Rupert Langer

Publications (76) View all

• Article: Clinical response to chemotherapy in oesophageal adenocarcinoma patients is linked to defects in mitochondria.

  Michaela Aichler, Mareike Elsner, Natalie Ludyga, Annette Feuchtinger, Verena Zangen, Stefan K Maier, Benjamin Balluff, Cédrik Schöne, Ludwig Hierber, Herbert Braselmann, [......], Michaela Aubele, Manfred Schmitt, Marcus Feith, Stefanie M Hauck, Marius Ueffing, Rupert Langer, Bernhard Kuester, Horst Zitzelsberger, Heinz Höfler, Axel K Walch
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  ABSTRACT: Chemotherapeutic drugs kill cancer cells, but it is unclear why this happens in responding patients but not in non-responders. Proteomic profiles of patients with oesophageal adenocarcinoma may be helpful in predicting response and selecting more effective treatment strategies. In this study, pre-therapeutic oesophageal adenocarcinoma biopsies were analysed for proteomic changes associated with response to chemotherapy by MALDI imaging mass spectrometry. Resulting candidate proteins were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and investigated for functional relevance in vitro. Clinical impact was validated in pretherapeutic biopsies from an independent patient cohort. Studies on the incidence of these defects in other solid tumours were included. We discovered that clinical response to cisplatin correlated with pre-existing defects in the mitochondrial respiratory chain complexes of cancer cells, caused by loss of specific cytochrome c oxidase (COX) subunits. Knockdown of a COX protein altered chemosensitivity in vitro, increasing the propensity of cancer cells to undergo cell death following cisplatin treatment. In an independent validation, patients with reduced COX protein expression prior to treatment exhibited favourable clinical outcomes to chemotherapy, whereas tumours with unchanged COX expression were chemoresistant. In conclusion, previously undiscovered pre-existing defects in mitochondrial respiratory complexes cause cancer cells to become chemosensitive: mitochondrial defects lower the cells' threshold for undergoing cell death in response to cisplatin. By contrast, cancer cells with intact mitochondrial respiratory complexes are chemoresistant and have a high threshold for cisplatin-induced cell death. This connection between mitochondrial respiration and chemosensitivity is relevant to anticancer therapeutics that target the mitochondrial electron transport chain.
  The Journal of Pathology 04/2013; · 6.32 Impact Factor
• Article: Factors predicting prognosis and recurrence in patients with esophago-gastric adenocarcinoma and histopathological response with less than 10 % residual tumor.

  Katja Ott, Susanne Blank, Karen Becker, Rupert Langer, Wilko Weichert, Wilfried Roth, Leila Sisic, Annika Stange, Dirk Jäger, Markus Büchler, Jörg-Rüdiger Siewert, Florian Lordick
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  ABSTRACT: PURPOSE: Neoadjuvant treatment is an accepted standard approach for treating locally advanced esophago-gastric adenocarcinomas. Despite a response of the primary tumor, a significant percentage dies from tumor recurrence. The aim of this retrospective exploratory study from two academic centers was to identify predictors of survival and recurrence in histopathologically responding patients. METHODS: Two hundred thirty one patients with adenocarcinomas (esophagus: n = 185, stomach: n = 46, cT3/4, cN0/+, cM0) treated with preoperative chemotherapy (n = 212) or chemoradiotherapy (n = 19) followed by resection achieved a histopathological response (regression 1a: no residual tumor (n = 58), and regression 1b < 10 % residual tumor (n = 173)). RESULTS: The estimated median overall survival was 92.4 months (5-year survival, 56.6 %) for all patients. For patients with regression 1a, median survival is not reached (5-year survival, 71.6 %) compared to patients with regression 1b with 75.3 months median (5-year survival, 52.2 %) (p = 0.031). Patients with a regression 1a had lymph node metastases in 19.0 versus 33.7 % in regression 1b. The ypT-category (p < 0.001), the M-category (p = 0.005), and the type of treatment (p = 0.04) were found to be independent prognostic factors in R0-resected patients. The recurrence rate was 31.7 % (n = 66) (local, 39.4 %; peritoneal carcinomatosis, 25.7 %; distant metastases, 50 %). Recurrence was predicted by female gender (p = 0.013), ypT-category (p = 0.007), and M-category (p = 0.003) in multivariate analysis. CONCLUSION: Response of the primary tumor does not guarantee recurrence-free long-term survival, but histopathological complete responders have better prognosis compared to partial responders. Established prognostic factors strongly influence the outcome, which could, in the future, be used for stratification of adjuvant treatment approaches. Increasing the rate of histopathological complete responders is a valid endpoint for future clinical trials investigating new drugs.
  Langenbeck s Archives of Surgery 12/2012; · 1.81 Impact Factor
• Article: Prognostic Implications of the Seventh Edition of the International Union Against Cancer Classification for Patients With Gastric Cancer: The Western Experience of Patients Treated in a Single-Center European Institution.

  Daniel Reim, Martin Loos, Fabian Vogl, Alexander Novotny, Tibor Schuster, Rupert Langer, Karen Becker, Heinz Höfler, Jens Siveke, Florian Bassermann, Helmut Friess, Christoph Schuhmacher
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  ABSTRACT: PURPOSEValidity of the seventh edition of the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) staging systems for gastric cancer has been evaluated in several studies, mostly in Asian patient populations. Only few data are available on the prognostic implications of the new classification system on a Western population. Therefore, we investigated its prognostic ability based on a German patient cohort.Patients And methodsData from a single-center cohort of 1,767 consecutive patients surgically treated for gastric cancer were classified according to the seventh edition and were compared using the previous TNM/UICC classification. Kaplan-Meier analyses were performed for all TNM stages and UICC stages in a comparative manner. Additional survival receiver operating characteristic analyses and bootstrap-based goodness-of-fit comparisons via Bayesian information criterion (BIC) were performed to assess and compare prognostic performance of the competing classification systems.ResultsWe identified the UICC pT/pN stages according to the seventh edition of the AJCC/UICC guidelines as well as resection status, age, Lauren histotype, lymph-node ratio, and tumor grade as independent prognostic factors in gastric cancer, which is consistent with data from previous Asian studies. Overall survival rates according to the new edition were significantly different for each individual's pT, pN, and UICC stage. However, BIC analysis revealed that, owing to higher complexity, the new staging system might not significantly alter predictability for overall survival compared with the old system within the analyzed cohort from a statistical point of view. CONCLUSION The seventh edition of the AJCC/UICC classification was found to be valid with distinctive prognosis for each stage. However, the AJCC/UICC classification has become more complex without improving predictability for overall survival in a Western population. Therefore, simplification with better predictability of overall survival of patients with gastric cancer should be considered when revising the seventh edition.
  Journal of Clinical Oncology 12/2012; · 18.37 Impact Factor
• Article: Epidermal growth factor receptor, phosphatidylinositol-3-kinase catalytic subunit/PTEN, and KRAS/NRAS/BRAF in primary resected esophageal adenocarcinomas: loss of PTEN is associated with worse clinical outcome.

  Marcus Bettstetter, Sabina Berezowska, Gisela Keller, Axel Walch, Annette Feuchtinger, Julia Slotta-Huspenina, Marcus Feith, Enken Drecoll, Heinz Höfler, Rupert Langer
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  ABSTRACT: Alterations of the epidermal growth factor receptor (EGFR) can be observed in a significant subset of esophageal adenocarcinomas (EACs), and targeted therapy against EGFR may become an interesting approach for the treatment of these tumors. Mutations of KRAS, NRAS, BRAF, and phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) and deregulation of PTEN expression influence the responsiveness against anti-EGFR therapy in colorectal carcinomas. We investigated the prevalence of these events in a collection of 117 primary resected EACs, correlated the findings with EGFR expression and amplification, and determined their clinicopathologic impact. KRAS mutations were detected in 4 (3%) of 117 tumors (3× G12D and 1 G12V mutation). One tumor had a PIK3CA E545K mutation. Neither NRAS nor BRAF mutations were detected. Sixteen (14%) of 117 cases were negative for PTEN expression, determined by immunohistochemistry. Loss of PTEN was observed predominantly in advanced tumor stages (P = .004). There was no association between PTEN and EGFR status. Loss of PTEN was associated with shorter overall and disease-free survival (P < .001 each) and also an independent prognostic factor in multivariate analysis (P = .015). EGFR status had no prognostic impact in this case collection. In summary, loss of PTEN can be detected in a significant subset of EAC and is associated with an aggressive phenotype. Therefore, PTEN may be useful as a prognostic biomarker. In contrast, mutations of RAS/RAF/PIK3CA appear only very rarely, if at all, in EAC. A possible predictive role of PTEN in anti-EGFR treatment warrants further investigations, whereas determination of RAS/RAF/PIK3CA mutations may only have a minor impact in this context.
  Human pathology 11/2012; · 3.03 Impact Factor
• Article: The severity of neural invasion is associated with shortened survival in colon cancer.

  Florian Liebl, Ihsan Ekin Demir, Robert Rosenberg, Alexandra Boldis, Esra Yildiz, Kristina Kujundzic, Timo Kehl, Dominic Dischl, Tibor Schuster, Matthias Maak, Karen Becker, Rupert Langer, Melanie Laschinger, Helmut Friess, Guralp O Ceyhan
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  ABSTRACT: PURPOSE: Neural invasion/NI is a histopathological feature of colon cancer/CC which receives little consideration. Therefore, we performed a morphological and functional characterization of NI in CC. EXPERIMENTAL DESIGN: NI was investigated in 673 patients with CC. Localization and severity of NI was determined and related to patient's prognosis and survival. The neuro-affinity of CC-cells (HT29, HCT-116, SW620, DLD-1) was compared to pancreatic cancer/PC- (T3M4 and SU86.86) and rectal cancer/RC-cells (CMT-93) in the in-vitro 3D-neural-migration assay and analyzed via live-cell-imaging. Immunoreactivity of the neuroplasticity marker GAP-43, and the neurotrophic-chemoattractant factors Artemin and NGF was quantified in CC and PC nerves. Dorsal root ganglia/DRG of newborn rats were exposed to supernatants of CC-, RC- and PC-cells and neurite density was determined. RESULTS: NI was detected in 210 of 673 patients (31.2%). Although increasing NI severity scores were associated with a significantly poorer survival, presence of NI was not an independent prognostic factor in CC. In the 3D migration assay, CC- and RC-cells demonstrated much less neurite-targeted migration when compared to PC-cells. Supernatants of PC- and RC-cells induced a much higher neurite density than those of CC-cells. Accordingly, NGF, Artemin and GAP-43 were much more pronounced in nerves in PC than in CC. CONCLUSIONS: I is not an independent prognostic factor in CC. The lack of a considerable biological affinity between CC-cells and neurons, the low expression profile of colonic nerves for chemoattractant molecules, and the absence of a major neuroplasticity in CC may explain the low prevalence and impact of NI in CC.
  Clinical Cancer Research 11/2012; · 7.74 Impact Factor