Muscle-invasive Cancer Research Articles

507 HIGH-RISK NMIBC (NON-MUSCLE INVASIVE BLADDER CANCER): PROGNOSTIC VALUE OF CIRCULATING TUMOR CELLS

You have accessJournal of UrologyBladder Cancer: Basic Research1 Apr 2011507 HIGH-RISK NMIBC (NON-MUSCLE INVASIVE BLADDER CANCER): PROGNOSTIC VALUE OF CIRCULATING TUMOR CELLS Ettore De Berardinis, Gian Maria Busetto, Arianna Petracce, Chiara Nicolazzo, Paola Gazzaniga, and Vincenzo Gentile Ettore De BerardinisEttore De Berardinis Roma, Italy More articles by this author , Gian Maria BusettoGian Maria Busetto Roma, Italy More articles by this author , Arianna PetracceArianna Petracce Roma, Italy More articles by this author , Chiara NicolazzoChiara Nicolazzo Roma, Italy More articles by this author , Paola GazzanigaPaola Gazzaniga Roma, Italy More articles by this author , and Vincenzo GentileVincenzo Gentile Roma, Italy More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1203AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The prognosis of T1G3 bladder cancer is highly variable and not predictable basing upon clinical and pathological prognostic factors. There is need for improvement in risk stratification in this population; understanding the molecular profile of individual patients could provide a more personalized and tailored treatment. Main objective was to evaluate the prognostic significance of Survivin in tumor tissues and that of Survivin expressing circulating tumor cells (CTCs) in T1G3 tumors. METHODS 141 patients with T1G3 non muscle invasive ladder cancer (NMIBC) were enrolled. Additional inclusion criteria were: absence of CIS and multifocality. Planned follow up was 24 mo. Survivin was evaluated by RT-PCR in tumoral tissues. CTCs were isolated from blood by CELLection™ Dynabeads coated with the monoclonal antibody towards the human Epithelial Cell Adhesion Molecule. Cells were lysed and Dynabeads Oligo(dT) was used to capture poly A_mRNA. cDNA was synthesised and analysed for the expression of CD45, CK8 and Survivin. The primary end point was disease free survival (DFS); the favourable group at 24 mo was defined as that without any clinical evidence of disease (NED); the unfavourable group was that with evidence of recurrent disease (RD) or progressive disease (PD). Tumoral Survivin expression and presence of CTC were correlated to DFS. Multivariate nalysis was used to investigate whether CTC presence was independent indicator of DFS. RESULTS Survivin was found in about 50% of tumors. Survivin - patients showed a longer DFS than Survivin + (/2:4.572; p=0.029). CTCs were found in 51/141 patients (47%); 94% of CTC were Survivin expressing. The difference in DFS between CTC - and CTC + patients was statistically significant (/2: 28.098; p<0.001). CTC presence was found an independent prognostic factor of DFS (p<0.001). CONCLUSIONS CTC presence is an independent prognostic factor in high risk NMIBC patients. In the future will be important the count of CTC and this will allow us to establish the correlation between CTC number and prognosis. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e205-e206 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ettore De Berardinis Roma, Italy More articles by this author Gian Maria Busetto Roma, Italy More articles by this author Arianna Petracce Roma, Italy More articles by this author Chiara Nicolazzo Roma, Italy More articles by this author Paola Gazzaniga Roma, Italy More articles by this author Vincenzo Gentile Roma, Italy More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Can we reliably identify patients for radical cystectomy without neoadjuvant chemotherapy?

258 Background: When neoadjuvant chemotherapy is administered prior to radical cystectomy in patients with muscle-invasive urothelial cancer, the patients who benefit most are those with pathologic T3-4 or N+ disease. Thus, some advocate reserving neoadjuvant chemotherapy for patients considered high risk based on presence of the following clinical parameters: lymphovascular invasion, hydroureteronephrosis, presence of a palpable or visible mass on exam under anesthesia or imaging (suggesting cT3 disease), and/or variant histology. The goal of this study was to report the outcome of patients who were classified as “not high risk” (i.e., lacking the above-mentioned criteria) and underwent radical cystectomy without neoadjuvant chemotherapy. Methods: On retrospective review of 858 patients who underwent radical cystectomy from 2000 to 2008, we identified 174 patients with muscle-invasive disease (cT2) who were classified as “not high risk” (i.e., did not have lymphovascular invasion, hydroureteronephrosis, variant histology, and/or palpable or visible mass on imaging studies) and underwent radical cystectomy without neoadjuvant chemotherapy. Endpoints of interest included pathologic upstaging (≥ pT3), pathologic lymph node positivity, need for adjuvant or salvage chemotherapy, disease recurrence, and disease specific survival (DSS). Results: Of the 174 patients, 155 (88.6%) were male and the median age was 67.6 years (range 39-86). At radical cystectomy, 75 patients (42.9%) were upstaged (pT3N0: 45; pT4N0: 6; pTxN+: 24). Thirteen patients (7.4%) received adjuvant chemotherapy for adverse pathology. After a median interval of 27 months, 38 patients (21.7%) developed recurrent disease; isolated pelvic recurrences: 4, distant recurrences: 34, and 2 had both. Eighteen patients with recurrent disease went on to receive salvage chemotherapy. Overall, 25 patients (14.3%) died of disease with a 5-year DSS of 82.3%. Conclusions: Although clinical understaging remains a problem in the management of patients with muscle-invasive urothelial cancer, our criteria for selection of patients for primary radical cystectomy without neoadjuvant chemotherapy results in a cohort with a 5-year DSS of 83%. No significant financial relationships to disclose.

Tolerability of neoadjuvant chemotherapy with gemcitabine plus cisplatin in elderly (older than age 65) patients (pts) with muscle-invasive urothelial cancer.

296 Background: Urothelial cancer (UC) is a common tumor with a peak in the seventh decade. Locally advanced disease has a significant risk for developing metastases. Neoadjuvant, platinum-containing, combination chemotherapy improves survival over radical cystectomy (RC). Chemotherapy with gemcitabine plus cisplatin (GC) shows equivalent efficacy with less toxicity to methotrexate-vinblastine-doxorubicin- cisplatin (MVAC) in metastatic setting. Methods: We prospectively evaluated 23 elderly pts (8 female, 15 male) with a median age of 72 years, WHO performance status 0/1, with muscle invasive UC who received neoadjuvant GC (gemcitabine 1,000 mg/m2 days 1, 8, 15 and cisplatin 70 mg/m2, day 2 q28) for 3 cycles between 2006 and 2010 prior to RC. Assessments included toxicity of GC, pathologic response, progression free survival (PFS) and overall survival (OS). Results: 21 (91.3%) out of 23 pts finished intended chemotherapy. Two refused chemotherapy due to personal reasons. According to CTCAE guidelines 43.5% developed grade 3 hematologic toxicities; 13% developed grade 4 thrombopenia. Grade 3 non-hematologic toxicities included nausea in 2 patients. In 2 (8.7%) pts grade 4 thromboembolic events occurred. There was no treatment related febrile neutropenia or death. 15 (71.4%) of the pts underwent RC. 5 (23.8%) pts refused RC due to personal reasons. 1 of them agreed second look TURB. 1 patient underwent palliative radiotherapy due to progression of disease. Out of the 16 pts 43.75% achieved pathological response (18.75% pT0 stage and 25% pT1 stage). 56.25% had muscle invasive UC. 18.75% of them nodal positive disease. All 7 pts achieving &lt; pT2 pathologic stage remained progression-free at a median follow up of 16 months. Pts &gt; pT2 stage had a median PFS of 14 months. Median OS was not reached yet. Conclusions: Neoadjuvant GC is a well tolerated regiment in elderly pts and it seems to be less toxic than MVAC. Prophylactic anticoagulation during treatment should be considered. Although pathologic response is lower than in previously published retrospective data we recommend neoadjuvant treatment with GC in elderly pts. [Table: see text]

Current and Emerging Strategies for the Management of Bladder Cancer

Treatment strategies and outcome of bladder cancer depend on tumor progression. Non-muscle invasive urothelial cell carcinoma (NMI-UCC) is generally treated by transurethral resection (TUR). In addition, intravesical therapy is often followed to prevent the recurrence; however, its effect is not still enough. On the other hand, the prognosis of bladder cancer patients with muscle-invasive and/or metastatic tumors is poor, despite the availability of various therapies. Although radical cystectomy is the gold standard for patients with muscle-invasive disease, high frequency of recurrence and decreased quality of life are major disadvantages associated with this procedure. In recent years, various newly developed treatment strategies have progressed to clinical trials for the perioperative treatment of muscle-invasive cancer and for systematic therapy for advanced bladder cancer. Here, we review the current and emerging therapeutic strategies and discuss the recent clinical trials of anti-vascular endothelial growth factor (VEGF) family- and anti-endothelial growth factor receptor (EGFR)-based therapies.

Quality of Life Assessment After Concurrent Chemoradiation for Invasive Bladder Cancer: Results of a Multicenter Prospective Study (GETUG 97-015)

To evaluate bladder preservation and functional quality after concurrent chemoradiotherapy for muscle-invasive cancer in 53 patients included in a Phase II trial. Pelvic irradiation delivered 45 Gy, followed by an 18-Gy boost. Concurrent chemotherapy with cisplatin and 5-fluorouracil by continuous infusion was performed at Weeks 1, 4, and 7 during radiotherapy. Patients initially suitable for surgery were evaluated with macroscopically complete transurethral resection after 45 Gy, followed by radical cystectomy in case of incomplete response. The European Organization for Research and Treatment of Cancer quality of life questionnaire QLQ-C30, specific items on bladder function, and the Late Effects in Normal Tissues-Subjective, Objective, Management, and Analytic (LENT-SOMA) symptoms scale were used to evaluate quality of life before treatment and 6, 12, 24, and 36 months after treatment. Median age was 68 years for 51 evaluable patients. Thirty-two percent of patients had T2a tumors, 46% T2b, 16% T3, and 6% T4. A visibly complete transurethral resection was possible in 66%. Median follow-up was 8 years. Bladder was preserved in 67% (95% confidence interval, 52-79%) of patients. Overall survival was 36% (95% confidence interval, 23-49%) at 8 years for all patients, and 45% (28-61%) for the 36 patients suitable for surgery. Satisfactory bladder function, according to LENT-SOMA, was reported for 100% of patients with preserved bladder and locally controlled disease 6-36 months after the beginning of treatment. Satisfactory bladder function was reported for 35% of patients before treatment and for 43%, 57%, and 29%, respectively, at 6, 18, and 36 months. Concurrent chemoradiation therapy allowed bladder preservation with tumor control for 67% patients at 8 years. Quality of life and quality of bladder function were satisfactory for 67% of patients.

Intravesical therapy for bladder cancer

Importance of the field: Although transurethral resection of bladder tumor (TURBT) is effective therapy, up to 45% of patients will have a recurrence within 1 year after TURBT alone. Further, there is a 3 – 15% risk of tumor progression to muscle invasive and/or metastatic cancer. Depending on patient and tumor characteristics, a number of patients may benefit from some form of intravesical therapy. Adjuvant therapy is effective in avoiding post-TURBT implantation of tumor cells, eradicating residual disease, preventing tumor recurrence, and to delay or reduce tumor progression through direct cytoablation or immunostimulation.Areas covered in this review: The role of risk assessment in the management of nonmuscle invasive bladder cancer (NMIBC) and the indications for the use of intravesical agents are discussed. Findings from major randomized clinical trials on BCG, interferon and various chemotherapeutic agents are summarized; key aspects of drug pharmacology, drug efficacy, side effects, and toxicity are also covered.What the reader will gain: The reader will gain a basic understanding of the role of risk assessment in determining the need for intravesical therapy, as well as an overview of the different types of agents in use in the United States today.Take home message: The type of intravesical therapy used is based on the risk groups as noted in the European prognostic tables. Bacillus Calmette–Guerin (BCG) is the most commonly used first-line agent immunotherapeutic agent for prophylaxis and treatment of carcinoma in situ and high-grade bladder cancer. Other immunotherapeutic options include the interferons, interleukins 2 and 12, and tumor necrosis factor, all of which have activity in BCG refractory patients, although with low durable remission rates. Studies have shown that chemotherapy prevents recurrence but not progression. The available data on intravesical chemotherapy do not indicate that any single agent currently in use is clearly better than any other. Therefore, the selection of a chemotherapeutic agent is usually based on cost, toxicity, and availability as well as on physician preference and experience.

Efficacy of Transurethral Resection of the Bladder Tumor (TUR-BT) for Huge Bladder Cancer

There are no guidelines regarding whether to perform either a radical transurethral resection of the bladder tumor (TUR-BT) or a total cystectomy after TUR biopsy for huge bladder cancer, and this decision is entrusted to each institution. Of 439 patients in whom TUR-BT was performed from 2005 through 2009, the weight of the total resected volume was > 50 g in 6 patients, and among these 6 patients the following variables were compared: operating time, weight of resected volume, transfusion volume, presence or absence of hydronephrosis, preoperative urinary cytology, serum cytokeratin 19 fragment (CYFRA) level, intraoperative bladder compliance, and histopathological findings. The median age, operating time, weight of resected volume, transfusion volume, and length of follow-up were 72 years, 300 minutes, 88 g, 202 mL, 16 months, respectively. The serum CYFRA level in patients with muscle-invasive cancer (11.8 ng/mL) was higher than that in patients with non-muscle-invasive cancer (5.06 ng/mL). All patients with non-muscle-invasive bladder cancer survived without recurrence. Although the mean length of follow-up was only 16 months (5-59 months), the 1 patient who was followed up for 59 months had no recurrence. In cases of muscle-invasive bladder cancer, all patients, except for a relatively recent patient, have died. In cases without muscle invasion, lymph node metastasis, distal metastasis, or preoperative renal dysfunction accompanied by hydronephrosis, with favorable bladder compliance, we believe that radical TUR-BT should be actively performed to preserve the bladder. A second TUR-BT should be performed in cases of non-muscle-invasive cancer without G3 components to treat the huge bladder cancer.

Is T1G3 Bladder Cancer Having a Definite Muscle Layer in TUR Specimens a Highly Progressive Disease?

Patients with T1G3 bladder cancer are at high risk of progression to muscle-invasive cancer, and early cystectomy is considered as a treatment option in this particular situation. On the other hand, understaging of T1G3 bladder cancer has been gradually proven as second or repeat transurethral resection (TUR) has been widely applied. To evaluate the real rate of progression, we investigated the prognosis of T1G3 bladder cancer in which a muscle layer was histologically confirmed in the TUR specimens. We retrospectively reviewed 48 patients with primary T1G3 bladder cancer in which a muscle layer in the TUR specimens was confirmed between 1990 and 2006 in our institute. We investigated recurrence and progression in 45 patients, excluding 3 who were immediately treated with radical cystectomy. Fifteen and 12 patients received intravesical treatment with bacillus Calmette-Guérin (BCG) and anticancer agents just after TUR, respectively. The remaining 18 did not have any such treatment. Recurrence and progression were observed in 21 (47%) and 3 patients (6.7%), respectively, during a median follow-up period of 42.1 months. The 3-year recurrence-free and progression-free survival rates were 54% and 91%, respectively. No significant differences were observed in the rates between the patients with and without BCG treatment in the study. There is a possibility that the progression rate in patients with T1G3 bladder cancer is not as high as previously reported when only patients whose muscle layer was histologically confirmed were analyzed. An adequate technique for TUR that unmistakably collects the muscle layer may be important to predict the outcome accurately.

ST3Gal.I sialyltransferase relevance in bladder cancer tissues and cell lines

BackgroundThe T antigen is a tumor-associated structure whose sialylated form (the sialyl-T antigen) involves the altered expression of sialyltransferases and has been related with worse prognosis. Since little or no information is available on this subject, we investigated the regulation of the sialyltransferases, able to sialylate the T antigen, in bladder cancer progression.MethodsMatched samples of urothelium and tumor tissue, and four bladder cancer cell lines were screened for: ST3Gal.I, ST3Gal.II and ST3Gal.IV mRNA level by real-time PCR. Sialyl-T antigen was detected by dot blot and flow cytometry using peanut lectin. Sialyltransferase activity was measured against the T antigen in the cell lines.ResultsIn nonmuscle-invasive bladder cancers, ST3Gal.I mRNA levels were significantly higher than corresponding urothelium (p < 0.001) and this increase was twice more pronounced in cancers with tendency for recurrence. In muscle-invasive cancers and matching urothelium, ST3Gal.I mRNA levels were as elevated as nonmuscle-invasive cancers. Both non-malignant bladder tumors and corresponding urothelium showed ST3Gal.I mRNA levels lower than all the other specimen groups. A good correlation was observed in bladder cancer cell lines between the ST3Gal.I mRNA level, the ST activity (r = 0.99; p = 0.001) and sialyl-T antigen expression, demonstrating that sialylation of T antigen is attributable to ST3Gal.I. The expression of sialyl-T antigens was found in patients' bladder tumors and urothelium, although without a marked relationship with mRNA level. The two ST3Gal.I transcript variants were also equally expressed, independently of cell phenotype or malignancy.ConclusionST3Gal.I plays the major role in the sialylation of the T antigen in bladder cancer. The overexpression of ST3Gal.I seems to be part of the initial oncogenic transformation of bladder and can be considered when predicting cancer progression and recurrence.

Pathological Upstaging During Radical Cystectomy Is Associated With Worse Recurrence-free Survival in Patients With Bacillus Calmette-Guerin-refractory Bladder Cancer

To compare the outcomes of patients who were upstaged to pT2 at the time of radical cystectomy (RC) to those who were correctly staged as T2 before RC. The clinical and pathologic data were reviewed of 496 patients who underwent RC from 1994 to 2008. Patients who underwent RC for high-grade T1 (HGT1) or carcinoma in situ (CIS) (184) were compared with those with known muscle-invasive cancer (312) before RC. Patients were substratified based on preoperative intravesical therapy status. Recurrence-free survival (RFS) for patients who were upstaged to muscle-invasive disease was compared with patients who were correctly staged T2 preoperatively. Patients who were upstaged to pT2 disease had significantly worse 3- and 5-year RFS compared with those who where accurately staged (cT2 = pT2) (64% and 61% vs 83% and 74%, respectively; P = .04). Upstaging to pT2 in patients with a history of bacillus Calmette-Guerin treatment resulted in worse 3- and 5-year RFS rates compared with those accurately staged (69% and 57% vs 100% and 86%, respectively; P = .03). Upstaging to pT2 among patients with HGT1 or CIS is associated with worse RFS compared with patients with known muscle invasion before RC (HGT1/CIS = pT2 vs cT2 = pT2). This finding was most significant among patients with a history of bacillus Calmette-Guerin treatment. Factors such as understaging of disease or treatment delay may contribute to worse outcomes among this subset of patients and should be considered when discussing treatment options.

Bladder Cancer

Bladder cancer is a complex disease of older patients with coexisting medical problems requiring multimodal therapy. For patients with localized bladder cancer, standard management for superficial disease includes transurethral resection with or without intravesical therapy, while muscle-invasive cancer is managed with neoadjuvant cisplatin- based chemotherapy followed by radical cystectomy. Comorbid conditions prevent many older patients from receiving cisplatin-based chemotherapy and/or undergoing surgery. Tri-modality bladder preservation approaches including a complete transurethral resection of the bladder tumor (TURBT) followed by combined chemotherapy and radiation have generally included only those patients who are candidates for a salvage cystectomy. Future research must specifically focus on older adults with bladder cancer including non-cisplatin-based neoadjuvant regimens; bladder preservation strategies using alternative non-cisplatin chemotherapy in noncystectomy candidates; clinical trials evaluating novel targeted agents in older adults; and geriatric assessment tools to assist in decision making.

TaT1 (Non-muscle invasive) Bladder Cancer

Non–muscle-invasive bladder cancer—previously termed superficial bladder cancer—is a common disease that urologists are confronted with every day. Four papers in this issue by experts in the field provide the current knowledge needed to deal with this costly disease. Recurrence rates associated with TaT1 bladder cancer remain high; therefore, treatment must aim at reducing the likelihood of recurrence as much as possible. In addition, some cancers have a definite risk of progression, and these must be identified by risk stratification. While the primary diagnosis of bladder cancer is still usually driven by symptoms, the diagnosis of recurrence is partly based on examinations using urine. The value of urine markers and cytology is examined in detail by Bas van Rhijn and colleagues. Transurethral resection (TUR) is the method used to make a definite (histological) diagnosis of bladder cancer and is the primary treatment. Its technique and adjunctive measures are of crucial importance for the rate of recurrence, as described byMarko Babjuk. Matthew Braasch et al, in a review that is largely centered around the immunotherapy with bacillus Calmette-Guerin, analyze the indications, complications, and results of intravesical treatment. In any bladder-sparing approach in high-risk non–muscle-invasive cancer, intravesical treatment is of utmost importance. Understanding what the risk strategy is and also how to deal with treatment failures is critical. Van der Heijden andWitjes review the current knowledge about the known risk factors of non–muscle-invasive bladder cancer, epidemiological aswell asmolecularandgenetic, that impact the risk of recurrence and progression with different treatment strategies. They discuss the European Organization for Research and Treatment of Cancer risk tables as well as the follow-up strategies that are currently recommended.

High frequency of MAGE‐A4 and MAGE‐A9 expression in high‐risk bladder cancer

Cancer-testis (CT) genes encode proteins that are ideal targets for cancer immunotherapy because of their restricted expression in normal tissues and frequent expression in cancers. We previously observed that MAGE-A9 was one of the CT genes most frequently expressed in bladder tumors. To confirm that observation and evaluate the potential prognostic value of MAGE-A9 protein, we analyzed its expression by immunohistochemistry in 493 primary bladder tumors and 33 lymph node metastases, in comparison with MAGE-A4 protein, also frequently expressed in bladder tumors. Overall, MAGE-A4 and MAGE-A9 were observed, respectively, in 38% and 63% of nonmuscle-invasive tumors, 48% and 57% of muscle-invasive tumors, 65% and 84% of carcinomas in situ and in 73% and 85% of lymph node metastases. Expression was associated with higher grade (MAGE-A4, p = 0.007; MAGE-A9, p = 0.012). In multivariate Cox regression analyses, expression of MAGE-A9 in pTa tumors was associated with recurrence (HR = 1.829; p = 0.010). In univariate analyses, MAGE-A4 expression in these same tumors was associated with progression to muscle-invasive cancer (HR = 7.417, p = 0.013). MAGE-A9 expression was even more predictive of progression as all tumors that progressed expressed this antigen. In muscle-invasive bladder tumors, no association was found between expression of either MAGE and bladder cancer-specific death. In conclusion, MAGE-A9 is a target of choice for bladder cancer immunotherapy as it is expressed in 60% of bladder tumors, predominantly high-grade tumors, and at higher frequency in pTis and metastatic tumors. Moreover, in pTa tumors, an immunotherapy targeting MAGE-A9 could be protective against recurrence and progression to more advanced cancer.

UHRF1 is a novel molecular marker for diagnosis and the prognosis of bladder cancer

Background:Bladder cancer is the second most common cancer of the urinary system. Early diagnosis of this tumour and estimation of risk of future progression after initial transuretherial resection have a significant impact on prognosis. Although there are several molecular markers for the diagnosis and prognosis for this tumour, their accuracy is not ideal. Previous reports have shown that UHRF1 (ubiquitin-like with PHD and ring-finger domains 1) is essential for cellular proliferation. In this study, we examined whether UHRF1 can be a novel molecular marker of bladder cancer.Methods:We performed real-time TaqMan quantitative reverse transcription–PCR and immunohistochemistry to examine expression levels of UHRF1 in bladder and kidney cancers.Results:Significant overexpression of UHRF1 was observed in bladder cancer. The overexpression was correlated with the stage and grade of the cancer. Although UHRF1 expression in muscle-invasive cancer was greater than in non-invasive (pTa) or superficially invasive (pT1) cancers, UHRF1 could still be detected by immunohistochemistry in these early-stage cancers. Overexpression of UHRF1 in bladder cancer was associated with increased risk of progression after transurethral resection. High expression of UHRF1 in kidney cancer was also observed. But the increased levels of UHRF1 in kidney cancer were less significant compared with those in bladder cancer.Conclusion:Our result indicates that an immunohistochemistry-based UHRF1 detection in urine sediment or surgical specimens can be a sensitive and cancer-specific diagnostic and/or prognosis method, and may greatly improve the current diagnosis based on cytology.

CEACAM1: A Novel Urinary Marker for Bladder Cancer Detection

BackgroundCarcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein; CEACAM1) is expressed in normal bladder urothelium and in angiogenically activated endothelial cells, where it exhibits proangiogenic properties. ObjectiveThe aim of this study was to evaluate the value of urinary CEACAM1 for detection of urothelial carcinoma of the bladder (UCB). Design, setting, and participantsThis prospective study included 175 patients. MeasurementsImmunohistochemistry for CEACAM1 was performed on UCB sections of 10 patients. Enzyme-linked immunosorbent assay (ELISA) for CEACAM1 was performed on urine specimens of healthy volunteers (n=30), patients with benign prostatic hyperplasia (BPH; n=5), severe cystitis (n=5), non–muscle-invasive UCB (n=72), muscle-invasive UCB (n=21), or past history of UCB without evidence of disease (n=42). Western blot analysis was performed on a subgroup of these subjects (n=53). Results and limitationsCEACAM1 immunostaining in normal urothelium disappears in noninvasive UCB but appears in endothelial cells of adjacent vessels. Western blotting revealed presence of CEACAM1 in the urine of no healthy volunteers, of 76% of noninvasive UCB patients, and of 100% of invasive UCB patients. ELISA analysis confirmed that urinary CEACAM1 levels were significantly higher in UCB patients compared with control subjects (median: 207ng/ml vs 0ng/ml; p<0.001). The area under the curve for UCB detection was 0.870 (95% confidence interval [CI]: 0.810–0.931). In multivariable logistic regression analyses that adjusted for the effects of age and gender, higher CEACAM1 levels were associated with cancer presence (hazard ratio [HR]: 2.89; 95% CI: 2.01–4.15; p<0.001) and muscle-invasive cancer (HR: 5.53; 95% CI: 1.68–18.24; p=0.005). The cut-off level of 110ng/ml yielded sensitivity of 74% and specificity of 95% for detecting UCB. Sensitivity was 88% for detecting high-grade UCB and 100% for detecting invasive-stage UCB. Larger studies are necessary to establish the diagnostic and prognostic roles of this highly promising novel marker in UCB. ConclusionsUrinary CEACAM1 levels discriminate UCB patients from non-UCB subjects. Moreover, urinary levels of CEACAM1 increased with advancing stage and grade.

Commentary on A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: A retrospective experience

Neoadjuvant cisplatin-based chemotherapy improves survival in muscle-invasive urothelial cancer, with MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) considered the standard regimen. Gemcitabine plus cisplatin (GC) has similar efficacy and less toxicity than MVAC in metastatic disea]se, but is untested as neoadjuvant treatment. The authors retrospectively evaluated patients with muscle-invasive urothelial carcinoma who received neoadjuvant GC before radical cystectomy between November 2000 and December 2006 at Memorial Sloan-Kettering Cancer Center. Post-therapy pathological downstaging to either residual disease at cystectomy (pT0) or no residual muscle-invasion ( Four cycles of neoadjuvant GC were given over 12 weeks ( n = 42). Thirty-nine (93%) of 42 patients received 4 cycles, with a median 91% drug delivery for cisplatin and 90% for gemcitabine. The pT0 proportion was 26% (95% confidence interval [CI], 14–42), and no residual muscle-invasive disease proportion ( Neoadjuvant GC is feasible and allows for timely drug delivery. The proportion of GC-treated patients whose primary tumors were downstaged, with prolonged disease-free survival and minimal or no residual disease, was similar to MVAC-treated patients.

Selective bladder-preserving therapy for muscle-invasive cancer

Transurethral resection of the bladder and adjuvant chemoradiation can permit eradication of the tumor and micrometastases. Close monitoring by sequential cystoscopy and biopsy can achieve similar survival outcomes to radical cystectomy, and could avoid invasive treatment.

Quantitative Fluorescence in Situ Hybridization and its Ability to Predict Bladder Cancer Recurrence and Progression to Muscle-Invasive Bladder Cancer

Fluorescence in situ hybridization (FISH) testing is used to detect bladder cancer in urine specimens. The purpose of this study was to determine whether there are associations between the percentage of chromosomally abnormal cells by FISH and time to bladder cancer recurrence and progression to metastasis. Clinical records were searched to identify patients with urine FISH results, history of non-invasive bladder cancer, and at least one follow-up pathological diagnosis. Covariates analyzed included age, gender, smoking status, treatment after FISH, cystoscopy result, and prior stage of bladder cancer. The percentage of abnormal cells (hazard ratio [HR] 1.03, 95% CI 1.02-1.03; P < 0.001), age (HR 1.02, 95% CI 1.00-1.03; P = 0.033), male gender (HR 0.60, 95% CI 0.41-0.87; P < 0.001), treatment (HR 0.37, 95% CI 0.25-0.55; P < 0.001), and history of TIS/T1-stage tumors (HR 1.66, 95% CI 1.23-2.24; P = 0.001) were significantly associated with time to cancer recurrence. Time to invasive cancer was significantly associated with the percentage of abnormal cells (HR 1.02, 95% CI 1.01, 1.03; P < 0.001), history of TIS/T1 tumor (HR 3.73, 95% CI 1.88, 7.38; P = 0.001), and treatment (HR 0.33, 95% CI 0.13, 0.83; P = 0.019), suggesting that the percentage of abnormal cells independently predicts cancer recurrence and progression to invasive disease in patients with a history of non-invasive bladder cancer.

Major risk factors for the development of muscle invasive baldder cancer in Upper Egypt

In our randomised, controlled, phase 3 trial NeOAdjuvant Herceptin (NOAH) trial in women with HER2-positive locally advanced or inflammatory breast cancer, neoadjuvant trastuzumab significantly improved pathological complete response rate and event-free survival. We report updated results from our primary analysis to establish the long-term benefit of trastuzumab-containing neoadjuvant therapy.We did this multicentre, open-label, randomised trial in women with HER2-positive locally advanced or inflammatory breast cancer. Participants were randomly assigned (1:1), by computer program with a minimisation technique, to receive neoadjuvant chemotherapy alone or with 1 year of trastuzumab (concurrently with neoadjuvant chemotherapy and continued after surgery). A parallel group with HER2-negative disease was included and received neoadjuvant chemotherapy alone. Our primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered at www.controlled-trials.com, ISRCTN86043495.Between June 20, 2002, and Dec 12, 2005, we enrolled 235 patients with HER2-positive disease, of whom 118 received chemotherapy alone and 117 received chemotherapy plus trastuzumab. 99 additional patients with HER2-negative disease were included in the parallel cohort. After a median follow-up of 5·4 years (IQR 3·1–6·8) the event-free-survival benefit from the addition of trastuzumab to chemotherapy was maintained in patients with HER2-positive disease. 5 year event-free survival was 58% (95% CI 48–66) in patients in the trastuzumab group and 43% (34–52) in those in the chemotherapy group; the unadjusted hazard ratio (HR) for event-free survival between the two randomised HER2-positive treatment groups was 0·64 (95% CI 0·44–0·93; two-sided log-rank p=0·016). Event-free survival was strongly associated with pathological complete remission in patients given trastuzumab. Of the 68 patients with a pathological complete response (45 with trastuzumab and 23 with chemotherapy alone), the HR for event-free survival between those with and without trastuzumab was 0·29 (95% CI 0·11–0·78). During follow-up only four cardiovascular adverse events were regarded by the investigator to be drug-related (grade 2 lymphostasis and grade 2 lymphoedema, each in one patient in the trastuzumab group, and grade 2 thrombosis and grade 2 deep vein thrombosis, each in one patient in the chemotherapy-alone group).These results show a sustained benefit in event-free survival from trastuzumab-containing neoadjuvant therapy followed by adjuvant trastuzumab in patients with locally advanced or inflammatory breast cancer, and provide new insight into the association between pathological complete remission and long-term outcomes in HER2-positive disease.F Hoffmann-La Roche.

Organ preservation for muscle-invasive bladder cancer by transurethral resection: Leibovici D, Kassouf W, Pisters LL, Pettaway CA, Wu X, Dinney CP, Grossman HB, Department of Urology, University of Texas, M.D. Anderson Cancer Center, Houston, TX.

To determine the feasibility of bladder preservation using transurethral resection for patients with muscle-invasive cancer and to determine the proportion of patients with muscle-invasive disease who would be eligible for this approach. A retrospective review demonstrated that 327 patients with muscle-invasive bladder cancer were treated in our institution from 1997 to 2002. Resection was repeated in all patients, and bladder preservation was offered to patients with no residual tumor, normal examination findings under anesthesia, and normal upper urinary tract findings. Patients were followed up by routine cystoscopy for a median of 2.45 years. The study endpoints included overall and disease-specific survival rates, the need for additional systemic chemotherapy, and cystectomy-free survival. Of 327 patients, 35 (11%) were eligible for bladder preservation; 27 elected to pursue this approach and 8 opted for immediate cystectomy. Of the 27 patients, 15 experienced subsequent tumor recurrence, 8 of whom underwent radical cystectomy. Thus, the bladder was preserved in 19 (70%) of the 27 patients. Of the patients who underwent cystectomy, 5 also received chemotherapy. Five patients died, including 3 of unrelated diseases, 1 of metastatic cancer, and 1 of surgical complications. The overall and disease-specific survival rate was 81% and 93%, respectively. Bladder preservation using transurethral resection is feasible in selected patients. Only a small proportion of patients with muscle-invasive bladder cancer, however, are candidates for this approach.