Jan Harder

University of Freiburg, Freiburg, Baden-Württemberg, Germany

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Publications (31)110.62 Total impact

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    ABSTRACT: To investigate the expression and clinical relevance of inhibitor of differentiation (ID) proteins in biliary tract cancer. ID protein expression was analyzed in 129 samples from patients with advanced biliary tract cancer (BTC) (45 extrahepatic, 50 intrahepatic, and 34 gallbladder cancers), compared to normal controls and correlated with clinical an pathological parameters. ID1-3 proteins are frequently overexpressed in all BTC subtypes analyzed. No correlation between increased ID protein expression and tumor grading, tumor subtype or treatment response was detected. Survival was influenced primary tumor localization (extrahepatic vs intrahepatic and gall bladder cancer, OS 1.5 years vs 0.9 years vs 0.7 years, P = 0.002), by stage at diagnosis (OS 2.7 years in stage I vs 0.6 years in stage IV, P < 0.001), resection status and response to systemic chemotherapy. In a multivariate model, ID protein expression did not correlate with clinical prognosis. Nevertheless, there was a trend of shorter OS in patients with loss of cytoplasmic ID4 protein expression (P = 0.076). ID protein expression is frequently deregulated in BTC but does not influence clinical prognosis. Their usefulness as prognostic biomarkers in BTC is very limited.
    World Journal of Gastroenterology 12/2013; 19(48):9334-42. DOI:10.3748/wjg.v19.i48.9334 · 2.37 Impact Factor
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    ABSTRACT: Unresectable cholangiocarcinoma (CCC) has a poor prognosis. Patients with intrahepatic CCC have a very limited benefit from systemic chemotherapy (ChT). The aim of this prospective study was to evaluate the feasibility, safety, and efficacy of conventional transarterial chemoembolization (cTACE) with mitomycin-C and of irinotecan-eluting beads (iDEB-TACE), and to retrospectively compare them with ChT with oxaliplatin and gemcitabine. Between June 2002 and June 2010, three independent prospective trials were carried out and compared retrospectively. Following predefined study protocols, 26 patients with histologically proven intrahepatic CCC were treated with iDEB-TACE (200 mg irinotecan), 10 patients were treated with cTACE using 15 mg mitomycin-C mixed with 5-10 ml of ionized oil (lipiodol), followed by embolization with gelfoam, and 31 patients received systemic ChT with gemcitabine and oxaliplatin. Treatment response and progression-free survival (PFS) were assessed by computer tomography or MRI every 2 months according to Response Evaluation Criteria in Solid Tumors. Clinical and laboratory data were assessed for side-effects according to National Cancer Institute-Common Toxicity Criteria. iDEB-TACE resulted in PFS of 3.9 months and overall survival (OS) of 11.7 months, compared with a PFS of 1.8 months and OS of 5.7 months, respectively, in patients treated with cTACE, and a PFS of 6.2 months and OS of 11.0 months, respectively, in patients treated with oxaliplatin and gemcitabine. The medium follow-up of patients treated with iDEB-TACE was 12 months; 2 months after treatment, 13 patients (50%) had progressive disease, 11 patients (42%) had stable disease, and one patient had a partial response and became eligible for secondary liver resection. Local tumor control was achieved in 66% of patients; 4% had a partial response, 62% had stable disease, and 27% progressive disease. Common Toxicity Criteria grade III or IV toxicities for iDEB-TACE were abdominal pain (n=7), hepatic abscess (n=1), pleural empyema due to biliary leakage (n=1), and one death due to cholangitis with hepatic failure in a patient with liver cirrhosis. No hematological side-effects were observed. Almost every patient experienced a 'postembolization syndrome' with low-grade fever, nausea, and abdominal pain for up to 2 weeks. This is the first study demonstrating that treatment of patients suffering from intrahepatic CCC with iDEB-TACE is safe in patients with normal liver function, and results in a prolongation of PFS and OS. Local tumor control, PFS and OS seem similar to systemic ChT with oxaliplatin and gemcitabine, but superior to cTACE.
    European journal of gastroenterology & hepatology 04/2012; 24(4):437-43. DOI:10.1097/MEG.0b013e3283502241 · 2.25 Impact Factor
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    ABSTRACT: Adjuvant chemotherapy for 6 months is the current standard of care after potentially curative resection of pancreatic cancer and yields an overall survival of 15-20 months. Early tumor recurrence before or during adjuvant chemotherapy has not been evaluated so far. These patients may not benefit from adjuvant treatment. Thirty-five patients with resection of ductal pancreatic carcinoma and adjuvant chemotherapy with gemcitabine were analyzed between 2005 and 2007. All patients had a computed tomography (CT) scan before and during adjuvant chemotherapy after 2-3 months, 12/35 patients had a histologically confirmed R1 resection. Recurrence of pancreatic cancer was determined by CT scan and the clinical course. Median survival of 35 patients with resected pancreatic cancer was 19.7 months, and the 2-year survival was 44%. Thirteen (37%) of the 35 patients analyzed with a CT scan showed tumor recurrence during adjuvant chemotherapy. Overall survival of patients with tumor recurrence was 9.3 months with a 2-year survival rate of 13%, whereas median overall survival of patients without early relapse was 26.3 months (P<0.001). Local recurrence of pancreatic cancer occurred in 38% (5/13); 46% (6/13) of patients developed distant metastasis, and 38% (5/13) developed lymph node metastasis. Early tumor recurrence during or adjuvant chemotherapy did not correlate with R status (R1 vs R0, P=0.69), whereas histologically confirmed lymph node invasion (pN0 vs pN1) and grading showed a statistically significant correlation with early relapse (P<0.05). A significant fraction of patients with resected pancreatic cancer have early relapse during adjuvant chemotherapy, especially those with lymph node metastasis. Radiologic examinations prior to and during adjuvant chemotherapy will help to identify patients with tumor recurrence who are unlikely to benefit from adjuvant treatment and will need individualized palliative chemotherapy.
    Saudi Journal of Gastroenterology 03/2012; 18(2):118-21. DOI:10.4103/1319-3767.93815 · 1.12 Impact Factor
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    ABSTRACT: Auron Misheil Therapy was developed based on similarities between carcinogenesis and inflammation. Auron Misheil Therapy is a combination of natural and synthetic compounds, including anti-inflammatory drugs and insulin, expected to exhibit synergistic effects. Here, we report the case of a 78-year-old Caucasian male patient who presented with multifocal hepatocellular carcinoma and chronic hepatitis C virus infection. Over a four-year period our patient was treated with radiofrequency ablation and transarterial chemoembolization. After these treatments there was tumor progression, with new hyperperfused lesions without evidence of extrahepatic tumor involvement. Our patient refused sorafenib therapy. Therefore, he received twice daily intramuscular injections of Auron Misheil Therapy on an outpatient basis for two months. Partial remission of the hepatic lesions was observed eight weeks after the start of treatment, and confirmed four weeks later. Unfortunately, at that time our patient refused therapy due to dizziness. During follow-up two target lesions remained stable, but one lesion increased in size. At the latest follow-up, one year later, there was still tumor control. While the mechanisms underlying the antitumor effects of Auron Misheil Therapy are not fully understood, stable disease and remissions have been observed in different types of tumors, including hepatocellular carcinoma.
    Journal of Medical Case Reports 09/2011; 5:478. DOI:10.1186/1752-1947-5-478
  • MJ Fuchs · A Schmitt-Graeff · J Hasskarl · V Gumpp · OG Opitz · J Harder ·

    Zeitschrift für Gastroenterologie 08/2011; 49(08). DOI:10.1055/s-0031-1285571 · 1.05 Impact Factor
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    ABSTRACT: Diagnosis of acute intestinal GVHD (aGVHD) following allogeneic hematopoietic cell transplantation is based on clinical symptoms and histological lesions. This retrospective analysis aimed to validate the 'Freiburg Criteria' for the endoscopic grading of intestinal aGVHD. Grade 1: no clear-cut criteria; grade 2: spotted erythema; grade 3: aphthous lesions; and grade 4: confluent defects, ulcers, denudation of the mucosa. Having excluded patients with infectious diarrhea, we evaluated 175 consecutive patients between January 2001 and June 2009. Setting a cutoff between grade 1 (no change in therapy) and grade 2 (intensification of immunosuppression), macroscopy had a sensitivity of 89.2% (95% confidence interval (CI): 80.4-94.9%), a specificity of 79.4% (95% CI: 69.6-87.1%), a positive-predictive value of 79.6% (95% CI: 70.0-87.2%) and a negative-predictive value of 89.0% (95% CI: 80.2-94.9%). In all, 20% of patients with aGVHD in the lower gastrointestinal tract (GIT) had lesions only in the terminal ileum. In all patients with aGVHD ≥2 of the upper GIT, typical lesions were also found in the lower GIT. Ileo-colonoscopy showed the highest diagnostic yield for aGVHD. In conclusion, the 'Freiburg Criteria' for macroscopic diagnosis of intestinal aGVHD provide high accuracy for identifying aGVHD ≥2.
    Bone marrow transplantation 06/2011; 47(3):430-8. DOI:10.1038/bmt.2011.137 · 3.57 Impact Factor
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    ABSTRACT: Telomerase plays an important role during immortalization and malignant transformation as crucial steps in the development of human cancer. In a cellular model of oral-esophageal carcinogenesis, recapitulating the human disease, immortalization occurred independent of the activation of telomerase but through the recombination-based alternative lengthening of telomeres (ALT). In this stepwise model, additional overexpression of EGFR led to in vitro transformation and activation of telomerase with homogeneous telomere elongation in already immortalized oral squamous epithelial cells (OKF6-D1_dnp53). More interestingly, EGFR overexpression activated the PI3K/AKT pathway. This strongly suggested a role for telomerase in tumor progression in addition to just elongating telomeres and inferring an immortalized state. Therefore, we sought to identify the regulatory mechanisms involved in this activation of telomerase and in vitro transformation induced by EGFR. In the present study we demonstrate that telomerase expression and activity are induced through both direct phosphorylation of hTERT by phospho-AKT as well as PI3K-dependent transcriptional regulation involving Hif1-alpha as a key transcription factor. Furthermore, EGFR overexpression enhanced cell cycle progression and proliferation via phosphorylation and translocation of p21. Whereas immortalization was induced by ALT, in vitro transformation was associated with telomerase activation, supporting an additional role for telomerase in tumor progression besides elongating telomeres.
    Cancer Science 02/2011; 102(2):351-60. DOI:10.1111/j.1349-7006.2010.01796.x · 3.52 Impact Factor
  • F Makowiec · H Neeff · O Drognitz · J Harder · R Thimme · UT Hopt ·

    Zeitschrift für Gastroenterologie 01/2010; 48(01). DOI:10.1055/s-0029-1246481 · 1.05 Impact Factor

  • Zeitschrift für Gastroenterologie 09/2009; 47(09). DOI:10.1055/s-0029-1241601 · 1.05 Impact Factor
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    ABSTRACT: To analyze the pathogenetic role and potential clinical usefulness of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2) in patients with advanced biliary tract cancer (BTC). EGFR and HER2 expression was studied in biopsy samples from 124 patients (51% women; median age 64.8 years), with advanced BTC diagnosed between 1997 and 2004. Five micrometers sections of paraffin embedded tissue were examined by standard, FDA approved immunohistochemistry. Tumors with scores of 2+ or 3+ for HER2 expression on immunochemistry were additionally tested for HER2 gene amplification by fluorescence in situ hybridisation (FISH). 34/124 patients (27.4%) had gallbladder cancer, 47 (37.9%) had intrahepatic BTC and 43 (34.7%) had extrahepatic or perihilar BTC. EGFR expression was examined in a subset of 56 samples. EGFR expression was absent in 22/56 tumors (39.3%). Of the remaining samples expression was scored as 1+ in 12 (21.5%), 2+ in 13 (23.2%) and 3+ in 9 (16%), respectively. HER2 expression was as follows: score 0 73/124 (58.8%), score 1+ 27/124 (21.8%), score 2+ 21/124 (17%) and score 3+ 4/124 (3.2%). HER2 gene amplification was present in 6/124, resulting in an overall amplification rate of 5%. Our data suggest that routine testing and therapeutic targeting of HER2 does not seem to be useful in patients with BTC, while targeting EGFR may be promising.
    World Journal of Gastroenterology 09/2009; 15(36):4511-7. · 2.37 Impact Factor
  • J. Harder · R. Grotelüschen · J.S. Kim · J. Izbicki ·
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    ABSTRACT: Cholangiokarzinome oder cholangiozelluläre Karzinome (CCC) sind seltene Tumoren des biliären Systems mit einer Inzidenz von 2–4/100.000 Einwohner und pro Jahr. Zu ihnen zählen die perihilären Gallengangskarzinome (Klatskin-Tumoren, mit ca. 60% die häufigste Cholangiokarzinome), die peripheren (intrahepatischen) Cholangiokarzinome, das Gallenblasenkarzinom, die Karzinome der extrahepatischen Gallengänge und das periampulläre Karzinom. Zum Zeitpunkt der Diagnose ist nur bei etwa 30% der Patienten eine chirurgische Resektion als einzige kurative Therapieoption möglich. Die Lebertransplantation ist wegen der hohen Rezidivrate derzeit nur in ausgewählten Einzelfällen indiziert. Die Prognose von nichtresektablen Cholangiokarzinomen ist mit einer mittleren Überlebenszeit von 6–8 Monaten schlecht. Die wichtigste therapeutische Maßnahme im Rahmen der „best supportive care“ ist die Beseitigung der Cholestase (endoskopisch, perkutan oder chirurgisch), um einer Cholangitis oder Cholangiosepsis vorzubeugen. Durch eine systemische Chemotherapie lässt sich eine Tumorstabilisierung in ca. 60% der Fälle erreichen. 5-FU und Gemcitabin sind die derzeit am häufigsten eingesetzten Substanzen, mit den besten Ansprechraten, wenn sie mit einem Platinderivat kombiniert werden. Multimodale Therapiekonzepte unter Einbeziehung einer photodynamischen Therapie, einer transarteriellen Chemoembolisation oder einer perkutanen Strahlentherapie können im Einzelfall erfolgreich sein und zu langjähriger Tumorkontrolle führen. Cholangiocellular carcinomas (CCC) are rare tumors with an incidence of 2–4/100,000 per year. They are a heterogeneous group of neoplasias that includes the perihilar or Klatskin tumors (at 60%, the most common of the CCC), the intrahepatic (peripheral) CCC, extrahepatic bile duct cancer, gallbladder cancer, and cancer of the ampulla of Vater. At the time of diagnosis, only 30% of patients are eligible for surgery, which offers the only chance for cure. Due to high recurrence rates, liver transplantation is restricted to select patients with small but nonresectable tumors. Patients with advanced nonresectable carcinoma have a dismal prognosis, with an overall survival of only 6–8months. In inoperable patients, prevention or treatment of cholestasis is the main objective. This can be achieved endoscopically, percutaneously, or by surgical biliodigestive anastomosis. Palliative chemotherapy results in tumor stabilization rates of up to 60%. The most frequently used agents are fluoropyrimidines and gemcitabine in combination with a platin derivative. When different treatment modalities are combined, significant survival can be achieved in some patients.
    Der Gastroenterologe 07/2009; 4(4):312-321. DOI:10.1007/s11377-009-0306-2
  • H Neeff · F Makowiec · J Harder · V Gumpp · A Klock · R Thimme · O Drognitz · U T Hopt ·
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    ABSTRACT: Hepatocellular carcinoma (HCC) is the fifth-leading cause of cancer death world-wide. Although less frequent in Western Europe, its incidence is increasing in this region. Causes involved in the pathogenesis of HCC are, besides viral hepatitis, metabolic and nutritional factors (alcohol, diabetes, obesity). The therapeutic management depends strongly on the initial extent of disease and includes hepatic resection, liver transplantation and local ablation. In this context, we present our results on liver resection for HCC and a discussion of the current literature about (potentially curative) treatment for HCC. From 1999 until 2008 93 patients [83 % male, median age 64 (range: 39-94) years] underwent hepatic resection for HCC. Postoperative follow-up was available in 85 patients [median follow-up: 1.2 (0.25-8) years]. In contrast to data, especially from Asia, a viral hepatitis as the origin of HCC was found in only 28 % of the patients in our series. Half of the patients had proven liver cirrhosis. The median number of intrahepatic tumours was one (1-11), median size of the largest tumour was 55 mm (5-250 mm). 58 % of the HCC were removed by atypical or segmental resection, 42 % of the patients underwent hemihepatectomy or extended -hemihepatectomy. Tumor-free resection margins were -achieved in 95 %. Total postoperative morbidity was 61 %. A reoperation for complications was -necessary in 10 %. Hospital mortality was 8.6 % in the entire study period but decreased from 14.9 % in 1999-2004 to 2.2 % in 2005 to 2008 (p = 0.03). Actuarial survival was 81 % after 1 year, 58 % after 3 years and 26 % after 5 years. The T-stage could be identified tendentially as a prognostic factor influencing survival. With the proper selection of patients, liver resection for HCC may be performed with a curative intention (i. e., free resection margins) in over 90 %. Although it decreased during the study period peri-operative mortality was higher than after resection of other hepatic tumours. Long-term survival in our series was comparable to reports from other European centres.
    Zentralblatt für Chirurgie 05/2009; 134(2):127-35. · 1.05 Impact Factor

  • Gastroenterology 05/2009; 136(5). DOI:10.1016/S0016-5085(09)62124-7 · 16.72 Impact Factor

  • Gastroenterology 05/2009; 136(5). DOI:10.1016/S0016-5085(09)62643-3 · 16.72 Impact Factor

  • Gastroenterology 05/2009; 136(5). DOI:10.1016/S0016-5085(09)62856-0 · 16.72 Impact Factor
  • H. Neeff · F. Makowiec · J. Harder · V. Gumpp · A. Klock · R. Thimme · O. Drognitz · U. Hopt ·

    Zentralblatt für Chirurgie 04/2009; 134(02):127-135. DOI:10.1055/s-0028-1098881 · 1.05 Impact Factor
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    ABSTRACT: Pancreatic cancer is the fourth most common cause of cancer related death in Western countries. Advantages in surgical techniques, radiation and chemotherapy had almost no impact on the long term survival of affected patients. Therefore, the need for better treatment strategies is urgent. HER2, a receptor tyrosine kinase of the EGFR family, involved in signal transduction pathways leading to cell growth and differentiation is overexpressed in a number of cancers, including breast and pancreatic cancer. While in breast cancer HER2 has already been successfully used as a treatment target, there are only limited data evaluating the effects of inhibiting HER2 tyrosine kinases in patients with pancreatic cancer. Here we report the design of a prospective, non-randomized multi-centered Phase II clinical study evaluating the effects of the Fluoropyrimidine-carbamate Capecitabine (Xeloda) and the monoclonal anti-HER2 antibody Trastuzumab (Herceptin) in patients with non-resectable, HER2 overexpressing pancreatic cancer. Patients eligible for the study will receive Trastuzumab infusions on day 1, 8 and 15 concomitant to the oral intake of Capecitabine from day 1 to day 14 of each three week cycle. Cycles will be repeated until tumor progression. A total of 37 patients will be enrolled with an interim analysis after 23 patients. Primary end point of the study is to determine the progression free survival after 12 weeks of bimodal treatment with the chemotherapeutic agent Capecitabine and the anti-HER2 antibody Trastuzumab. Secondary end points include patient's survival, toxicity analysis, quality of life, the correlation of HER2 overexpression and clinical response to Trastuzumab treatment and, finally, the correlation of CA19-9 plasma levels and progression free intervals.
    BMC Surgery 02/2009; 9(1):1. DOI:10.1186/1471-2482-9-1 · 1.40 Impact Factor
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    ABSTRACT: Patients with UICC stage II colorectal cancer (CRC) have a risk of approximately 20% to develop disease recurrence after tumour resection. The presence and significance of micrometastases for locoregional recurrence in these patients lacking histopathological lymph node involvement on routine stained HE sections is undefined. Oestrogen receptor (ER) promoter methylation has earlier been identified in CRC. Therefore, we evaluated the methylation status of the ER promoter in lymph nodes from 49 patients with CRC UICC stage I and II as a molecular marker of micrometastases and predictor of local recurrence. DNA from 574 paraffin-embedded lymph nodes was isolated and treated with bisulphite. For the detection of methylated ER promoter sequences, quantitative real-time methylation-specific PCR was used. Of the 49 patients tested, 15 (31%) had ER methylation-positive lymph nodes. Thirteen of those (86%) remained disease free and two (14%) developed local recurrence. In the resected lymph nodes of 34 of the 49 patients (69%), no ER promoter methylation could be detected and none of these patients experienced a local relapse. The methylation status of the ER promoter in lymph nodes of UICC stage I and II CRC patients may be a useful marker for the identification of patients at a high risk for local recurrence.
    British Journal of Cancer 02/2009; 100(2):360-5. DOI:10.1038/sj.bjc.6604859 · 4.84 Impact Factor
  • J. Harder · R. Grotelüschen · J. S. Kim · J. Izbicki ·

    Der Gastroenterologe 01/2009; 4(4):312-321.
  • Jan Harder ·

    World Journal of Gastroenterology 01/2009; 15(36):4511. DOI:10.3748/wjg.15.4511 · 2.37 Impact Factor

Publication Stats

319 Citations
110.62 Total Impact Points


  • 2004-2011
    • University of Freiburg
      • • Institute of Molecular Medicine and Cell Research
      • • Department of Pathology
      Freiburg, Baden-Württemberg, Germany
  • 2008-2009
    • Universitätsklinikum Freiburg
      Freiburg an der Elbe, Lower Saxony, Germany