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Patrick M Lynch

Publications and source records attributed to Patrick M Lynch.

30 records · Page 2Linked to original sources
PubMed2004

Serum proteomic profiles suggest celecoxib-modulated targets and response predictors.

Cyclooxygenase-2 is a valid target for cancer prevention and treatment. This has been shown in preclinical and clinical cancer prevention studies by using a cyclooxygenase-2 inhibitor, celecoxib. When used in a randomized cancer prevention clinical trial on patients with the inherited autosomal dominant condition, familial adenomatous polyposis, celecoxib proved efficacious. However, a remarkable heterogeneity in patients' responses to the chemopreventive effects of celecoxib was observed. Proteomic profiling of sera from these patients identified several markers, the expression of which was specifically modulated after treatment with celecoxib. A decision tree algorithm identified classifiers for response to celecoxib with relatively high sensitivity but moderate to low specificity. In particular, a spectral feature at m/z 16,961.4 was identified as a strong discriminator between response and nonresponse to celecoxib at the highest dose.

Adenomatous Polyposis Coli↗
PubMed2004

Unusual tumors associated with the hereditary nonpolyposis colorectal cancer syndrome.

The molecular pathogenesis of tumors outside the usual tumor spectrum for hereditary nonpolyposis colorectal cancer (HNPCC) is currently controversial. Specifically, it is not known whether these tumors are related to defects in DNA mismatch repair or arise independently of this defect in these patients. Here, we report two young patients, each with a known MSH2 mutation in the family, who developed rare tumors (adrenal cortical carcinoma and anaplastic carcinoma of the thyroid) that are not usually associated with HNPCC. Both of these patients were members of families that fulfilled modified Amsterdam (Amsterdam II) criteria for this familial cancer syndrome. Both the adrenal tumor and the thyroid tumor showed complete loss of immunohistochemical expression for MSH2 protein. Neither tumor was considered microsatellite instability-high following microsatellite instability analysis using the established National Cancer Institute panel of five microsatellite markers. To our knowledge, MSH2 defects in these types of tumors have not been previously reported in patients with the HNPCC syndrome. Our results suggest that microsatellite instability analysis using the National Cancer Institute panel of five microsatellite markers may not detect microsatellite instability in tumors that fall outside the usual tumor spectrum of this syndrome. Therefore, when analyzing unusual tumors in patients with known or suspected HNPCC syndrome, we advocate the performance of immunohistochemistry for mismatch repair gene products in addition to microsatellite instability analysis.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Endoscopic ultrasound after preoperative chemoradiation can help identify patients who benefit maximally after surgical esophageal resection.

BACKGROUND: We investigated whether differences in postoperative survival exist based on the presence and site of residual tumor (esophagus vs regional lymph nodes) after preoperative chemoXRT in patients with esophageal cancer. Based on these data, we reevaluated the role of EUS in identifying patients who maximally benefit from surgical esophageal resection after preoperative chemoXRT. METHODS: We studied 97 consecutive esophageal cancer patients treated with preoperative chemoXRT and a potentially curative surgical procedure between 1998 to 2001. All patients had EUS examination prior to chemoXRT and 53 had a repeat EUS examination after chemoXRT but prior to surgery. Surgical resection specimens were analyzed for absence or presence of residual tumor and its location. RESULTS: Patients with residual tumor in the esophagus (pathT1-3N0) and patients without residual tumor (pathT0N0) had similar cumulative survival (p= 0.92). Patients with residual cancer in lymph nodes showed a trend toward shorter cumulative survival compared to patients without residual tumor in lymph nodes (p= 0.086). The actuarial survival in pathN1 group was lower than pathN0 group at 1, 2, and 3 yr. Patients with significant residual lymphadenopathy detected by EUS after therapy had significantly worse postoperative survival compared to patients with no residual lymphadenopathy (p= 0.028). In eight patients, we found that reliable cytologic identification of residual malignancy was technically feasible by EUS-FNA after chemoradiation therapy. CONCLUSIONS: Following preoperative chemoXRT and surgery, patients with residual tumor in the regional lymph nodes have lower actuarial survival at 1, 2, and 3 yr after surgery, compared to patients with path CR or with residual tumor only in the esophagus. EUS and EUS-guided FNA can be helpful in identifying residual tumor in the lymph nodes after preoperative chemoXRT to select patients who benefit maximally from surgery.

Adenocarcinoma↗
PubMed2004

Frequent CpG island methylation in sporadic and syndromic gastric fundic gland polyps.

We studied methylation of 2 tumor suppressor genes (p14, p16) and 4 MINT (methylated in tumor) clones (MINT1, MINT2, MINT25, MINT31) among 51 fundic gland polyps (FGPs) and 27 normal gastric body biopsy samples using bisulfite treatment of genomic DNA followed by methylation-specific polymerase chain reaction. Thirty-two FGPs were syndromic polyps from 14 patients with familial adenomatous polyposis (FAP); 19 were sporadic FGPs from 15 patients without FAP. Significantly higher mean methylation indices were found between FGPs and normal gastric mucosa (P = .012). FGPs arising in a background of proton pump inhibitor (PPI) effect had significantly higher mean methylation indices than those that did not (P = .023). Perhaps because sporadic FGPs were more likely to be associated with PPI effect than were FAP-associated FGPs, they also demonstrated higher mean methylation indices than syndromic polyps (P = .024). Among FAP-associated FGPs, there was no statistical difference in methylation indices between polyps that were dysplastic, indefinite for dysplasia, or nondysplastic (P = .87). Epigenetic alterations involving methylation of CpG islands might have a role in the development of some FGPs, particularly those with a PPI effect. They do not account for the presence or absence of a dysplastic phenotype in FGPs.

Adenomatous Polyposis Coli↗
PubMed2004

Cell proliferation and apoptotic indices predict adenoma regression in a placebo-controlled trial of celecoxib in familial adenomatous polyposis patients.

BACKGROUND: Celecoxib was shown to regress colorectal adenomas in familial adenomatous polyposis (FAP) patients relative to placebo. To address the mechanism of polyp regression, we determined whether celecoxib can modulate cell proliferation, apoptosis, and prostaglandin E(2) (PGE(2)) levels in colorectal epithelia from FAP trial participants and whether such alterations correlate with observed reductions in polyp number. MATERIALS AND METHODS: Colorectal mucosal biopsies were obtained at baseline and on last day of celecoxib (100 or 400 mg twice daily) or placebo administration (6 months). Residual paraffin-embedded adenomas and normal mucosa from the same patients (n = 17) or normal tissue alone (n = 15) were analyzed. Immunoperoxidase staining for Ki-67 was performed and apoptotic cells were identified by their morphology. Ki-67 and apoptotic labeling indices and their ratios were calculated in superficials (s) and nonsuperficial (ns) regions of adenomas and normal mucosa, and baseline to 6-month differences were calculated. PGE(2) levels were analyzed by mass spectroscopy (normal, n = 64; adenoma, n = 56). Biomarkers were analyzed by treatment arm and correlated with previously determined mean percentage reductions in colorectal polyp number. RESULTS: In adenomas, a reduction in the superficial proliferative activity i.e., Ki-67(s) labeling index, accompanied polyp regression (r = -0.76, P = 0.006). An increase in the apoptotic ratio [i.e., superficial apoptotic index (AI(s))/nonsuperficial apoptotic index (AI(ns))] was found to correlate with reduced polyp counts in that higher apoptotic ratios correlated with better response to celecoxib (r = 0.71, P = 0.004). Furthermore, the AI(s)/Ki-67(s) ratio (r = 0.58, P = 0.026) accompanied polyp regression. In normal mucosa, a trend toward increased AI(s) (r = 0.33, P = 0.053) and polyp regression was found. PGE(2) levels did not significantly correlate with polyp regression. Changes in biomarker levels (baseline to 6 months) were correlated in adenomas and normal mucosa (AI(s), r = 0.29, P = 0.024; AI(ns), r = 0.34, P = 0.009; PGE(2), r = 0.50, P = 0.059) within individual patients. CONCLUSION: Suppression of cell proliferation and an increased apoptotic ratio, as well as the ratio of apoptosis to cell proliferation, accompany polyp regression in a chemoprevention trial in FAP patients. These findings suggest potential mechanisms for the efficacy of celecoxib and warrant further study of these biomarkers as intermediate endpoints in FAP patients.

Adenomatous Polyposis Coli↗
PubMed2003

Association of the CpG island methylator phenotype with family history of cancer in patients with colorectal cancer.

Methylation of promoter CpG islands in colorectal cancer (CRC) falls into two categories: age related and cancer specific. Most cancer-specific methylation at CpG islands occurs in a subset of cases that display the CpG island methylator phenotype (CIMP). The underlying cause of CIMP is not known. Using methylation-specific PCR, we studied 47 CRC patients for methylation at five loci to determine whether the methylation status of CpG islands is associated with family history of cancer. Four of the loci were differentially methylated between the CRC cases with a family history and those with no family history. Patients with methylation at all four loci were 14 times more likely to have a family history of cancer than patients with methylation at none of the four loci. These findings suggest that there may be a genetic component to CIMP in CRC.

Chromosome Mapping↗
PubMed2003

Small bowel tumors.

Primary tumors of the small bowel are rare, and their clinical presentation is nonspecific. Consequently, preoperative diagnosis remains the exception rather than the rule. Although the small intestine makes up 75% of the length and 90% of the surface area of the gastrointestinal tract, small bowel tumors make up approximately 3% of all malignant gastrointestinal neoplasms. Primary neoplasms of the small intestine are notorious for their insidious presentation and vague symptoms, including abdominal pain, anorexia, and weight loss. These nonspecific symptoms, coupled with the lack of physical findings, often cause a significant delay in reaching a diagnosis. Because the small bowel has been a relatively inaccessible area to standard endoscopic techniques, contrast radiography has been regarded historically as the gold standard diagnostic modality. The management of primary malignant small bowel tumors is invariably surgical. However, adjuvant chemotherapy and radiotherapy may be warranted, depending on the type of tumor.

Diagnosis, Differential↗
PubMed2002

Different familial adenomatous polyposis phenotypes resulting from deletions of the entire APC exon 15.

Germline mutations of the adenomatous polyposis coli ( APC) gene cause familial adenomatous polyposis (FAP), an autosomal, dominantly inherited disease that predisposes patients to colorectal cancer. The APC gene is composed of 15 coding exons and encodes an open reading frame of 8.5 kb. The 3' 6.5 kb of the APCopen reading frame is encoded by a single exon, exon 15. Most identified APC mutations are at the 5' half of the APC open reading frame and are nucleotide substitutions and small deletions or insertions that result in truncation of the APC protein. Very few well-characterized gross alterations of APC have been reported. Patients with FAP typically develop hundreds to thousands of colorectal tumors beginning in their adolescence. A subgroup of patients with FAP who develop fewer tumors at an older age have what is called attenuated FAP (AFAP). Accumulating evidence indicates that patients carrying germline APC mutations in the first four coding exons, in the alternatively spliced region of exon 9, or in the 3' half of the coding region usually develop AFAP. We characterized two germline APC alterations that deleted the entire APC exon 15 as the result of 56-kb and 73-kb deletions at the APC locus. A surprising finding was that one proband had the typical FAP phenotype, whereas the other had a phenotype consistent with that of AFAP.

Adenomatous Polyposis Coli↗
PubMed2002

Common deletion of SMAD4 in juvenile polyposis is a mutational hotspot.

Juvenile polyposis (JP) is an autosomal dominant syndrome in which affected patients develop upper- and/or lower-gastrointestinal (GI) polyps. A subset of families with JP have germline mutations in the SMAD4 (MADH4) gene and are at increased risk of GI cancers. To date, six families with JP have been described as having the same SMAD4 deletion (1244-1247delAGAC). The objective of the present study is to determine whether this deletion is a common ancestral mutation or a mutational hotspot. DNA from members of four families with JP, from Iowa, Mississippi, Texas, and Finland, that had this 4-bp deletion was used to genotype 15 simple tandem repeat polymorphism (STRP) markers flanking the SMAD4 gene, including 2 new STRPs within 6.3 and 70.9 kb of the deletion. Haplotypes cosegregating with JP in each family were constructed, and the distances of the closest markers were determined from the draft sequence of the human genome. No common haplotype was observed in these four families with JP. A 14-bp region containing the deletion had four direct repeats and one inverted repeat. Because no common ancestor was suggested by haplotype analysis and the sequence flanking the deletion contains repeats frequently associated with microdeletions, this common SMAD4 deletion in JP most likely represents a mutational hotspot.

Adenomatous Polyposis Coli↗