Michael A.S. Jewett

European Consensus Conference on Diagnosis and Treatment of Germ Cell Cancer: A Report of the Second Meeting of the European Germ Cell Cancer Consensus group (EGCCCG): Part I

OBJECTIVES The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, Amsterdam, The Netherlands. METHODS Medical oncologists, urological surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference, and incorporated the new data into updated and revised guidelines. As for the first meeting, the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. RESULTS The first part of the consensus paper describes the clinical presentation of the primary tumor, its treatment, the importance and treatment of testicular intraepithelial neoplasia (TIN), histological classification, staging and prognostic factors, and treatment of stage I seminoma and non-seminoma. CONCLUSIONS Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early- and advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

The Uncertainty Of Radio Frequency Treatment Of Renal Cell Carcinoma: Findings At Immediate And Delayed Nephrectomy

PURPOSE Radio frequency thermal therapy for the ablation of renal cell carcinoma has been reported. Outcomes are usually measured by imaging alone. We have performed ex vivo and in vivo experiments using radio frequency in porcine models in our laboratory. We now report our early experience in the treatment of renal cell carcinoma in patients who underwent post-radio frequency radical or partial nephrectomy. MATERIALS AND METHODS We treated 10 patients diagnosed with small renal masses with radio frequency. All masses were biopsied before treatment. In 4 patients 5 renal cell carcinomas were treated with radio frequency after surgical exposure of the tumor followed immediately by partial or radical nephrectomy (acute group). Six other patients were treated percutaneously with ultrasound or computerized tomography guided radio frequency under local anesthesia and intravenous sedation 7 days before partial or radical nephrectomy (delayed group). A median of 2 radio frequency cycles was applied. Mean total heating time was 17 minutes 15 seconds. Specimens were analyzed grossly and histologically. Triphasic contrast-enhanced computerized tomography and/or magnetic resonance imaging was performed before and 7 days after radio frequency treatment in the delayed group. RESULTS Mean radiological largest diameter of all 11 masses was 2.4 cm. and mean gross diameter was 2.2 cm. Pathological examination demonstrated residual viable tumor in approximately 5% of the volume in 4 of the 5 tumors in the acute group and in 3 of the 6 masses of the delayed group. In 1 delayed case the viable tumor appeared to be in contact with the renal vein. No significant complications were observed in 9 of the 10 patients. In 1 delayed case, a subcapsular hepatic hematoma, biliary fistula and pneumonia developed and resolved. CONCLUSIONS Based on our experience, we continue to consider percutaneous radio frequency for the treatment of small renal cell carcinomas as a potentially curative therapy. However, complete tumor cell death appears to be difficult to achieve with our current treatment protocol. More phase II testing is indicated to ensure that this technique is an effective and reproducible treatment alternative.

Small renal masses progressing to metastases under active surveillance: a systematic review and pooled analysis.

The authors systematically reviewed the literature and conducted a pooled analysis of studies on small renal masses who underwent active surveillance to identify the risk progression and the characteristics associated with metastases.

VHL Promotes E2 Box-Dependent E-Cadherin Transcription by HIF-Mediated Regulation of SIP1 and Snail

ABSTRACT The product of the von Hippel-Lindau gene (VHL) acts as the substrate-recognition component of an E3 ubiquitin ligase complex that ubiquitylates the catalytic α subunit of hypoxia-inducible factor (HIF) for oxygen-dependent destruction. Although emerging evidence supports the notion that deregulated accumulation of HIF upon the loss of VHL is crucial for the development of clear-cell renal cell carcinoma (CC-RCC), the molecular events downstream of HIF governing renal oncogenesis remain unclear. Here, we show that the expression of a homophilic adhesion molecule, E-cadherin, a major constituent of epithelial cell junctions whose loss is associated with the progression of epithelial cancers, is significantly down-regulated in primary CC-RCC and CC-RCC cell lines devoid of VHL. Reintroduction of wild-type VHL in CC-RCC (VHL−/−) cells markedly reduced the expression of E2 box-dependent E-cadherin-specific transcriptional repressors Snail and SIP1 and concomitantly restored E-cadherin expression. RNA interference-mediated knockdown of HIFα in CC-RCC (VHL−/−) cells likewise increased E-cadherin expression, while functional hypoxia or expression of VHL mutants incapable of promoting HIFα degradation attenuated E-cadherin expression, correlating with the disengagement of RNA polymerase II from the endogenous E-cadherin promoter/gene. These findings reveal a critical HIF-dependent molecular pathway connecting VHL, an established “gatekeeper” of the renal epithelium, with a major epithelial tumor suppressor, E-cadherin.

Contemporary Results of Percutaneous Biopsy of 100 Small Renal Masses: A Single Center Experience

PURPOSE Percutaneous biopsy of small renal tumors has not been historically performed because of concern about complications and accuracy. We reviewed our experience with percutaneous needle biopsy of small renal masses to assess the safety and accuracy of the procedure, the potential predictors of a diagnostic result and the role of biopsy in clinical decision making. MATERIALS AND METHODS A total of 100 percutaneous needle biopsies of renal masses less than 4 cm were performed between January 2000 and May 2007 with 18 gauge needles and a coaxial technique under ultrasound and/or computerized tomography guidance. A retrospective chart review was performed to document the complication rate and the ability to obtain sufficient tissue for diagnosis. Tumor size, tumor type (solid vs cystic), image guidance, biopsy number and core length were assessed for the ability to predict a diagnostic biopsy. RESULTS No tumor seeding or significant bleeding was observed. Of the core biopsies 84 (84%) were diagnostic for a malignant (66) or a benign (18) tumor. Larger tumor size and a solid pattern were significant predictors of a diagnostic result. Histological subtyping and grading were possible on core biopsies in 93% and 68% of renal cell carcinomas, respectively. A total of 20 patients underwent surgery after a diagnostic biopsy. The histological concordance of biopsies and surgical specimens was 100%. CONCLUSIONS Percutaneous needle biopsy of renal masses less than 4 cm is safe and provides adequate tissue for diagnosis in most cases. Larger tumor size and a solid pattern are significant predictors of a successful biopsy. Renal tumor biopsy decreases the rate of unnecessary surgery for benign tumors and can assist the clinician with treatment decision making, especially in elderly and unfit patients.

Stage I testicular seminoma: results of adjuvant irradiation and surveillance.

PURPOSE To assess the results of treatment and patterns of relapse in a contemporary group of patients with stage I testicular seminoma managed by adjuvant radiation therapy (RT) and surveillance. PATIENTS AND METHODS Between January 1981 and December 1991, 364 patients with stage I seminoma were treated at Princess Margaret Hospital. Of these, 194 were treated with adjuvant RT (92% received a dose of 25 Gy in 20 fractions for 4 weeks) and 172 were managed by surveillance. Two patients were included in this series twice--both had postorchiectomy RT for stage I disease, developed a contralateral seminoma, and were placed on surveillance and analyzed for outcome of both primary tumors. The median follow-up period for patients treated with adjuvant RT was 8.1 years (range, 0.2 to 12), and for patients managed by surveillance, it was 4.2 years (range, 0.6 to 10.1). RESULTS The overall 5-year actuarial survival rate for all patients was 97%, and the cause-specific survival rate was 99.7%. Only one patient died of seminoma. Of 194 patients treated with RT, 11 have relapsed, with a 5-year relapse-free rate of 94.5%. Prognostic factors for relapse included histology, tunica invasion, spermatic cord involvement, and epididymal involvement. Twenty-seven patients developed disease progression on surveillance, which resulted in a 5-year progression-free rate of 81.9%. The only factor identified to predict progression on surveillance was age at diagnosis: patients aged < or = 34 years had a 26% risk of progression at 5 years, in contrast to a 10% risk of progression in those greater than 34 years of age. CONCLUSION The outcome of patients with stage I testicular seminoma is excellent, with only one of 364 patients (0.27%) dying of disease. In our experience, both a policy of adjuvant RT and of surveillance resulted in a high probability of cure. Our surveillance experience showed that four of five patients with stage I seminoma are cured with orchiectomy alone. The benefit of adjuvant RT was reflected in a decreased relapse rate. We have identified a number of prognostic factors for relapse in patients managed with both approaches, but further study of prognostic factors is required, particularly to identify patients at high risk of disease progression on surveillance.

Comparison of Health-Related Quality of Life 5 Years After SPIRIT: Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial

PURPOSE The American College of Surgeons Oncology Group phase III Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial comparing radical prostatectomy (RP) and brachytherapy (BT) closed after 2 years due to poor accrual. We report health-related quality of life (HRQOL) at a mean of 5.3 years for 168 trial-eligible men who either chose or were randomly assigned to RP or BT following a multidisciplinary educational session. PATIENTS AND METHODS After initial lack of accrual, a multidisciplinary educational session was introduced for eligible patients. In all, 263 men attended 47 sessions. Of those, 34 consented to random assignment, 62 chose RP, and 94 chose BT. Five years later, these 190 men underwent HRQOL evaluation by using the cancer-specific 50-item Expanded Prostate Cancer Index Composite, the Short Form 12 Physical Component Score, and Short Form 12 Mental Component Score. Response rate was 88.4%. The Wilcoxon rank sum test was used to compare summary scores between the two interventions. RESULTS Of 168 survey responders, 60.7% had BT (9.5% randomly assigned) and 39.3% had RP (9.5% randomly assigned). Median age was 61.4 years for BT and 59.4 for RP (P = .05). Median follow-up was 5.2 years (range, 3.2 to 6.5 years). For BT versus RP, there was no difference in bowel or hormonal domains, but men treated with BT scored better in urinary (91.8 v 88.1; P = .02) and sexual (52.5 v 39.2; P = .001) domains, and in patient satisfaction (93.6 v 76.9; P < .001). CONCLUSION Although treatment allocation was random in only 19%, all patients received identical information in a multidisciplinary setting before selecting RP, BT, or random assignment. HRQOL evaluated 3.2 to 6.5 years after treatment showed an advantage for BT in urinary and sexual domains and in patient satisfaction.

Treatment of Localised Renal Cell Carcinoma

CONTEXT The increasing incidence of localised renal cell carcinoma (RCC) over the last 3 decades and controversy over mortality rates have prompted reassessment of current treatment. OBJECTIVE To critically review the recent data on the management of localised RCC to arrive at a general consensus. EVIDENCE ACQUISITION A Medline search was performed from January 1, 2004, to May 3, 2011, using renal cell carcinoma, nephrectomy (Medical Subject Heading [MeSH] major topic), surgical procedures, minimally invasive (MeSH major topic), nephron-sparing surgery, cryoablation, radiofrequency ablation, surveillance, and watchful waiting. EVIDENCE SYNTHESIS Initial active surveillance (AS) should be a first treatment option for small renal masses (SRMs) <4 cm in unfit patients or those with limited life expectancy. SRMs that show fast growth or reach 4 cm in diameter while on AS should be considered for treatment. Partial nephrectomy (PN) is the established treatment for T1a tumours (<4 cm) and an emerging standard treatment for T1b tumours (4-7 cm) provided that the operation is technically feasible and the tumour can be completely removed. Radical nephrectomy (RN) should be limited to those cases where the tumour is not amenable to nephron-sparing surgery (NSS). Laparoscopic radical nephrectomy (LRN) has benefits over open RN in terms of morbidity and should be the standard of care for T1 and T2 tumours, provided that it is performed in an advanced laparoscopic centre and NSS is not applicable. Open PN, not LRN, should be performed if minimally invasive expertise is not available. At this time, there is insufficient long-term data available to adequately compare ablative techniques with surgical options. Therefore ablative therapies should be reserved for carefully selected high surgical risk patients with SRMs <4 cm. CONCLUSIONS The choice of treatment for the patient with localised RCC needs to be individualised. Preservation of renal function without compromising the oncologic outcome should be the most important goal in the decision-making process.

Contemporary Management of Small Renal Masses

CONTEXT An increasing number of small renal masses (SRMs) with heterogeneous histology and clinical behaviour are being detected with modern radiologic imaging. Although surgical removal is the standard of care for small renal tumours, alternative minimally invasive and conservative treatment options are possible in selected patients with shorter life expectancy. OBJECTIVE To systematically review indications, techniques, and outcomes of surgical and conservative treatments of SRMs. EVIDENCE ACQUISITION A literature search of English-language publications was performed using the Medline database from January 2000 to February 2011 using the terms renal mass and renal carcinoma in conjunction with the evaluated management options. The articles that provided the highest level of evidence were selected with the consensus of all the authors and reviewed. EVIDENCE SYNTHESIS Only one randomised controlled trial comparing the results of elective nephron-sparing surgery and radical nephrectomy for low-stage renal tumours is available. Few comparative studies of different treatment options for SRMs have been published. The assessment of oncologic outcomes is therefore based mainly on observational studies. Most series of nonsurgical therapies have strong selection biases and relatively short follow-up. Treatment selection is based on the clinical and histologic characteristics of SRMs, on patient age and comorbidities, and on personal preferences and experience of the urologist. CONCLUSIONS Partial nephrectomy (PN) is the standard treatment for solitary SRMs whenever it is technically feasible. Laparoscopic PN is an alternative to open PN in experienced hands. The rationale of ablative treatments is to treat incidental cortical SRMs in patients at high surgical risk with potentially reduced morbidity. Active surveillance is considered an appropriate strategy for the elderly or for patients with significant comorbidity who have a shorter life expectancy. Percutaneous biopsies are increasingly being used to establish histology of SRMs and support treatment decisions, especially for patients who are candidates for nonsurgical treatment.

Human HIF-3α4 is a dominant-negative regulator of HIF-1 and is down-regulated in renal cell carcinoma

A universal response to changes in cellular oxygen tension is governed by a family of heterodimeric transcription factors called hypoxia‐inducible factor (HIF). Tumor hypoxia, as well as various cancer‐causing mutations, has been shown to elevate the level of HIF‐1α, signifying a critical role of the HIF pathway in cancer development. The recently identified third member of the human HIF‐α family, HIF‐3α, produces multiple splice variants that contain extra DNA binding elements and protein‐protein interaction motifs not found in HIF‐1α or HIF‐2α. Here we report the molecular cloning of the alternatively spliced human HIF‐3α variant HIF‐3α4 and show that it attenuates the ability of HIF‐1 to bind hypoxia‐responsive elements located within the enhancer/promoter of HIF target genes. The overexpression of HIF‐3α4 suppresses the transcriptional activity of HIF‐1 and siRNAmediated knockdown of the endogenous HIF‐3α4 increases transcription by hypoxia‐inducible genes. HIF‐3α4 itself is oxygen‐regulated, suggesting a novel feedback mechanism of controlling HIF‐1 activity. Furthermore, the expression of HIF‐3α4 is dramatically down‐regulated in the majority of primary renal carcinomas. These results demonstrate an important dominant‐negative regulation of HIF‐1‐mediated gene transcription by HIF‐3α4 in vivo and underscore its potential significance in renal epithelial oncogenesis. Maynard, M. A., Evans, A. J., Hosomi, T., Hara, S., Jewett, M. A. S., Ohh, M. Human HIF‐3α4 is a dominant‐negative regulator of HIF‐1 and is down‐regulated in renal cell carcinoma. FASEB J. 19, 1396–1406 (2005)