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OBJECTIVES: The objective of this study was to determine the extent to which diets with a higher inflammatory potential, as measured by the Dietary Inflammatory Index (DII), are associated with cancer development in a cohort of rural post-menopausal women. METHODS: This study was a secondary analysis of participants of a randomized control trial evaluating the effect of vitamin D and calcium supplementation on cancer development in rural, post-menopausal women in Nebraska. From this cohort, diets were evaluated via a 2005 Block Food Frequency Questionnaire (FFQ) at baseline and four years later (Visit 9). DII scores were calculated at both time points for each participant, including an unadjusted and energy-adjusted DII score. The relationship with DII scores and cancer development were evaluated using a chi-squared test and logistic regression, controlling for pertinent confounders. The difference in DII scores at baseline and Visit 9 for participants who developed cancer and non-cancer participants was examined via a repeated measure ANOVA test. RESULTS: There were 1977 participants with baseline and Visit 9 DII scores available for analysis. There was a significant difference in DII scores between baseline and Visit 9, with a significantly larger change in DII scores in the participants who developed cancer (p = 0.0194), shifting to higher pro-inflammatory scores at Visit 9. Cancer status was not associated with baseline DII scores, nor was DII score a predictor of cancer status, when controlling for confounders. CONCLUSIONS: These findings illustrate how dietary patterns in persons diagnosed with cancer had significant changes over time, increasing inflammatory diet potential. This increase in inflammatory potential in cancer patients may impact outcomes like treatment success, overall survival, and cancer recurrence, creating a need for more research to further analyze the impact of cancer diagnoses on diet changes, and if these changes are detrimental to cancer survivor outcomes. FUNDING SOURCES: None.

Women with similar areal Bone Mineral Densities (BMD) may show divergent fracture incidence due to differences in bone quality. The hypothesis tested in the present pilot study is that postmenopausal (PM) women who have sustained osteoporotic fractures have altered organic matrix quality compared to those who have not. We used Raman microspectroscopy to analyze transiliac biopsies collected from fracturing (n = 6, mean age 62.5 ± 7.4 yrs; Cases) and non-fracturing PM women (n = 6, age- and BMD-matched; mean age 62.2 ± 7.3 yrs; Controls). Previous results show differences in intrinsic material properties by nanoindentation that are more homogenously distributed and could facilitate microcrack propagation in Cases, along with lower mineral carbonate/phosphate ratio by Fourier transform infrared spectroscopic imaging, and no differences in bone tissue mineralization by digitized microradiography. No differences between groups were seen by conventional histomorphometry. Spectra were acquired 2 μm away from previously performed nanoindents, in cortical and cancellous compartments. The determined parameters were: mineral to matrix ratio (MM), and nanoporosity (a surrogate for tissue water (TW)), glycosaminoglycan (GAG), pyridinoline (Pyd; trivalent enzymatic collagen cross-link), N(6)-carboxymethyllysine (CML; advanced glycation endproduct), and pentosidine (PEN; advanced glycation endproduct) content. ANCOVA indicated no differences in any of the spectroscopic outcomes between cancellous and cortical compartments. On the other hand, Cases had lower nanoporosity (TW) and GAG, and elevated Pyd, and CML content compared to Controls. In conclusion, the results of the present study indicate significant differences in organic matrix quality in PM women that sustain fragility fractures versus age- and BMD-matched controls, highlighting its importance as a potential independent determinant of fracture incidence.

Childhood and adolescence are critical periods of bone mineral content (BMC) accrual that may have long-term consequences for osteoporosis in adulthood. Adequate dietary calcium intake and weight-bearing physical activity are important for maximizing BMC accrual. However, the relative effects of physical activity and dietary calcium on BMC accrual throughout the continuum of pubertal development in childhood remains unclear. The purpose of this study was to determine the effects of self-reported dietary calcium intake and weight-bearing physical activity on bone mass accrual across the five stages of pubertal development in a large, diverse cohort of US children and adolescents. The Bone Mineral Density in Childhood study was a mixed longitudinal study with 7393 observations on 1743 subjects. Annually, we measured BMC by dual-energy X-ray absorptiometry (DXA), physical activity and calcium intake by questionnaire, and pubertal development (Tanner stage) by examination for up to 7 years. Mixed-effects regression models were used to assess physical activity and calcium intake effects on BMC accrual at each Tanner stage. We found that self-reported weight-bearing physical activity contributed to significantly greater BMC accrual in both sexes and racial subgroups (black and nonblack). In nonblack males, the magnitude of the activity effect on total body BMC accrual varied among Tanner stages after adjustment for calcium intake; the greatest difference between high- and low-activity boys was in Tanner stage 3. Calcium intake had a significant effect on bone accrual only in nonblack girls. This effect was not significantly different among Tanner stages. Our findings do not support differential effects of physical activity or calcium intake on bone mass accrual according to maturational stage. The study demonstrated significant longitudinal effects of weight-bearing physical activity on bone mass accrual through all stages of pubertal development.

The level of serum 25-Hydroxyvitamin D [25(OH)D] has high heritability, suggesting that genes may contribute to variations in serum 25(OH)D level and vitamin D dose-response. As vitamin D deficiency has been linked to numerous diseases, understanding how genetic variation contributes to vitamin D dose-response is important for personalized vitamin D treatment and cost-effective disease prevention. To identify genetic variants responsible for vitamin D status and dose-response, we performed two vitamin D3 and calcium clinical supplementation trials in 2,207 postmenopausal Caucasian women. We examined the association of 291 SNPs with baseline serum 25(OH)D levels and 25(OH)D dose-response. Five SNPs, rs10500804 (P = 4.93 × 10−7), rs2060793 (P = 6.63 × 10−7), rs10741657 (P = 1.49 × 10−6), rs10766197 (P = 1.05 × 10−5) and rs11023380 (P = 7.67 × 10−5) in the CYP2R1 gene, as well as 6 SNPs, rs4588 (P = 7.86 × 10−7), rs2298850 (P = 1.94 × 10−6), rs1155563 (P = 6.39 × 10−6), rs705119 (P = 2.80 × 10−5), rs705120 (P = 1.08 × 10−4) and rs222040 (P = 1.59 × 10−4) in the GC gene were associated with baseline serum 25(OH)D levels. SNP rs11185644 near the RXRA was significantly associated with 25(OH)D dose-response (P = 1.01 × 10−4). Our data suggest that polymorphisms in the CYP2R1 and GC gene may contribute to variation in baseline serum 25(OH)D concentration, and that polymorphism rs11185644 may contribute to variation in 25(OH)D dose-response in healthy postmenopausal Caucasian women.

Background and aim To compare the prevalence of extra-esophageal cancers in patients diagnosed with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) with SEER database. Methods Patients with BE and EAC are part of a NIH supported Familial Barrett's investigation involving personal and family history and pathology correlation recorded in the database. Data pertaining to extra-esophageal cancers in the proband was extracted into an excel datasheet for analysis. Expected prevalence obtained from SEER (Surveillance, Epidemiology and End Results) NIH database (1973-2006) for the general population, matched for age, was compared with our cohort. Chi-square test was used for statistical analysis. Results There were 1091 probands in the database of whom 876 had complete personal history. The mean age was 57.6 (5-84 years) with 807 Caucasians and 710 males. Overall incidence of extra-esophageal cancers was higher in our cohort when compared with the general population. Conclusion There is a strong association of certain cancer types in patients with BE and EAC. However, further epidemiologic and genetic research is needed for investigation and development of genetic fingerprints.

Hereditary ovarian cancer (HOC) is heterogeneous, with at least three distinctive syndromes, namely, hereditary site-specific ovarian cancer, hereditary breast-ovarian cancer (HBOC) syndrome, and Lynch syndrome II. Ovarian cancer, in accord with virtually all varieties of adult onset cancer, displays an increasing incidence with advancing age; however, it shows an earlier age of onset in hereditary settings.Detailed medical and pathology studies were performed on extended ovarian cancer-prone pedigrees, with special attention given to age at ovarian cancer onset.The age of onset of ovarian cancer is heterogeneous, wherein the average age of onset in HBOC is 52 years, in hereditary site-specific ovarian cancer it is 49 years, and in the Lynch syndrome II it is 45 years, in contrast to its occurrence in the general population, at an average age of 59 years.These differences are important for the initiation of surveillance and management strategies. Age of onset of ovarian cancer differences in these several hereditary subsets are less striking than they are in the case of other integral forms of cancer in the respective syndromes, such as the breast in the HBOC syndrome. In addition, the phenomenon of extremely early age of onset of ovarian cancer occurs infrequently in HOC when compared to other forms of cancer, such as the breast in HBOC or the colon in Lynch syndrome II. Knowledge about age of onset heterogeneity in HOC may harbor important clues about etiology, pathogenesis, and cancer control.

Background: Calcium is an essential cotherapy in osteoporosis treatment. The relative effectiveness of various calcium salts for this purpose is uncertain. Many older women with osteoporosis have phosphorus intakes of ,70% of the Recommended Dietary Allowance. Objective: Our objective was to test the hypothesis that calcium phosphate would better support anabolic bone building than would calcium carbonate. Design: This study was a 12-mo, randomized, positive-comparator, 2-arm, single-blind clinical trial in 211 patients treated with teriparatide who consumed ,1000 mg phosphorus/d. Participants were randomly assigned to receive, in addition to teriparatide and 1000 IU cholecalciferol, 1800 mg calcium/d as either tricalcium phosphate or calcium carbonate. The primary endpoints were changes in lumbar spine and total hip bone mineral densities (BMDs); secondary endpoints were changes in bone resorption biomarkers and serum and urine calcium and phosphorus concentrations. Results: In the combined group, the lumbar spine BMD increased by 7.2%, and total hip BMD increased by 2.1% (P , 0.01 for both). However, there was no significant difference between calcium-treatment groups, and there were no significant between-group differences in serum calcium and phosphorus concentrations or in urine calcium concentrations. Bone resorption biomarkers increased in both groups, as expected with teriparatide, but the increases in the 2 calcium groups did not differ significantly. Conclusions: Tricalcium phosphate and calcium carbonate appear to be approximately equally effective in supporting bone building with a potent anabolic agent; phosphate salt may be preferable in patients with restricted phosphorus intakes. This trial was registered at clinicaltrials.gov as NCT00074711. Am J Clin Nutr doi: 10. 3945/ajcn.2009.29085.

PURPOSE: The purpose of the study was to determine the advantages and disadvantages of prophylactic/extended colectomy (subtotal colectomy) in patients with Lynch syndrome who manifest colorectal cancer. METHODS: A retrospective cohort using Creighton University's hereditary cancer database was used to identify cases and controls. Cases are patients who underwent subtotal colectomy, either with no colorectal cancer diagnosis (prophylactic) or at diagnosis of first colorectal cancer; controls for these 2 types of cases were, respectively, patients who underwent no colon surgery or those having limited resection at time of diagnosis of first colorectal cancer. The Kaplan-Meier and proportional hazard regression models from the Statistical Analysis Software program was used to calculate the difference in survival, time to subsequent colorectal cancer, and subsequent abdominal surgery between cases and controls. RESULTS: The event-free survival of our study did not reach 50%, so we used the event-free survival at 5 years as our parameter to compare the 2 groups. The event-free survival for subsequent colorectal cancer, subsequent abdominal surgery, and death was 94%, 84%, and 93%, respectively, for cases and 74%, 63%, and 88%, respectively, for controls. Times to subsequent colorectal cancer and subsequent abdominal surgery were significantly shorter in the control group (P < .006 and P < .04, respectively). No significant difference was identified with respect to survival time between the cases and controls. CONCLUSIONS: Even though no survival benefit was identified between the cases and controls the increased incidence of metachronous colorectal cancer and increased abdominal surgeries among controls warrant the recommendation of subtotal colectomy in patients with Lynch syndrome.

Field carcinogenesis detection represents a promising means for colorectal cancer (CRC) screening, although current techniques (e.g., flexible sigmoidoscopy) lack the requisite sensitivity. The novel optical technology low-coherence enhanced backscattering (LEBS) spectroscopy, allows identification of microscale architectural consequences of the field carcinogenesis in preclinical CRC models with unprecedented accuracy. To investigate the potential clinical translatability of this approach, we obtained biopsies from the normal-appearing rectal mucosa from patients undergoing colonoscopy (n = 219). LEBS signals were recorded through a bench-top instrument. Four parameters characterizing LEBS signal were linearly combined into a single marker. We found that LEBS signal parameters generally mirrored neoplasia progression from patients with no neoplasia, to 5 to 9 mm adenoma and to advanced adenomas. The composite LEBS marker calculated from the LEBS signal paralleled this risk status (ANOVA P < 0.001). Moreover, this was independent of CRC risk factors, benign colonic findings, or clinically unimportant lesions (diminutive adenomas, hyperplastic polyps). For advanced adenomas, the LEBS marker had a sensitivity of 100%, specificity of 80%, and area under the receiver operator characteristic curve of 0.895. Leave-one-out cross-validation and an independent data set (n = 51) supported the robustness of these findings. In conclusion, we provide the first demonstration that LEBS-detectable alterations in the endoscopically normal rectum were associated with the presence of neoplasia located elsewhere in the colon. This study provides the proof of concept that rectal LEBS analysis may potentially provide a minimally intrusive CRC screening technique. Further studies with an endoscopically compatible fiber optic probe are under way for multicenter clinical validation. [Cancer Res 2009;69(10):4476–83]

The ability of the host to mount an appropriate immune response to aberrant cells is one factor that determines prognosis in cancer patients. Naturally occurring regulatory T cells (T regs; CD4+ CD25+ cells) are key regulators of peripheral tolerance. It has been suggested that high levels of T regs are detrimental to the patient in some forms of cancer, but the role of these antigen-specific cells in individuals with colorectal cancers with high levels of microsatellite instability is unknown. Herein, we examined the ability of individuals with MSI-H or microsatellite stable colon cancer to recruit lymphocytes to the tumor site. Immunohistochemical staining was performed on archived paraffin-embedded specimens from a total of 38 individuals with MSI-H (n = 25) or MSS (n = 13) colon cancers to determine the proportion of CD3+, CD8+ and CD25+ cells infiltrating the tumor site. Patients with MSI-H colon cancers had increased percentages of CD8+ TILs (cytotoxic T cells) as compared to individuals with MSS colon cancer (47.3 vs. 24.04% of the infiltrate CD8+, respectively). No differences in the levels of CD25+ T cells were observed between individuals with MSI-H colon cancers and MSS colon cancers (0.53 vs. 0.54% CD25+, respectively). Together, these data suggest that the survival advantage enjoyed by patients with MSI-H colorectal cancer may, in part, be attributed to the increased cytolytic response, but not to an antigen-specific immunosuppressive response in MSS patients.

Persons with the Lynch syndrome (LS) are at high risk for cancer, including cancers of the small bowel, stomach, upper urologic tract (renal pelvis and ureter), ovary, biliary tract and brain tumors, in addition to the more commonly observed colorectal and endometrial cancers. Cancer prevention strategies for these less common cancers require accurate, age-specific risk estimation. We pooled data from 4 LS research centers in a retrospective cohort study, to produce absolute incidence estimates for these cancer types, and to evaluate several potential risk modifiers. After elimination of 135 persons missing crucial information, cohort included 6,041 members of 261 families with LS-associated MLH1 or MSH2 mutations. All were either mutation carriers by test, probable mutation carriers (endometrial/colorectal cancer-affected), or first-degree relatives of these. Among mutation carriers and probable carriers, urologic tract cancer (N = 98) had an overall lifetime risk (to age 70) of 8.4% (95% CI: 6.6-10.8); risks were higher in males (p < 0.02) and members of MSH2 families (p < 0.0001). Ovarian cancer (N = 72) had an lifetime risk of 6.7% (95% CI: 5.3-9.1); risks were higher in women born after the median year of birth (p < 0.008) and in members of MSH2 families (p < 0.006). Brain tumors and cancers of the small bowel, stomach, breast and biliary tract were less common. Urologic tract cancer and ovarian cancer occur frequently enough in some LS subgroups to justify trials to evaluate promising prevention interventions. Other cancer types studied occur too infrequently to justify strenuous cancer control interventions.

Colorectal and endometrial cancer are the characteristic tumors of the Lynch syndrome. We reviewed the available evidence on the occurrence of other types of cancer in the syndrome, aiming to identify those types that can be included in the tumor spectrum, based on this evidence. We chose to define the tumor spectrum as comprising the cancers for which Lynch syndrome patients are at elevated risk. We found sufficiently strong and consistent evidence to include gastric cancer, small bowel cancer, hepatobiliary tract cancer, upper urologic tract cancer, ovarian cancer, and brain tumors in this spectrum, in addition to colorectal and endometrial cancer. We predict that the spectrum will expand as additional studies are reported, especially as prospective studies of mutation carriers are completed.

Importance Evidence suggests that low vitamin D status may increase the risk of cancer. Objective To determine if dietary supplementation with vitamin D 3 and calcium reduces the risk of cancer among older women. Design, Setting, and Participants A 4-year, double-blind, placebo-controlled, population-based randomized clinical trial in 31 rural counties (June 24, 2009, to August 26, 2015—the final date of follow-up). A total of 2303 healthy postmenopausal women 55 years or older were randomized, 1156 to the treatment group and 1147 to the placebo group. Duration of treatment was 4 years. Interventions The treatment group (vitamin D 3 + calcium group) received 2000 IU/d of vitamin D 3 and 1500 mg/d of calcium; the placebo group received identical placebos. Main Outcomes and Measures The primary outcome was the incidence of all-type cancer (excluding nonmelanoma skin cancers), which was evaluated using Kaplan-Meier survival analysis and proportional hazards modeling. Results Among 2303 randomized women (mean age, 65.2 years [SD, 7.0]; mean baseline serum 25-hydroxyvitamin D level, 32.8 ng/mL [SD, 10.5]), 2064 (90%) completed the study. At year 1, serum 25-hydroxyvitamin D levels were 43.9 ng/mL in the vitamin D 3 + calcium group and 31.6 ng/mL in the placebo group. A new diagnosis of cancer was confirmed in 109 participants, 45 (3.89%) in the vitamin D 3 + calcium group and 64 (5.58%) in the placebo group (difference, 1.69% [95% CI, −0.06% to 3.46%]; P = .06). Kaplan-Meier incidence over 4 years was 0.042 (95% CI, 0.032 to 0.056) in the vitamin D 3 + calcium group and 0.060 (95% CI, 0.048 to 0.076) in the placebo group; P = .06. In unadjusted Cox proportional hazards regression, the hazard ratio was 0.70 (95% CI, 0.47 to 1.02). Adverse events potentially related to the study included renal calculi (16 participants in the vitamin D 3 + calcium group and 10 in the placebo group), and elevated serum calcium levels (6 in the vitamin D 3 + calcium group and 2 in the placebo group). Conclusions and Relevance Among healthy postmenopausal older women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL, supplementation with vitamin D 3 and calcium compared with placebo did not result in a significantly lower risk of all-type cancer at 4 years. Further research is necessary to assess the possible role of vitamin D in cancer prevention. Trial Registration clinicaltrials.gov Identifier:NCT01052051

Objective. Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary cancer susceptibility disorder associated with a very high risk for carcinoma of the colon and an elevated risk for certain extracolonic cancers including ovarian cancer. Our aim in this study was to describe the clinicopathologic features of ovarian cancer in HNPCC family members. Methods. Members of the International Collaborative Group on HNPCC collected retrospective data on 80 ovarian cancer patients who were members of HNPCC families, including 31 known mutation carriers, 35 presumptive carriers (by colorectal/endometrial cancer status), and 14 at-risk family members. Results. Mean age at diagnosis of ovarian cancer was 42.7. Nonepithelial tumors made up only 6.4% of the cancers, and borderline tumors comprised just 4.1% of the epithelial cancers. Among frankly malignant epithelial cases, most cancers were well or moderately differentiated, and 85% were FIGO stage I or II at diagnosis. Synchronous endometrial cancer was reported in 21.5% of cases. Conclusions. Ovarian cancer in HNPCC differs from ovarian cancer in the general population in several clinically important respects. It occurs at a markedly earlier age. It is more likely to be epithelial. If it is a frankly invasive epithelial cancer, it is more likely to be well or moderately differentiated. HNPCC patients with ovarian cancer are more likely to have a synchronous endometrial cancer than other ovarian cancer patients and are more likely to be diagnosed at an early stage.

BACKGROUND Cells with deficient DNA mismatch repair develop microsatellite instability. Extensive microsatellite instability (MSI-high) is characteristic of colorectal carcinomas in hereditary nonpolyposis colorectal carcinoma (HNPCC) and in 10–% 15% of sporadic colorectal carcinomas. Microsatellite instability-high colorectal carcinomas differ from others in important clinical and pathologic features. However, MSI typing is expensive and not widely available. Microsatellite instability type may be predicted by tumor-infiltrating lymphocytes (TILs), which can be evaluated with ordinary light microscopy. METHODS The authors evaluated TILs as a pathology screen for MSI-high status in 138 colorectal carcinomas that had been evaluated for MSI in a variety of studies. This case series was systematically enriched with HNPCC and other MSI-high cases to allow accurate sensitivity and specificity estimation. Tumor-infiltrating lymphocytes were quantitated as TILs per 10 high-power microscopic fields by an observer blinded to MSI status. RESULTS Of the 138 carcinomas studied, 67 (48.6%) were MSI-high, 22 (15.9%) were MSI-low, and 49 (35.5%) were MSI-stable. All 25 HNPCC colorectal carcinomas were MSI-high. Tumor-infiltrating lymphocytes counts ranged from 0 to 300, with a markedly skewed distribution (median, 11; mean, 36). Sensitivity and specificity for selected cut points of TIL count were computed. Using a TIL count of 5 as a cut point yields a sensitivity of 93% and specificity of 62%. In a population in which 12% were MSI-high, consideration of TIL could reduce the number of colorectal carcinomas referred for MSI testing by greater than one-half, and still 93% of the MSI-high carcinomas would be identified. CONCLUSIONS The presence of MSI defines a subset of colorectal carcinomas with special molecular etiology and characteristic clinical, pathologic features, inclusive of increased survival. The authors conclude that quantification of TILs may provide a simple, single criterion for choosing which colorectal carcinomas are candidates for MSI testing. Cancer 2001;91:2417–22. © 2001 American Cancer Society.

Optimally accurate and valid estimates of cancer risk in genetically-defined subgroups requires population-based research. For rare genetic traits, very large studies are needed. Such is the case in hereditary nonpolyposis colorectal cancer syndrome (HNPCC), caused by mutations in mismatch repair (MMR) genes. A potentially more efficient approach is genotyped-proband design (GPD), in which probands are genotyped and the phenotypes of their relatives are investigated. However, to date most information comes from registry-based studies, where ascertainment bias makes interpretation difficult. Development in testing technology will lead to more identified mutation carriers, producing a clinical imperative to estimate risk, despite these problems. We reviewed the available results, and concluded that male mutation carriers have a lifetime colorectal cancer risk of 74% or more; female mutation carriers have a lower risk which is still many times higher than the risk in the general population. Risk is highest between the ages of 40 and 60, but considerable even before age 40. Lifetime endometrial cancer risk is 42% or more; the highest incidence is between age 40 and 60, and diagnosis before the age of 35 is rare. MMR mutation carriers are at elevated risk for ovarian, gastric, urologic tract, small bowel, hepatobiliary tract cancer, and for brain tumors. The risk of these cancer types is much lower than the risk for colorectal and endometrial cancer, but accurate, especially age-related estimates of risk are not available. Prevention strategies depend on estimates of age-specific risk. Clearly, multicenter studies to obtain such estimates are needed.

Hereditary nonpolyposis colorectal carcinoma (HNPCC) is the most common hereditary form of colorectal carcinoma (CRC) and may account for 5-10% of the total CRC burden. The discovery of DNA mismatch repair (MMR) genes, inclusive of hMSH2, hMLH1, hPMS2, and hMSH6, has enabled the identification of who has and who does not have inordinately increased susceptibility to CRC as well as a litany of extracolonic cancers. Mutation testing has focused on hMSH2 and hMLH1, the most common mutations in HNPCC. The protocol for DNA testing and DNA-based genetic counseling is described in Part I of this study. One hundred ninety-nine bloodline relatives were tested and counseled from five hMLH1 and two hMSH2 families. Their major reason for seeking genetic counseling and DNA testing was to inform their children and other loved ones of their mutation status. Those who sought counseling overestimated their risk for inheriting the mutation and showed a high rate of interest in prophylactic surgery, and many were greatly concerned about insurance discrimination. Knowledge about HNPCC, its molecular genetic diagnosis, surveillance and management opportunities, and genetic counseling implications are still emerging, all in the face of a greater need for physician education regarding all facets of hereditary cancer.

Background The availability of genetic testing for inherited mutations in the BRCA1 gene provides potentially valuable information to women at high risk of breast or ovarian cancer; however, carriers of BRCA1 mutations have few clinical management options to reduce their cancer risk. Decreases in ovarian hormone exposure following bilateral prophylactic oophorectomy (i.e., surgical removal of the ovaries) may alter cancer risk in BRCA1 mutation carriers. This study was undertaken to evaluate whether bilateral prophylactic oophorectomy is associated with a reduction in breast cancer risk in BRCA1 mutation carriers. Methods We studied a cohort of women with disease-associated germline BRCA1 mutations who were assembled from five North American centers. Surgery subjects (n = 43) included women with BRCA1 mutations who underwent bilateral prophylactic oophorectomy but had no history of breast or ovarian cancer and had not had a prophylactic mastectomy. Control subjects included women with BRCA1 mutations who had no history of oophorectomy and no history of breast or ovarian cancer (n = 79). Control subjects were matched to the surgery subjects according to center and year of birth. Results We found a statistically significant reduction in breast cancer risk after bilateral prophylactic oophorectomy, with an adjusted hazard ratio (HR) of 0.53 (95% confidence interval [CI] = 0.33-0.84). This risk reduction was even greater in women who were followed 5-10 (HR = 0. 28; 95% CI = 0.08-0.94) or at least 10 (HR = 0.33; 95% CI = 0.12-0.91) years after surgery. Use of hormone replacement therapy did not negate the reduction in breast cancer risk after surgery. Conclusions Bilateral prophylactic oophorectomy is associated with a reduced breast cancer risk in women who carry a BRCA1 mutation. The likely mechanism is reduction of ovarian hormone exposure. These findings have implications for the management of breast cancer risk in women who carry BRCA1 mutations.

Mismatch repair deficiency is a characteristic molecular finding in hereditary nonpolyposis colorectal cancer (HNPCC), and has been demonstrated in both colorectal cancers and benign adenomas. Endometrial and ovarian cancers are common extracolonic tumors in this syndrome; however, few studies have investigated whether genetic changes occur in histologically normal endometrial and ovarian epithelia from HNPCC family members. If early genetic changes exist, they might be used as molecular markers to detect susceptibility to endometrial and ovarian cancers. In this study, we analyzed microsatellite instability (MSI) and MLH1 and MSH2 immunohistochemical expression in 20 histologically normal epithelia (12 endometrial and 8 ovarian) and 8 cancers (4 endometrial and 4 ovarian) obtained from 20 individuals representing 7 unrelated HNPCC families. While MSI was observed in endometrial (75%) and ovarian (100%) cancers, no case was determined to exhibit MSI in histologically normal epithelia of the endometrium or ovary. Similarly, in immunohistochemical expressions for MLH1 and MSH2, histologically normal epithelia had no genetic changes predisposing to malignancy. In cancer cases, a correlation existed between the expression of MLH1 and MSH2, the presence of germline mutations in the hMLH1 and hMSH2 genes, and the presence of tumor MSI. These data suggest that MSI and MLH1 and MSH2 expression are not useful biomarkers for the early detection of endometrial and ovarian malignancy in cancer-unaffected HNPCC germline mutation carriers. Further studies of other genetic changes in normal and premalignant precursor lesions are needed.

One of the first successful efforts of the International Collaborative Group on HNPCC (ICG-HNPCC) at its meeting in Amsterdam in 1990 was the establishment of a set of selection criteria for families with hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) to provide a basis for uniformity in collaborative studies (Table 1).1 Until 1990, such criteria were lacking and the descriptions of the syndrome in the literature varied widely. In the absence of a common nomenclature it was impossible to compare the results of different studies on HNPCC. The wide acceptance of the ICG criteria is reflected by the fact that almost all investigators currently make use of them. However, the criteria have also been criticized. Some investigators feel that the criteria exclude some classic HNPCC families because they do not take into account the extracolonic cancers that are part of the syndrome. There is also concern that the criteria are being used inappropriately for the diagnosis of HNPCC. As criteria for the selection of families for research, they were originally aimed at specificity more than sensitivity. It is now considered that many true HNPCC families would be missed if the criteria are applied to clinical diagnosis, and that families not meeting the criteria might be falsely reassured and excluded from genetic counseling, DNA testing, or surveillance. To resolve these problems, many investigators have developed additional criteria.2–6 At the ninth meeting of the ICG-HNPCC held in Noordwijk, the Netherlands, in 1997, a definition of HNPCC was proposed that was aimed at helping clinicians to identify families. This provided a detailed description of the specific features of HNPCC rather than the rigid criteria required for collaborative studies. In addition, at the ninth meeting, and also at the tenth held in Coimbra, Portugal, in 1998, new selection criteria for collaborative studies were proposed that included the extracolonic cancers associated with HNPCC. Definition of HNPCC

BACKGROUND, Small bowel carcinoma is uncommon. However, hereditary nonpolyposis colorectal carcinoma (HNPCC) patients are at increased risk of small bowel carcinoma. The purpose of this study was to characterize small bowel tumors in HNPCC patients. METHODS. A questionnaire was mailed to the members of International Collaborative Group on HNPCC (ICG-HNPCC) requesting clinicopathologic data in their registries on HNPCC patients with small bowel carcinoma. Survival was estimated utilizing the Kaplan-Meier method. RESULTS. Forty-two individuals from 40 HNPCC families developed 42 primary and 7 metachronous small bowel tumors. There were 46 adenocarcinomas and 3 carcinoid tumors. The median age at diagnosis of the index small bowel tumor was 49 years. Mismatch repair gene mutations were present in 15 of 42 patients (36%). There were nine hMLH1 and six hMSH2 mutations. The small bowel was the first site of carcinoma in 24 patients (57%). The median survival for the 42 patients was 47 months (range, 0-447 months). The overall 5- and 10-year survival rates were 44% and 33%, respectively. CONCLUSIONS. Small bowel tumors can be the presenting neoplasms in HNPCC patients. Similar to colorectal carcinoma in HNPCC, small bowel adenocarcinomas in HNPCC patients occur at an earlier age and appear to have a better prognosis than those occurring in the general population.

A blood culture cohort study investigating issues related to isolation of coagulase-negative staphylococci (CoNS) and other skin microflora is reported. Data were collected over 12 weeks to determine the incidence of significant CoNS bacteremia versus that of pseudobacteremia (contaminants) and to evaluate drug therapy in patients with cultures positive for CoNS. In addition, the effectiveness of 0.2% chlorine peroxide as a bactericidal disinfectant was compared to that of 10% providone iodine. A total of 3,276 cultures of blood from 1,433 patients were evaluated in the study. Eighty-nine cultures were positive for skin flora, with 81 of 89 (91%) involving CoNS. The incidence of significant CoNS bacteremia was 20 of 81 (24.7%), that of indeterminate bacteremia was 10 of 81 (12.3%), and that of contamination was 59 of 81 (72.8%). The incidence of significant bacteremia involving CoNS was double the 10 to 12% rate based on previous estimations at our institutions. In tests with the two bactericidal disinfectants, 22 of 1,639 cultures (1.3%) in the chlorine peroxide group versus 37 of 1,637 (2.3%) in the providone iodine group were considered contaminated ( P = 0.065). Rates of contamination for venipuncture versus catheter collection were not significantly different ( P = 0.46). The overall contamination rate was 59 of 3,276 (1.8%), which is consistent with the lower end of published quality assurance benchmark standards. The low rate was believed to be due to the professional phlebotomy staff in our institutions. There was excellent agreement between retrospective analysis by reviewers, when formal criteria were used, and the attending physicians’ intuitive clinical impressions in the classification of significant bloodstream infections (100% agreement) or contamination (95% agreement). However, physicians still used antimicrobial agents to treat nearly one-half of the patients with contaminated blood cultures, with vancomycin being misused in 34% of patients. In addition, 10% of patients with significant bacteremia were treated with inappropriate agents. There were no significant adverse events or prolonged hospital stays due to the unnecessary use of vancomycin; however, the additional costs of treating patients whose cultures contained CoNS contaminants was estimated to be $1,000 per patient. Measures to limit the unnecessary use of vancomycin (and other agents) are important.

PURPOSE: This clinical case review aimed to identify phenotypic variations in colorectal and extracolonic cancer expression between hereditary nonpolyposis colorectal cancer (HNPCC) families with MLH1 and MSH2 germline mutations and the general population. METHODS: Colorectal cancer onset and site distribution were compared among 67 members of MLH1 kindreds, 45 members of MSH2 kindreds, and 1,189 patients from the general population. Synchronous and metachronous cancer rates, tumor stage, extracolonic cancer incidence, and survival were also compared. RESULTS: Mean ages of colorectal cancer onset were 44, 46, and 69 years for MLH1, MSH2, and the general population, respectively (P

To determine the validity of observations suggesting a significant dichotomy of gynecologic cancers determined by linkage to specific genetic defects associated with two major autosomal dominant hereditary cancer syndromes; the Creighton University Hereditary Cancer Registry was searched for female carriers of germ line mutations in BRCA1 and BRCA2, associated with the Hereditary Breast Ovarian Cancer syndrome, and in the mismatch repair (MMR) genes MLH1, MSH2 and MSH6, associated with Lynch syndrome, who were registered with invasive uterine, ovarian, fallopian tube or peritoneal cancers between January 1, 1959 and December 31, 2010. From 217 such cases, a total of 174 subjects, consisting of 95 BRCA1 and BRCA2 mutation carriers and 79 carriers of mutations in MMR genes, were identified who had current signed Health Insurance Portability and Accountability Act forms and complete primary diagnostic pathology reports and clinical records. Data meticulously extracted from these cases were categorized and statistically analyzed. There were highly significant differences between carriers of BRCA1 and BRCA2 mutations and carriers of MMR gene mutations in the proportion of serous carcinomas compared with endometrioid carcinomas of the uterus, including cervix and endometium (p < 0.002), ovaries (p < 0.001) and overall, including fallopian tube and peritoneum cancers (p < 0.001). Endometrioid carcinoma was found in one and transitional carcinoma in another of the 14 BRCA1 mutation carriers with fallopian tube cancer, and endometrioid carcinoma was found in two of four MMR gene mutation carriers with fallopian tube cancers. All other fallopian tube cancers were serous carcinomas. Seven BRCA1 and one BRCA2 mutation carriers were diagnosed with primary peritoneal serous carcinoma; no peritoneal carcinomas were registered in MMR gene mutation carriers. Nine of 14 gynecologic cancers with associated endometriosis in mutation carriers were endometrioid or endometrioid mixed carcinomas compared with just three of other histologic types. Primary breast cancers, that characterize the HBOC syndrome, were much more frequent in BRCA1 and BRCA2 mutation carriers; while multiple gynecologic cancers and associated colorectal and urinary tract cancers, which are features of Lynch syndrome, were more common in MMR gene mutation carriers. Both serous and endometrioid carcinomas were diagnosed in MMR gene mutation carriers at significantly younger ages than in BRCA1 and BRCA2 mutation carriers (p < 0.0006). These findings confirm a clear dichotomy of uterine, ovarian and fallopian tube cancers associated with inheritance of mutations in BRCA1 and BRCA2 contrasted with inheritance of MMR gene mutations. This opens possibilities for new approaches to molecular genetic research into carcinogenic pathways and raises important new considerations regarding counseling, screening, prophylaxis and treatment of mutation carriers.

BACKGROUND 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. METHODS On the basis of linkage to chromosomes 17q or 13q and/or the presence of ovarian and male breast cancer, HBC families were classified as either “BRCA1-related” (26 families, 90 breast cancer pathology cases) or “Other” (26 families, 85 cases), in which most BRCA2 cases were likely to reside. Cases were compared with 187 predominantly non-HBC cases. Tumors were assessed for histologic type, grade, and ploidy and S-phase fraction by quantitative DNA flow cytometry. Clinical presentation and available follow-up data were obtained. RESULTS BRCA1-related and Other HBC patients each presented at lower stage (P = 0.003) and earlier age than non-HBC patients (mean, 42.8 years and 47.1 years vs. 62.9 years, P < 0.0001). Compared with non-HBC, invasive BRCA1-related HBC had a lower diploidy rate (13% vs. 35%; P = 0.002), lower mean aneuploid DNA index (1.53 vs. 1.73; P = 0.002), and strikingly higher proliferation rates (mitotic grade 3; odds ratio [OR] = 4.42; P = 0.001; aneuploid mean S-phase fraction 16.5% vs. 9.3%, P < 0.0001). Other HBC patients, including patients in two BRCA2-linked families, had more tubular-lobular group (TLG) carcinomas (OR = 2.56, P = 0.007). All trends were independent of age. A nonsignificant trend toward better crude survival in both HBC groups was age- and stage-dependent. Compared with Other HBC, BRCA1-related HBC patients had fewer recurrences (P = 0.013), a trend toward lower specific death rates, and fared no worse than breast cancer patients at large. Other HBC patients, despite neutral prognostic indicators, fared worse. CONCLUSIONS BRCA1-related HBCs are more frequently aneuploid and have higher tumor cell proliferation rates compared with Other HBC. Despite these adverse prognostic features, BRCA1-related HBC patients have paradoxically lower recurrence rates than Other HBC patients. The excess of TLG cancers in the “Other” HBC group may be associated with BRCA2 linkage. Cancer 1996; 697-709.

Previous studies have shown that male BRCA mutation carriers stand at increased risk of developing prostate cancer and have concerns about developing cancer. Genetic counseling practitioners often discuss strategies for reducing the risk of cancer for patients at high risk due to their genetic background. Addressing modifiable health habits is one such strategy. Unfortunately, modifiable risk factors for prostate cancer have only been documented in the general population and have not yet been studied in the BRCA carrier subpopulation. Therefore, this study aimed to identify modifiable risk factors for prostate cancer in BRCA carriers. We examined prostate cancer risk factors in 74 men who were part of families with a BRCA mutation. This study examined nine dichotomous variables including: exercise, history of vasectomy, smoking history, alcohol use, finasteride use, statin use, aspirin use, coffee use, and vitamin use. The survey was sent to all cases of prostate cancer in the Hereditary Cancer Center Database at Creighton University with a known BRCA status. This study confirmed the protective benefits of daily aspirin use, which have been observed in previous studies of the general population, and suggests its benefit in BRCA carriers. Protective benefits from regular vigorous exercise and daily coffee use trended towards significance, but neither factor withstood the Bonferroni Correction for multiple comparisons.

Objective: To determine if Apache II Trauma Score or obesity correlate with measured resting energy expenditure (REE) and influence the validity of calculated REE. Design: Descriptive case series. Setting: Hospitalized care at an urban medical center. Patients: Consecutive sample of sixty-six patients having indirect calorimetry measurements. Analysis: Patients were assigned Apache II Scores and classified by body weight (15 obese, 25 normal weight and 11 underweight patients). Estimates of REE were calculated using Harris-Benedict and Mifflin equations. Main Outcomes: Measured REE did not correlate significantly with Apache II scores. Correlation of Harris-Benedict calculated REE with measured REE was moderate (r=0.54, p

(1995). Medical Genetic Study of Eight Pancreatic Cancer-Prone Families. Cancer Investigation: Vol. 13, No. 2, pp. 141-149.

Objective To assess the impact of calcium-fortified food and dairy food on selected nutrient intakes in the diets of adolescent girls. Design Randomized controlled trial, secondary analysis. Setting and Participants Adolescent girls (n = 149) from a midwestern metropolitan area participated in randomized controlled trials of bone physiology from 1997 to 2008. Intervention Subjects randomly assigned to a high-calcium (HC) diet supplying 1,500 mg calcium/d, or their usual diet (UC). Main Outcome Measures Dietary intake was assessed from 3-day food records and calcium intakes categorized by food source. Food group composites, representing calcium-fortified and dairy food categories, were examined for their relative nutrient contributions. Student t tests were used to evaluate differences in selected nutrient intakes between the 2 study groups. Results Dairy food contributed 68% of the total mean 1,494 mg calcium/d in the HC group, and calcium-fortified food contributed 304 mg calcium. In the UC group, dairy food contributed 69% of the total mean 765 mg calcium/d and calcium-fortified food contributed 50 mg calcium. Nutrient profiles of the dairy composites differed significantly from the calcium-fortified composites (P Conclusions and Implications Dairy food was the primary source of calcium selected by these adolescent girls; calcium-fortified food augmented calcium intakes.

Hereditary nonpolyposis colorectal cancer (HNPCC) dates to Warthin's description of family G, which he began studying in 1895. Warthin's observations were not fully appreciated until 1966 when two families with an autosomal dominant inheritance pattern of nonpolyposis colorectal cancer (CRC) and endometrial cancer were described. This condition was first termed the "cancer family syndrome" and was later renamed HNPCC. Some have proposed that HNPCC consists of at least two syndromes: Lynch syndrome I, with hereditary predisposition for CRC having early (approximately 44 years) age of onset, a proclivity (70%) for the proximal colon, and an excess of synchronous and metachronous colonic cancers and Lynch syndrome II, featuring a similar colonic phenotype accompanied by a high risk for carcinoma of the endometrium. Transitional cell carcinoma of the ureter and renal pelvis and carcinomas of the stomach, small bowel, ovary, and pancreas also afflict some families. Current estimates indicate that HNPCC may account for as much as 6% of the total CRC burden. There are no known premonitory phenotypic signs or biomarkers of cancer susceptibility in the Lynch syndromes. This report will summarize current knowledge, with emphasis on the manner in which this knowledge can be employed effectively for diagnosis and management of HNPCC.

Published studies of families with hereditary nonpolyposis colorectal cancer (HNPCC) frequently report the occurrence of cancers at extracolonic sites. Our purpose in this study was to compare the observed frequency of cancer at specific sites in members of 18 unrelated HNPCC kindreds with expectations based on general population incidence in order to determine whether there were specific types of cancer for which family members were at elevated risk. We were able to stratify family members according to their risk of carrying the putative HNPCC gene. We found that putative HNPCC gene carriers and their high risk relatives have been diagnosed with cancers other than uterine and colorectal more frequently than expected based on general population incidence figures. Specific sites where elevations are seen include the stomach, small intestine, biliary system (especially the bile ducts), urological system (especially the kidney and ureter), and ovary.

Background It is undetermined whether calcium supplementation has an effect on obesity or body composition in postmenopausal women. The purpose of the study is to detect the effect of calcium supplementation on indices of obesity and body composition. Methods This is a secondary analysis of data from a population-based, double-blind, placebo-controlled, randomized trial designed to determine the effects of calcium and vitamin D on osteoporotic fractures. The cohort included 1179 postmenopausal women who were randomly assigned into one of three groups: 1) supplemental calcium (1400 mg/d or 1500 mg/d) plus vitamin D placebo (Ca-only group); 2) supplemental calcium (1400 mg/d or 1500 mg/d) plus supplemental vitamin D3 (1100 IU/d) (Ca + D group); or, 3) two placebos (placebo group). After applying the exclusion criteria for this analysis, 870 subjects were included in this study. The primary outcomes for the present study were changes in body mass index, trunk fat, trunk lean, and percentage of trunk fat after calcium supplementation. Results Changes in trunk fat, trunk lean, and percentage of trunk fat were significantly different between the calcium intervention groups (Ca-only group or Ca + D group) and the placebo group during the trial (P < 0.05). The calcium intervention groups gained less trunk fat and maintained more trunk lean when compared to the placebo group. No significant difference was observed for body mass index between groups. Conclusion Calcium supplementation over four years has a beneficial effect on body composition in postmenopausal women.

We describe the clinical and pathologic features in four extended kindreds that are consistent with the hereditary flat adenoma syndrome (HFAS). This colon cancer susceptibility disorder is believed to be inherited as an autosomal dominant. The principal phenotypic marker is multiple colonic adenomas (usually less than 100), with a tendency for proximal location. The majority of these adenomas are flat or slightly raised and plaquelike, as opposed to polypoid. Colon cancers have typically developed in middle age and show no unusual histologic features. There are a variety of extracolonic manifestations, including adenomas and carcinomas of the small bowel and fundic gland polyps. The HFAS is contrasted with hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis (FAP) and shown to be distinct from both in the numbers and distribution of colonic adenomas and the typical age of cancer diagnosis. The clinical implications of these findings are discussed. Given its linkage to the FAP locus on 5q and the phenotypic parallels between HFAS and FAP, we conclude that HFAS is a variant of FAP.

Hereditary nonpolyposis colorectal cancer (HNPCC) is common, accounting for about 4-6% of the total colorectal cancer burden. It is heterogeneous and appears to be delineated into two clinical subsets, Lynch syndromes I and II. Lynch syndrome I is characterized by an autosomal dominantly inherited proclivity to early onset colonic cancer with proximal predominance and an excess of multiple primary colonic cancer. Lynch syndrome II has all of these features plus extracolonic cancer sites, the most common of which is endometrial carcinoma. The lack of premonitory physical signs or biomarkers of HNPCC makes diagnosis difficult. A careful family history, tempered by an understanding of the clinical and pathologic features of HNPCC, is the key to its assessment. This paper reviews HNPCC's natural history, its integral extracolonic cancer associations, its differential diagnosis, surveillance, and management strategies. Attention is focused upon the need for biomarker research in the interest of improving control of HNPCC.

An unknown fraction of the ovarian cancer burden occurs in women with a family history indicative of a putative autosomal dominantly inherited cancer susceptibility syndrome. The results from a five-generation, extended, hereditary breast-ovarian cancer kindred are described 10 years after it was initially ascertained. Significantly more cancers were observed in high-risk family members during this decade than were expected (P less than 0.001). The age of ovarian cancer diagnosis was studied in additional ovarian cancer-prone families of three types: site-specific ovarian cancer syndrome, the breast-ovarian cancer syndrome, and Lynch syndrome II. The age of onset in each of the three sets was significantly (P less than 0.001) earlier than the general population mean of 59, and there were significant differences in the age of onset (P = 0.050) among these three cohorts. Ovarian cancer histology was similar to that of patients with negative family histories. There may be clinically significant heterogeneity in the age at diagnosis of ovarian cancer among these ovarian cancer-prone syndromes. This has important implications for understanding its natural history and targeting surveillance-management strategies.

We describe a family with five cases of multiple myeloma, three cases of monoclonal gammopathy of undetermined significance (MGUS), and five cases of prostate cancer in two generations. The putative progenitor had progeny with two female partners. The progeny had prostate cancer, multiple myeloma, and MGUS.

Clinical, pathologic, and genetic studies on two colorectal cancer-prone families have disclosed right-sided colonic flat adenomas and colorectal cancer. Adenomatous polyp counts exceeded those found in hereditary nonpolyposis colorectal cancer (HNPCC) but were fewer than in familial adenomatous polyposis (FAP). Colon cancer occurred at a later age than in HNPCC or FAP and showed right-sided predominance. The older age of patients with colonic cancer, the right-sided predominance of colon cancer, and the paucity of rectal adenomas make FAP unlikely. Vertical transmission of polyps and colon cancer fit the pattern of autosomal dominant inheritance. A characteristic feature of this phenotype is the predominance of flat adenomas. Molecular genetic studies, with careful description of phenotype, should help clarify classification.

Forty-four asymptomatic putative Lynch syndrome patients participated in a colonoscopy screening program. There were 18 men and 26 women; mean age was 44 yr. Thirty percent of Lynch syndrome patients had at least one adenoma; 20% had multiple adenomas. In 18% of the patients, adenomas were discovered proximal to the splenic flexure. In a reference group of 88 age- and sex-matched patients, 11% had adenomas, 4 % had multiple adenomas, and 1 % had right-sided adenomas. Twenty-one Lynch syndrome patients had follow-up colonoscopies. Of 7 patients with adenomas on initial examinations, 6 had adenomas at follow-up. Of 14 patients with negative initial examination results, 3 had adenomas at follow-up. The prevalence of adenomas in the Lynch syndromes is greater than in an unselected reference group. The adenomas are more proximally located, corresponding to the site of cancer distribution in the Lynch syndromes. A high rate of synchronous and metachronous lesions is found. Our findings support the hypothesis that adenomatous changes are the premalignant lesion in the Lynch syndromes. We also found evidence of heterogeneity among Lynch syndrome families in adenoma incidence.

AIM: To investigate whether a fuzzy logic model could predict colorectal cancer (CRC) risk engendered by smoking in hereditary non-polyposis colorectal cancer (HNPCC) patients. METHODS: Three hundred and forty HNPCC mismatch repair (MMR) mutation carriers from the Creighton University Hereditary Cancer Institute Registry were selected for modeling. Age-dependent curves were generated to elucidate the joint effects between gene mutation (hMLH1 or hMSH2), gender, and smoking status on the probability of developing CRC. RESULTS: Smoking significantly increased CRC risk in male hMSH2 mutation carriers (P < 0.05). hMLH1 mutations augmented CRC risk relative to hMSH2 mutation carriers for males (P < 0.05). Males had a significantly higher risk of CRC than females for hMLH1 non smokers (P < 0.05), hMLH1 smokers (P < 0.1) and hMSH2 smokers (P < 0.1). Smoking promoted CRC in a dose-dependent manner in hMSH2 in males (P < 0.05). Females with hMSH2 mutations and both sexes with the hMLH1 groups only demonstrated a smoking effect after an extensive smoking history (P < 0.05). CONCLUSION: CRC promotion by smoking in HNPCC patients is dependent on gene mutation, gender and age. These data demonstrate that fuzzy modeling may enable formulation of clinical risk scores, thereby allowing individualization of CRC prevention strategies.

Purpose TGFBR1☆6A is a tumor susceptibility gene that increases breast, colon, and ovarian cancer risk. Fourteen percent of the general population carries TGFBR1☆6A, and TGFBR1☆6A homozygotes have a greater than 100% increased colon cancer risk compared with noncarriers. Low-penetrance genes such as TGFBR1☆6A may account for a sizable proportion of familial colorectal cancer occurrences. To test this hypothesis, we determined whether TGFBR1☆6A contributes to a proportion of mismatch repair (MMR) gene mutation–negative hereditary nonpolyposis colorectal cancer (HNPCC) patients. Patients and Methods A case-case study was performed of 208 index patients with HNPCC meeting the Amsterdam criteria. Patients were examined for mutations and genomic rearrangements in the MLH1, MSH2, and MSH6 genes and genotyped for TGFBR1☆6A. Tumor microsatellite instability status was available for 95 patients. Results A total of 144 patients (69.2%) carried a deleterious mutation and were classified as positive for MMR gene mutation; 64 patients (30.8%) had no evidence of mutations and were classified as MMR negative. TGFBR1☆6A allelic frequency was significantly higher among MMR-negative patients (0.195) than among MMR-positive patients (0.104; P = .011). The proportion of TGFBR1☆6A homozygotes was nine-fold higher among MMR-negative (6.3%) than among MMR-positive patients (0.7%; P = .032). The highest TGFBR1☆6A allelic frequency was found among MMR-negative patients with tumors exhibiting no microsatellite instability (0.211), and the lowest frequency was found among MMR-positive patients with tumors exhibiting microsatellite instability (0.121); the difference was not statistically significant (P = .17). Conclusion TGFBR1☆6A may be causally responsible for a proportion of HNPCC occurrences.

OBJECTIVE: Women with hereditary nonpolyposis colorectal cancer syndrome have a 40 - 60% lifetime risk for colon cancer, a 40 - 60% lifetime risk for endometrial cancer, and a 12% lifetime risk for ovarian cancer. A number ofwomen with hereditary nonpolyposis colorectal cancer syndrome will have more than one cancer in their lifetime. The purpose of this study was to estimate whether women with hereditary nonpolyposis colorectal cancer syndrome who develop 2 primary cancers present with gynecologic or colon cancer as their sentinel cancer. METHODS: Women whose families fulfilled Amsterdam criteria for hereditary nonpolyposis colorectal cancer syndrome and who developed 2 primary colorectal/gynecologic cancers in their lifetime were identified from 5 large hereditary nonpolyposis colorectal cancer syndrome registries. Information on age at cancer diagnoses and which cancer (colon cancer or endometrial cancer/ovarian cancer) developed first was obtained. RESULTS: A total of 117 women with dual primary cancers from 223 Amsterdam families were identified. In 16 women, colon cancer and endometrial cancer/ovarian cancer were diagnosed simultaneously. Of the remaining 101 women, 52 (51%) women had an endometrial or ovarian cancer diagnosed first. Forty-nine (49%) women had a colon cancer diagnosed first. For women who developed endometrial cancer/ovarian cancer first, mean age at diagnosis of endometrial cancer/ovarian cancer was 44. For women who developed colon cancer first, the mean age at diagnosis of colon cancer was 40. CONCLUSION: In this large series of women with hereditary nonpolyposis colorectal cancer syndrome who developed 2 primary colorectal/gynecologic cancers, endometrial cancer/ovarian cancer was the sentinel cancer, preceding the development of colon cancer, in half of the cases. Therefore, gynecologists and gynecologic oncologists play a pivotal role in the identification of women with hereditary nonpolyposis colorectal cancer syndrome.

Background The marked variability in age at onset of colorectal cancer (CRC) in patients with hereditary nonpolyposis colorectal cancer (HNPCC) makes management decisions difficult. Environmental factors governing the phenotypic variability of cancer-associated syndromes such as HNPCC have not been elucidated. Methods We determined whether tobacco use would alter CRC risk in carriers of HNPCC-associated mutations, using a retrospective cohort study of germline mutation ( hMLH1 or hMSH2 ) carriers from the Hereditary Cancer Institute at Creighton University, one of the oldest and largest registries of HNPCC patients. The main outcome measure was age at CRC onset, estimated by means of Cox proportional hazards modeling. Results Tobacco use, hMLH1 mutation carriage (as opposed to hMSH2 ), and male sex were significantly associated with increased risk of CRC (hazard ratios, 1.43, 2.07, and 1.58, respectively). Alcohol use did not alter CRC risk. Conclusions Smoking cessation should be an integral part of HNPCC management. This study underscores the gene × environment interactions in cancer development.

Objective Prophylactic surgical removal of the ovaries has been offered for many years as a potential preventative of ovarian cancer in women deemed to be at increased hereditary risk for this disease. Now, it is possible to test for specific mutations of the BRCA1 and BRCA2 genes that render members of hereditary breast ovarian cancer (HBOC) syndrome families susceptible to cancer. Widespread intra-abdominal carcinomatosis, which mimics metastatic ovarian serous carcinoma, has been reported following oophorectomy in individuals at increased hereditary risk. This study was undertaken to examine and report particularly the occurrence of intra-abdominal carcinomatosis, as well as other cancers, following prophylactic oophorectomy in patients who carry cancer susceptibility mutations of BRCA1 and BRCA2 and to assess the cumulative risks for this disease in order to assist in developing appropriate surgical interventions, based on currently available information, and to counsel patients who choose prophylactic surgery, concerning the potential prognosis, thereafter. Methods The Creighton University Hereditary Cancer Institute registry was searched for members of HBOC syndrome families who had undergone prophylactic oophorectomy. The histories and results of DNA testing for the BRCA1 and BRCA2 mutations carried in their families were recorded, tabulated and examined, and the aggregate data are reported along with pertinent details of those individuals who developed neoplastic diseases after prophylactic oophorectomy. All available histologic and cytologic materials of patients who were diagnosed with intra-abdominal carcinomatosis were reviewed, and life-table calculations were performed to assess cumulative risks for this disease following prophylactic oophorectomy. Results From 72 HBOC syndrome families that carried either BRCA1 or BRCA2 cancer-associated mutations, 238 individuals who had undergone prophylactic oophorectomy were recorded in our registry between January 1985 and December 2002. During a mean follow-up of 9.3 years, cancers were diagnosed in 27 subjects, including 16 individuals with breast cancer and five patients with intra-abdominal carcinomatosis. Breast cancers were stage I in 10 of 12 proven carriers of cancer-associated mutations. All five cases of intra-abdominal carcinomatosis were serous carcinomas, and all occurred in BRCA1 mutation carriers. Histologic review of the prophylactically removed ovaries found borderline lesions in two cases, one with possible early stromal invasion. Two of the five patients who developed intra-abdominal carcinomatosis were among 78 patients in this series who were diagnosed and treated for breast cancer before prophylactic oophorectomy. A 3.5% cumulative risk for all mutation carriers and a 3.9% cumulative risk for BRCA1 mutation carriers were calculated through 20 years of follow-up after prophylactic oophorectomy. Conclusions Intra-abdominal carcinomatosis in our series was diagnosed only in BRCA1 mutation carriers. The calculated cumulative risks of developing intra-abdominal carcinomatosis after prophylactic oophorectomy in members of HBOC syndrome families, specifically those who carry deleterious mutations, are well below the estimated risks of ovarian cancer published in the literature for similar patients. Breast cancers, which tended to be small and localized, were the most common malignancy in BRCA1 and BRCA2 mutation carriers after prophylactic oophorectomy.

Context : In hereditary cancer syndrome families with an identified cancer associated mutation, mutation testing changes the carrier risk status of the tested person and may change the carrier risk status of relatives. Objective : This study aimed to describe the change in the distribution of carrier risk status resulting from testing in hereditary breast-ovarian cancer (HBOC) and hereditary non-polyposis colorectal cancer (HNPCC) families. Design : This was an observational cohort study. Patients : The cohort included members of 75 HBOC and 47 HNPCC families. Of the 10 910 cohort members, 1408 were tested for a mutation and learned their test results. Outcome measure : Carrier risk for all cohort members was assessed before and after mutation testing. Results : There was a change in carrier risk status in 2906 subjects after testing of 1408 family members. The most common type of carrier risk change, from at risk to non-carrier status, accounted for 77% of the risk changes; 12% were a change to known carrier status from a lower risk. Sixty percent of persons with a carrier risk status change were not themselves tested; their risk status changed because of a relative’s test result. Conclusions : Carrier risk status changes from uncertainty to certainty (that is, to carrier or to non-carrier) account for 89% of risk changes resulting from testing. These risk changes affect cancer prevention recommendations, most commonly reducing their burden. Current practices do not ensure that untested family members are informed about changes in their carrier risk status which result from mutation testing of their relatives.

AIM: With successful surgical treatment of gastroesophageal reflux disease (GERD), there is interest in understanding the anti-reflux barrier and its mechanisms of failure. To date, the potential use of vector volumes to predict the DeMeester score has not been adequately explored. METHODS: 627 patients in the referral database received esophageal manometry and ambulatory 24-hour pHmonitoring. Study data included LES resting pressure (LESP), overall LES length (OL) and abdominal length (AL), total vector volume (TVV) and intrabdominal vector volume (IVV). RESULTS: In cases where LESP, TVV or IVV were all below normal, there was an 81.4% probability of a positive DeMeester score. In cases where all three were normal, there was an 86.9% probability that the DeMeester score would be negative. Receiver-operating characteristics (ROC) for LESP, TVV and IVV were nearly identical and indicated no useful cut-off values. Logistic regression demonstrated that LESP and IVV had the strongest association with a positive DeMeester score; however, the regression formula was only 76.1% accurate. CONCLUSION: While the indices based on TVV, IVV and LESP are more sensitive and specific, respectively, than any single measurement, the measurement of vector volumes does not add significantly to the diagnosis of GERD.

The purpose of this study was to measure the length of the esophagus and assess its relationship to sex, weight, age, height, and various esophageal disorders. A retrospective analysis was undertaken of 617 esophageal manometric studies, which included 51 normal control subjects (27 males and 24 females) and 566 patients (297 males and 269 females) with esophageal disorders (50 with achalasia, 6 with diffuse esophageal spasm, 64 with strictures, 38 with nutcracker esophagus, 398 with gastroesophageal reflux disease [GERD] with positive 24-hour pH monitoring, and 66 with possible GERD but negative 24-hour pH monitoring). Manometry was performed in all of them by the station pull-through technique. The length of the esophagus was defined as the distance between the proximal end of the upper esophageal sphincter and the distal end of the lower esophageal sphincter. In the control group the mean (+/- standard deviation) length of the esophagus was 28.3 +/- 2.41 cm. In patients with esophageal disorders the mean length of the esophagus was 28.0 +/- 2.87 cm. Length of the esophagus is related to height but not to weight, sex, age, diffuse esophageal spasm, or nutcracker esophagus. Achalasia is associated with a longer esophagus, and GERD is associated with a shorter esophagus. Stricture is associated with a shorter esophagus, but this is in part due to the association between stricture and GERD. Patients with possible GERD but negative 24-hour pH monitoring have an esophageal length similar to that of GERD patients with positive 24-hour pH monitoring. Patients with GERD and stricture formation showed esophageal shortening in shorter patients. Achalasia, GERD, and GERD with stricture formation influence esophageal length. GERD-related strictures shorten the esophagus more significantly in short patients.

PURPOSE: This study compared characteristics of colorectal cancer between families with dominant breast cancer inheritance and the general population. The cumulative incidence of colorectal cancer was also studied in genetically determined breast cancer syndrome subjects with BRCA1 and BRCA2 mutations and compared with the general population. METHODS: Subjects included 42 patients with colorectal cancer from 32 clinically determined hereditary breast cancer kindreds based on the autosomal dominant inheritance of breast cancers and early age of onset. The general population colorectal cancer cohort was composed of 755 patients from a tumor registry. Lifetime risk of colorectal cancer was determined in 164 BRCA1 and 88 BRCA2 gene mutation carriers and compared with the general population. Mean age of colorectal cancer onset, anatomic site distribution, histologic stage at presentation, and five year stage-stratified survival rates were compared between clinically determined hereditary breast cancer family members and the general population. RESULTS: The lifetime risk of colorectal cancer in male BRCA1 and BRCA2 mutation carriers was 5.6 percent, which was not different from 6 percent in males from the general population. Likewise, the lifetime colorectal cancer risk in female BRCA1 and BRCA2 mutation carriers was 3.2 percent, which was not different from 5.9 percent in females from the general population. Mean age of onset ± standard error for patients with colorectal cancer was 60±2 years for hereditary breast cancer kindreds compared with 67±0.4 years for the general population (P=0.0004). Colorectal cancer site distribution did not vary between hereditary breast cancer and the general population. Overall colorectal cancer stage distribution was significantly different, with more Stage I and fewer Stage IV cancers in subjects with hereditary breast cancer compared with the general population (P=0.01). Overall five year stage-stratified colorectal cancer survival rate ± standard error was 66±8 percent for hereditary breast cancer kindreds and 46±2 percent for the general population (P=0.023). CONCLUSION: Lifetime cumulative colorectal cancer incidence in subjects with BRCA1 and BRCA2 gene mutations was not different from the general population. However, significant differences in colorectal cancer were noted between hereditary breast cancer family members and the general population. Hereditary breast cancer-associated colorectal cancer had an earlier age of onset, lower tumor stage, and better survival rate than the general population. Except for age of onset, colorectal cancer in hereditary breast cancer kindreds exhibited more favorable characteristics than colorectal cancer in the general population.