Biomedical subjects
Publications and source records attributed to M L Fitzsimmons.
Individuals with one of the highest known risks of developing colorectal cancer are members of hereditary colorectal cancer families. Familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC) are the most commonly recognized hereditary colorectal cancer syndromes. Surveillance, family identification, and education are of major importance. Genetic screening holds further promise.
Fractional absorption of calcium from bread made either from intrinsically or extrinsically labeled whole-wheat flour was compared in 11 healthy adult women. The intrinsic label was provided by 45Ca injected individually into stems of wheat plants during growth. The extrinsic tag was introduced by adding 45Ca to unlabeled flour via the water used in dough making. The two labeled breads were tested in a randomized crossover design using a standardized breakfast administered after an overnight fast. Approximately 80 g labeled bread was consumed by each subject, providing a total calcium load of 13.3 mg. Fractional absorption from the intrinsically labeled bread averaged 0.812 +/- 0.130 (mean +/- SE) and from the extrinsically labeled bread 0.792 +/- 0.113. The mean difference, within subject, was only 0.025 +/- 0.016 and was not significantly different from zero. Extrinsic labeling of the calcium of whole-wheat flour results in a degree of labeling homogeneity equivalent to that of intrinsic labeling, at least for a leavened bread product.
Absorption of calcium from soybeans with low and high phytate contents, intrinsically labeled with 45Ca, was measured in 16 normal women and compared in 15 of these same subjects with absorption of calcium from labeled milk. The average test load of calcium for all three sources was 2.45 mmol. Fractional calcium absorption (+/- SD) from the high-phytate soybeans averaged 0.310 +/- 0.070; from the low phytate soybeans, 0.414 +/- 0.074; and from milk, 0.377 +/- 0.056. The mean difference (+/- SEM) in fractional calcium absorption for the two phytate levels was 0.104 +/- 0.014 (P less than 0.001).
Fractional calcium absorption from wheat products and the influence of co-ingested wheat products on calcium absorption from milk were measured in a series of randomized crossover studies in healthy adult women. The wheat had been intrinsically labeled with 45Ca during growth. In the first study, fractional calcium absorption from leavened whole-wheat bread averaged 0.817 +/- 0.124. By comparison, absorption from milk, ingested at a comparable load in the same women, averaged only 0.589 +/- 0.111. When labeled bread was co-ingested with milk, at the same aggregate load as for bread alone, bread calcium absorption fell to 0.748 +/- 0.103 (P less than 0.05). In a second study, calcium absorption from an extruded cereal prepared from intrinsically labeled wheat bran was compared with milk. Calcium absorption from the cereal (0.223 +/- 0.046) was significantly less than from milk (0.375 +/- 0.072) (P less than 0.001). When the two were co-fed at the same total load, milk calcium absorption fell to 0.258 +/- 0.055 (P less than 0.001). In a third study, the effect of phytate hydrolysis through yeast fermentation and of Maillard browning on calcium absorption was investigated using leavened bread and underbaked and overbaked cookies, each made with intrinsically labeled wheat flour. Calcium absorption from cookies was not affected by the extent of browning and averaged 0.652 +/- 0.087. However, calcium absorption from bread in these same women averaged 0.703 +/- 0.108. This was significantly more than from the cookies (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
True calcium absorption was studied as a function of the size of the ingested load in healthy adult women, under meal conditions and at loads ranging from 15 to 500 mg calcium. Fractional absorption was highly inversely correlated with the logarithm of load (P less than 0.001). At the lowest loads, absorption averaged 64.0% and at the highest, 28.6%. The parameters of the best-fit relationship permit reasonably precise calculation of the impact of various calcium dosing and dietary strategies.
Calcium absorption efficiency was measured two or three times each in 74 premenopausal and 142 postmenopausal women under conditions predicted to alter absorptive performance. A woman's absorptive consistency was evaluated across differing loads, differing intervals, and substances of differing intrinsic absorbability. In all these circumstances there was a statistically significant correlation between a woman's absorption under differing test situations accounting for up to 60% of the variance typically found in cross-sectional studies. For example, when the same substance but at differing load levels was tested three times over an 8 week period, various coefficients of correlation ranged from +0.773 to +0.849 (P less than 0.001). Even over intervals as long as 5 years correlation of absorption fraction within individuals remained significant (r = +0.487, P less than 0.001).
Increasing attention has been given to host factors in the etiology of ovarian carcinoma. Case/control studies have shown a significant excess of this disease among primary relatives of ovarian cancer affected. Pedigree studies have demonstrated its occurrence on a site-specific basis, in association with carcinoma of the breast (breast/ovarian carcinoma syndrome), and in other hereditary disorders. The complexity of this heterogeneity clearly warrants more intensive family studies. We have described genetic and clinicopathologic nuances in two extended ovarian cancer-prone families. The absence of premonitory physical stigmata and/or biomarkers which signify the cancer-prone genotype compels the physician to employ the best posits from the pedigree to identify those patients who are at inordinately high risk for ovarian and/or syndrome-associated cancer so that surveillance strategies can be more focused. Because of limitations of current surveillance strategies for the early detection of ovarian carcinoma, the clinician's responsibility includes the identification and counseling of candidates for prophylactic oophorectomy.
We have provided a description of the current state of knowledge relevant to familial/hereditary pancreatic cancer. Since the most important clinical ramifications of this disease, whose incidence and mortality are essentially the same, rests upon its earlier detection, we have also characterized available diagnostic tests, surgical strategies, and current knowledge about its pathology. We believe that advances in control of pancreatic cancer will be heavily impacted by progress in the search for new and better diagnostic tests. These could include monoclonal antibodies targeted to pancreatic tumor tissue, and possibly pancreatic site-specific P450's, as well as biomolecular/genetic techniques, particularly when focused on individuals at high risk. Thus, family studies are important in this disease because if an autosomal dominantly inherited form of pancreatic cancer is delineated, one could identify individuals at high risk early in life. Comparison could then be made with individuals in branches of the family where the disease is not segregating. Thus, there would be a greater potential for discovery of methods for early detection with evaluation of sensitivity and specificity in families wherein the predictability for pancreatic cancer occurrence is high.
Host factors have been given scant attention in the search for etiology in pancreatic cancer. Several anecdotal reports have identified its familial clustering, whereas a recent population-based case/control study has shown that 6.7% of cases and 0.7% of controls had positive family histories of this disease (p less than 0.001). Forty-seven individuals with pancreatic cancer from 18 families were identified from a review of the medical records of all kindreds on file at our Hereditary Cancer Institute. The observed sex ratio, age of onset, histologic type, and survival were comparable to published data on unselected patients. We did not identify any pattern of extra-pancreatic cancer association. A serious limitation of our study is its lack of a population-based case/control design. Whereas our data are primarily descriptive, they do indicate the need to learn more about the role of familial factors in the etiology of pancreatic cancer. Pancreatic cancer is increasing in incidence, and its prognosis is almost uniformly dismal; identification of persons at high risk may improve cancer control.
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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-Hodgkin's lymphoma, while a granddaughter had Hodgkin's 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.
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There is a significant hiatus between existing knowledge about hereditary forms of cancer and the application of this information at the bedside. We believe that the HCCC concept will effectively bridge this gap between medical knowledge and its service application. Priority areas for assuring long-range success of this mission will require: a) greater public and physician awareness of the hereditary portion of the total cancer problem; b) generation of cost-benefit information relevant to the surveillance and management of patients at risk for hereditary cancer so that third party carriers might be more responsive to patient needs: c) enhancement of patient/family compliance with surveillance/management protocols leading to early detection of cancer and improved survival; and d) research into biomarkers which demonstrate acceptable sensitivity and specificity for the cancer-prone genotype, one day enabling identification of the deleterious gene(s). Thus, we may achieve the ultimate goal of identifying biochemical agents which will effectively ameliorate the deleterious products of the cancer-prone gene(s), improve clinical outlook, or even prevent cancer expression.
Since full breast cancer screening is not generally recommended for young women, it is important to identify individuals who are at higher risk for early onset breast cancer. We investigated the relationship between age of onset of breast cancer in 328 probands (consecutively ascertained patients from our oncology clinic) and breast cancer incidence and age of onset in their female relatives. We found that a family history of early onset breast cancer was associated with higher risk of early onset breast cancer. A family history of early onset breast cancer occurred more frequently among young (less than 40) breast cancer probands than among older (greater than or equal to 40) breast cancer probands (p less than 0.001; OR = 23). This relationship was particularly evident when the analysis was restricted to the hereditary breast cancer probands (p less than 0.001; OR = 44). We also observed a positive family history of breast cancer (any age) more frequently in young breast cancer probands than in older breast cancer probands (p less than 0.001; OR = 2.8). These observations have important pragmatic implications for surveillance. We recommend intense surveillance for breast cancer, initiated earlier, for women with close relatives diagnosed with early onset breast cancer.
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 HBC's 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.
Hereditary breast cancer is common and accounts for about 8% of all breast cancer. It has a distinctive natural history characterized by early age of onset, excess bilaterality, and vertical transmission consonant with an autosomal dominant inheritance pattern. We describe an informative kindred wherein this knowledge was effectively applied, with resultant high yield: early breast cancer diagnosis in a mother who was a putative obligate gene carrier, and a contralateral breast cancer diagnosis in her daughter. A more intensive stance on breast cancer diagnosis must be employed in members of hereditary breast cancer kindreds who are judged to be at inordinately increased risk. Breast cancer control through application of genetic knowledge is readily achievable in the clinical practice setting.
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Cancer often clusters in a particular family. Such clusterings may be due to chance but also may result from common environmental factors, from heredity, or from an interaction of the two. This article focuses on those families with hereditary cancer; specifically, cancers of the breast, skin, and colon. Key indicators for each site have been identified to aid in hereditary cancer diagnosis. Surveillance and management strategies differ with each hereditary cancer necessitating varying approaches. The educational and support needs of families provide clear opportunities for the oncology nurse.