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Molecular subtyping has been a major focus of bladder cancer research over the past decade. Despite many promising associations with clinical outcomes and treatment response, its clinical impact has yet to be defined. As part of the 2022 International Society of Urological Pathology Conference on Bladder Cancer, we reviewed the current state of the science for bladder cancer molecular subtyping. Our review included several different subtyping systems. We derived the following 7 principles, which summarize progress and challenges of molecular subtyping: (1) bladder cancer has 3 major molecular subtypes: luminal, basal-squamous, and neuroendocrine; (2) signatures of the tumor microenvironment differ greatly among bladder cancers, particularly among luminal tumors; (3) luminal bladder cancers are biologically diverse, and much of this diversity results from differences in features unrelated to the tumor microenvironment, such as FGFR3 signaling and RB1 inactivation; (4) molecular subtype of bladder cancer associates with tumor stage and histomorphology; (5) many subtyping systems include idiosyncrasies, such as subtypes recognized by no other system; (6) there are broad fuzzy borders between molecular subtypes, and cases that fall on these fuzzy borders are often classified differently by different subtyping systems; and (7) when there are histomorphologically distinct regions within a single tumor, the molecular subtypes of these regions are often discordant. We reviewed several use cases for molecular subtyping, highlighting their promise as clinical biomarkers. Finally, we conclude that data are currently insufficient to support the routine use of molecular subtyping to guide bladder cancer management, an opinion shared with the majority of conference attendees. We also conclude that molecular subtype should not be considered an “intrinsic” property of a tumor but should instead be considered the result of a specific laboratory test, performed using a specific testing platform and classification algorithm, validated for a specific clinical application.

Emerging data on T1 bladder cancer subcategorization (aka substaging) suggests a correlation with oncological outcomes. The International Society of Urological Pathology (ISUP) organized the 2022 consensus conference in Basel, Switzerland to focus on current issues in bladder cancer and tasked working group 3 to make recommendations for T1 subcategorization in transurethral bladder resections. For this purpose, the ISUP developed and circulated a survey to their membership querying approaches to T1 bladder cancer subcategorization. In particular, clinical relevance, pathological reporting, and endorsement of T1 subcategorization in the daily practice of pathology were surveyed. Of the respondents of the premeeting survey, about 40% do not routinely report T1 subcategory. We reviewed literature on bladder T1 subcategorization, and screened selected articles for clinical performance and practicality of T1 subcategorization methods. Published literature offered evidence of the clinical rationale for T1 subcategorization and at the conference consensus (83% of conference attendants) was obtained to report routinely T1 subcategorization of transurethral resections. Semiquantitative T1 subcategorization was favored (37%) over histoanatomic methods (4%). This is in line with literature findings on practicality and prognostic impact, that is, a shift of publications from histoanatomic to semiquantitative methods or by reports incorporating both methodologies is apparent over the last decade. However, 59% of participants had no preference for either methodology. They would add a comment in the report briefly stating applied method, interpretation criteria (including cutoff), and potential limitations. When queried on the terminology of T1 subcategorization, 34% and 20% of participants were in favor of T1 (microinvasive) versus T1 (extensive) or T1 (focal) versus T1 (nonfocal), respectively.

The 2022 International Society of Urological Pathology (ISUP) Consensus Conference on Urinary Bladder Cancer Working Group 2 was tasked to provide evidence-based proposals on the applications of grading in noninvasive urothelial carcinoma with mixed grades, invasive urothelial carcinoma including subtypes (variants) and divergent differentiations, and in pure non-urothelial carcinomas. Studies suggested that predominantly low-grade noninvasive papillary urothelial carcinoma with focal high-grade component has intermediate outcome between low- and high-grade tumors. However, no consensus was reached on how to define a focal high-grade component. By 2004 WHO grading, the vast majority of lamina propria-invasive (T1) urothelial carcinomas are high-grade, and the rare invasive low-grade tumors show only limited superficial invasion. While by 1973 WHO grading, the vast majority of T1 urothelial carcinomas are G2 and G3 and show significant differences in outcome based on tumor grade. No consensus was reached if T1 tumors should be graded either by the 2004 WHO system or by the 1973 WHO system. Because of the concern for underdiagnosis and underreporting with potential undertreatment, participants unanimously recommended that the presence of urothelial carcinoma subtypes and divergent differentiations should be reported. There was consensus that the extent of these subtypes and divergent differentiations should also be documented in biopsy, transurethral resection, and cystectomy specimens. Any distinct subtype and divergent differentiation should be diagnosed without a threshold cutoff, and each type should be enumerated in tumors with combined morphologies. The participants agreed that all subtypes and divergent differentiations should be considered high-grade according to the 2004 WHO grading system. However, participants strongly acknowledged that subtypes and divergent differentiations should not be considered as a homogenous group in terms of behavior. Thus, future studies should focus on individual subtypes and divergent differentiations rather than lumping these different entities into a single clinicopathological group. Likewise, clinical recommendations should pay attention to the potential heterogeneity of subtypes and divergent differentiations in terms of behavior and response to therapy. There was consensus that invasive pure squamous cell carcinoma and pure adenocarcinoma of the bladder should be graded according to the degree of differentiation. In conclusion, this summary of the International Society of Urological Pathology Working Group 2 proceedings addresses some of the issues on grading beyond its traditional application, including for papillary urothelial carcinomas with mixed grades and with invasive components. Reporting of subtypes and divergent differentiation is also addressed in detail, acknowledging their role in risk stratification. This report could serve as a guide for best practices and may advise future research and proposals on the prognostication of these tumors.

Background: Hyperglycemia can promote the development of prostate cancer (PCa). Differential expression levels of miRNAs between PCa patients and controls were also reported. Therefore, we examined the relationship between hyperglycemia and miRNA levels in PCa. Methods: Relative expression of urinary miR-574-3p, miR-375, miR-205-5p, miR-200b-3p, miR-187-3p, miR-182-5p, and miR-100-5p were investigated in 105 PCa patients and 138 noncancer controls by Real-Time quantitative PCR. Fasting plasma glucose measurements were retrieved from clinical records. The differential miRNA expressions among groups were compared using non-parametric tests. Correlations with glucose and prostate-specific antigen (PSA) were tested using Pearson correlation coefficient. Results: When we analyzed miRNA expression according to glycemic state, significant down-regulations were found for miR-200b-3p, miR-187-3p, miR-182-5p, and miR-100-5p in noncancer controls with high glucose. The lowest down-regulations were observed for miR-187-3p, miR-182-5p, and miR-100-5p. Subsequently, when hyperglycemia was considered in PCa, significant dysregulations of selected miRNAs were found in hyperglycemic PCa patients than in controls with high glucose. In particular, miR-375 and miR-182-5p showed a 3-FC in hyperglycemic PCa patients than controls who left hyperglycemia untreated. Conversely, only a down-regulation of miR-574-3p was observed in PCa patients regardless of glycemic status and only modest down-regulation of miR-574-3p, miR-200b-3p, miR-187-3p and miR-182-5p were found in normoglycemic PCa patients. Next, significant correlations between miRNAs and glucose (miR-200b-3p, miR-100-5p) and PSA (miR-205-5p and miR-187-3p) were detected in controls. Similarly, miR-205-5p and miR-187-3p were correlated with glucose in PCa patients, while miR-574-3p and miR-375 showed inverse relationships. Conclusions: miRNA dysregulations can occur in hyperglycemic PCa patients as compared to noncancer controls who left hyperglycemia untreated. Hyperglycemia can consistently promote the expression of miR-375 and miR-182-5p. Uncontrolled hyperglycemic state could contribute to the creation of a suitable microenvironment for later PCa development by promoting gene expression.

Endometrial cancer is one of the most common cancers among women. The International Collaboration on Cancer Reporting (ICCR) developed a standardized endometrial cancer data set in 2011, which provided detailed recommendations for the reporting of resection specimens of these neoplasms. A new data set has been developed, which incorporates the updated 2020 World Health Organization Classification of Female Genital Tumors, the Cancer Genome Atlas (TCGA) molecular classification of endometrial cancers, and other major advances in endometrial cancer reporting, all of which necessitated a major revision of the data set. This updated data set has been produced by a panel of expert pathologists and an expert clinician and has been subject to international open consultation. The data set includes core elements which are unanimously agreed upon as essential for cancer diagnosis, clinical management, staging, or prognosis and noncore elements which are clinically important, but not essential. Explanatory notes are provided for each element. Adoption of this updated data set will result in improvements in endometrial cancer patient care.

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

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

According to current studies, COVID-19 might have an impact on semen quality. Therefore, SARS-CoV-2 may affect other traits of male reproductive system, including the prostate. Thus, we recruited patients who experienced COVID-19 infection in-between prostate biopsy and radical prostatectomy and compared prostate samples inflammation, measured with IRANI score, to those who did not. Indeed, we recruited 20 patients, aged 69 (62–73) years, finding no difference between the 10 patients with COVID-19 infection and the others in IRANI score and all its sub-scores. Hence, according to our exploratory and limited results, COVID-19 infection might have no gross effect on prostate inflammation.

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms with unpredictable behavior. They are characterized by epithelioid cells, which stain with melanocytic markers, associated with spindle cells reactive for smooth muscle markers. PEComas may be sporadic or associated with the tuberous sclerosis complex, with mutations affecting mostly tuberous sclerosis complex (TSC) 2 and less frequently TSC1genes. More recently a subtype of PEComa harboring TFE3gene rearrangement, mutually exclusive with TSCcomplex mutations, has been identified. The bladder and the other genitourinary tract organs are an infrequent site of origin; to date, only 3 cases of primitive bladder PEComas, 1 prostatic PEComa, and 2 epithelioid angiomyolipomas of the kidney with TFE3rearrangement have been described in literature. We report a bladder PEComa case with Xp11 rearrangement in a patient who previously had undergone chemotherapy for chronic lymphatic leukemia. We assessed the meaning of the presence of TFE3rearrangement in genitourinary tract PEComas and the possible correlation of these uncommon lesions with previous chemotherapy. A better understanding of this entity’s genetics may help suggest appropriate targeted therapy, which is still lacking in genitourinary tract PEComas.

Background: The PreImplantation Factor (PIF)—a peptide secreted by viable embryos—exerts autotrophic protective effects, promotes endometrial receptivity and controls trophoblast invasion. Synthetic PIF (sPIF) has both immune-protective and regenerative properties, and reduces oxidative stress and protein misfolding. PIF is detected by immunohistochemistry (IHC) in hyperplastic endometriotic lesions and advanced uterine cancer. sPIF reduces graft-versus-host disease while maintaining a graft-versus-leukemia effect.Methods: PIF detection in prostate cancer was assessed in 50 human prostate samples following radical prostatectomy using tumor-microarray-based IHC correlating PIF immune staining with Gleason score (GS) and cancer aggressiveness.Results: PIF was detected in moderate-to-high risk prostate cancer (GS 4+3 and beyond, prognostic groups 3 to 5). In prostate cancer (GS (WHO Grade Group (GG)5), PIF was detected in 50% of cases; in prostate cancer (GS 4+4 GG4), PIF was observed in 62.5% of cases; in prostate cancer (GS 4+3 GG3), PIF immunostaining was observed in 57.1% of cases. In prostate cancer, (GS 3+4 GG2) and (GS 3+3 GG1) cases where PIF staining was negative to weak, membranous staining was observed in 20% of cases (staining pattern considered negative). High-grade prostate intraepithelial neoplasia PIF positive stain in 28.57% of cases (6 of 21) was observed. In contrast, PIF was not detected in normal prostate glands. Importantly, sPIF added to the PC3 cell line alone or combined with prostate cancer fibroblast feeder-cells did not affect proliferation. Only when peripheral blood mononuclear cells were added to the culture, a minor increase in cell proliferation was noted, reflecting local proliferation control.Conclusions: Collectively, PIF assessment could be a valuable, simple-to-use immunohistochemical biomarker to evaluate aggressiveness/prognosis in specimens from prostate cancer patients.

Prostate cancer is the most frequent non-cutaneous malignancy in men in the United States. In the last few years, many recommendations have been made available from the 2014 International Society of Urologic Pathology consensus conference, 2016 World Health Organization blue book and 2018 8th edition of American Joint Committee on Cancer Staging System. Here, we focus on four topics which are considered relevant on the basis of their common appearance in routine practice, clinical importance and ‘need to improve communication between pathology reports and clinicians’: prostate cancer classification, prostate cancer grading, prostate cancer staging, and current definition of clinically significant prostate cancer. Tissue biomarkers that can predict significant disease and/or upgrading and tissue-based genomics for the purpose of diagnosis and prognosis are mentioned briefly.

To investigate the role of Cumulative Cancer Length (CCL) and PCa positive core number (PCapcn) in random prostate biopsies as predictors of Adverse Pathology (AP) at definitive pathology.

Low-risk prostate cancer (PCa) is currently managed also with active surveillance (AS). However, up to 40% of patients in AS may require radical treatment at a long-term follow-up. The aim of our study is to further investigate the role of prostate-specific antigen (PSA) density in AS.

Cancer-associated fibroblasts (CAFs) are the major cellular stromal component of many solid tumors. In prostate cancer (PCa), CAFs establish a metabolic symbiosis with PCa cells, contributing to cancer aggressiveness through lactate shuttle. In this study, we report that lactate uptake alters the NAD+/NADH ratio in the cancer cells, which culminates with SIRT1-dependent PGC-1α activation and subsequent enhancement of mitochondrial mass and activity. The high exploitation of mitochondria results in tricarboxylic acid cycle deregulation, accumulation of oncometabolites and in the altered expression of mitochondrial complexes, responsible for superoxide generation. Additionally, cancer cells hijack CAF-derived functional mitochondria through the formation of cellular bridges, a phenomenon that we observed in both in vitro and in vivo PCa models. Our work reveals a crucial function of tumor mitochondria as the energy sensors and transducers of CAF-dependent metabolic reprogramming and underscores the reliance of PCa cells on CAF catabolic activity and mitochondria trading.

Leukocyte infiltration plays an active role in controlling tumor development. In the early stages of carcinogenesis, T cells counteract tumor growth. However, in advanced stages, cancer cells and infiltrating stromal components interfere with the immune control and instruct immune cells to support, rather than counteract, tumor malignancy, via cell–cell contact or soluble mediators. In particular, metabolites are emerging as active players in driving immunosuppression. Here we demonstrate that in a prostate cancer model lactate released by glycolytic cancer-associated fibroblasts (CAFs) acts on CD4+T cells, shaping T-cell polarization. In particular, CAFs exposure (i) reduces the percentage of the antitumoral Th1 subset, inducing a lactate-dependent, SIRT1-mediated deacetylation/degradation of T-bet transcription factor; (ii) increases Tregcells, driving naive T cells polarization, through a lactate-based NF-kB activation and FoxP3 expression. In turn, this metabolic-based CAF-immunomodulated environment exerts a pro-invasive effect on prostate cancer cells, by activating a previously unexplored miR21/TLR8 axis that sustains cancer malignancy.

Nested urothelial carcinoma (NUC) and large nested urothelial carcinoma (LNUC) of the upper urinary tract are exceedingly rare. This has contributed to the paucity of information regarding their clinicopathological and molecular characteristics. To address this knowledge gap, we explored the largest cohort to date of these rare tumors, comprising resection specimens of 10 LNUC and 7 NUC, from 7 participating institutions. Clinicopathological data were retrieved and documented. Whole exome sequencing and RNA sequencing were performed on the Illumina NovaSeq 6000 sequencer. The data generated were analyzed using the genome analysis toolkit pipeline. Somatic mutations were annotated using funcotator tool to identify pathogenic/likely pathogenic variants. Tumor mutational burden was calculated using python-based “pyTMB” tool. Microsatellite instability analysis was done using MSIsensor2 and the Idylla platform. Differential expression analysis of genes in LNUC and NUC along with mRNA expression–based molecular subtyping was performed by analyzing expression pattern of markers used in The Cancer Genome Atlas subclassification of bladder carcinoma. Both tumor types were more common in older males, were unifocal, and occurred more commonly mixed with minor components of predominantly conventional urothelial carcinoma. Overlying low-grade papillary urothelial carcinoma was significantly more common in LNUC (P = .034). On follow-up (LNUC: median, 10 months; range, 3-84 months; NUC: median, 9 months; range, 2-48 months), LNUC had better clinical outcomes (P = .031). Pathogenic mutations in FGFR3and PIK3CAwere significantly more common in LNUC (P = .049 and P = .044, respectively), with the latter present exclusively in LNUC. Seventy-five percent of the cases showed tumor mutational burden of <10, and all cases were microsatellite-stable. FGFR3mutations were also more common in low-stage tumors. This study expands on the clinicopathological spectrum of NUC and LNUC of the upper urinary tract and is the first to comprehensively analyze the molecular profile of these tumors, highlighting pathogenic genetic alterations of potential therapeutic and prognostic value.

Intravesical immunotherapy, chemotherapy, and neoadjuvant systemic chemotherapy are among the most frequent therapeutic procedures to treat malignancies of the urinary bladder. These treatment modalities produce reactive morphologic changes in the urothelium that can mimic urothelial carcinoma in situ, urothelial dysplasia or true invasive urothelial neoplasia. Mitomycin C used after transurethral resection of bladder tumor to reduce recurrences, BCG intravesical immunotherapy to treat high risk non-muscle invasive bladder cancer and urothelial carcinoma in situ, and platinum-based systemic chemotherapy to improve post-cystectomy disease-specific survival some of the causes of therapy related atypia in urinary bladder. In addition, a number of systemic drugs in use to treat other systemic diseases, such as cyclophosphamide used to treat certain auto-immune disorders or hematologic malignancies, or the anesthetics ketamine increasingly used as illegal recreational drug, may produce similarly relevant atypical changes in the urothelium, and therefore, need to be differentiated from intraepithelial neoplasia. Immunohistochemical approach to reactive urothelium from CIS using CK20, p53, and CD44 may also be of utility in the pos-therapy scenario.

Clear cell renal cell carcinoma (ccRCC) is an heterogeneous tumour at architectural, cellular and molecular level, a reason why the 2014 International Society of Urological Pathology consensus recommended wide sampling of RCC masses to include at least 1 block/cm of tumour together with perpendicular sections of the tumour/perinephric fat interface and the tumour/renal sinus interface. Intratumoural molecular heterogeneity may be a limitation at the moment of defining precision medicine strategies based on gene mutation status. This study analyses the presence of any mutation of KRAS, NRAS, BRAF, PIK3CA, ALK, ERBB2, DDR2, MAP2K1, RETand EGFRgenes in 20 tissue blocks from a case of ccRCC and its metastasis. We observed the presence of the mutation at pH1047R of PIK3CAgene in five samples of the tumour, while the remaining 15 samples did not show any mutation at PIK3CAor any other investigated gene. There is a great need to develop novel RCC sampling strategies to overcome tumour heterogeneity prior to define precision oncology strategies.

Radical cystoprostatectomy (RCP) followed by bilateral pelvic lymphadenectomy and urinary diversion remains the gold-standard therapy for men with localized muscle-invasive bladder cancer (MIBC). Prostate cancer might be incidentally detected at the time of RCP with a reported prevalence of 24–51%. Typically, these patients are considered to have clinically insignificant disease, but data from emerging series challenge this assumption and suggest that some of these tumours might be aggressive, or somehow increase the aggressiveness of the associated MIBC, and can negatively influence the patient's overall survival outcomes. Furthermore, the potential use of prostate-sparing cystectomy in patients with less-aggressive MIBC might lead to newly diagnosed incidental cases of prostate cancer, with characteristics suggestive of clinically significant disease, requiring a specific, separate workup. The development of evidence-based, validated protocols to define the necessary steps for diagnosis of prostate cancer in these patients, including the role of serum PSA testing, digital rectal examination, the role of imaging methods and the indication and type of biopsy protocol, is of major importance to the multidisciplinary management of patients with urological cancer. Finally, the retrospective nature of the available data account for much of the variability in the prevalence of coexisting bladder and prostate cancer and emphasizes the need for randomized trials in this controversial area of urological oncology.

Background: To date more than 3000 miRNA sequences have been described in humans and registered at miRBase since their discovery. However, the functions of only a few of these miRNAs have been experimentally determined using deep sequencing technology. Aberrant miRNA expression has been associated with differentiation, invasion and metastasis in several cancers. In this context, recent reports have suggested that miRNAs play important roles in the regulation of target genes by binding to complementary regions of messenger transcripts to repress their translation or regulate degradation. In addition, the expression profiles of certain miRNAs can function biologically as oncogenes and tumor suppressor genes. Method: In this review, we summarize the relationship between miRNAs expression and Bladder Cancer (BC). A comprehensive review of the literature has shown a differential expression between malignant and normal tissues, and that miRNAs could be the driving molecules of the BC progression. Similarly, the expression levels of miRNAs in urine and blood samples of BC patients have been demonstrated to be different from healthy people, a finding that might have diagnostic value. Conclusion: In conclusion, the understanding of miRNAs mechanisms and cell distribution provides new opportunities for diagnosis, prognostic, disease monitoring and personalized therapy of BC patients.

ABSTRACTIntroduction: Despite more than 30 years of research on p53 resulting in >50,000 publications, we are now beginning to figure out the complexity of the p53 pathway, gene ontology and conformational structure of the molecule. Recent years brought great advances in p53 related drugs and the potencial ways in which p53 is inactivated in cancer.Areas covered: We searched for related publications on Pubmed and ClinicalTrial.gov using the following keywords ‘p53, Tp53, p53 and bladder cancer, p53 and therapeutic target’. Relevant articles improved the understanding on p53 pathways and their potential as candidate to targeted therapy in bladder cancer.Expert opinion: Novel strategies developed to restore the function of mutants with chemical chaperones or by using compounds to improved pharmacokinetic properties are in development with potential to be applied in the oncology clinic. Other strategies targeting aberrantly overexpressed p53 regulators with wild-type p53 are also an active area of research. In particular, studies inhibiting the interaction of p53 with its negative regulators MDMX and MDM2 are an important field in drug discovery. Small molecules for inhibition of MDM2 are now in clinical trials process. However, personalized anticancer therapy might eventually advance through analyses of p53 status in cancer patients.

The R.E.N.A.L. nephrometry nomogram (RNN) is a statistical tool to predict the malignancy or aggressiveness of renal masses. In this study, we tried an external validation in a cohort of 506 cT1a tumors submitted to partial nephrectomy (PN), showing a poor predictive ability. We can conclude that this nomogram cannot contribute to the preoperative management of small renal masses (SRM).

We focused on the clinical and morphologic similarities that may cause a misdiagnosis between histologic variants of seminoma and we highlighted the differences between spermatocytic seminoma and high–mitotic rate seminoma or plasmocytic testicular lymphoma or plasmacytoma of the testis. We emphasized on the difficult points in the differential diagnosis, with a critical review of the literature, reporting a case series to discuss problems in differential diagnosis.

We herein report an uncommon case of renal metastasis from the lung in a 72-year-old man who 2 years before underwent surgical treatment for a pulmonary adenocarcinoma. During follow-up, a computed tomography scan revealed the presence of a solid mass located in the right kidney. Histopathologic and immunohistochemical examination of the enucleated lesion demonstrated the renal localization of an adenocarcinoma of the lung. Clinically recognized renal metastatic lesions from pulmonary cancer are a rare finding with only 35 cases reported to date in the English literature, and renal localization of adenocarcinoma of the lung is extraordinarily uncommon. Together with suggestive clinical data and negativity for markers of adenocarcinomas of different origin, thyroid transcription factor-1, when positive, is considered to be the most reliable marker for the differential diagnosis.

We tested a selected series of patients with single urothelial high-grade pT1 stage (pT1 HG) or urothelial carcinoma in situ (CIS) with a set of immunohistochemical markers to elaborate a risk score for progression. We retrospectively reviewed all first diagnoses of single, <3 cm, urothelial papillary carcinoma pT1 HG or isolated CIS between 2006 and 2009. Galectin-3, CD44, E-cadherin, CD138, p16, survivin, HYAL-1, and topoisomerase-II were used. A grading score 0 or 1 for each immunohistochemical staining was assigned to obtain a total score for assessing the progression. The median “progression score” was selected as cutoff value for statistical analysis. Overall, 23 patients (19 pT1 HG and 4 CIS) were included in the study. After a median follow-up of 21 months (range, 12 to 34 mo), 9 patients (39.1) showed disease recurrence whereas 4 patients (17.4) showed tumor progression. Topoisomerase-II , p16, survivin, galectin-3, and CD138 were significantly associated with progression. Progression score ranged from 0 (best prognosis) to 7 (worst prognosis). Using a score ≥5 as a threshold, specificity was 78.9, sensitivity 100, positive predictive value 50, and negative predictive value 100. ROC area (a 95 confidence interval, 0.807-1.000; P<0.001). This immunohistochemistry-based progression score using a threshold ≥5, might help the clinician to focus on patients with HG pT1 or extended CIS at high risk for disease progression. These patients might benefit from a more intensive follow-up program or early cystectomy.

Rhabdoid tumor is an uncommon neoplasia characterized by a monotonous population of large, noncohesive cells with vesicular nuclei and large nucleoli. The misleading name was originally suggested because of the striking morphologic resemblance to other skeletal muscle tumors, but neither ultrastructural nor immunohistochemical features support a myogenic origin for this tumor. The rhabdoid tumors of the kidney in pediatric age are characterized by mutation or deletion of 22q11. In adults, tumors with rhabdoid features are uncommon neoplasia reported in different anatomic sites, but their histogenesis is still unclear. We focused on the literature data regarding the rhabdoid features in pelvic and renal tumors, and we describe a carcinoma involving the pelvis and the kidney with exclusive rhabdoid features, which make the anatomical allocation of the tumor difficult. The tumor did not exhibit any similarities to conventional histologic types of renal cell cancer, not even of the sarcomatous type. Tumor cells showed a strong positivity for epithelial markers (AE1AE3 and CK 8) and for vimentin, whereas they were negative for skeletal and smooth muscle markers. The nuclei of the tumor cells demonstrated a INI1-positive immunohistochemical stain, indicating the lack of mutation or deletion of the 22q11 chromosome. The appropriate diagnosis is that of an extrarenal high-grade rhabdoid carcinoma originating from the urothelium of the renal pelvis. The decision as to whether the tumor arose primarily in the renal parenchyma or in the renal pelvis could be of therapeutic importance. Appropriate immunohistochemical markers can help in the difficult differential diagnosis.

Hepatoid adenocarcinoma is a rare neoplasm, which has a striking morphologic similarity to hepatocarcinoma. It has been described in different organs, the most common are stomach, lung, and pancreas. In some cases, it is characterized by high serum levels of -fetoprotein. This tumor has a pattern similar to the hepatocarcinoma. The typical features are a combination of histopathologic aspects of solid nests and trabecular structures of polygonal atypical cells with eosinophil and granular cytoplasm and immunohistochemical expression of -fetoprotein and of carcinoembryonic antigen in half of cases. Here, we report the case of an old female patient affected by hepatoid adenocarcinoma of the ureter with ovarian, small intestine, and hepatic involvement. We discuss the clinical aspects, the morphologic features, and the immunoistochemical staining useful for differential diagnosis.

Introduction Solitary fibrous tumor (SFT) of the kidney represents a rare neoplasm, and its malignant potential seems to be scarce. Classically, a radical nephrectomy is regarded as the treatment of choice for this condition.Case Report We present the case of a 37-year-old male patient who underwent left robotic clampless partial nephrectomy of an SFT of the kidney. Our patient has been followed-up carefully, and at 15-month examination, he is free of recurrence. This is the second case of an SFT managed through a conservative approach.Conclusions In our opinion, according to tumor's dimensions, partial nephrectomy may be considered for treating small SFTs.

Recent insights and emerging strategies for individualized therapeutic approaches in patients with genitourinary (GU) cancers are based on patient's genomic and cancer's molecular profiles. This depends on the significant advances made in molecular biology technologies, such as next-generation sequencing and whole-exome sequencing. The rise of such novel techniques has grayly increased our knowledge on cancer cell biology and development, thus allowing to identify complex abnormalities at the genomic level. These findings have paved the way toward what is called precision medicine, thus providing healthcare from an individual perspective in patients with GU tumors.

The incidence of Wilms’ tumour (WT) among adult individuals accounts for less than 1% of kidney cancer cases, with a prognosis usually less favourable when compared to younger individuals and an overall survival rate of 70% for the adult patients versus 90% for the pediatric cases.

The current study was conducted to evaluate the cost‐effectiveness of triaging for colposcopy using human papillomavirus (HPV) testing.HPV tests were performed in a consecutive series of women who were referred for colposcopy for persistent atypical squamous cells of undetermined significance (ASCUS)‐favor reactive (n = 35 women), ASCUS‐favor squamous epithelial lesion (n = 164 women), atypical glandular cells of undetermined significance (n = 74 women), low‐grade squamous epithelial lesion (n = 161 women), or high‐grade squamous epithelial lesion (n = 78 women). The cost effectiveness of triaging women with ASCUS results using HPV testing was determined compared with the current protocol.The sensitivity of HPV testing for cervical intraepithelial neoplasia > Grade 2 was very high. Cost analysis showed a moderate increase in cost with the addition of HPV triage.Because HPV testing is highly sensitive, it may be useful as an alternative to the current policy of 6‐month repeat cytology for women with ASCUS. Cancer (Cancer Cytopathol) 2005. © 2004 American Cancer Society.

The validation of atmospheric remote-sensing measurements involves the comparison of vertical profiles of atmospheric constituents obtained by different instruments. This operation is a complex one because it has to take into account the measurement errors that are described by the variance-covariance matrices and the different features of the two observing systems that are described by the averaging kernels. The procedure is discussed and a method of comparison that is rigorous and does not involve degradation of the available information is developed by use of the formalism of functional spaces. The functional spaces that can be used for representation of the two profiles are reviewed, and criteria are determined for the choice of the most convenient functional space to minimize degradation of the measurements. Once the functional spaces are chosen, the components of the profiles are compared in the intersection space of these two functional spaces. If the intersection space coincides with the null vector, a pseudointersection space with useful geometrical properties can be used instead. A test of the method is made with a realistic simulation. In the test the profiles retrieved by two real instruments are simulated and quantitatively compared.

AbstractThe aim of this study was to test the prognostic value of p-glycoprotein expression and the proliferative index of tumor cells on the clinical response to chemotherapy, on the brief disease-free interval (<12 months) and on cause-specific survival in advanced ovarian carcinoma. We evaluated 83 ovarian carcinoma patients homogeneous for stage, type and grade histological. Brief disease-free interval and cause-specific survival rates (Kaplan-Meier method) were compared using the log rank test. Multivariate analysis (Cox proportional hazards models) was used to determine the independent effect of each variable on prognosis. In the uni-variate analysis, P-glycoprotein expression (P<0.0005) and proliferative index (P=0.0003 and P=0.0006) were independent predictors of survival and brief disease-free interval; residual disease was associated with survival (P=0.021). In multivariate analysis (Cox proportional hazards models), P-glycoprotein expression (P=0.001 and P=<0.0005) and proliferative index (P=0.081 and P=0.041) were independent predictors of brief disease-free interval and survival. P-glycoprotein expression (P<0.0005) and proliferative index (P=0.008) were associated with clinical response to chemotherapy.

We propose a new approach to the analysis of limb-scanning measurements of the atmosphere that are continually recorded from an orbiting platform. The retrieval is based on the simultaneous analysis of observations taken along the whole orbit. This approach accounts for the horizontal variability of the atmosphere, hence avoiding the errors caused by the assumption of horizontal homogeneity along the line of sight of the observations. A computer program that implements the proposed approach has been designed; its performance is shown with a simulated retrieval analysis based on a satellite experiment planned to fly during 2001. This program has also been used for determining the size and the character of the errors that are associated with the assumption of horizontal homogeneity. A computational strategy that reduces the large number of computer resources apparently demanded by the proposed inversion algorithm is described.

The processes of discretization, interpolation, and resampling are frequently used in data analysis. Here the formalism of functional spaces is used as a framework for the description and characterization of both the measurement operation and these subsequent processes. The tools provided by this formalism are applied to the problem of resampling of atmospheric volume mixing ratio vertical profiles obtained with limb-sounding measurements. In particular, a resampling method that uses the conservation of the vertical column as a constraint is presented and compared with other methods. The effects of the resampling process in terms of error propagation and loss of vertical resolution are also evaluated.

An optimized code to perform the near-real-time retrieval of profiles of pressure, temperature, and volume mixing ratio (VMR) of five key species (O_3, H_2O, HNO_3, CH_4, and N_2O) from infrared limb spectra recorded by the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) experiment on board the European Space Agency (ESA) Environmental Satellite ENVISAT-1 was developed as part of a ESA-supported study. The implementation uses the global fit approach on selected narrow spectral intervals (microwindows) to retrieve each profile in sequence. The trade-off between run time and accuracy of the retrieval was optimized from both the physical and the mathematical points of view, with optimizations in the program structure, in the radiative transfer model, and in the computation of the retrieval Jacobian. The attained performances of the retrieval code are noise error on temperature <2 K at all the altitudes covered by the typical MIPAS scan (8–53 km with 3-km resolution), noise error on tangent pressure <3%, and noise error on VMR of the target species <5% at most of the altitudes covered by the standard MIPAS scan, with a total run time of less than 1 min on a modern workstation.

A simple model of an emission Fourier-transform spectrometer is provided for a beam splitter with infinitesimal thickness but with general optical properties otherwise. Using the principle of conservation of energy, we derived the rigorous expressions that relate the interferograms from three different signals (source, reference, and beam-splitter emission), which are simultaneously observed by the detector. The relationship among phase and amplitude of the three interferograms is evaluated. The results indicate that the behavior of a Fourier-transform emission spectrometer may be more complicated than what is assumed in some models. Calibration procedures should reflect the implications of this rigorous approach.

The IR emission limb sounder MIPAS will be operated as an ESA core instrument on the ENVISAT-1 satellite. Near real time retrieval of pressure, temperature and volume mixing ratio of five key species from calibrated spectra will be performed in the Level 2 processor of the ENVISAT Payload Data Segment. In order to develop an optimized retrieval algorithm suitable for the implementation in MIPAS Level 2 processor, an ESA supported study is being carried out. In the framework of this study, an optimized forward/retrieval code based on the global fit approach was implemented. In this approach all the spectra of a limb-scanning sequence are simultaneously fitted, so that error propagation in the altitude domain is avoided. The attained accuracy performances of the retrieval code are the following: (i) temperature accuracy < 2 K at all the altitudes covered by the standard MIPAS scan; (ii) tangent pressure error: < 3 percent; (iii) error on the retrieved VMR of the key species: < 5 percent at most of the latitudes of scientific interest covered by the standard MIPAS scan. The run-time required to perform p,T and VMR retrieval of the five MIPAS target species from a limb-scanning sequence of 16 limb-views is less than 6 minutes on a SUN SPARCstation 20. The most effective code optimization were implemented in the radiative transfer model and in the computation of the jacobian of the retrieval.

We report an experimental investigation of the 6S–8S transition of cesium atoms by using Doppler-free two-color spectroscopy. We consider the case in which one of the laser frequencies is nearly resonant with the 6S1/2–6P3/2 transition while a second one is swept around the 6P3/2–8S1/2 transition. The lineshapes of two-photon absorption spectra are analyzed taking into account the effects of saturation and collisions. Both counterpropagating and copropagating laser-beam schemes are studied. Although for the linewidths are broader copropagating beams, such a scheme has proved advantageous to fully resolve the hyperfine structure of the final state 8S1/2 and, hence, to measure the dipole magnetic constantA of this state.

A recovery procedure has been developed to correct instrument line-shape distortions observed in Fourier transform spectroscopy. The procedure can be described as a phase-error correction performed in the spectral domain to correct for path-difference-dependent phase errors observed in sharp spectral features. The technique has been applied successfully to high-resolution atmospheric emission spectra. The inherent broadening of the real features has been separated accurately from instrumental distortions. Using models for the path-difference-dependent error sources and data from two narrow window regions at 50 and 118 cm^−1, we show that the distortion has a simple dependence on the spectral frequency.

Background and objectives: Limited information is available on the level of satisfaction of clinicians with services delivered by blood banks. The purpose of this study was to evaluate the satisfaction of clinicians with our blood transfusion service. Materials and methods:We prepared a questionnaire based on SERVQUAL, a method used to measure customers' appreciation of quality of service, by assessing the gap between perceived and expected quality. The questionnaire consisted of 14 items grouped according to five dimensions of quality of service: assurance, empathy, responsiveness, reliability, tangibles. Clinicians were asked to give two scores on a scale from 1 to 7 for each item, score (e) representing what they expected from an 'excellent' service, score (r) how they graded the service received. We considered wide differences in scores of service expectation and receipt for a question to be indicative of either service above expected levels (r>e) or service below expectation (r&lt;e); similar scores for both expected and received service (within 1 point on the grading scale) were taken to indicate that the service received was that which was expected. Results: A total of 184 questionnaires (49%) were returned. For the 14 items considered, the proportion of clinicians expressing levels of satisfaction similar to or above expectation ranged from 67 to 96%. Three critical areas, which clinicians considered important (expectation scores 6-7) were associated with satisfaction below expectation in more than 20% of responders. They were: clarity of procedures, clarity of blood request forms, and convenience of blood request and issuing times, which were rated as important by 77, 80 and 72% of clinicians, respectively. Conclusion: SERVQUAL was useful to gather information on the level of clinicians' satisfaction with our transfusion service.

Experimental results on the temporal distributions of the Čerenkov light from EAS, detected by using very fast techniques, are reported. The values obtained of rise time and pulse width are analysed and they agree with the results previously given by our group. Besides, we have analysed in detail the shape of the pulses. Results concerning a number of abnormal pulses, observed during the measurements are also reported and discussed. Si descrivono i risultati sperimentali sulla distribuzione temporale della luce Čerenkov degli sciami atmosferici rivelati con tecniche ultra-veloci. I risultati ottenuti del tempo di salita e della larghezza degli impulsi sono stati analizzati e sono in accordo con i risultati dati dal nostro gruppo precedentemente. Inoltre è stata analizzata in dettaglio la forma degli impulsi. Sono ancho riportati i risultati riguardanti un numero di impulsi anormali osservati in misura. Сообщаются эксперим ентальные результат ы для временных распре делений черенковско го излучения из EAS, заре гистрированного с по мощью очень из EAS, зарегистрированн ого с помощью очень быстрой техники. Пров одится анализ получе нных величин для времени в озрастания и ширины импиЛьса. Пол ученные величины сог ласуются с результатами, получе нными ранее нашей гру ппой. Кроме того, мы под робно проанализиров али форму того, мы подробно проа нализировали форму импульсов. Также Прив одятся результаты и п роводится обсуждение анормаль ных импульсов, наблюденн ых во время измерений.

Abstract: Primary testicular leiomyosarcoma is an uncommon tumor with only few cases described in literature. In young people this rare tumor seems to be related to radiotherapy and anabolic steroids abuse. In older people there are apparently no risk factors. We describe one further case in a 77-years old man with full histological and ultrastructural evaluation. A short term follow-up of one year signals no recurrence of the disease.

Lichen sclerosus (LS) is a chronic inflammatory disease of unknown cause which is found most often in the vulvar region. Vulvar LS has been associated with squamous-cell carcinoma (SCC) of the vulva; estimates of the prospective risk of malignant transformation range from 3% to 5%. In this study, the proliferative index was determined using the cell proliferation marker Ki67 and expression of the tumor suppressors p16 and p53 was quantified in 8 women with histologically confirmed vulvar LS who, after 10 months to 9 years of follow-up, developed vulvar SCC. A comparison group consisted of 8 women with vulvar LS who did not develop cancer during follow-up for 9 years or longer. Immunoperoxidase staining utilized the monoclonal antibody MIBI.

Apodization, which is a tool frequently used for cosmetic representation and efficient modeling of a spectrum, is now also adopted in techniques for the quantitative retrieval of parameters from observed spectra. Whether apodization can help in quantitative spectroscopy is the subject of debate in the literature. We find that, when the considered spectral range is wide enough to accurately model the instrument line shape, the same results can be obtained with and without apodization of the spectrum. However, when a truncation error is introduced by the limited extension of the modeled spectral interval, apodization can efficiently reduce this error. Therefore it is possible to save computing time by using apodization.

Papillary renal cell carcinoma derives from renal progenitors in an adenoma-carcinoma sequence, and acute kidney injury is a preventable risk factor.