Novel Circulating Tumor Cell Assay for Detection of Colorectal Adenomas and Cancer.
Clinical and translational gastroenterology
2019; 10 (10): e00088
Outcomes of screening and surveillance in people with two parents affected by colorectal cancers: experiences from the Familial Bowel Cancer Service.
Hereditary cancer in clinical practice
2019; 17: 25
OBJECTIVES: There is a significant unmet need for a blood test with adequate sensitivity to detect colorectal cancer (CRC) and adenomas. We describe a novel circulating tumor cell (CTC) platform to capture colorectal epithelial cells associated with CRC and adenomas.METHODS: Blood was collected from 667 Taiwanese adults from 2012 to 2018 before a colonoscopy. The study population included healthy control subjects, patients with adenomas, and those with stage I-IV CRC. CTCs were isolated from the blood using the CellMax platform. The isolated cells were enumerated, and an algorithm was used to determine the likelihood of detecting adenoma or CRC. Nominal and ordinal logistic regression demonstrated that CTC counts could identify adenomas and CRC, including CRC stage.RESULTS: The CellMax test demonstrated a significant association between CTC counts and worsening disease status (Cuzick's P value < 0.0001) with respect to the adenoma-carcinoma sequence. The test showed high specificity (86%) and sensitivity across all CRC stages (95%) and adenomatous lesions (79%). The area under the curve was 0.940 and 0.868 for the detection of CRC and adenomas, respectively.DISCUSSION: The blood-based CTC platform demonstrated high sensitivity in detecting adenomas and CRC, as well as reasonable specificity in an enriched symptomatic patient population.TRANSLATIONAL IMPACT: If these results are reproduced in an average risk population, this test has the potential to prevent CRC by improving patient compliance and detecting precancerous adenomas, eventually reducing CRC mortality.
View details for DOI 10.14309/ctg.0000000000000088
View details for PubMedID 31663904
Thalidomide Use Reduces Risk of Refractory Gastrointestinal Bleeding in Patients with Continuous Flow Left Ventricular Assist Devices.
ASAIO journal (American Society for Artificial Internal Organs : 1992)
The Familial Bowel Cancer Service at The Royal Melbourne Hospital was started in 1980 in order to offer bowel cancer screening services to those felt to be at a higher risk of CRC due to their family history, and upon registration in this service, patients gave consent for recording of their individual and familial medical history as pertaining to colorectal cancer in the FamBIS database. Using the FamBIS database, we sought to understand whether the subpopulation of individuals in whom both parents were diagnosed with colorectal cancer carried a higher risk of colorectal cancer or neoplastic polyps and should therefore undergo more intensive screening above that of the average-risk individual.We conducted a single-centre retrospective cohort-study of adults (18?years of age and older) in the FamBIS database, with review of their medical histories as pertaining to CRC diagnosis, screening, and surveillance from 1980 to 2015.We identified and reviewed the medical histories of 96 registrants from 62 unique families. Registrants began screening as early as 24?years of age, with the mean age of first screening being at 44.6?±?10.7?years old. The mean duration of screening was 17.3?±?10.1?years, and through their screening period, registrants underwent an average of 11.5?±?9.1 FOBTs and 4.4?±?3.1 colonoscopies or sigmoidoscopies.Over the course of screening, 41 (42.7%) registrants were found to have at least one neoplasm of any kind (including adenomas, advanced adenomas, and CRC) as their first positive colonoscopic finding. In total, 12 (12.5%) of the registrants were found to have an advanced neoplasm over the course of screening and surveillance, while only 2 patients were found to be diagnosed with CRC.The prevalence rates for neoplasms, advanced neoplasms, and CRC in our current study were statistically significantly higher compared with those seen in average-risk populations. This supports the importance of more intensive screening for this subpopulation in preventing colorectal cancers, as well as pre-and early-cancerous neoplasms.
View details for DOI 10.1186/s13053-019-0122-8
View details for PubMedID 31428211
View details for PubMedCentralID PMC6697919
Arteriovenous malformations respond poorly to argon plasma coagulation in patients with continuous flow left ventricular assist devices.
European journal of gastroenterology & hepatology
2019; 31 (7): 792?98
Gastrointestinal (GI) bleeding is a common complication seen in patients with implanted continuous flow left ventricular assist devices (CF-LVAD), often attributed to arteriovenous malformations (AVMs). Whether thalidomide reduces recurrent GI bleeding risk in CF-LVAD patients has been incompletely evaluated. We conducted a retrospective review of all CF-LVAD patients at our institution with GI bleeding from AVMs who had a trial both off and on thalidomide. The primary endpoint was time to rebleed, while secondary endpoints included overall GI bleeding events, packed red blood cell (PRBC) transfusion requirements, and adverse events related to thalidomide. We report on 24 patients with recurrent AVM-associated GI bleeding who met criteria for and received thalidomide therapy, of which 17 had sufficient follow-up to be ultimately included for final analysis. We found the risk of rebleeding was significantly reduced in those on thalidomide therapy versus off (hazard ratio = 0.23, p = 0.022). The median number of GI bleeds per year was reduced from 4.6 to 0.4 (p = 0.0008) and the PRBC requirement was lower (36.1 vs. 0.9 units per year, p = 0.004) in those on thalidomide therapy. The adverse event rate with thalidomide was 59%, with symptoms resolution in most following dose reduction without increased bleeding. Thalidomide reduced the risk of AVM-associated GI rebleeding, number of bleeding events, and PRBC requirements in CF-LVAD patients. When initiating therapy, potential side effects and overall clinical context should be considered.
View details for DOI 10.1097/MAT.0000000000001054
View details for PubMedID 31425265
Worldwide Practice Patterns in Lynch Syndrome Diagnosis and Management, Based on Data From the International Mismatch Repair Consortium.
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
Gastrointestinal bleeding in patients with continuous flow left ventricular assist devices (LVADs) causes significant morbidity. Arteriovenous malformations (AVMs) cause 30-60% of bleeds, yet the efficacy of endoscopic interventions and risk factors for rebleeding have not been studied.The charts of all LVAD patients undergoing endoscopy for gastrointestinal bleeding at Stanford between January 2010 and December 2017 were reviewed. Cox proportional hazard modeling was used to evaluate risk factors for rebleeding, including the type of endoscopic treatment, patient characteristics, and endoscopic findings.Of 54 total LVAD patients presenting with gastrointestinal bleeding, 23 (42.6%) had AVMs documented on endoscopy. Treatment with argon plasma coagulation (APC) alone was associated with a higher risk of rebleeding compared to no treatment [hazard ratio (HR)=4.77, P=0.012], and compared with clip±APC (HR=7.47, P=0.012). The 90-day bleed-free rate was 10.9% with APC, 100% with clipping±APC, and 83.3% with no endoscopic treatment. Additional risk factors for rebleeding included the presence of gastric AVMs (HR=3.64, P=0.024), and presence of hematochezia (HR=5.15, P=0.05). In a multiple Cox regression model, only the presence of gastric AVMs (HR=5.50, P=0.029) and APC use (HR=14.3, P=0.008) remained significant predictors of rebleeding.The use of APC alone for the treatment of AVMs in LVAD patients had a high failure rate. The presence of gastric AVMs was a significant risk factor for rebleeding in LVAD patients. Management decisions should take these factors into account.
View details for DOI 10.1097/MEG.0000000000001427
View details for PubMedID 31150365
Efficacy of Video Capsule Endoscopy in the Management of Suspected Small Bowel Bleeding in Patients With Continuous Flow Left Ventricular Assist Devices.
2017; 10 (5): 280?87
Families with a history of Lynch syndrome often do not adhere to guidelines for genetic testing and screening. We investigated practice patterns related to Lynch syndrome worldwide, to ascertain potential targets for research and public policy efforts METHODS: We collected data from the International Mismatch Repair Consortium [IMRC], which comprises major research and clinical groups engaged in the care of families with Lynch syndrome worldwide. IMRC institutions were invited to complete a questionnaire to characterize diagnoses of Lynch syndrome and management practice patterns.Fifty-five providers, representing 63 of 128 member institutions (49%) in 21 countries, completed the questionnaire. For case finding, 55% of respondents reported participating in routine widespread population tumor testing among persons with newly diagnosed Lynch syndrome-associated cancers, whereas 27% reported relying on clinical criteria with selective tumor and/or germline analyses. Most respondents (64%) reported using multi-gene panels for germline analysis, and only 28% reported testing tumors for biallelic mutations for cases where suspected pathogenic mutations were not confirmed by germline analysis. Respondents reported relying upon passive dissemination of information to at-risk family members, and there was variation in follow through of genetic testing recommendations. Reported risk management practices varied-nearly all programs (98%) recommended colonoscopy every 1-2 years, but only 35% recommended chemoprevention with aspirin.There is widespread heterogeneity in management practices for Lynch syndrome worldwide among IMRC member institutions. This may reflect the rapid pace of emerging technology, regional differences in resources, and the lack of definitive data for many clinical questions. Future efforts should focus on the large numbers of high-risk patients without access to state of the art Lynch syndrome management.
View details for PubMedID 29702294
Association of Aurora-A (STK15) kinase polymorphisms with clinical outcome of esophageal cancer treated with preoperative chemoradiation
2012; 118 (17): 4346-4353
Continuous flow left ventricular assist device (CF-LVAD) patients have a high prevalence of gastrointestinal bleeding from the small bowel. Video capsule endoscopy (VCE) is often used for diagnosis in these patients, but efficacy has yet to be determined. In this study, we evaluated the efficacy of VCE in the management of CF-LVAD patients with suspected small bowel bleeding by comparing to a non-VCE CF-LVAD control group.We retrospectively reviewed the charts of all patients with CF-LVADs implanted at Stanford Hospital from January 2010 to October 2015. Patients were included in the study if there was a clinical suspicion of small bowel bleeding and either a negative upper endoscopy or colonoscopy.A total of 26 patients met inclusion criteria for a total of 15 encounters where VCE was done, and 25 where VCE was not done. There were no statistical differences when comparing these groups in terms of medical therapy use (thalidomide or octreotide), enteroscopy use (double-balloon or push), intervention on lesions, or any 30-day outcomes. There was no advantage to VCE with regard to the composite endpoint time to re-bleed or death related to re-bleeding (median 114 vs. 161 days, P = 0.15) after removing patients who did not get a VCE due to death or critical illness.We did not find VCE changed management or outcomes in CF-LVAD patients with suspected small bowel bleeding at our institution when compared to a non-VCE control group. Our experience is small and single center, and larger, multi-center studies could further elucidate the utility of VCE in this patient population.
View details for PubMedID 29118868
View details for PubMedCentralID PMC5667693
Genetic susceptibility to esophageal cancer: the role of the nucleotide excision repair pathway
2009; 30 (5): 785-792
Aurora-A/STK15 is a serine/threonine kinase critical for regulated chromosome segregation and cytokinesis. We investigated the association between 2 nonsynonymous single nucleotide polymorphisms in the coding region of STK15, T91A (Phe31Ile) and G169A (Val57Ile), and clinical outcome of esophageal cancer treated with preoperative chemoradiation.Genotypes at Phe31Ile and Val57Ile were assessed from peripheral blood lymphocytes of 190 esophageal cancer patients and were correlated to response to treatment, recurrence rate, risk of death, disease-free survival (DFS) and median survival time (MTS).All patients had resectable esophageal or gastroesophageal junction cancer and received preoperative chemoradiation followed by esophagectomy. The heterozygous variant Phe31/Ile variant was significantly associated with tumor recurrence (odds ratio [OR] = 4.39; 95% confidence interval [CI], 2.12-8.94; P < .001), shorter DFS (P = .0001), and shorter MTS (P = .012). For patients receiving cisplatin-based therapy, only the variant Phe31/Ile had an adverse effect on response (OR = 2.8; 95% CI, 1.01-5.17; P = .048) and MTS (P = .026). The variant 91A-169G haplotype carried a significant risk for lack of complete response (OR = 2.54; 95% CI, 1.15-5.54) and higher rate of recurrence (OR = 2.73; 95%CI, 1.00-7.29). The presence of at least 1 variant allele at each locus further increased the risk of recurrence (adjusted OR = 6.21; 95% CI, 2.28-17.11; P = <.001), and was associated significantly shorter DFS (P = .003).Our study shows that functional SNPs in the STK15 gene are associated with higher rate of recurrence, higher likelihood of chemoratiotherapy-resistance, shorter DFS, and shorter MTS. Confirmation of our data and understanding the mechanisms through which STK15 functional SNPs mediate resistance to chemoradiotherapy are warranted.
View details for DOI 10.1002/cncr.26581
View details for Web of Science ID 000307845200033
View details for PubMedID 22213102
Cyclin D1 guanine/adenine 870 polymorphism with altered protein expression is associated with genomic instability and aggressive clinical biology of esophageal adenocarcinoma
JOURNAL OF CLINICAL ONCOLOGY
2007; 25 (6): 698-707
In this case-control study with 387 White esophageal patients and 462 White controls matched to cases by age and sex, we evaluated the associations between 13 potential functional polymorphisms in eight major nucleotide excision repair (NER) genes and esophageal cancer risk. In individual single nucleotide polymorphism analysis, after adjustment for multiple comparisons, the heterozygous GT genotype of the ERCC1 3' untranslated region (UTR) was associated with an increased risk, whereas the homozygous variant genotype TT was associated with 60% reduction in risk with an odds ratio (OR) of 0.40 (95% confidence interval [CI] = 0.19-0.86). The heterozygous AG genotype of XPA 5' UTR was at 2.11-fold increased risk (95% CI = 1.33-3.35) and the risk reached 3.10-fold (95% CI = 1.94-4.95) for the homozygous variant GG genotype. These associations were also significant when restricted the analyses in patients with esophageal adenocarcinoma. Further, the CT genotype of the RAD23B Ala249Val was associated with increased esophageal cancer risk (OR = 1.44; 95% CI = 1.05-1.97), whereas the poly-AT-/+ genotype of the XPC intron 9 conferred a decreased risk (OR = 0.71, 95% CI = 0.51-0.97). In joint analysis, individuals carrying 1 (OR = 2.64, 95% CI = 1.57-4.52) and > or = 2 (OR = 2.74, 95% CI = 1.58-4.75) unfavorable genotypes exhibited significantly increased risk for esophageal cancer risk with significant dose-response trend (P for trend = 0.006). The pathway-based risk was more evident in ever smokers, overweight/obese individuals, men and ever drinkers. Our results support the hypothesis that increasing numbers of unfavorable genotypes in the NER predispose susceptible individuals to increased risk of esophageal cancer. These findings warrant further replications in different populations.
View details for DOI 10.1093/carcin/bgp058
View details for Web of Science ID 000265740000010
View details for PubMedID 19270000
Monovalent ligation of the B cell receptor induces receptor activation but fails to promote antigen presentation
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2006; 103 (9): 3327-3332
Altered cyclin D1 (CD1), a cell cycle regulator, may play an important role in imparting aggressive nature to esophageal adenocarcinoma (EAC). CD1 gene single nucleotide polymorphism G/A870 results in two alternatively spliced transcripts, CD1a and CD1b. CD1b, preferentially encoded by the A870 allele, is putatively oncogenic. We hypothesized that CD1 A870 allele would be associated with higher CD1 protein expression, and increased genomic instability during EAC evolution, leading to more aggressive phenotype.One hundred twenty-four archival specimens of EAC, and 39 associated Barrett's esophagus (BE) specimens were examined for CD1 genotype, CD1 protein expression, and chromosome 9 polysomy (representing genomic instability). We correlated CD1 genotypes with CD1 protein expression, genomic instability, age at diagnosis of EAC, and overall survival (OS).The A870 allele was associated with higher levels of CD1 protein expression in EAC (P = .032); in BE (P = .01) where it was associated with concomitant increased chromosome 9 polysomy (P = .002); and with a younger age at diagnosis (P < .001) and poor OS (P = .0003) of EAC patients.Our data suggest that CD1 A870 background may be imparting aggressive phenotype to EAC. It provides a molecular basis to explain the clinical biology associated with CD1 polymorphism whereas aberrant nuclear accumulation of CD1 protein enhances the acquisition of genomic instability (ie, clonal diversity), thus leading to early age of EAC diagnosis and poor OS. CD1 genotyping with other biomarkers may help create a biomarker-based prognostic model for EAC and CD1 may also serve as a therapeutic target.
View details for DOI 10.1200/JCO.2006.08.0283
View details for Web of Science ID 000244384000015
View details for PubMedID 17308274
We explored the role of antigen valency in B cell receptor (BCR) activation and rearrangement of intracellular MHC class II compartments as factors that contribute to the efficacy of antigen presentation. Using primary B cells that express a hen egg lysozyme (HEL)-specific BCR, we found that oligomeric HEL more efficiently promoted both BCR activation and internalization than did monovalent HEL, although monovalent HEL, unlike monovalent Fab fragments of anti-Ig, readily triggered the BCR. Nonetheless, oligovalent ligation positions the BCR in a membrane microdomain that is distinct from one engaged in the course of monovalent ligation, as judged by detergent extraction of the BCR. Furthermore, oligovalent HEL induced more pronounced rearrangement of MHC class II-containing antigen-processing compartments. Using videomicroscopy we observed in real time the rearrangement of MHC class II compartments as well as delivery of antigen in primary B cells. The observed increase in rearrangement of MHC class II-positive compartments and the disposition of antigen-bound BCRs therein correlates with improved presentation of a HEL-derived epitope. Although monomeric HEL efficiently engages the BCR, presentation of HEL-derived epitopes is impaired compared to oligovalent antigens. This trait may help explain the known ability of soluble, disaggregated antigen to induce a state of B cell tolerance.
View details for DOI 10.1073/pnas.0511315103
View details for Web of Science ID 000235780700059
View details for PubMedID 16492756