Michael Ghadimi

Publications (11)44.28 Total impact

• Article: Frequency of HER-2 Positivity in Rectal Cancer and Prognosis.

  Lena-Christin Conradi, Hanna Styczen, Thilo Sprenger, Hendrik A Wolff, Claus Rödel, Manuel Nietert, Kia Homayounfar, Jochen Gaedcke, Julia Kitz, Recca Talaulicar, Heinz Becker, Michael Ghadimi, Peter Middel, Tim Beissbarth, Josef Rüschoff, Torsten Liersch
  [show abstract] [hide abstract]
  ABSTRACT: In patients with advanced rectal cancer (cUICC II and III) multimodality therapy resulted in better long-term local tumor control. Ongoing clinical trials are focusing on therapy intensification to improve disease-free (DFS) and cancer-specific survival (CSS), the integration of biomarkers for prediction of individual recurrence risk, and the identification of new targets. In this context, we investigated HER-2, a member of the epidermal growth factor receptor family, whose expression pattern and role was unclear in rectal cancer. A total of 264 patients (192 male, 72 female; median age 64 y) received standardized multidisciplinary treatment according to protocols of phase II/III trials of the German Rectal Cancer Study Group. HER-2 status was determined in pretherapeutic biopsies and resection specimens using immunohistochemistry scoring and detection of silver in situ hybridization amplification. Tumors with an immunohistochemistry score of 3 or silver in situ hybridization ratios of ≥2.0 were classified HER-2 positive; these results were correlated with clinicopathologic parameters [eg, resection (R) status, nodal status ((y)pN)], DFS, and CSS. Positive HER-2 status was found in 12.4% of biopsies and in 26.7% of resected specimens. With a median follow-up of 46.5 months, patients with HER-2 positivity showed in trend a better DFS (P=0.1) and a benefit in CSS (P=0.03). The 5-year survival rate was 96.0% (HER-2 positive) versus 80.0% (HER-2 negative). In univariate and multivariate analyses, HER-2 was an independent predictor for CSS (0.02) along with the (y)pN status (P<0.00001) and R status (P=0.011). HER-2 amplification is detectable in a relevant proportion (26.7%) of rectal cancer patients. For the development of innovative new therapies, HER-2 may represent a promising target and should be further assessed within prospective clinical trials.
  The American journal of surgical pathology 12/2012; · 4.06 Impact Factor
• Article: Induction Chemotherapy before Chemoradiotherapy and Surgery for Locally Advanced Rectal Cancer

  Claus Rödel, Dirk Arnold, Heinz Becker, Rainer Fietkau, Michael Ghadimi, Ullrich Graeven, Clemens Hess, Ralf Hofheinz, Werner Hohenberger, Stefan Post, Rudolf Raab, Rolf Sauer, Frederick Wenz, Torsten Liersch
  [show abstract] [hide abstract]
  ABSTRACT: Background: In the era of preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME), the development of distant metastases is the predominant mode of failure in rectal cancer patients today. Integrating more effective systemic therapy into combined modality programs is the challenge. The question that needs to be addressed is how and when to apply systemic treatment with adequate dose and intensity. Material and Methods: This review article focuses on phase II–III trials designed to improve 5-fluorouracil (5-FU)-based combined modality treatment for rectal cancer patients through the inclusion of concurrent, adjuvant or, most recently, induction combination chemotherapy. Computerized bibliographic searches of PubMed were supplemented with hand searches of reference lists and abstracts of ASCO/ASTRO/ESTRO meetings. Results: After preoperative CRT and surgical resection, approximately one third of patients do not receive adjuvant chemotherapy, mainly due to surgical complications, patients’ refusal, or investigator’s discretion. In order to be able to apply chemotherapy with sufficient dose and intensity, an innovative approach is to deliver systemic therapy prior to preoperative CRT rather than adjuvant chemotherapy. Emerging evidence from several phase II trials and, recently, randomized phase II trials indicate that induction chemotherapy is feasible, does not compromise CRT or surgical resection, and enables the delivery of chemotherapy in adequate dose and intensity. Although this approach did not increase local efficacy in recent trials (e.g., pathological complete response rates, tumor regression, R0 resection rates, local control), it may help to improve control of distant disease. Conclusion: Whether this improvement in applicability and dose density of chemotherapy will ultimately translate into improved disease-free survival will have to be tested in a larger phase III trial. Hintergrund: Nach Einführung der präoperativen Radiochemotherapie (RCT) und der totalen mesoerektalen Excision manifestieren sich Rezidive beim Rektumkarzinom am häufigsten als Fernmetastasen. Daher ist die Integration einer systemisch effektiveren Therapie in das multimodale Behandlungskonzept derzeit die entscheidende Herausforderung. Die Frage ist, wann und wie diese Systemtherapie mit adäquater Dosis und Intensität verabreicht werden kann. Material und Methoden: Der Übersichtsartikel beschreibt Phase II–III Studien, deren Ziel es war, die allein 5-FU-basierte multimodale Behandlung durch Hinzunahme einer Kombinations-Chemotherapie, simultan zur Radiotherapie, adjuvant oder als Induktionstherapie, zu verbessern. Dazu diente eine Suchabfrage in Pubmed, in Referenzlisten publizierter Arbeiten sowie Abstrakts von ASCO/ASTRO/ESTRO-Konferenzen. Ergebnisse: Nach präoperativer RCT und Operation erhalten etwa ein Drittel aller Patienten wegen postoperativer Komplikationen, patientenseitiger Ablehnung oder Entscheidung des betreuenden Arztes keine adjuvante Chemotherapie. Ein innovativer Ansatz ist die Induktionschemotherapie vor präoperativer RCT und Operation, um die systemische Therapie in ausreichender Dosierung und Intensität durchführen zu können. Eine Vielzahl an Phase II-Studien, und zuletzt auch randomisierter Phase- II-Studien, zeigte, dass dieses Konzept durchführbar ist, die anschließende RCT und Operation nicht kompromittiert sowie die systemische Komponente in adäquater Dosis und Intensität applizierbar macht. Wenngleich dadurch die lokale Wirksamkeit (histopathologisch bestätigte Komplettremission, Tumorregression, R0-Resektionsrate, lokale Kontrolle) nicht verbessert wurde, könnte sich dieses Vorgehen positiv auf die systemische Tumorkontrolle auswirken. Schlussfolgerung: Eine Phase-III-Studie muss klären, ob die verbesserte Durchführbarkeit und Dosisdichte einer Induktionschemotherapie das krankheitsfreie Überleben verbessern kann. Key WordsRectal cancer–Induction chemotherapy–Chemoradiotherapy SchlüsselwörterRektumkarzinom–Induktionschemotherapie–Radiochemotherapie
  Strahlentherapie und Onkologie 04/2012; 186(12):658-664. · 3.56 Impact Factor
• Article: Gold markers for tumor localization and target volume delineation in radiotherapy for rectal cancer

  Hilke Vorwerk, Thorsten Liersch, Hilka Rothe, Michael Ghadimi, Hans Christiansen, Clemens Friedrich Hess, Robert Michael Hermann
  [show abstract] [hide abstract]
  ABSTRACT: Background and Purpose: In locally advanced rectal cancer, neoadjuvant radiochemotherapy is indicated. To improve target volume definition for radiotherapy planning, the potential of implanted gold markers in the tumor region was evaluated. Patients and Methods: In nine consecutive patients, two to three gold markers were implanted in the tumor region during rigid rectoscopy. Computed tomography scans were performed during treatment planning. All electronic portal imaging devices (EPIDs) recorded during treatment series were analyzed. All patients underwent complete tumor resection with meticulous histopathologic examination. Results: The gold markers could easily be implanted into the mesorectal tissue at the caudal tumor border without any complications. They were helpful in identifying the inferior border of the planning target volume in order to spare normal tissue (in particular anal structures). No significant shift of the markers was found during the course of therapy. Marker matching of the EPIDs did not improve patient positioning in comparison to bone structure matching. The former position of at least one marker could be identified in all patients during histopathologic examination. Conclusion: The use of gold marker enables a more precise definition of the target volume for radiotherapy in patients with rectal cancer. This could eventually allow a better protection of anal structures of patients with a tumor localization ≥ 5 cm cranial of the anal sphincter. The implantation of the gold markers improved communication between the surgeon, the radiooncologist and the pathologist resulting in intensified exchange of relevant informations. Hintergrund und Ziel: Bei Patienten mit fortgeschrittenem Rektumkarzinom ist eine neoadjuvante Radiochemotherapie indiziert. Um die Definition des Zielvolumens zu verbessern, wurde das Potential von implantierten Goldmarkern in der Tumorregion untersucht. Patienten und Methodik: Bei neun konsekutiven Patienten wurden während der prätherapeutischen starren Rektoskopie zwei bis drei Goldmarker in die Tumorregion implantiert. Für die Bestrahlungsplanung wurden computertomographische Bilder aufgenommen. Alle während der Bestrahlung aufgenommenen Portal-Image-Bilder wurden analysiert. Alle Patienten erhielten eine komplette Tumorresektion mit anschließender histopathologischer Untersuchung. Ergebnisse: Die Goldmarker konnten einfach und komplikationslos in das mesorektale Gewebe am kaudalen Tumorrand gelegt werden. Sie waren hilfreich bei der Identifikation des unteren Tumorrands während der Bestrahlungsplanung, um Normalgewebe (insbesondere die analen Strukturen) bei der Bestrahlung schonen zu können. Es fand sich keine signifikante Verschiebung der absoluten Markerpositionen während der Bestrahlung. Eine Korrektur der Lagerung der Patienten nach Markern ergab keinen Vorteil gegenüber der Korrektur mit knöchernen Landmarken. Die ehemalige Position von mindestens einem Marker konnte bei jedem Patienten in der histopathologischen Untersuchung bestimmt werden. Schlussfolgerung: Die Verwendung von Goldmarkern bei Patienten mit Rektumkarzinom ermöglicht eine präzisere Definition der Zielvolumens für die Bestrahlungsplanung. Dadurch könnten evtl. anale Strukturen bei einer Tumorlage von ≥ 5 cm kranial des Analsphinkters geschont werden. Die Implantation von Goldmarkern verbessert die Kommunikation zwischen Chirurgen, Radioonkologen und Pathologen, was in einem intensivierten Austausch relevanter Informationen resultiert.
  Strahlentherapie und Onkologie 04/2012; 185(2):127-133. · 3.56 Impact Factor
• Article: Comparison of the Micronucleus and Chromosome Aberration Techniques for the Documentationof Cytogenetic Damage in Radiochemotherapy-Treated Patients with Rectal Cancer

  Hendrik Andreas Wolff, Steffen Hennies, Markus Karl Alfred Herrmann, Margret Rave-Fränk, David Eickelmann, Patricia Virsik, Klaus Jung, Markus Schirmer, Michael Ghadimi, Clemens Friedrich Hess, Robert Michael Hermann, Hans Christiansen
  [show abstract] [hide abstract]
  ABSTRACT: Purpose: The goal of the interdisciplinary Clinical Research Unit KFO179 (Biological Basis of Individual Tumor Response in Patients with Rectal Cancer) is to develop an individual Response and Toxicity Score for patients with locally advanced rectal cancer treated with neoadjuvant radiochemotherapy. The aim of the present study was to find a reliable and sensitive method with easy scoring criteria and high numbers of cell counts in a short period of time in order to analyze DNA damage in peripheral blood lymphocytes. Thus, the cytokinesis-block micronucleus (CBMN) assay and the chromosome aberration technique (CAT) were tested. Materials and Methods: Peripheral blood lymphocytes obtained from 22 patients with rectal cancer before (0 Gy), during (21.6 Gy), and after (50.4 Gy) radiochemotherapy were stimulated in vitro by phytohemagglutinin (PHA); the cultures were then processed for the CBMN assay and the CAT to compare the two methods. Results: A significant increase of chromosomal damage was observed in the course of radiochemotherapy parallel to increasing radiation doses, but independent of the chemotherapy applied. The equivalence of both methods was shown by Westlake’s equivalence test. Conclusion: The results show that the CBMN assay and the CAT are equivalent. For further investigations, we prefer the CBMN assay, because it is simpler through easy scoring criteria, allows high numbers of cell counts in less time, is reliable, sensitive, and has higher statistical power. In the future, we plan to integrate cytogenetic damage during radiochemotherapy into the planned Response and Toxicity Score within our interdisciplinary Clinical Research Unit. Ziel: Ziel der interdisziplinären Klinischen Forschergruppe KFO179 (Biological Basis of Individual Tumor Response in Patients with Rectal Cancer) ist es, einen individuellen Response-/Toxizitätsscore für Patienten zu entwickeln, die bei diagnostiziertem lokal fortgeschrittenem Rektumkarzinom mit neoadjuvanter Radiochemotherapie behandelt werden. Ziel der vorliegenden Arbeit war, eine einfache und zuverlässige Methode zur Detektion des individuellen zytogenetischen Schadens durch die Radiochemotherapie herauszuarbeiten, die im weiteren Verlauf der Arbeit der Forschergruppe Anwendung finden soll. Wir verglichen dabei den Mikronukleustest (MN) mit der Chromosomenaberrationsanalyse (CAA). Patienten und Methodik: Periphere Blutlymphozyten von 22 Patienten wurden vor (0 Gy), während (21,6 Gy) und nach (50,4 Gy) Radiochemotherapie untersucht. Der zytogenetische Schaden wurde mittels MN und CAA analysiert und die Äquivalenz beider Methoden geprüft. Ergebnisse: Eine signifikante Zunahme chromosomaler Schädigungen durch die Bestrahlung in Abhängigkeit von der applizierten Dosis konnte bei beiden Techniken, unabhängig von der applizierten Chemotherapie, beobachtet werden. Die Gleichwertigkeit beider Methoden konnte durch den Äquivalenztest nach Westlake gezeigt werden. Schlussfolgerung: Es zeigte sich eine Äquivalenz der angewandten Methoden, was uns nun die Möglichkeit bietet, den MN gleichwertig gegenüber der CAA anzuwenden und für die geplanten Analysen bezüglich des individuellen Response-/Toxizitätsscores zu verwenden. Die Mikronukleustechnik ermöglicht durch leichtere Zählkriterien in kürzerer Zeit eine größere Anzahl von Zellen zu zählen, was zu einem valideren statistischen Endergebnis führt. Key WordsRectal cancer–Neoadjuvant radiochemotherapy–Micronuclei–Chromosome aberration technique–Lymphocytes SchlüsselwörterRektumkarzinom–Neoadjuvante Radiochemotherapie–Mikronuklei–Chromosomaberrationstechnik–Lymphozyten
  Strahlentherapie und Onkologie 04/2012; 187(1):52-58. · 3.56 Impact Factor
• Article: Irradiation with protons for the individualized treatment of patients with locally advanced rectal cancer: a planning study with clinical implications.

  Hendrik Andreas Wolff, Daniela Melanie Wagner, Lena-Christin Conradi, Steffen Hennies, Michael Ghadimi, Clemens Friedrich Hess, Hans Christiansen
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  ABSTRACT: Ongoing clinical trials aim to improve local control and overall survival rates by intensification of therapy regimen for patients with locally advanced rectal cancer. It is well known that whenever treatment is intensified, risk of therapy-related toxicity rises. An irradiation with protons could possibly present an approach to solve this dilemma by lowering the exposure to the organs-at-risk (OAR) without compromising tumor response. Twenty five consecutive patients were treated from 04/2009 to 5/2010. For all patients, four different treatment plans including protons, RapidArc, IMRT and 3D-conformal-technique were retrospectively calculated and analyzed according to dosimetric aspects. Detailed DVH-analyses revealed that protons clearly reduced the dose to the OAR and entire normal tissue when compared to other techniques. Furthermore, the conformity index was significantly better and target volumes were covered consistent with the ICRU guidelines. Planning results suggest that treatment with protons can improve the therapeutic tolerance for the irradiation of rectal cancer, particularly for patients scheduled for an irradiation with an intensified chemotherapy regimen and identified to be at high risk for acute therapy-related toxicity. However, clinical experiences and long-term observation are needed to assess tumor response and related toxicity rates.
  Radiotherapy and Oncology 11/2011; 102(1):30-7. · 5.58 Impact Factor
• Article: CpG island methylator phenotype infers a poor disease-free survival in locally advanced rectal cancer.

  Peter Jo, Klaus Jung, Marian Grade, Lena-Christin Conradi, Hendrik A Wolff, Julia Kitz, Heinz Becker, Josef Rüschoff, Arndt Hartmann, Tim Beissbarth, Annegret Müller-Dornieden, Michael Ghadimi, Regine Schneider-Stock, Jochen Gaedcke
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  ABSTRACT: Locally advanced rectal cancers are treated with preoperative radiochemotherapy (RCT). However, subsets of patients have no benefit from preoperative treatment. Since epigenetic modifications, including DNA methylation, may influence response to neoadjuvant treatment we studied the CpG island methylator phenotype (CIMP) in patients who received a 5-fluouracil based RCT. One hundred fifty patients with locally advanced rectal cancer, treated within a phase III clinical trial (CAO/ARO/AIO-94 and -04), were included in this analysis. CIMP was assessed by methylation specific PCR (MSP) using RUNX3, SOCS1, NEUROG1, IGF2, and CACNA1G as a marker panel. Loss of mismatch repair gene (MMR) expression was assessed by immunohistochemistry for a subset of patients. KRAS and BRAF mutation status were assessed using Sanger sequencing. The CIMP status could be established in all 150 patients. Fifteen (10%) revealed CIMP positivity (≥3 methylated promoters), whereas 135 patients (90%) where classified as CIMP negative. Analysis for MMR status did not reveal any microsatellite instability (MSI). A single mutation of the BRAF gene (D594G) was detected. The KRAS gene (exon 1, 2, and 3) was mutated in 65 tumors (43%) but was not correlated to a specific CIMP status. Three- and 5-year disease-free survival was notably worse in CIMP positive patients (56% and 0% vs 80% and 75%; P < .01) suggesting an increased likelihood of poor clinical outcome (HR 5.5; 95%CI: [2.1, 13.9]). CIMP positivity, defined by methylation of at least 3 specific gene promoters, is an infrequent event in locally advanced rectal cancer. However, it increases the likelihood of distant metastases. Therefore, the CIMP status may be included as a molecular marker for the identification of high-risk patients and might contribute to individual treatment stratification.
  Surgery 10/2011; 151(4):564-70. · 3.10 Impact Factor
• Article: Acute toxicity of radiochemotherapy in rectal cancer patients: a risk particularly for carriers of the TGFB1 Pro25 variant.

  Markus Anton Schirmer, Caroline Patricia Nadine Mergler, Margret Rave-Fränk, Markus Karl Herrmann, Steffen Hennies, Jochen Gaedcke, Lena-Christin Conradi, Peter Jo, Tim Beissbarth, Clemens Friedrich Hess, Heinz Becker, Michael Ghadimi, Jürgen Brockmöller, Hans Christiansen, Hendrik Andreas Wolff
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  ABSTRACT: Transforming growth factor-beta1 is related to adverse events in radiochemotherapy. We investigated TGFB1 genetic variability in relation to quality of life-impairing acute organ toxicity (QAOT) of neoadjuvant radiochemotherapy under clinical trial conditions. Two independent patient cohorts (n = 88 and n = 75) diagnosed with International Union Against Cancer stage II/III rectal cancer received neoadjuvant radiation doses of 50.4 Gy combined with 5-fluorouracil-based chemotherapy. Toxicity was monitored according to Common Terminology Criteria for Adverse Events. QAOT was defined as a CTCAE grade ≥2 for at least one case of enteritis, proctitis, cystitis, or dermatitis. Nine germline polymorphisms covering the common genetic diversity in the TGFB1 gene were genotyped. In both cohorts, all patients carrying the TGFB1 Pro25 variant experienced QAOT (positive predictive value of 100%, adjusted p = 0.0006). In a multivariate logistic regression model, gender, age, body mass index, type of chemotherapy, or disease state had no significant impact on QAOT. The TGFB1 Pro25 variant could be a relevant marker for individual treatment stratification and carriers may benefit from adaptive clinical care or specific radiation techniques.
  International journal of radiation oncology, biology, physics 10/2011; 83(1):149-57. · 4.59 Impact Factor
• Article: Comparison of the micronucleus and chromosome aberration techniques for the documentation of cytogenetic damage in radiochemotherapy-treated patients with rectal cancer.

  Hendrik Andreas Wolff, Steffen Hennies, Markus Karl Alfred Herrmann, Margret Rave-Fränk, David Eickelmann, Patricia Virsik, Klaus Jung, Markus Schirmer, Michael Ghadimi, Clemens Friedrich Hess, Robert Michael Hermann, Hans Christiansen
  [show abstract] [hide abstract]
  ABSTRACT: The goal of the interdisciplinary Clinical Research Unit KFO179 (Biological Basis of Individual Tumor Response in Patients with Rectal Cancer) is to develop an individual Response and Toxicity Score for patients with locally advanced rectal cancer treated with neoadjuvant radiochemotherapy. The aim of the present study was to find a reliable and sensitive method with easy scoring criteria and high numbers of cell counts in a short period of time in order to analyze DNA damage in peripheral blood lymphocytes. Thus, the cytokinesis-block micronucleus (CBMN) assay and the chromosome aberration technique (CAT) were tested. Peripheral blood lymphocytes obtained from 22 patients with rectal cancer before (0 Gy), during (21.6 Gy), and after (50.4 Gy) radiochemotherapy were stimulated in vitro by phytohemagglutinin (PHA); the cultures were then processed for the CBMN assay and the CAT to compare the two methods. A significant increase of chromosomal damage was observed in the course of radiochemotherapy parallel to increasing radiation doses, but independent of the chemotherapy applied. The equivalence of both methods was shown by Westlake's equivalence test. The results show that the CBMN assay and the CAT are equivalent. For further investigations, we prefer the CBMN assay, because it is simpler through easy scoring criteria, allows high numbers of cell counts in less time, is reliable, sensitive, and has higher statistical power. In the future, we plan to integrate cytogenetic damage during radiochemotherapy into the planned Response and Toxicity Score within our interdisciplinary Clinical Research Unit.
  Strahlentherapie und Onkologie 01/2011; 187(1):52-8. · 3.56 Impact Factor
• Article: Induction chemotherapy before chemoradiotherapy and surgery for locally advanced rectal cancer : is it time for a randomized phase III trial?

  Claus Rödel, Dirk Arnold, Heinz Becker, Rainer Fietkau, Michael Ghadimi, Ullrich Graeven, Clemens Hess, Ralf Hofheinz, Werner Hohenberger, Stefan Post, Rudolf Raab, Rolf Sauer, Frederick Wenz, Torsten Liersch
  [show abstract] [hide abstract]
  ABSTRACT: in the era of preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME), the development of distant metastases is the predominant mode of failure in rectal cancer patients today. Integrating more effective systemic therapy into combined modality programs is the challenge. The question that needs to be addressed is how and when to apply systemic treatment with adequate dose and intensity. this review article focuses on phase II-III trials designed to improve 5-fluorouracil (5-FU)-based combined modality treatment for rectal cancer patients through the inclusion of concurrent, adjuvant or, most recently, induction combination chemotherapy. Computerized bibliographic searches of PubMed were supplemented with hand searches of reference lists and abstracts of ASCO/ASTRO/ESTRO meetings. after preoperative CRT and surgical resection, approximately one third of patients do not receive adjuvant chemotherapy, mainly due to surgical complications, patients' refusal, or investigator's discretion. In order to be able to apply chemotherapy with sufficient dose and intensity, an innovative approach is to deliver systemic therapy prior to preoperative CRT rather than adjuvant chemotherapy. Emerging evidence from several phase II trials and, recently, randomized phase II trials indicate that induction chemotherapy is feasible, does not compromise CRT or surgical resection, and enables the delivery of chemotherapy in adequate dose and intensity. Although this approach did not increase local efficacy in recent trials (e.g., pathological complete response rates, tumor regression, R0 resection rates, local control), it may help to improve control of distant disease. whether this improvement in applicability and dose density of chemotherapy will ultimately translate into improved disease-free survival will have to be tested in a larger phase III trial.
  Strahlentherapie und Onkologie 12/2010; 186(12):658-64. · 3.56 Impact Factor
• Source

  Available from: Hendrik Andreas Wolff

  Article: KRAS and BRAF mutations in patients with rectal cancer treated with preoperative chemoradiotherapy.

  Jochen Gaedcke, Marian Grade, Klaus Jung, Markus Schirmer, Peter Jo, Christoph Obermeyer, Hendrik A Wolff, Markus K Herrmann, Tim Beissbarth, Heinz Becker, Thomas Ried, Michael Ghadimi
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  ABSTRACT: KRAS and BRAF are mutated in 35% and 10% of colorectal cancers, respectively. However, data specifically for locally advanced rectal cancers are scarce, and the frequency of KRAS mutations in codons 61 and 146 remains to be established. DNA was isolated from pre-therapeutic biopsies of 94 patients who were treated within two phase-III clinical trials receiving preoperative chemoradiotherapy. Mutation status of KRAS exons 1-3 and BRAF exon 15 was established using the ABI PRISM Big Dye Sequencing Kit and subsequently correlated with clinical parameters. Overall, KRAS was mutated in 45 patients (48%). Twenty-nine mutations (64%) were located in codon 12, 10 mutations (22%) in codon 13, and 3 mutations (7%) in codons 61 and 146. No V600E BRAF mutation was detected. The presence of KRAS mutations was correlated neither with tumor response or lymph node status after preoperative chemoradiotherapy nor with overall survival or disease-free survival. When KRAS exon 1 mutations were separated based on the amino-acid exchange, we again failed to detect significant correlations (p=0.052). However, G12V mutations appeared to be associated with higher rates of tumor regression than G13D mutations (p=0.012). We are the first to report the mutation status of KRAS and BRAF in pre-therapeutic biopsies from locally advanced rectal cancers. The high number of KRAS mutations in codons 61 and 146 emphasizes the importance to expand current mutation analyses, whereas BRAF mutations are not relevant for rectal carcinogenesis. Although the KRAS mutation status was not correlated with response, the subtle difference between G12V and G13D mutations warrants analysis of a larger patient population.
  Radiotherapy and Oncology 11/2009; 94(1):76-81. · 5.58 Impact Factor
• Article: Gold markers for tumor localization and target volume delineation in radiotherapy for rectal cancer.

  Hilke Vorwerk, Thorsten Liersch, Hilka Rothe, Michael Ghadimi, Hans Christiansen, Clemens Friedrich Hess, Robert Michael Hermann
  [show abstract] [hide abstract]
  ABSTRACT: In locally advanced rectal cancer, neoadjuvant radiochemotherapy is indicated. To improve target volume definition for radiotherapy planning, the potential of implanted gold markers in the tumor region was evaluated. In nine consecutive patients, two to three gold markers were implanted in the tumor region during rigid rectoscopy. Computed tomography scans were performed during treatment planning. All electronic portal imaging devices (EPIDs) recorded during treatment series were analyzed. All patients underwent complete tumor resection with meticulous histopathologic examination. The gold markers could easily be implanted into the mesorectal tissue at the caudal tumor border without any complications. They were helpful in identifying the inferior border of the planning target volume in order to spare normal tissue (in particular anal structures). No significant shift of the markers was found during the course of therapy. Marker matching of the EPIDs did not improve patient positioning in comparison to bone structure matching. The former position of at least one marker could be identified in all patients during histopathologic examination. The use of gold marker enables a more precise definition of the target volume for radiotherapy in patients with rectal cancer. This could eventually allow a better protection of anal structures of patients with a tumor localization > or = 5 cm cranial of the anal sphincter. The implantation of the gold markers improved communication between the surgeon, the radiooncologist and the pathologist resulting in intensified exchange of relevant informations.
  Strahlentherapie und Onkologie 03/2009; 185(2):127-33. · 3.56 Impact Factor