Lessons learned after one year of COVID-19 from a urologist and radiotherapist view: A German survey on prostate cancer diagnosis and treatment.

INTRODUCTION: Since the beginning of the pandemic in 2020, COVID-19 has changed the medical landscape. International recommendations for localized prostate cancer (PCa) include deferred treatment and adjusted therapeutic routines. MATERIALS AND METHODS: To longitudinally evaluate changes in PCa treatment strategies in urological and radiotherapy departments in Germany, a link to a survey was sent to 134 institutions covering two representative baseline weeks prior to the pandemic and 13 weeks from March 2020 to February 2021. The questionnaire captured the numbers of radical prostatectomies, prostate biopsies and case numbers for conventional and hypofractionation radiotherapy. The results were evaluated using descriptive analyses. RESULTS: A total of 35% of the questionnaires were completed. PCa therapy increased by 6% in 2020 compared to 2019. At baseline, a total of 69 radiotherapy series and 164 radical prostatectomies (RPs) were documented. The decrease to 60% during the first wave of COVID-19 particularly affected low-risk PCa. The recovery throughout the summer months was followed by a renewed reduction to 58% at the end of 2020. After a gradual decline to 61% until July 2020, the number of prostate biopsies remained stable (89% to 98%) during the second wave. The use of RP fluctuated after an initial decrease without apparent prioritization of risk groups. Conventional fractionation was used in 66% of patients, followed by moderate hypofractionation (30%) and ultrahypofractionation (4%). One limitation was a potential selection bias of the selected weeks and the low response rate. CONCLUSION: While the diagnosis and therapy of PCa were affected in both waves of the pandemic, the interim increase between the peaks led to a higher total number of patients in 2020 than in 2019. Recommendations regarding prioritization and fractionation routines were implemented heterogeneously, leaving unexplored potential for future pandemic challenges.

Expression of TIP60 (tat-interactive protein) and MRE11 (meiotic recombination 11 homolog) predict treatment-specific outcome of localised invasive bladder cancer.

UNLABELLED: 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.

Quadrimodal treatment of high-risk T1 and T2 bladder cancer: transurethral tumor resection followed by concurrent radiochemotherapy and regional deep hyperthermia.

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.

Distribution of immune cells in head and neck cancer: CD8+ T-cells and CD20+ B-cells in metastatic lymph nodes are associated with favourable outcome in patients with oro- and hypopharyngeal carcinoma.

BACKGROUND: Tumour infiltrating lymphocytes (TIL) are generally considered to represent a host immune response directed against tumour antigens. TIL are also increasingly recognised as possible prognostic parameters. However, the effects observed are variable indicating that results cannot be extrapolated from type of tumour to another. Moreover, it has been suggested that primary solid tumours may be ignored by the immune system and that a meaningful immune response is only mounted in regional lymph nodes. METHODS: We have examined the local distribution of immune cells in tumour-related compartments in head and neck squamous cell carcinomas (HNSCC). In a second step, the prognostic impact of these cells on disease-free survival (DFS) was analysed. A total of 198 tissue cores from 33 patients were evaluated using tissue mircroarray technique and immunohistochemistry. Tumour-infiltrating immune cells were identified using antibodies specific for CD3, CD8, GranzymeB, FoxP3, CD20 and CD68 and quantified using an image analysis system. RESULTS: We demonstrate a relative expansion of FoxP3+ regulatory T-cells (Treg) and of cytotoxic T-cells among tumour infiltrating T-cells. We also show that intratumoural CD20+ B-cells are significantly more frequent in metastatic deposits than in primary tumours. Furthermore, we observed a reduced number of peritumoural CD8+ T-cells in metastatic lymph nodes as compared to univolved regional nodes suggesting a local down-modulation of cellular immunity. All other immune cells did not show significant alterations in distribution. We did not observe an association of tumour infiltrating immune cells at the primary site with outcome. However, increased numbers of intraepithelial CD8+ TIL in metastatic tumours as well as large numbers of peritumoural B-cells in lymph node metastases were associated with favourable outcome. Unexpectedly, no effect on patient outcome was observed for Treg in any compartment. CONCLUSION: Our results suggest that alterations in lymphocyte distribution in regional lymph nodes rather than at the primary tumour site may be relevant for patient prognosis. Moreover, we demonstrate that in addition to cellular immunity humoral immune responses may be clinically relevant in anti-tumour immunity.

Survivin expression as a predictive marker for local control in patients with high-risk T1 bladder cancer treated with transurethral resection and radiochemotherapy.

PURPOSE: The objectives of this study were to investigate the expression of survivin in tumor samples from patients with high-risk T1 bladder cancer and to correlate its expression with clinicopathologic features as well as clinical outcomes after initial transurethral resection (TURBT) followed by radiotherapy (RT) or radiochemotherapy (RCT). METHODS AND MATERIALS: Survivin protein expression was evaluated by immunohistochemistry on tumor specimen (n = 48) from the initial TURBT, and was correlated with clinical and histopathologic characteristics as well as with 5-year rates of local failure, tumor progression, and death from urothelial cancer after primary bladder sparring treatment with RT/RCT. RESULTS: Survivin was not expressed in normal bladder urothelium but was overexpressed in 67% of T1 tumors. No association between survivin expression and clinicopathologic factors (age, gender, grading, multifocality, associated carcinoma in situ) could be shown. With a median follow-up of 27 months (range, 3-140 months), elevated survivin expression was significantly associated with an increased probability of local failure after TURBT and RCT/RT (p = 0.003). There was also a clear trend toward a higher risk of tumor progression (p = 0.07) and lower disease-specific survival (p = 0.10). CONCLUSIONS: High survivin expression is a marker of tumor aggressiveness and may help to identify a subgroup of patients with T1 bladder cancer at a high risk for recurrence when treated with primary organ-sparing approaches such as TURBT and RCT.

Treatment options for high-risk T1 bladder cancer: status quo and future perspectives of radiochemotherapy.

PURPOSE: 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). MATERIAL AND METHODS: A systematic review of the literature on developments in diagnosis and management of high-risk T1 bladder cancer was performed. RESULTS: 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-Guérin (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. CONCLUSION: 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.

Management of superficial recurrences in an irradiated bladder after combined-modality organ-preserving therapy.

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 (< or = 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 < 0.001). 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.

Time and dose-dependent activation of p53 serine 15 phosphorylation among cell lines with different radiation sensitivity.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.