Frank Bergmann

Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany

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Publications (119)549.18 Total impact

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    ABSTRACT: The purpose of the study was to evaluate the effect of radiation therapy and chemoradiation with gemcitabine (GEM) after R1 resection in patients with pancreatic adenocarcinoma (PAC). We performed a retrospective analysis of 25 patients who were treated with postoperative radiotherapy (RT) or chemoradiation (CRT) after surgery with microscopically positive resection margins for primary pancreatic cancer (PAC). Median age was 60 years (range 34 to 74 years), and there were 17 male and 8 female patients. Fractionated RT was applied with a median dose of 49.6 Gy (range 36 to 54 Gy). Eight patients received additional intraoperative radiotherapy (IORT) with a median dose of 12 Gy. Median overall survival (mOS) of all treated patients was 22 months (95% confidence interval (CI) 7.9 to 36.1 months) after date of resection and 21.1 months (95% CI 7.6 to 34.6 months) after start of (C)RT. Median progression-free survival (mPFS) was 13.0 months (95% CI 0.93 to 25 months). Grading (G2 vs. G3, P = 0.005) and gender (female vs. male, P = 0.01) were significantly correlated with OS. There was a significant difference in mPFS between male and female patients (P = 0.008). A total of 11 from 25 patients experienced local tumour progression, and 19 patients were diagnosed with either locoregional or distant failure. We demonstrated that GEM-based CRT can be applied in analogy to neoadjuvant protocols in the adjuvant setting for PAC patients at high risk for disease recurrence after incomplete resection. Patients undergoing additive CRT have a rather good OS and PFS compared to historical control patient groups.
    World Journal of Surgical Oncology 04/2015; 13(1):149. DOI:10.1186/s12957-015-0560-3 · 1.20 Impact Factor
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    ABSTRACT: Many cancers harbor oncogenic mutations of KRAS. Effectors mediating cancer progression, invasion, and metastasis in KRAS-mutated cancers are only incompletely understood. Here we identify cancer cell-expressed murine TRAIL-R, whose main function ascribed so far has been the induction of apoptosis as a crucial mediator of KRAS-driven cancer progression, invasion, and metastasis and in vivo Rac-1 activation. Cancer cell-restricted genetic ablation of murine TRAIL-R in autochthonous KRAS-driven models of non-small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) reduces tumor growth, blunts metastasis, and prolongs survival by inhibiting cancer cell-autonomous migration, proliferation, and invasion. Consistent with this, high TRAIL-R2 expression correlates with invasion of human PDAC into lymph vessels and with shortened metastasis-free survival of KRAS-mutated colorectal cancer patients. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer cell 04/2015; DOI:10.1016/j.ccell.2015.02.014 · 23.89 Impact Factor
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    ABSTRACT: Objectives: This study aimed to analyze a large single-center population of resected intraductal papillary mucinous neoplasms (IPMN) of the pancreas with respect to risk factors of malignant transformation. Background: There is international consensus that main-duct (MD) as well as mixed-type IPMNs should be treated surgically due to a high risk of malignancy. In contrast, there is an ongoing controversy about surgery of branch-duct type IPMN (BD-IPMN). Methods: All consecutive patients who underwent surgery for IPMN between January 2004 and December 2012 were included. Clinical characteristics and preoperative imaging were correlated with histopathological features. Results: A total of 512 patients underwent pancreatic surgery and had a histological proof of IPMN. According to preoperative imaging, 74 patients had MD-IPMN (14%), 205 mixed-type (40%), and 233 suspected BD-IPMN (46%). On histopathology, 162 of 512 patients revealed low-grade, 105 moderate, and 52 high-grade dysplasia. One hundred ninety-three IPMN patients (38%) suffered from invasive carcinoma. Among invasive IPMNs, the majority (58%) were mixed-type lesions according to preoperative imaging. Of 141 Sendai negative BD-IPMNs, a malignancy rate of 18% (high-grade dysplasia and invasive carcinoma) was found. Most interesting, 29% of suspected BD-IPMNs (67/233) revealed histological involvement of the main pancreatic duct not evident in preoperative imaging. Conclusions: All subtypes of IPMNs display a relevant risk for malignant transformation. By abdominal imaging, many IPMNs are misclassified as BD-IPMNs but reveal mixed-type lesions in histopathology. Because currently available preoperative diagnostics are not sufficient to reliably diagnose BD-IPMNs, surgical resection for suspected small branch-duct IPMN should be considered in patients fit for surgery.
    Annals of Surgery 11/2014; 260(5):848-856. DOI:10.1097/SLA.0000000000000980 · 7.19 Impact Factor
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    ABSTRACT: Objectives: Because neural invasion (NI) is still inconsistently reported and not well characterized within gastrointestinal malignancies (GIMs), our aim was to determine the exact prevalence and severity of NI and to elucidate the true impact of NI on patient's prognosis. Background: The union internationale contre le cancer (UICC) recently added NI as a novel parameter in the current TNM classification. However, there are only a few existing studies with specific focus on NI, so that the distinct role of NI in GIMs is still uncertain. Materials and Methods: NI was characterized in approximately 16,000 hematoxylin and eosin tissue sections from 2050 patients with adenocarcinoma of the esophagogastric junction (AEG)-I-III, squamous cell carcinoma (SCC) of the esophagus, gastric cancer (GC), colon cancer (CC), rectal cancer (RC), cholangiocellular cancer (CCC), hepatocellular cancer (HCC), and pancreatic cancer (PC). NI prevalence and severity was determined and related to patient's prognosis and survival. Results: NI prevalence largely varied between HCC/6%, CC/28%, RC/34%, AEG-I/36% and AEG-II/36%, SCC/37%, GC/38%, CCC/58%, and AEG-III/65% to PC/100%. NI severity score was uppermost in PC (24.9 +/- 1.9) and lowest in AEG-I (0.8 +/- 0.3). Multivariable analyses including age, sex, TNM stage, and grading revealed that the prevalence of NI was significantly associated with diminished survival in AEG-II/III, GC, and RC. However, increasing NI severity impaired survival in AEG-II/III and PC only. Conclusions: NI prevalence and NI severity strongly vary within GIMs. Determination of NI severity in GIMs is amore precise tool than solely recording the presence of NI and revealed dismal prognostic impact on patients with AEG-II/III and PC. Evidently, NI is not a concomitant side feature in GIMs and, therefore, deserves special attention for improved patient stratification and individualized therapy after surgery.
    Annals of Surgery 11/2014; 260(5):900-908. DOI:10.1097/SLA.0000000000000968 · 7.19 Impact Factor
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    ABSTRACT: Background Radical resection with total mesorectal excision (TME) is the accepted standard of care for most rectal cancers. However, T1 rectal cancers may be at low risk for metastases and are therefore treatable with local resection. The aim of our study was to investigate whether the identification of these patients is possible through existing selection criteria. Methods Between 2001 and 2012, radical resection with TME was performed in 68 patients with a histologically confirmed T1 adenocarcinoma of the rectum. Each patient was staged preoperatively as lymph node negative. Patients at low risk to metastasize were defined as proposed by Hermanek and Gall (Int J Colorectal Dis 1(2):79–84, 1986), Kikuchi et al. (Dis Colon Rectum 38(12):1286–1295, 1995) and Hase et al. (Dis Colon Rectum 38(1):19–26, 1995) Postoperative morbidity, mortality, and oncological outcome were analyzed. Results Despite nodal negative staging, 9 of 68 patients (13 %) were node positive. Following the proposal of Hermanek and Gall, Kikuchi et al., and Hase et al., 14 % (5/37), 12 % (3/26), and 16 % (6/38) of patients, respectively, with low-risk tumors had lymph node metastases. In the univariate analysis, none of the investigated parameters could predict lymph node metastases. Following radical resection, none of the patients, regardless of nodal involvement, developed a recurrence. Conclusions Preoperative diagnostics regarding lymphatic tumor propagation and histomorphological assessment of tumor samples as predictors of lymph node metastasis are unreliable. Following radical resection with TME, the oncological outcome of node-positive patients with T1 rectal adenocarcinoma is comparable with that of lymph node-negative patients. Considering the lymph node metastases rate, a local excision should always be complemented with additional therapy.
    Annals of Surgical Oncology 10/2014; 22(6). DOI:10.1245/s10434-014-4179-3 · 3.94 Impact Factor
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    ABSTRACT: Pancreatic acinar cell carcinomas (PACs) are rare but are distinct aggressive neoplasms that phenotypically differ from pancreatic ductal adenocarcinomas (PDACs) and pancreatic neuroendocrine neoplasms (PNENs). Despite recent work on the genetic changes of PACs, their molecular pathogenesis is still poorly understood. In this study, we focus on a comparative genomic hybridization analysis. Based on frequent chromosomal imbalances, the involvement of DCC and c-MYC in the pathogenesis of PACs is further investigated. Moreover, we examine markers harboring potential therapeutic relevance (K-RAS, BRAF, EGFR, MGMT, HSP90, L1CAM, Her2). PACs revealed a microsatellite stable, chromosomal unstable genotype, defined by recurrent chromosomal losses of 1p, 3p, 4q, 5q, 6q, 8p, 9p, 11q, 13q, 16q, and 18, as well as gains of 1q, 7, 8q, 12, 17q, and 20q. Subsets of PAC displayed reduction/loss of DCC (79 %) and c-MYC-amplification (17 %). Significant EGFR expression occurred in 42 %, HSP90 expression in 98 %, L1CAM expression in 72 %, and loss of MGMT in 26 %. Two cases carried a K-RAS mutation. Mutations of EGFR or BRAF were not detected. All cases were Her2/neu-negative. PACs display characteristic chromosomal imbalances which are distinctly different from those in pancreatic ductal adenocarcinomas and pancreatic neuroendocrine neoplasms. Our findings suggest that DCC and c-MYC alterations may play an important role in the pathogenesis of PACs. Furthermore, EGFR, MGMT, HSP90, and L1CAM may be useful as therapeutic markers and predictors of response to therapy in a subset of PACs.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 10/2014; DOI:10.1007/s00428-014-1657-8 · 2.56 Impact Factor
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    ABSTRACT: Solid pseudopapillary neoplasms of the pancreas (SPN) are rare tumors. There is no standard treatment for patients with unresectable liver metastases of SPN. We describe a 40-year-old woman with SPN and metastases confirmed to the liver, and disease progression after primary tumor resection and chemotherapy with gemcitabine and cisplatin. The patient was treated with chemosaturation with percutaneous hepatic perfusions of melphalan. The procedure was performed twice within 8 weeks after which the liver metastases showed a marked reduction in size and vascularization (partial response). Grade 3 leukopenia after the second procedure was managed effectively with granulocyte colony-stimulating factor. No other toxicities were observed. Ten months after initiating treatment, the patient had a good performance status and remained stable. For SPN with unresectable liver metastases and progression despite systemic treatment, repeat chemosaturation with high-dose melphalan may offer an effective regional treatment option.
    Pancreatology 09/2014; 14(6). DOI:10.1016/j.pan.2014.08.006 · 2.50 Impact Factor
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    ABSTRACT: Background Autoimmune pancreatitis (AIP) is characterized by diffuse or focal swelling of the pancreas. AIP has been divided into types 1 and 2. The aim of the study was to evaluate and compare the clinicopathological characteristics, therapy and outcome of patients with AIP.Methods The medical records of patients diagnosed with AIP between January 2003 and July 2011 were reviewed. Characteristics of patients with AIP types 1 and 2 were compared with those of patients with pancreatic ductal adenocarcinoma (PDAC).ResultsAIP was classified as type 1 in 40 patients and type 2 in 32 according to the HISORt (Histology, Imaging, Serology, Other organ involvement, Response to therapy) criteria. Patients with histologically confirmed AIP type 2 were younger than those with type 1 (P = 0·005). Some 30 of 32 patients with AIP type 2 were found to have a localized tumour-like pancreatic mass and underwent pancreatectomy, compared with only 16 of 40 with type 1 (P < 0·001). Three of 25 patients with AIP type 2 presented with raised serum levels of IgG4 compared with 21 of 38 with type 1 (P < 0·001). There was no difference in symptoms and involvement of other organs between AIP types 1 and 2. Presentation with weight loss was more common among patients with PDAC than those with AIP, but there was no difference in pain or jaundice between the groups. Raised serum carbohydrate antigen 19-9 levels were more prevalent in patients with PDAC.Conclusion Patients with AIP type 2 frequently present with abdominal pain and a tumour-like mass. Differentiating AIP from PDAC is difficult, so making the clinical decision regarding operative versus conservative management is challenging.
    British Journal of Surgery 09/2014; 101(10). DOI:10.1002/bjs.9574 · 5.21 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2014; 52(08). DOI:10.1055/s-0034-1386443 · 1.67 Impact Factor
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    ABSTRACT: The biology of pancreatic acinar cell cystadenomas has not been clearly defined. However, a non-neoplastic process, caused by a cell differentiation failure leading to a cystic transformation, has been discussed, as well as a benign neoplastic lesion. Pancreatic acinar cell cystadenomas usually consist of thin-walled unilocular or multilocular cysts, and mural nodules have been described in two cases of a recent series. In one of these nodules, chromosomal imbalances were detected, which provided preliminary evidence for a neoplastic process. The aim of the current study was to further characterize the lesions by molecular analyses. In four cases without mural nodules, the clonality was assessed by performing mutational analyses within the highly variable displacement-loop region of the mitochondrial DNA. As a result, no closer correlation was identified between different foci within the tumors than between the tumors and adjacent normal pancreatic acinar tissue, indicating polyclonality of these lesions. Further molecular analyses revealed no mutations of the β-catenin and K-ras genes. In addition, no immunohistochemical evidence was identified for mutations of Smad4 or p53. In conclusion, the results of the current study demonstrated that pancreatic acinar cell cystadenomas are non-neoplastic lesions, with the potential exception of those rare cases with mural nodules.
    Oncology letters 08/2014; 8(2):852-858. DOI:10.3892/ol.2014.2163 · 0.99 Impact Factor
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    ABSTRACT: Background The incidence of pancreatic neuroendocrine neoplasms (pNEN) is increasing. This study aimed to evaluate predictors of overall survival and the indication for surgery.Methods Data collected between October 2001 and December 2012 were analysed. Histological grading and staging was based on the classifications of the World Health Organization, the International Union Against Cancer and the European Neuroendocrine Tumour Society.ResultsSome 310 patients (150 female, 48·4 per cent) underwent surgical resection. The final survival analysis included 291 patients. Five-year overall survival differed according to tumour grade (G): 91·0 per cent among 156 patients with pancreatic neuroendocrine tumours (pNET) G1, 70·8 per cent in 111 patients with pNET G2, and 20 per cent in 24 patients with pancreatic neuroendocrine carcinomas (pNEC) G3 (P < 0·001). Tumours graded G3 (hazard ratio (HR) 6·96, 95 per cent confidence interval 3·67 to 13·21), the presence of distant metastasis (HR 2·41, 1·32 to 4·42) and lymph node metastasis (HR 2·10, 1·07 to 4·16) were independent predictors of worse survival (P < 0·001, P = 0·004 and P = 0·032 respectively). Eight of 61 asymptomatic patients with pNEN smaller than 2 cm had tumours graded G2 or G3, and six of 51 patients had lymph node metastasis. Among patients with pNEC G3, the presence of distant metastasis had a significant impact on the 5-year overall survival rate: 0 per cent versus 43 per cent in those without distant metastasis (P = 0·036).Conclusion Neuroendocrine tumours graded G3, lymph node and distant metastasis are independent predictors of worse overall survival in patients with pNEN.
    British Journal of Surgery 08/2014; 101(11). DOI:10.1002/bjs.9603 · 5.21 Impact Factor
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    ABSTRACT: Background: Lymph node (LN) involvement is a major prognostic factor in pancreatic adenocarcinoma. However, the distinction N0/N1 is not sufficient to accurately predict prognosis. To improve prognostic accuracy in N1 tumors, different LN parameters have been tested. Previous studies were based on series with variable numbers of examined lymph nodes (ELN) and came to inconsistent conclusions as to the value of the number of positive lymph nodes (PLN) and the lymph node ratio (LNR). Objective: To determine the prognostic value of PLN and LNR based on a large series with standardized lymphadenectomy and pathological workup. Methods: 811 patients who underwent pancreatoduodenectomy for pancreatic adenocarcinoma between October 2001 and June 2012 were identified from a prospective database. Clinicopathological parameters included LN status (N0/N1), ELN, PLN, and LNR. Univariate and multivariate survival analyses were performed. Results: The median number of ELN was 24 (interquartile range: 18-32). By univariate analysis, both PLN and LNR were significantly associated with survival in N1 tumors. However, by multivariate analysis, only the number of PLN was confirmed as independent predictor of survival. Median survival in patients with only 1 PLN was 31.1 months and comparable to the survival in N0 (33.2 months). With increasing numbers of PLN median survival significantly decreased (2-3 PLN: 26.1 months, 4-7 PLN: 21.9 months, >=8 PLN: 18.3 months, P < 0.0001). Conclusions: This study demonstrates that, based on high numbers of ELN, PLN is superior to LNR in predicting survival and allows to distinguish several N-categories that improve prognostic accuracy in LN-positive resectable pancreatic adenocarcinoma.
    Annals of Surgery 06/2014; 261(5). DOI:10.1097/SLA.0000000000000814 · 7.19 Impact Factor
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    ABSTRACT: Objective: To assess the long-term survival and quality of life in total pancreatectomies and to identify risk factors for perioperative morbidity and mortality. Background: Total pancreatectomy may be required in locally advanced or centrally located pancreatic neoplasms to achieve complete tumor clearance, but available data on short- and long-term results are limited. Methods: A total of 434 consecutive total pancreatectomies for primary pancreatic or periampullary tumors were performed between October 2001 and September 2012 at the authors' institution and were prospectively documented and analyzed. Long-term outcome was assessed using Kaplan-Meier and quality of life analysis (EORTC-QLQ-C30 and PAN26). Uni- and multivariate analysis was performed to identify perioperative risk factors and predictors for long-term survival. Results: Extended total pancreatectomies were performed in 54% of cases, with arterial and portal vein resections in 15% and 32%, respectively. Overall 30-day and in-hospital mortality rates were 3.7% and 7.8%, respectively. High blood loss, long operative time, and arterial resections were independently associated with increased perioperative mortality (P ≤ 0.018). In malignant disease, median and 5-year survival were good for standard total pancreatectomies (28.6 months and 24.3%, respectively) and were significantly impaired after vascular resections (P < 0.001). Poor tumor grading, high American Joint Commission on Cancer tumor stage, age more than70 years, and an R1 resection were independent prognostic parameters. Long-term global quality of life was comparable with a matched healthy control group. Conclusions: Standard total pancreatectomy, if needed, is associated with good long-term outcome in pancreatic cancer. Marked surgical morbidity and impaired survival associated with vascular resections reflect the invasiveness of extended total pancreatectomies and the underlying advanced malignant disease.
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    ABSTRACT: To asses the impact of CA 19-9 and weight loss/gain on outcome after neoadjuvant chemoradiation (CRT) in patients with locally advanced pancreatic cancer (LAPC).
    Annals of Surgical Oncology 06/2014; DOI:10.1245/s10434-014-3607-8 · 3.94 Impact Factor
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    ABSTRACT: To systematically characterize specific pain patterns in the most frequent pancreatic diseases.
    Pancreatology 06/2014; 14(3):S13. DOI:10.3748/wjg.v20.i27.9154 · 2.50 Impact Factor
  • Pancreatology 06/2014; 14(3):S17. DOI:10.1016/j.pan.2014.05.431 · 2.50 Impact Factor
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    ABSTRACT: The role of pancreatic acinar cells in initiating necro-inflammatory responses during the early onset of alcoholic acute pancreatitis (AP) has not been fully evaluated. We investigated the ability of acinar cells to generate pro- and anti-inflammatory mediators, including inflammasome-associated IL-18/caspase-1, and evaluated acinar cell necrosis in an animal model of AP and human samples. Rats were fed either an ethanol-containing or control diet for 14 weeks and killed 3 or 24 h after a single lipopolysaccharide (LPS) injection. Inflammasome components and necro-inflammation were evaluated in acinar cells by immunofluorescence (IF), histology, and biochemical approaches. Alcohol exposure enhanced acinar cell-specific production of TNFα, IL-6, MCP-1 and IL-10, as early as 3 h after LPS, whereas IL-18 and caspase-1 were evident 24 h later. Alcohol enhanced LPS-induced TNFα expression, whereas blockade of LPS signaling diminished TNFα production in vitro, indicating that the response of pancreatic acinar cells to LPS is similar to that of immune cells. Similar results were observed from acinar cells in samples from patients with acute/recurrent pancreatitis. Although morphologic examination of sub-clinical AP showed no visible signs of necrosis, early loss of pancreatic HMGB1 and increased systemic levels of HMGB1 and LDH were observed, indicating that this strong systemic inflammatory response is associated with little pancreatic necrosis. These results suggest that TLR-4-positive acinar cells respond to LPS by activating the inflammasome and producing pro- and anti-inflammatory mediators during the development of mild, sub-clinical AP, and that these effects are exacerbated by alcohol injury.
    Cell Death & Disease 10/2013; 4(10):e816. DOI:10.1038/cddis.2013.354 · 5.18 Impact Factor