Joseph N. Marcus

Hereditary breast cancer : pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage

The purpose of this investigation was to determine if there are pathobiologic differences between BRCA1‐related and BRCA2‐related hereditary breast cancer (HBC) and non‐HBC.

Experimental and Clinical Results with Proximal End-to-end Duodenojejunostomy for Pathologic Duodenogastric Reflux

Existing Roux-en-Y bile diversion procedures for duodenogastric reflux coupled with distal gastric resection or antrectomy and vagotomy have varied success due to interruption of the physiologic relationships between stomach and duodenum, the reduction of the gastric reservoir, the side effects of vagotomy, and the effect of the Roux limb on gastric emptying. A new bile diversion procedure, suprapapillary Roux-en-Y duodenojejunostomy, was studied, which eliminates the need for gastric resection to prevent jejunal ulcers by preserving duodenal inhibition of gastric acid secretion and the protective effects of duodenal secretion on the surrounding mucosa. Experimentally, the incidence of jejunal ulceration was significantly decreased by the preservation of the proximal duodenum. Clinically, bile diversion by suprapapillary Roux-en-Y duodenojejunostomy alleviates symptoms of duodenogastric reflux disease without being ulcerogenic (in the presence of normal gastric secretion) or prolonging gastric emptying.

Natural history of colorectal cancer in hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II)

Approximately 5 to 6 percent of the total colorectal cancer burden is accounted for by hereditary nonpolyposis colorectal cancer (HNPCC). Because clinical premonitory signs such as those seen in familial polyposis coli (FPC) are lacking, the clinician must recognize clinical findings and family history typical of HNPCC. The authors have described colorectal cancer expression from a survey of ten HNPCC kindreds. Kindred members with colorectal cancer differed significantly (P<.05) from patients with sporadic colorectal cancer: 1) mean age of initial colon cancer diagnosis was 44.6 years; 2) 72.3 percent of first colon cancers were located in the right colon, and only 25 percent were in the sigmoid colon and rectum; 3) 18.1 percent had synchronous colon cancers; and 4) 24.2 percent developed metachronous colon cancer, with a risk for metachronous lesions in ten years of 40 percent. Affecteds and their first-degree relatives should undergo early intensive education and surveillance. In families with an early age of onset, colonoscopy should begin at age 25, and biannually thereafter, with fecal occult blood testing of the stool semiannually. Third-party carriers must become more responsive to the costly surveillance measures required for these otherwise healthy patients.

Differential diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome I and Lynch syndrome II)

Increasing recognition of the statistical burden posed by HNPCC (5 to 6 percent of all colorectal cancer) mandates that physicians have a better understanding of the genetics, natural history, and distinction between the hereditary site-specific variant (Lynch syndrome I) and the Cancer Family Syndrome (Lynch syndrome II). The authors report detailed cancer (all sites) family histories on two prototype families with Lynch syndrome I (Family R) and Lynch syndrome II (Family N), which have been under investigation for more than two decades. Emphasis is placed on shared clinicogenetic features; namely, early age of onset of colonic cancer (approximately age 44), multiple primary colonic cancer (24 percent of cases showed metachronous colonic cancer), predominance of proximal colonic cancer location (approximately 65 percent in the proximal colon), and vertical transmission consonant with an autosomal dominantly inherited factor. An increased predilection for extracolonic cancer, particularly endometrial carcinoma, occurs in Lynch syndrome II and is the primary basis for distinction from Lynch syndrome I. Surveillance and management programs must be wholly responsive to these natural history features.

Genetics of Hodgkin's and Non-Hodgkin's Lymphoma: A Review

Host susceptibility factors have been documented in both HD and NHL wherein a subset of pedigrees provide evidence for an autosomal dominantly inherited factor. Families with both HD and NHL occurring in genetically informative patients provide evidence in support of a possible common pathogenetic pathway for these diseases, as does recent cytogenetic and molecular genetic evidence. AIDS as an unmasking factor for familial predisposition to lymphoma and other cancers may be a powerful tool for identifying lymphoma- and cancer-prone families, but to date has not been employed. In concert with ecogenetic research, it will be important that lymphoma-prone families be subjected to multidisciplined research involving experimental designs developed by geneticists and epidemiologists in concert with pathologists, immunologists, and molecular geneticists.

Age-of-onset heterogeneity in hereditary breast cancer: minimal clues for diagnosis

Knowledge of the family history of cancer may significantly influence diagnosis and surgical management. Hereditary breast cancer (HBC) is common and accounts for approximately 9% of the total breast cancer burden. The pattern of HBCs natural history, including age of onset, increased incidence of bilaterality, integral tumor combinations in certain kindreds, and vertical transmission consonant with an autosomal dominantly inherited factor, when observed in context with the family history, enables pattern recognition so that the diagnosis might be facilitated. We describe seven families from our Hereditary Cancer Consultation Center (HCCC) and the Creighton Oncology Clinic which are noteworthy for extraordinarily early age of onset. This appears to be an additional example of heterogeneity in HBC and may represent the first account of this remarkable subset. The manner in which age of onset can be incorporated with other aspects of natural history for expediting diagnosis is discussed.

Biological Implications of Organic Compounds in Comets

Organic chemicals — compounds that contain carbon — are the substance of life and pervade the universe. Is there a connection between comets, which are rich in prebiotic organics, and the origin of life? Current concepts of biomolecular evolution are first reviewed, including the important paradigm of catalytic RNA At the very least, impacting comets appear to have supplied a substantial fraction of the volatile elements required for life shortly after the Earth formed. Some impacting material may even have survived chemically intact to directly provide necessary complex prebiotic organic chemicals. For life to originate and evolve in comets themselves, liquid H2O would be absolutely required: arguments for and against 26A1 radiogenic melting of cometary cores are presented. Cometary panspermia, if theoretically possible, is not necessary to explain the origin of life on Earth. The Halley spacecraft provide evidence against Earth-type microorganisms in this comet’s dust.

Colorectal cancer in a nuclear family: Familial or hereditary?

Because of the high incidence of colorectal cancer, familial aggregations of this disease are common. Differentiation between etiologies contributing to familial clustering (which may have resulted either from common environmental exposure or from mere chance) and primary genetic factors may prove vexing to the physician. This report deals with the myriad problems encountered when attempting to make such etiologic distinctions in order to provide appropriate surveillance and management, based upon tumor spectrum and natural history, for patients at increased cancer risk.

Elevation of calcium in rat enterocytes byEscherichia coli heat-stable (STa) enterotoxin

The effect of STa enterotoxin on intracellular calcium in primary cultures of rat enterocytes was investigated. The enterocytes were loaded with a fluorescent calcium indicator, indo-1, and changes of intracellular calcium determined by flow cytometry. When the rat enterocytes were treated with EGTA, a calcium chelator, or ionomycin, a calcium ionophore, a decrease or increase, respectively, in free intracellular calcium was demonstrated. The addition of STa enterotoxin to rat enterocytes loaded with indo-1 caused an initial decrease, followed by a rapid increase, in free intracellular calcium. These effects on intracellular calcium occurred prior to or during an increase in the intracellular concentration of cyclic 3′,5′-guanosine monophosphate. The current results demonstrate that the activation of rat enterocytes by STa enterotoxin has an effect on transmembrane regulation of the receptor-dependent calcium signal and/or the release of calcium from intracellular storage sites.

Genetic and immunopathological findings in a lymphoma family

We have studied a remarkable family with seven cases of malignant lymphoma extending through three generations wherein five sisters and their mother had histopathologically documented non-Hodgkins lymphoma, while a granddaughter had Hodgkins disease. An immunological study of three lymphoma survivors, nine of their first degree relatives, and four spouse controls was undertaken. Significant findings consisted of a depressed serum IgG3 level in four of the nine first-degree relatives; in two of these four, lymphocyte stimulation by both pokeweed mitogen and concanavalin A were significantly depressed. The subtle immunological abnormalities present in this kindred may be associated with the pathogenesis of the lymphomas.