The impact of positive surgical margins after cystectomy on oncological outcomes: a nationwide study from the Prospective Bladder Cancer Infrastructure (ProBCI)
This nationwide cohort study evaluated if surgical margin status alongside existing postoperative risk indicators improves identification of bladder cancer patients who may benefit from adjuvant therapy following radical cystectomy (RC). Adults with cT2–4aN0/xM0 disease (November 2017–December 2020) who underwent RC were selected from the Netherlands Cancer Registry. Overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan-Meier method. Multivariable Cox regression analysis was performed to assess the independent prognostic effect of positive surgical margins (carcinoma in situ [CIS] only or invasive carcinoma) on PFS and OS. Among 1,445 patients (53% open, 47% robot-assisted), 9.3% had positive margins. In the entire cohort, OS was 79% at 12 and 60% at 48 months after RC. Multivariable Cox regression showed worse OS (HR 2.02, 95%-CI 1.58–2.58) in patients with surgical margins with invasive carcinoma versus patients with negative margins. Patients with only CIS in the margins showed no difference for OS versus negative margins (HR 1.30, 95%-CI 0.80–2.12). Invasive positive margins should be considered a ‘high-risk feature’ due to impaired survival, warranting investigation of the potential efficacy of adjuvant therapy (i.e., radiotherapy or systemic therapy).
The Prospective Bladder Cancer Infrastructure (ProBCI) is a prospective cohort of patients with high-risk non-muscle-invasive, muscle invasive or metastatic bladder cancer, which provides unique opportunities for bladder cancer research. ProBCI consists of two components: the Active Cohort and the Full Cohort.
The Active Cohort consists of patients who have been actively recruited by over twenty Dutch hospitals, obtaining a broad informed consent to cover multiple research goals. For these patients, extensive clinical data from diagnosis to death, longitudinal patient-reported outcome measures and biomaterials are available. Additionally, patients in the Active Cohort can be contacted for participation in other studies, for example single-arm, randomized or trials-within-cohorts interventional studies or observational studies with additional questionnaires. Furthermore, temporary expansion of prospective biomaterial collection for specific subgroups is facilitated by the ProBCI protocol. The Active Cohort therefore enables efficiently addressing a variety of clinical research questions, including those of biomarker studies and interventional studies, in an existing nationwide infrastructure.
The Full Cohort consists of all patients with high-risk non-muscle-invasive, muscle invasive or metastatic bladder cancer, diagnosed from 2020 onwards in the Netherlands, for whom clinical data from diagnosis to death are available, collected as an extension of the data within the Netherlands Cancer Registry. Through this, the Full Cohort provides a unique opportunity to use a population-based cohort to assess the treatment landscape and clinical outcomes among the full, unselected clinical practice patient population. This manuscript is an example of real-world studies facilitated by the Full Cohort.
ProBCI is an initiative of clinicians and researchers from UMC Utrecht, Radboudumc, Erasmus MC, Antoni van Leeuwenhoek hospital and the Netherlands comprehensive Cancer Organisation (IKNL), in collaboration with over 20 participating Dutch hospitals. ProBCI receives funding from multiple pharmaceutical companies to maintain the infrastructure. It was launched in 2020 and has since accrued more than 1,400 patients. Previous and ongoing research projects facilitated by ProBCI are listed at https://www.probci.nl/research.
For questions/collaborations, please reach out to: a.richters@iknl.nl or info@probci.nl or visit https://www.probci.nl.
Introduction
Localized muscle-invasive bladder cancer (MIBC) only yields 5-year survival rates of approximately 50% after treatment with curative intent [1, 2]. Radical cystectomy (RC) is recommended as the preferred curative treatment option for MIBC, with trimodality treatment as bladder-sparing alternative. The European Association of Urology (EAU) guidelines provide clear recommendations for the use of neoadjuvant treatment for patients undergoing RC [3]. Neoadjuvant chemotherapy (NAC) is recommended for cisplatin-eligible patients, providing a 8% survival benefit [4]. Nevertheless, survival rates after RC are still poor.
Adjuvant treatment provides another opportunity to improve survival outcomes. While EAU guidelines on adjuvant treatment are limited by the availability of strong evidence, there is a strong recommendation for offering adjuvant cisplatin-based combination chemotherapy when patients are diagnosed with pT3–4 and or pN+ disease and no neoadjuvant chemotherapy has been given. Nevertheless, current evidence on adjuvant radiotherapy is insufficient despite randomized studies [3]. Adjuvant immune checkpoint inhibition with nivolumab has shown a progression-free survival (PFS) benefit [5]. However, only interim overall survival data have been reported thus far, suggesting a benefit for patients treated with nivolumab, while mature overall survival (OS) data remain pending [6].
The current era with emergence of new therapeutic agents warrants reevaluation of identifying patients who might benefit from adjuvant treatment. Pending availability of accurate biomarkers, pathological features remain crucial [7]. Therefore, the aim of this study was to assess whether incorporating surgical margin status alongside existing postoperative risk indicators (i.e., pT3–4 and/or pN+) improves classification of patients at high risk for recurrent disease.
Methods
Cohort and data
Patients of ≥ 18 years, who received a first diagnosis of bladder cancer with localized, muscle-invasive disease (cT2–4aN0/xM0) between 1st of November 2017 and 31st of December 2020, were identified from the Netherlands Cancer Registry (NCR). Those who underwent RC as primary treatment, with or without neoadjuvant treatment, were included in this nationwide prospective cohort study. Patients who received simultaneous treatment for other cancers in the pelvic region, patients with missing data on margin status, patients with < 30 days of follow-up and patients with pathological M1 disease were excluded.
The NCR is hosted by the Netherlands Comprehensive Cancer Organisation (IKNL) and data are collected by trained IKNL data managers on all newly diagnosed cancers in the Netherlands, covering patient and tumor characteristics, disease stage, treatment, and vital status. Data on vital status are updated annually by linkage to the Dutch personal records database. In addition to the standard NCR data, more detailed data were collected concerning the surgical procedure and oncological follow-up (at least 2 years since diagnosis). This additional data collection was performed as part of the Dutch Cancer Society-funded BlaZIB project (BlaaskankerZorg in Beeld; Dutch for ‘Insight into bladder cancer care’) for patients diagnosed in 2017–2019, and the ProBCI initiative (Prospective Bladder Cancer Infrastructure) regarding patients diagnosed in 2020 [8, 9].
Subsequent linkage to the nationwide network and registry of histo- and cytopathology (Palga) was performed to obtain the pathology reports of all RCs. From these reports, additional data on surgical margins were retrieved.
This study was approved by the Privacy Review Board of the NCR (ref no. K23.262) and by the Palga review board (ref no. LZV2023-108).
Clinical, pathological data and definitions
Patient characteristics included patient’s sex, age at diagnosis, performance status, comorbidities and lab values (hemoglobin levels and renal function) at baseline. Performance status was defined according to the Eastern Cooperative Oncology Group (ECOG) performance status scale (or alternatively the Karnofsky performance scale converted to ECOG) and categorized as 0, 1, 2 and 3/4. If ECOG was reported in the medical record as a range between two values, it was categorized as the most favorable value (e.g., ECOG 0–1 becomes ECOG 0).
Tumor staging was defined in accordance with TNM Classification of Malignant Tumours (eighth edition) [10]. Morphology was documented and categorized into urothelial carcinoma (UC) in case of pure or predominant UC, or otherwise as non-UC.
Neoadjuvant treatment was categorized as chemotherapy or immuno(chemo)therapy directly prior to RC. Adjuvant therapy was defined as administration of radiotherapy, chemotherapy or immunotherapy initiated within 3 months of RC and prior to evidence of disease recurrence or progression.
The postoperative pathological determinants evaluated in this study included pathological T and N stages, lymphovascular invasion and the surgical margin characteristics (e.g., location and invasiveness). Pathological stages pT3–4 and/or pN+ without NAC or ypT2–4 and/or ypN+ following NAC were defined as high risk for disease recurrence (abbreviated to (y)pTN high-risk), whereas all other stages were considered low risk ((y)pTN low-risk). Lymphovascular invasion was reported positive, negative or unknown if not documented in the pathology report. The surgical margin status was determined based on the final findings in the pathology reports of the RC and lymph node dissection, not including frozen sections, and classified as negative, positive for carcinoma in situ (CIS) only (non-invasive margins) or positive for invasive carcinoma at the perivesical, ureter/urethra and uterus/prostate sites.
The oncological outcomes assessed in this study were PFS and OS. Progression was determined as local or distant evidence of disease after RC (including occurrence of metastases after RC), based on imaging, or death. Time-to-progression was calculated as time from RC until progression or death. Time-to-death was calculated as time from RC until death. Patients were censored if no event occurred at the time of last clinical follow-up date without an event, or at 2 years after RC for PFS and 4 years after RC for OS, whichever came first.
Statistical analysis
Baseline characteristics were described with frequencies and percentages, or median and the interquartile range (IQR) for continuous variables. The Kaplan-Meier method was used to evaluate 2-year PFS, and 4-year OS and the log-rank test was used to evaluate survival differences. Kaplan Meier curves were stratified by surgical margin status and (y)pTN stages.
Finally, a multivariable Cox proportional hazard regression was performed to assess the adjusted prognostic effect of positive surgical margins (CIS only or invasive carcinoma) on PFS and OS, taking into account other prognostic variables including pathological TNM stage, lymphovascular invasion and neoadjuvant therapy.
All the statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). Statistical significance was defined as p-values < 0.05.
Results
A total of 1,531 patients with newly diagnosed MIBC without clinical nodal or distant metastasis (cT2–4aN0/xM0) and RC as primary treatment were identified from the NCR. 55 patients were excluded for insufficient follow-up, including 35 patients who died within 30 days of RC. 12 patients with pathological stage M1 were excluded and for 19 patients data on margin status could not be retrieved, leaving 1,445 patients in the final cohort for analysis. The flowchart is shown in Fig. 1.
Fig. 1
Flowchart of cohort selection. Neoadjuvant radiotherapy for the following reasons: previous chemotherapy for another malignancy, histologic variant, treatment of haematuria while cystectomy postponed due to COVID-19 limitations
Patient and tumor characteristics stratified by margin status are summarized in Tab. 1. Positive surgical margins were observed in 135 patients (9.3%). Patients with positive margins more often were female, more often had advanced clinical tumor stage (cT3–4, N+) and more often had low Hb levels and worse renal function.
Table 1
Baseline data of patients and tumor characteristics for patients with localized, muscle-invasive bladder cancer treated with radical cystectomy
Neoadjuvant treatment was administered to approximately one third of the patients (30.8%), Tab. 2. Just over half (52.8%) of patients underwent an open RC with an ileal conduit urinary deviation (Bricker). The vast majority (77.0%) of patients with positive surgical margins had invasive tumor cells in the margins. The most common location of invasive surgical margins was the perivesical area, followed by the ureters. Among patients with only CIS in the surgical margins, this was most often located in (one of) the ureters.
Table 2
Descriptives of radical cystectomy, neoadjuvant and adjuvant treatments, and postoperative outcomes
Surgical margin status
All
Negative surgical margins
Positive surgical margins
n
%
n
%
n
%
Neoadjuvant treatment
None
995
68.9%
883
67.4%
112
83.0%
Cisplatin-based chemotherapy
387
26.8%
368
28.1%
19
14.1%
Immunotherapy
23
1.6%
21
1.6%
2
1.5%
Other
34
2.4%
33
2.5%
1
0.7%
Surgical approach
Open
763
52.8%
681
52.0%
82
60.7%
Robot-assisted laparoscopic
675
46.7%
623
47.6%
52
38.5%
Other/unknown
7
0.5%
6
0.5%
1
0.7%
Sexually sparing
No
1,414
97.9%
1,284
98.0%
130
96.3%
Yes
31
2.1%
26
2.0%
5
3.7%
Urinary diversion
Ileal conduit (Bricker)
1,336
92.5%
1,213
92.6%
123
91.1%
Neobladder
72
5.0%
70
5.3%
2
1.5%
Other/unknown
37
2.6%
27
2.1%
10
7.4%
Adjuvant treatment
Radiotherapy
9
0.6%
–
–
9
6.7%
Chemotherapy
14
1.0%
13
1.0%
1
0.7%
Immunotherapy
5
0.3%
5
0.4%
–
–
None
1,417
98.1%
1,292
98.6%
125
92.6%
Pathological TNM stage
(y)pT ≤ 1N0M0
461
31.9%
454
34.7%
7
5.2%
(y)pT2N0M0
234
16.2%
224
17.1%
10
7.4%
(y)pT3N0M0
344
23.8%
314
24.0%
30
22.2%
(y)pT4N0M0
84
5.8%
51
3.9%
33
24.4%
(y)pTanyN + M0
322
22.3%
267
20.4%
55
40.7%
Lymphovascular invasion
Yes
333
23.0%
280
21.4%
53
39.3%
No
419
29.0%
397
30.3%
22
16.3%
Not reported
693
48.0%
633
48.3%
60
44.4%
Surgical margin status*
Negative
1,310
90.7%
1,310
100.0%
–
–
Positive, carcinoma in situ only
31
2.1%
–
–
31
23.0%
– Perivesical/serosa
5
0.3%
–
–
5
3.7%
– Ureter/urethra
26
1.8%
–
–
26
19.3%
– Prostate/uterus/other
–
–
–
–
–
–
Positive, invasive tumor tissue
104
7.2%
–
–
104
77.0%
– Perivesical/serosa*
80
5.5%
–
–
80
59.3%
– Ureter/urethra*
30
2.1%
–
–
30
22.2%
– Prostate/uterus/other*
22
1.5%
–
–
22
16.3%
* Non-mutually exclusive categories, patients may have positive margins in more than one location
The median follow-up time among patients without events was 23.0 months (IQR 19.3–28.3) for PFS and 539 events (progression or death) occurred within 24 months. The median follow-up time among patients without events was 52.7 months (IQR 42.9–61.9) for OS and 566 events (death) occurred within 48 months.
Observed OS was 79% (95%-CI 77–81%), 68% (95%-CI 66–71%), 64% (95%-CI 62–67%) and 60% (95%-CI 57–62%) at 12, 24, 36 and 48 months after RC, respectively. PFS was 70% (95%-CI 68–73%) and 61% (95%-CI 58–63%) at 12 and 24 months after RC, respectively. Patients with negative margins had the best PFS and OS, followed by patients with only carcinoma in situ in margins and patients with invasive positive margins had worst PFS and OS (Fig. 2a, b).
Fig. 2
Observed progression-free and overall survival of patients stratified by pathological TNM and surgical margin status after radical cystectomy. a Observed 24-month progression-free survival and b 48-month overall survival stratified by surgical margin status. c Observed 24-month progression-free survival and d 48-month overall survival stratified by (y)pTN-stage* and surgical margin status. Four patients had the combination of (y)pTN low risk and positive invasive margins and were omitted from parts c and d because of small group size. *(y)pTN high-risk: pT3–4 and/or pN+ without neoadjuvant chemotherapy (NAC) or ypT2–4 and/or ypN+ following NAC. (y)pTN low-risk: all other stages
When surgical margin status was considered alongside the pathological T and N stage, patients with (y)pTN high-risk and invasive surgical margins had a worse PFS and OS compared to patients with (y)pTN high-risk without invasive margins (Fig. 2c, d).
The multivariable analyses taking into account the (y)pT stage, (y)pN stage, presence of lymphovascular invasion of the primary tumor and neoadjuvant therapy showed that patients with surgical margins with invasive carcinoma had worse PFS (HR 2.13, 95%-CI 1.67–2.72) and OS (HR 2.02, 95%-CI 1.58–2.58) compared to patients with negative margins (Tab. 3). Patients with only CIS in the margins appeared to have worse PFS as well (HR 1.60, 95%-CI 1.00–2.58) but results were not statistically significant. No difference was found for OS (HR 1.30, 95%-CI 0.80–2.12).
Table 3
Multivariable associations between pathological results of radical cystectomy and progression-free and overall survival
Progression-free survival
Overall survival
Hazard ratio
95%-CI
Hazard ratio
95%-CI
Pathological TNM stage
(y)pT ≤ 1N0M0
0.45
0.31–0.65
0.58
0.41–0.82
(y)pT2N0M0
Ref.
–
Ref.
–
(y)pT3N0M0
2.14
1.59–2.88
2.21
1.65–2.96
(y)pT4N0M0
3.50
2.40–5.10
4.03
2.78–5.83
(y)pTanyN + M0
4.17
3.12–5.59
3.83
2.87–5.11
Lymphovascular invasion
No
Ref.
–
Ref.
–
Yes
1.45
1.16–1.82
1.39
1.11–1.74
Not reported
1.14
0.92–1.42
1.11
0.90–1.36
Surgical margin status
Negative
Ref.
–
Ref.
–
Positive, carcinoma in situ only
1.60
1.00–2.58
1.30
0.80–2.12
Positive, invasive tumor tissue
2.13
1.67–2.72
2.02
1.58–2.58
Neoadjuvant therapy
No
Ref.
–
Ref.
–
Yes
1.12
0.92–1.36
0.92
0.76–1.11
Discussion
In this nationwide cohort, 9.3% of MIBC patients treated with RC had positive surgical margins, and 7.2% had invasive tumor tissue in the margins. The presence of invasive surgical margins was associated with poorer PFS and OS, also after taking into account established prognosticators including the pT and pN stage, presence of LVI and neoadjuvant therapy.
The proportion of patients with positive surgical margins in this Dutch cohort was similar to that reported in cohorts from Italy, France, the USA and a worldwide cohort [11‐14]. The cohorts from France, the USA and the worldwide cohort only included patients without NAC. Since NAC impacts the ypT-stage at surgery, it may also affect the risk of positive surgical margins. Within the Italian cohort, only 2.8% of patients received NAC, while in our cohort, 26.8% received NAC. Patients in all cohorts were free of metastatic disease at time of RC. In a US-based cohort of only patients with ≥ pT3b, a higher percentage had positive margins (23.5%) [15].
Consistent with our cohort, similar cohorts showed shorter PFS and OS in patients with positive margins compared to those with negative margins [16]. While most studies reported surgical margins as a binary determinant, our detailed data allowed classification of non-invasive positive surgical margins as well, demonstrating that invasive surgical margins are the main driver of prognostically worse outcomes.
Despite RC being a radical treatment, only approximately 50% of patients are alive 5 years post-surgery [1, 2]. To improve survival outcomes current EAU guidelines recommend NAC for cisplatin-eligible patients with non-metastatic MIBC and adjuvant chemotherapy for patients with pT3–4 and/or pN+ disease who have not been treated with NAC and have no contraindications [3].
In the current cohort, only 26.8% of patients received NAC. A recent Dutch study evaluating guideline adherence regarding NAC demonstrated that only a quarter of patients with cT2-disease received NAC and application was also low among cisplatin-eligible patients, possibly due to limited perceived benefit in this cT2 stage group [17]. The indication for NAC is stronger for cT3/4 patients [18], among whom only just over half received NAC, due to ineligibility or patient preference in the remaining patients.
The absolute 5-year survival benefit of adjuvant chemotherapy was estimated to be 6% based on a meta-analysis of 10 trials, which is similar to the survival benefit of NAC, and can be associated with severe toxicity [19]. The infrequent use of adjuvant chemotherapy (only 1% of the total cohort) may be attributed to these factors, underscoring the importance of identifying features for selecting patients associated with improved survival following adjuvant therapy. Patients with positive surgical margins were excluded from some adjuvant immunotherapy studies (CheckMate-274 and IMvigor010), but not all (AMBASSADOR) [5, 20, 21]. The POUT trial provides convincing evidence supporting the potential benefits of adjuvant chemotherapy for such patients, demonstrating improved disease-free survival in patients having undergone nephroureterectomy for locally advanced upper urinary tract carcinoma, including those with positive surgical margins. Given the similar clinicopathological characteristics of upper tract and bladder tumors, the findings from the POUT trial might also apply to patients treated with RC who have positive margins [22].
Based on the CheckMate-274 trial, the EAU guidelines recommend the use of adjuvant nivolumab for selected patients with pT3–4 and/or pN+ disease who are not eligible for or have rejected adjuvant chemotherapy, while mature OS data remain pending [3]. These patients are at high risk for adverse outcomes after RC. However, patients with positive surgical margins were not included in this trial, nor in the IMvigor010 trial investigating adjuvant atezolizumab [5, 20]. The AMBASSADOR trial, investigating adjuvant pembrolizumab, did include patients with positive surgical margins and demonstrated a significant improvement in disease-free survival for patients with high-risk muscle-invasive bladder cancer, and a potentially very strong subgroup effect for those with positive surgical margins, but not on OS [23]. Lack of OS benefit may have been influenced by a high rate of patients in the observation arm receiving subsequent immune checkpoint inhibition.
Thus, the data on definitive efficacy of adjuvant immunotherapy in this particular subgroup are insufficient. However, the results of the current study indicate that positive surgical margins may identify additional patients prone to poor survival outcomes after RC, yet not clearly in the palliative phase, who might benefit from adjuvant therapy.
The use of biomarkers may be another way to select patients potentially suitable for adjuvant therapy. Accumulating data indicate circulating tumor DNA (ctDNA) as a potential biomarker for residual disease and relapse, demonstrating improved oncological outcomes with atezolizumab in ctDNA-positive patients [24]. Several prospective studies are currently ongoing [25, 26]. Combining both positive surgical margins and emerging biomarkers, such as ctDNA, could allow for more precise risk stratification in the future.
The present study has several strengths. Firstly, its nationwide population-based design including a large number of patients over a recent period, provides a contemporary reflection of MIBC care in the Netherlands. In addition, the highly detailed data allow for robust comparisons. Furthermore, the prognostic effect of positive margins is well studied in the absence of adjuvant therapy, with only 1.9% of the total cohort receiving adjuvant therapy.
Nevertheless, two limitations of this study warrant consideration. First, in this observational study design, follow-up procedure data were collected according to routine clinical scheduling, without any changes to their timing by the research protocol. It is possible that patients with positive margins were scanned more often. However, we expect this to have minimal effect on the outcomes as the EAU-guidelines recommend a CT scan every 6 months for the first 3 years after RC for all patients and most hospitals have predetermined follow-up routines that do not take into account margin status [3]. Second, follow-up data of PFS were only available for all patients up to 2 years after RC. Late local recurrences can occur up to 5 years after RC and late distant recurrences have been found after more than 10 years [27]. However, the first 2 years following RC are critical, as local recurrence usually occurs during the initial 24 months and 90% of distant recurrences occur within the first 3 years after RC, mainly in the first 2 years [28].
In conclusion, approximately 10% of the patients in this nationwide Dutch cohort had positive surgical margins following RC for MIBC. Patients with positive surgical margins showed worse PFS and OS compared to patients with negative surgical margins, even when stratified by (y)pTN stage. Positive surgical margins provided relevant prognostic information on OS and PFS in addition to commonly used postoperative risk factors, particularly if invasive tumor tissue was observed in the margins. Despite markedly adverse outcomes among patients with invasive surgical margins, a substantial proportion survived past 12 (44%) and 24 (32%) months. These findings support further investigation of the potential efficacy of adjuvant therapy (i.e., radiotherapy and systemic therapy) among patients with positive invasive surgical margins.
Acknowledgements
The study investigators appreciate the support for the BlaZIB study provided by the Dutch Cancer Society (KWF; IKNL 2015-7914) and the current funding provided by Astellas, MSD, Janssen and Merck B.V. for the set-up and maintenance of the ProBCI infrastructure.
Funding
This project was financially supported by Gilead Sciences Netherlands. Furthermore, this study was carried out using data from the BlaZIB project and Prospective Bladder Cancer Infrastructure (ProBCI). The BlaZIB project was funded by the Dutch Cancer Society (KWF; IKNL 2015-7914). ProBCI receives current funding for set-up and maintenance of the infrastructure from Astellas, MSD, Janssen and Merck B.V. all paid to the Netherlands Comprehensive Cancer Organisation. The funding parties played no role in the concept or execution of the study or in reporting of the research results.
Conflict of interest
K.K.H. Aben has participated in an advisory board for bladder cancer, which received financially support from Janssen. J. Bosveld, T.Q. Nguyen, J.L. Boormans, A.G. van der Heijden, N. Mehra, L.A. Kiemeney, R.P. Meijer and A. Richters declare that they have no competing interests.
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The impact of positive surgical margins after cystectomy on oncological outcomes: a nationwide study from the Prospective Bladder Cancer Infrastructure (ProBCI)
Auteurs
Jikke Bosveld
Tri Q. Nguyen
Joost L. Boormans
Antoine G. van der Heijden
Niven Mehra
Lambertus A. Kiemeney
Katja K. H. Aben
Richard P. Meijer
Anke Richters
ProBCI Study Group
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