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Gastric adenocarcinoma is associated with the HLA class II gene DQB1∗0301
April1995
SSAT
A1229
• GASTRIC ADENOCARCINOMA IS ASSOCIATED WITH THE HLA CLASS II GENE DQBI*0301. I.E. Lee. M. Lu. g. Bell. P.F. Mansfield. D.B. Evans. t.M. Skibber. S.A. Curlev. and I.D. Reveille. Department of Surgical Ontology, U.T.M.D. Anderson Cancer Center, and Division of Rheumatology-Molecular Immunology, U.T. Health Science Center, Houston, Texas. We have previously demonstrated that the presence of Human Leukocyte Antigen (HI.A) class II DQBI*0301, a critical immune recognition gene, is strongly linked to melanoma incidence and is especially common in melanoma patients presenting with advanced disease. The present study was designed to determine if this same gene is associated with gastric, colorectal or pancreatic adenocarcinoma. Methods: Molecular oligotyping of HLA class II genes was performed for 104 patients with gastrointestinal adenocarcinoma (gastric-27, colorectal-47, pancreas-30), and compared to 200 non-cancer race-matched controls. HLA-DRB1 and -DQB1 genes were amplified from peripheral blood leukocyte genomic DNA using locus-specific primers. The presence of each of 49 HLA class II alleles was determined using sequence-specific oligonucleotide probes. Results: The HLA-DQ_BI*0301 gene was significantly more common in gastric adenocarcinoma patients compared to noncancer controls. A trend associating the 0301 allele with colorectal cancer did not reach statistical significance, and 0301 was not associated with pancreatic adenocarcinoma: DOBI*O30I I~ (chi-souare Group ~ene present vs. control/ gastric adenocarcinoma 67% (18/27) <0.0001 colorectal adenocarcinoma 40% ( 19/47 ) 0.07 pancreatic adenocarcinoma 27% (8/30) 0.75 controls 27% (54/200) -None of the other HLA class II alleles was present at significantly altered frequency in these patients. Conclusions: Patients with gastric adenocarcinoma are much more likely to carry the immune recognition gene DQ131"0301 than non-cancer controls. Association of this gene with gastric cancer as well as melanoma suggests it represents a genomic marker of cancer susceptibility. Identification of the presence of DQBI*0301 may help target individuals most likely to benefit from cancer screening and prevention programs.
EFFECTS OF IGF-I ON PANCREATIC AND GUT HORMONES, G R O W T H FACTORS, AND PROTEIN METABOLISM AFTER COLECTOMY IN MAN. Leinsk61d T, Permert J, Olaison G, Amelo U, Adrian TE. Larsson J. Depts. of Surgery, University of Link6ping and the Karolinska Institute, Stockholm, Sweden, and Biomedical Sciences, Creighton University, Omaha, NE, USA. Insulin like growth factor-I(IGF-l) has anabolic effects on protein and glucose metabolism. We investigated the effects of human recombinant IGF-I(80btg/kg, twice daily for 5 days, n=8) and placebo (n=7) on gastrointestinal and islet hormones, growth factors, and protein matabolism in patients after colonic resection. Insulin and lAPP levels were increased 6 days after surgery in controls, indicating insulin resistance, but this was not seen in the IGF-I group (P<0,01). Blood glucose was increased at day 4 (P<0.05), see table. Control IGF-I
INFECTED PANCREATIC NECROSIS MANAGED WITH REPEAT DEBRIDEMENT AND DRESSING CHANGES: OUTCOME, MORBIDITY AND LONG TERM FUNCTIONAL RESULTS. K.A. Leslie, N. Gauto, R.L Rossi, J.I. Tsao, J.L. Munson, L.B Sanders, L Braasch, Department of General Surgery, Lahey Clinic, Burlington, IVIA The surgical management of acute infected pancreatic necrosis is controversial. We reviewed the Lahey Clinic's experience over a 8 year period with open surgical debridement and multiple dressing changes through a bilateral subcostal incision with marlex mesh and zipper for acute infected pancreatic necrosis. Ten patients (8 men, 2 women) with a mean age of 52 years (range 30-76) were studied. Overall the mortality rate was 10 %. The mean hospital stay was 70 days (range 35-119) and mean SICU stay was 27 days (2-56). Etiology of the pancreatitis was 30% due to gallstones, 40% from alcohol and 30% from other causes. Mean Ranson scores for survivors was 2.9 and 6 for the non survivor. Patients required multiple procedures with a mean of 5.9. The mean number of dressing changes was 4.2 in the OR, 11.2 in the SICU and 17 on the floor. Morbidity was common with a 70% incidence of central line sepsis, 50% multipleorgan failure, 30% urinary tract infection, 20% pancreatic fistulas, and 10% pseudocyst. There were no intestinal, gastric or colonic fistulas. All patients had at least one complication while in hospital. The long term functional status of the patients was excellent with 89% returning to work or normal activity with no limitations and 11% on long term disability. Rehabilitation time (time to normal function) ranged from 1-24 months with a mean of 9 months. Thirty three percent of the patients developed diabetes and 33% require pancreatic enzyme supplementation during long term follow up. Surgery for acute infected pancreatic necrosis is labor intensive, associated with a long hospital stay, frequent complications and a long rehabilitation period but their long term functional status was excellent (89%) and their pancreatic function was good (66%) supporting that patients with acute infected pancreatic necrosis should be treated aggressively
0 ADJUVANT HORMONAL TREATMENT WITH PEPTIDE YY OR ITS ANALOG DECREASES HUMAN PANCREATIC CARCINOMA GROWTH AND EGF RECEPTOR EXPRESSION C.D. Liu. A. Ronaione, L. Garvev. A. Balasubramaniam, D.W. McFadden. Department of Surgery, UCLA Center for Health Sciences, LA, CA
Pre-op Glucose Insulin IAPP
5.14-0.5 42 4-3 8.54-0.5
post-op
pre-op
7.24-0.9 614-5 16:t=2.1
5.44-0.7 4.94-0.3 464-4 44-4-3 8.6=t=1.0 10.24-1.0
post-op
Surgery reduced plasma EGF and increased IGF-II levels in both patient groups, but these differences did not reach statistical significance. IGF-I had no effect on basal plasma TGFn, IGF-II, gastrin, glucagon, enteroglucagon, or PYY. The urinary nitrogen/creatinine ratio was reduced in the IGF-I group (P<0.01). The 3-methylhistidine/creatinine ratio and nitrogen balance were also reduced by IGF-I, but not significantly so. IGF-I levels increased 4-fold during treatment and the binding protein, IGFBP-3 but not IGFBP-I also increased significantly. These results suggest a nitrogen sparing effect of IGF-I, coupled with an improvement of insulin resistance after colectomy. IGF-I may provide valuable therapeutic support for catabolic patients after serious injury or major surgery.
Peptide YY (PYY) is a naturally occurring pancreatic peptide that decreases exocrine and endocrine secretion as well as cholecystokinin-mediated pancreatic growth. We examined whether adjuvant treatment with PYY or its synthetic analog, BIM-43004, would decrease human pancreatic adenocarcinoma growth when treated with the standard chemotherapeutic agents 5-flourouracil (5FU) and leucovofin. Methods: Human pancreatic duotal adenocarcinomas, Mia PaOa-2 and Bx PC-3, were cultured and assessed for growth by MTT assay. Pancreatic cancer cells were pretreated for 24 hours with 500 pmol of PYY or BIM-43004, 5FU and leucovorin were added to the cell cultures for an additional 24 hours. Controls received the equivalent volume of sterile water during peptide administration. Cell membrane EGF receptors were analyzed by Western immunoblotting after exposure to peptides and chemotherapy. Results: Cancer cell growth was reduced in all groups receiving hormonal pretreatment as compared to groups receiving 5FU and leucovorin only (SFU/L). (Data expressed as rnean+SEM, N=40/group, *P<0.05 vs. control by Student's t-test). EGF receptor expression was reduced by 30.1% in cells treated with PYY-5FU-leucovorin [ ill Bx PC-3 and 44,6% in cells treated with BIM-5FU"~ / [] MiaPaCa-2 leucovorin as compared to control cells without treatment, o 30 , , ** Conclusion: Human pancreatic cancer cell >~ 2 5 - . ~ L ~ . ~ ~ i growth is decreased when combined treatment ~ 20 with PYY or its synthetic analog and ~ 15 5FU/leucovorin are administered sequentially. ~ lo Cell membrane EGF receptor expression is decreased in pancreatic adenocarcinoma receiving combined therapy. PYY or its ~ ~_~ synthetic analog may be beneficial as an ~ ~. adjuvant hormonal treatment for pancreatic ductai ~_ adenocardnoma.
SSAT
A1229
• GASTRIC ADENOCARCINOMA IS ASSOCIATED WITH THE HLA CLASS II GENE DQBI*0301. I.E. Lee. M. Lu. g. Bell. P.F. Mansfield. D.B. Evans. t.M. Skibber. S.A. Curlev. and I.D. Reveille. Department of Surgical Ontology, U.T.M.D. Anderson Cancer Center, and Division of Rheumatology-Molecular Immunology, U.T. Health Science Center, Houston, Texas. We have previously demonstrated that the presence of Human Leukocyte Antigen (HI.A) class II DQBI*0301, a critical immune recognition gene, is strongly linked to melanoma incidence and is especially common in melanoma patients presenting with advanced disease. The present study was designed to determine if this same gene is associated with gastric, colorectal or pancreatic adenocarcinoma. Methods: Molecular oligotyping of HLA class II genes was performed for 104 patients with gastrointestinal adenocarcinoma (gastric-27, colorectal-47, pancreas-30), and compared to 200 non-cancer race-matched controls. HLA-DRB1 and -DQB1 genes were amplified from peripheral blood leukocyte genomic DNA using locus-specific primers. The presence of each of 49 HLA class II alleles was determined using sequence-specific oligonucleotide probes. Results: The HLA-DQ_BI*0301 gene was significantly more common in gastric adenocarcinoma patients compared to noncancer controls. A trend associating the 0301 allele with colorectal cancer did not reach statistical significance, and 0301 was not associated with pancreatic adenocarcinoma: DOBI*O30I I~ (chi-souare Group ~ene present vs. control/ gastric adenocarcinoma 67% (18/27) <0.0001 colorectal adenocarcinoma 40% ( 19/47 ) 0.07 pancreatic adenocarcinoma 27% (8/30) 0.75 controls 27% (54/200) -None of the other HLA class II alleles was present at significantly altered frequency in these patients. Conclusions: Patients with gastric adenocarcinoma are much more likely to carry the immune recognition gene DQ131"0301 than non-cancer controls. Association of this gene with gastric cancer as well as melanoma suggests it represents a genomic marker of cancer susceptibility. Identification of the presence of DQBI*0301 may help target individuals most likely to benefit from cancer screening and prevention programs.
EFFECTS OF IGF-I ON PANCREATIC AND GUT HORMONES, G R O W T H FACTORS, AND PROTEIN METABOLISM AFTER COLECTOMY IN MAN. Leinsk61d T, Permert J, Olaison G, Amelo U, Adrian TE. Larsson J. Depts. of Surgery, University of Link6ping and the Karolinska Institute, Stockholm, Sweden, and Biomedical Sciences, Creighton University, Omaha, NE, USA. Insulin like growth factor-I(IGF-l) has anabolic effects on protein and glucose metabolism. We investigated the effects of human recombinant IGF-I(80btg/kg, twice daily for 5 days, n=8) and placebo (n=7) on gastrointestinal and islet hormones, growth factors, and protein matabolism in patients after colonic resection. Insulin and lAPP levels were increased 6 days after surgery in controls, indicating insulin resistance, but this was not seen in the IGF-I group (P<0,01). Blood glucose was increased at day 4 (P<0.05), see table. Control IGF-I
INFECTED PANCREATIC NECROSIS MANAGED WITH REPEAT DEBRIDEMENT AND DRESSING CHANGES: OUTCOME, MORBIDITY AND LONG TERM FUNCTIONAL RESULTS. K.A. Leslie, N. Gauto, R.L Rossi, J.I. Tsao, J.L. Munson, L.B Sanders, L Braasch, Department of General Surgery, Lahey Clinic, Burlington, IVIA The surgical management of acute infected pancreatic necrosis is controversial. We reviewed the Lahey Clinic's experience over a 8 year period with open surgical debridement and multiple dressing changes through a bilateral subcostal incision with marlex mesh and zipper for acute infected pancreatic necrosis. Ten patients (8 men, 2 women) with a mean age of 52 years (range 30-76) were studied. Overall the mortality rate was 10 %. The mean hospital stay was 70 days (range 35-119) and mean SICU stay was 27 days (2-56). Etiology of the pancreatitis was 30% due to gallstones, 40% from alcohol and 30% from other causes. Mean Ranson scores for survivors was 2.9 and 6 for the non survivor. Patients required multiple procedures with a mean of 5.9. The mean number of dressing changes was 4.2 in the OR, 11.2 in the SICU and 17 on the floor. Morbidity was common with a 70% incidence of central line sepsis, 50% multipleorgan failure, 30% urinary tract infection, 20% pancreatic fistulas, and 10% pseudocyst. There were no intestinal, gastric or colonic fistulas. All patients had at least one complication while in hospital. The long term functional status of the patients was excellent with 89% returning to work or normal activity with no limitations and 11% on long term disability. Rehabilitation time (time to normal function) ranged from 1-24 months with a mean of 9 months. Thirty three percent of the patients developed diabetes and 33% require pancreatic enzyme supplementation during long term follow up. Surgery for acute infected pancreatic necrosis is labor intensive, associated with a long hospital stay, frequent complications and a long rehabilitation period but their long term functional status was excellent (89%) and their pancreatic function was good (66%) supporting that patients with acute infected pancreatic necrosis should be treated aggressively
0 ADJUVANT HORMONAL TREATMENT WITH PEPTIDE YY OR ITS ANALOG DECREASES HUMAN PANCREATIC CARCINOMA GROWTH AND EGF RECEPTOR EXPRESSION C.D. Liu. A. Ronaione, L. Garvev. A. Balasubramaniam, D.W. McFadden. Department of Surgery, UCLA Center for Health Sciences, LA, CA
Pre-op Glucose Insulin IAPP
5.14-0.5 42 4-3 8.54-0.5
post-op
pre-op
7.24-0.9 614-5 16:t=2.1
5.44-0.7 4.94-0.3 464-4 44-4-3 8.6=t=1.0 10.24-1.0
post-op
Surgery reduced plasma EGF and increased IGF-II levels in both patient groups, but these differences did not reach statistical significance. IGF-I had no effect on basal plasma TGFn, IGF-II, gastrin, glucagon, enteroglucagon, or PYY. The urinary nitrogen/creatinine ratio was reduced in the IGF-I group (P<0.01). The 3-methylhistidine/creatinine ratio and nitrogen balance were also reduced by IGF-I, but not significantly so. IGF-I levels increased 4-fold during treatment and the binding protein, IGFBP-3 but not IGFBP-I also increased significantly. These results suggest a nitrogen sparing effect of IGF-I, coupled with an improvement of insulin resistance after colectomy. IGF-I may provide valuable therapeutic support for catabolic patients after serious injury or major surgery.
Peptide YY (PYY) is a naturally occurring pancreatic peptide that decreases exocrine and endocrine secretion as well as cholecystokinin-mediated pancreatic growth. We examined whether adjuvant treatment with PYY or its synthetic analog, BIM-43004, would decrease human pancreatic adenocarcinoma growth when treated with the standard chemotherapeutic agents 5-flourouracil (5FU) and leucovofin. Methods: Human pancreatic duotal adenocarcinomas, Mia PaOa-2 and Bx PC-3, were cultured and assessed for growth by MTT assay. Pancreatic cancer cells were pretreated for 24 hours with 500 pmol of PYY or BIM-43004, 5FU and leucovorin were added to the cell cultures for an additional 24 hours. Controls received the equivalent volume of sterile water during peptide administration. Cell membrane EGF receptors were analyzed by Western immunoblotting after exposure to peptides and chemotherapy. Results: Cancer cell growth was reduced in all groups receiving hormonal pretreatment as compared to groups receiving 5FU and leucovorin only (SFU/L). (Data expressed as rnean+SEM, N=40/group, *P<0.05 vs. control by Student's t-test). EGF receptor expression was reduced by 30.1% in cells treated with PYY-5FU-leucovorin [ ill Bx PC-3 and 44,6% in cells treated with BIM-5FU"~ / [] MiaPaCa-2 leucovorin as compared to control cells without treatment, o 30 , , ** Conclusion: Human pancreatic cancer cell >~ 2 5 - . ~ L ~ . ~ ~ i growth is decreased when combined treatment ~ 20 with PYY or its synthetic analog and ~ 15 5FU/leucovorin are administered sequentially. ~ lo Cell membrane EGF receptor expression is decreased in pancreatic adenocarcinoma receiving combined therapy. PYY or its ~ ~_~ synthetic analog may be beneficial as an ~ ~. adjuvant hormonal treatment for pancreatic ductai ~_ adenocardnoma.