- Email: [email protected]
Gene expression profile using paired normal and cancer tissue predicts clinical outcome of esophageal cancer
up and clinical and pathological data were taken from patients records. Results: Patients with SCC were significantly more frequent smokers (95%) and heavy drinkers (85%) as compared to AC (71% smokers, p =0.04; 28% heavy drinkers, p =0.0009). P53 mutations were found in 13 of 28 SSC (46%) and in 8 of 14 AC (57%). Six patients showed multiple mutations (5 SCC/1 AC). 2 mutations were located in DNA-binding sites (Codon 281 / 282) and these patients showed rapid progressive tumor growth despite therapy. The majority (73%) of mutations were transversions. Frequency of mutations and mutational profile did not significantly differ between smokers versus nonsmokers, moderate versus heavy drinkers and patients with AC versus SCC, respectively. Conclusion: Despite the different risk factors in patients with AC and SCC, the frequency and mutational profile of mutant p53 is similar m both groups. Our data provide no evidence for an increased p53 mutation frequency in patients with heavy smoking or drinking.
of vessel diameter > = 4%, after the end of 5-FU application (median 11%, range 4,318,5), whereas no single contraction was noticed m 30 pts following non 5-FU based CTX. Vessel tonus generally normalized within 30 rain after stopping 5-FU application. 5 patients positive for 5-FU associated vessel contraction were repeatedly exposed to 5-FU. 5-FU associated vessel contractions were highly reproducible and reoccurred in 86% (18/21) of the cases. When these patterns were treated with glycerohrinitrate s.1. prior to 5-FU bolus applications no contraction of the brachial artery was detected in 5 of 5 occasions. With respect to possible secondary mediators of vasoconstrition there was a trend towards increased big endnthelin plasma levels after 5-FU applications (median 1,52 vs 1,99 fmol/ml; p = 0,07) whereas big endothelin levels remained unchanged after non 5-FU CTX (1,83 vs 1,83 fmol/ ml; p = 0,99). Conclusions: According to our study 5-FU is commonly accompanied by contractions of the brachial artery. This effect appears to be specific for 5-FU. 5-FU associated vessel contractions were highly reproducible on reexposure and were in case of bolus applications completely preventable by nitrate inhalation. We conclude that 5-FU-induced vasocontraction is involved in 5-FU specific cardiovascular complications and represents a valuable traget to investigate prophylactic strategie
M1039
Gene Expression Profile Using Paired Normal and Cancer Tissue Predicts Clinical Outcome of Esophageal Cancer M1042
Yoshio Ishibashi, Nobuyoshi Hanyn, Koji Nakada, Yutaka Suzuki, Takashi Yamamoto, Kiyeshi Ohkawa, Masato Matsushima, Mitsuyoshi Urashima, Noriko Hashimoto, Toshiharu Nakajima, Hirohisa Saitou
Frequency of Lymph Node Metastases in Early-Carcinoma of the Upper GastroIntestinal Tract Marcus Feith, Hubert J. Stein, J. Ruediger Siewert
Background: Esophageal sqnamons cell carcinoma has heterogeneous clinical outcomes that cannot be predicted well using any existing clinical or molecular prognostic factors. Gene expression profiling may enable more precise prediction of the clinical outcome of these patients. We developed a new approach using gene expression ratios of paired cancerous and normal tissue specimens from the same patient to reduce the effects of variation among indiwduals. Methods: Using ofigonucleotide microarrays, we analysed total RNA expression levels corresponding to 12,60.0 transcript sequences in 24 paired cancerous and normal tissue operative specimens from 12 patients with oesophageal squamous cell carcinoma. RESULTs: Hierarchical clustering analysis using gene expression ratios (cancer/normal) divided the 12 patients into 2 groups; all 7 patients in the 1st cluster survived without relapse (median follow-up 483 days), whereas all 5 patients in the 2nd cluster relapsed (median relapse free survival time: 280 days) (log-rank test: p = 0.006). in contrast, either clustering vclth cancerous tissue alone or with normal tissue alone did not show significant differences in the outcomes. Moreover, even clinical stages based on TNM classification did not predict outcome so well as profiling of gene expression ratios. The expressions of a variety of genes related to cell cycle, gene-repair, apoptosis and chemoradiotherpay resistance were up-regulated ni the poor prognostic cluster. CONCLUSION: These results suggest that ratios of paired gene expression profiles may more efficiently predict relapse free survival of esophageal squamons cell carcinoma than existing prognostic factors or than gene expression profiling with cancerous tissue alone.
Background: The optimal treatment for early carcinoma of the upper gastro-intestinal tract, limited to mucosa or submucosa, is controversy discussed. The treatment with endoscopic mucosa resection and ablation stays in contrast to the radical surgical resection and lymphadenectomy. The frequency of lymph node metastases in early carcinoma of the upper gi-tract, which are not reachable by endoscopic techniques, is unknown. Methods: We investigated 519 early carcinoma of the esophagus and stomach, limited to mucosa (pTla) and submucosa (pTlb). Including 295 gastric carcinoma, 118 adenocarcinoma of the distal esophagus and 106 squamons cell carcinoma of the esophagus. The frequency of lymph node metastases in relation to the mucosa or submucosa infiltration was evaluated. Results: Of the 519 resected pT1 a/b early carcinoma of the upper gi-tract showed 67 patients a lymph node involvement (12.9%). In the to the mucoss limited carcinoma were in eight patients a lymph node infiltration present. Only in the patients with a pTla adenocarcinoma of the distal esophagus was none lymph node infiltration detectable, in contrast the squamons cell carcinoma and gastric carcinoma showed even in mucosa pTla-carcinoma a lymph node infiltration (p<0.0001). Conclusion: Exclusively in patients with to the mucosa limited adenocarcinoma of the distal esophagus the local treatment with endoscopic ablation or mucosa resection without lymphadenectomy is oncological discussable. All other carcinoma of the upper gastro-intestinal tract present even in the pTla-category lymph node metastases and require a radical surgical resection with lymphadenectomy.
M1040 M1043
Screening of high-risk patients with head and neck cancer for early detection of synchronous esophageal squamous cell carcinoma by chromoendoscopy using Lugols solution
Prospective Evaluation Of Bone Scintigraphy As a Staging Investigation for Esophageal Carcinoma
Oliver Moesehler, Christina Middelberg-Bispnig, Wolfram Grosse-Thie, Bemd Christoph, Guentber Kloeppel, Michael K. Mueller
Peter Lamb, Arul immanuel, Jim Lloyd, David Richardson, John Wilsdon, Daya Karat, Nicholas Hayes, Michael Griffin
Objective: Patients with head and neck cancer have an increased incidence of synchronous esophageal squamous cell carcinoma. We evaluated the benefit of screening the oesophagus by using chromoendoscopy with Lugols solution in patients with known risk factors like nicotine and/or alcohol abuse. Methods: Between Sept. 2000 and Sept. 2002 we examined 70 patients. Clinical information was obtained using a standard questionnaire containing details about age, mmour state, drinking behaviour and nicotine consumption. Endoscopy was performed in slight sedation. Staining of the oesophageal mucosa was performed with 2% Lugols solution, which was applied via spraying catheter. Several biopsies were taken from all unstained areas for histopathological assessment. Results: We found esophageal carcinoma, which was not detectable by endoscopy alone in 8 patients (11%), dysplastic changes of the squamous epithelium in 11 patients (16%) and esophagitis in 36 patients (51%). Barrett oesophagus was found in 3 cases (5%). In all patients with newly detected cancer the therapeutic concept had to be changed from a curative neo-adjuvant approach to palliative treatment. In cases with dysplastic areas and newly detected Barret epithelium a careful follow-up regime was arranged. In one case with high grade dysplasia and inoperability a mucosectomy was performed. Conclusion: We recommend screening the oesophagus using Lugols solution to be included in the routine staging of all patients with head and neck cancer and known nicotine or alcohol abuse, considered eligible for neo-adjuvant therapy.
Purpose: Prom 1990 to 1999, 9% (11/125) of patients undergoing radical esophagectomy for node positive carcinoma re-presemed with symptomatic bone metastases within 12 momhs of surgery. The aim of this study was to prospectively evaluate the introduction of preoperative bone scintigraphy. Methods: Over a 12 month period from December 2000, 159 patients with esophageal carcinoma were assessed. Technetium-HDP bone scintigraphy was performed for patients identified as having transmural disease (T3) with lymph node involvement (N1) by conventional investigations (computed tomography & endoscopic ultrasound), who were otherwLse suitable for radical surgery. Results: 69 patients (43%) were suitable for radical surgery and of these 45 patients (median age 62 years, M:F ratio 3:1) staged with T3N1 disease underwent bone sclntlgraphy. The histological diagnosis was adenocarcinoma in 76% and squamous carcinoma in 24%. Bone scintigraphy was normal or showed degenerative change in 33 patients (73%), and demonstrated areas of abnormal radioisotope uptake requiring further investigation in 12 patients (27%). In 6 patients (13%) plain radiographs, MRI, and guided biopsy confirmed the presence of bone metastases; a single metastasis in 5 patients (iliao 2, humerus- 2, femur- 1) and multiple vertebral metastases in i patient. These 6 patients received palliative treatment with a median survival of 4 months. No patient undergoing bone scintigraphy has developed bone metastases following esophagectomy (n = 39) after an initial median follow up of 6 months. Conclusions: Bone scintigraphy is essential to exclude metastatic disease prior to radical surgery for advanced esophageal carcinoma. Bone is frequently the first site of distant metastatic spread and these patients are most appropriately managed by non-surgical palliation.
M1041 Arterial Vasocontraction ls a Frequent Finding Following 5-Fu Based
M1044
Chemotherapy Thomas Suedhoff, Markns Reiser, Markns Endede, Michaela Pahlke, Corinna Petz, Ullrich Graeven, Wolff 5chmiegel
Squamous Dysplasia Is the Histologic Precursor of Invasive Esophageal Squamous Cell Carcinoma: Results from a 13-ycar Prospective Follow-up Study in a High-Risk Population
Purpose: 5-Fluorouracil (5-FU) belongs to the most often used cytostatic drugs in mnltimodal treatment of esophageal carcinoma with 2-10% of patiems treated will develop cardiovascuhr complications. The underlying pathopbysiology of 5-FU-induced cardiotoxicity is unknown and noninvasive diagnostic procedures which allow a risk stratification are not established. Patients and Methods: We investigated the influence of cytostatic drugs (n=60) on the diameter of the brachial artery using high resolution ultrasound (ESAOTE/Biomedia, 13.0 MHz tranducer) in 57 patients with malignant tumors (31x GI cancer, 12x lung cancer, 9x NHL, 3x head and neck cancer, lx CUP and lx melanoma). Cytostatic drags investigated included 30 cases with 5-FU and 30 cases with non 5-FU CTX (16x cis/carboplatin, 7x anthracycline, 7x cyclophosphamide). Additionally, plasma levels of big endothelin were assessed prior and after CTX application using a commercially available ELISA assay. Results: 15 of 30 patients (50%) showed a contraction of the brachiafis artery, defined as reduction
Guo-Qing Wang, Chnstian C. Abner, Fu-Sbeng Liu, Klaus J. Lewin, Xiu-Di Sun, Mark J. Roth, You-l.in Qiao, Stereo D. Mark, Jin-Hu Fan, Philip R. Taylor, Zhi-Wei Dang, Sanford M. Dawsey Background: Linxian, China has extremely high rates of esophageal squamous cell carcinoma (ESCC). Previous authors have proposed that esophagitis, basal cell hyperplasia (BCH) and squamous dysplasia may be precursor lesions of ESCC in such high risk populations. The purpose of this study was to examine the relationship between esophageal squamous histology and subsequent development of ESCC in Linxian. Methods: 682 Linx~n adults who took part m an endoscopic survey in 1987 were followed prospectively for 13.5 years. The participants' worst initial biopsy diagnoses were compared with the later occurrence of
A-297
AGA
Abstracts
of vessel diameter > = 4%, after the end of 5-FU application (median 11%, range 4,318,5), whereas no single contraction was noticed m 30 pts following non 5-FU based CTX. Vessel tonus generally normalized within 30 rain after stopping 5-FU application. 5 patients positive for 5-FU associated vessel contraction were repeatedly exposed to 5-FU. 5-FU associated vessel contractions were highly reproducible and reoccurred in 86% (18/21) of the cases. When these patterns were treated with glycerohrinitrate s.1. prior to 5-FU bolus applications no contraction of the brachial artery was detected in 5 of 5 occasions. With respect to possible secondary mediators of vasoconstrition there was a trend towards increased big endnthelin plasma levels after 5-FU applications (median 1,52 vs 1,99 fmol/ml; p = 0,07) whereas big endothelin levels remained unchanged after non 5-FU CTX (1,83 vs 1,83 fmol/ ml; p = 0,99). Conclusions: According to our study 5-FU is commonly accompanied by contractions of the brachial artery. This effect appears to be specific for 5-FU. 5-FU associated vessel contractions were highly reproducible on reexposure and were in case of bolus applications completely preventable by nitrate inhalation. We conclude that 5-FU-induced vasocontraction is involved in 5-FU specific cardiovascular complications and represents a valuable traget to investigate prophylactic strategie
M1039
Gene Expression Profile Using Paired Normal and Cancer Tissue Predicts Clinical Outcome of Esophageal Cancer M1042
Yoshio Ishibashi, Nobuyoshi Hanyn, Koji Nakada, Yutaka Suzuki, Takashi Yamamoto, Kiyeshi Ohkawa, Masato Matsushima, Mitsuyoshi Urashima, Noriko Hashimoto, Toshiharu Nakajima, Hirohisa Saitou
Frequency of Lymph Node Metastases in Early-Carcinoma of the Upper GastroIntestinal Tract Marcus Feith, Hubert J. Stein, J. Ruediger Siewert
Background: Esophageal sqnamons cell carcinoma has heterogeneous clinical outcomes that cannot be predicted well using any existing clinical or molecular prognostic factors. Gene expression profiling may enable more precise prediction of the clinical outcome of these patients. We developed a new approach using gene expression ratios of paired cancerous and normal tissue specimens from the same patient to reduce the effects of variation among indiwduals. Methods: Using ofigonucleotide microarrays, we analysed total RNA expression levels corresponding to 12,60.0 transcript sequences in 24 paired cancerous and normal tissue operative specimens from 12 patients with oesophageal squamous cell carcinoma. RESULTs: Hierarchical clustering analysis using gene expression ratios (cancer/normal) divided the 12 patients into 2 groups; all 7 patients in the 1st cluster survived without relapse (median follow-up 483 days), whereas all 5 patients in the 2nd cluster relapsed (median relapse free survival time: 280 days) (log-rank test: p = 0.006). in contrast, either clustering vclth cancerous tissue alone or with normal tissue alone did not show significant differences in the outcomes. Moreover, even clinical stages based on TNM classification did not predict outcome so well as profiling of gene expression ratios. The expressions of a variety of genes related to cell cycle, gene-repair, apoptosis and chemoradiotherpay resistance were up-regulated ni the poor prognostic cluster. CONCLUSION: These results suggest that ratios of paired gene expression profiles may more efficiently predict relapse free survival of esophageal squamons cell carcinoma than existing prognostic factors or than gene expression profiling with cancerous tissue alone.
Background: The optimal treatment for early carcinoma of the upper gastro-intestinal tract, limited to mucosa or submucosa, is controversy discussed. The treatment with endoscopic mucosa resection and ablation stays in contrast to the radical surgical resection and lymphadenectomy. The frequency of lymph node metastases in early carcinoma of the upper gi-tract, which are not reachable by endoscopic techniques, is unknown. Methods: We investigated 519 early carcinoma of the esophagus and stomach, limited to mucosa (pTla) and submucosa (pTlb). Including 295 gastric carcinoma, 118 adenocarcinoma of the distal esophagus and 106 squamons cell carcinoma of the esophagus. The frequency of lymph node metastases in relation to the mucosa or submucosa infiltration was evaluated. Results: Of the 519 resected pT1 a/b early carcinoma of the upper gi-tract showed 67 patients a lymph node involvement (12.9%). In the to the mucoss limited carcinoma were in eight patients a lymph node infiltration present. Only in the patients with a pTla adenocarcinoma of the distal esophagus was none lymph node infiltration detectable, in contrast the squamons cell carcinoma and gastric carcinoma showed even in mucosa pTla-carcinoma a lymph node infiltration (p<0.0001). Conclusion: Exclusively in patients with to the mucosa limited adenocarcinoma of the distal esophagus the local treatment with endoscopic ablation or mucosa resection without lymphadenectomy is oncological discussable. All other carcinoma of the upper gastro-intestinal tract present even in the pTla-category lymph node metastases and require a radical surgical resection with lymphadenectomy.
M1040 M1043
Screening of high-risk patients with head and neck cancer for early detection of synchronous esophageal squamous cell carcinoma by chromoendoscopy using Lugols solution
Prospective Evaluation Of Bone Scintigraphy As a Staging Investigation for Esophageal Carcinoma
Oliver Moesehler, Christina Middelberg-Bispnig, Wolfram Grosse-Thie, Bemd Christoph, Guentber Kloeppel, Michael K. Mueller
Peter Lamb, Arul immanuel, Jim Lloyd, David Richardson, John Wilsdon, Daya Karat, Nicholas Hayes, Michael Griffin
Objective: Patients with head and neck cancer have an increased incidence of synchronous esophageal squamous cell carcinoma. We evaluated the benefit of screening the oesophagus by using chromoendoscopy with Lugols solution in patients with known risk factors like nicotine and/or alcohol abuse. Methods: Between Sept. 2000 and Sept. 2002 we examined 70 patients. Clinical information was obtained using a standard questionnaire containing details about age, mmour state, drinking behaviour and nicotine consumption. Endoscopy was performed in slight sedation. Staining of the oesophageal mucosa was performed with 2% Lugols solution, which was applied via spraying catheter. Several biopsies were taken from all unstained areas for histopathological assessment. Results: We found esophageal carcinoma, which was not detectable by endoscopy alone in 8 patients (11%), dysplastic changes of the squamous epithelium in 11 patients (16%) and esophagitis in 36 patients (51%). Barrett oesophagus was found in 3 cases (5%). In all patients with newly detected cancer the therapeutic concept had to be changed from a curative neo-adjuvant approach to palliative treatment. In cases with dysplastic areas and newly detected Barret epithelium a careful follow-up regime was arranged. In one case with high grade dysplasia and inoperability a mucosectomy was performed. Conclusion: We recommend screening the oesophagus using Lugols solution to be included in the routine staging of all patients with head and neck cancer and known nicotine or alcohol abuse, considered eligible for neo-adjuvant therapy.
Purpose: Prom 1990 to 1999, 9% (11/125) of patients undergoing radical esophagectomy for node positive carcinoma re-presemed with symptomatic bone metastases within 12 momhs of surgery. The aim of this study was to prospectively evaluate the introduction of preoperative bone scintigraphy. Methods: Over a 12 month period from December 2000, 159 patients with esophageal carcinoma were assessed. Technetium-HDP bone scintigraphy was performed for patients identified as having transmural disease (T3) with lymph node involvement (N1) by conventional investigations (computed tomography & endoscopic ultrasound), who were otherwLse suitable for radical surgery. Results: 69 patients (43%) were suitable for radical surgery and of these 45 patients (median age 62 years, M:F ratio 3:1) staged with T3N1 disease underwent bone sclntlgraphy. The histological diagnosis was adenocarcinoma in 76% and squamous carcinoma in 24%. Bone scintigraphy was normal or showed degenerative change in 33 patients (73%), and demonstrated areas of abnormal radioisotope uptake requiring further investigation in 12 patients (27%). In 6 patients (13%) plain radiographs, MRI, and guided biopsy confirmed the presence of bone metastases; a single metastasis in 5 patients (iliao 2, humerus- 2, femur- 1) and multiple vertebral metastases in i patient. These 6 patients received palliative treatment with a median survival of 4 months. No patient undergoing bone scintigraphy has developed bone metastases following esophagectomy (n = 39) after an initial median follow up of 6 months. Conclusions: Bone scintigraphy is essential to exclude metastatic disease prior to radical surgery for advanced esophageal carcinoma. Bone is frequently the first site of distant metastatic spread and these patients are most appropriately managed by non-surgical palliation.
M1041 Arterial Vasocontraction ls a Frequent Finding Following 5-Fu Based
M1044
Chemotherapy Thomas Suedhoff, Markns Reiser, Markns Endede, Michaela Pahlke, Corinna Petz, Ullrich Graeven, Wolff 5chmiegel
Squamous Dysplasia Is the Histologic Precursor of Invasive Esophageal Squamous Cell Carcinoma: Results from a 13-ycar Prospective Follow-up Study in a High-Risk Population
Purpose: 5-Fluorouracil (5-FU) belongs to the most often used cytostatic drugs in mnltimodal treatment of esophageal carcinoma with 2-10% of patiems treated will develop cardiovascuhr complications. The underlying pathopbysiology of 5-FU-induced cardiotoxicity is unknown and noninvasive diagnostic procedures which allow a risk stratification are not established. Patients and Methods: We investigated the influence of cytostatic drugs (n=60) on the diameter of the brachial artery using high resolution ultrasound (ESAOTE/Biomedia, 13.0 MHz tranducer) in 57 patients with malignant tumors (31x GI cancer, 12x lung cancer, 9x NHL, 3x head and neck cancer, lx CUP and lx melanoma). Cytostatic drags investigated included 30 cases with 5-FU and 30 cases with non 5-FU CTX (16x cis/carboplatin, 7x anthracycline, 7x cyclophosphamide). Additionally, plasma levels of big endothelin were assessed prior and after CTX application using a commercially available ELISA assay. Results: 15 of 30 patients (50%) showed a contraction of the brachiafis artery, defined as reduction
Guo-Qing Wang, Chnstian C. Abner, Fu-Sbeng Liu, Klaus J. Lewin, Xiu-Di Sun, Mark J. Roth, You-l.in Qiao, Stereo D. Mark, Jin-Hu Fan, Philip R. Taylor, Zhi-Wei Dang, Sanford M. Dawsey Background: Linxian, China has extremely high rates of esophageal squamous cell carcinoma (ESCC). Previous authors have proposed that esophagitis, basal cell hyperplasia (BCH) and squamous dysplasia may be precursor lesions of ESCC in such high risk populations. The purpose of this study was to examine the relationship between esophageal squamous histology and subsequent development of ESCC in Linxian. Methods: 682 Linx~n adults who took part m an endoscopic survey in 1987 were followed prospectively for 13.5 years. The participants' worst initial biopsy diagnoses were compared with the later occurrence of
A-297
AGA
Abstracts