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J F Lynch

Publications and source records attributed to J F Lynch.

159 records · Page 9Linked to original sources
PubMedDate not supplied

"Organic brain syndrome" secondary to 5-fluorouracil toxicity.

A 68-year-old woman, who was treated with 5-fluorouracil (5-FU) intravenous therapy weekly for variable periods following hemicolectomy for adenocarcinoma of the cecum, had at least two well-described episodes of mental confusion, disorientation, and deterioration, in the absence of cerebellar tract signs. The sensorium cleared after cessation of 5-FU, only to deteriorate following readministration of the drug. She was thought to have organic brain syndrome during her most recent mental relapse. Her mental status has now been intact for more than one year since her last exposure to 5-FU. This is believed to be the third patient who has shown mental changes which could be attributable to 5-FU toxicity. Since 5-FU is the most frequently used chemotherapy for the treatment of colonic cancer, it is important that this form of toxicity be recognized lest subject patients be judged to have irreversible organic brain syndrome or metastatic carcinoma.

Aged↗
PubMedDate not supplied

Breast cancer genetics: family history, heterogeneity, molecular genetic diagnosis, and genetic counselling.

Between 5% and 10% of breast cancer cases can be traced to primary genetic factors. Before the discovery of the BRCA1 and BRCA2 genes, if a first-degree relative in direct genetic lineage had hereditary breast cancer or hereditary breast-ovarian cancer syndrome, the best estimate of family members' genetic risk for breast cancer was 50%. Now the lifetime cancer destiny of a patient who carries a BRCA1 or BRCA2 germ line mutation can be determined with an extraordinary degree of precision. However, a major concern facing clinicians is how to use this powerful genetic knowledge without harming the patient. This presentation focuses on the need for (a) compilation of a detailed family history of cancer of all anatomic sites; (b) understanding of the natural history of hereditary breast cancer and its heterogeneous forms and the pathobiology of hereditary breast cancer; and (c) preparation for performance of genetic counseling that is based on the results of DNA sequencing to detect genes related to cancer susceptibility. The discussion addresses the advantages of this molecular genetic movement, which include the abilities (a) to predict who is and who is not at inordinately high risk for cancer; (b) to provide opportunities for highly targeted disease surveillance and management; (c) to give patients the information they need to make appropriate long-term decisions about matters such as procreation; and (d) to give genetic counselors the information they need to appreciate the emotions patients may encounter, such as fear, anxiety, and apprehension, and the ordeal of being subjected to discrimination by insurance companies and employers.

Adult↗
PubMedDate not supplied

Molecular genetics and clinical-pathology features of hereditary nonpolyposis colorectal carcinoma (Lynch syndrome): historical journey from pedigree anecdote to molecular genetic confirmation.

Hereditary nonpolyposis colorectal cancer (HNPCC), also termed Lynch syndrome, was originally called cancer family syndrome. Historically, in 1913 Aldred Warthin, a pathologist, published a family, now known as Family G, which had features of HNPCC. It was first delineated as a hereditary cancer syndrome in the mid-1960s by Lynch. There was an apparent autosomal dominant mode of inheritance of colorectal cancer and certain integral cancers, the most prominent of which was endometrial carcinoma. Prior to the discovery in 1993 and 1994 of genes (hMSH2, hMLH1, hPMS1, hPMS2) known as mis-match repair genes or mutator genes, the diagnosis of HNPCC rested exclusively upon evaluation of clinical findings in concert with a well-documented and extended pedigree. Thus, this disorder has evolved from a medical curiosity into a clinical syndrome wherein molecular biologists provided proof of its hereditary status. These discoveries should aid in elucidating its pathogenesis and carcinogenesis and in the next decade we likely will learn more about chemoprevention and surgical prophylaxis of HNPCC.

Australia↗
PubMedDate not supplied

Homocysteine thiolactone disposal by human arterial endothelial cells and serum in vitro.

Previous work with cultured mammalian cells and perfused laboratory animals suggested to us that hydrolysis of homocysteine thiolactone was catalyzed in these systems. We confirmed this finding by measuring the sulfhydryl-releasing activity of cultured endothelial cells from human umbilical arteries in homocysteine thiolactone solution, pH 7.4, 37 degrees C. The reaction was vigorous and stereospecific and showed saturation kinetics (Km values for L- and D,L-homocysteine thiolactone were 3.9 and 8.2 mmol/l, respectively, and Vmax values were 10.75 and 10.1 mumol/min/10(9) cells, respectively). L-Homocysteine thiolactone was quantitatively converted to homocysteine, as measured by amino acid analysis. Human serum also accelerated the elimination of homocysteine thiolactone, although in this process, the majority of the newly formed sulfhydryl-containing product was precipitable by sulfosalicylic acid, indicating likely homocysteinylation of serum proteins. However, approximately 38% of the sulfhydryl-containing product was not precipitated, and because thiolactone elimination stereospecifically favored the L-enantiomer, a possible subsidiary role for serum-catalyzed hydrolysis of the thiolactone was suggested. No homocysteine thiolactone could be found in serum samples from six patients with acute myocardial infarction, three patients with cystathionine beta-synthase deficiency, and six normal subjects. Thus, humans have active vascular systems for elimination of homocysteine thiolactone, a process that could be responsible for an absence of the compound in serum.

Benzenesulfonates↗
PubMedDate not supplied

Clinical implications of advances in the molecular genetics of colorectal cancer.

AIMS AND BACKGROUND: Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common occurring hereditary form of colorectal cancer (CRC) where it accounts for as much as 10 percent of the total CRC burden. HNPCC is characterized by an autosomal dominant inherited predisposition to early age of onset (= 44 years) of CRC with proximal predominance (= 70% proximal to the splenic flecture) with an excess of synchronous and metachronous CRC (45% 10 years after initial hemicolectomy or segmental resection as opposed to subtotal colectomy), features which characterize the Lynch syndrome I variant, while the Lynch syndrome II variant of HNPCC shows all of these features, but in addition, there is a marked excess of carcinoma of the endometrium, ovary, small bowel, stomach, pancreas, and transitional cell carcinoma of the ureter and renal pelvis, lesions which are integral to this syndrome. Because of the early onset, we recommend colonoscopy to be initiated at age 25 and repeated every other year through age 35 and then annually thereafter. Women need to undergo endometrial aspiration biopsy at the time of initial colonoscopy. METHODS AND RESULTS: Major advances in the molecular genetics of HNPCC have occurred during the past two years with identification of the hMSH2 gene at chromosome 2p and the hMLH1 gene at chromosome 3p, both of which have been cloned. PMS1 at chromosome 2p and PMS2 2 at chromosome 7q have also been implicated in HNPCC's etiology. CONCLUSIONS: Genetic counseling is mandatory for presymptomatic DNA testing and for delivering information about the patient's germline status. Patients with germline mutations are offered prophylactic subtotal colectomy as an option to continued colonoscopy. It is now important for physicians to take careful cancer family histories so that this disorder can be readily identified, thereby enabling the initiation of highly targeted surveillance and management programs.

Adult↗
PubMedDate not supplied

25 years of HNPCC.

Research on the genetic, molecular genetic, clinical features, and natural history of HNPCC has shown tremendous progress and evolution during the past 25 years. Specifically, HNPCC's autosomal dominant mode of genetic transmission has now been documented through linkage studies of the gene at 2p (MSH2) and at 3p (MLH1) with the cloning of these genes. Also, the tumor spectrum has increased, which now, in addition to carcinoma of the colon, endometrium, stomach, and ovary, includes transitional cell carcinoma of the ureter and renal pelvis, and adenocarcinomas of the small bowel and pancreas. Surveillance and management protocols for patients at high risk should include full colonoscopy since 70% of the colon cancers occur in the proximal colon. Because of the marked excess of synchronous and metachronous colorectal cancers (CRC), no less than a subtotal colectomy should be performed at the time of initial CRC. Women, in addition to colonoscopy, require endometrial aspiration biopsy. Should they develop CRC and if their procreation is completed, we recommend that they consider prophylactic hysterectomy and bilateral salpingo oophorectomy at the time of their subtotal colectomy. Now that the deleterious genes at 2p and 3p have been identified, we are offering candidates, in whom the MSH2 or MLH1 mutation has been verified, an option of prophylactic subtotal colectomy as opposed to annual life time colonoscopy. With the development of the International Hereditary Nonpolyposis Colorectal Cancer Collaborative Group, knowledge can be disseminated worldwide about the public health importance of HNPCC and the need to implement highly targeted surveillance and management strategies in all clinical practice settings.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMedDate not supplied

Adenoma follow-up in at-risk Lynch syndrome family members.

Persons at 50% risk of Lynch Syndrome were screened with colonoscopy at six or twelve month intervals. On initial exam, eight of fifty-five patients had adenomas. Follow-up was available in 27 patients (mean 35.5 months). Estimated time to finding new adenomas was 58 months for patients clear on first colonoscopy and 16 months for patients who had adenomas on first exam (p < 0.01). One adenocarcinoma has been found, arising in a tubulovillous adenoma. The short-term risk of colorectal cancer in Lynch syndrome relatives without adenomas is low, as is the risk in those who had all adenomas removed.

Adenoma↗