.C.; research, T.C. and P.V.; writing—original draft preparation, T.C.; writing—review and editing, T.E.B.J. All authors have read and agreed to the published version of the manuscript.The authors declare no conflict of interest.The interaction between internal and external dimensions when determining patients’ quality of life (QoL).The four broad health dimensions that summarize the specific QoL components.A simplified representation of the Dijkers’s model.The new concept of andrological patient aspects influencing QoL: the interaction between “insider and outsider view of the patient” and “insider and outsider view of the partner”, as well as their interaction with the outsider view of the “couple”.QoL assessment tools.Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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+Plasmacytoid variant of urothelial carcinoma is a rare subtype of urothelial carcinoma that has poor prognosis. We describe two cases of patients with the plasmacytoid variant of urothelial carcinoma (PVUC) who had initial response to neoadjuvant chemotherapy followed by radical cystoprostatectomy and lymph node dissection but presented with early relapse and disease progression manifesting with intestinal obstruction and peritoneal carcinomatosis. Tumor genomic sequencing revealed mutations and alterations in ARID1A, CDH1, PIK3CA, RB1 loss, and TERT promoter, as well as tumor mutational burden of 10 Muts/Mb treated with pembrolizumab with a minimal response. A further review of the literature regarding this rare variant is discussed here. The plasmacytoid variant of urothelial carcinoma (PVUC) makes up a rare subtype of urothelial cancers. This aggressive variant accounts for an estimated less than 5% of invasive cancers originating from the urothelial tract of the bladder that, in turn, account for 90% of diagnosed primary bladder cancers [1,2]. Variants of the urothelial carcinoma display morphologies distinct from usual or typical patterns of invasive urothelial carcinoma. The plasmacytoid variant is characterized by tumor cells that resemble plasma cells and/or monocytes, as well as a variable number of single cells with the appearance of signet ring cells [3]. The prognosis of this variant is often poor due to the commonly advanced disease presentation upon diagnosis warranting aggressive treatments [1,4,5].A 61-year-old Caucasian male presented with dysuria, with a 40-pack-years of smoking history, coronary artery disease, hypertension, and chronic gastroparesis. However, given symptoms of increased pelvic pain, urinary urgency, and hematuria, a cystoscopy was performed and showed a bladder tumor that was treated with primary transurethral resection of bladder tumor (TURBT). The pathology revealed high-grade PVUC invading the lamina propria and muscularis propria with viable cells in both layers (Figure 1). After also experiencing flank pain, an ultrasound and a CT scan were performed, revealing bilateral hydronephrosis for which nephrostomy tubes were placed and bladder wall thickening, increased renal echogenicity, and seminal vesicle calcifications were found (Figure 2). He completed three cycles of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC), which was complicated by multiple gastrointestinal (GI) symptoms of nausea, vomiting, resultant hypokalemia, and cytopenia, but he was able to successfully undergo definitive robot-assisted laparoscopic radical cystoprostatectomy, bilateral lymph node dissection with bilateral ureterolysis, and neobladder continent urinary diversion with ileum. The final pathology revealed ypT2N0Mx PVUC bladder cancer. While the resolution of bilateral hydronephrosis was seen initially, he developed persistent GI symptoms ten months later that warranted an eventual cholecystectomy. Regardless, symptoms of nausea, vomiting, and pain persisted, which necessitated obtaining a CT scan that showed changes that included recurrent bilateral hydronephrosis and bowel loop thickenings suggestive of the development of enteritis; a small bowel follow-through revealed intestinal obstruction (Figure 3C). A surgical exploratory laparotomy revealed multiple tumor deposits, and a thick, fibrous, mass-like tissue adhering the transverse colon to the anterior abdominal wall was dissected. However, given the extent of the adhesions and tumor deposits occurring diffusely in the abdomen and pelvis, it was elected to not remove the affected small bowel and instead bring up an end-ileostomy to relieve his obstruction. The pathology from these biopsies showed metastases of the high-grade PVUC with infiltrating plasmacytoid and signet ring cells in the small bowel and omentum with immunostaining positive for GATA-3, CD138, CK20, and CK7 (Figure 3). Further staging revealed mediastinal lymphadenopathy on a chest CT scan. Further genomic sequencing using FOUNDATIONONE® CDX genomic profiling showed alterations in ARID1A Q1095fs*10, CDH1 T364fs*3, PIK3CA M10431, RB1 loss, and TERT promoter −124C>T, as well as a tumor mutational burden of 10 Muts/Mb and a stable microsatellite status (MS-stable). He was only able to receive one dose of the PD-1 inhibitor pembrolizumab but with progressive physical and functional decline, as well as gastrointestinal complication symptoms; he declined further treatment and proceeded with hospice. He passed away two years and four months after his initial diagnosis.Case 2 is a 71 y/o male who presented with prostatic hyperplasia symptoms and acute renal insufficiency. Initial imaging showed bilateral hydronephrosis and bladder calcifications. He underwent TURP and TURBT, which revealed high-grade urothelial carcinoma with plasmacytoid and micropapillary features. CT staging showed a markedly thickened and nodular wall of the urinary bladder and calculus (Figure 4), which was consistent with bladder malignancy (suspicious for a diffuse infiltrating tumor) and an abnormal right ureteral dilation with wall thickening and enhancement suspicious for tumor involvement in the right ureter, as well as bilateral pelvic sidewall and retroperitoneal lymphadenopathy. He received chemotherapy with gemcitabine and cisplatin for six cycles with good partial response and ultimately underwent radical cystoprostatectomy, ileal diversion, and lymph node dissection with pathology that revealed high-grade urothelial carcinoma with a plasmacytic variant signet ring and micropapillary features with bulky residual disease pT4pN2Mx. Immunopathologic staining showed +CK20, p53, HER2+ IHC stains, negative PSA, and PD-L1 staining. Sequencing results showed ERBB2 amplification. However, he had ongoing gastrointestinal symptoms of nausea and vomiting, which led to further endoscopies that revealed peritoneal carcinomatosis. He received several cycles of pembrolizumab, and though initial symptom stabilization was seen, further progression ensued and hospice ultimately engaged.PVUC is a rare and aggressive variant that only accounts for a smaller proportion of diagnosed urothelial bladder cancers. It is predominantly observed in males above 55 years of age and is often associated with higher lymph node involvement, locally advanced tumors, and muscle-invasive disease, and it is more likely to be diagnosed at higher stages compared to pure urothelial carcinomas (UCs) [5,6]. The prognosis of urothelial cancers of the plasmacytoid variant is often poor, with high local recurrence rates and a decreased overall survival (OS); studies have shown a five-year OS of 27% for PVUC compared to 45% for pure urothelial cancers [2]. Initial presentation is typically similar to urothelial bladder cancers, often with gross or microscopic hematuria [7] and other urinary obstructive or irritative symptoms. The histological presentation of the plasmacytoid variant is characterized by atypical cells—specifically plasma-like cells with ample eosinophilic cytoplasm and displaced nuclei that may contain vacuoles or form signet rings often composing at least 50% of the tumor. Plasmacytoid variants can express the plasma cell marker CD138 (syndecan-1), and E-cadherin is often down regulated or negative, helping the diffuse permeation of the tumor cells [8]. Other products that may be found by the immunohistochemistry of PVUC include GATA3, p63, CK7, CK20, S100P, and protein-15 [9]. In our present case, tumor cells were initially found during the TURBT of the bladder, and while successful surgery was done with cystoprostatectomy and lymph node dissection with ileal diversion, recurrence occurred later on with metastasis to the omentum and the small bowel, as well as intraperitoneal spread. Immunohistochemical staining was utilized to confirm the origin of the metastasis and was positive for GATA3, CK7, CK20, and CD138, further confirming the metastasis of the PVUC to the omentum and small bowel in this patient. The results of genomic sequencing in these rare variants likely explains the poor prognosis and the potential for peritoneal carcinomatosis in part. Studies have shown the significant overexpression of CDH1 mutations in the plasmacytoid variant (50%) compared to pure UC (2%) [10]. The CDH1 mutation leads to the loss of E-cadherin that is often found on immunohistochemical staining. This loss of E-cadherin can lead to the enhanced cellular migration of the tumor cells and the potential for the peritoneal pattern of disease seen in PVUC, and it may also contribute to a poor prognosis [11]. The loss of RB, a tumor suppressor protein, is seen in various malignancies but has been observed to contribute to the progression of high-grade invasive cases of bladder cancer via various pathways [12]. A retrospective study on 81 patients with UC found ARID1A expression to have an inverse correlation with the stage of UC in both conventional pure UC and variants. ARID1A expression was also found to be lower in variants, which generally have a worse prognosis compared to conventional UC. Its encoded protein is involved in cellular proliferation and tumor suppression, possibly explaining the higher staging and poorer prognosis found in this study [13].In a particular study that looked at 10 cases of PVUC that were subjected to genomic sequencing, nine had a mutation in at least one gene from commonly involved genes including TERT, FGFR3, PIK3CA, TP53, HRAS, KRAS, ERBB2, CDKN2A, MET, MLL, and VHL. PIK3CA mutations do not seem to occur specifically based on a particular stage or type and can be found in tumors of all stages of bladder cancer. TERT promotor mutations are the most common mutations found in UCs, and in a retrospective study of 10 PVUC cases, six were found to have TERT promotor mutations. These commonly mutated genes have diagnostic potential and have been suggested for diagnostic panels for UC [14]. Genomic sequencing on our present case showed alterations in ARID1A, CDH1, PIK3CA, RB1 loss, and TERT promotor, as well as a high tumor mutational burden. The peritoneal carcinomatosis of this patient may have been contributed to by some of these gene mutations, especially CDH1. The finding of mutations in ARID1A, CDH1, and RB1 loss align with the poor prognosis of the case as well. In addition, mutations in PIK3CA have been found to be potent oncogenic drivers in urothelial cancers [15]. While the patient in Case 2 also had sequencing findings with the ERBB2 mutation, it may have been the concomitant micropapillary component that conferred this genomic sequencing finding [10].Given the rarity of plasmacytoid variants, treatment has not been uniformly defined. However, chemotherapy, which has been historically used for conventional or pure urothelial cancers, has often been used with relatively good success in PVUC, although the durability of response is often lacking [6]. However, a few reports have shown inconsistent benefit from the use of neoadjuvant or adjuvant chemotherapy [16,17,18], often used whenever possible, followed by consolidative surgery as the main therapeutic option of choice. In a retrospective study of 31 patients with PVUC, pathological down-staging was found in 80% of patients with resectable disease compared to the upstaging found in most patients who received surgery up-front. Despite the achieved pathological down-staging, recurrences still occurred in a majority of patients, most commonly in the peritoneum [6]. Given its often higher stage at diagnosis, those with PVUC are more likely to undergo more aggressive multimodality treatments with both chemotherapy, either adjuvant or neoadjuvant, and surgery. Chemotherapy regimens that are commonly utilized include MVAC, gemcitabine and cisplatin (GC), and a mixture of ifosfamide, doxorubicin, and gemcitabine. While immunotherapy has gained a major role in the treatment of conventional urothelial cancers [19], little is known about possible efficacy in plasmacytoid urothelial variants. In our particular case series, where both patients received pembrolizumab, there were no discernible responses, thus highlighting the need for alternative, more active agents in this aggressive variant.The plasmacytoid variant of urothelial carcinoma often confers a dismal prognosis with possible links to genomic mutations involving CDH1 and the loss of E-cadherin that explains its propensity for intraperitoneal spread. While surgery is often used for early localized disease, systemic therapy is often required for more advanced disease presentation. Treatment with chemotherapy, while initially effective, often does not lead to durable responses. The use of checkpoint inhibitors appears to have limited responses. This poses an area of increased unmet need for the discovery of novel therapeutics for this aggressive variant of urothelial cancer. Conceptualization, J.B.A.-C.; formal analysis, A.E., W.L., S.M.-L., S.C., J.B.A.-C.; investigation, resources, and data curation, A.E., W.L., S.M.-L., S.C., J.B.A.-C.; writing—original draft preparation, writing—review and editing, A.E., W.L., S.M.-L., S.C., J.B.A.-C.; All authors have read and agreed to the published version of the manuscript.This research received no external funding.Patient consent was waived due to subjects being deceased.We would like to acknowledge the David Wohlscheid Fund for administrative support.J.B.A.-C. reports consultant fees from Merck, Immunomedics, EMD Serono, Pfizer, but not related to this manuscript. All other authors declare no conflict of interest.Radical bladder cystoprostatectomy specimen: residual invasive carcinoma (<1% viable tumor cells in the tumor bed), focally invasive into muscularis propria, with ypT2a pN0. (A) Viable tumor cells in lamina propria (100×); (B) viable tumor cells in lamina propria (200×); (C) viable tumor cells in muscularis propria (200×); (D) pan-cytokeratin highlights the residual viable tumor cells (200×).CT scan showing bilateral hydronephrosis. (A) CT scan pre-cystectomy showing bladder thickening; (B) CT scan shows bilateral hydronephrosis; (C) Small bowel follow-through showing dilated small bowel loops, contrast ends before cecum, polypoid filling defects suggest stool in the small bowel.Metastatic high-grade urothelial carcinoma, plasmacytoid variant involving omentum and small bowel implant. (A,B) The infiltrative carcinoma consists of plasmacytoid and signet ring like cells (A:100×, B:200×); (C–F) Immunohistochemical stains demonstrate the tumor cells are positive for GATA-3 (C), CD138 (D), CK20 (E), and CK7 (F), (200×).Bladder thickening and hydronephrosis. (A) CT scan pre-cystectomy showing bilateral hydronephrosis for case 2; (B) CT scan shows bladder thickening for case 2 and calculi.Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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+Topical anesthetics are one of the first line therapeutical options for men with premature ejaculation (PE). Real-life PE management often involves a range of interventions including systemic drug treatments (such as off-label and on-label selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, phosphodiesterase-5 inhibitors (PDE5Is)), topical anesthetic creams and sprays, and behavioral approaches. Among them, on-demand dapoxetine and lidocaine/prilocaine spray formulations are the only approved treatment options for lifelong PE. The earliest strategy to treat PE was based on the use of topical anesthetic agents. The rationale behind the use of anesthetics is that by reducing the glans penis sensitivity, the spinal and cerebral input of sexual arousal impulses may also be reduced. Oral SSRI proved to be effective to treat PE, but their high rate of side effects limit treatment adherence and both short and long term follow up data are lacking. Conversely, topical anesthetics have proved to increase ejaculatory latency, control, and sexual satisfaction in couple affected by PE with limited rates of adverse events. In this context, we aimed to perform a narrative review to summarize the most recent findings regarding the use of topical treatments for PE.Among sexual dysfunctions, premature ejaculation (PE) is one of the most commonly reported symptoms in everyday clinical practice. PE pathophysiology and treatment efficacy are characterized by an unfolding history of contrasting hypotheses and arguable debates [1,2,3]. In this context, the European Association of Urology (EAU) Guidelines endorses the first Evidence-Based definition of PE, developed by the International Society for Sexual Medicine (ISSM). According to such definition, PE is a sexual dysfunction characterized by; (i) ejaculation that always, or nearly always, occurs before, or within, about one minute of vaginal penetration (lifelong PE) or a clinically significant and bothersome reduction in latency time, often to about three minutes or less (acquired PE); (ii) the inability to delay ejaculation on all or nearly all vaginal penetrations; and (iii) this condition determines negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy [1,4,5]. Over the last two decades, compelling evidence has accumulated regarding the pathophysiology of PE. As a matter of fact, positron emission tomography and functional magnetic resonance imaging studies have allowed a greater understanding of the involvement of neurotransmitters in sexual arousal and ejaculation, which contributed to improve the overall knowledge of ejaculatory disorders and orgasmic dysfunctions pathophysiology [6,7]. The increasing amount of novel evidence prompted urologists to stop considering PE as a mere psychogenic condition, and to acknowledge its possible different interconnected etiologies, i.e., organic, iatrogenic and psychogenic [6,8]. In this regard, selective serotonin reuptake inhibitors (SSRI) have been extensively investigated over the past decades and proved to be efficacious in increasing overall intravaginal ejaculation latency time (IELT) and control over ejaculation in men suffering from both, life-long and acquired PE [8,9,10]. However, patients commonly report SSRI-related side effects, which limits compliance and predisposes to treatment discontinuation in the long term [11]. In the light of these findings, topical anesthetic agents have regained popularity as a viable alternative to oral treatments [1,12]. For many years, the rationale behind the off-label prescription of topical anesthetic agents for PE was to raise the local sensitivity threshold in men who were presumed to be hypersensitive [13]. In fact, penile hypersensitivity has been considered one of the main pathologic mechanism of PE. However, the link between penile hypersensitivity and PE lacks a definitive conclusion. Xin et al. in a case-control study suggested that PE patients had hypersensitivity in the glans penis and penile shaft [13]. However, other investigations did not show a correlation between penile sensitivity and PE [14,15,16]. More recently, Guo et al. showed that patients with lifelong PE had a hypersensitivity profile in terms of peripheral sensory thresholds [17]. Penile hypersensitivity appeared to be a factor contributing to short intravaginal ejaculation latencies in lifelong PE men. Although evidence regarding penile hypersensitivity is mixed, few reports have proposed selective dorsal neurectomy as a potential treatment option for PE, due to the reduction in sensory input that are likely to attenuate central sexual arousal in men with PE [18]. Liu et al. in a group of Chinese men, showed that the dorsal penile nerve branches of patients with lifelong PE were more and thicker than those without lifelong PE, and that selective dorsal neurectomy was effective in improving IELT and ejaculatory control, with few postoperative complications [18].In this specific context, the role of topical anesthetic agents in reducing penile sensitivity in men with PE has emerged. In addition to this, more recent findings demonstrated how topical anesthetics could lead to significant benefits for both male patients and their partners in terms of increased ejaculatory latency, control, and sexual satisfaction [12,19]. This narrative review aims to discuss topical therapies for PE with a specific focus on newly released compounds.We performed a literature search for English-language original and review articles either published or e-published up until January 2021 using Google and the National Library of Medicine’s PubMed database. The mesh terms used for the search were: Premature ejaculation; topical treatment; anesthetic, cream, spray. The retrieved articles were gathered and examined. Reference lists of retrieved articles as well as relevant review articles were also studied.The exclusion criteria were as follows: (1) Editor letters and single case report; (2) non-English language publications; (3) studies with insufficient or unconfirmed information; and, (4) studies not involving PE patients. The evidence acquisition is presented according to PRISMA diagram (Figure 1).A limited number of pharmacological therapies are currently approved for PE [12]. This has led to the use of ‘off-label’ products such as local anesthetics in the everyday clinical practice [19]. When compared to PE treatments, topical agents are appealing since they are easy to use and can be applied on-demand. Moreover, local anesthetic agents do not cause systemic side effects [12,19,20]. Conversely, a downside of the application of a desensitizing substance to the glans is the potential for some degree of penile hypoesthesia. Furthermore, theoretically, the hypoesthesia might pass on to the partner, making sexual intercourse more difficult and leading to even more serious consequences such as erectile dysfunction [21]. The choice between oral therapy with SSRIs and topical anesthetics, either in cream or in spray formulation, is a decision that should be made in conjunction with the patient. Most physicians consider the use of topical therapy as a prudent first step for the treatment of PE, thanks to the favorable risk/benefit ratio of these products. Patients with PE often complain of augmented sensory responses to penile stimulation [16]. In support of this claim, the discovery of abnormal reflex pathways during ejaculation has led to the conclusion that penile hypersensitivity and PE are truly interconnected [16]. In this framework, EMLA (eutectic mixture of lidocaine-prilocaine) is an off-label anesthetic cream used for the treatment of both primary and acquired PE. In 1995, the first study on EMLA on 11 healthy men with PE showed encouraging results in delaying ejaculation [22]. Subsequently, Atikeler et al. investigated the efficacy of this preparation in a larger cohort of patients, observing a statistically significant increase in ejaculation time, which increased from around 1 min. to 6–8 min [23]. Additionally, they demonstrated that the optimal timing for EMLA application is 20 min before sexual intercourse [23]. Busato et al. demonstrated a significant increase of mean IELT among men using a lidocaine-prilocaine cream in comparison to placebo administration [24]. Similarly, Atan et al. compared the use of Sildenafil alone, Sildenafil plus EMLA and placebo confirming the superiority of topical anesthetics in delaying ejaculation as compared to placebo [25]. A recent study conducted by Gameel et al. compared the efficacy of Tramadol, Sildenafil, SSRI and a Lidocaine 2.5% anesthetic gel for the treatment of PE. Lidocaine 2.5% gel confirmed its superiority in respect to the other treatment regimens in increasing IELT (OR 5.23, p < 0.001) [26]. In conclusion, anesthetic creams have shown moderate efficacy for the treatment of primary and acquired PE. However, these preparations carry the risks of sensibility reduction for both patients and their partners, which may potentially lead to erectile dysfunction and skin irritation [27]. Additionally, cream preparations for PE are used on-demand, which could result in loss of spontaneity and subsequent loss of sexual arousal [28] causing treatment discontinuation and poor patient’s compliance.Lidocaine 9.6 % spray, marketed as ‘Studd 100’ or ‘Premjact’, has been available over-the-counter for over 25 years in some countries and it has been employed as an off-label drug to delay ejaculation. A recent study by Alghibary et al., analysed data from men with lifelong PE randomized to oral dapoxetine 60 mg or topical lidocaine 10% spray for 12 weeks and then asked to switch to the other treatment for another 12 weeks. Participants were evaluated using the Arabic Index for PE (AIPE) and the Sexual Health Inventory for Men (SHIM) questionnaire. Authors showed that both medications significantly increased both IELT and AIPE scores when compared with baseline evaluation, but the results were shown to be significantly better with topical lidocaine with respect to oral dapoxetine [28].TEMPE (topical eutectic mixture for premature ejaculation) is a proprietary formulation of lidocaine and prilocaine in a metered-dose aerosol delivery system specifically designed for use in PE. The system delivers 7.5 mg lidocaine base plus 2.5 mg prilocaine base per actuation. The mixture is alcohol-free, which limits the chance of stinging on application. Despite being oil-free, the mixture forms a clear, slightly oily, odorless solution that remains adherent to the application site and may be wiped off with a damp cloth if necessary, without the stringent need to apply a condom [29]. The metered-dose spray delivery system allows the desensitizing agents to be deposited in the form of a dose-controlled, concentrated film on the glans penis, which can then penetrate the glans within 5–10 min of its application [29]. The eutectic mixture penetrates intact keratinized skin more slowly and is therefore not likely to anesthetize the penis shaft or the hands [29]. In the first open-label pilot study, 11 patients recorded their IELT at baseline and on five subsequent encounters after the application of TEMPE 15 min before sexual intercourse [29]. The average IELT increased from 1 min 24 s to 11 min 21 s (p = 0.008), which represents an average eight-fold increase. In addition, 8 out of 11 patients and 7 out of 11 partners rated their sexual satisfaction as either ‘better’ or ‘much better’. In a more recently published phase 2, placebo-controlled trial, 54 patients using the prilocaine–lidocaine spray were able to prolong their IELT from a baseline of 1.0 min to 4.9 min [30]. The treatment was also well tolerated, with only 3 (12%) patients experiencing hypoesthesia and one patient experiencing loss of erection. None of the adverse events resulted in treatment discontinuation. The spray was also well tolerated by female partners, with only few experiencing a mild genital burning sensation during intercourse. Two double-blind placebo-controlled multi-centre phase 3 clinical trials have been completed thereafter [31,32], including over 550 PE patients assessed with the IELT and two questionnaires [index of premature ejaculation (IPE) and the premature ejaculation profile (PEP). IELT changes were mirrored in all domains of the IPE and PEP questionnaire as well as in the PEP domain scores from partners [31,33]. There was little or no evidence of systemic side effects, but only minimal desensitization of the genitalia in either patient or partner [31,33]. For decades topical anesthetic agents have been used as off-label treatments for PE, with the specific aim of raising the threshold of local sensitivity in people who were thought to be hypersensitive [16]. More recently, Fortacin™ was officially approved for use in the European Union in 2013 and finally launched in the United Kingdom in November 2016 for the treatment of men with primary PE [34]. Fortacin is a metered-dose aerosol spray and contains purely base (uncharged) forms of the local anesthetics lidocaine 150 mg/mL and prilocaine 50 mg/mL, with no excipients, except the spray propellant (norflurane) [34]. An original prescription information leaflet suggests using the compound as follows: One dose, namely three sprays, to be applied on the glans penis at least five minutes before sexual attempts [34]. Prost et al. found that Fortacin™ increased ejaculatory latency, control, and sexual satisfaction in men with primary PE, demonstrating the significant benefits for both patients and their partners when using the drug [20]. Likewise, other groups confirmed the above mentioned findings making local anesthetics a viable alternative for lifelong and acquired PE [13,15,29]. Recently, the results from an expert panel discussion on the management of PE reported that most patients perceive PE as a bother rather than a disease, and that on-demand treatment options and the topical route of administration are mostly preferred [35].This formulation has been reported to optimize the penetration through the glans surface leading to a rapid reduction in penile sensitivity (within 5 min)—namely termed desensitization—without adversely affecting the actual sensation of ejaculation. Moreover, Fortacin™ administration might be “personalized” in clinical practice in order to obtain a further patient-oriented treatment. Only few reports have investigated the efficacy and tolerability of a combination therapy of SSRI and topical anesthetics. Metin et al. [36] investigated the effect of on-demand fluoxetine 20 mg taken about 4 h before sexual intercourse, followed by 3 months of combination therapy of fluoxetine plus lidocaine ointment (applied 30 min prior to sexual activity) in 46 men with PE. Authors reported that PE grade and IELT improved with combination treatment and that 86.9% of patients reported a total significant and moderate improvement in PE rate. In another small trial fluoxetine 20 mg/day followed by fluoxetine 40 mg/day was compared to the outcome of a combination therapy of fluoxetine 20 mg/day plus local lidocaine for 2 months [25]. Patients under combination therapy showed higher rates of PE improvement compared to those in monotherapy. Only a limited number of studies investigated the efficacy of combination therapy of local anesthetics and phosphodiesterase type 5 inhibitors (PDE5i) for PE. Atan et al. assessed the effect of combination therapy with sildenafil and EMLA-cream vs. monotherapy and placebo in 84 men with PE. They found that combination treatment had a higher efficacy (86.4%) compared to placebo (40%) and to either monotherapy (sildenafil 50 mg: 55%; EMLA: 77.3%) [20]. In another study, including 78 men with primary PE, the efficacy of lidocaine spray 10 g/100 mL, tadalafil 5 mg daily and tadalafil 5 mg daily plus lidocaine spray was investigated over 3 months [37]. Mean IELT and satisfaction scores were significantly higher in patients with combination therapy than those of patients on monotherapy at 3 months.Despite being one of the most commonly reported sexual dysfunctions, which treatment is adequate and efficacious for PE remains controversial [38,39]. SSRI represented the cornerstone for PE treatment over the last few decades and dapoxetin, a short-acting SSRI, has been the only officially approved oral drug for PE in Europe and many countries worldwide. Nevertheless, SSRI treatment is associated with high rates of treatment discontinuation at both short and long-term follow up [9,12,40]. Commonly reported reasons for discontinuation are efficacy below expectations, costs, side effects and loss of interest in sexual activity [40]. In light of this issues, topical anesthetic agents have regained importance as possible alternatives to oral treatments.When compared to systemic therapy, topical anesthetic compounds offer various advantages such as lack of systemic side effects and limited number of local reactions. However, depending on the formulation, they may require a latency time between application and maximum effect. Furthermore, they should either to be used with a condom, washed-off or wiped-off before intercourse, which could have an effect on spontaneity during sex (Table 1). Local anesthetic cream formulations (lidocaine-prilocaine and dyclonine-alprostadil) require application 5–20 min beforehand and the potential use of a condom, whereas spray formulations (lidocaine–prilocaine, TEMPE) have to be applied 5–15 min in advance [21]. The new dose-metered lidocaine-prilocaine spray (Fortacin) has gained increasing popularity among PE-affected couples, especially because of its unique galenic preparation, which renders its handling effortless and customer friendly. In addition to this, several studies have proved the clinical efficacy of lidocaine-prilocaine spray in terms of IELT improvement, ejaculatory control, sexual satisfaction, and distress [19]. Physicians should always bear in mind that the pathophysiology of PE is multifactorial, with an interlink between psychogenic, organic and neurobiological factors. Consequently, it is likely that the most efficacious treatment of PE is multifactorial as well.Topical anesthetics proved to be safe and effective as a treatment option for men with PE of various types. Patients treatment compliance is higher than that for oral medications. The new dose-metered lidocaine-prilocaine spray has shown promising results for the treatment of lifelong PE in terms of efficacy, and because of its unique galenic preparation, its handling is easy and patient friendly. Combination therapy of local anesthetics and oral medications seems to be superior than monotherapy alone, but data is still scarce to support its systematic use.Conceptualization, L.B., F.B., A.S. and E.P.; methodology, E.P.; writing—original draft preparation, E.P., F.B., L.B.; writing—review and editing, L.B., C.B. and A.S.; All authors have read and agreed to the published version of the manuscript.This research received no external funding.The authors declare no conflict of interest.Evidence acquisition according to PRISMA diagram.Summary of advantages/disadvantages of topical treatment for PE.Significant increase in ejaculation time compared to placeboAdditive effect when used in combination therapyRisk for sensibility reduction for both partners and skin irritation with subsequent loss of sexual desire and erectile dysfunctionCondom use is advised with cream formulationsIncrease ejaculatory latency, control, and sexual satisfaction in men with primary PEMetered-dose aerosol delivery system allows for dose-controlled actionNot likely to anesthetize the penis shaft or the handsCondom use is not necessaryMild hypoesthesia and genital burningRare cases of erectile dysfunctionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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+(1) Background: The Adjustable Transobturator Male System (ATOMS) device is increasingly used to treat post-prostatectomy incontinence as it enhances residual urinary sphincteric function and allows continence recovery or improvement by dorsal compression of the bulbar urethra through a fixed transobturator mesh passage. The mode of action and the profile of the patients with best results are not totally understood. (2) Methods: Intraoperative urethral pressure measurements at different filling levels of the ATOMS device show increased urethral resistance and enhanced residual sphincteric activity. We evaluated whether the pattern of urethral pressure change secondary to serial progressive intraoperative filling of the cushion can predict postoperative results after ATOMS placement. (3) Results: The regression analysis showed a significant direct relationship between cushion volume and intraurethral pressure (p = 0.000). The median intraurethral pressure at atmospheric pressure was 51 ± 22.7 cm H2O, and at atmospheric pressure plus 4 mL was 80 ± 23.1 cm H2O). Cluster analyses defined a group of patients (n = 6) formed by patients with a distensible urethra and 100% continence after adjustment in contrast to another group (n = 3) with rigid urethras and 33% continence after adjustment. (4) Conclusions: As a part of its continence mechanism, the ATOMS device leads to continence by increasing intraurethral pressure owing to the stretching effect on the urethral wall caused by cushion filling that increases urethral resistance.Male stress urinary incontinence (SUI) is a distressful complication after prostatic surgery for either prostate cancer or benign prostatic hyperplasia. The Adjustable Transobturator Male System (ATOMS) is increasingly used for the surgical treatment of moderate to severe male SUI. This system is based on the ventral compression of the bulbar urethra exerted by a silicone cushion that can be filled both intraoperatively and postoperatively [1]. Compared to the artificial urinary sphincter (AUS), the ATOMS does not need patient manipulation. Other advantages of this system are its simplicity, the much lower risk of urethral atrophy or erosion, and the capability of postoperative adjustment [1,2,3]. There is accumulated evidence regarding both efficacy and safety of this incontinence device, without contraindication for the elderly and/or radiated population [4]. Currently, not only AUS, but also male slings and adjustable systems like ATOMS, are well-accepted therapies for male SUI [5].The ATOMS device is also advantageous over other adjustable systems, both for a diminished rate of complications compared to the male REEMEX system [6] and also for increased effectiveness and durability compared to ProACT [7]. However, its mode of action is not well understood and analyses using urodynamic studies are scarce [8]. Our hypothesis is that the compression produced by the cushion filling produces a stretching effect on the bulbar urethra that increases urethral resistance and enhances the residual sphincteric activity, and also that the different responses to serial filling of the cushion intraoperatively after ATOMS placement could help to define the patients with the best postoperative results. Therefore, the objective of our study was to analyze the relationship between cushion volume and intraurethral pressure at the place of ATOMS contact. Our secondary objective was to evaluate whether a “stress test” performed intraoperatively could help us delineate the profile of a patient that would have the best chance of objective continence results after ATOMS implantation and postoperative adjustment.We carried out a cross sectional study in nine consecutive male patients submitted to ATOMS placement for moderate and severe SUI. There were no exclusion criteria regarding leakage severity, concomitant radiotherapy, history of urethral stricture, or previous SUI surgery. Surgical technique and perioperative care followed the original description [1,3]. Sample size was calculated based on data published by Ito et al. [9]. Assuming that the standard deviation of maximum urethral pressure in adult men is 7.75 cm H2O with a precision of ±4 cm H2O and a confidence interval of 95%, the minimum sample size should be 7 patients. The study was IRB approved and all patients signed informed consent for inclusion in the study.Perioperative intraurethral pressure measurement was carried out before and after ATOMS placement but before closing the incision, so that we could be sure the measurement was performed at the level at which the ATOMS device compresses the urethra (Figure 1). We measured this pressure by a T-DOC® air charged catheter inside the urethra at the point of contact between the ATOMS cushion and the urethra (Laborie, Mississaugua, ON, Canada), connected to Solar® urodynamic equipment (MMS, Enschede, the Netherlands). The system was calibrated before each measurement. The initial pressure was measured with an empty cushion, followed by 5 mL serial fillings until 30 mL was reached (Figure 2).Afterwards, the cushion was completely emptied, and filled again up to atmospheric pressure (slightly different in every case), determined by the anatomic position and the degree of pressing when the mesh arms were tied to the cushion. Finally, we measured the pressure by filling to atmospheric pressure plus an additional 4 mL. With each measurement, we observed that filling causes a peak of pressure followed by accommodation. All pressure data for each patient were tabulated. We blinded the clinical information of each patient regarding baseline characteristics including stress incontinence severity (daily pad test), former radiotherapy, and patient age during the registration of intraoperative measurements.We carried out a regression analysis of filling cushion values on intraurethral pressures, and calculated the Pearson correlation coefficient between preoperative pad test, cushion volume, and intraurethral pressure. We also performed a multivariate cluster analysis to search for different filling and pressure patterns. Several months after surgery, once postoperative ATOMS adjustment was completed, we registered whether continence was achieved and the results of a postoperative pad test. Continence after adjustment, variables regarding incontinence severity baseline (pad count, pad test, ICIQ-SF with Q1-Q3 questions), and other clinical and preoperative urodynamic variables were evaluated. Their distribution according to the clusters identified was evaluated using Wilcoxon and chi2 tests.Table 1 shows each value of intraurethral pressure registered for every patient following the dynamic changes for each ATOMS cushion volume tested. We found that each patient followed a different pattern of pressure change and also that a great variation of pressure is exerted when the ATOMS filling exceeds 10 mL. Characteristically, 10 mL filling always increased urethral pressure beyond 60 cm H2O. Atmospheric pressure filling of the system led to intraurethral pressures in a range of 26–95 cm H2O (median 51 ± 22.7 cm H2O) and an additional 4 mL filling brought pressures to 45–110 cm H2O (median 80 ± 23.1 cm H2O). This is in agreement with the effects expected for ATOMS with a percentage of patients achieving continence after surgery and an additional population reaching continence after postoperative adjustment (i.e., adding some extra volume).The regression analyses showed significant direct relationships between cushion volumes and intraurethral pressure (beta coefficient = 0.072 cm H2O/mL, p = 0.000). Intraurethral pressures increased mildly to moderately with filling under 15 mL (73 ± 22.7 cm H2O) but above 20 mL, there was a wide variability in the pressure increment (233 ± 108.9 cm H2O) (Figure 3).There is a correlation between intraurethral pressure baseline with ATOMS placed unfilled and filled at atmospheric pressure (p = 0.038), and also between intraurethral pressure before ATOMS placement and with ATOMS placed and filled at atmospheric pressure plus 4 mL (p = 0.047). Additionally, a correlation was found between ATOMS filling to a medium-range volume (10 mL and 15 mL, p = 0.000; 15 mL and 20 mL, p = 0.004; 10 mL and 20 mL, p = 0.019) and also to a high-range volume (20 mL and 25 mL, p = 0.007; 25 mL and 30 mL, p = 0.003). These figures evidence that, although the pressure variation appears very variable, it can be determined by two ranges of volumes (i.e., 10–20 and 20–25 mL or beyond).Cluster analysis distributed the nine patients in two different patterns (cluster 1 and 2). Cluster 1 is formed by six patients with distensible urethras, while cluster 2 is formed by three patients with more rigid urethras (Figure 4). Patients in cluster 2 reach higher pressure than the rest at 25–30 mL filling volume.The clinical characteristics that define each cluster, based on clinical and urodynamic characteristics, are evaluated in Table 2. All six patients in cluster 1 (100%) achieved continence, but only one patient in cluster 2 (33%) did so. Despite the small numbers, preoperative severity of incontinence was higher in patients in cluster 2, as revealed by a pad test, pad count, and also ICIQ-SF Question 1 (each p < 0.05).Additionally, ultrasound images performed after ATOMS adjustment at different times for serial postoperative filling in a case needing progressive filling up to 25 mL show that ATOMS filling elongates the transversal urethral diameter whereas it reduces the antero-posterior diameter (Figure 5).From a physiological point of view, intraurethral resting pressure must be adequate to maintain continence. Urethral pressure measurements have indicated that normal urethral resting pressure is 70 ± 7.75 cm H2O [9]. According to Laplace’s law, intraurethral pressure is proportional to the tension of its wall. This tension increases in direct proportion to the degree to which the wall is stretched [10]. This may be the mechanism by which ATOMS increases intraurethral pressure.Tissue biomechanics inform us that the relationship between tension and stretch depends on the histologic composition of tissues. Elastin fibers and muscle tissues allow great deformations without a proportional boost of tension. These fibers have a high compliance. Other fibers like collagen allow initial deformation without a high tension. However, once they reach their working length, they strongly resist further stretching by sharply increasing their tension. Our cluster analysis confirms the existence of two patterns. We assume that the pattern in cluster 1 fits with normal urethras where elastin and muscle fibers are predominant and whose maximum intraoperative intraurethral pressure was 250 cm H2O; while the pattern in cluster 2 is formed by rigid urethras where collagen is predominant and maximum intraurethral pressure reached values of 425 cm H2O. In these urethras, overfilling does not guarantee continence status. This explains the finding previously reported that mean cushion filling in patients with ATOMS is higher in those who do not achieve continence than in continent patients [11]. The patients in cluster 2 are those with higher baseline SUI severity and also those with worst postoperative results (Table 2). In fact, clinical evidence with ATOMS implantation also confirmed that patients with higher SUI severity at baseline and patients who received prior radiation therapy are those with a lower possibility to achieve continence [2,4,11].However, direct compression is most probably not the only factor through which ATOMS exerts its mode of action. In fact, an elastic urethra and corpus spongiosum allows the distribution of pressure to the membranous urethra, an explanation that is perfectly in line with our results.Meta-analysis of outcomes reported for ATOMS reveals that 67% of the patients achieve continence after implantation and adjustment, and also that 90% improve their continence status [4]. Despite complications that may occur and possible pain after the implantation, which can hamper results in terms of patient satisfaction, overall satisfaction with the device remains very high [3,12,13]. Long-term outcomes appear reassuring as well [14], though a proportion of patients undergo device explantation for several reasons that include ineffectiveness, port erosion, and device infection [15,16].The main cornerstone of male SUI therapy using prosthetic surgery is the identification of the best candidate for each device. In this sense, the study we present gives an idea of the mode of action of ATOMS as a sphincteric-reinforcing mechanism that produces ventral compression of the bulbar urethra to stretch its walls, thereby increasing intraurethral pressure. We have no clinical evidence that the effect exerted by ATOMS causes bladder outlet obstruction, at least from a clinical point of view. More studies assessing urodynamics after ATOMS placement are needed. Meanwhile, dynamic urethral pressure profiling can help distinguish the population of patients more likely to achieve the best postoperative results.One of the main limitations of the study is the small number of cases evaluated. Another limitation is that repeat urethral pressure measurements were not performed after surgery, once postoperative adjustment was complete, to evaluate the pressure transmitted to the bulbar urethra once the fibrous capsule was formed around the ATOMS cushion. Additionally, future investigations should be conducted in larger series to better evaluate urodynamic changes caused by ATOMS in both the voiding and the filling phase in these patients.We confirm the hypothesis that ATOMS leads to continence by increasing intraurethral pressure owing to the stretching effect on the urethral wall caused by ATOMS cushion filling, thus increasing urethral resistance. We have demonstrated that the response to serial filling performed intraoperatively depends on urethral rigidity, reflects baseline SUI severity, and predicts postoperative results.The nine patients in this report signed an informed consent to participate in the study. All nine suffered incontinence after radical prostatectomy for prostate cancer. Three also received adjuvant radiotherapy. They were consecutive patients undergoing ATOMS placement in a university hospital between October 2019 and January 2020. The surgical team has intervened in more than 150 cases with ATOMS. Cystoscopy and urodynamic study were performed before ATOMS surgery. In one case, bladder outlet obstruction was confirmed despite previous endoscopic treatment of urethral stricture, but allowed urethral catheterization. Incontinence severity was evaluated by daily pad count, daily pad test (based on 3 consecutive days), and also a self-performed ICIQ-SF questionnaire, with three individual questions (Q1 dealing with urine leakage frequency from 0 to 5, Q2 dealing with incontinence severity from 0 to 6, and Q3 dealing with quality of life and patient discomfort).The urethral pressure study was performed intraoperatively as described in the Materials and Methods section. Perioperative and postoperative care followed standards. ATOMS adjustment was performed by postoperative filling of the system through a silicone-covered scrotal port in five cases, with multiple filling needed in three of them. Seven achieved continence, defined by use of no pads or one security pad per day. No intraoperative or postoperative complications occurred.Table 3 shows the most relevant clinical information for each patient included in the study regarding baseline SUI severity and other features like radiation and urethral stricture, operative data, and continence outcomes.All patients were followed for a year. Three patients suffered late complications. One patient had a device-related infection and it was explanted; another died of pneumonia related to COVID-19; and the third patient was diagnosed with superficial bladder cancer.Conceptualization, J.C.A. and M.V.-C.; methodology, M.V.-C.; validation, S.R., M.V.-C. and J.C.A.; formal analysis, J.C.A. and M.V.-C.; investigation, S.R., M.V.-C., F.Q., A.L., I.A. and J.C.A.; data curation, S.R. and A.L.; writing—original draft preparation, J.C.A. and M.V.-C.; writing—review and editing, S.R., F.Q., A.L. and I.A.; supervision, J.C.A.; project administration, J.C.A. All authors have read and agreed to the published version of the manuscript.This research received no external funding.The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Review Board of Hospital Universitario de Getafe, Madrid, Spain (protocol A02/20, finally approved 26 March 2020).Informed consent was obtained from all subjects involved in the study. Written informed consent was obtained from the patients to allow publication of figures.Data supporting reported results will be provided by the corresponding author upon reasonable request.We thank the patients participating in this study. We also thank Juan Dorado (PeRTICA statistical solutions) for statistical analysis; Xavier Genieser and Cristina Molina (Medicina y Mercado, MMS Laborie) for technical and instrumental support to perform the studies; and José Domínguez Pallas (Fotografía y Documentación Clínica, Hospital Universitario de Getafe, Madrid, Spain) for the iconographic support.The authors declare no conflict of interest.Operative view at the time of the ATOMS implant with a T-DOC air charged urethral catheter to perform intraoperative urodynamics. (a) Controlled system filling of the port through a perineal incision; (b) the ATOMS cushion inflated with variable volumes caused a change in intraurethral pressures that were registered by urodynamic equipment.Example of continuous intraoperative registry that corresponds to patient ID 281568. ATOMS progressive filling with 5 mL serial increment from baseline to 30 mL is followed by total deflation and refill up to atmospheric pressure (Atmospheric). Intraurethral pressure in cm H2O (Y-axis) and filling volume in ml (X axis) are specified at each time point in the graph. In this patient, ATOMS cushion at atmospheric pressure with 8 mL increased urethral pressure to 67 cm H2O.Correlation between urethral pressure and ATOMS cushion volume.Intraurethral pressure for different cushion volume: (a) Stress test performed for each patient, expressed as ID number; (b) cluster analysis distinguishes two different patterns of intraurethral pressure. Patients in cluster 2 are marked with asterisks.Sonographic perineal evaluation with lineal probe shows urethral diameter (antero-posterior) diminishes with the increase in ATOMS filling volume.Intraurethral pressure in cm H2O at different filling volumes of ATOMS for each patient. Medians in last row in bold.Cluster characterization according to features expressed; significant values in bold.Clinical data of patients included in the study, including baseline, operative, and postoperative information.Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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+(1) Background: Pelvic organ prolapse (POP) is common among post-menopausal women affecting more than 25% in their lifetime—with 11% having a lifetime risk of undergoing an operation for a POP. In April 2019, the Food and Drug Administration (FDA) took surgical mesh for transvaginal use off the market due to safety and effectiveness concerns. This leaves colporrhaphy or colporrhaphy with bio-graft options for a POP surgical repair. (2) Case: In this report, we look at a case with anterior mesh erosion complicated by poor wound healing secondary to heavy tobacco use and how it was successfully removed and augmented with a Coloplast axis allograft dermis biological graft secured with an Anchorsure sacrospinous ligament/arcus tendineus fascia pelvis fixation device and prolene suture. (3) Results: After failing two prior surgeries to rectify the mesh erosion, a final procedure was performed using a biologic dermal graft and a double-layer closure to aid in protecting and increasing the integrity of the tissue. (4) Conclusions: Collectively, the patient and her surgeries highlight the difficult nature of complete mesh removal and how tobacco use can significantly affect the proper healing of surgical sites. The number of surgeries necessary to address the patient’s chief complaint and the resolution of her symptoms with the biologic graft supports the challenges one faces with mesh removal and poor wound healing secondary to tobacco use. This case illustrates that complicated transvaginal mesh erosion should initially be augmented with a biologic dermal graft secured via sacrospinous ligament/arcus tendineus fascia pelvis fixation and double-layer closure and not only if visible mesh removal alone fails.Pelvic organ prolapse (POP) is common among post-menopausal women, affecting more than 25% in their lifetime. The treatments for POP include the following: Pelvic floor therapy, pessaries, and surgical treatment. The estimated number of women that have a lifetime risk of undergoing an operation for a POP is 11% [1]. In April 2019, the FDA took surgical mesh for transvaginal use off the market due to safety and effectiveness concerns (mesh erosion). This leaves colporrhaphy or colporrhaphy with bio-graft options for a POP surgical repair. The following will discuss a case with augmentation of an anterior mesh erosion complicated by poor tissue and wound healing with a bio-graft.DR is a 44-year-old Caucasian woman with a history of prior mesh removal and heavy tobacco use who presented to the office in January 2019 complaining of vaginal pain secondary to half a centimeter of mesh exposure at the vaginal apex. The patient also complained of foul-smelling vaginal discharge, bladder spasms, and stress incontinence. The patient was encouraged to quit smoking. In March 2019, she underwent a surgical procedure to remove the exposed mesh from the anterior vaginal wall. The mesh was exposed with a right angle retractor and the area of concern was grasped with 3 Allis clamps for a three-pronged technique. The exposed mesh was then grasped with a Kelly clamp and circumferentially sharply dissected and excised. The defect was closed in a running locking fashion with 2-0 Vicryl suture on a UR 6 needle with good hemostasis. During the 4-week post-op visit, she was doing as expected.In March 2020, a year after the first mesh removal, she returned with the same complaints of vaginal pain in the anterior wall and foul-smelling vaginal discharge for some time before presenting to the office. Due to the COVID-19 pandemic, all surgeries were postponed. The patient was encouraged to quit smoking and was counseled on the effects smoking has on the body, specifically on tissue healing—the patient claimed to have achieved smoking cessation in March 2020. The patient started on compounded Premarin vaginal cream to improve the health of the vaginal tissue before surgery.A second surgery took place in July 2020. The exposed vaginal mesh at the left vaginal sulcus area and vaginal apex were excised. Two Allis clamps placed on the area of concern at the vaginal apex allowed for visualization of the granulation tissue and the site of inflammation at the vaginal apex. Electrocautery was used to circumferentially dissect the mesh and granulation tissue from the vaginal apex, inspecting for any other exposed mesh. A UR 6 needle with a 2-0 Vicryl suture was used to close the vaginal epithelium in a running locking fashion with good hemostasis. Six weeks post-op from the second mesh removal, the patient was doing well with some vaginal discharge due to the sutures dissolving. Two months after the second mesh removal, the patient came into the office complaining of vaginal mesh exposure and the defect was closed in the office with 4-0 Monocryl suture in an interrupted fashion ×3. The importance of pelvic rest was emphasized to the patient to allow the vaginal tissue time to heal. The patient continued to experience delayed wound healing secondary to her heavy tobacco use. The patient has previously stated that she stopped smoking in March 2020, but later confessed she “cut down” but did not quit, still leaving her tissue fragile.During the following visit, the patient continued to complain of vaginal pain secondary to anterior mesh erosion. It was then decided to remove the exposed vaginal mesh and augment the area with a bio-graft to prevent recurrence as she had been dealing with the mesh complications for years and her tissue strength was not improving with the tried measures. Preparing the vaginal mucosa for surgery, she continued to use compounded Premarin vaginal cream nightly for a month.Figure 1 illustrates that the third and final surgery was in November 2020. The exposed vaginal mesh from her previous procedures in the past was present and was able to be excised from the tissue. After the removal of the frayed polypropylene mesh, a Coloplast axis allograft dermis biologic graft was placed over the friable tissue for protection from any invisible remaining mesh and to help with the integrity of the incision. The graft was then secured using an Anchorsure sacrospinous ligament/arcus tendineus fascia pelvis fixation device and prolene suture. Using 2-0 Vicryl a single layer closure followed by a second layer closure in an interrupted fashion completed the procedure. To help prevent infection Irrisept irrigation was applied to the surgical site allowing for visualization of hemostasis. Five days post-op, the patient was healing well with sutures still in place. Eight weeks post-op, the patient still had some vaginal pain resolved by the 12-week post-op visit. During the 12-week post-op visit there were no signs of anterior mesh, inflammation or infection. By 6 months post-op, she was still doing very well and had no signs of mesh erosion or complaints—she was satisfied with the procedure.The estimated number of women who have a lifetime risk of undergoing a single operation for a POP is 11%. Risk factors for POP consist of older age, post-menopausal status, multiparty, and obesity. The demand for services to treat pelvic floor disorders is expected to increase by 45% by the year 2030, leading to an increase in demand for effective and safe surgical options. Based on the Gomelsky et al. paper, any graft significantly reduces objective prolapse recurrence rates compared to no graft. Gomelsky et al. concluded that there is a lack of data supporting the use of biologics in pelvic prolapse repair and that more randomized controlled trials must be conducted to determine which graft is superior—synthetic vs. biologic [1].Both biologic and synthetic grafts have their own set of complications. In a study done by Sohlberg et al., biologic grafts led to an increased surgery rate for recurrence, and synthetic rates led to repeat surgeries for graft complications [4]. The meta-analysis done by Slade et al. noted, as well as other studies, that the long-term safety of mesh was unclear and that more studies needed to be conducted [5]. Due to such complications with synthetic mesh, the FDA did pull synthetic mesh off the market in April 2019 due to safety and effectiveness concerns.Gomelsky et al. noted how more clinical trials were needed to determine the effectiveness and safety of bio-grafts. McAlvany et al. did so and determined that dermal bio-grafts for POP repair were an effective and safe procedure [6]. Juma et al. conducted a longitudinal study looking at solvent-dehydrated dermal allograft augmented cystocele repair and concluded that augmented anterior repair is a safe procedure, with low morbidity, and its success is comparable to other techniques [7].Based on the research available, the synthetic mesh has an increased risk of postoperative complications, such as mesh erosion among others, and colporrhaphy alone has an increased risk of POP recurrence leaving colporrhaphy augmented with a dermal bio-graft as the safe and effective option for surgical POP repair, as well as augmentation for mesh erosion, especially in patients with poor tissue and poor wound healing.Collectively, the patient and her surgeries highlight the difficult nature of complete mesh removal and how tobacco use can significantly affect the proper healing of surgical sites. The number of surgeries necessary to address the patient’s chief complaint and the resolution of her symptoms with the biologic graft supports the challenges one faces with mesh removal and poor wound healing secondary to tobacco use. We hope to aid in the advancement of biological alternatives for the augmentation of mesh erosions in POP preventing the necessity of multiple surgical corrections. This case illustrates that complicated transvaginal mesh erosion should initially be augmented with a biologic dermal graft secured via sacrospinous ligament/arcus tendineus fascia pelvis fixation and double-layer closure and not only if visible mesh removal alone fails.S.L. collected the data and typed the article; E.M. collected the references and edited the article; C.W. examined, operated on the patient, and edited the article. All authors have read and agreed to the published version of the manuscript.No funding was received for this article.Ethical review and approval were waived for this study, due to the nature of the case report being an observatory of the standard of care for the patient’s diagnosis and not experimental.Informed consent was obtained from the patient.Williams is a surgical consultant of Coloplast Urology.Illustration of a transvaginal anterior wall repair with a biologic graft [2]. (A) Incision into the anterior vaginal wall; (B) Incision into the anterior vaginal wall; (C) Dissection of the pubocervical fascia from the anterior vaginal wall; (D) Visualization of the defect; (E) Plication of the defect; (F) Anchorsure deployment bilaterally into the sacrospinous ligaments and arcus tendineus fascia pelvis, the prolene suture is pierced through the dermal bio-graft and tied down creating a lift and barrier between the bladder and anterior vaginal wall *; (G) Trimming and re-approximation of the vaginal tissue. * A demonstration and visualization of the Anchorsure is available at the following link: https://www.youtube.com/watch?v=9oBXxdRu5gk [3] (accessed on 23 October 2017).Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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+Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare tubulopathy characterized by renal loss of calcium and magnesium leading to progressive renal failure. The disorder is caused by variants to the tight junction proteins claudin-16 and -19. While rare, this disorder causes a significant burden to patients based on its clinical manifestations of various electrolyte abnormalities, nephrocalcinosis, and early progression to renal failure. In this report we describe the diagnosis of a novel variant of CLDN16 which clinically presented with severe hypomagnesemia, hypocalcemia, nephrocalcinosis, and renal failure.Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder caused by pathogenic variants in CLDN16 and CLDN19, which encode the tight junction proteins claudin-16 and -19 [1,2,3]. Defects in these proteins lead to defective paracellular reabsorption of magnesium and calcium in the thick ascending limb of the loop of Henle and subsequent hypomagnesemia and hypercalciuria [4]. Sequela of these electrolyte abnormalities are responsible for FHHNC’s clinical presentation, characterized by polyuria, urinary tract infections, nephrocalcinosis, and chronic kidney disease (CKD) with early progression to renal failure [5]. Biochemical findings and clinical features are suggestive of FHHNC, but genetic testing has been increasingly used in a confirmatory role.The understanding of the pathophysiology of FHHNC continues to evolve with approximately 130 cases reported since its initial description in the 1970s. Here we add to that fund of knowledge with a case report of an individual with symptomology typical of FHHNC, with a novel variant of uncertain significance (VUS), and a pathogenic variant in CLDN16.A 43-year-old male with a longstanding history of nephrolithiasis was transferred to our hospital in late 2017. His first stone episode was at the age of 10 years and since then he has passed ‘hundreds to thousands of stones’. His past medical history is notable for gout, recurrent urinary tract infections (UTI) and CKD stage III, and creatinine (Cr) 1.7 (eGFR 53 mL/min/1.73 m2), stable over the past 13 years. He had no other hormonal or metabolic disorders. His past surgical history included multiple failed treatments with extracorporeal shockwave lithotripsy. He reported no family history of nephrolithiasis or renal disease. Prior to presentation, he was managed on hydrochlorothiazide (HCTZ) 12.5 mg daily, potassium chloride 15 mEq twice a day, colchicine 0.6 mg twice a day, and prophylactic trimethoprim/sulfamethoxazole (dose unknown).He was transferred to the Mayo Clinic due to severe electrolyte abnormalities in October 2017. His labs were notable for a Cr of 1.95 (eGFR 49 mL/min/1.73 m2), potassium of 2.6 mmol/L, bicarbonate 26.5 mmol/L, magnesium of 0.5 mg/dL, and calcium of 5.2 mg/dL. His parathyroid hormone (PTH) was 96.3 pg/mL, vitamin D 27 ng/mL, and 1,25-dihydroxy vitamin D 47 pg/mL. Of note, the patient had had a computational tomography of this neck in the past to evaluate his elevated PTH. This showed no parathyroid adenomas or masses. CT of the abdomen and pelvis during admission was notable for extensive calcifications of the medullary regions of both kidneys consistent with nephrocalcinosis and an obstructing 1 cm right renal pelvis stone (Figure 1). The patient had a ureteral stent placed for the obstructing stone and his electrolytes were normalized with supplementation. He was discharged on magnesium oxide 800 mg four times a day, calcium carbonate 1000 mg three times a day, amiloride 5 mg daily, colchicine 0.6 mg twice a day, and allopurinol 100 mg daily, and advised to continue HCTZ 12.5 mg daily and potassium chloride 15 mEq twice a day.He underwent a standard (30 fr) right percutaneous nephrolithotomy in December 2017. This demonstrated a large right renal pelvis stone as well as numerous stones in the collecting system and emanating from the parenchyma. Given the extensive stone burden, he was unable to be rendered visually stone-free. Stone analysis revealed a mixed composition stone, 70% calcium phosphate (apatite), 20% calcium oxalate monohydrate, and 10% calcium oxalate dehydrate. The patient underwent a metabolic urine evaluation in January 2018. This demonstrated hypercalciuria, severe hypocitraturia, elevated urinary pH, and adequate urinary volume (Table 1). The patient was started on chlorthalidone 12.5 mg daily in lieu of HCTZ for management of hypercalciuria, his allopurinol dose was increased to 200 mg daily and he was advised to continue electrolyte supplementation. Over the next 26 months, the patient had a total of eight ureteroscopic stone procedures to treat his extensive bilateral nephrocalcinosis. At each procedure complete stone clearance was attempted. Given the patients large stone burden, staged procedures were required. Ureteral stents were placed after each procedure and removed after 5 days unless a staged procedure was planned in the future. Of note, the patients most recent ureteroscopies were performed with the thulium fiber laser and, anecdotally, superior stone clearance was noted. Subsequent stone analysis revealed predominantly calcium phosphate (apatite) stones. Throughout this period, the patient continued to have hypercalciuria (269–320 mg/day) and hypomagnesaemia (1.2 mg/dL) on laboratory evaluations. The patient’s Cr ranged from 2.16 to 2.49 (37–30 eGFR mL/min/1.73 m2). His serum bicarbonate level ranged from 20 to 27 mmol/L. Most recently, the patient is being managed with chlorthalidone 25 mg daily, amiloride 5 mg in the morning and 10 mg nightly, 1000 mg of calcium supplementation four times a day, magnesium chloride 143 mg, and calcitriol 0.25 mg three times a week. He has been followed with renal ultrasounds and kidney–ureter–bladder X-rays every 6–9 months. Given the constellation of electrolyte abnormalities, urinary metabolic findings, nephrocalcinosis, and childhood onset of symptoms, he was recommended for genetic testing. The patient underwent genetic testing with a focused 41-gene panel (GeneDx, Gaithersburg, MD, USA) in April 2020. This showed two heterozygous variants in CLDN16: NM_006580.3:c.697G > T − p. (Gly233Cys) and NM_006580.3:c.310G > A − p. (Asp104Asn). The former variant was classified as likely pathogenic and the latter as a VUS following the ACMG/AMP 2015 guidelines [6]. A limitation of the genetic testing is that it cannot determine the phase of the reported CLDN16 variants (cis or trans). Therefore, family variant testing (FVT) was offered to the patient’s mother and brother. His mother underwent FVT, which confirmed that she carries the likely pathogenic variant and does not carry the VUS. These results, in addition to his clinical presentation, suggest the variants are in trans. The patient’s brother has not yet undergone genetic testing.As our clinical knowledge of FHHNC has grown so has our understanding of its underlying genetic causes. According to the Human Gene Mutation Database, there are 69 genetic variants described in CLDN16 and 22 variants in CLDN19 that have been associated with FHHNC [1,7]. Since FHHNC is inherited in an autosomal recessive manner, affected individuals are homozygous or compound heterozygous for the disease-causing variants. The reported pathogenic variants are located scattered across the gene, so there is no definitive genotype–phenotype correlation; although, individuals with biallelic loss-of-function variants usually progress more rapidly than individuals with missense variants. The most frequent CLDN16 pathogenic variant is the NM_006580.3:c.453G > T − p. (Leu151Phe) being found in up to 50% of the Eastern European and German individuals with FHHNC [4,8]. The p. (Gly233Cys) present in the patient reported here is classified as likely pathogenic since it has been reported in trans with other pathogenic variant in families with FHHNC and it is predicted to impact protein function by in silico tools—such as the combined annotation-dependent depletion (CADD) and the rare exome variant ensemble learner (REVEL) [9,10,11]. Furthermore, there are other pathogenic variants at the same amino acid that have been associated with the disease. Interestingly, the p. (Asp104Asn) was classified as a VUS by the clinical laboratory due to lack of evidence of pathogenicity. The variant lies at exon 1, in the first extracellular loop of the protein, a region very conserved throughout evolution. It is present in only one allele in the Genome Aggregation Database and it is predicted to be damaging by multiple in silico predictors [12,13]. Through family variant testing, it was proved that the CLDN16 variants were in trans. Based on the patient’s clinical presentation with a longstanding history of nephrolithiasis, gout, recurrent UTIs, early development of CKD, and classical laboratory findings, the VUS could be reclassified as likely pathogenic. Notably, most pathogenic variants reported in CLDN16 are missense located in one of the two extracellular loops, as is the case for the p. (Asp104Asn) identified in this patient [14]. The patient had manifestations of disease in childhood with a protracted course towards severe complications in adulthood. This slower disease progression highlights that the biallelic missense variants may cause partial loss of protein function. There are currently no guidelines for the specific treatment of FHHNC. Care focuses around medical management to limit the development of profound nephrocalcinosis, with surgical intervention used to keep stone burden at bay. Thiazide diuretics are one of the mainstays of treatment and have demonstrated decreased rates of hypercalciuria; however, their effect on the course of the disease long-term has not been determined [4]. In our patient, treatment with thiazides did produce a significant change in hypercalciuria levels—demonstrating the variability in treatment response among patient with FHHNC. Hypomagnesemia, and other electrolyte abnormalities, are treated with supplementation. Amiloride may also play a role in treating patients with FHHNC; however, the mechanism of magnesium conservation with the use of the potassium-sparing diuretic is not understood. The patient also suffered from profound hypocitraturia; however, in the context of his stone composition and urinary pH, supplementation with citrate may have increased his risk of stone precipitation. Such competing considerations are common in patients with FHHNC and provide challenges in optimizing their medical management. Despite optimal supplementation therapy, it is not uncommon for patients to require surgical intervention to address profound nephrocalcinosis. At present, our patient still has a significant stone burden despite multiple stone procedures. The development of advanced laser technology may offer opportunities for more efficient ureteroscopic procedures in the future [15]. The goals of disease management are ultimately to delay the development of renal failure. For those that do progress, renal transplantation is an effective option and has shown to resolve electrolyte abnormalities with no evidence of disease recurrence [14,16]. The etiology for renal deterioration in FHHNC patients has not been elucidated. Possible explanations include the effects of prolonged nephrocalcinosis, inflammation secondary to crystal nephropathy or renal dysplasia due to defective claudin-16 function [14,17,18]. The patient reported here has had a protracted decline which may be explained by a partial loss of function mutation, as prior studies have noted a more rapid decline when complete loss of function is seen [8]. Without an exact etiology for renal decline, management must focus on treatable sequalae. In summary, we have examined the clinical course, diagnosis, and treatment of a middle-aged man with FHHNC. Genetic testing found a novel variant, c.310G > A − p. (Asp104Asn), that is likely pathogenic and may produce partial loss of function of CLND16. The treatment of FHHNC is complex and currently directed by best practices—utilizing both medical and surgical options. As more is understood about FHHNC and the reasons for progression to renal failure are clarified, future treatments may be better tailored. Conceptualization, M.H. (Mitchell Humphreys), M.K., K.S.; methodology, M.H. (Mitchell Humphreys), M.K., K.S.; writing—original draft preparation, G.N., T.S., J.M., M.H. (Megan Hager), F.P.eV.; writing—review and editing, G.N., T.S., J.M., M.H. (Megan Hager), F.P.eV.; supervision, M.H. (Mitchell Humphreys), M.K., K.S. All authors have read and agreed to the published version of the manuscript.This research received no external funding.Ethical review and approval were waived for this study after consultation with our institutional ethics committee per institutional guidelines. Following institutional guidelines, the patient filled out a release of information form and provided verbal consent for this case report. The authors declare no conflict of interest.CT scan on presentation demonstrating bilateral large volume stone burden and an obstructing 1 cm right ureteropelvic junction stone. Burden of stone disease consistent with nephrocalcinosis.24 h urine samples.Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.