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Special Issue "Current Epidemiologic, Diagnostic, and Therapeutic Aspects of Cholangiocarcinoma (CCA)"

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Epidemiology and Prevention".

Deadline for manuscript submissions: 20 February 2024 | Viewed by 12058

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Dr. Sven Loosen

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Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany
Interests: GI oncology; endoscopy

Prof. Dr. Christoph Roderburg

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Clinic for Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany
Interests: GI oncology
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Dear Colleagues,

Cholangiocarcinoma (CCA) comprises a variety of heterogeneous biliary malignancies, which arises at some point of the bile duct system. CCA is associated with a globally increasing incidence, accounting for about 15% of all primary liver cancers. Due to its silent presentation of CCA in combination with the highly aggressive tumor nature and refractoriness to chemotherapy, patients are confronted with an alarmingly high mortality rate. Although the recently presented positive results on the use of checkpoint inhibitors herald a new era of palliative systemic therapy for CCA, it is currently still responsible for about 2% of all cancer-related deaths globally. New insights into epidemiological, diagnostic and therapeutic aspects, which are the focus of the current special issue, can contribute significantly to improve the care of CCA patients worldwide in order to reduce the high morbidity and mortality in the future.

Dr. Sven Loosen
Prof. Dr. Christoph Roerburg
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Biliary tract cancer
BTC
liver cancer
immunotherapy
biomarkers
prognosis
therapy

Published Papers (11 papers)

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Research

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Open AccessArticle

Metabolomics of Duodenal Juice for Biliary Tract Cancer Diagnosis

and

Cancers 2023, 15(17), 4370; https://doi.org/10.3390/cancers15174370 (registering DOI) - 01 Sep 2023

Abstract

The poor prognosis of malignant biliary diseases is partially caused by their difficult early diagnosis. Therefore, many patients are only diagnosed at advanced stages. This study aimed to improve diagnosis by clarifying the differences in the duodenal juice metabolomes of benign and malignant biliary diseases. From October 2021 to January 2023, duodenal juice was obtained from 67 patients with suspected biliary diseases who required endoscopic ultrasonography and endoscopic retrograde cholangiography for diagnosis/treatment. The samples metabolomes were analyzed via nuclear magnet resonance spectroscopy using an 800-MHz spectrometer. Metabolomes of malignant and benign diseases were then compared, and multivariate analysis was performed to determine the relevant factors for malignancy/benignancy. For benignancy, no significant predictors were observed. For malignancy, acetone was a significant predictor, with higher concentrations in the malignant group than in the benign group. Regarding the receiver operating characteristic curve analysis for biliary tract carcinoma diagnosis, the predictive value of acetone in duodenal juice was comparable with serum CA19-9 levels (area under the curve: 0.7330 vs. 0.691, p = 0.697). In conclusion, duodenal juice metabolomics is a feasible method that is available for differential diagnosis in the biliary disease field. Full article

(This article belongs to the Special Issue Current Epidemiologic, Diagnostic, and Therapeutic Aspects of Cholangiocarcinoma (CCA))

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Open AccessArticle

Multidisciplinary Treatment of Patients with Progressive Biliary Tract Cancer after First-Line Gemcitabine and Cisplatin: A Single-Center Experience

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Cancers 2023, 15(9), 2598; https://doi.org/10.3390/cancers15092598 - 03 May 2023

Viewed by 894

Abstract

Background: Patients with unresectable biliary tract cancer (uBTC) who progress despite first-line gemcitabine plus cisplatin (GC) treatment have limited systemic options with a modest survival benefit. Data are lacking on the clinical effectiveness and safety of personalized treatment based on multidisciplinary discussion for patients with progressing uBTC. Methods: This retrospective single-center study included patients with progressive uBTC who received either best supportive care or personalized treatment based on multidisciplinary discussion, including minimally invasive, image-guided procedures (MIT); FOLFIRI; or both (MIT and FOLFIRI), between 2011 and 2021. Results: Ninety-seven patients with progressive uBTC were identified. Patients received best supportive care (n = 50, 52%), MIT (n = 14, 14%), FOLFIRI (n = 19, 20%), or both (n = 14, 14%). Survival after disease progression was better in patients who received MIT (8.8 months; 95% CI: 2.60–15.08), FOLFIRI (6 months; 95% CI: 3.30–8.72), or both (15.1 months; 95% CI: 3.66–26.50) than in patients receiving BSC (0.36 months; 95% CI: 0.00–1.24, p < 0.001). The most common (>10%) grade 3–5 adverse events were anemia (25%) and thrombocytopenia (11%). Conclusion: Multidisciplinary discussion is critical for identifying patients with progressive uBTC who might benefit the most from MIT, FOLFIRI, or both. The safety profile was consistent with previous reports. Full article

(This article belongs to the Special Issue Current Epidemiologic, Diagnostic, and Therapeutic Aspects of Cholangiocarcinoma (CCA))

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Open AccessArticle

Liver Resection and Transplantation Following Yttrium-90 Radioembolization for Primary Malignant Liver Tumors: A 15-Year Single-Center Experience

Daniel Aliseda

Pablo Martí-Cruchaga

Gabriel Zozaya

Macarena Rodríguez-Fraile

José I. Bilbao

Alberto Benito-Boillos

Antonio Martínez De La Cuesta

Mercedes Iñarrairaegui

and

Cancers 2023, 15(3), 733; https://doi.org/10.3390/cancers15030733 - 25 Jan 2023

Cited by 6 | Viewed by 984

Abstract

Radioembolization (RE) may help local control and achieve tumor reduction while hypertrophies healthy liver and provides a test of time. For liver transplant (LT) candidates, it may attain downstaging for initially non-candidates and bridging during the waitlist. Methods: Patients diagnosed with HCC and ICC treated by RE with further liver resection (LR) or LT between 2005–2020 were included. All patients selected were discarded for the upfront surgical approach for not accomplishing oncological or surgical safety criteria after a multidisciplinary team assessment. Data for clinicopathological details, postoperative, and survival outcomes were retrospectively reviewed from a prospectively maintained database. Results: A total of 34 patients underwent surgery following RE (21 LR and 13 LT). Clavien–Dindo grade III-IV complications and mortality rates were 19.0% and 9.5% for LR and 7.7% and 0% for LT, respectively. After RE, for HCC and ICC patients in the LR group, 10-year OS rates were 57% and 60%, and 10-year DFS rates were 43.1% and 60%, respectively. For HCC patients in the LT group, 10-year OS and DFS rates from RE were 51.3% and 43.3%, respectively. Conclusion: Liver resection after RE is safe and feasible with optimal short-term outcomes. Patients diagnosed with unresectable or high biological risk HCC or ICC, treated with RE, and rescued by LR may achieve optimal global and DFS rates. On the other hand, bridging or downstaging strategies to LT with RE in HCC patients show adequate recurrence rates as well as long-term survival. Full article

(This article belongs to the Special Issue Current Epidemiologic, Diagnostic, and Therapeutic Aspects of Cholangiocarcinoma (CCA))

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Open AccessArticle

Golgi Protein 73 (GP73) Serum Levels Predict Outcome after Resection of Biliary Tract Cancer

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Cancers 2022, 14(18), 4428; https://doi.org/10.3390/cancers14184428 - 12 Sep 2022

Viewed by 1164

Abstract

Background: Tumor resection represents the only potentially curative therapy for patients with biliary tract cancer. Nevertheless, disease recurrence is observed in about 50% of patients, leading to a 5-years survival rate of less than 50%. The Golgi protein 73 (GP73), a type II Golgi transmembrane protein, exerts important functions of intracellular protein processing and transportation. Circulating GP73 has recently been suggested as a prognostic marker following resection of hepatocellular carcinoma (HCC) but its role in the context of BTC has remained unknown. In this study, we evaluate a potential role of circulating GP73 as a novel biomarker in patients with resectable BTC. Methods: GP73 serum levels were measured by immunoassay in n = 97 BTC and n = 40 HCC patients as well as n = 31 healthy controls. Results were correlated with clinical data. Results: Serum GP73 levels were significantly elevated in BTC patients compared to healthy controls but lower compared to HCC patients. The combination of GP73/CA19-9 showed a sensitivity and specificity of 83.5% and 90.3% regarding the differentiation of BTC patients and healthy controls. BTC patients with baseline GP73 levels above the ideal cut-off value (42.47 ng/mL) showed a significantly reduced median overall survival (193 days) compared to patients with preoperative GP73 levels below this cut-off (882 days). These results were confirmed in uni- and multivariate Cox-regression analysis including several clinicopathological parameters such as age, ECOG performance status, tumor stage as well as established tumor markers and parameters of liver and kidney function. Conclusions: GP73 represents a previously unrecognized biomarker in the patients with resectable BTC that identifies patients with an impaired postoperative outcome. If larger clinical trials confirmed these findings, measurement of GP73 serum levels might become a novel tool in the challenging preoperative stratification process of patients with resectable BTC. Full article

(This article belongs to the Special Issue Current Epidemiologic, Diagnostic, and Therapeutic Aspects of Cholangiocarcinoma (CCA))

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Open AccessArticle

Serum Levels of CXCL13 Are an Independent Predictor of Survival Following Resection of Biliary Tract Cancer

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Cancers 2022, 14(17), 4073; https://doi.org/10.3390/cancers14174073 - 23 Aug 2022

Cited by 2 | Viewed by 1056

Abstract

Background: The prognosis of biliary tract cancer (BTC) has remained very poor. Although tumor resection represents a potentially curative therapy for selected patients, tumor recurrence is common, and 5-year survival rates have remained below 50%. As stratification algorithms comprising the parameters of individual tumor biology are missing, the identification of ideal patients for extensive tumor surgery is often challenging. The CXC chemokine family exerts decisive functions in cell–cell interactions and has only recently been associated with cancer, but little is known about their function in BTC. Here, we aim to evaluate a potential role of circulating CXCL1, CXCL10 and CXCL13 in patients with resectable BTC. Methods: Serum levels of CXCL1, CXCL10 and CXCL13 were measured by multiplex immunoassay in a cohort of 119 BTC patients undergoing tumor resection and 50 control samples. Results: Circulating levels of CXCL1, CXCL10 and CXCL13 were all significantly elevated in BTC patients compared to healthy controls and increased the diagnostic power of established tumor markers such as CA19-9 when used in combination. Importantly, elevated levels of CXCL13 both before and after tumor resection identified a subgroup of patients with significantly impaired outcomes following tumor resection. As such, BTC patients with initial CXCL13 levels above the ideal prognostic cut-off value (25.01 pg/mL) had a median overall survival (OS) of 290 days compared to 969 days for patients with low initial CXCL13 levels. The prognostic value of circulating CXCL13 was further confirmed by uni- and multivariate Cox regression analyses. Finally, the individual kinetics of CXCL13 before and after tumor resection were also indicative of patient outcomes. Conclusion: Our data support a fundamental role of the CXC chemokine family in BTC and identified circulating levels of CXCL13 as a previously unrecognized marker for predicting outcomes following the resection of BTC. Full article

(This article belongs to the Special Issue Current Epidemiologic, Diagnostic, and Therapeutic Aspects of Cholangiocarcinoma (CCA))

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Open AccessArticle

Current Trends in Inpatient Care and In-Hospital Mortality of Cholangiocarcinoma in Germany: A Systematic Analysis between 2010 and 2019

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Cancers 2022, 14(16), 4038; https://doi.org/10.3390/cancers14164038 - 21 Aug 2022

Viewed by 1065

Abstract

Background: Cholangiocarcinoma (CCA) is a rare malignant disease of the biliary tract with an increasing incidence and a high mortality worldwide. Systematic data on epidemiological trends, treatment strategies, and in-hospital mortality of CCA in Germany are largely missing. However, the evaluation and careful interpretation of these data could help to further improve the treatment strategies and outcome of CCA patients in the future. Methods: Standardized hospital discharge data from the German Federal Statistical Office were used to evaluate epidemiological and clinical trends as well as the in-hospital mortality of CCA in Germany between 2010 and 2019. Results: A total of 154,515 hospitalized CCA cases were included into the analyses. The number of cases significantly increased over time (p < 0.001), with intrahepatic CCA (62.5%) being the most prevalent tumor localization. Overall, in-hospital mortality was 11.4% and remained unchanged over time. In-hospital mortality was significantly associated with patients’ age and tumor localization. The presence of clinical complications such as (sub)acute liver failure, acute respiratory distress syndrome (ARDS), or acute renal failure significantly increased in-hospital mortality up to 77.6%. In-hospital mortality was significantly lower among patients treated at high annual case volume centers. Finally, treatment strategies for CCA significantly changed over time and showed decisive differences with respect to the hospitals’ annual case volume. Conclusions: Our data provide a systematic overview on hospitalized CCA patients in Germany. We identified relevant clinical and epidemiological risk factors associated with an increased in-hospital mortality that could help to further improve framework conditions for the management of CCA patients in the future. Full article

(This article belongs to the Special Issue Current Epidemiologic, Diagnostic, and Therapeutic Aspects of Cholangiocarcinoma (CCA))

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Open AccessArticle

Association between Metabolic Disorders and Cholangiocarcinoma: Impact of a Postulated Risk Factor with Rising Incidence

Leonardo G. Da Fonseca

Pedro H. Hashizume

Irai Santana de Oliveira

Laura Izquierdo-Sanchez

Lisa Rodrigues da Cunha Saud

Mariana Pinheiro Xerfan

Venancio Avancini Ferreira Alves

Evandro Sobroza de Mello

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Cancers 2022, 14(14), 3483; https://doi.org/10.3390/cancers14143483 - 18 Jul 2022

Viewed by 1274

Abstract

Introduction and objectives: The incidence of cholangiocarcinoma (CCA) has been increasing globally. Although a concomitant increase in the incidence of metabolic disorders might suggest a causal relationship, the data are scarce. We aimed to describe the prevalence of metabolic disorders in patients with CCA and report the clinical features and outcomes. Patients and Methods: Retrospective study including patients with CCA. Patients were divided into: (1) past history of diabetes or/and overweight/obesity (“metabolic disorder group”) and (2) without any of these features (“non-metabolic-disorder group”). A Cox regression model was used to determine the prognostic factors. Results: 122 patients were included. In total, 36 (29.5%) had overweight/obesity, 24 (19.7%) had diabetes, and 8 (6.6%) had both. A total of 29 (23.8%) patients had resectable disease and received upfront surgery. A total of 104 (85.2%) received chemotherapy for advanced/recurrent disease. The overall survival of the cohort was 14.3 months (95% CI: 10.1–17.3). ECOG-PS 0 (p < 0.0001), resectable disease (p = 0.018) and absence of vascular invasion (p = 0.048) were independently associated with better prognosis. The “metabolic disorder group” (n = 52) had a median survival of 15.5 months (95% CI 10.9–33.9) vs. 11.5 months (95% CI 8.4–16.5) in the “non-metabolic-disorder group” (n = 70) (HR: 1.10; 95% CI 0.62–1.94). Patients with resectable disease in the “metabolic group” had longer survival than patients in the “non-metabolic group” (43.4 months (95% CI 33.9-NR) vs. 21.8 months (95% CI 8.6–26.9); HR = 0.12, 95% CI 0.03–0.59). Conclusion: Metabolic disorders are frequent among CCA patients. Underlying metabolic comorbidities may be associated with prognosis in resectable CCA. There is a need to explore the mechanism that drives CCA carcinogenesis in a metabolic background. Full article

(This article belongs to the Special Issue Current Epidemiologic, Diagnostic, and Therapeutic Aspects of Cholangiocarcinoma (CCA))

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Open AccessArticle

Recent Trends and In-Hospital Mortality of Transarterial Chemoembolization (TACE) in Germany: A Systematic Analysis of Hospital Discharge Data between 2010 and 2019

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Cancers 2022, 14(9), 2088; https://doi.org/10.3390/cancers14092088 - 22 Apr 2022

Cited by 1 | Viewed by 1339

Abstract

(1) Background: Transarterial chemoembolization (TACE) is a minimally invasive procedure, characterized by the selective occlusion of tumor-feeding hepatic arteries, via injection of an embolizing agent and an anticancer drug. It represents a standard of care for intermediate-stage hepatocellular carcinoma (HCC), and it is also increasingly performed in cholangiocarcinoma (CCA), as well as in liver metastases. Apart from the original method, based on intra-arterial infusion of a liquid drug followed by embolization, newer particle-based TACE procedures have been introduced recently. As yet, comprehensive data on current trends of TACE, as well as its in-hospital mortality in Germany, which could help to further improve outcome following TACE, are missing. (2) Methods: Based on standardized hospital discharge data, provided by the German Federal Statistical Office from 2010 to 2019, we aimed at systematically evaluating current clinical developments and in-hospital mortality related to TACE in Germany. (3) Results: A total of 49,595 individual cases undergoing TACE were identified within the observation period. The overall in-hospital mortality was 1.00% and significantly higher in females compared to males (1.12 vs. 0.93%; p < 0.001). We identified several post-interventional complications, such as liver failure (51.49%), sepsis (33.87%), renal failure (23.9%), and liver abscess (15.87%), which were associated with a significantly increased in-hospital mortality. Moreover, in-hospital mortality significantly differed between the underlying indications for TACE (HCC: 0.83%, liver metastases: 1.22%, and CCA: 1.40%), as well as between different embolization agents (liquid embolization: 0.80%, loaded microspheres: 0.92%, spherical particles: 1.54%, and non-spherical particles: 2.84%), for which we observed large geographic differences in their frequency of use. Finally, in-hospital mortality was significantly increased in centers with a low annual TACE case volume (<15 TACE/year: 2.08% vs. >275 TACE/year: 0.45%). (4) Conclusion: Our data provide a systematic overview of indications and embolization methods for TACE in Germany. We identified a variety of factors, such as post-interventional complications, the embolization method used, and the hospitals’ annual case volume, which are associated with an increased in-hospital mortality following TACE. These data might help to further reduce the mortality of this routinely performed local-ablative procedure in the future. Full article

(This article belongs to the Special Issue Current Epidemiologic, Diagnostic, and Therapeutic Aspects of Cholangiocarcinoma (CCA))

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Review

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Open AccessReview

Promising Highly Targeted Therapies for Cholangiocarcinoma: A Review and Future Perspectives

Masaki Kuwatani

and

Naoya Sakamoto

Cancers 2023, 15(14), 3686; https://doi.org/10.3390/cancers15143686 - 20 Jul 2023

Cited by 1 | Viewed by 688

Abstract

To overcome the poor prognosis of cholangiocarcinoma (CCA), highly targeted therapies, such as antibody-drug conjugates (ADCs), photodynamic therapy (PDT) with/without systemic chemotherapy, and experimental photoimmunotherapy (PIT), have been developed. Three preclinical trials have investigated the use of ADCs targeting specific antigens, namely HER2, MUC1, and glypican-1 (GPC1), for CCA. Trastuzumab emtansine demonstrated higher antiproliferative activity in CCA cells expressing higher levels of HER2. Similarly, “staphylococcal enterotoxin A-MUC1 antibody” and “anti-GPC1 antibody-monomethyl auristatin F” conjugates showed anticancer activity. PDT is effective in areas where appropriate photosensitizers and light coexist. Its mechanism involves photosensitizer excitation and subsequent reactive oxygen species production in cancer cells upon irradiation. Hematoporphyrin derivatives, temoporfin, phthalocyanine-4, talaporfin, and chlorine e6 derivatives have mainly been used clinically and preclinically in bile duct cancer. Currently, new forms of photosensitizers with nanotechnology and novel irradiation catheters are being developed. PIT is the most novel anti-cancer therapy developed in 2011 that selectively kills targeted cancer cells using a unique photosensitizer called “IR700” conjugated with an antibody specific for cancer cells. PIT is currently in the early stages of development for identifying appropriate CCA cell targets and irradiation devices. Future human and artificial intelligence collaboration has potential for overcoming challenges related to identifying universal CCA cell targets. This could pave the way for highly targeted therapies for CCA, such as ADC, PDT, and PIT. Full article

(This article belongs to the Special Issue Current Epidemiologic, Diagnostic, and Therapeutic Aspects of Cholangiocarcinoma (CCA))

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Open AccessReview

Update on Locoregional Therapies for Cholangiocellular Carcinoma

Janna Morawitz

Nils-Martin Bruckmann

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Cancers 2023, 15(8), 2368; https://doi.org/10.3390/cancers15082368 - 19 Apr 2023

Viewed by 676

Abstract

Locoregional therapy options for CCA are used, in particular, for non-resectable tumors and aim to reduce tumor viability or delay tumor growth and ultimately prolong overall survival. In addition to local ablative procedures such as radiofrequency- or microwave-ablation, transarterial procedures such as transarterial embolization (TAE), transarterial chemoembolization (TACE), or selective internal radiotherapy (SIRT) play a major role. In particular, in combination with advances in molecular medicine and immunotherapy, there has been a further development in the therapy of primary malignant liver tumors in recent years. In this review, we analyze data from recent studies and examine the implications for therapy of CCA, particularly with regard to the combination of locoregional therapies with modern systemic therapies. Full article

(This article belongs to the Special Issue Current Epidemiologic, Diagnostic, and Therapeutic Aspects of Cholangiocarcinoma (CCA))

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Other

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Open AccessSystematic Review

The Role of Single-Nucleotide Polymorphisms in Cholangiocarcinoma: A Systematic Review

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Cancers 2022, 14(23), 5969; https://doi.org/10.3390/cancers14235969 - 02 Dec 2022

Cited by 3 | Viewed by 2014

Abstract

Single-nucleotide polymorphisms (SNPs) play an essential role in various malignancies, but their role in cholangiocarcinoma (CCA) remains to be elucidated. Therefore, the purpose of this systematic review was to evaluate the association between SNPs and CCA, focusing on tumorigenesis and prognosis. A systematic literature search was carried out using PubMed, Embase, Web of Science and the Cochrane database for the association between SNPs and CCA, including literature published between January 2000 and April 2022. This systematic review compiles 43 SNPs in 32 genes associated with CCA risk, metastatic progression and overall prognosis based on 34 studies. Susceptibility to CCA was associated with SNPs in genes related to inflammation (PTGS2/COX2, IL6, IFNG/IFN-γ, TNF/TNF-α), DNA repair (ERCC1, MTHFR, MUTYH, XRCC1, OGG1), detoxification (NAT1, NAT2 and ABCC2), enzymes (SERPINA1, GSTO1, APOBEC3A, APOBEC3B), RNA (HOTAIR) and membrane-based proteins (EGFR, GAB1, KLRK1/NKG2D). Overall oncological prognosis was also related to SNPs in eight genes (GNB3, NFE2L2/NRF2, GALNT14, EGFR, XRCC1, EZH2, GNAS, CXCR1). Our findings indicate that multiple SNPs play different roles at various stages of CCA and might serve as biomarkers guiding treatment and allowing oncological risk assessment. Considering the differences in SNP detection methods, patient ethnicity and corresponding environmental factors, more large-scale multicentric investigations are needed to fully determine the potential of SNP analysis for CCA susceptibility prediction and prognostication. Full article

(This article belongs to the Special Issue Current Epidemiologic, Diagnostic, and Therapeutic Aspects of Cholangiocarcinoma (CCA))

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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Post-prgression treatment after failure of first-line therapy with gem/cis in locally advanced or metatstaic biliary duct cancer
Authors: Verena Keitel-Anselmino
Affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, 39106 Magdeburg, Germany

Title: Role bile acids and bile acid receptors in cholangiocarcinoma
Authors: Verena Keitel-Anselmino
Affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, 39106 Magdeburg, Germany

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