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Trimodal therapy (TMT) for muscle invasive bladder cancer has become an accepted alternative to radical cystectomy and has become integrated into national guidelines as standard a treatment option. The urologist plays a critical role in proper patient selection, thorough transurethral resection, ongoing cystoscopic surveillance and management of local recurrences. There exists multiple patient related and tumor related factors, which contribute to the selection of TMT vs. radical cystectomy for a patient with muscle invasive bladder cancer. Although the ideal patient for TMT has a tumor which can undergo a visibly complete resection, has no associated hydronephrosis, does not invade the prostatic urethra and is not associated with diffuse carcinoma in situ throughout the bladder, select patients who do not meet all these criteria can still be successfully treated with this approach. A multidisciplinary approach including urology, radiation oncology and medical oncology is paramount with clear communication of tumor location, timing of chemoradiation and repeat cystoscopic resection followed by surveillance. Nonmuscle invasive bladder cancer recurrences can occur in up to 26% of patients after completion of TMT, with many being treated by routine and standard therapy for non-muscle invasive bladder cancer. However, in this population after TMT, early salvage cystectomy should be considered in those with adverse features, including T1 disease, tumor greater than 3 cm, CIS, or lymphovascular invasion. Salvage cystectomy can be performed for local recurrences with acceptable oncologic control and no clear evidence of any greater risk of early complications; however, there may be a slightly increased risk for late complications, namely small bowel obstruction, ureteral stricture, and parastomal hernia. An understanding of these surgical considerations is of utmost importance to the treating urologist in selecting and managing a patient through TMT. [ABSTRACT FROM AUTHOR]

• The natural history of MIBC treated without curative intent is not well known. • Most patients (88%) were not treated due to low performance status. • 2-year cancer specific and overall survivals were 18% and 12%, respectively. • During follow-up 65% of patients suffered from recurrent hematuria. • About 59% of patients required catheter insertion and 37% had a nephrostomy tube. Muscle-invasive bladder cancer is an aggressive disease. Yet, many patients, especially those with advanced age and multiple comorbidities, do not receive treatment with curative intent. We evaluated the disease course and health care burden of these patients. Bi-center, retrospective analysis of patients diagnosed with muscle-invasive bladder cancer who did not undergo curative-intent treatment (radical cystectomy or trimodal therapy) between 2016 and 2021. Patient characteristics and treatment burden were described. Metastasis-free, cancer-specific, and overall survivals were evaluated using the Kaplan-Meier method. Sixty-six patients with a median age of 86 (IQR 78,90) were evaluated. The median follow-up for survivors was 29 months (IQR 9, 44). All patients were diagnosed with muscle-invasive bladder cancer, and 32 (48%) presented with clinical T3 and T4 disease. The median age adjusted Charlson comorbidity index at diagnosis was 7 (IQR 6,8). Treatment with curative intent was not provided due to comorbidities and low-performance status in 58 patients (88%) and patient refusal in 8 (12%). Two-year estimated metastasis-free survival, cancer-specific survival, and overall survival were 11%, 18%, and 12%, respectively. During follow-up, 7 patients (10%) were treated with chemotherapy, 4 (6%) received immunotherapy, 21 (32%) radiation, and 17 (26%) had emergent operations due to hematuria. Twenty-four patients (37%) required nephrostomy tubes, and 39 (59%) required an indwelling urinary catheter for various periods. Forty-three patients (65%) suffered from recurrent hematuria episodes. Overall, median emergency room visits were 4 (IQR 2, 6), and median hospital admission was 16 days (IQR 9, 29). Untreated muscle-invasive bladder cancer is associated with a limited lifespan and a high disease burden for the patient and health system. These data should be taken into consideration and portrayed to the patient when curative intent treatment is chosen to be avoided. [ABSTRACT FROM AUTHOR]

Background: Cytoplasmic linker-associated protein 2 (CLASP2) belongs to a family of microtubule plus-end tracking proteins that localize to the distal ends of microtubules and is involved in various microtubule-dependent processes. We previously showed that CLASP2 is involved in the epithelial-to-mesenchymal transition of bladder urothelial cancer. This research aimed to explore the significance of CLASP2 expression as a prognostic marker for muscle-invasive bladder urothelial cancer (MIBC) patients after radical cystectomy-pelvic lymph node dissection (RC-PLND).Methods: CLASP2 expression was analyzed in 76 benign bladder tissues and 160 MIBC tissues by tissue immunohistochemistry. Survival analysis and multiple regression analysis following propensity score matching were performed to investigate the correlation between high CLASP2 expression and MIBC patients' survival.Results: CLASP2 expression was increased in MIBC patients, especially those with high-stage tumors or lymph node metastasis. In the follow-up of MIBC patients after propensity score matching, whether MIBC patients received adjuvant chemotherapy after RC-PLND, high CLASP2 expression was significantly associated with a poor prognosis. MIBC patients with low CLASP2 expression who received adjuvant chemotherapy tended to have an improved survival prognosis.Conclusion: CLASP2 expression is correlated with malignant progression of MIBC. High CLASP2 expression predicted a poor prognosis for MIBC patients after RC-PLND. [ABSTRACT FROM AUTHOR]

• 5-yr RFS (accounting for non-cancer related deaths) was 65.6% in pT0, 59.1% in pT2, and 10.8% in pN+ patients with muscle invasive bladder cancer. • Only cT2 patients derived survival benefit from pre-surgical chemotherapy. • Patients with adverse pathologic features benefited from adjvuant chemotherapy. Despite abundant evidence supporting the use of perioperative chemotherapy from clinical trials, no study to date has comprehensively evaluated its use in the treatment of muscle-invasive bladder cancer (MIBC) in the real-world setting. Little is known regarding the impact of pretreatment disease stage and real-world factors such as patient comorbidities preventing timely completion of therapy on its effectiveness. This study aims to assess the usage of perioperative chemotherapy and examines its impact on pathologic downstaging rates and recurrence free survival in patients undergoing radical cystectomy. A retrospective review was conducted in 805 patients with muscle invasive bladder cancer undergoing radical cystectomy with no perioperative chemotherapy, 761 with presurgical chemotherapy followed by radical cystectomy, and 134 radical cystectomy followed by adjuvant chemotherapy. Relevant clinicopathologic features were reviewed. Recurrence-free survival and Overall Survival probability estimates were calculated using the Kaplan–Meier method and compared using the Log-rank or Gehan-Breslow tests. The prognostic effects of presurgical chemotherapy and adjuvant chemotherapy regimens were evaluated by estimating hazard ratio and 95% confidence interval from an adjusted Cox proportional hazards model. Statistical tests were 2-sided, and significance was defined as P -value < 0.05. In this contemporary, real-world cohort, 5-yr RFS was found to be 65.6% in pT0, 59.1%in pT2, and 10.8% in pN+ patients. Presurgical chemotherapy increased pathologic downstaging rates from 27.5% to 41.1% in patients with ≥cT2 BCa. Stratified by clinical T-stage, only cT2 patients derived recurrence-free survival (Median 45.3 months vs. 29.0 months, P < 0.01) and overall survival (Median 62.3 months vs. 41.9 months, P < 0.001) benefits. In patients with adverse pathologic features (≥pT3 or pN+), adjuvant chemotherapy improved recurrence-free survival (Median 22.8 months vs. 10.0 months, P < 0.0001) and overall survival (Median OS 32.4 months vs. 16.3 months, P < 0.0001). We report real-world outcomes from a large cohort of muscle-invasive bladder cancer patients undergoing surgical treatment with/out perioperative chemotherapy. Pathologic response rates to pre-surgical chemotherapy were modest and led to clinical benefit only in cT2 patients. Adjuvant chemotherapy provided survival benefit for pathologically advanced MIBC patients irrespective of pT/N staging. [ABSTRACT FROM AUTHOR]

Purpose: The role of androgen receptor (AR) signaling in bladder cancer (BCa) is not fully characterized. This study aimed to delineate the role of AR signaling in BCa and to determine whether the combination of AR inhibitor, Enzalutamide (Enz), and Cisplatin (Cis) efficiently inhibit the growth of BCa cells.Methods: AR expression was determined in 89 human urothelial BCa specimens by immunohistochemistry. A panel of BCa cell lines was treated with Cis, Enz, or a combination of both (Enz + Cis). We determined the expression of AR, changes in apoptotic signaling, DNA damage, and analyzed effect on epithelial mesenchymal transformation markers.Result: AR expression was detected in 61.4% of tumors from male BCa patients. Inhibition of AR signaling by Enz effectively inhibited the growth of AR+ BCa cells by inducing apoptosis (26%) in AR+ TCCSUP (P = 0.0201) and J82 (15%, P = 0.0386) cells. Interestingly, Enz + Cis synergistically inhibited the proliferation of BCa cells even at low concentrations by inducing proapoptotic signaling in AR+ BCa cells. Invasive and migratory potential of TCCSUP and J82 cells were reduced with Enz + Cis treatment, and associated with down-regulation of mesenchymal markers.Conclusions: A high percentage of the bladder tumors from male patients in our cohort expressed AR. The combination of Enz and Cis synergistically inhibited growth of BCa cells more efficiently than single agent alone. This supports the rationale for future investigation of AR antagonists in combination with standard chemotherapy in MIBC. [ABSTRACT FROM AUTHOR]

• Used a tapered match analysis to localize disparities in bladder cancer. • 5-year survival rates for black and white patients were significantly different. • More black patients experienced a treatment delay compared to white patients. • Treatment variables may be a large contributor to overall survival disparities. Examine patient, tumor, and treatment characteristics effect on the disparity between black and white patients with muscle-invasive bladder cancer (MIBC) who undergo radical cystectomy (RC). 1,286 black patients in the 2004 to 2016 National Cancer Database fit inclusion criteria. A tapered match was performed from 17,374 white patients sequentially matched to the black cohort on demographics (age, gender, insurance, income, education, county, diagnosis year), presentation (demographic variables, stage, grade, tumor size, Charlson score), and treatment (demographic and presentation variables, lymph node count, hospital volume, neoadjuvant chemotherapy [NAC], treatment delay), creating 3 matched cohorts. Chi-square and Kruskal-Wallis tests were used to compare cohorts. Kaplan-Meier analysis was used to compare 5-year overall survival (OS). 5-year OS rate was 40.4% and 35.6% for unmatched white and black cohorts (P < 0.001), respectively. Following demographics and presentation match, 5-year OS rate for white patients decreased to 39.2% (P = 0. 003) and 39.10% (P = 0.019), respectively. After treatment match, 5-year OS rate decreased to 36.7% for white patient (P = 0.32). Following presentation match, 7.2% of black patients vs. 5.8% of white patients had treatment delay, and 10.1% of black patients vs. 11.2% of white patients received NAC. The treatment match resulted in a 0.3% difference between groups for treatment delay and NAC. Our analysis demonstrates that disparity between black and white patients with muscle-invasive bladder cancer exists in demographic-, presentation-, and treatment-related variables. Treatment variables may be a large contributing factor to survival disparities. Further research is needed to identify social, biological, and organizational inputs that contribute to these disparities. [ABSTRACT FROM AUTHOR]

Introduction: Studies evaluating outcomes in bladder cancer sub stratified into T2a and T2b pathologic staging have demonstrated inconsistent results. Survival outcomes in a cohort of pure urothelial carcinoma patient undergoing radical cystectomy were evaluated to determine the prognostic value of T2 sub staging.Methods: Using our prospectively maintained institutional cystectomy database, we identified patients with pure urothelial carcinoma of the bladder, either pT2aN0 or pT2bN0. We excluded any patients with variant histology, patients that underwent neoadjuvant chemotherapy, and patients that had margin positive disease. Demographic and clinicopathologic data were collected, and Cox proportional hazard regression assessed overall survival (OS), cancer specific survival (CSS), and recurrence free survival (RFS).Results: From 2001 to 2019, we identified 1,929 patients that underwent radical cystectomy, 61 patients had pT2a and 65 had pT2b pure urothelial carcinoma that met inclusion criteria. Only age (P = 0.02) and the initial transurethral resection of bladder tumor pathology (P < 0.01) were notably different when comparing the clinical characteristics of patients with pT2a and pT2b. No differences were noted in OS, CSS, or RFS between the 2 groups on Kaplan-Meier analysis. On univariate Cox regression analysis, age, TURBT stage, cystectomy pathology stage, carcinoma in situ, and lymphovascular invasion status, and Bacillus Calmette-Guérin therapy status was not found to be significant factors for OS, CSS, or RFS between patients with pT2aN0 or pT2bN0 tumors.Conclusion: Prior studies have sub stratified pT2a and pT2b, studying survival outcomes with equivocal results. Many of these studies included variant histology or use of chemotherapy in the analysis. Here, we identified a pure urothelial cohort to compare survival outcomes between pT2a and pT2b and found no difference in OS, CSS, and RFS. [ABSTRACT FROM AUTHOR]

Abstract: At the 11th annual meeting of the Society of Urologic Oncology, an expert panel was convened to discuss the practical use of perioperative chemotherapy for muscle-invasive bladder cancer. The discussion was structured as a case-based debate among the panelists. The topics included: neoadjuvant chemotherapy with a focus on T2 disease, pros and cons, survival data, tolerability of cisplatin-based therapy, can we avoid radical cystectomy in complete responders, limitations and alternatives to cisplatin-based therapy, management of ‘suboptimal’ chemotherapy, residual disease after neoadjuvant chemotherapy, adjuvant chemotherapy, and key aspects of radical cystectomy and lymph-node dissection in multimodal therapy. The presentations were derived from published literature. The panelists agreed that patients with muscle-invasive bladder cancer should be managed with a multidisciplinary team, including urologist and medical oncologist. Cisplatin-based neoadjuvant chemotherapy has demonstrated improved survival and should be incorporated into the management of all eligible patients with muscle-invasive bladder cancer. However, in some centers, neoadjuvant chemotherapy is reserved for patients with >T2 disease or high-risk features. There are no data for the administration of non-cisplatin-based neoadjuvant chemotherapy, such as carboplatin-combinations. Cisplatin-ineligible patients should proceed directly to surgical extirpation with adjuvant cisplatin-based chemotherapy considered based on pathologic findings. However, the data for adjuvant chemotherapy is less compelling. As our refinement of the selection process continues, we may be able to better identify subsets of patients who may be spared chemotherapy, but much work remains to be done in this arena. The current standard for muscle-invasive bladder cancer patients is cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy and pelvic lymph-node dissection. [Copyright &y& Elsevier]

Background: Multiple single-arm clinical trials showed promising pathologic complete response rates with neoadjuvant immune checkpoint inhibitors (ICIs) in muscle-invasive bladder cancer. We conducted a cost-effectiveness analysis comparing neoadjuvant ICIs with cisplatin-based chemotherapy (CBC).Methods: We applied a decision analytic simulation model with a health care payer perspective to compare neoadjuvant ICIs vs. CBC. For the primary analysis we compared pembrolizumab with ddMVAC. We performed a secondary analysis with gemcitabine/cisplatin as CBC and exploratory analyses with atezolizumab or nivolumab/ipilimumab as ICI. We input pathologic complete response rates from trials or meta-analysis and costs from average sales price. Outcomes of interest included costs, 2-year recurrence-free survival (RFS), and incremental cost-effectiveness ratio (ICER) of cost per 2-year RFS. A threshold analysis estimated a price reduction for ICI to be cost-effective and one-way and probabilistic sensitivity analyses were performed.Results: The incremental cost of pembrolizumab compared with ddMVAC was $8,041 resulting in an incremental improvement of 1.5% in 2-year RFS for an ICER of $522,143 per 2-year RFS. A 21% reduction in cost of pembrolizumab would render it more cost-effective with an ICER of $100,000 per 2-year RFS. GC required an 89% pembrolizumab cost reduction to achieve an ICER of $100,000 per 2-year RFS. Atezolizumab appeared to be more cost-effective than ddMVAC.Conclusions: ICIs were not cost-effective as neoadjuvant therapies, except when atezolizumab was compared with ddMVAC. Randomized clinical trials, larger sample sizes and longer follow-up are required to better understand the value of ICIs as neoadjuvant treatments. [ABSTRACT FROM AUTHOR]

Background: The cell surface interleukin 22 (IL-22) receptor complex is mainly expressed in epithelial and tissue cells like pancreatitis cells. Recent studies described that IL-22R was overexpressed in malignant diseases and was associated with a poor overall survival (OS). The role of IL-22RA1 gene expression in muscle invasive bladder cancer (MIBC) has not been investigated, yet.Objectives: The aim of this study was to analyze the role of IL-22RA1 gene expression in patients with MIBC.Methods: In a cohort of 114 patients with MIBC who underwent radical cystectomy, IL-22RA1 gene expression was analyzed with qRT-PCR and correlated with clinical parameters. Furthermore, Kaplan-Meier and Cox regression analysis were performed. For validation, an in silico dataset (TCGA 2017, n=407) was reanalyzed.Results: IL-22RA1 gene expression was independent of clinicopathological parameters like age (P=0.2681), T stage (P=0.2130), nodal status (P=0.3238) and lymph vascular invasion (LVI, P=0.5860) in patients with MIBC. A high expression of IL-22RA1 was associated with a shorter OS (P=0.0040) and disease-specific survival (P=0.0385). Furthermore, a shorter disease-free survival (DFS) was also associated with a high expression of IL-22RA1 (P=0.0102). In the multivariable analysis, IL-22RA1 expression was an independent prognostic predictors regarding OS (P=0.0096, HR=0.48). In the TCGA cohort, IL-22RA1 expression was independent regarding to OS and DFS.Conclusion: A high IL-22RA1 gene expression was associated with worse outcome. Furthermore, IL-22RA1 represented an independent predictor regarding OS in our cohort and therefore might be used for risk stratification in patients with MIBC. [ABSTRACT FROM AUTHOR]

Background: There is an increasing demand for prognostic immune biomarkers of cancer. The prognostic significance of immune markers has been shown for various cancers, but biomarkers of bladder cancer (BCa) have not been fully evaluated. To clarify the role of human leukocyte antigen DR alpha chain (HLA-DRA) in BCa development, we examined expression of HLA-DRA mRNA in tissue samples of non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC).Materials and Methods: Tissues of 96 NMIBC, 43 MIBC and 59 controls comprising noncancerous BCa surrounding tissues were used to examine the expression of HLA-DRA gene by real-time polymerase chain reaction. The expression of up-stream genes regulating HLA-DRA were also measured to explain the role of HLA-DRA in BCa.Results: Patients with high grade NMIBC showed higher expression of HLA-DRA than those with low grade NMIBC (P < 0.05). In addition, NMIBC patients who progressed to MIBC showed high expression of HLA-DRA mRNA. Kaplan-Meier analysis showed that NMIBC patients with low expression of HLA-DRA had better progression-free survival than those with high expression (P = 0.004). Moreover, the expression of genes regulating HLA-DRA varied in NMIBC and MIBC, indicating a different immunoregulation effect of HLA-DRA in both cancers.Conclusions: High expression of HLA-DRA in NMIBC patients has implications for patient stratification strategies, as well as for BCa tumor immunology. [ABSTRACT FROM AUTHOR]

Objective: To identify the optimal selection criteria for bladder sparing strategy with transurethral resection of bladder tumor (TURBT) and systemic chemotherapy in patients with muscle-invasive bladder cancer (MIBC).Methods: We conducted a retrospective cohort study in 71 patients with MIBC (T2-4aN0M0) who desire to bladder preservation received neoadjuvant chemotherapy (NAC) after maximal TURBT, followed by clinical restaging and second-TURBT. Fifty-eight of 71 patients with no residual tumor on the second-TURBT were placed on conservative management for bladder sparing (BS). Noninvasive down-staging (NID) was defined as cT0/Ta/Tis/T1N0 at first-TURBT after NAC and no residual tumor on second-TURBT. Overall survival (OS) and cystectomy-free survival (CFS) were assessed according to the response of NAC in the BS group by using Kaplan-Meier methods. Cox proportional hazards regression model was used to identify independent variables predicting OS.Results: At a median follow-up of 40 months 5-year OS and CFS in patients with NID and non-NID were 89.1% versus 20.8% and 84.8% versus 16.7%, respectively. Multivariate analysis showed that the ≥3 cycles of NAC (hazard ratio [HR] 0.14, 95% confidential index [CI] 0.03-0.7; P = 0.017) and achievement of NID (HR 0.11, 95% CI 0.03-0.46, P = 0.002) favorably associated with OS.Conclusions: Patients who achieved NID might be optimal candidates for the bladder sparing strategy with maximum TURBT plus NAC followed by second-TURBT. [ABSTRACT FROM AUTHOR]

Objectives: Radical cystectomies (RCs) are increasingly centralized, but bladder cancer can be diagnosed in every hospital The aim of this study is to assess the variation between hospitals of diagnosis in a patient's chance to undergo a RC before and after the volume criteria for RCs, to identify factors associated with this variation and to assess its effect on survival.Methods and Materials: Patients diagnosed with muscle-invasive bladder cancer (cT2-4a,N0/X,M0/X) without nodal or distant metastases between 2008 and 2016 were identified through the Netherlands Cancer Registry. Multilevel logistic regression analysis was used to investigate the hospital specific probability of undergoing a cystectomy. Cox proportional hazard regression analysis was used to assess the case-mix adjusted effect of hospital-specific probabilities on survival.Results: Of the 9,215 included patients, 4,513 (49%) underwent a RC. The percentage of RCs varied between 7% and 83% by hospital of diagnosis before the introduction of the first volume criteria (i.e., 2008-2009; minimum of 10 RCs). This variation decreased slightly to 17%-77% after establishment of the second volume criteria (i.e., 2015-2016; minimum of 20 RCs). Age, cT-stage and comorbidity were inversely and socioeconomic status was positively associated with RC. Both being diagnosed in a community hospital and/or being diagnosed in a hospital fulfilling the RC volume criteria were associated with increased use of RC compared to academic hospitals and hospitals not fulfilling the volume criteria. For each 10% increase in the percentage of RC in the hospital of diagnosis, 2-year case-mix adjusted survival increased 4% (hazard ratio 0.96, 95% confidence interval 0.94-0.98).Conclusion: Probability of RC varied between hospitals of diagnosis and affected 2-year overall survival. Undergoing a RC was associated with age, cT-stage, socioeconomic status, type of hospital, and whether the hospital of diagnosis fulfilled the RC volume criteria. Future research is needed to identify patient, tumor, and hospital characteristics affecting utilization of curative treatment as this may benefit overall survival. [ABSTRACT FROM AUTHOR]

Background: Trials of adjuvant chemotherapy following radical cystectomy generally require chemotherapy to start within 90 days postoperatively. However, it is unclear, whether the interval between surgery and start of adjuvant therapy (S-AC-interval) impacts the oncological outcome.Methods: Using the Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC) data base, we identified patients who underwent radical cystectomy for muscle invasive bladder cancer and subsequent adjuvant chemotherapy. Univariate analysis of patient characteristics, surgical factors and tumor characteristics regarding their impact on S-AC-interval was performed using Kruskal-Wallis testing and Fisher's exact test. Analysis of progression-free (PFS) and overall survival (OS) (follow-up time beginning with the start date of adjuvant chemotherapy) was analyzed in relation to S-AC-interval (continuous and dichotomous with a cut-off at 90 days) using Kaplan-Meier method and COX regression analysis.Results: We identified 238 eligible patients (83.5% male, mean age: 63.4 years, 76.1% T3/T4, 66.4% pN+, 14.7% R+, 70.6% urothelial carcinoma, 71% cisplatin-based adjuvant chemotherapy). The majority of patients (n = 207, 87%) started chemotherapy within 90 days after surgery. Median S-AC-interval was 57 days (interquartile range 32.8). S-AC-interval did not have consistent association with any patient/tumor characteristics or surgery related factors (type of surgery, urinary diversion). Survival analysis using continuous S-AC-interval revealed a trend toward an impact of S-AC-interval on OS (hazard ratio 1.004, 95% confidence ratio 0.9997-1.0084, P = 0.071). With regards to PFS, that impact was shown to be statistically significant (hazard ratio 1.004, 95% confidence ratio 1.0003-1.0075, P = 0.032). In multivariate analysis, however, S-AC-interval was negated by tumor and patient related factors (pathological T-stage, N-stage, ECOG performance status). Accounting for eligibility criteria defined in some clinical trials, we extended our analysis dividing S-AC-interval in ≤90 and >90 days. Although we could confirm the trend toward better outcome in patients with a shorter S-AC interval in dichotomous analysis, neither differences in OS nor in PFS reached statistical significance (P = 0.438 and P = 0.056).Conclusions: In a large multi-institutional experience, 87% of patients who received adjuvant chemotherapy received it within the guideline recommended window of 90 days. While it was not possible to determine whether this is the optimal cut-off, early start of adjuvant chemotherapy seems to be reasonable. Regarding prognosis, tumor-related pathological factors abrogated the importance of the S-AC-interval in our analysis. [ABSTRACT FROM AUTHOR]