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Purpose: To explore in a panel of patient-derived xenograft models of human non–small cell lung cancer (NSCLC) whether high EGFR expression, was associated with cetuximab activity.Experimental Design: NSCLC patient-derived xenograft models (n = 45) were implanted subcutaneously into panels of nude mice and randomization cohorts were treated with either cetuximab, cisplatin, cisplatin plus cetuximab, vehicle control, or else were left untreated. Responses according to treatment were assessed at week 3 by analyzing the relative change in tumor volume and an experimental analogue of the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. An EGFR IHC score was calculated for each patient-derived xenograft model and response was assessed according to EGFR expression level.Results: When tumors were stratified into high and low EGFR expression groups (IHC score threshold 200; scale 0–300), a stronger antitumor activity was seen in the high EGFR expression group compared with the low EGFR expression group in both the cetuximab monotherapy and cisplatin plus cetuximab combination therapy settings. For tumors treated with cisplatin plus cetuximab, the objective response rate was significantly higher in the high EGFR expression group compared with the low EGFR expression group (68% vs. 29%). Objective response rates were similar in high and low expression groups for tumors treated with cisplatin alone (27% vs. 24%, respectively).Conclusion: Cetuximab activity in NSCLC patient-derived xenograft models was demonstrated clearly only in tumors that expressed high levels of EGFR, as defined by an IHC score of ≥200. Clin Cancer Res; 20(17); 4478–87. ©2014 AACR.

Table S2. Mann-Whitney test P-values relating to the differences in log2 tumor/control ratios at week 3 for cetuximab monotherapy/control and cisplatin plus cetuximab/cisplatin alone between tumors with low and high EGFR expression as determined by different EGFR immunohistochemistry score thresholds.

Background To evaluate the incidence of lymph node degeneration and its association with nodal metastatic pattern in prostate cancer. Methods A retrospective analysis of the submitted lymph node specimen of 390 prostatectomies in 2011 was performed. All lymph nodes were histologically re-evaluated and the degree of lymph node degeneration e.g. lipomatous atrophy, capsular and framework fibrosis, and calcifications as well as the lymph node size were recorded. Lymph node degeneration was compared in the anatomic regions of the pelvis as well as in lymph nodes with and without metastases of prostatic cancer. Results Eighty-one of 6026 lymph nodes demonstrated metastases. Complete histologic examination with analysis of a complete cross-section was possible in 5173 lymph nodes including all lymph nodes with metastases. The incidence of lymph node degeneration was different across the various landing sites. Lymph node metastases were primarily detected in less degenerative and therefore more functional lymph nodes. In metastatic versus non-metastatic lymph nodes low lipomatous atrophy was reported in 84.0% versus 66.7% (p = 0.004), capsular fibrosis in 14.8% versus 35.4% (p p = 0.072) and framework fibrosis in 69.8% versus 75.3% (p = 0.53). Metastases were also identified more frequently in larger than in smaller lymph nodes (63.0% vs. 47.5%; p = 0.007). Conclusions Degenerative changes in pelvic lymph nodes are commonly detectable but occur with variable frequency in the various nodal landing sites in the pelvis. The degree of lymph node degeneration of single lymph nodes has a significant influence on whether a lymph node is infiltrated by tumor cells and may harbour metastases.

Background The first global lipidomic profiles associated with urothelial cancer of the bladder (UCB) and its clinical stages associated with progression were identified. Objective To identify lipidomic signatures associated with survival and different clinical stages of UCB. Design, setting, and participants Pathologically confirmed 165 bladder-derived tissues (126 UCB, 39 benign adjacent or normal bladder tissues). UCB tissues included Ta ( n =16), T1 ( n =30), T2 ( n =43), T3 ( n =27), and T4 ( n =9); lymphovascular invasion (LVI) positive ( n =52) and negative ( n =69); and lymph node status N0 ( n =28), N1 ( n =11), N2 ( n =9), N3 ( n =3), and Nx ( n =75). Results and limitations UCB tissues have higher levels of phospholipids and fatty acids, and reduced levels of triglycerides compared with benign tissues. A total of 59 genes associated with altered lipids in UCB strongly correlate with patient survival in an UCB public dataset. Within UCB, there was a progressive decrease in the levels of phosphatidylserine (PS), phosphatidylethanolamines (PEs), and phosphocholines, whereas an increase in the levels of diacylglycerols (DGs) with tumor stage. Transcript and protein expression of phosphatidylserine synthase 1 , which converts DGs to PSs, decreased progressively with tumor stage. Levels of DGs and lyso-PEs were significantly elevated in tumors with LVI and lymph node involvement, respectively. Lack of carcinoma in situ and treatment information is the limitation of our study. Conclusions To date, this is the first study describing the global lipidomic profiles associated with UCB and identifies lipids associated with tumor stages, LVI, and lymph node status. Our data suggest that triglycerides serve as the primary energy source in UCB, while phospholipid alterations could affect membrane structure and/or signaling associated with tumor progression. Patient summary Lipidomic alterations identified in this study set the stage for characterization of pathways associated with these altered lipids that, in turn, could inform the development of first-of-its-kind lipid-based noninvasive biomarkers and novel therapeutic targets for aggressive urothelial cancer of the bladder.

Biopsien gehoren zunehmend zum Standardinstrument, um Nierentumoren abzuklaren. Die Diagnostik per Nadel ist zuverlassig und liefert wichtige Ergebnisse fur die Therapie. Entscheidend ist, ausreichend qualitatives Gewebe zu entnehmen — auch als Basis fur neue diagnostische Ansatze.

Colorectal cancer (CRC) is the second leading cause for cancer-related death in industrialized nations. Nodal involvement has been identified as a relevant prognostic feature in CRC. Extra nodal metastasis (ENM) describes the spread of malignant cells beyond the nodal capsule. ENM is thought to be an independent risk factor for poor survival. This study examined ENM as an independent risk factor for poor overall survival in patients with node-positive CRC. Data from a prospectively maintained CRC database was retrospectively analyzed. Blinded slides of patients with stage III and IV CRC following radical surgical resection were re-examined for the presence of ENM. The effect of ENM on overall survival was examined using Kaplan–Meier curves. One hundred forty-seven cases with node-positive CRC (UICC stages III and IV) including 78 cases with ENM were included for analysis. ENM was seen in 60 patients with colon cancer (58.8%) and in 18 patients with rectal cancer (40%), p = 0.033. ENM-positive patients had a significantly higher odd for cancer-related death compared to ENM-negative patients ratio of [OR 0.44: 0.22–0.88, CI 95%, p = 0.021], p = 0.02. The median overall survival was significantly longer in patients without ENM, 51.0 ± 33 vs. 30.5 ± 42 months, p = 0.02. Extra nodal metastasis is an independent prognostic factor in patients with node-positive colorectal cancer. Extra nodal metastasis is associated with high odds of tumor-related mortality and poor overall survival.

Smoking is a major risk factor for the development of bladder cancer; however, the functional consequences of the carcinogens in tobacco smoke and bladder cancer–associated metabolic alterations remain poorly defined. We assessed the metabolic profiles in bladder cancer smokers and non-smokers and identified the key alterations in their metabolism. LC/MS and bioinformatic analysis were performed to determine the metabolome associated with bladder cancer smokers and were further validated in cell line models. Smokers with bladder cancer were found to have elevated levels of methylated metabolites, polycyclic aromatic hydrocarbons, DNA adducts, and DNA damage. DNA methyltransferase 1 (DNMT1) expression was significantly higher in smokers than non-smokers with bladder cancer. An integromics approach, using multiple patient cohorts, revealed strong associations between smokers and high-grade bladder cancer. In vitro exposure to the tobacco smoke carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene (BaP) led to increase in levels of methylated metabolites, DNA adducts, and extensive DNA damage in bladder cancer cells. Cotreatment of bladder cancer cells with these carcinogens and the methylation inhibitor 5-aza-2'-deoxycytidine rewired the methylated metabolites, DNA adducts, and DNA damage. These findings were confirmed through the isotopic-labeled metabolic flux analysis. Screens using smoke-associated metabolites and DNA adducts could provide robust biomarkers and improve individual risk prediction in bladder cancer smokers. Noninvasive predictive biomarkers that can stratify the risk of developing bladder cancer in smokers could aid in early detection and treatment. Cancer Prev Res; 10(10); 588–97. ©2017 AACR.

OBJECTIVES Resection of tumour spread on a very thin visceral pleura might be challenging, and collateral damage to the lung parenchyma might occur. We aimed to develop an operative technique, which might facilitate the parenchyma-sparing destruction of the visceral pleura. This experimental work investigated the effects of a neodymium:yttrium aluminum garnet (Nd:YAG) laser on the visceral pleura in an ex vivo porcine lung model. METHODS We used a diode-pumped Nd:YAG laser (Limax® 120, KLS Martin, Tuttlingen, Germany) to investigate the effects on the visceral pleural in 20 porcine lungs. The laser was applied on a standardized length in 4 different settings: Group I (80 W, 6 s), Group II (80 W, 12 s), Group III (120 W, 6 s) and Group IV (120 W, 12 s). All specimens were analysed histologically. RESULTS The mean thickness of the visceral pleura was 81 ± 10 μm. Increasing power levels and longer application duration resulted in significantly enhanced laser destruction effects. The mean depths of the carbonization zone were 142 ± 42 µm, 378 ± 137 µm, 607 ± 155 µm and 1371 ± 271 μm for Groups I-IV, respectively (P

Background Cholecystolithiasis is a highly prevalent condition in the Western world. Gallbladder stone-related conditions represent the second most common gastrointestinal pathology. Cholesterol stones represent over 80% of gallstones. Cholesterol stones develop secondary to crystallization of bile cholesterol. Water resorption from gallbladder bile via aquaporin in the gallbladder mucosa might play a role in the development of cholesterol stones. This study investigated the expression of Aquaporin-1 (AQP1) and Aquaporin-8 (AQP8) in the human gallbladder mucosa and their possible association with the formation of gallbladder stones. Methods The expression of AQP1 and AQP8 in the gallbladder mucosa was examined via immunohistochemical staining. The expression of both AQP1 and AQP8 in the gallbladder mucosa of stone carriers (study group) was compared to that of nonstone carriers (control group). Results Eighty-four gallbladder specimens from 44 male (52·2%) and 40 female (47·6%) patients were analysed. The study group included 47 specimens from stone carriers, while 37 specimens from stone-free gallbladders were included in the control group. Immunostaining for both AQP1 and AQP8 was positive in 80 cases. AQP1 was expressed both over the apical and intercellular membrane, while AQP8 was expressed only over the apical membrane. A similar distribution was recorded in specimens from the cystic duct. Immunostaining with AQP1 was generally stronger in comparison with AQP8. No significant (P > 0·05) relationship was found between aquaporin expression and the presence or absence of gallbladder stones. Conclusion AQP1 and AQP8 are both expressed in the gallbladder and cystic duct mucosa. However, their role in the development of gallbladder stones is still to be proven.

Introduction: The phase III FLEX study (NCT00148798) in advanced non-small-cell lung cancer indicated that the survival benefit associated with the addition of cetuximab to cisplatin and vinorelbine was limited to patients whose tumors expressed high lev- els of epidermal growth factor receptor (EGFR) (immunohistochem- istry score of ≥200; scale 0-300). We assessed whether the treatment effect was also modulated in FLEX study patients by tumor EGFR mutation status. Methods: A tumor mutation screen of EGFR exons 18 to 21 included 971 of 1125 (86%) FLEX study patients. Treatment outcome in low and high EGFR expression groups was analyzed across efficacy end- points according to tumor EGFR mutation status. Results: Mutations in EGFR exons 18 to 21 were detected in 133 of 971 tumors (14%), 970 of which were also evaluable for EGFR expression level. The most common mutations were exon 19 dele- tions and L858R (124 of 133 patients; 93%). In the high EGFR expression group (immunohistochemistry score of ≥200), a survival benefit for the addition of cetuximab to chemotherapy was demon- strated in patients with EGFR wild-type (including T790M mutant) tumors. Although patient numbers were small, those in the high EGFR expression group whose tumors carried EGFR mutations may also have derived a survival benefit from the addition of cetuximab to chemotherapy. Response data suggested a cetuximab benefit in the high EGFR expression group regardless of EGFR mutation status. Conclusions: The survival benefit associated with the addition of cetuximab to first-line chemotherapy for advanced non-small-cell lung cancer expressing high levels of EGFR is not limited by EGFR mutation status.

The addition of cetuximab to first-line chemotherapy substantially prolonged survival in patients with advanced non-small cell lung cancer whose tumors expressed high levels of epidermal growth factor receptor (EGFR; immunohistochemistry score of ≥200 on a scale of 0-300).To evaluate the interobserver reproducibility of this EGFR immunohistochemistry scoring system, based on both the tumor cell membrane staining intensity (graded 0-3+) and the percentage of cells staining at each intensity.In parts 1 (initial feasibility study) and 2 of this 2-part round robin test, sections of different non-small cell lung cancer tissue microarrays were stained in a central reference laboratory. Following reference evaluation, EGFR expression in 30 selected tumor cores was characterized in serial sections by lung cancer pathology specialists. The reproducibility of scoring by different raters was assessed. Analysis of between-rater agreement was based on the allocation of EGFR immunohistochemistry scores into low- (200) and high- (≥200) EGFR expression groups.After discussion with raters of the issues impacting reproducibility identified in part 1 and following adjustment of processes, part 2 of the round robin test showed a high interobserver agreement in EGFR immunohistochemistry scoring, with an overall concordance rate of 90.9% and a mean κ coefficient of 0.812. Specimens with a reference EGFR immunohistochemistry score of lower than 200 and of 200 or higher showed mean concordance rates of 94.7% and 85.6%, respectively.After appropriate training, assessing EGFR expression by this immunohistochemistry-based method allowed a highly reproducible allocation of non-small cell lung cancers into clinically relevant high- or low-EGFR expression groups.

Background In a randomised trial, radical prostatectomy (RP) followed by adjuvant radiotherapy (aRT) was compared with RP alone in patients with pT3 pN0 prostate cancer with or without positive margin at local pathology (German Cancer Society trial numbers ARO 96-02/AUO AP 09/95). Objective A pathology review was performed on 85% of RP specimens of patients to investigate the influence of pathology review on the analysis. Design, setting, and participants Patients post-RP ( n =385) were randomised before achieving an undetectable prostate-specific antigen (PSA) level to either wait and see ( n =192) or 60Gy aRT ( n =193). Of 307 patients with undetectable PSA after RP, 262 had pathology review. These results were included prospectively into the analysis. Outcome measurements and statistical analysis Agreement between local and review pathology was measured by the total percentage of agreement and by simple kappa statistics. The prognostic reliability for the different parameters was analysed by Cox regression model. Event-free rates were determined by Kaplan-Meier analysis with a median follow-up of 40 mo for the wait-and-see arm and 38.5 mo for the aRT arm. Results and limitations There was fair concordance between pathology review and local pathologists for seminal vesicle invasion (pT3c: 91%; κ=0.76), surgical margin status (84%; κ=0.65), and for extraprostatic extension (pT3a/b: 75%; κ=0.74). Agreement was much less for Gleason score (47%; κ=0.42), whereby the review pathology resulted in a shift to Gleason score 7. In contrast to the analysis of progression-free survival with local pathology, the multivariate analysis including review pathology revealed PSMs and Gleason score >6 as significant prognostic factors. Conclusions Phase 3 studies of postoperative treatment of prostate cancer should be accomplished in the future with a pathology review. In daily practice, a second opinion by a pathologist experienced in urogenital pathology would be desirable, in particular, for high-risk patients after RP.

Bei der Nachresektion nach T1-Blasentumoren kann eine exakte Relokalisation des ehemaligen infiltrativen Tumorareals wegen reaktiver Veranderungen, multipler Narben oder wechselnder Operateure erschwert sein. In unserer Untersuchung haben wir die Bedeutung der exakten Tumordokumentation und die Lokalisation und Rate der Residualtumore analysiert. Von Juli 2007 bis Februar 2012 sind an unserer Klinik 167 Nachresektionen nach einem T1 high grade-Blasentumor durchgefuhrt worden. Neben der Residualtumorrate und klinischen Parametern wurde die Lokalisation der Residualtumore untersucht, die anhand unserer standardisierten Blasentumordokumentation evaluiert wurde. Es zeigte sich eine Residualtumorrate von 58,1 % (97 von 167 Patienten). In 85,6 % (83 von 97 Patienten) der Falle war das Residuum im Bereich des ehemaligen Tumorareals: davon 41,2 % (n = 40) ausschlieslich im Areal des ehemaligen Tumors, 44,3 % (n = 43) multifokal im ehemaligen Areal und zusatzlich an neuen Arealen. Bei 11 Patienten (11,3 %) lag ein Residualtumor im Bereich des ehemaligen Tumorareals vor, welches endoskopisch vom Operateur als unauffallig eingeschatzt und erst histologisch bestatigt wurde. T1 high grade-Blasentumore zeigten eine relevante Rate von Residualtumoren in der Nachresektion, was nach unseren Ergebnissen die leitliniengerechte obligate Nachresektion rechtfertigt. In den meisten Fallen ist das ehemalige Tumorareal betroffen. Eine exakte Nachresektion des ehemaligen Tumorareals ist durch die vorgestellte Blasentumordokumentation auch bei multiplen Narben, reaktiven Veranderungen und wechselnden Operateuren gezielt moglich.

In einer urologischen Ausbildungsklinik findet ein relevanter Teil der TURB als „teaching“-Eingriff statt. Ist der Ausbildungsstand des Operateurs fur das onkologische Ergebnis bei der TURB von Bedeutung? Von Juli 2007 bis Februar 2012 sind an unserer Klinik insgesamt 254 Nachresektionen nach Ta high grade- und T1 high grade-Blasentumoren durchgefuhrt worden. Die Operateure der Primar-TURB wurden aufgeteilt je nach klinischem Ausbildungsstand in „junge Assistenten“ (1. und 2. Ausbildungsjahr), „erfahrene ­Assistenten“ (3.–5. Jahr), Facharzte, Oberarzte und Chefarzt. Wir haben die Rezidivrate der Nachresektionen mit dem jeweiligen Operateur bei Primarresektion verglichen. Initial lag ein Ta high grade-Blasentumor bei 87 Patienten (34,3%) und ein T1 high-grade Blasentumor bei 167 (67,7%) vor. Die meisten TURB wurden von „erfahrenen Assistenten“ (3.–5. Jahr) und vom Chefarzt durchgefuhrt. Der Anteil von „teaching-TURBs“ war 36,6% (n=93). Die Rezidivrate bei Nachresektion war insgesamt 52,4%. Einen signifikanten Einfluss auf die Rezidivrate hatten die Anzahl der Primartumoren, die Tumorgrose und das T-Stadium. Die jeweiligen Operateure unterschieden sich nicht signifikant in ihren Rezidivraten. Zwischen den Operateuren zeigte die Detrusorrate, als Hinweis auf eine ausreichend tiefe Resektion, keine signifikanten Unterschiede. Ein Bias, dass „jungere“ Operateure gunstigere Tumoren (solitar, kleiner als 3 cm) operiert haben, konnten wir ausschliesen. Unsere Daten zeigten keine signifikant unterschiedlichen Rezidiv-und Detrusorraten fur den jeweiligen Ausbildungsstand des Operateurs. Aus onkologischer Sicht ist eine „teaching-TURB“ unter entsprechender Anleitung mit ungestorter Kommunikation und einer personlichen Supervision sicher und einer facharztlichen TURB nicht unterlegen.

Wir haben die Wertigkeit der TURB-Nachresektion nach T1-Blasentumoren an unserer Klinik uber einen Zeitraum von 4,5 Jahren untersucht. Von Juli 2007 bis Februar 2012 sind an unserer Klinik 2172 TURB durchgefuhrt worden. Von diesen waren 1 130 Initialresektionen bei einem Erstbefund oder Rezidivtumor der Blase. Bei 258 Patienten zeigte sich ein T1-Blasentumor. Es wurden sowohl der Tumorbefund der Initial-TURB und das Ergebnis der Nachresektion evaluiert. Die Inzidenz von T1 high grade-­Tumoren war in unseren Patienten 22,8% (N=258). Von 167 Patienten, die eine Nachresektion nach T1-Blasentumor erhielten, zeigte sich ein Rezidivtumoren in 58,1% (97 Patienten). Die Rezidivtumoren waren meist multifokal (61,9%) und kleiner als 3 cm (69,1%). Die Histologie der Nachresektion zeigte Ta-Tumoren in 24,6% (41 von 167 Patienten), Persistenz von T1 high grade in 19,8% (33 von 167 Patienten) und ein Upstaging auf T2 und mehr in 6,6% (11 von 167 Patienten). Die Anzahl der Initialtumoren zeigt einen signifikanten Einfluss auf die Rezidivrate bei Nachresektion: Pa­tienten mit multifokalen Tumoren hatte ein Rezidivrate von 69%, im Gegensatz zu 46,3% bei solitaren Tumoren. Ebenso zeigte sich ein tendenzieller Einfluss fur die Tumorgrose und fur das Vorhandensein von Detrusor im Praparat. T1 high grade-Blasentumoren zeigten eine relevante Rate von Rezidivtumoren in der Nachresektion, was nach unseren Ergebnissen die leitliniengerechte obligate Nachresektion rechtfertigt. Einen signifikanten Einfluss zugunsten einer tumorfreien Nachresektion zeigt sich in unseren Daten fur solitare Tumoren. Ein tendenzieller Einfluss konnte fur Detrusor im Praparat gezeigt werden. Es scheint somit die Tiefe der Initialresektion von Bedeutung zu sein. Fur das optimale Zeitintervall zur Nachresektion gibt es derzeit noch keine Daten.

Importance Girentuximab is a chimeric monoclonal antibody that binds carbonic anhydrase IX, a cell surface glycoprotein ubiquitously expressed in clear cell renal cell carcinoma (ccRCC). Its safety and activity in phase 2 studies prompted investigation into its use as adjuvant monotherapy in participants with high-risk ccRCC. Objective To evaluate the safety and efficacy of adjuvant girentuximab on disease-free survival (DFS) and overall survival (OS) in patients with localized completely resected high-risk ccRCC. Design, Setting, and Participants The ARISER trial (Adjuvant Rencarex Immunotherapy Phase 3 Trial to Study Efficacy in Nonmetastatic RCC) was a randomized, double-blind, placebo-controlled phase 3 clinical trial that took place between June 10, 2004, and April 2, 2013, at 142 academic medical centers in 15 countries in North and South America and Europe. Eligible adult patients had undergone partial or radical nephrectomy for histologically confirmed ccRCC and fell into 1 of the following high-risk groups: pT3/pT4Nx/N0M0 or pTanyN+M0 or pT1b/pT2Nx/N0M0 with nuclear grade 3 or greater. Patients were assigned via central computerized double-blind 1:1 randomization to receive either a single loading dose of girentuximab, 50 mg (week 1), followed by weekly intravenous infusions of girentuximab, 20 mg (weeks 2-24), or placebo, stratified by risk group and region. The data were analyzed from March 31, 2012, to April 2, 2013. Main Outcomes and Measures Co–primary end points were DFS and OS, based on imaging studies assessed by independent radiological review committee. Secondary end points included safety, assessed as the rate and grade of adverse events. Results A total of 864 patients (66% male; median [interquartile range] age, 58 [51-65] years) were randomized to girentuximab (n = 433) or placebo (n = 431). Compared with placebo, participants treated with girentuximab had no statistically significant DFS (hazard ratio, 0.97; 95% CI, 0.79-1.18) or OS advantage (hazard ratio, 0.99; 95% CI, 0.74-1.32). Median DFS was 71.4 months (interquartile range, 3 months to not reached) for girentuximab and never reached for placebo group. Median OS was never reached regardless of treatment. Drug-related adverse events occurred in 185 patients (21.6%), reported comparably between arms. Serious adverse events occurred in 72 patients (8.4%), reported comparably between arms. One drug-related serious adverse event occurred in a patient receiving placebo. Conclusions and Relevance Girentuximab had no clinical benefit as adjuvant treatment for patients with high-risk ccRCC. The surprisingly long DFS and OS in these patients represent a challenge to adjuvant ccRCC drug development. Trial Registration clinicaltrials.gov Identifier:NCT00087022

Background: The phase III EXTREME study demonstrated that combining cetuximab with platinum/5-fluorouracil (5-FU) significantly improved overall survival in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) compared with platinum/5-FU alone. The aim of this investigation was to evaluate elevated tumor EGFR gene copy number as a predictive biomarker in EXTREME study patients. Patients and methods: Dual-color FISH was used to determine absolute and relative EGFR copy number. Models of differing stringencies were used to score and investigate whether increased copy number was predictive for the activity of cetuximab plus platinum/5-FU. Results: Tumors from 312 of 442 patients (71%) were evaluable by FISH and met the criteria for statistical analysis. A moderate increase in EGFR copy number was common, with high-level amplification of the gene occurring in a small fraction of tumors (∼11%). Considering each of the models tested, no association of EGFR copy number with overall survival, progression-free survival or best overall response was found for patients treated with cetuximab plus platinum/5-FU. Conclusion: Tumor EGFR copy number is not a predictive biomarker for the efficacy of cetuximab plus platinum/5-FU as first-line therapy for patients with R/M SCCHN.

Background Grading of noninvasive papillary urinary bladder carcinoma (PUC) is routinely performed in clinical oncologic practice; however, reports regarding diagnostic and prognostic accuracy are contradictory. Objective To compare the 1973 and 2004 World Health Organisation (WHO) classifications in terms of interobserver variability and prognostic implications. Design, setting, and participants Two hundred PUC were retrospectively reviewed by four independent expert genitourinary pathologists blinded with respect to patient identity and clinical outcome. Tumour grading was assigned according to the 1973 and 2004 WHO classifications. Surveying a mean postsurgical follow-up of 71.8 mo (range: 18–163 mo), clinical outcome in terms of recurrence-free and progression-free survival was recorded for all patients. Intervention All of the patients underwent transurethral resection of the bladder. Measurements The generalised κ (kappa statistic) for interobserver variability was calculated, and Kaplan-Meier analysis as well as univariate regression analysis were performed to evaluate prognostic implications in terms of recurrence and progression rates. Results and limitations During the follow-up, a total of 84 (42%) patients experienced recurrence, whereas another 18 (9%) patients featured disease progression. Owing to the rare presence of papillary urothelial neoplasms of low malignant potential (PUNLMP) in our cohort (0–3.5%), the 2004 WHO classification approached a two-tier system (low and high grade), which showed less interobserver variability than the 1973 classification (κ: 0.30–0.52 vs 0–0.37, respectively). In comparing the power of both classifications to separate indolent from aggressive PUC, striking pathologist-dependent differences became apparent. Conclusions Both WHO classifications for grading of PUC suffer from substantial interobserver variability, with the 2004 WHO classification showing less interobserver variability. Stark differences in the prognostic power of the individual grading approaches were also found. These significant differences in the individual interpretation of the WHO grading schemes for noninvasive PUC highlight the necessity of better-defined criteria for conventional tumour grading; otherwise, the subdivision into prognostically different groups by conventional histomorphology might remain of limited value.

Purpose Local failure after radical prostatectomy (RP) is common in patients with cancer extending beyond the capsule. Two randomized trials demonstrated an advantage for adjuvant radiotherapy (RT) compared with a wait-and-see policy. We conducted a randomized, controlled clinical trial to compare RP followed by immediate RT with RP alone for patients with pT3 prostate cancer and an undetectable prostate-specific antigen (PSA) level after RP. Methods After RP, 192 men were randomly assigned to a wait-and-see policy, and 193 men were assigned to immediate postoperative RT. Eligible patients had pT3 pN0 tumors. Patients who did not achieve an undetectable PSA after RP were excluded from treatment according to random assignment (n = 78; 20%). Of the remaining 307 patients, 34 patients on the RT arm did not receive RT and five patients on the wait-and-see arm received RT. Therefore, 114 patients underwent RT and 154 patients were treated with a wait-and-see policy. The primary end point was biochemical progression-free survival. Results Biochemical progression-free survival after 5 years in patients with undetectable PSA after RP was significantly improved in the RT group (72%; 95% CI, 65% to 81%; v 54%, 95% CI, 45% to 63%; hazard ratio = 0.53; 95% CI, 0.37 to 0.79; P = .0015). On univariate analysis, Gleason score more than 6 and less than 7, PSA before RP, tumor stage, and positive surgical margins were predictors of outcome. The rate of grade 3 to 4 late adverse effects was 0.3%. Conclusion Adjuvant RT for pT3 prostate cancer with postoperatively undetectable PSA significantly reduces the risk of biochemical progression. Further follow-up is needed to assess the effect on metastases-free and overall survival.

Antibodies targeting epidermal growth factor receptor (EGFR) have proven to be effective in patients with non-small cell lung cancer (NSCLC) that express EGFR. We recently published a phase I study of weekly matuzumab plus paclitaxel. This therapy was well tolerated and showed clinical responses in the majority of patients. Although matuzumab displays potent antitumor activity in some patients, not all patients respond well to treatment. Whether dysregulation of EGFR-mediated pathways precludes or sensitizes cells to paclitaxel is unknown. We sought to determine molecular predictive factors for therapy response in a phase I/II study patient cohort treated with matuzumab ± paclitaxel. Twenty-three cases [including one complete response (CR), three partial responses (PR), 10 stable diseases (SD)] were screened using immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), PCR/sequencing and denaturing wave high performance liquid chromatography (D-HPLC) for expression, amplification, and mutation status of EGFR and downstream signaling pathways. All patients with PR or CR displayed an either high overall or single-cell EGFR expression in the majority of cells. In addition, all of the moderate responders, who achieved SD after at least two cycles of therapy, showed diffuse EGFR expression rates and/or strong single-cell EGFR expression. In contrast, 44% of the nonresponders showed low overall or single-cell EGFR expression levels. No low-expressing EGFR cases were present within the responder group. In addition, among patients with a gain-of-function mutation in KRAS primary therapy failure and/or short responses to therapy were observed. Our data suggest that EGFR expression and KRAS mutation status is predictive for clinical response to matuzumab ± paclitaxel in patients with advanced NSCLC. [Mol Cancer Ther 2009;8(3):481–9]

Alpha-methylacyl-CoA racemase (AMACR, p504S), an enzyme involved in cellular energy metabolism by the oxidation of branched-chain fatty acids, is a biomarker that is known to be overexpressed in prostatic and colorectal carcinoma as well as in papillary renal cell carcinoma. We aimed to correlate its immunohistochemically detected expression with histopathological grading in noninvasive bladder cancer in order to hint at a so far unknown role of AMACR in the pathobiology of this tumor entity. Therefore, a cohort of 163 patients (mean age 65.3 years) diagnosed with noninvasive bladder cancer was immunohistochemically investigated in terms of AMACR expression. There was variable positive AMACR staining in 52 (31.9%) of the cases investigated. All tumors were graded by three independent clinical histopathologists according to the 1973 World Health Organization (WHO) and the 1998 WHO/International Society of Urological Pathology (ISUP) system. We found a significant positive correlation between AMACR expression and higher tumor grades using both histopathologic grading schemes. These novel findings clearly allow including high-grade noninvasive bladder carcinomas in the group of AMACR-positive neoplasms and might reflect a so far unknown role of AMACR racemase in the pathobiology and tumor cell energy metabolism of the latter tumor entity.

PurposeWe used targeted mass spectrometry to study the metabolic fingerprint of urothelial cancer and determine whether the biochemical pathway analysis gene signature would have a predictive value in independent cohorts of patients with bladder cancer.Materials and MethodsPathologically evaluated, bladder derived tissues, including benign adjacent tissue from 14 patients and bladder cancer from 46, were analyzed by liquid chromatography based targeted mass spectrometry. Differential metabolites associated with tumor samples in comparison to benign tissue were identified by adjusting the p values for multiple testing at a false discovery rate threshold of 15%. Enrichment of pathways and processes associated with the metabolic signature were determined using the GO (Gene Ontology) Database and MSigDB (Molecular Signature Database). Integration of metabolite alterations with transcriptome data from TCGA (The Cancer Genome Atlas) was done to identify the molecular signature of 30 metabolic genes. Available outcome data from TCGA portal were used to determine the association with survival.ResultsWe identified 145 metabolites, of which analysis revealed 31 differential metabolites when comparing benign and tumor tissue samples. Using the KEGG (Kyoto Encyclopedia of Genes and Genomes) Database we identified a total of 174 genes that correlated with the altered metabolic pathways involved. By integrating these genes with the transcriptomic data from the corresponding TCGA data set we identified a metabolic signature consisting of 30 genes. The signature was significant in its prediction of survival in 95 patients with a low signature score vs 282 with a high signature score (p = 0.0458).ConclusionsTargeted mass spectrometry of bladder cancer is highly sensitive for detecting metabolic alterations. Applying transcriptome data allows for integration into larger data sets and identification of relevant metabolic pathways in bladder cancer progression.

Bei der retroperitonealen Fibrose (RPF, Morbus Ormond) handelt es sich um eine seltene, chronische, entzundlich-fibrosierende Erkrankung des hinteren Bauchraumes. Sie ist gekennzeichnet durch die gutartige Vermehrung von retroperitonealem Weichteilgewebe. In ihrer typischen Lokalisation breitet sich die Fibrose symmetrisch um die Aorta aus, beginnt unterhalb der Nierenstielgefase und reicht bis unterhalb der Aortenbifurkation. Bei ihrer Ausbreitung erreicht die Fibrose meist als erstes Organ die Ureteren, sodass eine obstruktive Uropathie mit konsekutiver Hydronephrose die haufigste Komplikation dieser Erkrankung ist.

Recent efforts in cytogenetic and molecular genetic research have brought insights and correlations of phenotypes and genotypes in renal cell carcinoma (RCC). Based on the knowledge of these different cytogenetic pathways, an intensive research investigated molecular changes that were associated with these chromosomal aberrations. This finally led to the discovery of important tumour suppressor genes such as the von Hippel-Lindau gene ( VHL ) in clear-cell RCC and oncogenes that are involved in cell cycle regulation and differentiation. Our refined understanding of the molecular pathways involved in renal carcinogenesis has provided a rationale for novel therapeutics that specifically target molecules of aberrantly activated pathways. This article provides an overview of pathology and genetics of renal neoplasms, insights into the pivotal role of the VHL protein, a description of techniques to identify genes that might play a role in tumour biology or represent candidate diagnostic markers, and a summary of molecular targets for the therapy of RCC.

Das Kapitel bietet eine umfassende Darstellung der neoplastischen Erkrankungen der Nieren. Auf der Basis der WHO-Klassifikation wird zu den haufigen wie auch zu den seltenen Nierentumoren Stellung genommen, wobei auser der Morphologie auch die Epidemiologie und die Genetik zur Sprache kommen. Hervorgehoben wird die Differentialdiagnose der Tumoren, insbesondere unter Anwendung immunhistochemischer Marker. Makroskopie und Histologie der Tumoren werden durch reprasentatives Bildmaterial verdeutlicht.

Renal cell carcinomas (RCCs) of the clear cell type are associated with alteration of the von Hippel-Lindau (VHL) tumor suppressor gene, the subsequent stabilization and overexpression of hypoxia inducible factor (HIF), which causes upregulation of transforming growth factor-alpha (TGFα), thereby generating an autocrine loop via the epidermal growth factor receptor (EGFR). So far, there is only limited information available about the differential expression of the EGFR and TGFα in clinical samples of RCCs harboring VHL alterations. In this study, we report comparative analyses of the EGFR and TGFα protein and messenger RNA (mRNA) expression in 99 RCCs of the clear cell type including 54 tumors with known VHL status and show that in comparison to their VHL wild type (wt) counterparts, TGFα and EGFR are more frequently expressed in RCCs harboring VHL alterations. Furthermore, upregulation of EGFR but not TGFα protein expression correlated to higher tumor stage. We speculate that EGFR expression is associated with the VHL status of RCCs and discuss the findings with respect to their potential impact on novel targeted therapeutic approaches to RCC.

Membrane C1q (mC1q) of macrophages (MPhi) is a precursor of the IgG-binding serum protein C1q. Thus, mC1q potentially provides one of several Fcgamma binding sites of mature MPhi and we analyzed whether simultaneous expression occurs of established receptors for IgG, FcgammaRI, II, and III, and mC1q during in vitro differentiation of MPhi. Using flow cytometry, immunoprecipitation combined with Western blotting and Northern blot analysis mC1q was hardly detected in freshly isolated blood monocytes, but increasingly in developing monocyte-derived MPhi. Laser scanning fluorescence microscopy confirmed the membrane localization of mC1q. Two-color-staining flow cytometry experiments indicated that mC1q and all three types of FcgammaRs are simultaneously expressed on mature monocyte-derived MPhi. A high correlation was found for the expression of mC1q and FcgammaRs, in particular FcgammaRII, but not mC1q and CD14, another marker of monocytes/MPhi.

Neurofibromatosis 1 (NF1) is one of the most common autosomal dominant diseases. Although there is a considerable variability in clinical expression, NF1 is almost fully penetrant in adult patients and may be associated with a variety of skeletal anomalies. Spinal deformities are the most common skeletal manifestation, with an incidence estimated from 10-25% in various studies. Some NF1 patients have a dystrophic form of scoliosis, which is characterized by early age at onset and rapid progression. Complications have been reported during spinal instrumentation of dystrophic curves due to soft, non-resistant vertebral bony tissue, suggesting that an alteration of bone quality may occur in NF1 patients. Recent studies have suggested that decreased bone mineral density (BMD) may occur among patients with NF1. We performed a cross-sectional study on 104 adults with NF1, using quantitative ultrasonometry (QUS) to investigate whether decreased BMD is a general phenomenon in NF1 patients. The data reveal that BMD, as measured by age- and gender- adjusted Z-scores, is significantly lower in NF1 patients than in the normal reference population. The decrease in BMD appears to be even more marked among NF1 patients with scoliosis that requires surgical treatment. The findings indicate that NF1 produces a generalized alteration of bone in addition to the focal osseous dysplasias of the vertebrae, tibia, and sphenoid wing that characterize this condition. The pathological mechanism underlying these bony changes remains to be elucidated.

Colorectal tumorigenesis has been associated with the progressive acquisition of a variety of genetic alterations. These include mutations of the Ki-ras proto-oncogene in codons 12 and 13, which account for 85% of genetic changes in colorectal cancer. In murine in vitro models of oncogenic transformation, an association between ras-mediated transformation and downregulation of different components of the MHC class I antigen processing machinery (APM) has been described. In order to investigate whether this association also exists in human tumors, 10 cases of high-grade intraepithelial neoplasia (HIN), as well as primary tumors and autologous lymph node metastases from 42 patients with colorectal carcinoma, were monitored by allele-specific restriction analysis for Ki-ras mutations. In parallel, APM component expression and tumor cell proliferation were analyzed by immunohistochemistry. In comparison to autologous colorectal mucosa, TAP1, LMP2 and tapasin loss was found in 68%, 67% and 80% of HIN, respectively. In contrast, impaired TAP1, LMP2 and tapasin expression was found in 42%, 42% and 63% of primary adenocarcinomas of stage III disease and in 63%, 47% and 79% of the matched lymph node metastases, respectively. More than 60% of colorectal tumor lesions with TAP1, LMP2 and/or tapasin defects displayed Ki-ras mutations. The frequency of TAP1, LMP2 and tapasin loss varied between 33% of primary adenocarcinomas, 40% of HIN to approximately 67% of metastases. These data suggest that i) APM component deficiencies occur more frequently in Ki-ras-mutated colorectal carcinoma lesions and ii) APM abnormalities in conjunction with Ki-ras mutations appear to be associated with disease stage. These findings support the hypothesis that Ki-ras mutations may contribute to immune escape mechanisms of tumors by downregulating the MHC class I APM component expression.

Neben dem Morbus Ormond existieren noch andere gutartige Erkrankungen, die das Retroperitoneum befallen konnen und oftmals ein typisches Erscheinungsbild haben. Zu diesen Erkrankungen zahlen die Weber-Christiansche Erkrankung und die Erdheim-Chester-Krankheit, die an dieser Stelle als Beispiele ohne Anspruch auf Vollstandigkeit fungieren sollen.

Purpose: We identified novel biological markers of prognosis in primary histopathological specimens from patients with metastatic renal cell carcinoma.Materials and Methods: Apoptotic indexes (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling), proliferation rates (Ki-67 antigen), p21 (WAF1/cip1) expression and CD95 (APO-1/Fas) expression were determined in paraffin embedded nephrectomy specimens from 73 patients with histologically confirmed, progressive metastatic disease. Kaplan-Meier survival analysis, log rank statistics and 2-proportional Cox regression analysis were done to identify new risk factors in addition to conventional classification criteria, and demonstrate statistical independence.Results: Multivariate analysis indicated that primary tumor apoptosis (p = 0.0116) and the interval from diagnosis to metastatic disease (p = 0.002) had a high predictive impact on overall survival after initial diagnosis. Patients were assigned to 2 risk groups, namely ...

We describe the morphology and comparative genomic hybridization findings in a tumor for which we propose the term "spiradenocylindroma" of the kidney. The tumor arose in the wall of a renal cyst in an otherwise healthy male patient who had a favorable clinical course after nephrectomy. Tumor cells formed either large nodules exhibiting a solid or trabecular architecture with conspicuous perivascular spaces or cylindromatous small tumor cell islands arranged in a jigsaw pattern. Focally, there were interspersed tubular structures and tumor cell rosettes with central deposits of periodic acid-Schiff-positive material. A minor tumor component showed epidermoid differentiation. The tumor cells were strongly positive for cytokeratins 5/6, high molecular weight cytokeratins 34betaE12 and AE1/3, and E-cadherin, but only weakly positive for cytokeratins 7, 8, 18, 19, and epithelial membrane antigen. Focal reactivity for actin, vimentin, and S-100 protein or lysozyme and alpha 1 -antichymotrypsin within tubular and cylindromatous areas suggested myoepithelial and apocrine differentiation, respectively. By comparative genomic hybridization, the only abnormality was loss of the long arm of chromosome 16 and gain of genetic material on the short arm of chromosome 16, suggesting isochromosome i(16p). This finding is unique among renal neoplasms and implies loss of heterozygosity at 16q12-13 of the CYLD1 gene that is critically involved in the oncogenesis of familial cylindromatosis and some sporadic spiradenocylindromas. We conclude that somatic mutation of the CYLD1 gene outside the skin can have a role in the oncogenesis of tumors with cylindromatous features.

In this study, immunohistochemical staining pattern of cytochrome c oxidase subunit 1 (CCO1) was investigated in the differentiation of renal oncocytoma (RO) from eosinophilic (EoC) and classic chromophobe renal cell carcinoma (ChRCC). A feature found in ChRCC/EoC but not in RO is the predominance of a perinuclear halo when stained for CCO1. In a cohort of 103 mixed cases including 44 RO, 37 classic ChRCC and 22 EoC, the diagnosis based on this immunohistochemical feature alone was consistent with the previous routine diagnosis in 95.7%. We reached 100% specificity and 81.4% sensitivity of this pattern in ChRCC. Specificity for RO was 93.2% and sensitivity correspondingly 95.5%. We propose a novel and easily interpretable immunohistochemical method for the discrimination of benign RO from certain subtypes of malignant ChRCC. Because of strong similarity in morphology of the 2 entities the diagnosis often cannot be made based on standard histopathology alone. The study describes for the first time the formation of a perinuclear halo in CCO1 immunohistochemistry as a highly specific marker for the diagnosis of ChRCC. We think this method can be a strong amendment for routine diagnostics in renal cell carcinoma.

Objective The ARO 96-02 trial primarily compared wait-and-see (WS, arm A) with adjuvant radiation therapy (ART, arm B) in prostate cancer patients who achieved an undetectable prostate-specific antigen (PSA) after radical prostatectomy (RP). Here, we report the outcome with up to 12 years of follow-up of patients who retained a post-RP detectable PSA and received salvage radiation therapy (SRT, arm C). Methods and Materials For the study, 388 patients with pT3-4pN0 prostate cancer with positive or negative surgical margins were recruited. After RP, 307 men achieved an undetectable PSA (arms A + B). In 78 patients the PSA remained above thresholds (median 0.6, range 0.05-5.6 ng/mL). Of the latter, 74 consented to receive 66 Gy to the prostate bed, and SRT was applied at a median of 86 days after RP. Clinical relapse-free survival, metastasis-free survival, and overall survival were determined by the Kaplan-Meier method. Results Patients with persisting PSA after RP had higher preoperative PSA values, higher tumor stages, higher Gleason scores, and more positive surgical margins than did patients in arms A + B. For the 74 patients, the 10-year clinical relapse-free survival rate was 63%. Forty-three men had hormone therapy; 12 experienced distant metastases; 23 patients died. Compared with men who did achieve an undetectable PSA, the arm-C patients fared significantly worse, with a 10-year metastasis-free survival of 67% versus 83% and overall survival of 68% versus 84%, respectively. In Cox regression analysis, Gleason score ≥8 (hazard ratio [HR] 2.8), pT ≥ 3c (HR 2.4), and extraprostatic extension ≥2 mm (HR 3.6) were unfavorable risk factors of progression. Conclusions A persisting PSA after prostatectomy seems to be an important prognosticator of clinical progression for pT3 tumors. It correlates with a higher rate of distant metastases and with worse overall survival. A larger prospective study is required to determine which patient subgroups will benefit most from which treatment option.

Purpose: To explore in a panel of patient-derived xenograft models of human non–small cell lung cancer (NSCLC) whether high EGFR expression, was associated with cetuximab activity. Experimental Design: NSCLC patient-derived xenograft models (n = 45) were implanted subcutaneously into panels of nude mice and randomization cohorts were treated with either cetuximab, cisplatin, cisplatin plus cetuximab, vehicle control, or else were left untreated. Responses according to treatment were assessed at week 3 by analyzing the relative change in tumor volume and an experimental analogue of the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. An EGFR IHC score was calculated for each patient-derived xenograft model and response was assessed according to EGFR expression level. Results: When tumors were stratified into high and low EGFR expression groups (IHC score threshold 200; scale 0–300), a stronger antitumor activity was seen in the high EGFR expression group compared with the low EGFR expression group in both the cetuximab monotherapy and cisplatin plus cetuximab combination therapy settings. For tumors treated with cisplatin plus cetuximab, the objective response rate was significantly higher in the high EGFR expression group compared with the low EGFR expression group (68% vs. 29%). Objective response rates were similar in high and low expression groups for tumors treated with cisplatin alone (27% vs. 24%, respectively). Conclusion: Cetuximab activity in NSCLC patient-derived xenograft models was demonstrated clearly only in tumors that expressed high levels of EGFR, as defined by an IHC score of ≥200. Clin Cancer Res; 20(17); 4478–87. ©2014 AACR.

Objective To investigate the histological and immunohistochemical behaviour of free buccal mucosa and full-skin grafts after exposure to urine. Materials and methods A buccal mucosal graft and a full-skin graft were freely transferred into the bladder of 12 minipigs, after stripping the bladder mucosa. Endoscopic investigations were carried out 2 and 5 months after surgery, and the grafts examined after death at 7 months, both histologically and immunohistochemically. Results Shrinkage of the full-skin graft was apparent endoscopically in five cases. Of the nine full-skin grafts, four showed severe inflammatory reactions, two necrosis and two ulcerations. Conversely, the 10 buccal mucosal grafts had fewer pathological findings (three minimal inflammation and three with scars) and a pronounced similarity on immunohistochemistry. Conclusion The buccal mucosal graft showed significantly fewer adverse histopathological findings after long-term exposure to urine than the full-skin graft and is therefore a preferable material for urethral reconstruction.

Metastatic disease is a well-known complicating factor in the treatment of renal cell cancer. Whereas radical nephrectomy usually is curative in cases of localized disease, no adequate treatment has been established for metastatic renal tumors. Identification of specific chromosome changes or genes responsible for metastatic behavior may lead to new strategies of treatment in the future. In light of this, we cytogenetically analyzed a metastasis of a chromophobe renal cell carcinoma arising in a 73-year-old male and compared the results with genetic data on primary chromophobe renal tumors. The chromosomal pattern of the present case showed, next to the extensive chromosome losses specific for the chromophobe subtype, structural rearrangements involving chromosomes 1, 5, 12, 15, and 18. Determining whether or not (some of) the observed structural changes are important for the metastatic behavior of chromophobe renal cell tumors will have to await further genetic studies on metastases of renal cancer. (C) Elsevier Science Inc., 1998.

Cytogenetic and molecular genetic investigations in cancer are important tools to address problems of oncogenesis and tumor progression, of classification, and of diagnosis of tumors. A combination of advanced molecular genetic, cytogenetic, and (immuno) histopathologic analysis will contribute significantly to the elucidation of the oncogenic steps that lead to immortalization and subsequent malignant behavior. In this review written on the occasion of Dr. Avery Sandberg's 75th anniversary, we will present a model for the pathogenesis of renal cell tumors based on a new cytomorphologic classification and our (cyto)genetic analysis of about 175 renal cell tumors, together with the accumulated data in the literature.

Local failure after radical prostatectomy (RP) is common in patients with cancer extending beyond the capsule. Three prospectively randomized trials demonstrated an advantage for adjuvant radiotherapy (ART) compared with a wait-and-see (WS) policy.To determine the efficiency of ART after a 10-yr follow-up in the ARO 96-02 study.After RP, 388 patients with pT3 pN0 prostate cancer (PCa) were randomized to WS or three-dimensional conformal ART with 60 Gy. The present analysis focuses on intent-to-treat patients who achieved an undetectable prostate-specific antigen after RP (ITT2 population)--that is, 159 WS plus 148 ART men.The primary end point of the study was progression-free survival (PFS) (events: biochemical recurrence, clinical recurrence, or death). Outcomes were compared by log-rank test. Cox regression analysis served to identify variables influencing the course of disease.The median follow-up was 111 mo for ART and 113 mo for WS. At 10 yr, PFS was 56% for ART and 35% for WS (p0.0001). In pT3b and R1 patients, the rates for WS even dropped to 28% and 27%, respectively. Of all 307 ITT2 patients, 15 died from PCa, and 28 died for other or unknown reasons. Neither metastasis-free survival nor overall survival was significantly improved by ART. However, the study was underpowered for these end points. The worst late sequelae in the ART cohort were one grade 3 and three grade 2 cases of bladder toxicity and two grade 2 cases of rectum toxicity. No grade 4 events occurred.Compared with WS, ART reduced the risk of (biochemical) progression with a hazard ratio of 0.51 in pT3 PCa. With only one grade 3 case of late toxicity, ART was safe.Precautionary radiotherapy counteracts relapse after surgery for prostate cancer with specific risk factors.

Until a few years ago, the treatment options for metastatic renal cell cancer (mRCC) were very limited. The growing understanding of the molecular pathomechanisms underlying RCC allowed the development of new treatment approaches. Meanwhile, several approved target-oriented substances from different drug classes are available for mRCC. The mechanism of action of vascular endothelial growth factor (VEGF) and VEGF receptor or mTOR inhibition is well documented by phase III trials and reflected in the current guidelines. However, no predictive biomarkers have been identified in mRCC so far to demonstrate a benefit by a specific compound in an individual patient. Meanwhile, the sequential use of ‘targeted therapies' in mRCC has been established as standard treatment. The optimal sequence of available agents is still unclear. A German RCC expert panel discussed and developed an algorithm for the choices of first- and second-line treatment in mRCC based on established clinical criteria.

The chromosomal pattern of 31 specimens of chromophilic renal-cell cancer (RCC), selected according to the criteria mentioned in the classification of Thoenes and Storkel, is presented. A high male preponderance was found (8.7:1). Cytogenetic analysis revealed a typical pattern of numeric alterations specific for this sub-type in the majority of cases (i.e., -Y, +7, +12, +16, +17, and/or +20), which is different from the chromosomal patterns found in other sub-types of RCC. Gain of chromosome 20, as well as loss of the extra copy of chromosome 17 or loss of 17p, was found to be related to the higher-grade chromophilic carcinomas. None of the 14 cases examined by SSCP analysis revealed mutations of the pP53 gene, indicating that other genes at 17(p) might be important in the progression of this sub-type of RCC. (C) 1996 Wiley-Liss, Inc.

Neuroblastoma is the most frequent extracranial solid tumor of early childhood. Histologically and genetically, neuroblastoma represents a heterogeneous group of tumors with significant differences in clinical behavior. In the past, several different characteristic chromosomal aberrations of neuroblastoma have been described, of which a deletion on chromosome 1p and N-myc amplification have been shown to be of major prognostic significance. However, the role of various other nonrandom DNA imbalances in tumor development and progression needs to be clarified. Taking advantage of the recently established comparative genomic hybridization (CGH), we show that this method is able to accurately detect chromosomal imbalances of known prognostic impact. As CGH gives a comprehensive picture of genetic imbalances in just one experiment, it additionally sheds light on other abnormalities of possible prognostic relevance. We therefore recommend further use of this method not only in the field of research but also for the purpose of genetic routine diagnostics in neuroblastoma.