- Email: [email protected]
British stomach cancer group
EJSO 2002; 28: 560±563 doi:10.1053/ejso.2002.1311, available online at http://www.idealibrary.com on
1
BRITISH STOMACH CANCER GROUP
The following abstracts were presented at the British Oesophago-gastric Cancer Group Conference held at the Royal College of Surgeons of England on 14 April 2002. 1. Interleukin-12 polymorphisms and gastro-oesophageal cancer E. I. Dickson, B. C. Calrns, J. Eskdale, G. Callagher, R. C. Stuart University Deptartment of Surgery, Glasgow Royal Infirmary, Glasgow Aim: The host immunological response to insult depends upon a balance between anti-inflammatory cytokines (e.g. interleukin-10, IL-10) and pro-inflammatory cytokines such as interleukin-12. A previous study by this group demonstrated that the IL-10R2 allele is over-represented in H. pylori negative gastric cancer. We therefore decided to test whether there were any associations of IL-12 with gastro-oesophageal cancer. Methods: DNA was prepared from 135 patients with gastric or oesophageal cancers and 95 normal controls. The samples were genotyped using allele-specific primer polymerase chain reaction, and the results were then analysed with respect to tumour type and H. pylori status. Results: There were no differences in allele frequencies between the cancer and the control groups (80% allele A, 20% allele C). The genotype frequencies were also similar between the two groups (P 0.9) and were not influenced by histological tumour type. However, in the H. pylori-positive group 71.1% of patients were genotype A/A and 26.7% were A/C compared to 51.4% A/A and 42.9% A/C in the H. pylori-negative group (P 0.07). Conclusions: Our results suggest that there is no significant relationship between this IL-12 marker and histological tumour type. However the trend to significance at this locus implicates a probable role for the IL-12 p40 C allele in H. pylori negative gastro-oesophageal cancer.
2. Investigation of candidate Barrett's oesophageal cancer genes within a minimal region of deletion on chromosome 17p J. R. Dunn, J. Garde, A. Ellis, F. Campbell, J. R. Gosney, A. J. M. Watson, J. K. Field Royal Liverpool University Hospital & The University of Liverpool, Liverpool, UK Aim: To identify an early molecular marker of malignant potential in Barrett's oesophageal cancer (BOC), which could be used to screen for high-risk individuals who may benefit from more intensive surveillance or intervention. We have previously identified a small region of deletion on chromosome 17p that is frequently clonally deleted in Barrett's intestinal metaplasia without dysplasia (BIM) and adjacent cancer tissue. This region was designated minimal region III (MRIII) and is a candidate region for an early Barrett's tumour suppressor gene. Methods: A physical map of MRIII consisting of three BAC clones has been constructed using sequencing data from the Human Genome Mapping Project (HGMP). Results: Two of the clones are fully sequenced, with the third in two unordered fragments containing a gap of unknown size, thus the size of MRIII is approximately 450 kb and more than 99% of the sequence is known. Sequence analysis of MRIII using a suite of gene prediction 0748±7983/02/$35.00
programmes has identified 22 candidate BOC genes, including two genes (designated MAGOH-LIKE and 06-LIKE) with a high degree of homology to other human genes with a cancer related function. Conclusions: Expression analysis of MAGOH-LIKE and 006-LIKE using RT-PCR has shown that both genes are differentially expressed in BOC and OSCC. Furthermore, both genes appear to be alternatively transcribed in oesophageal cancer. These results suggest that these genes are strong candidates for BOC.
3. The host mucosal response to Helicobacter pylori may be influenced by interleukin-12 polymorphisms E. J. Dickson1, A. J. Morris2, C. Craig1, J. Eskdale1, G. Gallagher1, R. C. Stuart1 University Departments of 1Surgery and 2Medicine, Glasgow Royal Infirmary Aim: Cytokine function is believed to play a role in benign and malignant mucosal disease cytokine polymorphisms at host genetic level may be important in determining susceptibility to different mucosal responses. The aim of this study was to examine the polymorphisms of interleukin-12 (IL-12), a pro-inflammatory cytokine, in a large benign dyspeptic group with a high prevalence of H. pylori infection. We then compared this to our gastro-oesophageal cancer cohort. Methods: The study cohort, a dyspeptic population (n 300) on acid suppression therapy, was subdivided into ulcer (n 96), non-ulcer (156) and `not investigated' (n 48) categories. DNA was extracted from peripheral blood leucocytes and the distribution of the IL-12 alleles was determined by polymerised chain reaction, followed by restriction enzyme digestion. Results: The genotype frequencies for the study population were A/A 66.3%, A/C 29.7% and C/C 4%, which are very similar to our normal control frequencies of 64.2%, 31.6% and 4.2%, respectively. However, the genotype frequencies for the ulcer (42 patients) versus non-ulcer (56 patients) in the helicobacter positive group were 59.5%, 38.1%, 2.4% and 78.6%, 16.1%, 5.4%, respectively (P 0.042). Conclusions: There is a significant difference between the helicobacter positive ulcer and non-ulcer patients. We previously demonstrated a similar increased frequency of the A/A genotype in H. pylori positive gastro-oesophageal cancer patients. This study suggests that the polymorphisms of the pro-inflammatory cytokine IL-12 may influence the host mucosal response to H. pylori infection, i.e. benign ulceration or progression to malignant change.
4. Identification and analysis of candidate genes causing familial tylosis with oesophageal cancer (TOC) A. Ellis, J. E. Langan, L. Rowbottom, J. K. Field, J. M. Risk Royal Liverpool University Hospital & The University of Liverpool, Liverpool, UK Aims: Tylosis has been associated with squamous cell oesophageal cancer in three families, two of them extensive. The skin disorder and oesophageal cancer segregate together in all three pedigrees thus implying #
2002 Published by Elsevier Science Ltd.
BRITISH STOMACH CANCER GROUP
561
that the same gene causes the two phenotypes in these individuals. The causative locus, the tylosis oesophageal cancer (TOC ) gene, has also been shown to be important in sporadic squamous cell oesophageal cancer, Barrett's adeocarcinoma, breast and ovarian cancer. Methods: Sequence data from the Human Genome Project and two complete physical maps of chromosome 17q25 have allowed the identification of candidate TOC genes following the refinement of the location of the causative locus by haplotyping. The TOC minimal region now spans approximately 250 kb. Results: Computer analysis of sequence data from this minimal region identified 5 previously described, candidate genes and one novel gene. Mutation analysis of the coding region and promoters of these genes has failed to identify any tylosis-specific polymorphisms. In addition, sequence annotation has established the presence of 5±10 other `gene fragments' as ESTs and/or predicted exons and genes including 1 strong candidate gene recently described in activated rat stellar cells. Conclusion: The TOC region of chromosome 17q25 is, therefore, relatively gene-rich, containing 6 known and possibly as many as 10 additional predicted genes, and we may expect additional candidate genes to be identified in this region by other methods. Characterisation and mutation analysis of the putative genes and the activation-induced stellar cell gene is continuing. 5. CDC25B protein expression is reduced in poorly differentiated oesophageal adenocarcinomas and correlates with the level of nodal involvement C. M. Pring*, C. Verbeke, P. J. Gulllou, G. W. B. Clark, P. A. Robinson Department of Surgery, St James's University Hospital, Leeds, UK Aims: The G2/M checkpoint phosphatase CDC25B dephosphorylates and activates CDK1, precipitating the passage of the cell into mitosis. Its expression has previously been described in a number of cancers, including gastric and colorectal tumours. We aimed to assess its protein expression in oesophageal adenocarcinoma and correlate it with tumour grade, stage and lymph node status. Methods: CDC25B expression was assessed in formalin fixed specimens of oesophageal adenocarcinoma by standard immunohistochemical techniques. For fifty one specimens, the immunohistochemical scores were correlated with tumour grade and for twenty three of these specimens, the level of CDC25B expression was correlated with tumour stage and lymph node status. Results: A bivariate analysis, the Kendall Tau Correlation Test was performed on the immunohistochemistry scores for each of the variables:
Variable Tumour grade Tumour stage Nodal status
Sample number 51 23 23
Correlation coefficient
P value
0.658 0.112 0.394
, 0.001 0.611 0.039
Poorly differentiated tumours demonstrated less expression of CDC25B, as did tumours with distal nodal involvement. Conclusions: A significant difference is observed between the immunohistochemistry score and tumour grade and the immunhistochemistry score and nodal status. CDC25B immunoexpression may provide a useful diagnostic tool in further clarifying the TNM status of oesophageal adenocarcinomas. 6. Interleukin-12 may influence the mucosal response to helicobacter in all tumour locations and histological types E. J. Dickson, J. Eskdale, G. Gallagher, R. C. Stuart University Department of Surgery, Glasgow Royal Infirmary Aims: We previously demonstrated that interleukin-12 (IL-12), a proinflammatory cytokine, may have a role in determining whether
patients with Helicobacter pylori infection progress to benign ulceration or malignant change of the upper gastro-intestinal epithelium. The aim of this study was to further examine our cohort with respect to anatomical site and histological type of malignancy. Methods: 135 patients with histologically proven gastro-oesophageal malignancy and their IL-12 genotype determined by PCR. Data on the site of the tumour and histology were obtained for all patients, and helicobacter status was available for 89 patients. Results: There were 3 IL-12 genotypes identified in this population (A/A 61%, A/C 35%, C/C 4%). There were no significant differences when IL-12 genotypes were analysed with respect to anatomical location of the malignancy. The possible role of IL-12 in determining mucosal response to H. pylori infection was reproduced for adenocarcinoma, squamous carcinoma and other types of upper GI tumours. Conclusion: Our results suggest that interleukin-12 may influence the progression to malignancy in response to H. pylori in all anatomical sites of the upper gastro-intestinal tract. This observation is valid for both adenocarcinoma and squamous carcinoma.
7. The expressions of CDC25B and Cyclin D1 do not predict the sensitivity of oesophageal adenocarcinomas to neoadjuvant chemoradiotherapy C. M. Pring*, C. Verbeke, D. M. Beardsmore, P. J. Guillou#, G. W. B. Clark, P. A. Robinson Department of Surgery, St James's University Hospital, Leeds, UK Aims: Neoadjuvant chemoradiotherapy (CRT) may downstage oesophageal tumours and provide a survival advantage. To evaluate biomarkers that could be used to predict the efficacy of CRT in oesophageal adenocarcinoma, CDC25B and Cyclin D1 expressions (which have been demonstrated to predict the sensitivity of oesophageal squamous cell carcinomas to radiotherapy and CRT respectively) were assessed in biopsy specimens and correlated with the pathological response of resected specimens. Methods: CDC25B and Cyclin D1 protein expressions were assessed in formalin fixed biopsy specimens from twenty eight patients with oesophageal adenocarcinoma who subsequently had neoadjuvant CRT prior to resection, by standard immunohistochemical techniques. Staining was scored by a recognised combined method. Following eleven weeks' administration of 5-fluoracil and cisplatin, 5 weeks' radiotherapy and 6 weeks' rest, the tumour was resected and assessed microscopically for CRT response. Immunohistochemistry scores were compared to the tumour CRT sensitivity. Results: 9/28 specimens were CRT resistant. 3/28 biopsies demonstrated no tumour when examined for Cyclin D1 expression. A Mann±Whitney U-test was applied:
Biomarker
CDC25B CDC25B Cyclin D1 Cyclin D1
CRT sensitivity CRT CRT CRT CRT
sensitive resistant sensitive resistant
Number
Median immuno score
IQR
19 9 18 7
2.0 1.0 1.5 2.0
0.5±2.0 0±3.0 1.0±2.0 1.0±3.0
P value
0.879 0.241
CRT: chemoradiotherapy; IQR: interquartile range. Conclusions: A significant difference is observed between CRT sensitive and CRT resistant tumours for neither CDC25B nor Cyclin D1 immunohistochemistry scores. Therefore CDC25B and Cyclin D1 do not appear to be useful biomarkers in predicting the sensitivity of oesophageal adenocarcinomas to CRT.
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BRITISH STOMACH CANCER GROUP
8. Significance of cardiac doses received during chemoradiation for oesophageal and oesophago-gastric junctional tumours S. Mukherjee, M. Minnett, D. Aston, T. D. L. Crosby Velindre Hospital, Cardiff
10. Surgical management of gastric cancer in the elderly: The ASCOT experience R. T. Gunasekera, P. G. McCulloch Academic Department of Surgery, University Hospital Aintree, Liverpool, UK
Aim: Pre-operative chemoradiotherapy (CT-RT) for oesophageal carcinoma improves survival compared to single modality regimens. Although radiation-induced cardiotoxicity has been described in patients with breast cancer and Hodgkin's disease, cardiovascular effect of oesophageal radiotherapy has not been evaluated. Quantification of cardiac dose received during CT-RT for oesophageal cancer, assessment of its impact on cardiac function, and methods of reducing cardiac dose. Method: A retrospective study of 15 patients with carcinoma of the mid and lower oesophagus undergoing combined modality treatment, in whom a pre- and post-treatment MUGA scans were available. Chemotherapy consisted of cisplatin and 5-fluorouracil with or without paclitaxel. The total dose of radiotherapy was 45±50 Gy in 25 fractions (60% given as anterior±posterior parallel opposed fields, remainder with 1 anterior and 2 posterior oblique fields to reduce spinal cord dose). Cardiac doses were calculated from dose-volume histograms. Results: Ejection fraction dropped in 12 of the 15 patients, with a significant drop in median ejection fraction post CT-RT (63±58%, P 0.003). Shielding blocks reduced the cardiac dose significantly (29.4 vs 34 Gy, P 0.001). The use of 3-field technique throughout also significantly reduced the mean cardiac dose and the volume of heart receiving 70% of total dose although it increased total lung dose. Conclusion: Oesophageal chemo-radiation causes a small but significant drop in ejection fraction. Careful CT-planned treatment reduces cardiac doses received. The cardiac as well as the pulmonary sideeffects of chemo-radiation need to be borne in mind, especially when considering radical surgery.
Aims: From the early 1990s one-quarter of newly diagnosed gastric cancer patients have been over 80 years of age. ASCOT is an on-going multi-centre study of Gastric and Oesophageal cancer. We analysed the results of the first 1055 patients recruited in order to establish the relationship between age, preoperative fitness and outcome following gastric cancer surgery. Methods: Data was collected prospectively on a purpose-designed computerized database and then analysed. Results: 264 of 504 patients with gastric cancer proceeded to have surgical resection. There ages ranged from 34 to 94 (median 65.5) years. ASA grade distribution was as follows: Grade I 17%, Grade II 49%, Grade III 31% & Grade IV 3%. 109 patients were aged ,70 (40%). 111 were aged 70±79 (40%) and 44 were over 80 years (20%). Surgical procedures were as follows:
9. Cisplatin and continuous 5FU chemotherapy combined with surgery and/or radiotherapy for early stage oesophageal cancer. A retrospective audit of patients treated October 1999±May 2001 inclusive E. Sherwin, D. Gilligan, S. E. Old, G. Stent Department of Oncology, Addenbrookes NHS Trust Aim: Cisplatin-based chemotherapy used pre-operatively, concurrently with radical radiotherapy, and as part of tri-modality therapy; concurrently with radiation followed by surgery, has been shown to be beneficial in terms of reducing relapse rates and improving survival in early stage oesophageal cancer. We have conducted a retrospective review of patients treated with cisplatin based chemotherapy as part of combined therapy in our department, October 1999±May 2001 inclusive. Method: Patients were identified by records held by clinical staff and through chemotherapy and surgical records. Case notes were reviewed. Information regarding staging, histology, treatment received, toxicity and pathological staging of surgical cases was recorded. Surgery was performed in the centre and three other hospitals within the Cancer Network. Results: Total of 33 patients were treated with cisplatin 5FU chemotherapy, median age 60 (33±79), pre-operative (n 16), concurrent chemoradiation (n 8), trimodality therapy (n 9). Treatment was in general well tolerated, details to be presented. Median survival following trimodality therapy 18 months. Median follow-up for chemoradiation group 14 months, 6/8 patient alive. Median follow-up for the pre-operative group is 12 months, 12/16 alive. Conclusion: In our centre, which is to be an approved centre under the COG guidelines, combined modality therapy for early oesophageal cancer with cisplatin and continuous 5FU chemotherapy is well tolerated and does not lead to excessive morbidity peri/post-operatively. Toxicity and survival data to be presented and correlation between clinical and pathological staging will be described where applicable.
Procedure Distal gastrectomy Proximal gastrectomy Total gastrectomy Other
No. of patients 111 24 113 16
The D1 : D2 Ratio for patients , 70 was 1 : 2.9, for patients aged 70±79, was 1 : 1, and for patients . 80 years was 2.25 : 1. Patients under 70 were twice as likely to have total gastrectomy as opposed to distal gastrectomy; the pattern was reversed in patients over 80 years. Overall mortality rate was 15.53%. Mortality for patients , 70 was 12.84%, for patients aged 70±79, 17.11% and for patients . 80 years 18.18%. Mortality rates were analysed for the three age ranges for ASA grades I & II and III & IV respectively. Mortality for patients , 70 and 70±79 years in ASA grades I & II were comparable. Older patients with higher ASA grades did less well (P , 0.05). Conclusions: Older patients appear to have different and often less radical surgery. Those with higher preoperative risk did less well following surgery, and careful consideration should be made prior to contemplating such resections in this group of patients. 11. ALA photodynamic therapy for dysplasia in Barrett's oesophagus. Identifying factors involved with success N. F. Jamieson1, M. Novell2, S. M. Thorpe1, A. Mosse1, S. G. Bown1, L. B. Lovat1 1 National Medical Laser Centre, 2Department of Histopathology, Royal Free and University College School of Medicine, University College London Aim: Oesophagectomy is the standard treatment for high-grade dysplasia (HGD) and intramucosal carcinoma (IMCa) associated with Barrett's oesophagus, but has significant morbidity and mortality. Photodynamic therapy (PDT) is a minimally-invasive alternative for ablation of dysplastic mucosa. Encouraging results have been obtained, but parameters involved with success are not well defined. Methods: 17 patients with HGD or IMCa who declined or were unfit for surgery were treated with PDT after photosensitisation using 5-aminolaevulinic acid (ALA). Follow-up was by multiple biopsies at endoscopy 2, 6 and 12 months after treatment. Dose of light (500±1000 J/cm diffuser fibre), length of Barrett's segment and extent of dysplasia were studied. Results: 8/17 (47%) patients are clear of HGD/IMCa with a median follow-up of 7.5 months (2±24 months). A total of 31 treatments have been given (median 2 per patient). Higher light doses were more
BRITISH STOMACH CANCER GROUP successful (success in 0/4 treatments at 500±625 J/cm fibre, 4/17 treatments at 750±785 J/cm and 5/6 treatments at l000 J/cm, P , 0.02). Success was more likely when HGD was confined to one oesophageal level (success in 7/9 treatments for unifocal disease vs 2/18 treatments for multi-focal disease, P , 0.001) and with a shorter Barrett's segment (mean 4.5 cm in successful group, vs 8.3 cm in failed group, P , 0.005). Conclusions: Eradication of dysplasia in Barrett's oesophagus by ALA PDT appears more successful with higher light doses, although outcome is dependent on the length of Barrett's segment and extent of dysplasia. Patients with multi-focal disease in a long Barrett's segment may need a more intensive regime. 12. The use of self-expanding metallic stents in the palliation of dysphagia A. G. N. Robertson, N. B. Teo, E. G. Wilmo, J. Kelly, S. Kettlewell, S. Millar, J. Richards Hairmyres Hospital, East Kilbride, Scotland Aim: Self-expanding metallic stents (SEMS) have been used with considerable success in the palliation of dysphagia in patients with malignant oesophageal obstruction. The aim of this retrospective study was to evaluate the clinical efficacy of SEMS in the treatment of patients with malignant oesophageal obstruction in the unit. Methods: Between March 1997 and February 2001, SEMS were inserted in 50 consecutive patients (30 men, 20 women) with a median age of 69 years (range 48±90 years). Dysphagia was graded on a 4-point scale (0 no dyspagia, 1 dysphagia to solids only, 2 dysphagia to liquids, 3 complete dysphagia). All patients were followed up until death. Results: The median follow up for these 50 patients was 51 days (range 3±472). A total of 75 stents were used. Additional stents were required in patients where stent migration occurred (n l1) and where the oesophageal lesion was exceedingly long (n 8). The mean dysphagia score improved from 2.18 before stenting to 0.64 within 3 days after stent deployment (P , 0.001). Complications occurred in 16 patients (32%) with no procedure-related mortality. The median hospital stay was 3 days (range 1±56). The 30 day survival was 60% (n 30). 18% (n 9) of patients survived for more than 3 months. Conclusion: This study suggests that oesophageal stenting with SEMS is a safe and effective palliative treatment for patients with inoperable malignant dysphagia and has the benefit of early patient discharge. 13. Preoperative assessment in upper GI cancer surgery: results of a Delphi consensus R. T. Gunasekara, P. G. McCulloch Academic Department of Surgery, University Hospital Aintree, Liverpool, UK Aim: Opinion on preoperative assessment of patients awaiting upper GI cancer surgery is divided. We conducted a Delphi survey
563 of the practise of leading experts in this field. Delphi is a formal method of distilling expert opinion involving a series of postal questionnaires, which allow an iterative feedback process amongst participants. Methods: 21 responses were received from 30 panel members who were contacted. One panel member had recently retired. Therefore 20 questionnaires were analysed (69% response rate). Results:
Table 1 Parameters used by experts Parameter Clinical Age Wt loss Obesity Alcohol Tobacco
% experts using 70 80 80 75 90
Simple investigation Spirometry ECG CXR LET'S
>80 >90 95 >90
Complex investigation Exercise tests 24-hour ECG Echocardiogram Arterial blood gases
>40 >5 >40 >50
Scoring system ASA POSSUM APACHE
65 30 10
Patient age was considered important in decision making by over 70% of responders. Over 75% considered clinical parameters to be important. Over 90% used simple investigations in decision making. More complex investigations and scoring systems were used by a minority, except ASA grade which 65% of experts used. Other parameters that were considered important by some experts included assessment of mobility, general and mental status and global subjective assessment of patients. Conclusion: Clinical parameters, simple investigations and spirometry together with experience and subjective assessment still form the mainstay in surgical decision making in upper GI cancer surgery. More sophisticated testing and risk scoring is currently used only by a minority of recognised experts.
1
BRITISH STOMACH CANCER GROUP
The following abstracts were presented at the British Oesophago-gastric Cancer Group Conference held at the Royal College of Surgeons of England on 14 April 2002. 1. Interleukin-12 polymorphisms and gastro-oesophageal cancer E. I. Dickson, B. C. Calrns, J. Eskdale, G. Callagher, R. C. Stuart University Deptartment of Surgery, Glasgow Royal Infirmary, Glasgow Aim: The host immunological response to insult depends upon a balance between anti-inflammatory cytokines (e.g. interleukin-10, IL-10) and pro-inflammatory cytokines such as interleukin-12. A previous study by this group demonstrated that the IL-10R2 allele is over-represented in H. pylori negative gastric cancer. We therefore decided to test whether there were any associations of IL-12 with gastro-oesophageal cancer. Methods: DNA was prepared from 135 patients with gastric or oesophageal cancers and 95 normal controls. The samples were genotyped using allele-specific primer polymerase chain reaction, and the results were then analysed with respect to tumour type and H. pylori status. Results: There were no differences in allele frequencies between the cancer and the control groups (80% allele A, 20% allele C). The genotype frequencies were also similar between the two groups (P 0.9) and were not influenced by histological tumour type. However, in the H. pylori-positive group 71.1% of patients were genotype A/A and 26.7% were A/C compared to 51.4% A/A and 42.9% A/C in the H. pylori-negative group (P 0.07). Conclusions: Our results suggest that there is no significant relationship between this IL-12 marker and histological tumour type. However the trend to significance at this locus implicates a probable role for the IL-12 p40 C allele in H. pylori negative gastro-oesophageal cancer.
2. Investigation of candidate Barrett's oesophageal cancer genes within a minimal region of deletion on chromosome 17p J. R. Dunn, J. Garde, A. Ellis, F. Campbell, J. R. Gosney, A. J. M. Watson, J. K. Field Royal Liverpool University Hospital & The University of Liverpool, Liverpool, UK Aim: To identify an early molecular marker of malignant potential in Barrett's oesophageal cancer (BOC), which could be used to screen for high-risk individuals who may benefit from more intensive surveillance or intervention. We have previously identified a small region of deletion on chromosome 17p that is frequently clonally deleted in Barrett's intestinal metaplasia without dysplasia (BIM) and adjacent cancer tissue. This region was designated minimal region III (MRIII) and is a candidate region for an early Barrett's tumour suppressor gene. Methods: A physical map of MRIII consisting of three BAC clones has been constructed using sequencing data from the Human Genome Mapping Project (HGMP). Results: Two of the clones are fully sequenced, with the third in two unordered fragments containing a gap of unknown size, thus the size of MRIII is approximately 450 kb and more than 99% of the sequence is known. Sequence analysis of MRIII using a suite of gene prediction 0748±7983/02/$35.00
programmes has identified 22 candidate BOC genes, including two genes (designated MAGOH-LIKE and 06-LIKE) with a high degree of homology to other human genes with a cancer related function. Conclusions: Expression analysis of MAGOH-LIKE and 006-LIKE using RT-PCR has shown that both genes are differentially expressed in BOC and OSCC. Furthermore, both genes appear to be alternatively transcribed in oesophageal cancer. These results suggest that these genes are strong candidates for BOC.
3. The host mucosal response to Helicobacter pylori may be influenced by interleukin-12 polymorphisms E. J. Dickson1, A. J. Morris2, C. Craig1, J. Eskdale1, G. Gallagher1, R. C. Stuart1 University Departments of 1Surgery and 2Medicine, Glasgow Royal Infirmary Aim: Cytokine function is believed to play a role in benign and malignant mucosal disease cytokine polymorphisms at host genetic level may be important in determining susceptibility to different mucosal responses. The aim of this study was to examine the polymorphisms of interleukin-12 (IL-12), a pro-inflammatory cytokine, in a large benign dyspeptic group with a high prevalence of H. pylori infection. We then compared this to our gastro-oesophageal cancer cohort. Methods: The study cohort, a dyspeptic population (n 300) on acid suppression therapy, was subdivided into ulcer (n 96), non-ulcer (156) and `not investigated' (n 48) categories. DNA was extracted from peripheral blood leucocytes and the distribution of the IL-12 alleles was determined by polymerised chain reaction, followed by restriction enzyme digestion. Results: The genotype frequencies for the study population were A/A 66.3%, A/C 29.7% and C/C 4%, which are very similar to our normal control frequencies of 64.2%, 31.6% and 4.2%, respectively. However, the genotype frequencies for the ulcer (42 patients) versus non-ulcer (56 patients) in the helicobacter positive group were 59.5%, 38.1%, 2.4% and 78.6%, 16.1%, 5.4%, respectively (P 0.042). Conclusions: There is a significant difference between the helicobacter positive ulcer and non-ulcer patients. We previously demonstrated a similar increased frequency of the A/A genotype in H. pylori positive gastro-oesophageal cancer patients. This study suggests that the polymorphisms of the pro-inflammatory cytokine IL-12 may influence the host mucosal response to H. pylori infection, i.e. benign ulceration or progression to malignant change.
4. Identification and analysis of candidate genes causing familial tylosis with oesophageal cancer (TOC) A. Ellis, J. E. Langan, L. Rowbottom, J. K. Field, J. M. Risk Royal Liverpool University Hospital & The University of Liverpool, Liverpool, UK Aims: Tylosis has been associated with squamous cell oesophageal cancer in three families, two of them extensive. The skin disorder and oesophageal cancer segregate together in all three pedigrees thus implying #
2002 Published by Elsevier Science Ltd.
BRITISH STOMACH CANCER GROUP
561
that the same gene causes the two phenotypes in these individuals. The causative locus, the tylosis oesophageal cancer (TOC ) gene, has also been shown to be important in sporadic squamous cell oesophageal cancer, Barrett's adeocarcinoma, breast and ovarian cancer. Methods: Sequence data from the Human Genome Project and two complete physical maps of chromosome 17q25 have allowed the identification of candidate TOC genes following the refinement of the location of the causative locus by haplotyping. The TOC minimal region now spans approximately 250 kb. Results: Computer analysis of sequence data from this minimal region identified 5 previously described, candidate genes and one novel gene. Mutation analysis of the coding region and promoters of these genes has failed to identify any tylosis-specific polymorphisms. In addition, sequence annotation has established the presence of 5±10 other `gene fragments' as ESTs and/or predicted exons and genes including 1 strong candidate gene recently described in activated rat stellar cells. Conclusion: The TOC region of chromosome 17q25 is, therefore, relatively gene-rich, containing 6 known and possibly as many as 10 additional predicted genes, and we may expect additional candidate genes to be identified in this region by other methods. Characterisation and mutation analysis of the putative genes and the activation-induced stellar cell gene is continuing. 5. CDC25B protein expression is reduced in poorly differentiated oesophageal adenocarcinomas and correlates with the level of nodal involvement C. M. Pring*, C. Verbeke, P. J. Gulllou, G. W. B. Clark, P. A. Robinson Department of Surgery, St James's University Hospital, Leeds, UK Aims: The G2/M checkpoint phosphatase CDC25B dephosphorylates and activates CDK1, precipitating the passage of the cell into mitosis. Its expression has previously been described in a number of cancers, including gastric and colorectal tumours. We aimed to assess its protein expression in oesophageal adenocarcinoma and correlate it with tumour grade, stage and lymph node status. Methods: CDC25B expression was assessed in formalin fixed specimens of oesophageal adenocarcinoma by standard immunohistochemical techniques. For fifty one specimens, the immunohistochemical scores were correlated with tumour grade and for twenty three of these specimens, the level of CDC25B expression was correlated with tumour stage and lymph node status. Results: A bivariate analysis, the Kendall Tau Correlation Test was performed on the immunohistochemistry scores for each of the variables:
Variable Tumour grade Tumour stage Nodal status
Sample number 51 23 23
Correlation coefficient
P value
0.658 0.112 0.394
, 0.001 0.611 0.039
Poorly differentiated tumours demonstrated less expression of CDC25B, as did tumours with distal nodal involvement. Conclusions: A significant difference is observed between the immunohistochemistry score and tumour grade and the immunhistochemistry score and nodal status. CDC25B immunoexpression may provide a useful diagnostic tool in further clarifying the TNM status of oesophageal adenocarcinomas. 6. Interleukin-12 may influence the mucosal response to helicobacter in all tumour locations and histological types E. J. Dickson, J. Eskdale, G. Gallagher, R. C. Stuart University Department of Surgery, Glasgow Royal Infirmary Aims: We previously demonstrated that interleukin-12 (IL-12), a proinflammatory cytokine, may have a role in determining whether
patients with Helicobacter pylori infection progress to benign ulceration or malignant change of the upper gastro-intestinal epithelium. The aim of this study was to further examine our cohort with respect to anatomical site and histological type of malignancy. Methods: 135 patients with histologically proven gastro-oesophageal malignancy and their IL-12 genotype determined by PCR. Data on the site of the tumour and histology were obtained for all patients, and helicobacter status was available for 89 patients. Results: There were 3 IL-12 genotypes identified in this population (A/A 61%, A/C 35%, C/C 4%). There were no significant differences when IL-12 genotypes were analysed with respect to anatomical location of the malignancy. The possible role of IL-12 in determining mucosal response to H. pylori infection was reproduced for adenocarcinoma, squamous carcinoma and other types of upper GI tumours. Conclusion: Our results suggest that interleukin-12 may influence the progression to malignancy in response to H. pylori in all anatomical sites of the upper gastro-intestinal tract. This observation is valid for both adenocarcinoma and squamous carcinoma.
7. The expressions of CDC25B and Cyclin D1 do not predict the sensitivity of oesophageal adenocarcinomas to neoadjuvant chemoradiotherapy C. M. Pring*, C. Verbeke, D. M. Beardsmore, P. J. Guillou#, G. W. B. Clark, P. A. Robinson Department of Surgery, St James's University Hospital, Leeds, UK Aims: Neoadjuvant chemoradiotherapy (CRT) may downstage oesophageal tumours and provide a survival advantage. To evaluate biomarkers that could be used to predict the efficacy of CRT in oesophageal adenocarcinoma, CDC25B and Cyclin D1 expressions (which have been demonstrated to predict the sensitivity of oesophageal squamous cell carcinomas to radiotherapy and CRT respectively) were assessed in biopsy specimens and correlated with the pathological response of resected specimens. Methods: CDC25B and Cyclin D1 protein expressions were assessed in formalin fixed biopsy specimens from twenty eight patients with oesophageal adenocarcinoma who subsequently had neoadjuvant CRT prior to resection, by standard immunohistochemical techniques. Staining was scored by a recognised combined method. Following eleven weeks' administration of 5-fluoracil and cisplatin, 5 weeks' radiotherapy and 6 weeks' rest, the tumour was resected and assessed microscopically for CRT response. Immunohistochemistry scores were compared to the tumour CRT sensitivity. Results: 9/28 specimens were CRT resistant. 3/28 biopsies demonstrated no tumour when examined for Cyclin D1 expression. A Mann±Whitney U-test was applied:
Biomarker
CDC25B CDC25B Cyclin D1 Cyclin D1
CRT sensitivity CRT CRT CRT CRT
sensitive resistant sensitive resistant
Number
Median immuno score
IQR
19 9 18 7
2.0 1.0 1.5 2.0
0.5±2.0 0±3.0 1.0±2.0 1.0±3.0
P value
0.879 0.241
CRT: chemoradiotherapy; IQR: interquartile range. Conclusions: A significant difference is observed between CRT sensitive and CRT resistant tumours for neither CDC25B nor Cyclin D1 immunohistochemistry scores. Therefore CDC25B and Cyclin D1 do not appear to be useful biomarkers in predicting the sensitivity of oesophageal adenocarcinomas to CRT.
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8. Significance of cardiac doses received during chemoradiation for oesophageal and oesophago-gastric junctional tumours S. Mukherjee, M. Minnett, D. Aston, T. D. L. Crosby Velindre Hospital, Cardiff
10. Surgical management of gastric cancer in the elderly: The ASCOT experience R. T. Gunasekera, P. G. McCulloch Academic Department of Surgery, University Hospital Aintree, Liverpool, UK
Aim: Pre-operative chemoradiotherapy (CT-RT) for oesophageal carcinoma improves survival compared to single modality regimens. Although radiation-induced cardiotoxicity has been described in patients with breast cancer and Hodgkin's disease, cardiovascular effect of oesophageal radiotherapy has not been evaluated. Quantification of cardiac dose received during CT-RT for oesophageal cancer, assessment of its impact on cardiac function, and methods of reducing cardiac dose. Method: A retrospective study of 15 patients with carcinoma of the mid and lower oesophagus undergoing combined modality treatment, in whom a pre- and post-treatment MUGA scans were available. Chemotherapy consisted of cisplatin and 5-fluorouracil with or without paclitaxel. The total dose of radiotherapy was 45±50 Gy in 25 fractions (60% given as anterior±posterior parallel opposed fields, remainder with 1 anterior and 2 posterior oblique fields to reduce spinal cord dose). Cardiac doses were calculated from dose-volume histograms. Results: Ejection fraction dropped in 12 of the 15 patients, with a significant drop in median ejection fraction post CT-RT (63±58%, P 0.003). Shielding blocks reduced the cardiac dose significantly (29.4 vs 34 Gy, P 0.001). The use of 3-field technique throughout also significantly reduced the mean cardiac dose and the volume of heart receiving 70% of total dose although it increased total lung dose. Conclusion: Oesophageal chemo-radiation causes a small but significant drop in ejection fraction. Careful CT-planned treatment reduces cardiac doses received. The cardiac as well as the pulmonary sideeffects of chemo-radiation need to be borne in mind, especially when considering radical surgery.
Aims: From the early 1990s one-quarter of newly diagnosed gastric cancer patients have been over 80 years of age. ASCOT is an on-going multi-centre study of Gastric and Oesophageal cancer. We analysed the results of the first 1055 patients recruited in order to establish the relationship between age, preoperative fitness and outcome following gastric cancer surgery. Methods: Data was collected prospectively on a purpose-designed computerized database and then analysed. Results: 264 of 504 patients with gastric cancer proceeded to have surgical resection. There ages ranged from 34 to 94 (median 65.5) years. ASA grade distribution was as follows: Grade I 17%, Grade II 49%, Grade III 31% & Grade IV 3%. 109 patients were aged ,70 (40%). 111 were aged 70±79 (40%) and 44 were over 80 years (20%). Surgical procedures were as follows:
9. Cisplatin and continuous 5FU chemotherapy combined with surgery and/or radiotherapy for early stage oesophageal cancer. A retrospective audit of patients treated October 1999±May 2001 inclusive E. Sherwin, D. Gilligan, S. E. Old, G. Stent Department of Oncology, Addenbrookes NHS Trust Aim: Cisplatin-based chemotherapy used pre-operatively, concurrently with radical radiotherapy, and as part of tri-modality therapy; concurrently with radiation followed by surgery, has been shown to be beneficial in terms of reducing relapse rates and improving survival in early stage oesophageal cancer. We have conducted a retrospective review of patients treated with cisplatin based chemotherapy as part of combined therapy in our department, October 1999±May 2001 inclusive. Method: Patients were identified by records held by clinical staff and through chemotherapy and surgical records. Case notes were reviewed. Information regarding staging, histology, treatment received, toxicity and pathological staging of surgical cases was recorded. Surgery was performed in the centre and three other hospitals within the Cancer Network. Results: Total of 33 patients were treated with cisplatin 5FU chemotherapy, median age 60 (33±79), pre-operative (n 16), concurrent chemoradiation (n 8), trimodality therapy (n 9). Treatment was in general well tolerated, details to be presented. Median survival following trimodality therapy 18 months. Median follow-up for chemoradiation group 14 months, 6/8 patient alive. Median follow-up for the pre-operative group is 12 months, 12/16 alive. Conclusion: In our centre, which is to be an approved centre under the COG guidelines, combined modality therapy for early oesophageal cancer with cisplatin and continuous 5FU chemotherapy is well tolerated and does not lead to excessive morbidity peri/post-operatively. Toxicity and survival data to be presented and correlation between clinical and pathological staging will be described where applicable.
Procedure Distal gastrectomy Proximal gastrectomy Total gastrectomy Other
No. of patients 111 24 113 16
The D1 : D2 Ratio for patients , 70 was 1 : 2.9, for patients aged 70±79, was 1 : 1, and for patients . 80 years was 2.25 : 1. Patients under 70 were twice as likely to have total gastrectomy as opposed to distal gastrectomy; the pattern was reversed in patients over 80 years. Overall mortality rate was 15.53%. Mortality for patients , 70 was 12.84%, for patients aged 70±79, 17.11% and for patients . 80 years 18.18%. Mortality rates were analysed for the three age ranges for ASA grades I & II and III & IV respectively. Mortality for patients , 70 and 70±79 years in ASA grades I & II were comparable. Older patients with higher ASA grades did less well (P , 0.05). Conclusions: Older patients appear to have different and often less radical surgery. Those with higher preoperative risk did less well following surgery, and careful consideration should be made prior to contemplating such resections in this group of patients. 11. ALA photodynamic therapy for dysplasia in Barrett's oesophagus. Identifying factors involved with success N. F. Jamieson1, M. Novell2, S. M. Thorpe1, A. Mosse1, S. G. Bown1, L. B. Lovat1 1 National Medical Laser Centre, 2Department of Histopathology, Royal Free and University College School of Medicine, University College London Aim: Oesophagectomy is the standard treatment for high-grade dysplasia (HGD) and intramucosal carcinoma (IMCa) associated with Barrett's oesophagus, but has significant morbidity and mortality. Photodynamic therapy (PDT) is a minimally-invasive alternative for ablation of dysplastic mucosa. Encouraging results have been obtained, but parameters involved with success are not well defined. Methods: 17 patients with HGD or IMCa who declined or were unfit for surgery were treated with PDT after photosensitisation using 5-aminolaevulinic acid (ALA). Follow-up was by multiple biopsies at endoscopy 2, 6 and 12 months after treatment. Dose of light (500±1000 J/cm diffuser fibre), length of Barrett's segment and extent of dysplasia were studied. Results: 8/17 (47%) patients are clear of HGD/IMCa with a median follow-up of 7.5 months (2±24 months). A total of 31 treatments have been given (median 2 per patient). Higher light doses were more
BRITISH STOMACH CANCER GROUP successful (success in 0/4 treatments at 500±625 J/cm fibre, 4/17 treatments at 750±785 J/cm and 5/6 treatments at l000 J/cm, P , 0.02). Success was more likely when HGD was confined to one oesophageal level (success in 7/9 treatments for unifocal disease vs 2/18 treatments for multi-focal disease, P , 0.001) and with a shorter Barrett's segment (mean 4.5 cm in successful group, vs 8.3 cm in failed group, P , 0.005). Conclusions: Eradication of dysplasia in Barrett's oesophagus by ALA PDT appears more successful with higher light doses, although outcome is dependent on the length of Barrett's segment and extent of dysplasia. Patients with multi-focal disease in a long Barrett's segment may need a more intensive regime. 12. The use of self-expanding metallic stents in the palliation of dysphagia A. G. N. Robertson, N. B. Teo, E. G. Wilmo, J. Kelly, S. Kettlewell, S. Millar, J. Richards Hairmyres Hospital, East Kilbride, Scotland Aim: Self-expanding metallic stents (SEMS) have been used with considerable success in the palliation of dysphagia in patients with malignant oesophageal obstruction. The aim of this retrospective study was to evaluate the clinical efficacy of SEMS in the treatment of patients with malignant oesophageal obstruction in the unit. Methods: Between March 1997 and February 2001, SEMS were inserted in 50 consecutive patients (30 men, 20 women) with a median age of 69 years (range 48±90 years). Dysphagia was graded on a 4-point scale (0 no dyspagia, 1 dysphagia to solids only, 2 dysphagia to liquids, 3 complete dysphagia). All patients were followed up until death. Results: The median follow up for these 50 patients was 51 days (range 3±472). A total of 75 stents were used. Additional stents were required in patients where stent migration occurred (n l1) and where the oesophageal lesion was exceedingly long (n 8). The mean dysphagia score improved from 2.18 before stenting to 0.64 within 3 days after stent deployment (P , 0.001). Complications occurred in 16 patients (32%) with no procedure-related mortality. The median hospital stay was 3 days (range 1±56). The 30 day survival was 60% (n 30). 18% (n 9) of patients survived for more than 3 months. Conclusion: This study suggests that oesophageal stenting with SEMS is a safe and effective palliative treatment for patients with inoperable malignant dysphagia and has the benefit of early patient discharge. 13. Preoperative assessment in upper GI cancer surgery: results of a Delphi consensus R. T. Gunasekara, P. G. McCulloch Academic Department of Surgery, University Hospital Aintree, Liverpool, UK Aim: Opinion on preoperative assessment of patients awaiting upper GI cancer surgery is divided. We conducted a Delphi survey
563 of the practise of leading experts in this field. Delphi is a formal method of distilling expert opinion involving a series of postal questionnaires, which allow an iterative feedback process amongst participants. Methods: 21 responses were received from 30 panel members who were contacted. One panel member had recently retired. Therefore 20 questionnaires were analysed (69% response rate). Results:
Table 1 Parameters used by experts Parameter Clinical Age Wt loss Obesity Alcohol Tobacco
% experts using 70 80 80 75 90
Simple investigation Spirometry ECG CXR LET'S
>80 >90 95 >90
Complex investigation Exercise tests 24-hour ECG Echocardiogram Arterial blood gases
>40 >5 >40 >50
Scoring system ASA POSSUM APACHE
65 30 10
Patient age was considered important in decision making by over 70% of responders. Over 75% considered clinical parameters to be important. Over 90% used simple investigations in decision making. More complex investigations and scoring systems were used by a minority, except ASA grade which 65% of experts used. Other parameters that were considered important by some experts included assessment of mobility, general and mental status and global subjective assessment of patients. Conclusion: Clinical parameters, simple investigations and spirometry together with experience and subjective assessment still form the mainstay in surgical decision making in upper GI cancer surgery. More sophisticated testing and risk scoring is currently used only by a minority of recognised experts.