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PLOS ONE 17(6), e0269827 (2022). doi:10.1371/journal.pone.0269827, Published by PLOS, San Francisco, California, US

What's known on the subject? and What does the study add? Several studies have shown that defects in DNA-damage response are associated with good survival after chemotherapy and radiotherapy. Furthermore, loss of cell cycle regulators may be prognostic indicators of poor survival after cystectomy. However, the potential clinical impact of previous findings is hampered by insufficient validation of significant results in suitable cystectomy and radiotherapy cohorts. Here we use a large cohort of patients receiving radiotherapy to successfully validate the importance of MRE11 as a predictive marker of disease-specific survival (DSS). Furthermore, using two independent patient cohorts we show for the first time that TIP60 is a predictive marker of DSS after cystectomy. We show that combined use of TIP60 and MRE11 may hold the potential to guide treatment decisions. OBJECTIVE • To determine the association between the proteins: tat-interactive protein 60 kDa (TIP60), p16, meiotic recombination 11 homolog (MRE11), phosphorylated ataxia telangiectasia mutated (ATM), retinoblastoma protein (Rb), Ki67, and p53 and clinical outcome in invasive lymph node-negative bladder cancer. PATIENTS AND METHODS • Protein expression was measured by immunohistochemistry in cancer specimens from two independent cohorts of patients with bladder cancer treated with cystectomy (162 patients and 273) and one cohort of patients receiving radiotherapy (148). • Disease-specific survival (DSS) was used as the outcome measure, and patients with no disease-specific death were followed for a minimum of 36 months. RESULTS • TIP60 was significantly correlated with DSS in both cystectomy cohorts (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.26–0.68, P < 0.001 and HR 0.45, 95% CI 0.28–0.72, P= 0.001). • MRE11 was significantly correlated with DSS in the cohort receiving radiotherapy (HR 0.64, 95% CI 0.47–0.86, P= 0.005). • P16 was significantly correlated with DSS in all three cohorts (HR 0.46, 95% CI 0.30–0.75, P= 0.032; HR 0.60, 95% CI 0.37–0.97, P= 0.032; HR 0.52, 95% CI 0.28–0.96, P= 0.001). • Rb was significantly correlated with DSS in one cystectomy cohort (HR 1.71, 95% CI 1.13–2.75, P= 0.017). • Ki67, p53, and pATM were not significantly correlated with DSS in any of the cohorts. CONCLUSIONS • TIP60 protein expression was a predictive marker for DSS after cystectomy in two independent cohorts. This novel marker was the strongest predictive factor in multivariate analysis in patients receiving cystectomy. • MRE11 was shown to be a predictive marker for DSS after radiotherapy. • We have shown that TIP60 and MRE11 hold the potential to guide patients with invasive bladder cancer to either cystectomy or radiotherapy. This study was based on retrospective material and consequently we suggest that these markers should be validated in a prospective study.

Background and purpose To assess the safety and effectiveness of treating high-risk T1 and T2 bladder cancer with transurethral resection (TUR-BT) followed by radiochemotherapy (RCT) combined with regional deep hyperthermia (RHT). Material and methods Between 2003 and 2007, 45 patients were enrolled. After TUR-BT patients received radiotherapy (RT) of the bladder and regional lymph nodes with 50.4 Gy, and a boost to the bladder of 5.4–9 Gy. RCT was applied to 43/45 patients. RHT was administered once weekly. Response was re-evaluated 6 weeks after RT by restaging-TUR. Toxicity was graded with the CTCAE, version 3.0. QoL was evaluated by a dedicated questionnaire. Results The median follow-up was 34 months (range 12–60). The median number of hyperthermia treatments was 5 (range 1–7). Acute toxicity grades 3 and 4 occurred in 20% (9/45) and 9% (4/45), respectively. Late toxicity grades 3/4 were seen in 24% (11/45). Complete response rate was 96% (43/45). Local recurrence-free survival was 85%, overall survival was 80%, disease-specific survival was 88%, metastasis-free survival was 89%, and the bladder-preserving rate was 96% (43/45) at 3 years. Eighty percent (24/30) were at least mostly satisfied with their bladder function. Conclusions The quadrimodal treatment was feasible and well tolerated. Local control and bladder-preserving rates were encouraging.

To review the standards and new developments in diagnosis and management of high-risk T1 bladder cancer with emphasis on the role of radiotherapy (RT) and radiochemotherapy (RCT). A systematic review of the literature on developments in diagnosis and management of high-risk T1 bladder cancer was performed. First transurethral resection (TUR), as radical as safely possible, supported by fluorescence cystoscopy, shows higher detection and decreased recurrence rates. An immediate single postoperative instillation with a chemotherapeutic drug reduces the relative risk of recurrence by 40%. A second TUR is recommended to assess residual tumor. For adjuvant intravesical therapy, bacille Calmette-Guerin (BCG) demonstrated the highest efficacy. Early cystectomy should be reserved for selected patients. A recent phase III trial comparing RT versus conservative treatment in T1 G3 tumors could not show any advantage for RT. Data from Erlangen, Germany, using combined RCT in 80% of the patients, compare favorably with most of the contemporary BCG series. Results of intravesical therapy are still unsatisfying and early cystectomy is associated with morbidity and mortality. RT alone proved not superior to other conservative treatment strategies. However, data on RCT are promising and demonstrate an alternative to intravesical therapy and radical cystectomy.

What's known on the subject? and What does the study add? Several studies have shown that defects in DNA-damage response are associated with good survival after chemotherapy and radiotherapy. Furthermore, loss of cell cycle regulators may be prognostic indicators of poor survival after cystectomy. However, the potential clinical impact of previous findings is hampered by insufficient validation of significant results in suitable cystectomy and radiotherapy cohorts. Here we use a large cohort of patients receiving radiotherapy to successfully validate the importance of MRE11 as a predictive marker of disease-specific survival (DSS). Furthermore, using two independent patient cohorts we show for the first time that TIP60 is a predictive marker of DSS after cystectomy. We show that combined use of TIP60 and MRE11 may hold the potential to guide treatment decisions.• To determine the association between the proteins: tat-interactive protein 60 kDa (TIP60), p16, meiotic recombination 11 homolog (MRE11), phosphorylated ataxia telangiectasia mutated (ATM), retinoblastoma protein (Rb), Ki67, and p53 and clinical outcome in invasive lymph node-negative bladder cancer.• Protein expression was measured by immunohistochemistry in cancer specimens from two independent cohorts of patients with bladder cancer treated with cystectomy (162 patients and 273) and one cohort of patients receiving radiotherapy (148). • Disease-specific survival (DSS) was used as the outcome measure, and patients with no disease-specific death were followed for a minimum of 36 months.• TIP60 was significantly correlated with DSS in both cystectomy cohorts (hazard ratio [HR] 0.42, 95% confidence interval [CI] 0.26-0.68, P0.001 and HR 0.45, 95% CI 0.28-0.72, P = 0.001). • MRE11 was significantly correlated with DSS in the cohort receiving radiotherapy (HR 0.64, 95% CI 0.47-0.86, P = 0.005). • P16 was significantly correlated with DSS in all three cohorts (HR 0.46, 95% CI 0.30-0.75, P = 0.032; HR 0.60, 95% CI 0.37-0.97, P = 0.032; HR 0.52, 95% CI 0.28-0.96, P = 0.001). • Rb was significantly correlated with DSS in one cystectomy cohort (HR 1.71, 95% CI 1.13-2.75, P = 0.017). • Ki67, p53, and pATM were not significantly correlated with DSS in any of the cohorts.• TIP60 protein expression was a predictive marker for DSS after cystectomy in two independent cohorts. This novel marker was the strongest predictive factor in multivariate analysis in patients receiving cystectomy. • MRE11 was shown to be a predictive marker for DSS after radiotherapy. • We have shown that TIP60 and MRE11 hold the potential to guide patients with invasive bladder cancer to either cystectomy or radiotherapy. This study was based on retrospective material and consequently we suggest that these markers should be validated in a prospective study.

Standard treatment for muscle-invasive bladder cancer is cystectomy. Multimodality treatment, including transurethral resection of the bladder tumour, radiation therapy, chemotherapy and deep regional hyperthermia, has been shown to produce survival rates comparable with those of cystectomy. With these programmes, cystectomy has been reserved for patients with incomplete response or local relapse. During the past two decades, organ preservation by multimodality treatment has been investigated in prospective series from single centres and co-operative groups, with more than 1000 patients included. Five-year overall survival rates in the range of 50-60% have been reported, and about three-quarters of the surviving patients maintained their bladder. Clinical criteria helpful in determining patients for bladder preservation include such variables as small tumour size (

Purpose Standard treatment for superficial bladder cancer is transurethral resection of the bladder tumor (TURBT) followed by intravesical therapy. Little is known about the biologic behavior and treatment response of superficial disease within an irradiated bladder. We specifically analyzed patients who developed superficial recurrence after TURBT and radiotherapy or radiochemotherapy. Patients and Methods Between 1982 and 2006, a total of 531 consecutive patients with invasive bladder cancer were treated by using various bladder-sparing protocols at our institution. Of these, 389 (76%) achieved a complete response after TURBT and radiotherapy/radiochemotherapy. During follow-up, 68 of 389 patients (17%) developed a superficial local relapse (≤T1) and form the subject of this study. Results Sixty-four of 68 patients underwent conservative TURBT with or without intravesical treatment (4 patients underwent immediate cystectomy): 31 of 64 patients (48%) had no further bladder recurrence, 21 (33%) experienced additional superficial recurrences, and 12 (19%) ultimately progressed to muscle-invasive disease. Disease-specific survival rates were 87% and 72% at 5 and 10 years, respectively. Compared with 255 patients without local bladder relapse after primary treatment, no significant difference was found for disease-specific survival rates (72% after superficial vs. 79% without local relapse at 10 years, p = 0.78). However, significantly fewer patients with a superficial relapse survived with their native bladder (50% after superficial vs. 76% without local relapse at 10 years, p Conclusion A further bladder-sparing approach with TURBT and intravesical therapy is reasonable for patients with superficial relapse after combined-modality treatment without compromising survival. However, these patients are at greater risk of requiring late cystectomy.

Proper detection of DNA damage and signal transduction to other proteins following irradiation (IR) is essential for cellular integrity. The serine 15 (Ser15) on p53 is crucial for p53 stabilization and a requirement for transient and permanent cell cycle arrest. Here, we sought to determine the relationship between p53 serine 15 phosphorylation (p53-p-Ser15) on cellular sensitivity and if this modification is associated with DNA double-strand break (DSB) repair.Eight lymphoblastoid cell lines including ataxia-telangiectasia (A-T), Nijmegen breakage syndrome (NBS) and radiosensitive patient derived cell lines were irradiated with 1 Gy, 2 Gy and 5 Gy. Then growth inhibition, p53 induction and phosphorylation on Ser15 as assessed by immunoblotting and DNA DSB repair as assessed by constant field gel electrophoresis were examined.Phosphorylation of p53 at Ser15 in control cells rapidly increased, peaking at 3-6 hours and then sustained a low level of phosphorylation for up to 6 days following IR. For these cell lines, the amount of p53-p-Ser15 corresponded to the sensitivity of cells and the amount of DNA DSB. In A-T cells, p53-p-Ser15 was reduced in spite of increased DNA DSB. NBS cells had similar phosphorylation dynamics as the control cell line, which was not consistent with their increased sensitivity. Radiosensitive patients' cell lines differed only slightly from controls.Cells that are competent in signal transduction have p53-p-Ser15 kinetics corresponding to cellular radiosensitivity as assessed by clonogenicity and DNA DSB repair, and cells impaired in signal transduction lack this correspondence. Therefore, using p53-p-Ser15 as a general marker of radiation sensitivity has confounding factors which may impair proper radiosensitivity prediction.

5512 Background: Are 6 cycles of once weekly DDP plus one cycle of 5-FU with concurrent HART superior to 2 cycles of MMC plus one cycle of 5-FU in terms of overall survival (OS) and metastases-free survival (MFS)? Methods: Eligibility: Stage IV SCC of oro(OP)- and hypopharynx(HP), KFS of ≥80% stratified for sites, N-status, grading, hemoglobin and center. The HART schedule was reported elsewhere (V.Budach, JCO 23;2005). HART was applied concurrently with DDP/5-FU at 30mg/m² days 1,8,15,22,29,36 or MMC/5-FU at 10mg/m2 day 1+36 and for both arms with 600mg/m² 5-FU days 1-5 as 120 hrs. c.i. TVD dose prescription was 72 Gy using 3D-conformal or IMRT-TP. 364 patients were analysed using an ITT principle for OS, MFS, progression-free survival (PFS) and loco-regional control (LRC). Hazard ratio (HR) calculations were adjusted for competing risk factors. Results: Median follow-up was 48 mos. for both arms. Mean age was 55.4 years, 83/17% were male/female and 100% stage IV patients (UICC 2002). 58.5%/41.5% of all patients suffered from OP- or HP cancer, respectively. The OS and MFS at 4 years for the DDP- versus MMC-arm was 42.1% vs. 38.8% (n.s.) and 67.3% vs. 56.6% (p=.05), respectively. The LRC and PFS for the DDP versus MMC-arm was 58.6% vs. 57.2% (n.s.) and 46.4% vs. 38.7% (n.s.). Seven items recorded for acute toxicity and 9 for late morbidity showed no significant differences between the treatment arms except for creatinine for the DDP-arm (p < 0.001) using nonparametric analyses of variances for repeated measurements. The overall compliance rates for RTX were 96%, DDP: 72%, 5-FU: 97%, MMC: 86%, respectively. Conclusions: This phase III trial first establishes level IB-evidence for a once weekly DDP chemoradiation regimen. For MFS at 4 yrs., DDP/5 FU-HART is superior to MMC/5 FU HART at equal levels of acute and late radiation sequelae for both treatment arms. No significant differences were seen yet for OS, PFS or LRC. Chemoradiation with weekly DDP/5-FU or MMC/5-FU shows excellent compliance rates and can easily compete with other concurrent chemo- or bio-radiation schedules including induction TPF followed by radiation.