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Biomedical subjects

P M Lynch

Publications and source records attributed to P M Lynch.

At least 19 recordsLinked to original sources
PubMed2005

Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome.

PURPOSE: Preoperative chemoradiotherapy may increase the R0 (curative) resection rate, overall survival (OS) duration, and disease-free survival (DFS) duration. We evaluated paclitaxel-based induction chemotherapy and chemoradiotherapy in patients with localized gastric or gastroesophageal adenocarcinoma to determine its feasibility, impact on the R0 resection rate, type of pathologic response, OS, and DFS. PATIENTS AND METHODS: Patients with operable, localized gastric, or gastroesophageal adenocarcinoma were eligible. Staging included endoscopic ultrasonography (EUS) and laparoscopy. Patients received two 28-day cycles of induction chemotherapy of fluorouracil, paclitaxel, and cisplatin followed by 45 Gy of radiation and concurrent fluorouracil plus paclitaxel. The cancer was restaged and surgery was attempted. Postsurgery pathologic findings and R0 resection were correlated with OS and DFS. RESULTS: Forty-one patients were enrolled. Most carcinomas were proximal (83%) and pretreatment stage EUST3 (85%). Forty patients (98%) underwent surgery, and 78% had an R0 resection. We observed a pathologic complete response (pathCR) rate of 20% and a pathologic partial response (pathPR) rate of 15% (< 10% residual cancer cells in the resected specimen). No pretreatment parameter (sex, cancer location, baseline T stage, or baseline N stage) predicted the type of postsurgery pathologic response, OS, or DFS. However, pathCR (P = .02), pathCR + pathPR (P = .006), R0 resection (P < .001), and postsurgery T and N stages (P = .01 and P < .001, respectively) were associated with OS. Same parameters were significantly correlated with DFS. Toxicity was manageable. CONCLUSION: The type of pathologic response but not pretreatment parameters was associated with OS and DFS. Efforts to increase the rate of pathologic response and better systemic cancer control are warranted.

Adenocarcinoma↗
PubMed2004

Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma.

PURPOSE: In the West, curative (R0) resection is achieved in approximately 50% of patients with localized gastric carcinoma, and more than 60% die of cancer following an R0 resection. A multi-institutional study of preoperative chemoradiotherapy was done to assess the R0 resection rate, pathologic complete response (pathCR) rate, safety, and survival in patients with resectable gastric carcinoma. PATIENTS AND METHODS: Operable patients with localized gastric adenocarcinoma were eligible. Staging also included a laparoscopy and endoscopic ultrasonography (EUS). Patients received up to two 28-day cycles of induction chemotherapy of fluorouracil, leucovorin, and cisplatin, followed by 45 Gy of radiation plus concurrent fluorouracil. Patients were then staged and surgery was attempted. RESULTS: Thirty-four patients were registered at three institutions. One ineligible patient was excluded. Most patients had a promixal cancer and EUST3N1 designation. Twenty-eight (85%) of 33 patients underwent surgery. The R0 resection rate was 70% and pathCR rate was 30%. A pathologic partial response (< 10% residual carcinoma in the primary) occurred in eight patients (24%). EUS T plus N and postsurgery T plus N correlation showed significant downstaging (P = <.01). The median survival time for 33 patients was 33.7 months. Patients achieving a pathCR or pathPR had a significantly longer median survival time (63.9 months) than those achieving less than pathPR (12.6 months; P =.03). There were two treatment-related deaths. CONCLUSION: Our data suggest that the three-step strategy of preoperative induction chemotherapy followed by chemoradiotherapy resulted in substantial pathologic response that resulted in durable survival time. This strategy is worthy of a direct comparison with postoperative adjuvant chemoradiotherapy.

Adenocarcinoma↗
PubMed2004

Significance of post-chemoradiation biopsy in predicting residual esophageal carcinoma in the surgical specimen.

Pathologic complete response in the resected esophagus can be achieved in approximately 30% of patients with locally advanced esophageal or gastroesophageal junction carcinoma after preoperative chemoradiation therapy. These patients tend to have a longer survival than those who have less than pathologic complete response. Post-chemoradiation esophageal biopsy (PCEB) is used to check for the presence of residual tumor before a definitive resection is performed, but the clinical significance of PCEB findings is not clear due to the possibility of sampling bias and the superficial nature of the specimen obtained. We evaluated the use of PCEB (defined as biopsy taken within 30 days before esophagectomy) in predicting residual cancer in post-treatment esophagectomy specimens. PCEB was performed in 65 of 183 (36%) patients with locally advanced esophageal or gastroesophageal junction carcinoma, who received preoperative chemoradiation therapy. The cancer status in PCEB was correlated with the residual cancer in the esophagectomy specimens. PCEB had no cancer in 80% (52 of 65) of patients (Bx-negative) and cancer in 20% (13 of 65) of patients (Bx-positive). There was no difference in the presence of residual cancer (either in esophagus or lymph node) in esophagectomy specimens between Bx-negative patients (77%, 40 of 52) or Bx-positive patients (92%, 12 of 13), P = 0.44. The positive predictive value of biopsy was 92% (12 of 13), negative predictive value 23% (12 of 52), sensitivity 23% (12 of 52) and specificity 92% (12 of 13). There was no difference in the residual cancer staging in the esophagectomy specimen between Bx-positive and Bx-negative patients. In contrast, residual metastatic carcinoma in lymph nodes was more frequent in Bx-positive patients (69.2%, 9 of 13) than in Bx-negative patients (28.8%, 15 of 52), P = 0.01. Our data suggest that PCEB is a specific but not a sensitive predictor of residual cancer following esophagectomy. Bx-positive patients tend to have more frequent residual tumor in lymph nodes. The utility of PCEB in predicting residual cancer in the lymph nodes needs to be explored further along with molecular predictors of response to preoperative therapy.

Biopsy, Needle↗
PubMed2004

Genotype-phenotype correlations in Peutz-Jeghers syndrome.

BACKGROUND AND AIMS: Peutz-Jeghers syndrome (PJS) is a dominantly inherited disorder often caused by mutations in STK11. Time to onset of symptoms was characterised for a large collection of individuals with PJS who had been tested for STK11 mutations and genotype-phenotype correlations were evaluated. METHODS: We characterised mutations in 42 independent probands and also used a historical cohort design to study 51 individuals with Peutz-Jeghers syndrome who had completed self-administered questionnaires. RESULTS: Mutations were detected in 22/32 (69%) probands with PJS and 0/10 probands referred to rule out PJS. Real-time PCR analysis to quantitate DNA failed to detect any large deletions in PJS participants without STK11 mutations. The median time to onset for gastrointestinal symptoms or polypectomy was 13 years of age but showed a wide variability. Gastric polyps were frequent in PJS participants, with a median age at onset of 16 years. Individuals with missense mutations had a significantly later time to onset of first polypectomy (p = 0.04) and of other symptoms compared with those participants either with truncating mutations or no detectable mutation. CONCLUSION: STK11 mutation analysis should be restricted to individuals who meet PJS criteria or their close relatives. Direct sequencing of STK11 yields a high rate of point mutations in individuals who meet phenotypic PJS criteria. Individuals with missense mutations of STK11 typically had a later time to onset for PJS symptoms. The common occurrence of gastric polyps may facilitate chemopreventive studies for this disorder.

AMP-Activated Protein Kinase Kinases↗
PubMed2002

A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis.

BACKGROUND: Non-selective cyclooxygenase (COX) inhibitors (non-steroidal anti-inflammatory drugs) inhibit large bowel carcinogenesis in patients with familial adenomatous polyposis (FAP). Their role in the duodenum of these patients is less certain. The disease modifying activity of specific COX-2 inhibitors has not been explored in humans. PATIENTS AND METHODS: This was a randomised, double blind, placebo controlled study of celecoxib (100 mg twice daily (n=34) or 400 mg twice daily (n=32)) versus placebo (n=17), given orally twice daily for six months to patients with FAP. Efficacy was assessed qualitatively by blinded review of shuffled endoscopy videotapes comparing the extent of duodenal polyposis at entry and at six months and quantitatively by measurement of the percentage change in duodenal area covered by discrete and plaque-like adenomas from photographs of high and low density polyposis. RESULTS: Shuffled and blinded video review showed a statistically significant effect of 400 mg twice daily celecoxib compared with placebo treatment (p=0.033) with all five independent observers scoring a beneficial effect. Overall, patients taking celecoxib 400 mg twice daily showed a 14.5% reduction in involved areas compared with a 1.4% for placebo (p=0.436). However, patients with clinically significant disease at baseline (greater than 5% covered by polyps) showed a 31% reduction in involved areas with celecoxib 400 mg twice daily compared with 8% on placebo (p=0.049). CONCLUSIONS: A panel of five endoscopists found a significant reduction in duodenal polyposis after six months of treatment with celecoxib 400 mg twice daily. COX-2 inhibition may help this otherwise untreatable condition.

Adenomatous Polyposis Coli↗
PubMed2001

A three-step strategy of induction chemotherapy then chemoradiation followed by surgery in patients with potentially resectable carcinoma of the esophagus or gastroesophageal junction.

BACKGROUND: Patients with locoregional carcinoma of the esophagus or gastroesophageal junction have a poor survival rate after surgery. Preoperative chemotherapy or chemoradiotherapy has not improved the outcome for these patients. Our study was designed to assess the feasibility of preoperative induction combination chemotherapy in addition to chemoradiotherapy to improve the curative resection rate, local control, and survival. PATIENTS AND METHODS Patients having histologic proof of localized carcinoma (either squamous cell carcinoma or adenocarcinoma) of the esophagus or gastroesophageal junction underwent full classification including endoscopic ultrasonography (EUS). Patients first received up to two courses of induction chemotherapy consisting of 5-fluorouracil at 750 mg/m(2)/day as continuous infusion on Days 1--5, cisplatin at 15 mg/m(2)/day as an intravenous bolus on Days 1--5, and paclitaxel at 200 mg/m(2) as a 24-hour intravenous infusion on Day 1. The second course was repeated on Day 29. This was followed by radiotherapy (45 grays in 25 fractions) and concurrent admission of 5-fluorouracil (300 mg/m(2)/day as a continuous infusion 5 days/week) and cisplatin (20 mg/m(2) on Days 1--5 of radiotherapy). After chemoradiotherapy, patients underwent surgery. The feasibility of this approach, curative resection rates, patient survival, and patterns of failure were assessed. RESULTS: Thirty-seven of 38 patients enrolled were evaluable for toxicity and survival. Adenocarcinoma and distal esophageal location of carcinoma were observed frequently. Thirty-five (95%) of the 37 patients underwent surgery, all of whom had an R0 (curative) resection. A pathologic complete response was noted in 11 (30%) of the 37 total patients. In addition, 5 patients (14%) had only microscopic carcinoma. According to EUS classification, 31 (89%) of the 35 patients who underwent surgery had a T3 carcinoma whereas according to pathologic classification only 3 (9%) had a T3 carcinoma (P </= 0.01). Similarly, according to EUS classification, 23 patients (66%) had an N1 carcinoma, whereas according to pathologic classification only 7 patients (20%) had an N1 carcinoma (P < or = 0.01). At a median follow-up of 20 months (minimum follow-up, 13+ months; maximum follow-up, 36+ months), the median survival duration for the 37 patients had not yet been reached. In addition, there were two deaths related to surgery. CONCLUSIONS: These data show that the three-step strategy of preoperative paclitaxel-based induction chemotherapy then chemoradiotherapy followed by surgery is feasible and appears quite active in patients having locoregional carcinoma of the esophagus or gastroesophageal junction. Future investigations should focus on substituting cisplatin with less toxic agents and including more systemic therapy with newer classes of agents.

Adenocarcinoma↗
PubMed2001

Age-associated risk of cancer among individuals with N-acetyltransferase 2 (NAT2) mutations and mutations in DNA mismatch repair genes.

Mutations in N-acetyltransferase 2 (NAT2), a highly polymorphic enzyme involved in the metabolism of xenobiotics and carcinogens, may affect risk for colorectal cancer (CRC), especially among individuals with germ-line mutations in DNA mismatch repair genes. We determined the NAT2 genotypes and allele frequencies for 86 individuals with CRC who had mutations in hMLH1, hMSH2, or hPMS1. No significant difference in time to onset was observed between rapid (NAT2*4) and slow (NAT2*5, NAT2*6, and NAT2*7) acetylators. However, when individuals were stratified separately by NAT2 polymorphism (NAT2*5, NAT2*6, and NAT2*7), those who were heterozygous at the mutant locus NAT2*7 after adjustment for the NAT2 mutant loci NAT2*5 and NAT2*6 had a significantly higher risk of CRC (hazard ratio, 2.96; P = 0.012) and all of the cancers (hazard ratio, 3.37; P = 0.00004) than individuals homozygous for wild type at the NAT2*7 allele. These findings suggest that NAT2 genotype may be an important factor in tumorigenesis of CRC and cancers related to hereditary nonpolyposis CRC among individuals with mismatch repair defects.

Acetylation↗
PubMed2001

COX-2 inhibition in clinical cancer prevention.

Colorectal cancer is an excellent model for studying cancer prevention by means of secondary (e.g., polypectomy to remove a precursor adenoma) and primary (chemoprevention) strategies. Evidence has shown that regular users of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have a reduction in risk of colorectal cancer. A possible mechanism of this benefit is decreased prostaglandin production, which is achieved through inhibition of cyclooxygenase (COX) activity, and possibly other pathways. Two isoforms of COX--COX-1 and COX-2--have been identified. COX-2 is expressed in colorectal adenomas and carcinomas, both in humans and rodents. Inhibition of COX-2 has been shown to decrease the incidence of carcinogen-induced neoplasia in rats and to lower the incidence of adenomas in murine models. Several COX-2 inhibitors, with the potential for less toxicity than that associated with traditional NSAIDs, are under development. This paper reviews potential chemoprevention of colorectal cancer using COX-2 inhibitors in patients at increased risk, e.g., patients with familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, and sporadic adenomas. Included are the rationale for use of such agents, results of a study showing a significant reduction in adenoma burden in familial adenomatous polyposis patients who received the selective COX-2 inhibitor celecoxib (Celebrex), and the design of other ongoing or planned clinical trials.

Adenocarcinoma↗
PubMed2000

Inactivation of germline mutant APC alleles by attenuated somatic mutations: a molecular genetic mechanism for attenuated familial adenomatous polyposis.

Germline mutations of the adenomatous polyposis coli (APC) tumor-suppressor gene result in familial adenomatous polyposis (FAP). Patients with FAP typically develop hundreds to thousands of benign colorectal tumors and early-onset colorectal cancer. A subset of germline APC mutations results in an attenuated FAP (AFAP) phenotype, in which patients develop fewer tumors and develop them at an older age. Although a genotype-phenotype correlation between the locations of APC germline mutations and the development of AFAP has been well documented, the mechanism for AFAP has not been well defined. We investigated the mechanism for AFAP in patients carrying a mutant APC allele (APC(AS9)) that has a mutation in the alternatively spliced region of exon 9. APC(AS9) was found to down-regulate beta-catenin-regulated transcription, the major tumor-suppressor function of APC, as did the wild-type APC. Mutation analysis showed that both APC(AS9) and the wild-type APC alleles were somatically mutated in most colorectal tumors from these patients. Functional analysis showed that 4666insA, a common somatic mutation in APC(AS9) in these tumors, did not inactivate the wild-type APC. Our results indicate that carriers of APC(AS9) develop fewer colorectal tumors than do typical patients with FAP because somatic inactivation of both APC alleles is necessary for colorectal tumorigenesis. However, these patients develop colorectal tumors more frequently than does the general population because APC(AS9) is inactivated by mutations that do not inactivate the wild-type APC.

Adenomatous Polyposis Coli↗
PubMed2000

The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis.

BACKGROUND: Patients with familial adenomatous polyposis have a nearly 100 percent risk of colorectal cancer. In this disease, the chemopreventive effects of nonsteroidal antiinflammatory drugs may be related to their inhibition of cyclooxygenase-2. METHODS: We studied the effect of celecoxib, a selective cyclooxygenase-2 inhibitor, on colorectal polyps in patients with familial adenomatous polyposis. In a double-blind, placebo-controlled study, we randomly assigned 77 patients to treatment with celecoxib (100 or 400 mg twice daily) or placebo for six months. Patients underwent endoscopy at the beginning and end of the study. We determined the number and size of polyps from photographs and videotapes; the response to treatment was expressed as the mean percent change from base line. RESULTS: At base line, the mean (+/-SD) number of polyps in focal areas where polyps were counted was 15.5+/-13.4 in the 15 patients assigned to placebo, 11.5+/-8.5 in the 32 patients assigned to 100 mg of celecoxib twice a day, and 12.3+/-8.2 in the 30 patients assigned to 400 mg of celecoxib twice a day (P=0.66 for the comparison among groups). After six months, the patients receiving 400 mg of celecoxib twice a day had a 28.0 percent reduction in the mean number of colorectal polyps (P=0.003 for the comparison with placebo) and a 30.7 percent reduction in the polyp burden (the sum of polyp diameters) (P=0.001), as compared with reductions of 4.5 and 4.9 percent, respectively, in the placebo group. The improvement in the extent of colorectal polyposis in the group receiving 400 mg twice a day was confirmed by a panel of endoscopists who reviewed the videotapes. The reductions in the group receiving 100 mg of celecoxib twice a day were 11.9 percent (P=0.33 for the comparison with placebo) and 14.6 percent (P=0.09), respectively. The incidence of adverse events was similar among the groups. CONCLUSIONS: In patients with familial adenomatous polyposis, six months of twice-daily treatment with 400 mg of celecoxib, a cyclooxygenase-2 inhibitor, leads to a significant reduction in the number of colorectal polyps.

Adenomatous Polyposis Coli↗
PubMed2000

Colitis associated with docetaxel-based chemotherapy in patients with metastatic breast cancer.

BACKGROUND: Docetaxel and vinorelbine as combined treatment for metastatic breast cancer can have the dose-limiting toxic effects of mucositis and neutropenic fever. We report unexpected ischaemic colitis in six patients associated with docetaxel-based therapy, three of whom were treated in a phase I study designed to establish the maximum tolerated dose of this combination with the prophylactic use of granulocyte-colony-stimulating factor. METHODS: Between August, 1997, and December, 1998, 14 patients with metastatic breast cancer were treated with vinorelbine, docetaxel, and granulocyte-colony-stimulating factor in a phase I study. Three patients developed colitis similar to that seen in typhlitis. Three additional patients were identified during scheduled review of toxic effects in patients participating in clinical trials involving docetaxel. FINDINGS: Three patients on combined vinorelbine and docetaxel developed colitis-like symptoms. Two patients died, one from necrotic bowel and the other from neutropenic fever and colitis. Two of the patients presented on day 7 and day 8 of chemotherapy, respectively, with neutropenic fever and abdominal pain; the third patient developed neutropenia without fever and abdominal pain on day 8. The other three patients were treated with docetaxel, docetaxel and pamidronate disodium, or docetaxel and cyclophosphamide. All three patients presented with abdominal pain on days 10, 5, and 4, respectively. One had non-neutropenic fever, another had neutropenic fever, and the third was afebrile and non-neutropenic at the time of presentation with abdominal pain. Three patients had blood in their diarrhoea, abdominal tenderness, or both. Computed tomography of the abdomen and pelvis showed features of colitis in three patients. INTERPRETATION: This serious complication may result from the use of docetaxel and may be exacerbated by its combination with vinorelbine. Study of hospital-based patients treated with taxane-based chemotherapy is underway to find out the frequency of such complications.

Aged↗
PubMed2000

Effects of cyclin D1 polymorphism on age of onset of hereditary nonpolyposis colorectal cancer.

A common polymorphism in the cyclin D1 gene enhances the gene's alternate splicing. The alternatively spliced product encodes an altered protein that does not contain sequences involved in the turnover of the protein. We found that hereditary nonpolyposis colorectal carcinoma patients who were homozygous or heterozygous for the mutant allele developed colorectal cancer an average of 11 years earlier than patients who were homozygous for the normal alleles. This is the first report indicating that the cyclin D1 polymorphism influences age of onset of cancer. Because cyclin D1 plays an important role in the G1 to S phase transition of the cell cycle, our findings suggest that cells with the mutant allele accumulate mutations as a result of defective mismatch repair and may also bypass the G1-S checkpoint of the cell cycle more easily than in cells not carrying the polymorphism. The polymorphism has a dominant phenotype.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Genomic rearrangements of the APC tumor-suppressor gene in familial adenomatous polyposis.

Germline mutations of the adenomatous polyposis coli (APC) tumor-suppressor gene result in the hereditary colorectal cancer syndrome familial adenomatous polyposis (FAP). Almost all APC mutations that have been identified are single-nucleotide alterations, small insertions, or small deletions that would truncate the protein product of the gene. No well-characterized intragenic rearrangement of APC has been described, and the prevalence of this type of mutation in FAP patients is not clear. We screened 49 potential FAP families and identified 26 different germline APC mutations in 30 families. Four of these mutations were genomic rearrangements resulting from homologous and nonhomologous recombinations mediated by Alu elements. Two of these four rearrangements were complex, involving deletion and insertion of nucleotides. Of these four rearrangements, one resulted in the deletion of exons 11 and 12 and two others resulted in either complete or partial deletion of exon 14. The fourth rearrangement grossly altered the sequence within intron 14. Although this rearrangement did not affect any coding sequence of APC at the genomic DNA level, it caused inappropriate splicing of exon 14. These rearrangements were initially revealed by analyzing cDNAs and could not have been identified by using mutation detection methods that screened each exon individually. The identification of a rearrangement that did not alter any coding exons yet affected the splicing further underscores the importance of using cDNA for mutation analysis. The identification of four genomic rearrangements among 30 mutations suggests that genomic rearrangements are frequent germline APC mutations.

Adenomatous Polyposis Coli↗
PubMed2000

Phase I study of irinotecan and concurrent radiation therapy for upper GI tumors.

Irinotecan (Camptosar) is an active chemotherapeutic agent for lung, gastric, esophageal, and colorectal cancers and a potent radiosensitizer. This phase I study was designed to assess the maximum tolerated dose of weekly irinotecan combined with concurrent radiotherapy for patients with locally advanced, unresectable gastric, gastroesophageal junction, or esophageal cancer. Patients who received previous chemotherapy (excluding irinotecan) or who experienced recurrent cancer after surgery were eligible for this protocol. The total dose of radiation did not exceed 50.4 Gy (28 fractions of 1.8 Gy each). The starting dose level of irinotecan was 30 mg/m2 infused over 90 minutes given weekly for 5 weeks. Subsequent dose levels were increased in 10 mg/m2 increments to 40, 50, 60, and 70 mg/m2. Of 15 patients who have been enrolled to date, all are evaluable for toxicities and 12 for response. Major hematologic toxicities (grade 3/4) were neutropenia, chills, hemorrhage, and anemia. Grade 3/4 gastrointestinal toxicities included nausea, vomiting, dehydration, anorexia, and constipation. Other severe nonhematologic toxicities included fatigue, hypotension, and hypothermia, as well as cardiovascular toxicities. There was no severe diarrhea and no treatment-related deaths. Of the 12 evaluable patients, 7 (58%) responded, including 2 complete responses; 4 (30%) had no change and 1 had progressive disease. Survival ranged from 1 month to 15 months, with a median survival of 8 months. When the total dose of irinotecan given concurrently with radiotherapy was higher than 250 mg/m2, patients experienced significantly more severe grade 3/4 toxicities than with lower doses (P = .04), with no improvement in response rate. It was concluded that weekly doses of irinotecan of up to 60 mg/m2 with concurrent radiotherapy given over 5 weeks was feasible and demonstrated good response. This regimen did not cause severe diarrhea or pneumonitis, but neutropenia and fatigue were major toxicities. The study continues to accrue.

Adolescent↗