Given the need to improve the sensitivity of non-invasive methods to detect colorectal neoplasia, particularly adenomas, we compared a fecal test using a monoclonal antibody (Mab) raised against ...constituents of colonic adenomas designated Adnab-9 (Adenoma Antibody 9), recognizing an N-linked 87 kDa glycoprotein, to gFOBT, which is shown to reduce CRC mortality. p87 immunohistochemistry testing is significantly more sensitive (OR 3.64CI 2.37-5.58) than gFOBT (guaiac-based fecal occult blood test) for adenomas (<3 in number), advanced adenomas (OR 4.21CI 2.47-7.15), or a combination of the two (OR 3.35CI 2.47-4.53). p87 immunohistochemistry shows regional Paneth cell (PC) expression mainly in the right-sided colon and is significantly reduced in the ceca of African Americans (
< 0.0001). In a subset of patients, we obtained other body fluids such as urine, colonic effluent, and saliva. Urine tests (organ-specific neoantigen) showed a significant difference for advanced adenomas (
< 0.047). We conclude that fecal p87 testing is more sensitive than gFOBT and Adnab-9 and could be used to better direct the colonoscopy screening effort.
Abstract
While cigarette smoking and drinking of alcohol have been implicated in carcinogenesis, their role in the genesis of liver metastasis (LM) is undefined. Animal studies support a role for ...alcohol consumption but it appears that alcoholic liver cirrhosis may be protective. Given this conundrum, we prospectively evaluated a VA cohort of patients at high risk of cancer and therefore LM taking into account self- reported and serum-based substance abuse at baseline, documenting future development of cancer and LM correlated with tumor markers.
Methods: Patients who completed a questionnaire to assess colorectal cancer (CRC) risk factors and scored positively were enrolled into the study. Data were compared to those in the computerized record and objective clinical data such as serum alcohol and CEA levels were recorded. Cumulative cancer diagnosis was noted on follow-up and LM had to be confirmed by biopsy or imaging. Tumor markers were serum CEA and stool p87 ELISA.
Results: 21 patients developed LM (Group A), 529 cancer patients (Group B), and 588 remained cancer free (Group C). Follow up time was similar (A 9.7±5.4; B 9.4±5.4 and C 10.1±6.9 years). Mortality was 83, 42 and 38% in groups A,B,C respectively. In group A the LM were: 3 of each lung, CRC, breast, metastatic hepatocellular cancer and unknown primary; two of each: pancreatic cancer and bladder; and 1 of each B-cell lymphoma, prostate and renal cell carcinoma. These categories were represented in B by 88% of all cancer types. Smoking percentage was highest in the A (63% ;p=0,002 compared to cancer group), 46% in C (p=0.0001 compared to B), and 27% in B. Serum alcohol levels were highest in A 30.7±75.2 vs B 26.6±89.8 and C 25.9±85.8 mg/dL). Percent of active drinkers were lowest in A 12% and highest in C with B intermediate with no significant differences. Serum CEA levels were highest in A (12.24±13.66) vs B (3.59±4.81: p=0.063);B vs C (2.56±2.15 ng/ml: p=0.026). A direct correlation was found between serum alcohol and CEA levels (r=0.996;p=0.059). p87 Stool tests (81, 50 and 47% in A,B,C respectively) correlated with CEA (r=0.999;p<0.011) and ethanol levels (r=0.993,p=0.06).
Conclusions: Only 1.8% of this sample developed LM but smoking would appear to be a factor as 62% of the LM were from cancers associated with smoking-risk. The combination of both factors was accordingly highest in A (38%) but significance was found only between groups B and C (24 vs 35% respectively, p=0.004) perhaps reflecting the habits of the entire VA population rather than cancer-associated. In an animal model for LM resistance we also confirmed a direct correlation between CEA and p87 in tissue extracts. Alcohol intake is more difficult to quantify than smoking and the ability to correlate the 2 serum analytes suggests a relevant assumption of the basis proof. CEA has long been recognized as being pro-metastatic in LM and the direct correlation of alcohol with CEA suggests that alcohol is a promoter for LM.
Citation Format: Martin Tobi, Fadi Antaki, Mary Ann Rambus, Edi Levi, Harvinder Talwar, Michael Lawson, Benita McVicker. Effect of tobacco and alcohol intake on the future development of liver metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2830.
Background and Aim
Sporadic pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer. No proven screening strategies are available and frequent cross-sectional imaging studies (CT/MRI) are ...impractical even in patients thought to be at higher risk than the general population. Few PDA biomarkers have been studied prospectively for screening. Here, we prospectively evaluated the Adnab-9 monoclonal antibody in stool, pancreaticobiliary secretions, and tissue for screening and prognostic value in sporadic PDA. We also evaluated the prognostic value of characterized early biomarkers in pancreaticobiliary secretions.
Methods
Adnab-9 diagnostic ability was tested in stool in 249 and 1,132 patients from China and the US, respectively. Immunohistochemistry was performed in 22 tissue samples with Adnab-9 antibody and anti-Defensin 5, a constituent of Paneth cells. Pancreatobiliary secretions were collected from 12 PDA patients and 9 controls. The enriched PCR method was performed to detect K-ras mutations. ELISA was performed with Adnab-9, anti-Her-2/
neu
, and monoclonal antibody D4 (anti-Reg I).
Results
Adnab-9 alone was diagnostic and prognostic when measured in pancreatic secretions, feces, and tissues of PDA patients compared to controls (
p
< 0.05). Significantly, Adnab-9 fecal binding can precede the clinical diagnosis by 2.3 years, potentially allowing earlier clinical intervention. In pancreatic secretions, a combination of K-ras and Her-2/
neu
when appropriately standardized can be diagnostic in 75 % of PDA.
Conclusions
Our study suggests that Adnab-9 may be an effective marker for diagnosis and prognosis of PDA. Adnab-9 may be reflective of the presence of Paneth cells confirmed by Defensin-5 staining. These cells may modulate the biological activity of the cancer and confer a better prognosis.
Abstract
Adenomas with high-grade dysplasia (HGD) are recognized to be harbingers of future neoplastic lesions and colonoscopy is repeated in a year. There is little data regarding the neoplastic ...potential of the colon bearing such lesions. We postulated that lesions >1cm, in contrast to their smaller counterparts, would progress through an adenoma-carcinoma sequence. Conversely, smaller sized lesions might have a greater propensity for recurrence since there may be a priori more biological aggressiveness. Methods: We used the Adnab-9 monoclonal anti-adenoma risk marker to investigate high risk patients with HGD adenomas. Immunohistochemistry on normal-appearing colonic mucosa, ELISA of effluent acquired during colonoscopy and fecal Western blotting and ELISA, the stool collected prospectively was performed. Results: 23 patients with HGD adenomas, the majority found on the index colonoscopy were evaluated (table). A trend existed for increased NSAID intake in the large HGD group 5/7 (71%) compared to 2/7 (29%) in the small (p=0.28) and for increased numbers of metachronous adenomas in the small HGD group. More had symptoms in the large HGD group (67%) compared to 40% in small (NSS). No small HGD lesion was associated with a field effect (FE) in contrast to 100% in those patients with large lesion HGD (p<0.01). Concurrence with location of FE with synchronous adenomas was 5/6 (83%) and 2/5 (40%) with metachronous polyps in those with large HGD (p=0.24).
Conclusions: Small HGD lesions appear to progress by pathways beyond the purview of the adenoma carcinoma sequence characterized by the significant lack of a field effect. They arise in a colon that may be destined for greater than usual risk for CRN even than that seen with larger HGD lesions. Larger prospective studies should be undertaken to confirm these preliminary findings and determine the tumorigenic pathway but in the interim surveillance for smaller lesions should not be limited to a single 1 year of follow-up.ParameterLarge HGDSmall HGDAll HGDN131023Age x±sd (years)65.5±10.064.7±8.765.2±9.3%Race AA53.93043.5BMI30.3±7.127.9±6.229.3±6.6%Left-sided76.97073.9%TA/TVA/VA69.2/23.1/7.760/40/063/32.7/4.3Size x±sd (mm)21.5±13.76.7±3.115.1±12.8Follow-up yrs3.6±2.15.3±2.7(p=0.15)4.2±2.4Synchronous adenomas1.8±3.3 6/14 46.2%1.4±1.5 5/10 50%1.5±2.7 11/24 45.8%Metachronous adenomas1.3±1; 7/10 70%2.1±2.34* 4/7 57% (p=0.6)1.3±1.7 11/17 64.7%%Ad-9 WB+12.528.620FecalAdnab-92/8 (25%)2/7(28.6%)4/15(26.7%)Effluent Elisa+4/9(44.4%)2/7(28.6%)p=.66/16(38%)%Field Effect6/6 (100)**0/5 (0%)6/11(55.5%)**OR 0.007:CI 0.0001-.415;p=0.0022; *p=0.3 Note: F/U time NSS
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2903.
Background and Purposes
Most colorectal tumors develop from adenomatous polyps, which are detected by colonoscopy. African Americans (AAs) have higher incidence of colorectal cancer (CRC) and greater ...mortality from this disease than Caucasian Americans (CAs). We investigated whether differences in predisposition to CRC and its surrogate (colonic adenomas) between these ethnic groups were related to numbers of cancer stem or stem-like cells (CSCs) in colonocytes.
Methods
We analyzed colonic effluent from 11 AA and 14 CA patients who underwent scheduled colonoscopy examinations at the John D. Dingell Veterans Affairs Medical Center. We determined proportions of cells that expressed the CSC markers CD44 and CD166 by flow cytometry.
Results
The proportion of colonocytes that were CD44
+
CD166
−
in effluent from patients with adenomas was significantly greater than from patients without adenomas (
P
= 0.01); the proportion of CD44
+
CD166
+
colonocytes was also greater (
P
= 0.07). Effluent from AAs with adenomas had 60 % more CD44
+
166
−
colonocytes than from CAs with adenomas. Using cutoff values of 8 % for AAs and 3 % for CAs, the proportion of CD44
+
166
−
colonocytes that had positive predictive value for detection of adenomas was 100 % for AAs and CAs, determined by receiver operator characteristic curve analysis.
Conclusion
The proportion of CD44
+
166
−
colonocytes in colonic effluent can be used to identify patients with adenoma. AAs with adenomas have a higher proportion of CD44
+
166
−
colonocytes than CA. The increased proportion of CSCs in colonic tissue from AA might be associated with the increased incidence of CRC in this population.
Abstract
CRC incidence in patients <50 years of age has increased by 17% in the last decade predominantly rectal cancer in Whites (Siegel et al, 2009). This age group is rarely screened. We ...determined the rectal binding Adnab-9 antibody in patients <50 years and a >50 year control at high clinical CRC risk of cancer. Methods: Adnab-9 is an adenoma-carcinoma sequence marker. We performed Adnab-9 immunohistocemistry on colonoscopic rectal biopsies. Results: Our study found that of 25 patients age <50 years, 48% had rectal binding of Adnab-9 versus 21.8% in 220 patients ≥50yrs (p<0.01) and with BMI was confirmed as an independent risk factor by multivariate analysis. Demographics are summarized (Table) and significant differences were seen for gender, ASA intake and BMI, however female gender was equally distributed 58.3 in the positive and 61.5% in the negative group. Hematochezia tended (p=0.23) to associate with positive rectal binding (50 versus 23%) and the colonoscopic finding was more likely to reveal adenomatous tissue in the positive group (58.3 versus 23.1%, p=0.11). Older patients were significantly more likely to take ASA which may have reduced the polyp number in this group and they also have an decreased BMI (p<0.02). In the entire group Adnab-9 positivity correlated with BMI as a continuous variable (U=0.03; p<0.01). Conclusions: Adnab-9 is an independent CRC risk marker in patients <50 years of age suggesting that they are more prone to development of neoplasia. The mechanism appears to be that of an adenoma-carcinoma sequence. ASA may be a factor but was not an independent mitigating marker in this study. BMI is also greater in the younger group and may be the underlying cause of the observed increase in neoplasia in the young. Adnab-9 staining of sigmoidoscopic rectal biopsies may be a convenient way of identifying a high-risk population of patients <50 years of age for CRC surveillance in this population hithertofore not afforded screening.Parameter (n)Patients <50 (25)Patients >50 (220)Age(mean+st.deviationSD)44.8 (5.4)62.4 (9.3)% Non-Hispanic Whites4041.4% Female Gender60 (OR 11.0, CI 4.4-27.2; p<0.0001)10.9Any NSAID/Statin/ASA(%)30.4/44/41.18/4.6 (less ASA-p<0.02)37.6/46.6/30.5Symptom %/BMI(SD)60/31.6(6.1) (BMI p<0.02)*42.9/28.7(5.4)
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2905.
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