Complex treatment of residual metastatic germ cell cancer: A single center experience.

BACKGROUND: Testicular cancer is the most common solid malignancy among men aged 15-35. Radical orchiectomy and platinum-based chemotherapy (BEP) are curative in the majority of patients, including advanced, metastatic cases. According to current urooncology guidelines all non-seminoma patients harbouring post-chemotherapy residual masses of ≥ 1 cm should undergo salvage retroperitoneal lymph node dissection (RPLND). However, only 10% of residual tumors contain viable disease. OBJECTIVE: To assess patient outcomes and complications considering different treatment regimens and clinical characteristics. MATERIALS AND METHODS: In a retrospective cross-sectional study patients (n=127) who underwent postchemotherapy RPLND between 2007 and 2023 at our referral center were evaluated. The patients received systemic treatment at various oncology centers. The number of BEP cycles received were occasionally different from standard. Only patients with normal postchemotherapy serum tumor markers and primary testicular or extragonadal germ cell neoplasms were included. Treatment groups were established according to the number of BEP cycles received, and the extent of RPLND (bilateral or modified template). Treatment outcomes and complications were assessed. RESULTS: Standard 3-4 courses of BEP were received by 100 (78,7%) patients, while 11 (8,7%) patients underwent less, and 16 (12,6%) more courses than standard. On histopathologic evaluation viable germ cell tumor, teratoma, and necrosis/fibrosis was present in 26 (20,5%), 67 (52,7%) and 34 (26,8%) of specimen, respectively. In the 5-6 BEP series subgroup high rate of viable disease (37,5%) was found and significantly more nephrectomies were performed, than other chemotherapy subgroups. Extratesticular GCT, viable disease in residual mass or progression after RPLND indicated lower survival. Mild (Clavien-Dindo I-II) or no postoperative complications were reported in 93,7% of cases. CONCLUSIONS: The study suggests no significant benefit from exceeding 3-4 courses of BEP. Timely salvage RPLND should be performed in high volume centers for optimal treatment outcomes with acceptable complication rates. Adherence to the Heidenreich criteria is advisable where practical.

G Protein Coupled Receptor 87 (GPR87) in End Stage Kidney and Associated Tumors.

BACKGROUND/AIM: End-stage renal disease (ESRD) and acquired cystic renal disease (ACRD) are characterized by progressive inflammation, structural remodeling and by development of unique cancer types. Eosinophilic-vacuolated and chromophobe-like renal cell carcinoma develop exclusively in ACRD kidney. The aim of the study was to investigate the molecular mechanism of ESRD/ACRD carcinogenesis. MATERIALS AND METHODS: Our previous Affymetrix array analysis detected GPR87 as one of the highly and specifically expressed genes in ESRD/ACRD kidneys. In this study we analyzed normal and ESRD/ACRD kidneys and related tumors for GPR87 expression by PCR, RT-PCR, and immunohistochemistry. RESULTS: Immunohistochemistry revealed a strong GPR87 expression in proliferating epithelial cells in ESRD/ACRD kidneys and in cells of eosinophilic-vacuolated and chromophobe-like renal cell carcinoma. CONCLUSION: GPR87 signaling plays an important role in the structural remodeling of ESRD/ACRD kidney and development of ACRD-associated tumors with unique histology.

FAPα and αSMA mark different subsets of fibroblasts in normal kidney and conventional renal cell carcinoma.

Several studies suggested a correlation between cancer associated fibroblasts (CAF) and cancer progression, but data on conventional renal cell carcinoma (cRCC) is still lacking. We aimed to analyse the impact of αSMA positive myo-CAF and FAPα expressing i-CAF on postoperative relapse of cRCC. We applied immunohistochemistry on tissue-multiarray (TMA) containing 736 consecutively operated cRCC without metastasis at the time of diagnosis. We analysed the correlation between the amount and pattern of αSMA and FAPα expressing CAFs and tumour cells and postoperative tumour relapse. Stromal fibroblasts of each cRCC displayed αSMA immunreaction but only 142 of the 736 tumours showed positive FAPα staining. There was no correlation between the amount of αSMA and or FAPα positive CAFs and tumour progression. However, tumours with large tourtous vessels with strong αSMA positive immunreaction have more then two times higher risk of postoperative tumour relapse (RR=2.198, p = 0.005). Patients with cRCC (57) showing cytoplasmic αSMA staining of tumour cells had a nearly two times higher risk for postoperative progression (RR=1.776, p = 0.014). There is no significant correlation between the density of αSMA or FAPα positive CAFs and postoperative relapse of cRCCs, therefore CAFs in cRCC are not suitable targets for therapy. Further limitation of anti-CAF therapy of cRCC that stromal cells of normal kidney are positive with αSMA antibody.

The first experience in Hungary with split-course multimodal treatment in high risk bladder cancer / Az osztott dózisú trimodális kezelés elso hazai alkalmazása nagy kockázatú húgyhólyagdaganat esetében.

Összefoglaló. Az izominvazív vagy nagyon nagy kockázatú, felületes hólyagdaganatok kezelésének arany standardja a radikális húgyhólyag-eltávolítás (cystectomia). Válogatott betegek esetében hasonló hatékonyságú kezelés lehet az osztott dózisú (split-course) trimodális terápia, az endoszkópos tumorreszekció és a kemoirradiáció megszakított ciklusokkal történo alkalmazása. A split-course trimodális terápia a radikális cystectomiához hasonló eredményességu, a késobbi életminoség szempontjából pedig ígéretes kezelési lehetoség lehet megfeleloen kiválasztott betegek esetében. Hazánkban elso alkalommal végzett kezelést ismertetünk a téma szakirodalmi áttekintése mellett. A húgyhólyagtumor transurethralis reszekciója, maximális eradikációja után kemoirradiáció kezdodik, melyet 45 Gy sugárdózis elérésekor ismételt szövettani mintavétel szakít meg. Negatív szövettani eredmény esetén a megkezdett terápia a teljes dózis eléréséig folytatandó. Amennyiben a reszekció során élo tumor észlelheto, a radikális mutét elvégzése javasolt. A korábban transurethralis daganatreszekción négyszer átesett 54 éves beteg lokális immunterápia utáni recidívájának szövettana pT1, 'high grade' urothelialis carcinoma volt. A jól informált, kiváló fizikális statusú beteg kérését figyelembe véve split-course trimodális kezelést végeztünk. Negatív 'staging' vizsgálatok után maximális endoszkópos reszekció, majd kemoirradiáció következett. A 45 Gy besugárzás elérésekor elvégzett ismételt mintavétel azonnal feldolgozott szövettana negatív eredményt mutatott, így késedelem nélkül folytatódott a kemoirradiációs kezelés. Az eddigi kontrollvizsgálatok alapján a beteg komplett remisszióban van. A split-course trimodális terápia a radikális hólyageltávolítás megfelelo alternatívája jól informált, gondosan megválogatott betegek esetében. A szervmegtartó eljárás jobb életminoséget eredményezhet, ugyanakkor a beteget feltétlenül tájékoztatni kell, hogy sikertelenség esetén a radikális mutét is szükségessé válhat. A kezelés sikeres menedzselése csak a társszakmák szoros, jól tervezett együttmuködésével lehetséges. Orv Hetil. 2021; 162(50): 2017-2022. Summary. While radical cystectomy remains the gold standard to treat muscle-invasive or very high risk superficial bladder cancer, well selected patients can be offered split-course multimodal treatment as a similarly effective alternative, combining endoscopic tumor resection and split-course chemoradiotherapy. In highly selected patients, split-course trimodality therapy can lead to survival rates comparable to radical cystectomy with better quality of life outcomes. We present our experience with split-course trimodality treatment used for the very first time in Hungary. Maximal transurethral resection of bladder neoplasm is followed by chemoradiotherapy with repeated bladder biopsy after 45 Gy of irradiation. With negative biopsy results, chemoirradiation should be continued until full dose given. Salvage cystectomy is recommended if viable tumor is detected. Our patient (54), who previously underwent four transurethral bladder tumor resections and local immunotherapy, presented with pT1, high grade urothelial carcinoma recurrence. The well-informed, high performance status patient opted for split-course trimodality treatment. After negative staging scan results, the patient underwent complete endoscopic tumor eradication, followed by chemoradiotherapy. After 45 Gy of irradiation, repeated bladder biopsy was performed. The immediate histopathological examination found no viable tumor, therefore chemoradiotherapy was completed. Follow-up examinations suggest our patient in complete remission. Split-course trimodality treatment can be offered to well-informed and selected patients as a reasonable alternative to radical cystectomy. Though the bladder-sparing approach results in better quality of life, patients must know that in the case of treatment failure, radical cystectomy will likely be offered. Excellent multidisciplinary cooperation is a key to conduct this treatment alternative successfully. Orv Hetil. 2021; 162(50): 2017-2022.

Development and Initial Testing of a Modified UroVysion-Based Fluorescence In Situ Hybridization Score for Prediction of Progression in Bladder Cancer.

OBJECTIVES: Our aim was to predict progression of non-muscle-invasive bladder urothelial carcinomas (NMIUCs) into muscle-invasive disease by assessing cytogenetic abnormality of tumors with a new UroVysion scoring system. METHODS: Seventy-five bladder cancer cases (including 57 NMIUCs) were classified according to the quantitatively assessed degree of UroVysion-detected chromosomal abnormalities into urine fluorescence in situ hybridization score (UFS) groups: UFS I, II, and III. Cox time-to-event, Kaplan-Meier, and C-statistics analyses were performed. RESULTS: UFS proved to be an independent prognostic factor of progression-free survival (PFS) and time to progression (TTP). NMIUCs with UFS III had a 34.05-fold increased hazard for progression to muscle-invasive cancer (TTP; 95% confidence interval, 5.841-198.5; P < .001) in comparison with UFS I to II cases. The addition of UFS to conventional risk scores increased the C-index for PFS and TTP. CONCLUSIONS: UFS can indicate an increased risk for progression into muscle-invasive disease in patients with NMIUC and improves prognostic accuracy of the current clinical risk assessment systems.

Lack of TMEM27 expression is associated with postoperative progression of clinically localized conventional renal cell carcinoma.

PURPOSE: In spite of early detection of conventional renal cell carcinoma (RCC) by widespread use of abdominal imaging, approximately 10-15 % of patients will die due to disease. The aim of this study was to identify new biomarkers predicting the postoperative progression of conventional RCC. METHODS: Tissue multiarrays (TMA) of conventional RCC from a cohort of 486 patients were analysed by immunohistochemistry for expression of the transmembrane protein TMEM27, which was identified as a candidate biomarker by Affymetrix U133 Plus 2.0 array. Univariate and multivariate Cox regression models were addressed to assess cancer-specific survival in association with clinicopathological variables and TMEM27 expression. Cancer-specific survival time was estimated with Kaplan-Meier analysis, and the comparison of survival curves was made with the log-rank test. RESULTS: The Kaplan-Meier survival analysis indicated a poor disease-specific survival rates for tumours without TMEM27 staining. Univariate analysis revealed an association of patient survival with T stadium, grade, stage and size of tumour and TMEM27 expression in all cases as well as in the cohort of patients with postoperative tumour progression. In multivariate analysis, only T stadium and TMEM27 staining showed a significant association with postoperative cancer-specific death (p < 0.001). CONCLUSIONS: Lack of expression of the TMEM27 in conventional RCC defines a group of patients at high risk for cancer-related death.

Sciellin is a marker for papillary renal cell tumours.

There are no adequate immunohistochemical markers for papillary renal cell tumours. The aim of this study was to establish a gene expression profile of papillary renal cell tumours using an expression microarray approach. Through hierarchical clustering and significant analysis of microarrays, we have selected the best 13 genes and analysed their expression by real-time polymerase chain reaction (RT-PCR). Of these genes, we selected SCEL as potential marker of interest. Immunohistochemical staining of tissue microarrays containing all major types of kidney cancers revealed positive staining for sciellin in 87 of 114 papillary renal cell tumours and in 13 of 19 precursor lesions. No other renal tumour types were positive for sciellin. Our study indicates that although not all tumours express sciellin, its expression may help to confirm the diagnosis papillary renal cell tumour.

Homozygous losses detected by array comparative genomic hybridization in multiplex urothelial carcinomas of the bladder.

Urothelial carcinomas (UCs) may present at first as a solitary or multifocal neoplasm. We applied high resolution array comparative genomic hybridization to 24 solitary and 32 multiplex UCs and used the hidden Markov model algorithm to identify the copy number changes at the probe level. Copy number losses and homozygous deletions at the chromosome 9p region affecting the CDKN2A and MTAP genes were the most frequent alterations in both groups of tumors. We have delineated two new tumor suppressor gene regions at chromosome 9p that harbor the PTPRD and BNC2 genes. Copy number losses at chromosomal regions 2q, 8p, and 18p occurred preferentially in solitary UCs, whereas multiplex UCs displayed loss of large chromosomal regions at 9q, 10q, 11q, 18q, and 21q. Homozygous deletions harboring loci of cell adhesion genes such as claudins, desmocollins, and desmogleins were seen exclusively in multiplex UCs. Amplifications occurred only in invasive G3 UCs irrespective of staging. Our study suggests that solitary and multiplex UCs may have divergent genetic pathways. The biallelic inactivation of cellular adhesion genes by homozygous deletions in multiplex UCs may explain the frequent intravesical spreading of tumor cells. .

[New methods in the treatment of localized prostate cancer: use of dynamic arc therapy and kV cone-beam CT positioning]. / Új módszerek a prosztatadaganatok sugárkezelésében: dinamikus ívbesugárzás és kilovoltos "cone-beam" komputertomográfiás ellenorzés.

INTRODUCTION: Prostate cancer is a common disease among elderly male patients in developed countries. In addition to prostatectomy, definitive irradiation plays an increasing role in the treatment of localized disease. AIM: The authors wanted to share their experience obtained with the use of the Novalis TX linear accelerator for the application of dose-escalation, dynamic, intensity modulated arc therapy with the routine usage of cone-beam computer tomography based or image guided radiotherapy in patients with prostate cancer. METHOD: Between 2011, December and 2013, February the authors performed 102 treatments. In 10 low risk and 10 high risk prostate cancer patients (median age: 72.5 years) three-dimensional conformal plans with the same target volume coverage were created and tolerance doses of organs at risk (OAR) were compared. RESULTS: Compared to three-dimensional conformal techniques, intensity modulated arc therapy treatments produced a significantly lower dose at organ at risk that led to a more favorable early toxicity rate. CONCLUSIONS: The intensity modulated arc therapy with image guided radiotherapy proved to be a safe standard treatment mode in the daily routine in the institute of the authors. Late toxicity and local control rates need to be further examined.

P53 mutation and LOH at chromosome 9 in urothelial carcinoma.

BACKGROUND: Mutation of the p53 gene has been implicated in the development of carcinoma in situ (CIS) to invasive solid urothelial carcinomas (UC) whereas loss of heterozygosity (LOH) at chromosome 9 has been suggested to plag part in the development of papillary UCs. PATIENTS AND METHODS: The p53 mutation and LOH at chromosomes 17p13.1 and 9 were analysed in 120 UCs. Tumor and matched normal DNA were used for microsatellite allelotyping of chromosome 17p and the entire chromosome 9. RESULTS: LOH at 17p13.1 was found in each grade and stage of the UCs, but mutation of the p53 occurred only in the highly malignant G3 tumors including papillary pT1G3 UCs. LOH were found at one or more of the seven tumor suppressor gene loci along chromosome 9 in all but two of the UCs with p53 mutation. CONCLUSION: Mutation of the p53 gene is not a pathway correlated genetic change, but is associated with the increased cell proliferation of G3 UCs.

Laparoscopic repair of circumcaval ureter: one-year follow-up of three patients and literature review.

OBJECTIVES: To describe our experience and 1-year follow-up of 3 patients with circumcaval ureter (CU) treated laparoscopically, with the introduction of a new stenting method and review of the published data. Because of its rarity, more reports are needed to advocate more comprehensive knowledge about the preferred surgical technique for the treatment of CU. METHODS: Since November 2005, 3 patients with symptomatic CU have undergone laparoscopic repair of their anomaly at our institutes. In all 3 cases, the ureter was transected and positioned anteriorly with an end-to-end anastomosis. In 2 cases, the retrocavally located ureteral segment was resected. RESULTS: The mean operative time in our series was 210 minutes, without any intraoperative or early postoperative complications. In 1 patient, a slight ureteral stricture was detected that resolved with reinsertion of a double-J stent. Histopathologic examination of the resected ureteral segments revealed sclerosis and muscular hypertrophy. All patients remained symptom free during the 1 year of follow-up. CONCLUSIONS: With all the advantages of a minimally invasive procedure and preserving therapeutic efficacy, the laparoscopic approach should be considered a standard choice for surgical treatment of CU in symptomatic patients. Care should be taken to diagnose and excise the pathologically narrowed ureteral segment.

Deletion of chromosome 3p14.2-p25 involving the VHL and FHIT genes in conventional renal cell carcinoma.

Loss of heterozygosity (LOH) at chromosome 3p and inactivation of the VHL gene are associated with the development of conventional renal cell carcinomas (RCCs). Recently, it was suggested that LOH at the FHIT gene at 3p14.2 is an early event in the development of RCC and is characteristic for all types of RCC. We have analyzed 88 conventional, 30 papillary, and 22 chromophobe RCCs for LOH at the VHL and FHIT regions and at other loci on chromosome 3p. A continuous deletion of 3p14.2-p25 harboring the VHL and FHIT genes occurred in 96% of the conventional RCCs but only in 10% of the papillary RCCs and 18% of the chromophobe RCCs. Our data indicate that LOH at chromosome 3p14.2-p25 is specific for conventional RCC and that loss of one allele of both the VHL and FHIT genes occurs in early stage of tumorigenesis.