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Urinary transforming growth factor activity: A marker of gastrointestinal malignancy
A518
AGA ABSTRACTS
ACCEPTABILITY OF A FAMILIAL COLORECTAL CANCER SCREENING PROGRAMME IN MAJORCA (SPAIN). A. Obrador, E. Cabeza#, A. Llompart, M. Zaforteza#, M. Pons, F.X. Bosch*, J. Gay&. Dept. of Gastroent., Son Dureta Hospital, Palma #Cancer Epidemiology Unit of Majorca and *Registry, Cancer Control and Epidemiology Unit, Hospital "Duran i Reynals" Barcelona. First degree relatives of patients diagnosed with colorectal cancer have a two-to-threefold increased risk of developing this neoplasm over the general population. A pilot screening programme has been started in Majorca adressed to this high risk population, and now we evaluate the initial acceptability. The siblings of 173 cancer cotorectal patients who had participated in a previous study were selected. They were contacted by a letter explaining the aims of the study and motivating them to participate. Subsequently a specialized nurse arranged by telephone an appointment to be held in their homes, in order to explain what the study consisted of, carry out a familial medical history and, if they agreed to participate, she left information explaining the faecal occult blood test and the preparation for a sigmoidoscopy. Following this approach we made 21 interviews in which only 13% agreed to participate. Because of the low acceptability of the programme, and realising that one of the greatest difficulties seemed to be the sigmoidoscopy, we decided to modify the strategy of approach to the programme. During the visit to the home, the nurse now describes the objectives of the study, completes the family medical history, and explains how to carry out the hemoccult. When we receive the hemoccult, a doctor arranges for a personal interview in order to explain the convenience of having a sigmoidoscopy. In this way the acceptability has increased to 75%. CONCLUSIONS: 1) In our study, acceptability of the cancer colorectal screening programme directed to first-degree relatives is low when hemoccult and sigmoidoscopy are proposed together. 2) We can increase acceptability of the programme if initially we plan only the hemoccult and subsequently s medical doctor explains the convenience of realizing a sigmoidoscopy. This work was funded by Fondode InvestigacionesSanitarias(Spain)94/0026-01
• URINARY TRANSFORMING GROWTH FACTOR ACTIVITY: A MARKER OF GASTROINTESTINAL MALIGNANCY F. O*Brien, J.K. Collins, S. Herlihy, F. Shanahan, G.C. O'Sullivan. University College Cork, IRELAND. Several biologically active peptides including transforming growth factors are produced by tumors, and are detectable in urine. Detection of tumor-associated urinary transforming growth factor (TGF) activity may have significant clinical diagnostic potential. We have evaluated 80 consecutive patients with gastrointestinal cancers using a bioassay of TGF activity in early morning urinary specimens. These included 18 with gastric adenocarcinoma, 20 with esophageal squamous and 42 with colorectal cancer. Patients with known proteinuria, genitourinary inflammatory or infectious disease or genitourinary malignancy were excluded. The TGF bioassay was the standard NRK transformation assay of clonogenic colony formation in soft agar. TGF values were standardized based on urinary protein concentration. Results were compared with normal subjects (n = 30) and inflammatory bowel disease controls (n = 20). A clear separation between controls and the majority of patients with malignancy was evident. Thus, 90% of patients with gastric cancer, 80% of those with esophageal and 93% of those with colonic carcinoma had values in excess of the highest detected level of urinary TGF activity found in the controls. In patients where curative surgical resection was performed, the urinary TGF activity fell toward normal in all cases. Using HPLC gel filtration, we fractionated urines into multiple peaks of TGF activity. The activity profile corresponded with the profile found in supematants of tumor-derived cell lines that were generated from some of these patients. Studies with neutralizing antibodies to TGF-I~and EGF revealed that while these factors were present, the majority of the urinary TGF activity could not be attributed to them. To determine whether urinary TGF activity correlated with tumor burden and to confirm that the TGF activity was produced by the tumor itself, we established xenograft tumors with the tumor-derived cell lines in athymic nude mice. Urinary TGF output was measured and compared with that in immune,competent sibling controls which rejected the xenograft challenge. We found that with increasing xenograft tumor growth, there is a proportional urinary excretion of TGF activity. In conclusion, detection of urinary TGF activity is a simple, noninvasive marker of gastrointestinal malignancy. Activity correlates with tumor burden, and prospective studies in humans (ongoing) are required to determine predictive value as a marker of disease recurrence.
GASTROENTEROLOGY, Vol. 108, No. 4
MANDIBULAR OSTEOMAS IN PATIENTS WITH FAMILIAL ADENOMATOUS POLYPOSlS (FAP) IN MAJORCA (SPAIN) A. Obrado[, A. Llompart, I. Forteza-Rei*, J. Gay&, J. Riera, P. Vaquer, A. Sans0. Depts. of Gastroenterology & *Maxilo-Facial Surgery, Son Dureta Hospital. Palma (Majorca). Spain. The bone abnormalities associated with FAP are areas of bone condensation in the bones of the skull and face, with preference for the maxilla and the mandible. The reported incidences of madibular osteomas range from 78% to 93%. In the FAP registry of Majorca mandibular pantomographies have been performed on patients with polyposis and on risk relatives with the aim to evaluate the frequency of mandibular osteomas. Forty-four pantomographies have been performed on 25 polyposis patients and on 19 risk relatives (2 of them refused sigmoidoscopy and are excluded from the analysis). Panoramic radiographies are interpreted without knowing the individual situation. Seventeen polyposis patients have osteomas in the mandible and only one risk relative has osteomas. All the studied persons in one family (Family A) (4 patients and 4 risk relatives) have no osteomatous lesions. Overall frequency of osteomatous lesions in the mandible is 68% in this series, whereas, after excluding family A, this frequency increases to 85%. Diagnostic precision indices of mandibular osteomas in the overall series and excluding family A (table) Sensibility
Specificity
PPV
NPV
All
0.68
0.94
0.94
0.66
Without FamilyA
0.80
0.92
0.94
0.75
i
CONCLUSIONS: 1) In this series the frequency of mandibular osteomas is between 68% and 85%. 2) The precision diagnostic indices in families with polyposis patients that have mandibular osteomas are very high.
FLOW-CYTOMETRIC MEASUREMENT OF COLONIC MUCOSAL P R O L I F E R A T I O N IN E N D O S C O P I C B I O P S Y SPECIMENS T. Ochsenk~hn, E. ~ a y e r d S r f f e r d M. Schinkel~ A. Meining, V. N~ssler , C. Thiede r, A. Neubauer r, ~. Paumgartner. Dept. Int. Medicine II & III-, K l i n i k u m GroBhadern, U n i v e r g i t y of Munich, Dept. Int. M e d i c i n e & H e m a t o l o g y r, Free U n i v e r s i t y of Berlin. Background: Measurement of epithelial p r o l i f e ration in colonic mucosa is of interest in the i n v e s t i g a t i o n and understanding of early m e t a b o l i c steps i n v o l v e d in the pathogenesis of colorectal cancer. A p p r o a c h e s to this problem have m o s t l y i n v o l v e d in v i t r o incorporation of 3H-thymidine or 5-bromodeoxy-uridine. In the case of few studies measuring DNA by flow-cytometry, a doublet d i s c r i m i n a t i o n module has not been available. Aim: The aim of this study was to establish and v a l i d a t e a sensitive and reproducible m e t h o d for cell cycle analysis applicable to endoscopic biopsy(specimens. Ma%thods~ A c r u d e nuclei fraction was p r e p a r e d from e n d o s c o p i c b i o p s y specimens from three colonic regions of 30 patients. The nuclei were fixed in 70 % ethanol and stained by p r o p i d i u m iodide i m m e d i a t e l y before m e a s ~ e m e n t . The nuclei were a n a l y s e d u s i n g a FACScan flow cytometer equiped w i t h a T ~ O U b l e t discrimination module using the CelIFIT s o f t w a r e package. Results: T h e coefficient of variance (CV) was 1.26 % for nuclei in the GO/G1 fraction, 11.8 % for the S fraction, and 8.2 % in the G2M fraction. In h e a l t h y persons, 87.0 ± 3.2 % of the nuclei were found in the G0/G1 fraction, 9.3 ± 2.8 % in S, and 3.7 ± 1.2 % in G2M. Conclusion: W e e s t a b l i s h e d a new method to m e a s u r e colonic mucosal proliferation by cell cycle analysis in endoscopic biopsy specimens. This method will provide an useful tool for investigating exogenic factors, such as bile acids, calcium, colonic pH, and others, w h i c h may be i n v o l v e d in colorectal carcinogenesis.
AGA ABSTRACTS
ACCEPTABILITY OF A FAMILIAL COLORECTAL CANCER SCREENING PROGRAMME IN MAJORCA (SPAIN). A. Obrador, E. Cabeza#, A. Llompart, M. Zaforteza#, M. Pons, F.X. Bosch*, J. Gay&. Dept. of Gastroent., Son Dureta Hospital, Palma #Cancer Epidemiology Unit of Majorca and *Registry, Cancer Control and Epidemiology Unit, Hospital "Duran i Reynals" Barcelona. First degree relatives of patients diagnosed with colorectal cancer have a two-to-threefold increased risk of developing this neoplasm over the general population. A pilot screening programme has been started in Majorca adressed to this high risk population, and now we evaluate the initial acceptability. The siblings of 173 cancer cotorectal patients who had participated in a previous study were selected. They were contacted by a letter explaining the aims of the study and motivating them to participate. Subsequently a specialized nurse arranged by telephone an appointment to be held in their homes, in order to explain what the study consisted of, carry out a familial medical history and, if they agreed to participate, she left information explaining the faecal occult blood test and the preparation for a sigmoidoscopy. Following this approach we made 21 interviews in which only 13% agreed to participate. Because of the low acceptability of the programme, and realising that one of the greatest difficulties seemed to be the sigmoidoscopy, we decided to modify the strategy of approach to the programme. During the visit to the home, the nurse now describes the objectives of the study, completes the family medical history, and explains how to carry out the hemoccult. When we receive the hemoccult, a doctor arranges for a personal interview in order to explain the convenience of having a sigmoidoscopy. In this way the acceptability has increased to 75%. CONCLUSIONS: 1) In our study, acceptability of the cancer colorectal screening programme directed to first-degree relatives is low when hemoccult and sigmoidoscopy are proposed together. 2) We can increase acceptability of the programme if initially we plan only the hemoccult and subsequently s medical doctor explains the convenience of realizing a sigmoidoscopy. This work was funded by Fondode InvestigacionesSanitarias(Spain)94/0026-01
• URINARY TRANSFORMING GROWTH FACTOR ACTIVITY: A MARKER OF GASTROINTESTINAL MALIGNANCY F. O*Brien, J.K. Collins, S. Herlihy, F. Shanahan, G.C. O'Sullivan. University College Cork, IRELAND. Several biologically active peptides including transforming growth factors are produced by tumors, and are detectable in urine. Detection of tumor-associated urinary transforming growth factor (TGF) activity may have significant clinical diagnostic potential. We have evaluated 80 consecutive patients with gastrointestinal cancers using a bioassay of TGF activity in early morning urinary specimens. These included 18 with gastric adenocarcinoma, 20 with esophageal squamous and 42 with colorectal cancer. Patients with known proteinuria, genitourinary inflammatory or infectious disease or genitourinary malignancy were excluded. The TGF bioassay was the standard NRK transformation assay of clonogenic colony formation in soft agar. TGF values were standardized based on urinary protein concentration. Results were compared with normal subjects (n = 30) and inflammatory bowel disease controls (n = 20). A clear separation between controls and the majority of patients with malignancy was evident. Thus, 90% of patients with gastric cancer, 80% of those with esophageal and 93% of those with colonic carcinoma had values in excess of the highest detected level of urinary TGF activity found in the controls. In patients where curative surgical resection was performed, the urinary TGF activity fell toward normal in all cases. Using HPLC gel filtration, we fractionated urines into multiple peaks of TGF activity. The activity profile corresponded with the profile found in supematants of tumor-derived cell lines that were generated from some of these patients. Studies with neutralizing antibodies to TGF-I~and EGF revealed that while these factors were present, the majority of the urinary TGF activity could not be attributed to them. To determine whether urinary TGF activity correlated with tumor burden and to confirm that the TGF activity was produced by the tumor itself, we established xenograft tumors with the tumor-derived cell lines in athymic nude mice. Urinary TGF output was measured and compared with that in immune,competent sibling controls which rejected the xenograft challenge. We found that with increasing xenograft tumor growth, there is a proportional urinary excretion of TGF activity. In conclusion, detection of urinary TGF activity is a simple, noninvasive marker of gastrointestinal malignancy. Activity correlates with tumor burden, and prospective studies in humans (ongoing) are required to determine predictive value as a marker of disease recurrence.
GASTROENTEROLOGY, Vol. 108, No. 4
MANDIBULAR OSTEOMAS IN PATIENTS WITH FAMILIAL ADENOMATOUS POLYPOSlS (FAP) IN MAJORCA (SPAIN) A. Obrado[, A. Llompart, I. Forteza-Rei*, J. Gay&, J. Riera, P. Vaquer, A. Sans0. Depts. of Gastroenterology & *Maxilo-Facial Surgery, Son Dureta Hospital. Palma (Majorca). Spain. The bone abnormalities associated with FAP are areas of bone condensation in the bones of the skull and face, with preference for the maxilla and the mandible. The reported incidences of madibular osteomas range from 78% to 93%. In the FAP registry of Majorca mandibular pantomographies have been performed on patients with polyposis and on risk relatives with the aim to evaluate the frequency of mandibular osteomas. Forty-four pantomographies have been performed on 25 polyposis patients and on 19 risk relatives (2 of them refused sigmoidoscopy and are excluded from the analysis). Panoramic radiographies are interpreted without knowing the individual situation. Seventeen polyposis patients have osteomas in the mandible and only one risk relative has osteomas. All the studied persons in one family (Family A) (4 patients and 4 risk relatives) have no osteomatous lesions. Overall frequency of osteomatous lesions in the mandible is 68% in this series, whereas, after excluding family A, this frequency increases to 85%. Diagnostic precision indices of mandibular osteomas in the overall series and excluding family A (table) Sensibility
Specificity
PPV
NPV
All
0.68
0.94
0.94
0.66
Without FamilyA
0.80
0.92
0.94
0.75
i
CONCLUSIONS: 1) In this series the frequency of mandibular osteomas is between 68% and 85%. 2) The precision diagnostic indices in families with polyposis patients that have mandibular osteomas are very high.
FLOW-CYTOMETRIC MEASUREMENT OF COLONIC MUCOSAL P R O L I F E R A T I O N IN E N D O S C O P I C B I O P S Y SPECIMENS T. Ochsenk~hn, E. ~ a y e r d S r f f e r d M. Schinkel~ A. Meining, V. N~ssler , C. Thiede r, A. Neubauer r, ~. Paumgartner. Dept. Int. Medicine II & III-, K l i n i k u m GroBhadern, U n i v e r g i t y of Munich, Dept. Int. M e d i c i n e & H e m a t o l o g y r, Free U n i v e r s i t y of Berlin. Background: Measurement of epithelial p r o l i f e ration in colonic mucosa is of interest in the i n v e s t i g a t i o n and understanding of early m e t a b o l i c steps i n v o l v e d in the pathogenesis of colorectal cancer. A p p r o a c h e s to this problem have m o s t l y i n v o l v e d in v i t r o incorporation of 3H-thymidine or 5-bromodeoxy-uridine. In the case of few studies measuring DNA by flow-cytometry, a doublet d i s c r i m i n a t i o n module has not been available. Aim: The aim of this study was to establish and v a l i d a t e a sensitive and reproducible m e t h o d for cell cycle analysis applicable to endoscopic biopsy(specimens. Ma%thods~ A c r u d e nuclei fraction was p r e p a r e d from e n d o s c o p i c b i o p s y specimens from three colonic regions of 30 patients. The nuclei were fixed in 70 % ethanol and stained by p r o p i d i u m iodide i m m e d i a t e l y before m e a s ~ e m e n t . The nuclei were a n a l y s e d u s i n g a FACScan flow cytometer equiped w i t h a T ~ O U b l e t discrimination module using the CelIFIT s o f t w a r e package. Results: T h e coefficient of variance (CV) was 1.26 % for nuclei in the GO/G1 fraction, 11.8 % for the S fraction, and 8.2 % in the G2M fraction. In h e a l t h y persons, 87.0 ± 3.2 % of the nuclei were found in the G0/G1 fraction, 9.3 ± 2.8 % in S, and 3.7 ± 1.2 % in G2M. Conclusion: W e e s t a b l i s h e d a new method to m e a s u r e colonic mucosal proliferation by cell cycle analysis in endoscopic biopsy specimens. This method will provide an useful tool for investigating exogenic factors, such as bile acids, calcium, colonic pH, and others, w h i c h may be i n v o l v e d in colorectal carcinogenesis.