Markus W Buchler

University of Liverpool, Liverpool, England, United Kingdom

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Publications (96)402.54 Total impact

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    ABSTRACT: BACKGROUND: Two recent genome-wide association studies (GWAS) of pancreatic ductal adenocarcinoma (PDAC), conducted respectively in a Japanese and in a Chinese population, identified eight novel loci affecting PDAC risk. METHODS: We attempted to replicate the novel loci in a series of PDAC and healthy controls of European ancestry in the context of the newly formed PANcreatic Disease ReseArch (PANDoRA) consortium. We genotyped seven single nucleotide polymorphisms (SNPs): rs12413624, rs1547374, rs372883, rs5768709, rs6464375, rs708224, rs9502893 (one SNP identified in the Chinese GWAS is not polymorphic in Caucasians) in 1299 PDAC cases and 2884 controls. We also attempted stratified analysis considering the different stages of the disease and addressed the possible involvement of the selected SNPs on the survival of patients. RESULTS: None of the SNPs were significantly associated with PDAC risk if considering the overall population of the consortium. When stratifying for country of origin we found that in the Polish subgroup the G allele of rs372883 was statistically significantly associated with increased risk (OR=6.40; CI 95% 2.28-17.91). However the sample size of the subgroups was rather small, therefore this result can be due to chance. None of the SNPs was associated with disease progression or survival. Conclusions and Impact: None of the SNPs associated with PDAC risk in two Asian populations were convincingly associated with PDAC risk in individuals of European descent. This study illustrates the importance of evaluation of PDAC risk markers across ethnic groups.
    Cancer Epidemiology Biomarkers &amp Prevention 12/2012; · 4.56 Impact Factor
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    ABSTRACT: BACKGROUND: The investigational oral DNA vaccine VXM01 targets the vascular endothelial growth factor receptor 2 (VEGFR-2) and uses Salmonella typhi Ty21a as a vector. The immune reaction elicited by VXM01 is expected to disrupt the tumor neovasculature and, consequently, inhibit tumor growth. VXM01 potentially combines the advantages of anti-angiogenic therapy and active immunotherapy. METHODS: This phase I trial examines the safety, tolerability, and immunological and clinical responses to VXM01. The randomized, placebo-controlled, double blind dose-escalation study includes up to 45 patients with locally advanced and stage IV pancreatic cancer. The patients will receive four doses of VXM01 or placebo in addition to gemcitabine as standard of care. Doses from 106 cfu up to 1010 cfu of VXM01 will be evaluated in the study. An independent data safety monitoring board (DSMB) will be involved in the dose-escalation decisions. In addition to safety as primary endpoint, the VXM01-specific immune reaction, as well as clinical response parameters will be evaluated. DISCUSSION: The results of this study shall provide the first data regarding the safety and immunogenicity of the oral anti-VEGFR-2 vaccine VXM01 in cancer patients. They will also define the recommended dose for phase II and provide the basis for further clinical evaluation, which may also include additional cancer indications.Trial registrationEudraCT No.: 2011-000222-29, NCT01486329, ISRCTN68809279.
    BMC Cancer 08/2012; 12(1):361. · 3.33 Impact Factor
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    ABSTRACT: The non-ABC transport protein RalBP1 has been shown to be overexpressed in various cancer cell lines and implicated in the process of metastasis formation, but its expression in tissue samples and prognostic significance has not been shown. In this study matched tumor-mucosa tissue samples from 78 CRC patients were investigated. The RalBP1 mRNA and protein levels were quantified by real-time quantitative PCR (qPCR) and ELISA. RalBP1 was found to be overexpressed in tumor at the mRNA level both overall (p = 0.027), and for stages I (p = 0.024), II (p = 0.038) and IV (p = 0.004). At the protein level, RalBP1 was only significantly overexpressed in stage IV patients (p = 0.018). Expression of RalBP1 mRNA and protein were inversely correlated (r = 0.4173; p = 0.0004). Multivariate Cox regression analysis including sex, age, stage, grade, and nodal status as covariates showed that overexpression of RalBP1 protein, but not mRNA, was an independent predictor of both decreased disease free survival (p = 0.016, RR = 6.892) and overall survival (p = 0.039, RR = 5.986). These results suggest that RalBP1 protein is an independent predictor of poor survival and early relapse for CRC patients. Owing to its multifunctional intermediary role in cell survival, chemotherapeutic resistance, and metastasis formation, RalBP1 represents a promising novel therapeutic target.
    Cancer biology & therapy 06/2012; 13(8):694-700. · 3.29 Impact Factor
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    ABSTRACT: Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms. The study included 1072 patients who had undergone previous surgery for their cancer and for which at least 2 years of follow-up from 1990 to 2007 was available. Data on 28 variables were collected, and the performance of the two TNM staging systems was compared by Cox regression analysis and multivariable analyses. All statistical tests were two-sided. Differences in distribution of sex and age were observed for the ENETS TNM staging system. At Cox regression analysis, only the ENETS TNM staging system perfectly allocated patients into four statistically significantly different and equally populated risk groups (with stage I as the reference; stage II hazard ratio [HR] of death = 16.23, 95% confidence interval [CI] = 2.14 to 123, P = .007; stage III HR of death = 51.81, 95% CI = 7.11 to 377, P < .001; and stage IV HR of death = 160, 95% CI = 22.30 to 1143, P < .001). However, the UICC/AJCC/WHO 2010 TNM staging system compressed the disease into three differently populated classes, with most patients in stage I, and with the patients being equally distributed into stages II-III (statistically similar) and IV (with stage I as the reference; stage II HR of death = 9.57, 95% CI = 4.62 to 19.88, P < .001; stage III HR of death = 9.32, 95% CI = 3.69 to 23.53, P = .94; and stage IV HR of death = 30.84, 95% CI = 15.62 to 60.87, P < .001). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second most effective independent predictor of survival in the absence of staging information. Though both TNM staging systems were independent predictors of survival, the UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability. Our data suggest the ENETS TNM staging system is superior to the UICC/AJCC/WHO 2010 TNM staging system and supports its use in clinical practice.
    CancerSpectrum Knowledge Environment 04/2012; 104(10):764-77. · 14.07 Impact Factor
  • Pancreas 01/2012; 41(8):1390-1390. · 2.95 Impact Factor
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    ABSTRACT: PURPOSE: Extralevator abdominoperineal resection (APR) for low rectal cancer has been adopted by centers to improve oncological outcome. The present study aimed to investigate oncological results, wound complications, and quality of life (QoL). METHODS: Patients who underwent extralevator APR for rectal cancer between 2007 and 2011 were identified retrospectively. QoL status was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-CR30 and CR29 questionnaires. RESULTS: Thirty laparoscopic (n = 7) or open (n = 23) extralevator APRs were performed in 17 male and 13 female patients. The mortality was zero; circumferential margin involvement occurred in two cases (6.7 %); and there was no bowel perforation. No local recurrence was noted after a median follow-up of 28.3 months; however, six patients died, and eight developed distant metastases. Perineal wound complications were found in 46.6 % of patients, and all were managed conservatively. Fifty percent of the patients reported persistent perineal pain at the follow-up exam. QoL was assessed 7 to 46 months after surgery, and the global health status (70.6) was comparable to the EORTC reference group and published conventional APR series. The QLQ-CR29 module revealed high mean symptom scores for urinary frequency (48.1), incontinence (30.5), and impotence (79.1). CONCLUSIONS: Extralevator APR can control local recurrence but not distant metastases of low rectal cancer. The extended perineal resection appears not to decrease general QoL, but it results in a high rate of perineal wound complications. Genitourinary functions are often impaired, even in the long term, and further improvements to the technique must seek to reduce genitourinary harm.
    Int J Colorectal Dis. 01/2012;
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    ABSTRACT: The surgical approach to benign goiter is becoming increasingly radical due to the risk of recurrent goiter. The aim of this prospective study was to evaluate the impact of surgery on health-related quality of life (HRQoL) of patients with benign goiter. HRQoL data from 115 patients with benign goiter were analyzed. Thirty-three patients (group 1) had a hemithyroidectomy. Sixty-five patients (group 2) had a so-called Dunhill operation (hemithyroidectomy + near-total thyroidectomy of the opposite side), and in 17 patients, a total resection of the goiter was performed. The validated HRQoL instrument, the EuroQol-5D, was applied to measure the health-related quality of life. With an overall complication rate of 10% and no permanent recurrent laryngeal nerve palsy, it was shown that surgery for benign goiter is safe. In the validated HRQoL questionnaire (EQ-5D), no significant variance could be found between different surgical procedures such as thyroidectomy, hemithyroidectomy, or Dunhill procedure. Further, no significant differences in QoL were found in EQ-5D questionnaire compared to normal population. Thyroid surgery can be done safely and without impairment of life quality, regardless of the extent of the operation.
    Langenbeck s Archives of Surgery 08/2011; 396(8):1157-63. · 1.89 Impact Factor
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    ABSTRACT: Due to the increase of cardiovascular diseases acetylsalicylic acid (ASA) has become one of the most frequently prescribed drugs these days. Despite the rising number of patients with ASA medication presenting for elective general and abdominal surgery and the potentially increased risk of hemorrhage in these patients, there are no clear, evidence-based guidelines for the perioperative use of antiplatelet agents. The present randomised controlled trial was designed to evaluate the safety and optimize the use of ASA in the perioperative management of patients undergoing general and abdominal surgery. This is a two-arm, monocenter randomised controlled trial. Patients scheduled for elective surgical treatment (i.e. inguinal hernia repair, cholecystectomy and colorectal resections) with ASA as a permanent medication are randomised equally to perioperative continuation or discontinuation of ASA. Patients who are randomised in the discontinuation group stop the administration of ASA five days prior to surgical treatment and start intake of ASA on postoperative day 5. Fifty-two patients will be enrolled in this trial. The primary outcome is the incidence of postoperative bleeding and cardiovascular events at 30 days after surgery. In addition a set of general as well as surgical variables are analysed. This is a randomised controlled two-group parallel trial designed to assess the safety and optimize the use of ASA in the perioperative management of patients undergoing general and abdominal surgery. The results of this pilot study build the basis for a confirmative randomised controlled trial that may help to clarify the use and potential risk/benefits of perioperative ASA medication in patients undergoing elective surgery. The trial is registered with Current Controlled Trials ISRCTN45810007.
    BMC Surgery 03/2011; 11:7. · 1.97 Impact Factor
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    ABSTRACT: Despite spontaneous or vaccination-induced immune responses, pancreatic cancer remains one of the most deadly immunotherapy-resistant malignancies. We sought to comprehend the spectrum of pancreatic tumor-associated antigens (pTAAs) and to assess the clinical relevance of their immunogenicity. An autologous SEREX-based screening of a cDNA library constructed from a pancreatic T3N0M0/GIII specimen belonging to a long-term survivor (36 months) revealed 18 immunogenic pTAA. RT-PCR analysis displayed broad distribution of the identified antigens among normal human tissues. PNLIPRP2 and MIA demonstrated the most distinct pancreatic cancer-specific patterns. ELISA-based screening of sera for corresponding autoantibodies revealed that although significantly increased, the immunogenicity of these molecules was not a common feature in pancreatic cancer. QRT-PCR and immunohistochemistry characterized PNLIPRP2 as a robust acinar cell-specific marker whose decreased expression mirrored the disappearance of parenchyma in the diseased organ, but was not related to the presence of PNLIPRP2 autoantibodies. Analyses of MIA-known to be preferentially expressed in malignant cells-surprisingly revealed an inverse correlation between intratumoral gene expression and the emergence of autoantibodies. MIA(high) patients were autoantibody-negative and had shorter median survival when compared with autoantibody-positive MIA(low) patients (12 vs. 34 months). The observed pTAA spectrum comprised molecules associated with acinar, stromal and malignant structures, thus presenting novel targets for tumor cell-specific therapies as well as for approaches based on the bystander effects. Applying the concept of cancer immunoediting to interpret relationships between gene expression, antitumor immune responses, and clinical outcome might better discriminate between past and ongoing immune responses, consequently enabling prognostic stratification of patients and individual adjustment of immunotherapy.
    Cancer Immunology and Immunotherapy 09/2010; 59(9):1389-400. · 3.64 Impact Factor
  • Zeitschrift Fur Gastroenterologie - Z GASTROENTEROL. 01/2010; 48(08).
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    ABSTRACT: Esophagectomy with reconstruction by collar anastomosis has an impact on the patients quality of life (QOL). The aim of this study was to explore a potential difference in QOL between elective and emergency esophagectomy with collar reconstruction. Quality of life questionnaires were evaluated in 17 patients prior to esophagectomy, shortly after surgery, hospital discharge, and at least > 9 months after surgery using the EORTC QLQ C30 and EORTC OES 18 forms. In all patients reconstruction was per-formed by high collar anastomosis. Patients in group A received elective esophageal resection. In group B emergency esophagectomy was performed because of esophageal perforation for various reasons apart from cancer. In this group, delayed reconstruction was performed in a second operation 3-6 months after esophagectomy. There was a temporary decrease of postoperative QOL in both groups, which re-turned to preoperative values in the follow-up except for physical functioning, which remained decreased in group A (p < 0,05). There were no persisting differences in QOL after elective and emergency esophagectomy in the follow-up. Patients with elective and emergency esophagectomy and reconstruction by high collar anastomosis gained a good long-term QOL in our cohort of patients. This gives evidence that the observed QOL after elective resection of esophageal cancer is not only caused by a relief of cancer burden, but also due to a surgical procedure which is able to provide a good long-term QOL.
    Scandinavian journal of surgery: SJS: official organ for the Finnish Surgical Society and the Scandinavian Surgical Society 01/2010; 99(1):3-8. · 1.17 Impact Factor
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    ABSTRACT: BACKGROUND: A recently published systematic review indicated superiority of duodenum-preserving techniques when compared with pancreatoduodenectomy, for the treatment of patients with chronic pancreatitis in the head of the gland. A multicentre randomised trial to confirm these results is needed. METHODS/DESIGN: ChroPac aims to investigate differences in quality of life, mortality and morbidity during 24 months after surgery (duodenum-preserving pancreatic head resection versus pancreatoduodenectomy) in patients with chronic pancreatitis of the pancreatic head. ChroPac is a randomised, controlled, observer and patient blinded multicentre surgical trial with two parallel comparison groups. The primary outcome measure will be the average quality of life during 24 months after surgery. Statistical analysis is based on the intention-to-treat population. Analysis of covariance will be applied for the intervention group comparison adjusting for age, centre and quality of life before surgery. Level of significance is set at 5% (two-sided) and sample size (n = 100 per group) is determined to assure a power of 90%. DISCUSSION: The ChroPac trial will explore important outcomes from different perspectives (e.g. surgeon, patient, health care system). Its pragmatic approach promises high external validity allowing a comprehensive evaluation of the surgical strategy for treatment of patients with chronic pancreatitis. TRIAL REGISTRATION: Controlled-trials.com ISRCTN38973832.
    Trials. 01/2010; 11:47.
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    ABSTRACT: Renin-angiotensin system blockade retards the progression of diabetic and non-diabetic chronic kidney disease of the native kidneys. Though most patients suffer from a significant renal insufficiency (chronic kidney disease stage III) and a concomitant heart disease after renal transplantation, there is up to now no evidence supporting the use of inhibitors of the renin-angiotensin system in these patients. We wish to summarize the available evidence on the use of inhibitors of the renin-angiotensin system after renal transplantation. We specifically discuss potential beneficial as well as adverse effects of a renin-angiotensin system blockade. In addition, we review their influence on morphologic and biochemical markers as well as on renal function, graft and patient survival after renal transplantation.
    Clinical Transplantation 12/2009; 23 Suppl 21:33-6. · 1.63 Impact Factor
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    ABSTRACT: The outcome of simultaneous pancreas-kidney (SPK) transplantation in type 1 diabetes has dramatically improved in recent years because of optimized surgical techniques and new immunosuppressive drug regimens. Normoglycemia is followed by stabilization or even regression of diabetic lesions, i.e., of heart and kidneys. However, these effects are only visible after more than five yr of normoglycemia (achieved by a functioning allograft). This is also a likely explanation for the conflicting results of studies that investigated patient or kidney graft survival in SPK transplantation compared to kidney transplantation alone. Most studies had too short follow-up periods, i.e., less than five yr, to compare effectively different transplant strategies in patients with type 1 diabetes and therefore failed to discover a survival benefit in favor of simultaneously transplanted patients. Recent data now indicate that, with a longer follow-up, there is an increasing survival benefit for simultaneously transplanted patients compared to patients who received a single kidney transplant. This is paralleled by the comparison of simultaneously transplanted patients to patients who received a single kidney transplant from a living donor. A survival benefit for the combined procedure was here visible after 10 yr of follow-up. We give a short overview on SPK transplantation, with a focus on the effects of this procedure on diabetic complications as well as patient and kidney graft survival.
    Clinical Transplantation 12/2009; 23 Suppl 21:115-20. · 1.63 Impact Factor
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    ABSTRACT: The purpose of this study is to analyze the pooled results of multimodality treatment of locally advanced rectal cancer (LARC) in four major treatment centers with particular expertise in intraoperative radiotherapy (IORT). A total of 605 patients with LARC who underwent multimodality treatment up to 2005 were studied. The basic treatment principle was preoperative (chemo)radiotherapy, intended radical surgery, IORT and elective adjuvant chemotherapy (aCT). In uni- and multivariate analyses, risk factors for local recurrence (LR), distant metastases (DM) and overall survival (OS) were studied. Chemoradiotherapy lead to more downstaging and complete remissions than radiotherapy alone (P < 0.001). In all, 42% of the patients received aCT, independent of tumor-node-metastasis stage or radicality of the resection. LR rate, DM rate and OS were 12.0%, 29.2% and 67.1%, respectively. Risk factors associated with LR were no downstaging, lymph node (LN) positivity, margin involvement and no postoperative chemotherapy. Male gender, preoperatively staged T4 disease, no downstaging, LN positivity and margin involvement were associated with a higher risk for DM. A risk model was created to determine a prognostic index for individual patients with LARC. Overall oncological results after multimodality treatment of LARC are promising. Adding aCT to the treatment can possibly improve LR rates.
    Annals of Oncology 11/2009; 21(6):1279-84. · 7.38 Impact Factor
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    ABSTRACT: A prospective study to determine the value of multidetector CT (MD-CT) in assessing the course of nonresectable pancreatic carcinoma during therapy. 26 patients with nonresectable pancreatic carcinoma underwent MD-CT before and after therapy. The examinations were evaluated with regard to tumor size and vascular invasion using an invasion score (IS) by 2 radiologists independently (kappa analysis). Diagnosis was confirmed surgically, by biopsy or clinical course. Sensitivity for the assessment of irresectability was 100%. Following therapy, 54% of all the tumors were smaller (14/26), 42% had increased in volume (11/26), and one tumor remained stable (1/26). The IS (veins) during follow-up changed in 26 patients (portal vein: 5 higher (mean score 10.4/16.2), 4 lower (mean score 17.5/11.5); superior mesenteric vein: 12 higher (11/14.4), 5 lower (16.2/14.6); p = 0.026). The IS (arteries) changed in 13 patients (celiac trunk: 3 higher (3.3/10); hepatic artery: 4 higher (5.7/10.2), 3 lower (11.6/10.3); superior mesenteric artery: 2 higher (4.5/9.5), 1 lower (12/11)). The kappa values were calculated between 0.56 and 0.87. MD-CT is suitable for evaluating tumor spread during therapy for nonresectable pancreatic carcinoma. The IS is useful for assessing the degree of change in vessel invasion.
    Pancreatology 09/2009; 9(5):621-30. · 2.04 Impact Factor
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    ABSTRACT: Microcirculatory disturbances are known to play a pivotal role in the pathogenesis of severe necrotizing pancreatitis (SNP). Calcitonin gene-related peptide (CGRP) is a vasodilatatory neuropeptide with potential anti-inflammatory effects. This study characterizes the protective effects and the anti-inflammatory pathway of exogenous CGRP in SNP. SNP was induced in rats using the glycodeoxycholic acid model. CGRP was injected prophylactically before or therapeutically after initiation of the disease. Pancreatic damage was assessed using intravital microscopy, histology, NF-kappaB p50/p65 electrophoretic mobility shift assay, serum cytokine assay and ICAM-1 immunohistochemistry at 6 or 12 h after the onset of disease. Pancreatic microcirculatory disturbances, nuclear NF-kappaB levels and pancreatic ICAM-1 expression were increased in SNP compared to controls. After CGRP application, microcirculatory disturbances, NF-kappaB levels and pancreatic ICAM-1 expression were attenuated compared to pancreatitis alone. Moreover, pancreatic morphologic damage was significantly reduced by both prophylactic and therapeutic application of CGRP. CGRP is a neuropeptide that ameliorates the development of SNP in rats and may provide new treatment options. Its anti-inflammatory effects appear to be mediated by the modulation of pancreatic microcirculation and the inflammatory cascade.
    Pancreatology 09/2009; 9(5):662-9. · 2.04 Impact Factor
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    ABSTRACT: We analyzed our experience with intraoperative electron radiotherapy (IOERT) followed by moderate doses of external beam radiotherapy (EBRT) after organ-sparing surgery in patients with primary or recurrent aggressive fibromatosis. Indication for IOERT and postoperative EBRT as an individual treatment approach to avoid mutilating surgical procedures was seen when complete surgical removal seemed to be unlikely or impossible. A total of 31 lesions in 30 patients were treated by surgery and IOERT with a median dose of 12 Gy. Median age was 31 years (range, 13-59 years). Resection status was close margin in six lesions, microscopically positive in 13, and macroscopically positive in 12. Median tumor size was 9 cm. In all, 25 patients received additional EBRT, with a median dose of 45 Gy (range, 36-54 Gy). After a median follow-up of 32 months (range, 3-139 months), no disease-related deaths occurred. A total of five local recurrences were seen, resulting in actuarial 3-year local control rates of 82% overall and 91% inside the IOERT areas. Trends to improved local control were seen for older age (>31 years) and negative margins, but none of these factors reached significance. Perioperative complications were found in six patients, in particular as wound healing disturbances in five patients and venous thrombosis in one patient. Late toxicity was seen in five patients. Introduction of IOERT into a multimodal treatment approach in patients with aggressive fibromatosis is feasible with low toxicity and yielded good local control rates even in patients with microscopical or gross residual disease.
    International journal of radiation oncology, biology, physics 07/2009; 76(4):1154-60. · 4.59 Impact Factor
  • Fuel and Energy Abstracts 01/2009; 75(3).
  • M. N. Wente, M. W. Buchler
    Archives of Surgery - ARCH SURG. 01/2009; 144(6):581-581.

Publication Stats

2k Citations
402.54 Total Impact Points

Institutions

  • 2012
    • University of Liverpool
      • Cancer Research Centre
      Liverpool, England, United Kingdom
  • 2006–2007
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
  • 2003–2006
    • Universität Heidelberg
      • • Department of Spine Surgery
      • • Institute of Pathology (Mannheim)
      • • Department of Pathology
      Heidelberg, Baden-Wuerttemberg, Germany
    • Southeast University (China)
      Nan-ching-hsü, Jiangxi Sheng, China
    • Peking Union Medical College Hospital
      • Department of General Surgery
      Beijing, Beijing Shi, China
  • 2005
    • University of Verona
      Verona, Veneto, Italy
  • 2001
    • General Hospital of Shenyang Military Region
      Feng-t’ien, Liaoning, China
  • 1994–1996
    • Inselspital, Universitätsspital Bern
      Berna, Bern, Switzerland
  • 1993–1995
    • University of California, Irvine
      • Department of Medicine
      Irvine, CA, United States
    • Cleveland Clinic
      • Department of Cancer Biology
      Cleveland, OH, United States