Advancing the field of rare genitourinary tumors:Challenges and opportunities

Firstly,I would like to congratulate the editorial team of the Asion Journol of Urology for dedicating a speclial isue of the joumal to this important toplc.With recent advances in our fundamental understanding of the pathophysiology for many of these tumors in addition to access to high throughput comprehensive genamic profiling.

Genitourinary manifestations of Lynch syndrome in the urological practice

Objective:Lynch syndrome(LS)is an autosomal dominant hereditary disorder resulting from germline mutation in at least one of the four mismatch repair genes or in EPCAM gene.From a clinical perspective,LS patients exhibit an increased predisposition to multiple primary malignancies and early age of onset compared to general population.We aimed to provide a comprehensive overview of all the genitourinary manifestations of LS,focusing on incidence,diagnosis,clinical features,therapeutic strategies,and screening protocols.Methods:Previous literature was assessed through Medline,Scopus,and Google Scholar data-bases.A narrative review of the most relevant articles from January 1996 to June 2021 on urological manifestations of LS was provided.Results:In the LS tumor spectrum,upper tract urothelial carcinoma(UTUC)represents the third most frequent malignancy,and the first most common cancer in the urological field,with an approximately 14-fold increased risk of developing UTUC compared to general population.LS diagnosis among patients experiencing UTUC as first malignancy is a step-by-step process,including(i)clinical criteria,(ii)molecular testing,and(iii)genetic testing to confirm the hereditary disorder.The current European Association of Urology(EAU)guidelines recommend to perform molecular testing among UTUC patients under 65 years old,or UTUC patients with personal history of LS-related tumor,or UTUC patients with one first-degree relative under the age of 50 years with LS-related tumor,or UTUC patients with two first-degree relatives with LS-related tumor regardless of age of onset.Newly diagnosed LS patients should be referred to a multidisci-plinary management,including gastroenterologists and gynecologists.Finally,considering the increased risk of metachronous recurrence,treatments other than radical nephroureterectomy may be a valuable therapeutic alternative.Whether urological malignancies other than UTUC should be included in the LS tumor spectrum is still controversial.Conclusion:Considering the strict association between UTUC and LS,we believe that the urologist should recognize patients at increased risk for hereditary disease according to current EAU clinical criteria and address them to a comprehensive diagnostic algorithm,including molecular evaluationandgenetic testing.To date,literature lacks clear evidence regarding the role of LS in developing bladder cancer,prostate cancer,or renal cell carcinoma,and current data are still inconclusive,highlighting the urgent need for further studies.

Low-grade myofibrosarcoma of the maxillary sinus:Two case reports

BACKGROUND Low-grade myofibroblastic sarcoma(LGMS)is an extremely rare tumor characterized by the malignant proliferation of myofibroblasts.LGMS most commonly develops in adults,predominantly in males,in the head and neck region,oral cavity,especially on the tongue,mandible,and larynx.This article presents 2 cases of LGMS localized to the maxillary sinus and provides an overview of the available literature.CASE SUMMARY Two patients with LGMS located in the maxillary sinus underwent surgery at the Department of Head and Neck Surgery.Case 1:A 46-year-old patient was admitted to the clinic with suspected LGMS recurrence in the right maxillary sinus(rT4aN0M0),with symptoms of pain in the suborbital area,watering of the right eye,thick discharge from the right nostril,and augmented facial asymmetry.After open biopsy-confirmed LGMS,the patient underwent expanded maxillectomy of the right side with immediate palate reconstruction using a microvascular skin flap harvested surgically from the middle arm.The patient qualified for adjuvant radiotherapy for the postoperative bed,with an additional margin.Currently,the patient is under 1.5 years of observation with no evidence of disease.Case 2:A 45-year-old man was admitted to our clinic with facial asymmetry,strabismus,exophthalmos,and visual impairment in the right eye.Six months earlier,the patient had undergone partial jaw resection at another hospital for fibromatosis.A contrast-enhanced computed tomography scan revealed a tumor mass in the postoperative log after an earlier procedure.An open biopsy confirmed lowgrade fibrosarcoma(rT4aN0M0).The patient qualified for an extended total right maxillectomy with orbital excision and right hemimandibulectomy with immediate microvascular reconstruction using an anterolateral thigh flap.The patient subsequently underwent adjuvant radiotherapy to the postoperative area.After 9 months,recurrence occurred in the right mandibular arch below the irradiated area.The lesion infiltrated the base of the skull,which warranted the withdrawal of radiotherapy and salvage surgery.The patient qualified for palliative chemotherapy with a regimen of doxorubicin+dacarbazine+cyclophosphamide and palliative radiotherapy for bone metastases.The patient died 26 months after surgical treatment.The cases have been assessed and compared with cases in the literature.CONCLUSION No specific diagnostic criteria or treatment strategies have been developed for LGMS.The treatment used for LGMS is the same as that used for sinonasal cancer radical tumor excision;adjuvant radiotherapy or chemoradiotherapy should also be considered.They have low malignant potential but are highly invasive,tend to recur,and metastasize to distant sites.Patients should undergo regular follow-up examinations to detect recurrence or metastasis at an early stage.Patients should be treated and observed at the highest referral centers.

Contemporary approach to diagnosis and classification of renal cell carcinoma with mixed histologic features

Renal cell carcinoma (RCC) is an important contributor to cancer-specific mortality worldwide. Targeted agents that inhibit key subtype-specific signaling pathways have improved survival times and have recently become part of the standard of care for this disease. Accurately diagnosing and classifying RCC on the basis of tumor histology is thus critical. RCC has been traditionally divided into clear-cell and non-clearcell categories, with papillary RCC forming the most common subtype of non-clear-cell RCC. Renal neoplasms with overlapping histologies, such as tumors with mixed clear-cell and papillary features and hybrid renal oncocytic tumors, are increasingly seen in contemporary practice and present a diagnostic challenge with important therapeutic implications. In this review, we discuss the histologic, immunohistochemical, cytogenetic, and clinicopathologic aspects of these differential diagnoses and illustrate how the classification of RCC has evolved to integrate both the tumor's microscopic appearance and its molecular fingerprint.

Novel anti-androgen receptor signaling agents:Understanding the mechanisms of resistance

Prostate cancer remains an intractable threat to the lives of men worldwide.Although deaths from prostate cancer(PCa)in the United States have declined in recent years,in other parts of the world Pca mortality is increasing.The introduction of 2nd generation antiandrogen receptor agents into the therapeutic armamentarium for metastatic castrationresistant prostate cancer(mCRPC)has resulted in modestly increased survival advantages as demonstrated by initial clinical trials.However,analysis of the molecular pathways affected by these agents may lead to new insight into mechanisms of resistance that drive mCRPC,including proliferation and survival signaling pathways that are derepressed by maximum repression of androgen signaling.Combination therapies that involve anti-AR signaling agents together with agents that target these pathways establish a paradigm for the development of more effective treatment of mCRPC.In this review,we briefly summarize the current clinical trial literature with regard to novel anti-AR signaling agents such as abiraterone acetate and enzalutamide.We discuss observational data that point to mechanisms of resistance that emerged from these studies.We further present and discuss recent experimental studies that address the mechanisms of resistance to these treatments.Finally,we discuss novel and rational therapeutic approaches,including combination therapy,for patients with mCRPC.

Poly （ADP-ribose） polymerase inhibitor： an evolving paradigm in the treatment of prostate cancer

Recent phase I studies have reported single-agent activities of poly （ADP-ribose） polymerase （PARP） inhibitor in sporadic and in BRCA-mutant prostate cancers. Two of the most common genetic alterations in prostate cancer, ETS gene rearrangement and loss of PTEN, have been linked to increased sensitivity to PARP inhibitor in preclinical models. Emerging evidence also suggests that PARP1 plays an important role in mediating the transcriptional activities of androgen receptor （AR） and ETS gene rearrangement. In this article, the preclinical work and early-phase clinical trials in developing PARP inhibitor-based therapy as a new treatment paradigm for metastatic prostate cancer are reviewed.

Genitourinary melanoma:An overview for the clinician

Genitourinary (GU) melanoma is a rare presentation of melanoma accounting for approximately 0.5% of all melanomas.GU melanomas include primary melanomas of the vulva,vagina,uterine cervix,ovary,penis,scrotum,urethra,bladder,ureter,and kidney.These melanomas are often diagnosed in advanced stages and stigma is thought to contribute to delays in presentation.As the likely diagnosing provider,it is imperative that dermatologists,urologists,and gynecologists are aware of these uncommon sites of presentation.While there have been major advances in the treatment of melanomas as a whole in the last 10 years,their applications to GU melanomas have often been overlooked.GU melanomas have not been included in many of the major phase II clinical trials which brought contemporary advanced treatments to market and the prognoses for GU melanomas remain poor.Due to the rarity of GU melanomas,much of the literature provides gener alized recommendations across multiple different organs affected by GU melanomas or omits certain topics,making it difficult to appreciate the funda-mentals of the individual presentations.This review aimed to provide background information on the pathogenesis and epidemiology of the different sites of GU melanomas and categorize data specific to the presentation,staging,treatment,and prognosis of each type of GU melanoma to guide the clinician.It was also meant to encourage a multidisciplinary approach to the management of these patients as it spans the expertise of surgical oncologists,medical oncologists,radiation oncologist,dermatologists,urologists,and gynecologists.

Updates in the use of radiotherapy in the management of primary and locally-advanced penile cancer

Objective:Penile cancer is a rare malignancy in most developed countries,but may represent a significant oncologic challenge in certain African,Asian,and South American regions.Various treatment approaches have been described in penile cancer,including radio-therapy.This review aimed to provide a synopsis of radiotherapy use in penile cancer management and the associated toxicities.In addition,we aimed to discuss palliative radiation for metastases to the penis and provide a brief overview of how tumor biology may assist with treatment decision-making.Methods:Peer-reviewed manuscripts related to the treatment of penile cancer with radio-therapy were evaluated by a PubMed search(1960-2021)in order to assess its role in the definitive and adjuvant settings.Selected manuscripts were also evaluated for descriptions of radiation-related toxicity.Results:Though surgical resection of the primary is an excellent option for tumor control,select patients may be treated with organ-sparing radiotherapy by either external beam radiation or brachytherapy.Data from randomized controlled trials comparing radiotherapy and surgery are lacking,and thus management is frequently determined by institutional practice patterns and available expertise.Similarly,this lack of clinical trial data leads to divergence in opinion regarding lymph node management.This is further complicated in that many cited studies evaluating lymph node radiotherapy used non-modern radiotherapy delivery techniques.Groin toxicity from either surgery or radiotherapy remains a challenging problem and further risk assessment is needed to guide intensification with multi-modal therapy.Intrinsic differences in tumor biology,based on human papillomavirus infection,may help aid future prognostic and predictive models in patient risk stratification or treatment approach.Conclusion:Penile cancer is a rare disease with limited clinical trial data driving the majority of treatment decisions.As a result,the goal of management is to effectively treat the disease while balancing the importance of quality of life through integrated multidisciplinary discussions.More international collaborations and interrogations of penile cancer biology are needed to better understand this disease and improve patient outcomes.

DNA Damage Response Inhibitor and Anti-PD-L1 Therapy for Prostate Cancer: Development of Predictive Biomarkers

1.Introduction Although androgen receptor biosynthesis and signaling inhibi-tors have significantly improved outcomes in patients with castra-tion-resistant prostate cancer(CRPC),there is still a dearth of effective treatment options for men with advanced prostate cancer.

Detection of Polymorphisms of DNA Repair Genes (XRCC1 and XPC) in Prostate Cancer

Prostate cancer is a common disease with a multifactorial and complex etiology. It is the most common male malignancy and the second leading cause of death in many countries. The widespread use of PSA testing has increased the detection of this cancer at earlier stages, although this diagnostic method has proved to be insufficient to identify the disease. DNA in most cells is regularly damaged by endogenous and exogenous mutagens. At least four main partially overlapping damage repair pathways operate in mammals. Common polymorphisms in DNA repair genes may alter protein function and an individual’s capacity to repair damaged DNA;deficits in repair capacity may lead to genetic instability and carcinogenesis. In the present study, we investigated the genotypic distribution of XRCC1 and XPC polymorphisms and its association with prostate cancer risk, pathological staging and Gleason’s scoring. The present study was conducted in the departments of Clinical Pathology, Pathology, and Urology Faculty of Medicine, Alexandria University-Egypt. A total number of 50 patients with pathologically confirmed prostate cancer and 50 age-matched control subjects were enrolled in this study. The diagnosis was made on the basis of histopathological findings, following radical prostatectomy or transurethral resection of the prostate (TURP). Genomic DNA was extracted from peripheral blood using QIAamp blood DNA isolation kits. PCR followed by enzymatic digestion of the PCR products for (XRCC1, XPC) was used for the genotyping of these polymorphisms. Statistical analyses were performed using SPSS statistics version 20. The genotype frequencies of the studied polymorphisms in all the samples (n = 100), PC patients (n = 50) and healthy controls (n = 50) were consistent with the Hardy-Weinberg equilibrium distribution (p-value > 0.05). There was no statistical difference in the genotypes of the XRCC1 Arg399Gln and XPC Lys939Gln between cases and controls. The “Gln” allele frequency of XPC Lys939Gln as well as the “Gln” allele frequency of XRCC1 Arg399Gln tended to be lower in controls than in PC patients. Yet, these decreases were not statistically significant. We also examined the combined effect of XPC and XRCC1 and we found a decreased PC risk when XPC 939 Lys/Lys + Lys/Gln and XRCC1 399 Arg/Arg + Arg/Gln are combined (OR = 0.370, 95% CI = 0.142 - 0.962).

Assessment of the expression pattern of HER2 and its correlation with HER2-targeting antibody-drug conjugate therapy in urothelial cancer

Background:Human epidermal growth factor receptor 2(HER2)overexpression is related to anti-HER2 therapy in many tumors.RC48-antibody-drug conjugate(ADC)has shown promising efficacy in patients with HER2-positive locally advanced or metastatic urothelial carcinoma(UC).The characteristic expression and scoring systems of HER2 are nonexistent in UC.We aimed to explore HER2 status and its correlation with the efficacy of HER2-targeting ADC therapy in UC.Methods:A total of 137 and 43 patients were enrolled in cohort 1 and cohort 2,respectively,from March 2009 to December 2018.The patients in cohort 2 were enrolled in a phase II study of RC48-ADC.UC samples were tested for HER2 status using immunohistochemistry(IHC)and/or fluorescence in situ hybridization(FISH).The 2018 ASCO/CAP HER2 scoring system was adopted and modified to score HER2 expression in UC.Results:The HER2-positive(IHC 2+or 3+)rate was 24.1%(33/137).In HER2 IHC 2+or 3+patients,the HER2 gene amplification rate was 31%(13/42).The objective response rates(ORRs)in RC48-ADC-treated patients with IHC 3+,IHC 2+and FISH+,IHC 2+and FISH-were 58.8%,66.7%and 40%,respectively.The ORR showed a trend toward a better benefit for RC48-ADC therapy in patients with HER2 amplification than in those without amplification(61.5%vs.44.8%,P=0.059).The heterogeneity of HER2 expression in the primary tumor was 55.5%(15/27),and the ORR was not significantly different between patients with tumor heterogeneity and homogeneity.Conclusions:IHC testing should be performed to assess the HER2 status before the initiation of HER2-ADC therapy.There was a trend toward a better benefit for patients with HER2 amplification,and tumor heterogeneity did not influence the drug efficacy.

siRNA干扰UBCH10表达对乳腺癌细胞的影响

目的:探讨UbcH10在乳腺癌细胞系MCF-7中的作用及机制。方法:使用UbcH10 siRNA干扰乳腺癌细胞系MCF-7中UbcH10的表达,并采用MTT法检测干扰后细胞的增殖变化,同时用流式细胞仪比较干扰后细胞周期的变化。结果:与正常空白对照组及siRNA阴性对照组比较,siUbcH10干扰组细胞增殖明显受抑制,转染后48h,细胞周期中G2/M期细胞比例明显增加(空白对照组9.98%,阴性对照组8.32%,干扰组18.18%)。结论:UbcH10在乳腺癌细胞周期G2/M期中发挥重要作用,抑制MCF-7中UbcH10的表达可明显抑制乳腺癌细胞增殖,UbcH10有望成为乳腺癌靶向治疗中新的潜在靶点。

Environmental and Psycho-social Factors Related to Prostate Cancer Risk in the Chinese Population:a Case-control Study

Objective To study the risk environmental and psycho-social factors associated to prostate cancer （PCa） in Chinese population. Methods 250 PCa patients and 500 controls were enrolled in this case-control study. Information was collected and logistic regression analysis was used to estimate the odds ratios （OR） and 95% confidence intervals （95% CI） for relationship between lifestyle, eating habits and psycho-social factors with PCa risk. Results Green vegetables and green tea were associated with a decreased risk of PCa （0R=0.39, 95% CI： 0.28-0.53; 0R=0.59, 95% Cl： 0.40-0.87, respectively）. Family history of PCa （0R=7.16, 95% CI： 2.01-25.49）, history of prostate diseases （0R=2.28, 95% Cl： 1.53-3.41）, alcohol consumption （0R=1.97, 95% CI： 1.33-2.90）, red meat consumption （0R=1.74, 95% CI： 1.20-2.52）, barbecued （0R=2.29, 95% CI： 1.11-4.73） or fried （0R=2.35, 95% CI： 1.24-4.43） foods were related with increased PCa risk. Negative psycho-social factors including occupational setbacks （0R=1.61, 95% CI： 2.00-2.59）, marital separation （0R=1.94, 95% CI： 1.29-2.91）, self-contained suffering {0R=2.37, 95% CI： 1.58-3.55）, and high sensitivity to the personal comments （0R=1.73, 95% CI： 1.18-2.54） were related to PCa. Conclusion Regular consumption of green vegetables and green tea may suggest protective effects on PCa. Alcohol consumption, red meat consumption and barbecued or fried foods were associated with PCa. Negative psycho-social factors may also play a role in the incidence of PCa in Chinese population.

动态增强MRI对前列腺前部癌形态学评价及其与根治性前列腺切除所见的相关性

本研究的目的是评价前列腺前部癌动态增强MRI显示的形态特征与组织病理学的相关性。对可疑前列腺癌的病人在活检前行动态增强MRI检查，将MRI上可疑前列腺前部癌且活检阳性的病人纳入分析。如有可能，在MRI和组织病理学上均分析肿瘤形态、边界、最大表面积和体积。前列腺前部肿瘤的定位根据前列腺移行带和外周带或前部纤维肌性间质的边界。

Non-seminomatous germ cell tumor with bone metastasis only at diagnosis:A rare clinical presentation

Bone metastasis of non-seminomatous germ cell tumors(NSGCT)of the testes is a rare event and even more uncommon at initial presentation.Generally,bone lesions are discovered in the presence of concurrent retroperitoneal lymph node or visceral disease.However,in this case,a 37 years old male complaining of a growing testicular mass was found to have isolated bone metastasis with associated caudaequina syndrome without apparent abnormal findings on initial computed tomography(CT)scans.Continued neurologic symptoms prompted further evaluation with magnetic resonance imaging(MRI),which demonstrated multiple sites of bone metastasis without evidence of retroperitoneal lymph node or visceral organ involvement.This case represents a rare clinical presentation and disease manifestation of NSGCT.

5%咪喹莫特乳膏引起的重度湿疹1例

Imiquimod 5%cream,an immune response modifier licensed for treatment of external ano-genital warts and superficial basal cell carcinomata,is known to cause local erythema,oedema and,rarely,exacerbation of psoriasis.We describe a case of exacerbation of eczema following application of this cream in a man with penile warts.

Penile cancer:Updates in systemic therapy

Penile cancer is a rare genitourinary malignancy with a greater incidence in parts of Asia,South America,and Africa.Outcomes are very poor in patients with advanced disease and in those who do not respond to frstine mutimodal therapy.Among systemic therapy options,platinum-based chemotherapy is used in the frst line;however,approximately half of patients do not benefit.Response rates to systeric therapy as subsequent line treatment are historically dismal.There is also a paucity of prognostic and predictive tools within the context of penile cancer.As such,there remains an urgent need to expand systemic treatment options for patients with advanced penile cancer.The purpose of this review is to summarize the existing evidence for standard-of-care lines of systemic treatment,examine the potential of novel lines of systemic therapy,and provide an update as to the status of these new therapies within the context of penile cancer.

FGF Signaling in Prostate Cancer Progression

Objective: prostate cancer is the second leading cause of cancer death in men in the United States. Localized prostate cancer can be cured by androgen ablation, but when the disease escapes the confines of the gland,

泌尿生殖医疗环境中临床诊断性活检的应用:新经验及文献回顾

Genital diseases include a wide range of lesions e.g. infectious and inflammatory. In most cases a clinical diagnosis is reached without the need for a biopsy. Nonetheless, a genital biopsy is safe and may help to confirm the diagnosis. We established a dedicated diagnostic biopsy clinic in 2003. Our objective was to evaluate the effectiveness of our diagnostic biopsy clinic and compare it with other Genitourinary medicine (GUM) clinics in the UK. A retrospective case-note study was performed on 71 patients referred to the biopsy clinic with persistent genital lesions over a 12-month period. Forty-seven biopsies were performed (71%biopsy rate). 43 specimens (92%) were appropriate for histopathological diagnosis. Of these 15%were lichen planus, 15%lichen sclerosis, 10%psoriasis, 7.5%each: eczema, Zoon’s and non-specific balanitis. The remainder represented a variety of other conditions. In 27 cases (68%) the clinical diagnosis was consistent with the histological result. The possibility of self-referral and walk-in nature of our GUM service substantially decrease the waiting times for assessment of anogenital disorders. We had a lower biopsy rate for the diagnosis of non-specific balanitis (7.5%) compared with the average rate (21.5%) in 14 UK GUM clinics and good agreement between clinical and histological diagnosis. An empirical first treatment, with simple emollients before biopsy, appears to be a safe clinical approach for the treatment of non-specific balanitis. A multidisciplinary approach (GUM physicians, dermatologists and urologists/gynaecologists) could help prevent unnecessary biopsies and improve correlation between clinical and histological diagnosis.

Profiling of immune features to predict immunotherapy efficacy

Immune checkpoint blockade(ICB)therapies exhibit substantial clinical benefit in different cancers,but relatively low response rates in the majority of patients highlight the need to understand mutual relationships among immune features.Here,we reveal overall positive correlations among immune checkpoints and immune cell populations.Clinically,patients benefiting from ICB exhibited increases for both immune stimulatory and inhibitory features after initiation of therapy,suggesting that the activation of the immune microenvironment might serve as the biomarker to predict immune response.As proof-of-concept,we demonstrated that the immune activation score(ISD)based on dynamic alteration of interleukins in patient plasma as early as two cycles(4-6 weeks)after starting immunotherapy can accurately predict immunotherapy efficacy.Our results reveal a systematic landscape of associations among immune features and provide a noninvasive,cost-effective,and time-efficient approach based on dynamic profiling of pre-and on-treatment plasma to predict immunotherapy efficacy.