Publications by authors named "Christoph Springfeld"

64 Publications

Treatment stage migration and treatment sequences in patients with hepatocellular carcinoma: drawbacks and opportunities.

J Cancer Res Clin Oncol 2021 Feb 4. Epub 2021 Feb 4.

Liver Cancer Center Heidelberg LCCH, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.

Purpose: This retrospective analysis focuses on treatment stage migration in patients with hepatocellular carcinoma (HCC) to identify successful treatment sequences in a large cohort of real-world patients.

Methods: 1369 HCC patients referred from January 1993 to January 2020 to the tertiary center of the Heidelberg University Hospital, Germany were analyzed for initial and subsequent treatment patterns, and overall survival.

Results: The most common initial treatment was transarterial chemoembolization (TACE, n = 455, 39.3%) followed by hepatic resection (n = 303, 26.1%) and systemic therapy (n = 200, 17.3%), whereas the most common 2nd treatment modality was liver transplantation (n = 215, 33.2%) followed by systemic therapy (n = 177, 27.3%) and TACE (n = 85, 13.1%). Kaplan-Meier analysis revealed by far the best prognosis for liver transplantation recipients (median overall survival not reached), followed by patients with hepatic resection (11.1 years). Patients receiving systemic therapy as their first treatment had the shortest median overall survival (1.7 years; P < 0.0001). When three or more treatment sequences preceded liver transplantation, patients had a significant shorter median overall survival (1st seq.: not reached; 2nd seq.: 12.4 years; 3rd seq.: 11.1 years; beyond 3 sequences: 5.5 years; P = 0.01).

Conclusion: TACE was the most common initial intervention, whereas liver transplantation was the most frequent 2nd treatment. While liver transplantation and hepatic resection were associated with the best median overall survival, the timing of liver transplantation within the treatment sequence strongly affected median survival.
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http://dx.doi.org/10.1007/s00432-021-03528-3DOI Listing
February 2021

Integrative analysis reveals early and distinct genetic and epigenetic changes in intraductal papillary and tubulopapillary cholangiocarcinogenesis.

Gut 2021 Jan 19. Epub 2021 Jan 19.

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

Objective: A detailed understanding of the molecular alterations in different forms of cholangiocarcinogenesis is crucial for a better understanding of cholangiocarcinoma (CCA) and may pave the way to early diagnosis and better treatment options.

Design: We analysed a clinicopathologically well-characterised patient cohort (n=54) with high-grade intraductal papillary (IPNB) or tubulopapillary (ITPN) neoplastic precursor lesions of the biliary tract and correlated the results with an independent non-IPNB/ITPN associated CCA cohort (n=294). The triplet sample set of non-neoplastic biliary epithelium, precursor and invasive CCA was analysed by next generation sequencing, DNA copy number and genome-wide methylation profiling.

Results: Patients with invasive CCA arising from IPNB/ITPN had better prognosis than patients with CCA not associated with IPNB/ITPN. ITPN was localised mostly intrahepatic, whereas IPNB was mostly of extrahepatic origin. IPNB/ITPN were equally associated with small-duct and large-duct type intrahepatic CCA. IPNB exhibited mutational profiles of extrahepatic CCA, while ITPN had significantly fewer mutations. Most mutations were shared between precursor lesions and corresponding invasive CCA but mutations occurred exclusively in invasive CCA and mutations were mainly present in precursor lesions. In addition, IPNB and ITPN differed in their DNA methylation profiles and analyses of latent methylation components suggested that IPNB and ITPN may have different cells-of-origin.

Conclusion: Integrative analysis revealed that IPNB and ITPN harbour distinct early genetic alterations, IPNB are enriched in mutations typical for extrahepatic CCA, whereas ITPN exhibited few genetic alterations and showed distinct epigenetic profiles. In conclusion, IPNB/ITPN may represent a distinctive, intermediate form of intrahepatic and extrahepatic cholangiocarcinogenesis.
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http://dx.doi.org/10.1136/gutjnl-2020-322983DOI Listing
January 2021

Poly(ADP-ribose) polymerase inhibition in pancreatic cancer.

Genes Chromosomes Cancer 2020 Dec 20. Epub 2020 Dec 20.

Department of Medical Oncology, Heidelberg University Hospital, National Center for Tumor Diseases, Heidelberg, Germany.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited treatment options. Recently, the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib has been approved for maintenance therapy after successful platinum-based chemotherapy in patients with germline mutations in BRCA1 and BRCA2. Approval was based on the POLO study that has shown a significant improvement in progression-free survival for patients with metastatic PDAC after at least 4 months of platinum-based chemotherapy. Hopefully, this first biomarker-directed targeted therapy for a relevant subgroup of pancreatic cancer patients is only the beginning of an era of personalized therapy for pancreatic cancer. The potential role for PARPi in improving survival in patients with pancreatic cancer containing somatic tumor mutations has yet to be established. Multiple studies investigating whether PARPi therapy might benefit a larger group of pancreatic cancer patients with homologous recombination repair deficiency and whether combinations with chemotherapy, immunotherapy, or small molecules can improve efficacy are currently underway. We here review the molecular basis for PARPi therapy in PDAC patients and recent developments in clinical studies.
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http://dx.doi.org/10.1002/gcc.22932DOI Listing
December 2020

Quality of life and outcome of patients with metastatic pancreatic cancer receiving first-line chemotherapy with nab-paclitaxel and gemcitabine: Real-life results from the prospective QOLIXANE trial of the Platform for Outcome, Quality of Life and Translational Research on Pancreatic Cancer registry.

Int J Cancer 2021 Mar 23;148(6):1478-1488. Epub 2020 Oct 23.

Krankenhaus Nordwest, UCT-University Cancer Center, Frankfurt, Germany.

Few data exist on health-related quality of life (QoL) in patients with metastatic pancreatic cancer (mPC) receiving first-line chemotherapy (Awad L ZE, Mesbah M Boston, MA. Applying survival data methodology to analyze quality of life data, in Mesbah M, Cole BF, Ting Lee M-L (eds): Statistical Methods for Quality of Life Studies: Design, Measurements and Analysis. Kluwer Academic Publishers 2002). The QOLIXANE study is a prospective, noninterventional, multicenter substudy of the Platform for Outcome, Quality of Life and Translational Research on Pancreatic Cancer (PARAGON) registry, which evaluated QoL in patients with mPC receiving first-line gemcitabine and nab-paclitaxel chemotherapy in real-life setting. QoL was prospectively measured via EORTC QLQ-C30 questionnaires at baseline and every month thereafter. Therapy and efficacy parameters were prospectively collected. Main objectives were the rate of patients without deterioration of Global Health Status/QoL (GHS/QoL) at 3 and 6 months. Six hundred patients were enrolled in 95 German study sites. Median progression-free survival was 5.9 months (95% confidence interval [CI], 5.2-6.3). Median overall survival (OS) was 8.9 months (95% CI, 7.9-10.2), while median time to deterioration of GHS/QoL was 4.7 months (95% CI, 4.0-5.6). With a baseline GHS/QoL score of 46 (SD, 22.8), baseline QoL of the patients was severely impaired, in most cases due to loss in role functioning and fatigue. In the Kaplan-Meier analysis, 61% and 41% of patients had maintained GHS/QoL after 3 and 6 months, respectively. However, in the QoL response analysis, 35% and 19% of patients had maintained (improved or stable) GHS/QoL after 3 and 6 months, respectively, while 14% and 9% had deteriorated GHS/QoL with the remaining patients being nonevaluable. In the Cox regression analysis, GHS/QoL scores strongly predicted survival with a hazard ratio of 0.86 (P < .0001). Patients with mPC have poor QoL at baseline that deteriorates within a median of 4.7 months. Treatment with gemcitabine and nab-paclitaxel is associated with maintained QoL in relevant proportions of patients. However, overall, results remain poor, reflecting the aggressive nature of the disease.
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http://dx.doi.org/10.1002/ijc.33336DOI Listing
March 2021

Improving radiologic communication in oncology: a single-centre experience with structured reporting for cancer patients.

Insights Imaging 2020 Sep 29;11(1):106. Epub 2020 Sep 29.

Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany.

Objectives: Our aim was to develop a structured reporting concept (structured oncology report, SOR) for general follow-up assessment of cancer patients in clinical routine. Furthermore, we analysed the report quality of SOR compared to conventional reports (CR) as assessed by referring oncologists.

Methods: SOR was designed to provide standardised layout, tabulated tumour burden documentation and standardised conclusion using uniform terminology. A software application for reporting was programmed to ensure consistency of layout and vocabulary and to facilitate utilisation of SOR. Report quality was analysed for 25 SOR and 25 CR retrospectively by 6 medical oncologists using a 7-point scale (score 1 representing the best score) for 6 questionnaire items addressing different elements of report quality and overall satisfaction. A score of ≤ 3 was defined as a positive rating.

Results: In the first year after full implementation, 7471 imaging examinations were reported using SOR. The proportion of SOR in relation to all oncology reports increased from 49 to 95% within a few months. Report quality scores were better for SOR for each questionnaire item (p < 0.001 each). Averaged over all questionnaire item scores were 1.98 ± 1.22 for SOR and 3.05 ± 1.93 for CR (p < 0.001). The overall satisfaction score was 2.15 ± 1.32 for SOR and 3.39 ± 2.08 for CR (p < 0.001). The proportion of positive ratings was higher for SOR (89% versus 67%; p < 0.001).

Conclusions: Department-wide structured reporting for follow-up imaging performed for assessment of anticancer treatment efficacy is feasible using a dedicated software application. Satisfaction of referring oncologist with report quality is superior for structured reports.
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http://dx.doi.org/10.1186/s13244-020-00907-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524991PMC
September 2020

Successful BRAF/MEK inhibition in a patient with -mutated extrapancreatic acinar cell carcinoma.

Cold Spring Harb Mol Case Stud 2020 08 25;6(4). Epub 2020 Aug 25.

Department of Medical Oncology, University Hospital Heidelberg, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, 69120, Germany.

Pancreatic acinar cell carcinoma (PAC) is a rare disease with a poor prognosis. Treatment options for metastatic PAC are limited and often follow chemotherapeutic regimens for pancreatic ductal adenocarcinoma. Although recurrent genomic alterations, such as fusions and defects in genes involved in homologous recombination DNA repair, have been described in PAC, data on the clinical efficacy of molecularly guided, targeted treatment are scarce. Here we describe the case of a 27-yr-old patient with -mutated PAC who was successfully treated with a combination of BRAF and MEK inhibitors. The patient presented to our clinic with abdominal pain and weight loss. Imaging showed extensive retroperitoneal disease as well as mediastinal lymphadenopathy. Because of elevated α-fetoprotein (AFP) levels and inconclusive histologic findings, a germ cell tumor was suspected; however, PEI chemotherapy was unsuccessful. A repeat biopsy yielded the diagnosis of PAC and treatment with FOLFIRINOX was initiated. Comprehensive molecular profiling within the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program revealed a somatic mutation and a germline stop-gain mutation. Therapy was therefore switched to BRAF/MEK inhibition, resulting in almost complete remission and disease control for 12 mo and a remarkable improvement in the patient's general condition. These results indicate that alterations are a valid therapeutic target in PAC that should be routinely assessed in this patient population.
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http://dx.doi.org/10.1101/mcs.a005553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476408PMC
August 2020

miRNA profiling of biliary intraepithelial neoplasia reveals stepwise tumorigenesis in distal cholangiocarcinoma via the miR-451a/ATF2 axis.

J Pathol 2020 11 15;252(3):239-251. Epub 2020 Sep 15.

Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

Distal cholangiocarcinoma (dCCA) is a biliary tract cancer with a dismal prognosis and is often preceded by biliary intraepithelial neoplasia (BilIN), representing the most common biliary non-invasive precursor lesion. BilIN are histologically well defined but have not so far been characterised systematically at the molecular level. The aim of this study was to determine miRNA-regulated genes in cholangiocarcinogenesis via BilIN. We used a clinicopathologically well-characterised cohort of 12 dCCA patients. Matched samples of non-neoplastic biliary epithelia, BilIN and invasive tumour epithelia of each patient were isolated from formalin-fixed paraffin-embedded tissue sections by laser microdissection. The resulting 36 samples were subjected to total RNA extraction and the expression of 798 miRNAs was assessed using the Nanostring® technology. Candidate miRNAs were validated by RT-qPCR and functionally investigated following lentiviral overexpression in dCCA-derived cell lines. Potential direct miRNA target genes were identified by microarray and prediction algorithms and were confirmed by luciferase assay. We identified 49 deregulated miRNAs comparing non-neoplastic and tumour tissue. Clustering of these miRNAs corresponded to the three stages of cholangiocarcinogenesis, supporting the concept of BilIN as a tumour precursor. Two downregulated miRNAs, i.e. miR-451a (-10.9-fold down) and miR-144-3p (-6.3-fold down), stood out by relative decrease. Functional analyses of these candidates revealed a migration inhibitory effect in dCCA cell lines. Activating transcription factor 2 (ATF2) and A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) were identified as direct miR-451a target genes. Specific ATF2 inhibition by pooled siRNAs reproduced the inhibitory impact of miR-451a on cancer cell migration. Thus, our data support the concept of BilIN as a direct precursor of invasive dCCA at the molecular level. In addition, we identified miR-451a and miR-144-3p as putative tumour suppressors attenuating cell migration by inhibiting ATF2 in the process of dCCA tumorigenesis. © The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5514DOI Listing
November 2020

Actual Five-year Survival After Upfront Resection for Pancreatic Ductal Adenocarcinoma: Who Beats the Odds?

Ann Surg 2020 Jul 7. Epub 2020 Jul 7.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.

Objective: To determine actual five-year survival (5YS) rates associated with a strategy of upfront surgery and adjuvant therapy in pancreatic ductal adenocarcinoma (PDAC).

Background: The rate of actual 5YS in PDAC remains controversial. Available data is restricted to cohorts acquired over several decades and series of resection after patient selection by neoadjuvant therapy.

Methods: All patients undergoing upfront resection for resectable and borderline-resectable PDAC from 10/2001 to 12/2011 were identified from a prospective database. Actual overall survival was assessed after a follow-up of at least 5 years. Uni- and multivariable logistic regression analyses were performed.

Results: Median survival of 937 patients was 22.1 months. The actual 5YS rate was 17.0% (n = 159) including 89 (9.5%) patients without evidence of disease >5 years after resection. 5YS rates in patients with or without adjuvant therapy were 18.8% vs. 12.2%, respectively. Tumor grading, number of positive lymph nodes, a context of intraductal papillary mucinous neoplasia, and vascular resections were independently associated with 5YS. Patient-related parameters and CA 19-9 levels were associated with observed survival up to 3 years, but lost relevance thereafter. The extent of lymph node involvement was the strongest predictor of 5YS. Patients with pN0R0 had a 5YS rate of 38.2%. In patients with exclusively favorable factors the observed 5YS rate was above 50%.

Conclusions: This is the largest series of long-term survivors with histologically confirmed PDAC. With upfront resection and adjuvant therapy an actual overall 5YS rate of 18.8% can be expected. In favorable subgroups actual 5YS is above 50%.
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http://dx.doi.org/10.1097/SLA.0000000000004147DOI Listing
July 2020

NUC-1031/cisplatin versus gemcitabine/cisplatin in untreated locally advanced/metastatic biliary tract cancer (NuTide:121).

Future Oncol 2020 Jun 6;16(16):1069-1081. Epub 2020 May 6.

Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Gemcitabine/cisplatin is standard of care for first-line treatment of patients with advanced biliary tract cancer (aBTC); new treatments are needed. NUC-1031 is designed to overcome key cancer resistance mechanisms associated with gemcitabine. The tolerability/efficacy signal of NUC-1031/cisplatin in the Phase Ib ABC-08 study suggested that this combination may represent a more efficacious therapy than gemcitabine/cisplatin for patients with aBTC, leading to initiation of the global NuTide:121 study which will include 828 patients ≥18 years with untreated histologically/cytologically-confirmed aBTC (including cholangiocarcinoma, gallbladder or ampullary cancer); randomized (1:1) to NUC-1031 (725 mg/m)/cisplatin (25 mg/m) or gemcitabine (1000 mg/m)/cisplatin (25 mg/m), on days 1/8, Q21-days. Primary objectives are overall survival and objective response rate. Secondary objectives: progression-free survival, safety, pharmacokinetics, patient-reported quality of life and correlative studies. : 139058, : EudraCT Number 2019-001025-28, : NCT04163900).
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http://dx.doi.org/10.2217/fon-2020-0247DOI Listing
June 2020

Metastatic adult pancreatoblastoma: Multimodal treatment and molecular characterization of a very rare disease.

Pancreatology 2020 Apr 29;20(3):425-432. Epub 2020 Feb 29.

Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) and DKFZ Dresden, Dresden, Germany; Center for Personalized Oncology, National Center for Tumor Diseases (NCT) Dresden and University Hospital Carl Gustav Carus Dresden at TU Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany. Electronic address:

Background: Pancreatoblastoma is a rare malignancy that occurs predominantly in children. Less than 50 adult cases, including 17 patients with metastatic disease, have been published to date. Recent outcome data from children with advanced-stage disease suggest an intensive multimodal treatment approach; however, little is known about the most beneficial therapy in adults. Molecular characterization of pancreatoblastoma is limited to a small number of pediatric cases and revealed few recurrent genetic events without immediate clinical relevance.

Methods: Patients were treated between 2013 and 2018 at a high-volume German university cancer center. Molecular analyses included whole genome, exome, transcriptome, and fusion gene panel sequencing. Molecularly guided treatment recommendations were discussed within a dedicated molecular tumor board (MTB) embedded in a precision oncology program (NCT MASTER).

Results: We identified four adult patients with metastatic pancreatoblastoma. In three patients, local approaches were combined with systemic treatment. Oxaliplatin-containing protocols showed an acceptable tumor control as well as an adequate toxicity profile. Overall survival was 15, 17, 18 and 24 months, respectively. Three tumors harbored genetic alterations involving the FGFR pathway that included an oncogenic FGFR2 fusion.

Conclusion: Oxaliplatin-containing chemotherapy seems to be a reasonable approach in adult patients with advanced pancreatoblastoma, whereas the benefit of intensified treatment including local ablative techniques or surgical resection remains unclear. Our finding of FGFR alterations in three of four cases indicates a potential role of FGFR signaling in adult pancreatoblastoma whose clinical significance warrants further study.
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http://dx.doi.org/10.1016/j.pan.2020.02.017DOI Listing
April 2020

Applicability of scoring systems predicting outcome of transarterial chemoembolization for hepatocellular carcinoma.

J Cancer Res Clin Oncol 2020 Apr 27;146(4):1033-1050. Epub 2020 Feb 27.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, INF 110, 69120, Heidelberg, Germany.

Purpose: Several scoring systems have been proposed to predict the outcome of transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC). However, the application of these scores to a bridging to transplant setting is poorly validated. Evaluation of the applicability of prognostic scores for patients undergoing TACE in palliative intention vs. bridging therapy to liver transplantation (LT) is necessary.

Methods: Between 2008 and 2017, 148 patients with HCC received 492 completed TACE procedures (158 for bridging to transplant; 334 TACE procedures in palliative treatment intention at our center and were analyzed retrospectively. Scores (ART, CLIP, ALBI, APRI, SNACOR, HAP, STATE score, Child-Pugh, MELD, Okuda and BCLC) were calculated and evaluated for prediction of overall survival. ROC analysis was performed to assess prediction of 3-year survival and treatment discontinuation.

Results: In patients receiving TACE in palliative intention most scores predicted OS in univariate analysis but only mSNACOR score (p = 0.006), State score (p < 0.001) and Child-Pugh score (p < 0.001) revealed statistical significance in the multivariate analysis. In the bridging to LT cohort only the BCLC score revealed statistical significance (p = 0.002).

Conclusions: Clinical usability of suggested scoring systems for TACE might be limited depending on the individual patient cohorts and the indication. Especially in patients receiving TACE as bridging to LT none of the scores showed sufficiently applicability. In our study Child-Pugh score, STATE score and mSNACOR score showed the best performance assessing OS in patients with TACE as palliative therapy.
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http://dx.doi.org/10.1007/s00432-020-03135-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085483PMC
April 2020

Sequencing of serially passaged measles virus affirms its genomic stability and reveals a nonrandom distribution of consensus mutations.

J Gen Virol 2020 04 13;101(4):399-409. Epub 2020 Feb 13.

Ottawa Hospital Research Institute, Cancer Therapeutics Program, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada.

Oncolytic virotherapy is an emerging treatment option for numerous cancers, with several virus families currently being evaluated in clinical trials. More specifically, vaccine-strain measles virus has arisen as a promising candidate for the treatment of different tumour types in several early clinical trials. Replicating viruses, and especially RNA viruses without proofreading polymerases, can rapidly adapt to varying environments by selecting quasispecies with advantageous genetic mutations. Subsequently, these genetic alterations could potentially weaken the safety profile of virotherapy. In this study, we demonstrate that, following an extended period of virus replication in producer or cancer cell lines, the quasispecies consensus sequence of vaccine strain-derived measles virus accrues a remarkably small number of mutations throughout the nonsegmented negative-stranded RNA genome. Interestingly, we detected a nonrandom distribution of genetic alterations within the genome, with an overall decreasing frequency of mutations from the 3' genome start to its 5' end. Comparing the serially passaged viruses to the parental virus on producer cells, we found that the acquired consensus mutations did not drastically change viral replication kinetics or cytolytic potency. Collectively, our data corroborate the genomic stability and excellent safety profile of oncolytic measles virus, thus supporting its continued development and clinical translation as a promising viro-immunotherapeutic.
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http://dx.doi.org/10.1099/jgv.0.001395DOI Listing
April 2020

HER2 gene (ERBB2) amplification is a low-frequency driver with potential predictive value in gallbladder carcinoma.

Virchows Arch 2020 Jun 14;476(6):871-880. Epub 2019 Dec 14.

Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.

Gallbladder carcinoma (GBC) is an aggressive type of cancer with a dismal prognosis. Recent case reports have highlighted the human epidermal growth factor receptor 2 (HER2) as a promising target for individualized therapy in biliary tract cancer; however, current data on HER2 positivity in GBC is contradictory. This study aimed to assess the proportion of HER2 positivity and its clinical implications in a large and well-characterized European GBC cohort. HER2 status was determined in 186 cases of surgically resected gallbladder adenocarcinoma and a subset of coexistent high-grade biliary intraepithelial neoplasia (BilIN, n = 74) in accordance with the up-to-date consensus for HER2 testing in gastric cancer by immunohistochemistry and dual-color chromogenic in situ hybridization. Positivity for HER2 was observed in 5.4% of all cases (n = 10). In those patients with concomitant high-grade BilIN, two of four positive samples also showed amplification in the precursor lesion, while in the two remaining cases, positivity was either confined to invasive tumor or high-grade BilIN, exclusively. Equivocal staining found in eleven cases was not accompanied by gene amplification. Staging of the HER2-positive group was significantly different from the HER2-negative group with most cases presenting at stage IV, paralleled by a trend towards decreased survival. One patient who received dual HER2 inhibition almost went into full clinical remission despite treatment initiation in a metastasized state. Our results reveal a low prevalence of HER2 positivity and highlight HER2 gene amplification as an early, potentially driving event in gallbladder carcinogenesis. Prospective standardized HER2 testing and randomized control studies are needed to prove clinical efficacy of targeted HER2 inhibition in GBC.
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http://dx.doi.org/10.1007/s00428-019-02706-6DOI Listing
June 2020

HER2 gene (ERBB2) amplification is a rare event in non-liver-fluke associated cholangiocarcinogenesis.

BMC Cancer 2019 Dec 5;19(1):1191. Epub 2019 Dec 5.

Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.

Background: Cholangiocarcinoma is a rapidly fatal cancer entity with a median survival of less than one year. In contrast to many other malignancies, no substantial therapeutic breakthrough has been made in the past few decades, thereby limiting the treatment to cytotoxic chemotherapy with little beneficial effect for most patients. Targeted therapy tailored to the individual has shown substantial success in the recent past as a promising avenue for cancer therapy.

Methods: In this study, we determined the frequency of amplification of the HER2 gene in a comprehensive and well-characterized European cholangiocarcinoma cohort encompassing 436 patients including intrahepatic (n = 155), proximal (n = 155) and distal (n = 126) cholangiocarcinoma by strict application of a combined immunohistochemical and in situ hybridization algorithm following the current guidelines for HER2 assessment in gastric cancer.

Results: We identified a proportion of 1.4% (n = 6) patients that demonstrated HER2 gene amplification, with the highest rate among the distal cholangiocarcinoma patients (2.4%). None of the patients with equivocal (2+) immunohistochemical staining results exhibited gene amplification molecularly. In four of the five patients with HER2 positivity, gene amplification was already present in concomitantly tested high-grade biliary intraepithelial neoplasia (80%). HER2 gene amplification was not significantly associated with other clinical parameters, including survival.

Conclusions: This study identifies HER2 gene amplification as a rare event in cholangiocarcinoma of the Western population, occurring already in high-grade BilIN in a subset of patients. Furthermore, we provide a robust testing algorithm that may be used prior to therapy administration in future clinical trials evaluating the role of HER2 as a predictive marker in cholangiocarcinoma.
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http://dx.doi.org/10.1186/s12885-019-6320-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896712PMC
December 2019

Cetuximab in Pancreatic Cancer Therapy: A Systematic Review and Meta-Analysis.

Oncology 2020 2;98(1):53-60. Epub 2019 Oct 2.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany,

Introduction: The present study evaluated the potential benefit of adding cetuximab to neoadjuvant, adjuvant, or palliative standard therapy for pancreatic cancer.

Methods: A systematic literature search was performed in MEDLINE, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL). Only randomised controlled trials (RCTs) investigating the effect of adding cetuximab to standard chemotherapy in pancreatic cancer were included. Evaluated outcomes were overall survival, progression-free survival, objective response, and toxicity. For overall survival and progression-free survival, hazard ratios (HR) with 95% confidence intervals (CI) were chosen as effect measure. For objective response, odds ratios (OR) with 95% CI were used. Analysis was based on a random effects model.

Results: After screening 568 publications, a total of 4 RCTs with 924 patients were included. In all trials, patients were adequately randomised with balanced intervention and control groups. There was no significant difference in overall survival (HR 1.04; 95% CI: 0.90-1.19; p = 0.60), progression-free survival (HR 1.06; 95% CI: 0.93-1.22; p = 0.36), or objective response (OR 0.99; 95% CI: 0.66 -1.49; p = 0.96) when adding cetuximab to a standard therapy. Toxicity was the same or higher in each of the included trials. According to GRADE, the certainty of the evidence is high. Therefore, adding cetuximab to pancreatic cancer therapy has no clinically relevant benefit.

Conclusion: In the presence of no survival benefit, increased toxicity, and higher costs, a decreased cost-benefit ratio compared to the standard care must be suggested. Conducting further RCTs in unselected pancreatic cancer populations is unlikely to change this conclusion.
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http://dx.doi.org/10.1159/000502844DOI Listing
January 2020

RNA-Based Detection of Gene Fusions in Formalin-Fixed and Paraffin-Embedded Solid Cancer Samples.

Cancers (Basel) 2019 Sep 5;11(9). Epub 2019 Sep 5.

Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.

Oncogenic gene fusions are important drivers in many cancer types, including carcinomas, with diagnostic and therapeutic implications. Hence, sensitive and rapid methods for parallel profiling in formalin-fixed and paraffin-embedded (FFPE) specimens are needed. In this study we analyzed gene fusions in a cohort of 517 cases where standard treatment options were exhausted. To this end the Archer DX Solid tumor panel (AMP; 285 cases) and the Oncomine Comprehensive Assay v3 (OCA; 232 cases) were employed. Findings were validated by Sanger sequencing, fluorescence in situ hybridization (FISH) or immunohistochemistry. Both assays demonstrated minimal dropout rates (AMP: 2.4%; = 7/292, OCA: 2.1%; = 5/237) with turnaround times of 6-9 working days (median, OCA and AMP, respectively). Hands-on-time for library preparation was 6 h (AMP) and 2 h (OCA). We detected = 40 fusion-positive cases (7.7%) with TMPRSS2::ERG in prostate cancer being most prevalent ( = 9/40; 22.5%), followed by other gene fusions identified in cancers of unknown primary ( = 6/40; 15.0%), adenoid cystic carcinoma ( = 7/40; 17.5%), and pancreatic cancer ( = 7/40; 17.5%). Our results demonstrate that targeted RNA-sequencing of FFPE samples is feasible, and a well-suited approach for the detection of gene fusions in a routine clinical setting.
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http://dx.doi.org/10.3390/cancers11091309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769558PMC
September 2019

Protocol of a prospective, monocentric phase I/II feasibility study investigating the safety of multimodality treatment with a combination of intraoperative chemotherapy and surgical resection in locally confined or borderline resectable pancreatic cancer: the combiCaRe study.

BMJ Open 2019 08 20;9(8):e028696. Epub 2019 Aug 20.

Department of General, Visceral and Transplantation Surgery, Universitätsklinikum Heidelberg, Heidelberg, Germany

Introduction: Pancreatic cancer is a devastating disease with an exceptionally poor prognosis. Complete resection of the primary tumour followed by adjuvant chemotherapy is the current standard treatment for patients with resectable disease and the only curative treatment option. However, long-term survival remains rare. Tumour cell dissemination due to manipulation during surgery may increase the rate of future metastases and local recurrence, and perioperative chemotherapy might diminish local, distant and circulating minimal residual disease. Yet, safety and feasibility of systemic chemotherapeutic treatments during pancreatic cancer resection have to be evaluated in a first instance.

Methods And Analysis: This is a prospective, single-centre phase I/II feasibility study to investigate the safety and tolerability of a combination of intraoperative chemotherapy and surgical resection in pancreatic cancer. Forty patients with locally confined or borderline resectable pancreatic cancer, meeting all proposed criteria will be included. Participants will receive 400 mg/m calcium folinate over 2 hours and 2000 mg/m 5-fluorouracil over 48 hours, started on the day before pancreatic surgery and thus continuing during surgery. Participants will be followed until 60 days after surgery. The primary endpoint is the 30-day overall complication rate according to the Clavien-Dindo classification. Secondary endpoints comprise toxicity and treatment associated complications. Patients receiving perioperative chemotherapy will be compared with a propensity score matched contemporary control group of 70 patients with pancreatic cancer receiving the standard treatment. This trial also contains an ancillary translational study to analyse disseminated tumour cells and effects of pharmacological interventions in pancreatic cancer.

Ethics And Dissemination: CombiCaRe has been approved by the German Federal Institute for Drugs and Medical Devices (reference number 4042787) and the Medical Ethics Committee of Heidelberg University (reference number AFmo-269/2018). The results of this trial will be presented at national and international conferences and published in peer-reviewed journals.

Trial Registration Number: German Clinical Trials Register (DRKS00015766).
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http://dx.doi.org/10.1136/bmjopen-2018-028696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707702PMC
August 2019

Impact of interventions and tumor stage on health-related quality of life in patients with hepatocellular carcinoma.

J Cancer Res Clin Oncol 2019 Nov 19;145(11):2761-2769. Epub 2019 Aug 19.

Department of Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.

Purpose: This study aims to examine the health-related quality of life in patients with hepatocellular carcinoma.

Methods: 181 patients attending a tertiary center outpatient clinic were interviewed and completed the short form 36 (SF36) questionnaire. The SF36 was used to assess health-related QoL. Cross-sectional analyses by group (age, gender, clinical scores, systemic, and local interventions) as well sequel questionnaires were conducted.

Results: Participants included were 79% (143/181) men [mean age at first SF36: 63.8 (± 12.3; 18.4-85.8) years]. Barcelona Clinic Liver Cancer (BCLC) stadium C was associated with significantly lower SF36 total scores, and elevated initial alpha-fetoprotein (AFP) concentrations were associated with lower SF36 functional and mental health sum scores throughout the course of the third questionnaire. Patients treated with sorafenib had within the sub-dimension scores a significantly lower result for role limitations due to physical health compared to patients without sorafenib treatment. Patients who underwent a transarterial chemoembolization (TACE) had within the sub-dimension scores a significantly higher result for control of pain compared to patients without TACE. Kaplan-Meier analysis revealed significant survival benefits for patients who underwent any intervention at the first SF36 (mean survival in years 4.3 vs. 1.6; P < 0.01) as well as for patients who underwent hepatic resection (mean survival in years 6.3 vs. 2.7; P < 0.0001).

Conclusion: Advanced tumor stages marked by BCLC stadium C and elevated initial AFP concentrations were associated with lower SF36 total scores and functional sum scores, respectively. During the course of sorafenib treatment, the sub-dimensional score for role limitations due to physical health decreased significantly, whereas TACE performance was associated with a significant improvement of the control of body pain.
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http://dx.doi.org/10.1007/s00432-019-03005-yDOI Listing
November 2019

Induction chemotherapy in pancreatic cancer: CA 19-9 may predict resectability and survival.

HPB (Oxford) 2020 02 30;22(2):224-232. Epub 2019 Jul 30.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. Electronic address:

Background: Preoperative/Neoadjuvant treatment (NT) is increasingly used in unresectable pancreatic cancer (PDAC). However, ∼40% of patients cannot be resected after NT and reliable preoperative response evaluation is currently lacking. We investigated CA 19-9 levels and their dynamics during NT for prediction of resectability and survival.

Methods: We screened our institution's database for patients who underwent exploration or resection after NT with gemcitabine-based therapy (GEM) or FOLFIRINOX (FOL). Pre- and post-NT CA 19-9, resection rate and survival were analyzed.

Results: Of 318 patients 165 (51.9%) were resected and 153 (48.1%) received exploration. In the FOL group (n = 103; 32.4%), a post-NT CA 19-9 cutoff at 91.8 U/ml had a sensitivity of 75.0% and a specificity of 76.9% for completing resection with an AUC of 0.783 in the ROC analysis (95% CI: 0.692-0.874; p < 0.001. PPV: 84.2%, NPV: 65.2%). Resected patients above the cutoff did not benefit from resection. Post-NT CA 19-9 <91.8 U/ml (OR 11.63, p < 0.001) and CA 19-9 ratio of <0.4 (OR 5.77, p = 0.001) were independent predictors for resectability in FOL patients.

Discussion: CA 19-9 levels after neoadjuvant treatment with FOLFIRINOX predict resectability and survival of PDAC more accurately than dynamic values and should be incorporated into response evaluation and surgical decision-making.
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http://dx.doi.org/10.1016/j.hpb.2019.06.012DOI Listing
February 2020

Low frequency of mismatch repair deficiency in gallbladder cancer.

Diagn Pathol 2019 May 8;14(1):36. Epub 2019 May 8.

Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.

Background: DNA mismatch repair (MMR) deficiency is a major pathway of genomic instability in cancer. It leads to the accumulation of numerous mutations predominantly at microsatellite sequences, a phenotype known as microsatellite instability (MSI). MSI tumors have a distinct clinical behavior and commonly respond well to immune checkpoint blockade, irrespective of their origin. Data about the prevalence of MSI among gallbladder cancer (GBC) have been conflicting. We here analyzed a well-characterized cohort of 69 Western-world GBCs.

Methods: We analyzed the mononucleotide MSI marker panel consisting of BAT25, BAT26, and CAT25 to determine the prevalence of MMR deficiency-induced MSI.

Results: MSI was detected in 1/69 (1.4%) of analyzed GBCs. The detected MSI GBC had a classical histomorphology, i.e. of acinar/tubular/glandular pancreatobiliary phenotype, and showed nuclear expression of all four MMR proteins MLH1, MSH2, MSH6, and PMS2. The MSI GBC patient showed a prolonged overall survival, despite having a high tumor stage at diagnosis. The patient had no known background or family history indicative of Lynch syndrome.

Conclusions: Even though the overall number of MSI tumors is low in GBC, the potentially therapeutic benefit of checkpoint blockade in the respective patients may justify MSI analysis of GBC.
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http://dx.doi.org/10.1186/s13000-019-0813-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506936PMC
May 2019

Chemotherapy for pancreatic cancer.

Presse Med 2019 Mar 15;48(3 Pt 2):e159-e174. Epub 2019 Mar 15.

Heidelberg University Hospital, Department of Surgery, Heidelberg, Germany.

Chemotherapy is an important part of multimodality pancreatic cancer treatment. After curative resection, adjuvant chemotherapy can significantly improve disease free survival and overall survival. The current standard of care is six months adjuvant chemotherapy with modified folinic acid, 5-fluorouracil, irinotecan and oxaliplatin (mFOLFIRINOX) in patients fit enough for this protocol, otherwise six months of gemcitabine and capecitabine based on the European Study Group for Pancreatic Cancer (ESPAC)-4 study. In patients with metastatic disease, combination chemotherapy according to the FOLFIRINOX protocol or with gemcitabine plus nab-paclitaxel is an important improvement to gemcitabine monotherapy that was the standard for many years. Patients not fit for combination chemotherapy however may still benefit from gemcitabine. Patients with good performance status may benefit from second-line chemotherapy. Chemoradiation has long been used in locally advanced pancreatic cancer but is now tempered following the LAP07 study. This trial showed no difference in overall survival in those patients with stable disease after four months of gemcitabine (with or without erlotinib) randomized to either continuation of gemcitabine therapy or chemoradiation (54Gy with capecitabine). As an alternative to radiation, other forms local therapies including radiofrequency ablation, irreversible electroporation, high-intensity focused ultrasound, microwave ablation and local anti-KRAS therapy (using siG12D-LODER) are currently under investigation. Given the systemic nature of pancreas cancer from an early stage, the success of any local approach other than complete surgical resection (with adjuvant systemic therapy) is likely to be very limited. In patients with locally advanced, irresectable cancer, chemotherapy may offer the chance for secondary resection with a survival similar to patients with primary resectable disease. Downstaging regimens need to be evaluated in prospective randomized trials in order to make firm recommendations. Selection of patient groups for specific therapy including cytotoxics is becoming a reality using assays based on drug cellular transport and metabolism, and molecular signatures. Going forward, high throughput screening of different chemotherapy agents using molecular signatures based on patients' derived organoids holds considerable promise.
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http://dx.doi.org/10.1016/j.lpm.2019.02.025DOI Listing
March 2019

Prognostic Impact of Carboxylesterase 2 in Cholangiocarcinoma.

Sci Rep 2019 03 13;9(1):4338. Epub 2019 Mar 13.

Institute for Medical Immunology, Campus Virchow, Berlin, Charité, Germany.

Carboxylesterase 2 (CES2) is instrumental for conversion of ester-containing prodrugs in cancer treatment. Novel treatment strategies are exceedingly needed for cholangiocarcinoma (CCA) patients. Here, we assessed CES2 expression by immunohistochemistry in a CCA cohort comprising 171 non-liver fluke associated, intrahepatic (n = 72) and extrahepatic (perihilar: n = 56; distal: n = 43) CCAs. Additionally, 80 samples of high-grade biliary intraepithelial neoplastic tissues and 158 corresponding samples of histological normal, non-neoplastic biliary tract tissues were included. CES2 expression was highest in non-neoplastic biliary tissue and significantly decreased in CCA. Patients showing any CES2 expression in tumor cells had a significantly better overall survival compared to negative cases (p = 0.008). This survival benefit was also maintained after stratification of CES2-positive cases, by comparing low, medium and high CES2 expression levels (p-trend = 0.0006). Evaluation of CCA subtypes showed the survival difference to be restricted to extrahepatic tumors. Correlation of CES2 expression with data of tumor-infiltrating immune cells showed that particularly CD8+ T cells were more frequently detected in CES2-positive CCAs. Furthermore, treatment of CCA cell lines with the prodrug Irinotecan reduced cell viability, increased cytotoxicity and modulated inflammatory gene expression. In conclusion, reduced CES2 expression is associated with poor outcome and low CD8+ T cell infiltration in CCA patients. Further clinical studies could show, whether CES2 expression may serve as a predictive marker in patients treated with prodrugs converted by CES2.
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http://dx.doi.org/10.1038/s41598-019-40487-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416336PMC
March 2019

Programmed cell death ligand 1 (PD-L1, CD274) in cholangiocarcinoma - correlation with clinicopathological data and comparison of antibodies.

BMC Cancer 2019 Jan 15;19(1):72. Epub 2019 Jan 15.

Institute of Pathology, University Heidelberg, Im Neuenheimer Feld 224, Heidelberg, Germany.

Background: Cholangiocarcinoma (CCA) may arise in the intra- or extrahepatic biliary tract and is associated with a poor prognosis. Despite recent advances, to date there is still no established targeted therapeutic approach available. Non-surgical therapeutic agents are urgently needed, as most patients are non-eligible to surgical resection. Anti-PD-L1 therapy prevents cancer cells from evading the immune system and has emerged as a new treatment option in several cancer entities. Recently, PD-L1 expression has been analyzed in comparably small CCA patient cohorts. However, a systematic validation of different PD-L1 antibodies has not been performed in CCA so far.

Methods: We stained a tissue microarray consisting of 170 patients, including 72 intrahepatic cholangiocarcinomas (iCCAs), 57 perihilar cholangiocarcinomas (pCCAs) and 41 distal cholangiocarcinomas (dCCAs) by immunohistochemistry and evaluated PD-L1 positivity in tumor and stromal cells. We analyzed three different PD-L1 antibodies (clones 28-8, SP142, and SP263) that are frequently used and recommended for predictive diagnostic testing in other cancer types.

Results: For PD-L1 antibody clone SP263, 5% of iCCAs, 4% of pCCAs and 3% of dCCAs exhibited PD-L1 expression on tumor cells, thereby showing the highest frequencies of PD-L1 positivity. Accordingly, highest PD-L1 positivity rates of stromal cells with 31% in iCCA, 40% in pCCA and 61% in dCCA were detected for clone SP263. Agreement of PD-L1 positivity in tumor cells was moderate for clone 28-8 and SP263 (κ = 0.44) and poor between 28-8 and SP142 (κ = 0.13), as well as  SP142 and SP263 (κ = 0.11), respectively. Statistical analyses of PD-L1 expression (clone SP263) on tumor cells with clinicopathological data revealed a positive correlation with shortened overall survival in CCA patients.

Conclusions: Selection of appropriate PD-L1 antibodies and careful evaluation of immunohistochemical staining patterns have a significant impact on PD-L1 testing in CCA. Clinical trials are necessary to investigate the putative beneficial effects of PD-L1 targeted immunotherapy in CCA patients.
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http://dx.doi.org/10.1186/s12885-018-5254-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332835PMC
January 2019

Survival of Hepatocellular Carcinoma Patients Treated with Sorafenib beyond Progression.

Gastrointest Tumors 2018 Sep 11;5(1-2):38-46. Epub 2018 Apr 11.

Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany.

Background/aim: Sorafenib leads to improved survival in advanced hepatocellular carcinoma (HCC) patients. Continuation of sorafenib beyond progression has been a possible treatment strategy when further approved therapeutic agents are lacking.

Methods: We performed a retrospective analysis of all HCC patients at our institution with documented disease progression under treatment with sorafenib. Overall survival (OS) from start of sorafenib treatment was compared between patients who received sorafenib for > 3 weeks beyond progression (group 1) and those who discontinued sorafenib ≤3 weeks after progression (group 2). Group 1 was further subdivided into those patients who received sorafenib for > 3 months (group 1a) and those who received it for ≤3 months (group 1b).

Results: A total of 71 patients were analyzed. Median OS for all patients was 15.4 months. OS in group 1 (15.6 months) and 2 (13.0 months) was similar ( = 0.90). Patients in group 1a showed significantly prolonged median OS (19.7 months) compared to that of patients in group 1b (13.6 months, = 0.004), and they showed a trend towards prolonged OS compared to group 2 ( = 0.126). For patients with a poor prognosis according to their Child-Pugh stage, performance status, alpha-fetoprotein, and response to prior sorafenib treatment, OS was significantly prolonged in group 1 versus group 2 (12.1 vs. 6.4 months, = 0.019).

Conclusion: In HCC patients, continuing sorafenib beyond progression for > 3 months is associated with improved survival compared to discontinuing sorafenib within 3 months. Furthermore, patients with a poor prognosis who continue sorafenib beyond progression in general show significantly prolonged survival.
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http://dx.doi.org/10.1159/000487635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288626PMC
September 2018

Prognostic significance of microsatellite-instability in gastric and gastroesophageal junction cancer patients undergoing neoadjuvant chemotherapy.

Int J Cancer 2019 04 4;144(7):1697-1703. Epub 2019 Jan 4.

Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

Perioperative systemic treatment is standard of care for Caucasian patients with locally advanced, resectable gastric adenocarcinoma. The prognostic relevance of the microsatellite instability (MSI) status in patients undergoing neoadjuvant chemotherapy followed by resection is unclear. We analyzed the association of the MSI status with histological regression and clinical outcome in patients undergoing neoadjuvant systemic treatment. Tumor tissue from patients undergoing neoadjuvant chemotherapy followed by resection for gastric or gastroesophageal-junction adenocarcinoma was analyzed for MSI status using a mononucleotide marker panel encompassing the markers BAT25, BAT26, and CAT25. Histological regression, relapse-free survival and overall survival were calculated and correlated with MSI status. We identified the MSI-H phenotype in 9 (8.9%) out of 101 analyzed tumors. Though a poor histological response was observed in eight out of nine MSI-H patients, overall survival was significantly better for patients with MSI-H compared to MSS tumors (median overall survival not reached vs. 38.6 months, log-rank test p = 0.014). Among MSI-H patients, an unexpected long-term survival after relapse was observed. Our data indicate that the MSI-H phenotype is a favorable prognostic marker in gastric cancer patients undergoing neoadjuvant treatment. The benefit of perioperative cytotoxic treatment in patients with MSI-H gastric cancer, however, remains questionable. Future trials should stratify patients according to their MSI status, and novel treatment modalities focusing on MSI-H tumors should be considered.
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http://dx.doi.org/10.1002/ijc.32030DOI Listing
April 2019

Mismatch repair deficiency is a rare but putative therapeutically relevant finding in non-liver fluke associated cholangiocarcinoma.

Br J Cancer 2019 01 31;120(1):109-114. Epub 2018 Oct 31.

Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany.

Background: A major molecular pathway of genetic instability in cancer is DNA mismatch repair deficiency. High-level microsatellite instability (MSI-H) is currently the best predictor of responsiveness towards immune checkpoint blockade. Data about the prevalence of high-level microsatellite instability in cholangiocarcinoma (CCA) has been conflicting.

Methods: We employed a cohort comprising 308 Western-world, non-liver fluke-associated CCAs (159 intrahepatic, 106 perihilar, and 43 distal). We analysed the mononucleotide microsatellite instability marker panel consisting of BAT25, BAT26, and CAT25 and detected MSI-H in 4/308 CCAs (1.3%).

Results: Patients affected by MSI-H CCA had mostly an atypical histomorphology (p = 0.004), showed a longer overall survival, although having a high tumour stage, and were of younger age. Correlation analysis of microsatellite instability status with tumour-infiltrating immune cells, MHC I, and PD-L1 expression in the same cholangiocarcinoma cohort showed higher numbers of CD8 + T cells, FOXP3 + regulatory T cells, CD20 + B cells and high or at least moderate MHC I expression levels in MSI-H CCAs.

Conclusions: Even though the overall number of MSI-H CCAs is low, the dismal prognosis of the disease and the therapeutic option of immune checkpoint blockade in the respective patients justify MSI testing of cholangiocarcinoma, particularly in younger patients showing an atypical histomorphology.
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http://dx.doi.org/10.1038/s41416-018-0199-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325153PMC
January 2019

Prostatic metastasis from intrahepatic cholangiocarcinoma.

Urol Case Rep 2018 Sep 18;20:90-91. Epub 2018 Jul 18.

Department of Urology, University of Heidelberg, Heidelberg, Germany.

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http://dx.doi.org/10.1016/j.eucr.2018.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072907PMC
September 2018

Enhanced Control of Oncolytic Measles Virus Using MicroRNA Target Sites.

Mol Ther Oncolytics 2018 Jun 12;9:30-40. Epub 2018 Apr 12.

Department of Medical Oncology, National Center for Tumor Diseases (NCT) and Heidelberg University Hospital, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.

Measles viruses derived from the live-attenuated Edmonton-B vaccine lineage are currently investigated as novel anti-cancer therapeutics. In this context, tumor specificity and oncolytic potency are key determinants of the therapeutic index. Here, we describe a systematic and comprehensive analysis of a recently developed post-entry targeting strategy based on the incorporation of microRNA target sites (miRTS) into the measles virus genome. We have established viruses with target sites for different microRNA species in the 3' untranslated regions of either the , , , or genes and generated viruses harboring microRNA target sites in multiple genes. We report critical importance of target-site positioning with proximal genomic positions effecting maximum vector control. No relevant additional effect of six versus three miRTS copies for the same microRNA species in terms of regulatory efficiency was observed. Moreover, we demonstrate that, depending on the microRNA species, viral mRNAs containing microRNA target sites are directly cleaved and/or translationally repressed in presence of cognate microRNAs. In conclusion, we report highly efficient control of measles virus replication with various miRTS positions for development of safe and efficient cancer virotherapy and provide insights into the mechanisms underlying microRNA-mediated vector control.
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http://dx.doi.org/10.1016/j.omto.2018.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026446PMC
June 2018

Fusions in Wild-Type Pancreatic Cancer.

Cancer Discov 2018 09 25;8(9):1087-1095. Epub 2018 May 25.

Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany.

We used whole-genome and transcriptome sequencing to identify clinically actionable genomic alterations in young adults with pancreatic ductal adenocarcinoma (PDAC). Molecular characterization of 17 patients with PDAC enrolled in a precision oncology program revealed gene fusions amenable to pharmacologic inhibition by small-molecule tyrosine kinase inhibitors in all patients with wild-type () tumors (4 of 17). These alterations included recurrent rearrangements predicted to drive PDAC development through aberrant ERBB receptor-mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in 2 patients with -rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of patients with PDAC. Advanced PDAC is a malignancy with few treatment options that lacks molecular mechanism-based therapies. Our study uncovers recurrent gene rearrangements such as fusions as disease-driving events in tumors, thereby providing novel insights into oncogenic signaling and new therapeutic options in this entity. .
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http://dx.doi.org/10.1158/2159-8290.CD-18-0036DOI Listing
September 2018

An undifferentiated carcinoma at Klatskin-position with long-term complete remission after chemotherapy.

Oncotarget 2018 Apr 24;9(31):22230-22235. Epub 2018 Apr 24.

Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.

Background: Neoplasms anatomically adjacent to the bile duct usually derive from malignantly transformed cholangiocytes forming cholangiocarcinoma (CCA). CCAs are divided in extrahepatic (eCCA) and intrahepatic (iCCA) tumors. Patients with irresectable CCAs are treated with systemic chemotherapy and have an unfavorable prognosis with a median survival of about one year. Here, we report a case of an undifferentiated carcinoma in Klatskin-position with long-term remission after systemic chemotherapy.

Case Presentation: A 65-year-old Caucasian male presented with painless jaundice caused by an undifferentiated carcinoma in Klatskin-position (Type IIIb). Alpha fetoprotein (AFP; 3675 IU/mL) and carbohydrate antigen 19-9 (CA 19-9; 183 U/ml) were elevated. An exploratory laparotomy was carried out, but the patient was found to be irresectable due to severe fibrosis caused by biliary obstruction. Histology showed an undifferentiated carcinoma with high proliferation rate, and the patient was therefore subjected to poly-chemotherapy treatment according to the FOLFOX6-protocol. During therapy, AFP decreased to normal. Subsequent CT scans and ERC revealed a complete remission. Four years past initial diagnosis, a new suspicious lesion in the liver is visible on MRT; however, AFP and CA 19-9 are still in the normal range.

Conclusions: Our case demonstrates that histopathological defined diagnosis may significantly inform therapeutic decision-making in irresectable cholangiocarcinoma even in regard to conventional systemic therapy. In case of an undifferentiated carcinoma poly-chemotherapy may provide significant success.
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http://dx.doi.org/10.18632/oncotarget.25125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955137PMC
April 2018