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Biomedical subjects

Patrick M Lynch

Publications and source records attributed to Patrick M Lynch.

At least 19 recordsLinked to original sources
PubMed2007

Evolving role of self-expanding metal stents in the treatment of malignant dysphagia and fistulas.

BACKGROUND: Self-expanding metal stents (SEMS) are touted as the cornerstone of endoscopic palliation of unresectable esophageal cancer. However, usage at MD Anderson has fallen in recent years, despite a greater volume of patients with esophageal cancer. OBJECTIVE: To compare our more recent experience with that of earlier reported institutional experience and to assess how esophageal stent use has evolved. DESIGN: A retrospective chart review. SETTING: A tertiary referral cancer center. PATIENTS: Ninety-seven patients with malignant dysphagia who had SEMS placed from 2000 to 2003. INTERVENTIONS: Placement of SEMS for malignant disease. MAIN OUTCOMES MEASUREMENTS: Dysphagia scores, overall survival, and complication rates. RESULTS: Dysphagia scores improved in 86%, and tracheoesophageal fistula symptoms improved in 90%. Complications were seen in a majority of the patients and major complications in 37%. Ten patients had hematemesis, migrations occurred in 5, and early unexpected deaths in 2. Adenocarcinoma and female sex were factors associated with increased odds of a major complication. Prior chemoradiation, age, stricture location, and length were not associated with complications. Median survival was 77 days. LIMITATIONS: Noncomparative retrospective single-center study. CONCLUSIONS: SEMS fall short of an ideal palliative method, because complications that require additional intervention are frequent. Usage has declined despite higher numbers of patients with esophageal cancer. However, for patients with tracheoesophageal fistulas, SEMS are the treatment of choice. For patients who are not candidates for chemoradiation or who failed to achieve adequate palliation with such therapy, SEMS offer a viable, albeit imperfect, endoscopic approach.

Adenocarcinoma↗
PubMed2006

IGF1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Insulin-like growth factor-I (IGF-I) is involved in colorectal carcinogenesis, and elevated plasma IGF-I levels are associated with sporadic colorectal cancer (CRC) risk. We investigated the relationship between IGF1 promoter cytosine-adenine (CA) dinucleotide-repeat polymorphism length and CRC risk in 121 MMR gene mutation carriers using Cox regression and Kaplan-Meier analysis. All statistical tests were two-sided. Time to onset for CRC increased for each decrease in CA-repeat number (median = 19 repeats, range = 12-22 repeats; hazard ratio [HR] = 1.17, 95% confidence interval [CI] = 1.05 to 1.31; P = .006). Patients carrying a CA(< or = 17) repeat allele had a statistically significantly higher CRC risk (HR = 2.36; 95% CI = 1.28 to 4.36; P = .006) than all others and were younger at onset (44 years versus 56.5 years; P = .023). These findings indicate a statistically significant association between shorter IGF1 CA-repeat lengths and increased risk for CRC in HNPCC. This is the first report, to our knowledge, to show that IGF1 variant genotypes modify risk of a hereditary form of cancer.

Adenine↗
PubMed2006

Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications.

Lynch syndrome is the most common form of hereditary colorectal cancer (CRC). This review covers the cardinal features of Lynch syndrome with particular emphasis upon its diagnostic criteria, molecular genetics, natural history, genetic counseling, surveillance and management. Considerable attention has been given to the etiologic role of mismatch repair (MMR) genes as well as low penetrance alleles and modifier genes. The American founder mutation, a deletion of exons 1-6 of MSH2, is discussed in some detail, owing to its high frequency in the US (19 000-30 000 carriers). Genetic counseling is essential prior to patients' undergoing DNA testing and again when receiving their test results. Families with a lower incidence of CRC and extracolonic cancers, in the face of being positive for Amsterdam I criteria but who do not have MMR deficiency by tumor testing, are probably not Lynch syndrome, and thereby should preferably be designated as familial CRC of undetermined type. Patients who are either noncompliant or poorly compliant with colonoscopy, and who are MMR mutation positive, may be candidates for prophylactic colectomy, while MMR mutation-positive women who are noncompliant with gynecologic surveillance may be candidates for prophylactic hysterectomy and bilateral salpingo-oophorectomy.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2006

Sebaceous skin lesions as clues to hereditary non-polyposis colorectal cancer.

Cutaneous lesions consonant with Muir-Torre syndrome strongly suggest hereditary non-polyposis colorectal cancer (HNPCC). Ponti et al. discuss the importance of combining molecular genetic features of the sebaceous neoplasms, including microsatellite instability and immunohistochemistry, with family history, to determine the likelihood of HNPCC. Proof of diagnosis is identification of one of the mismatch repair germline mutations.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2006

DNMT3b polymorphism and hereditary nonpolyposis colorectal cancer age of onset.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome of familial malignancies resulting from germ-line mutations in DNA mismatch repair genes. Colorectal and endometrial cancers are most frequently observed. A polymorphic C-to-T change in the promoter region of the DNMT3b gene, -149 bp from the transcription start site, is reported to greatly increase promoter activity and is associated with increased risk for lung cancer and decreased postsurgical survival in patients with small cell carcinoma of the head and neck. We studied the influence of this DNMT3b polymorphism on HNPCC age of onset. We determined the DNMT3b genotype of 146 mismatch repair mutation carriers from 72 families. Of these, 74 participants had colorectal cancer. The participants were genotyped by single-strand conformational polymorphism analysis and DNA sequencing. We tested the association between age of onset and DNMT3b genotypes by comparing Kaplan-Meier survival curves, evaluating the homogeneity of the curves using the log-rank test, Wilcoxon's test, and Fleming-Harrington test and estimating the strength and direction of the association using the Cox proportional hazards regression model adjusting for potential demographic and genetic confounding factors. HNPCC patients carrying one or two copies of the DNMT3b variant T allele developed their colorectal cancer significantly earlier than HNPCC patients who were homozygous for the wild-type DNMT3b allele. Combining knowledge of an individual's DNMT3b genotype with information on other genetic and environmental risk factors may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.

Adult↗
PubMed2006

Current approaches in familial colorectal cancer: a clinical perspective.

Individuals with a family history of colorectal cancer or colorectal adenomas have an increased risk for colorectal cancer. When no hereditary syndrome is evident, screening is based on empiric risk estimates. The risk is greatest for individuals with specific inherited cancer-predisposing disorders. When conditions such as familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer are diagnosed, specific neoplasm risk estimates can usually be performed based on advances in molecular genetics. These estimates lead to more straightforward and cost-effective approaches to surveillance and management. The National Comprehensive Cancer Center Network (NCCN) and other groups have provided detailed guidelines for evaluating patients based on recognition of clinical syndrome characteristics, followed by appropriate genetic counseling, genetic testing, and optimal surveillance. The NCCN guidelines are used as a frame of reference for this discussion of selected recent advances in human cancer genetics as they apply to clinical practice.

Adenomatous Polyposis Coli↗
PubMed2005

Failure patterns correlate with the proportion of residual carcinoma after preoperative chemoradiotherapy for carcinoma of the esophagus.

BACKGROUND: The current study was conducted to test the hypothesis that patterns of failure are correlated with the degree of residual carcinoma after preoperative chemoradiotherapy (CRT) in patients with esophageal carcinoma. METHODS: The authors analyzed the clinical characteristics of patients with carcinoma of the esophagus who underwent preoperative CRT. The residual carcinoma in the resected specimen was categorized into 3 groups (0%, 1-50%, and > 50%). The initial patterns of failure were analyzed according to these categories. RESULTS: Of the 235 patients who underwent CRT, 69 (29%) achieved a pathologic complete response (pathCR; Group A), 109 patients (46%) achieved a response but it was less than a pathCR (1-50% residual carcinoma; Group B), and 57 (24%) had no response (> 50% residual carcinoma; Group C). The time to locoregional recurrence was significantly longer for Group A compared with Group C (P = 0.05). The rate of distant metastases was significantly lower in Groups A and B compared with Group C (14% in Group A, 29% in Group B, and 33% in Group C; P = 0.03). The distant metastases-free survival was found to be significantly longer in Groups A and B compared with Group C (Group A vs. Group B, P = 0.01; Group A vs. Group C, P < 0.0001; and Group B vs. Group C, P = 0.03). A significantly higher proportion of patients in the responding groups (Groups A and B) had no disease recurrence compared with Group C (81% in Group A, 67% in Group B, and 61% in Group C; P = 0.04). The overall survival and disease-free survival were found to be significantly longer in Groups A and B compared with Group C. CONCLUSIONS: Data from the current study demonstrate that the proportion of residual carcinoma after preoperative CRT is significantly correlated with patterns of locoregional and distant failure. Future investigations should focus on reducing the proportion of residual carcinoma and metastatic disease progression in patients with esophageal carcinoma.

Adult↗
PubMed2005

Psychological impact of genetic testing for hereditary nonpolyposis colorectal cancer.

PURPOSE: This study examines the impact of hereditary nonpolyposis colorectal cancer (HNPCC) genetic test results on psychological outcomes among cancer-affected and -unaffected participants up to 1 year after results disclosure. PATIENTS AND METHODS: A total of 155 persons completed study measures before HNPCC genetic testing, and at 2 weeks and 6 and 12 months after disclosure of test results. RESULTS: Mean scores on all outcome measures remained stable and within normal limits for cancer-affected participants, regardless of mutation status. Among unaffected carriers of HNPCC-predisposing mutations, mean depression, state anxiety, and cancer worries scores increased from baseline to 2 weeks postdisclosure and decreased from 2 weeks to 6 months postdisclosure. Among unaffected noncarriers, mean depression and anxiety scores did not differ, but cancer worries scores decreased during the same time period. Affected and unaffected carriers had higher mean test-specific distress scores at 2 weeks postdisclosure compared with noncarriers in their respective groups; scores decreased for affected carriers and all unaffected participants from 2 weeks to 12 months postdisclosure. Classification of participants into high- versus low-distress clusters using mean scores on baseline psychological measures predicted significantly higher or lower follow-up scores, respectively, on depression, state anxiety, quality of life, and test-specific distress measures, regardless of mutation status. CONCLUSION: Although HNPCC genetic testing does not result in long-term adverse psychological outcomes, unaffected mutation carriers may experience increased distress during the immediate postdisclosure time period. Furthermore, those with higher levels of baseline mood disturbance, lower quality of life, and lower social support may be at risk for both short- and long-term increased distress.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2005

ATM polymorphism and hereditary nonpolyposis colorectal cancer (HNPCC) age of onset (United States).

OBJECTIVE: We examined a G-to-A single nucleotide polymorphism of the ATM gene, to determine if it influences hereditary non-polyposis colorectal cancer (HNPCC) age of onset. HNPCC is caused by mutations in mismatch repair genes, especially hMLH1 and hMSH2. ATM germline mutations have been associated with breast and digestive cancers. In a smaller European study, the G-to-A polymorphism was associated with an increased risk of developing an HNPCC-related cancer within HNPCC families. MATERIALS AND METHODS: We genotyped 109 mismatch repair gene (MMR) mutation carriers from 53 HNPCC families for the ATM polymorphism using PCR and single strand conformational polymorphism (SSCP) analysis. We tested the association between the ATM genotypes and HNPCC age of onset by survival analysis. RESULTS: The ATM polymorphism did not significantly modify HNPCC age of onset, nor overall risk, in our population. CONCLUSIONS: Although a modifier effect was not seen in our study, future studies that examine the polymorphism in combination with other genetic and environmental factors may elucidate an association. Revealing such associations in MMR mutation carriers may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Hereditary nonpolyposis colorectal cancer family members' perceptions about the duty to inform and health professionals' role in disseminating genetic information.

This study's aim was to ascertain hereditary nonpolyposis colorectal cancer (HNPCC) families' views on the duty to inform with particular focus on the role of health professionals in disseminating familial genetic information. Eighty members of 16 families with a clinical or molecular diagnosis of HNPCC completed qualitative interviews regarding views on family members' right to know and who should disseminate familial genetic information. Most indicated that everyone in the family should know about the presence of a mutation in the family, with family members themselves being the preferable informant, supported by health professionals who were seen as helpful in overcoming barriers. All but one respondent indicated that if a parent did not test and presumably did not inform his/her child about the family mutation, the child should be informed by other family members or by a health professional. Many were attuned to confidentiality concerns, but judged them to be outweighed by the importance of family members knowing about the mutation and undertaking proper surveillance. Respondents were more private about the disclosure of individual results to other family members, clearly distinguishing personal results from familial genetic information. These families with a hereditary colon cancer syndrome favor open sharing of genetic information within the family, and desire the supportive involvement of health care professionals in disseminating genetic information.

Adult↗
PubMed2004

p53 polymorphism and age of onset of hereditary nonpolyposis colorectal cancer in a Caucasian population.

PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome of familial malignancies. Colorectal and endometrial cancers are most frequently observed. The syndrome results mainly from germ-line mutations in DNA mismatch repair genes. A common G-to-C polymorphism at codon 72 in the p53 gene has been associated with increased risk for lung, nasopharyngeal, oral, prostate, and breast cancers and may be a marker for genetic susceptibility to colorectal cancer. We studied the influence of this p53 polymorphism on HNPCC age of onset. EXPERIMENTAL DESIGN: We determined the p53 genotype of 92 Caucasian mismatch repair mutation carriers, of which, 47 had colorectal cancer. The subjects were genotyped by single-strand conformational polymorphism analysis. We tested the association between age of onset and the p53 genotypes by comparing Kaplan-Meier survival curves, evaluating the homogeneity of the curves using the log-rank test and Wilcoxon's test, and estimating the association using the Cox proportional hazards regression model to adjust for potential demographic confounding factors. RESULTS: The HNPCC patients who were heterozygous developed their colorectal cancer 13 years earlier than HNPCC patients who were homozygous for the wild-type allele. CONCLUSIONS: Combining knowledge of an individual's p53 genotype with information on other genetic and environmental risk factors may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Preoperative induction of CPT-11 and cisplatin chemotherapy followed by chemoradiotherapy in patients with locoregional carcinoma of the esophagus or gastroesophageal junction.

BACKGROUND: Patients with localized esophageal carcinoma often develop locoregional and distant disease recurrence. The current study investigated the outcome of a new chemotherapy combination as induction therapy before chemoradiotherapy. METHODS: Forty-three patients with resectable carcinoma of the esophagus or gastroesophageal junction were enrolled. Most of the tumors were endoscopic ultrasonography (EUS) (EUS)T3 (84%) and (EUS)N1 (63%). The patients received < or = 2 6-week cycles of CPT-11 and cisplatin followed by chemoradiotherapy (45 grays with 5-fluorouracil and paclitaxel). Five to six weeks after chemoradiotherapy, the patients underwent staging and surgery. The feasibility, curative resection rates, overall and disease-free survival rates, rate of significant pathologic response, and patterns of disease recurrence were assessed. RESULTS: Of the 43 patients, 39 (91%) underwent an R0 resection. Two patients (5%) died after surgery. A pathologic complete response (pathCR) was observed in 11 (28%) of the 39 patients (or 26% of the 43 patients). In addition, 16 patients (41% of 39 patients or 37% of 43 patients) had < 10% viable tumor in the surgical specimen (pathPR). A comparison of endoscopic ultrasonograpy T and N classifications with surgical T and N classifications demonstrated significant down-staging (P < 0.01). The median survival period of all 43 patients was 22.1 months. Patients who had achieved a pathCR or pathPR had a longer median survival (25.6 months) than those who achieved less than a pathPR (18.5 months; P = 0.52). None of the clinical parameters examined were found to correlate with survival or pathologic response. CONCLUSIONS: CPT-11-based induction chemotherapy resulted in substantial pathCR and pathPR rates, both of which lead to a favorable survival outcome. The three-step strategy needs to be developed further, with the investigation of targeted therapies with chemotherapy and radiotherapy.

Adenocarcinoma↗