Jan Roigas

Positive Surgical Margin Appears to Have Negligible Impact on Survival of Renal Cell Carcinomas Treated by Nephron-Sparing Surgery

BACKGROUND The occurrence of positive surgical margins (PSMs) after partial nephrectomy (PN) is rare, and little is known about their natural history. OBJECTIVE To identify predictive factors of cancer recurrence and related death in patients having a PSM following PN. DESIGN, SETTING, AND PARTICIPANTS Some 111 patients with a PSM were identified from a multicentre retrospective survey and were compared with 664 negative surgical margin (NSM) patients. A second cohort of NSM patients was created by matching NSM to PSM for indication, tumour size, and tumour grade. MEASUREMENTS PSM and NSM patients were compared using student t tests and chi-square tests on independent samples. A Cox proportional hazards regression model was used to test the independent effects of clinical and pathologic variables on survival. RESULTS AND LIMITATIONS Mean age at diagnosis was 61+/-12.5 yr. Mean tumour size was 3.5+/-2 cm. Imperative indications accounted for 39% (43 of 111) of the cases. Some 18 patients (16%) underwent a second surgery (partial or total nephrectomy). With a mean follow-up of 37 mo, 11 patients (10%) had recurrences and 12 patients (11%) died, including 6 patients (5.4%) who died of cancer progression. Some 91% (10 of 11) of the patients who had recurrences and 83% of the patients (10 of 12) who died belonged to the group with imperative surgical indications. Rates of recurrence-free survival, of cancer-specific survival, and of overall survival were the same among NSM patients and PSM patients. The multivariable Cox model showed that the two variables that could predict recurrence were the indication (p=0.017) and tumour location (p=0.02). No other variable, including PSM status, had any effect on recurrence. None of the studied parameters had any effect on the rate of cancer-specific survival. CONCLUSIONS PSM status occurs more frequently in cases in which surgery is imperative and is associated with an increased risk of recurrence, but PSM status does not appear to influence cancer-specific survival. Additional follow-up is needed.

Prognostic accuracy of individual uropathologists in noninvasive urinary bladder carcinoma: a multicentre study comparing the 1973 and 2004 World Health Organisation classifications.

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.

Evaluation of Magnetic Fluid Hyperthermia in a Standard Rat Model of Prostate Cancer

PURPOSE To examine the feasibility and potential of magnetic fluid hyperthermia (MFH) as a minimally invasive method for hyperthermia treatment of prostate cancer. MATERIALS AND METHODS Orthotopic Dunning R3327 prostate tumors were induced in 20 male Copenhagen rats. The animals either received MFH treatment following intratumoral administration of magnetic fluids or were used as either tumor growth controls for determination of iron distribution in selected organs or as histologic controls without MFH treatment. The MFH treatments were carried out at 45 degrees C or 50 degrees C using an AC magnetic field applicator system designed for small animals. RESULTS Sequential treatments with MFH were possible following a single intratumoral injection of magnetic fluid. Intratumoral temperatures of 50 degrees C and more were obtained and were monitored online using fluoro-optic thermometry. Four days after MFH treatments, 79% of the injected dose of ferrites was still present in the prostate. CONCLUSIONS The successful intraprostatic nanoparticle infiltration and stable steady-state intratumoral treatment temperatures demonstrate the feasibility of MFH in a prostate cancer model. Efficacy and survival benefit must be confirmed in further experiments.

Can Tyrosine Kinase Inhibitors be Discontinued in Patients with Metastatic Renal Cell Carcinoma and a Complete Response to Treatment? A Multicentre, Retrospective Analysis

BACKGROUND Discontinuation of treatment with tyrosine kinase inhibitors (TKIs) and readministration in case of recurrence could improve quality of life (QoL) and reduce treatment costs for patients with metastatic renal cell carcinoma (mRCC) in which a complete remission (CR) is achieved by medical treatment alone or with additional resection of residual metastases. OBJECTIVE To evaluate whether TKIs can be discontinued in these selected patients with mRCC. DESIGN, SETTING, AND PARTICIPANTS A retrospective analysis of medical records and imaging studies was performed on all patients with mRCC treated with TKIs (n=266) in five institutions. Patients with a CR under TKI treatment alone or with additional metastasectomy of residual disease following a partial response (PR), in which TKIs were discontinued, were included in the analysis. Outcome criteria analysed were time to recurrence of previous metastases, occurrence of new metastases, symptomatic progression, improvement of adverse events, and response to reexposure to TKIs. INTERVENTIONS Sunitinib 50mg/day for 4 wk on and 2 wk off, sorafenib 800mg/day. MEASUREMENTS Response according to Response Evaluation Criteria in Solid Tumours (RECIST). RESULTS AND LIMITATIONS We identified 12 cases: 5 CRs with sunitinib, 1 CR with sorafenib, and 6 surgical CRs with sunitinib followed by residual metastasectomy. Side-effects subsided in all patients off treatment. At a median follow-up of 8.5 mo (range: 4-25) from TKI discontinuation, 7 of 12 patients remained without recurrence and 5 had recurrent disease, with new metastases in 3 cases. Median time to progression was 6 mo (range: 3-8). Readministration of TKI was effective in all cases. The study is limited by small numbers and retrospective design. CONCLUSIONS Discontinuation of TKI in patients with mRCC and CR carries the risk of progression with new metastases and potential complications. Further investigation in a larger cohort of patients is warranted before such an approach can be regarded as safe.

Lymph Node Density Affects Cancer-Specific Survival in Patients with Lymph Node–Positive Urothelial Bladder Cancer Following Radical Cystectomy

BACKGROUND The prognosis for patients with lymph node (LN)-positive bladder cancer (BCa) is likely affected by the extent of lymphadenectomy in radical cystectomy (RC) cases. Specifically, the prognostic significance of the LN density (ratio of positive LNs to the total number removed) has been demonstrated. OBJECTIVE To evaluate the prognostic signature of lymphadenectomy variables, including the LN density, for a large, multicentre cohort of RC patients with LN-positive BCa. DESIGN, SETTING, AND PARTICIPANTS The clinical and histopathologic data from 477 patients with LN-positive urothelial BCa (pN1-2) were analysed. The median follow-up period for all living patients was 28 mo. MEASUREMENTS Multivariable Cox regression analysis was used to test the effect of various pelvic lymph node dissection (PLND) variables on cancer-specific survival (CSS) based on colinearity in various models. RESULTS AND LIMITATIONS The median number of LNs removed was 12 (range: 1-66), and the median number of positive LNs was 2 (range: 1-25). Two hundred ninety (60.8%) of the patients presented with stage pN2 disease. The median and mean LN density was 17.6% and 29% (range: 2.3-100), respectively, where 268 (56.2%) and 209 (43.8%) patients exhibited am LN density of ≤20% and >20%, respectively. In separate multivariable Cox regression models adjusted for age, sex, pTN stage, grade, associated Tis, and adjuvant chemotherapy, the interval-scaled LN density (hazard ratio [HR]: 1.01; p=0.002) and the LN density, ordinal-scaled by 20% (HR: 1.65; p<0.001) exhibit independent effects on CSS. In addition, an independent contribution appears from the pT but not the pN stage. Limitations include surgeon selection bias when determining the extent of lymphadenectomy. CONCLUSIONS Our results support the prognostic relevance of LN density in patients with LN-positive BCa, where a threshold value of 20% stratifies the population into two prognostically distinct groups. Before LN density is integrated into the clinical decision-making process, these results should be validated by prospective studies with defined LN templates and standardised histopathologic methods.

High Dose Rate Brachytherapy of Localized Prostate Cancer

Abstract Objective: We evaluated the safety and efficacy of high dose rate (HDR) brachytherapy using Iridium-192 (Ir 192) and 3D conformal external beam radiotherapy in patients with localized prostate cancer. Methods: A total of 444 patients with localized prostate cancer underwent combined radiotherapy with interstitial Ir 192 and 3D conformal external beam radiotherapy between December 1992 and March 2001. The 230 patients, treated between December 1992 and December 1997 were analyzed. All patients underwent laparoscopic pelvic lymph node dissection to exclude patients with lymphatic involvement. Ir 192 was delivered twice with a 1-week interval in HDR remote control technique. The interstitial dose from December 1992 to December 1993 was 10Gy, after December 1993 the dose was reduced to 9Gy per treatment session. The interstitial application was followed by external beam radiation of 45Gy for cT1–cT2 and 50.4Gy for cT3 tumor (40Gy from December 1992 to December 1993). Progression was defined as biochemical failure according to ASTRO criteria, e.g. three consecutive PSA rises following the PSA nadir. Results: The median PSA value decreased from 12.8 to 0.93ng/ml 12 months after treatment. Median PSA value was 0.47 after 24 months, 0.30ng/ml after 36 months and 0.18ng/ml after 60 months. 68% of the biopsies were negative 24 months after therapy. Progression-free rate was 100% for cT1 tumors, 75% for cT2 and 60% for stage-cT3 on 5-year follow-up. Five-year overall survival was 93%, 5-year disease-specific survival was 98%. Initial PSA value Conclusions: Combined HDR brachytherapy with Ir 192 is an alternative treatment option especially for patients with cT3 prostate cancer. Initial PSA value, stage and grade, are important prognostic factors.

Die laparoskopische radikale Prostatektomie Erfahrungen mit 145 Eingriffen

ZusammenfassungErmutigt durch die ersten erfolgreichen Berichte über die laparoskopische radikale Prostatektomie haben wir diesen Eingriff im Juni 1999 in unser Operationsprogramm aufgenommen. Bis Ende November 2000 führten wir insgesamt 145 dieser Eingriffe durch. Die Indikation zur laparoskopischen Prostatektomie entsprach genau der, die wir für die offene Operation anwenden.Abdominelle Voroperationen, transurethrale Resektionen bzw. eine mäßige Adipositas sind keine Kontraindikationen. Eine Konversion zur offenen Operation war in keinem Fall erforderlich. Die postoperative Komplikationsrate betrug 11,7%, wobei es sich vorwiegend um Minorkomplikationen handelte. Auch hinsichtlich der Kontinenz und Potenz sind die Ergebnisse sehr gut.Unserer Meinung nach ist die laparoskopische radikale Prostatektomie eine echte Alternative zur offenen Operation, da sie eine Reihe von Vorteilen für den Patienten und den Operateur aufweist.AbstractEncouraged by the groups in Paris, we performed 145 laparoscopic radical prostatectomies between June 1999and the end of November 2000. The indication for laparoscopic prostatectomy is the same as for open surgery: an organ-confined cancer.Previous abdominal surgery, transurethral resection, and/or relative adiposity are not considered to be contraindications for this laparoscopic procedure. The mean operating time was 255 min; the last 60 procedures took an average of 200 min. In no case was it necessary to convert to open surgery. Worthy of note was the low blood loss of 185 ml on average so that in 98% of the patients no blood transfusion was required. After completing the learning curve, the average indwelling catheter time was only 5.5 days. The postoperative complication rate was 11.7%, consisting mainly of minor complications. Also with regard to continence and potency, the results were representative. Postoperatively, 75%, 86%, 92%, and 93% of the patients were continent after 3, 6, 9, and 12 months, respectively.In our opinion, laparoscopic radical prostatectomy is an alternative to open prostatectomy, offering a number of advantages for the patient and surgeon as well.

Analysis of sex differences in cancer-specific survival and perioperative mortality following radical cystectomy: results of a large German multicenter study of nearly 2500 patients with urothelial carcinoma of the bladder.

BACKGROUND Outcome of patients with urothelial carcinoma of the bladder (UCB) varies between sexes. Although overall incidence is higher in men, cancer-specific survival (CSS) has been suggested to be lower in women. Although the former effect is attributed to greater exposure to carcinogens in men, the latter has not been elucidated. OBJECTIVES The aim of the study was to identify sex-specific outcomes based on one of the largest databases of patients with UCB who underwent radical cystectomy (RC). METHODS This retrospective multicenter series comprised 2483 patients in Stage M0 who underwent RC for UCB from 1989 to 2008; 20.4% of patients were women. The impact of sex on CSS in the entire study group and in specific subgroups was analyzed. The median follow-up time was 42 months (interquartile range, 21-79). RESULTS Histopathologic criteria of pathologic tumor (pT), pathologic nodal (pN), grade, lymphovascular invasion (LVI), and associated carcinoma in situ (CIS) of the study did not differ between sexes. The percentage of female patients increased over time. Five-year CSS in female patients was significantly lower than in male patients (60% vs 66%; P = 0.005). In multivariate analysis adjusted to other covariates, tumor stage ≥pT3 (hazard ratio [HR] = 2.44; P < 0.001), positive pN status (HR = 1.91; P < 0.001), LVI (HR = 1.48; P < 0.001), lower count of lymph nodes removed (HR = 0.98; P = 0.002), older age (HR = 1.01; P < 0.001), and female gender (HR = 1.26; P = 0.011) had an independent impact on CSS. Deterioration of CSS in female patients was pronounced when LVI was present (HR = 1.57; P < 0.001) and when RC was performed in the earlier time period (HR = 2.44; P < 0.001). However, women showed significantly lower perioperative mortality (within 90 days after RC) compared with men. CONCLUSIONS After RC for UCB, cancer-specific mortality was higher in female patients; this disadvantage was more pronounced in earlier time periods. In addition, worse outcome of women with verified LVI was shown to be comparable with men. These findings were suggestive of different tumor biology and potentially unequal access to timely RC in earlier time periods because of reduced awareness of UCB in women. Further studies are required to improve UCB outcome in both sexes, notably in female patients.

Effects of combined treatment of chemotherapeutics and hyperthermia on survival and the regulation of heat shock proteins in dunning R3327 prostate carcinoma cells

Hyperthermia can enhance the clinical response of chemotherapeutic agents in prostate cancer, but optimal sequencing of this combination therapy needs to be developed. Given the role of heat shock proteins (HSPs) in the development of resistance (thermotolerance) to subsequent hyperthermic stresses as well as to certain chemotherapeutics, the study of HSP regulation is important in the establishment of effective schedules in multimodal treatment strategies.

Heat Shock Protein (HSP72) Surface Expression Enhances the Lysis of a Human Renal Cell Carcinoma by IL-2 Stimulated NK Cells

Patients with advanced renal cell carcinoma (RCC) have a poor prognosis due to the failure of this tumor entity to respond to conventional therapeutic approaches such as irradiation or chemotherapy. Since the introduction of interleukin-2 based immunotherapy by Rosenberg et al. there has been some clinical progress in the treatment of metastatic RCC [1].