Multivitamin, calcium and folic acid supplements and the risk of colorectal cancer in Lynch syndrome.

BACKGROUND: People with a DNA mismatch repair (MMR) gene mutation have a substantially elevated risk of colorectal cancer (CRC) but the modifiers of this risk are not well established. We investigated the association between dietary supplement intake and CRC risk for carriers. METHODS: This study included 1966 (56% female) carriers of an MMR gene mutation (719 MLH1, 931 MSH2, 211 MSH6 and 105 PMS2) who were recruited from the USA, Canada, Australia and New Zealand into the Colon Cancer Family Registry between 1997 and 2012. Information on lifestyle factors including supplement intake was collected at the time of recruitment. Using Cox proportional hazards regression weighted to correct for ascertainment bias, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between self-reported multivitamin, calcium and folic acid supplement intake and CRC risk. RESULTS: Of 744 carriers with CRC, 18%, 6% and 5% reported intake of multivitamin, calcium and folic acid supplements for at least 1 month, respectively, compared with 27%, 11% and 10% of 1222 carriers without CRC. After adjusting for identified confounding variables, a decreased CRC risk was associated with multivitam inintake for at least 3 years (HR 0.47, 95% CI 0.32-0.69) and calcium intake for at least 3 years(HR 0.42, 95% CI 0.23-0.74), compared with never users. There was no evidence of an association between folic acid supplement intake and CRC risk (P = 0.82). CONCLUSION: Intake of multivitamin and calcium supplements might be associated with a decreased risk of CRC for MMR gene mutation carriers.

Female Hormonal Factors and the Risk of Endometrial Cancer in Lynch Syndrome.

IMPORTANCE: Apart from hysterectomy, there is no consensus recommendation for reducing endometrial cancer risk for women with a mismatch repair gene mutation (Lynch syndrome). OBJECTIVE: To investigate the association between hormonal factors and endometrial cancer risk in Lynch syndrome. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study included 1128 women with a mismatch repair gene mutation identified from the Colon Cancer Family Registry. Data were analyzed with a weighted cohort approach. Participants were recruited between 1997 and 2012 from centers across the United States, Australia, Canada, and New Zealand. EXPOSURES: Age at menarche, first and last live birth, and menopause; number of live births; hormonal contraceptive use; and postmenopausal hormone use. MAIN OUTCOMES AND MEASURES: Self-reported diagnosis of endometrial cancer. RESULTS: Endometrial cancer was diagnosed in 133 women (incidence rate per 100 person-years, 0.29; 95% CI, 0.24 to 0.34). Endometrial cancer was diagnosed in 11% (n = 70) of women with age at menarche greater than or equal to 13 years compared with 12.6% (n = 57) of women with age at menarche less than 13 years (incidence rate per 100 person-years, 0.27 vs 0.31; rate difference, -0.04 [95% CI, -0.15 to 0.05]; hazard ratio per year, 0.85 [95% CI, 0.73 to 0.99]; P = .04). Endometrial cancer was diagnosed in 10.8% (n = 88) of parous women compared with 14.4% (n = 40) of nulliparous women (incidence rate per 100 person-years, 0.25 vs 0.43; rate difference, -0.18 [95% CI, -0.32 to -0.04]; hazard ratio, 0.21 [95% CI, 0.10 to 0.42]; P < .001). Endometrial cancer was diagnosed in 8.7% (n = 70) of women who used hormonal contraceptives greater than or equal to 1 year compared with 19.2% (n = 57) of women who used contraceptives less than 1 year (incidence rate per 100 person-years, 0.22 vs 0.45; rate difference, -0.23 [95% CI, -0.36 to -0.11]; hazard ratio, 0.39 [95% CI, 0.23 to 0.64]; P < .001). There was no statistically significant association between endometrial cancer and age at first and last live birth, age at menopause, and postmenopausal hormone use. CONCLUSIONS AND RELEVANCE: For women with a mismatch repair gene mutation, some endogenous and exogenous hormonal factors were associated with a lower risk of endometrial cancer. These directions and strengths of associations were similar to those for the general population. If replicated, these findings suggest that women with a mismatch repair gene mutation may be counseled like the general population in regard to hormonal influences on endometrial cancer risk.

Aspirin, Ibuprofen, and the Risk of Colorectal Cancer in Lynch Syndrome.

BACKGROUND: Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 causes a high risk of colorectal and other cancers (Lynch Syndrome). Use of aspirin has been shown to be associated with a reduced risk of colorectal cancer for the general population as well as for MMR gene mutation carriers. The aim of this study was to determine whether use of aspirin and ibuprofen in a nontrial setting is associated with the risk of colorectal cancer risk for MMR gene mutation carriers. METHODS: We included 1858 participants in the Colon Cancer Family Registry who had been found to have a pathogenic germline mutation in a MMR gene (carriers). We used weighted Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: A total of 714 carriers (38%) were diagnosed with colorectal cancer at a mean age of 42.4 (standard deviation 10.6) years. A reduced risk of colorectal cancer was associated with aspirin use (for 1 month to 4.9 years: HR = 0.49, 95% CI = 0.27 to 0.90, P = .02; for ≥5 years: HR = 0.25, 95% CI = 0.10 to 0.62, P = .003) and ibuprofen use (for 1 month to 4.9 years: HR = 0.38, 95% CI = 0.18 to 0.79, P = .009; for ≥5 years: HR = 0.26, 95% CI = 0.10 to 0.69, P = .007), compared with less than one month of use. CONCLUSION: Our results provide additional evidence that, for MMR gene mutation carriers, use of aspirin and ibuprofen might be effective in reducing their high risk of colorectal cancer.

The osteoregenerative effects of platelet-derived growth factor BB cotransplanted with mesenchymal stem cells, loaded on freeze-dried mineral bone block: a pilot study in dog mandible.

Due to shortcomings associated with autogenous bone graft, the gold standard of craniofacial grafting, investigators seek alternatives that are accessible, efficient, and affordable. Accordingly, in the present pilot study, bone regeneration was induced using bone marrow-derived mesenchymal stem cells (BMSCs) loaded onto freeze-dried mineral bone block (FDMBB) in the presence or absence of recombinant platelet-derived growth factor-BB (rh PDGF-BB). Eight weeks after the bilateral extraction of premolars of four mongrel dogs, 25 × 10 mm defects were created at both sides of the mandible. The right mandible received autogenous-BMSC loaded on FDMBB (MSC group), whereas the left mandible received cellular blocks impregnated with rhPDGF-BB (MSC + PDGF Group). Animals were euthanized 8 weeks after grafting. Micro-computed tomography (micro-CT) and histomorphometric analysis demonstrated higher levels of bone formation for the test group (10.34% ± 0.20 and 26.63% ± 3.14, respectively) when compared to the control group (8.20% ± 0.20 and 21.38% ± 5.11). The differences were not statistically significant (P > 0.05). According to the performed micro-CT and histomorphometric analysis, adding 0.5 mg rhPDGF-BB (0.3 mg/mL) to the combination of BMSC/FDMBB did not significantly increase bone formation in supracrestal defect in dog mandible.

Osteoblastic differentiation of human stem cells derived from bone marrow and periodontal ligament under the effect of enamel matrix derivative and transforming growth factor-beta.

PURPOSE: To increase the understanding of the applicability of biomaterials and growth factors in enhancing stem cell-based bone regeneration modalities, this study evaluated the effects of enamel matrix derivative (EMD) and recombinant human transforming growth factor-beta (rhTGF-ß) on osteoblastic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) as well as human periodontal ligament stem cells (hPDLSCs). MATERIALS AND METHODS: hBMSCs and hPDLSCs were obtained, and identification of stem cell surface markers was performed according to the criteria of the International Society for Cellular Therapy. Each group of stem cells was separately treated with a serial dilution of EMD (10, 50, and 100 µg/mL) or rhTGF-ß (10 ng/mL). Osteoblastic differentiation was examined through in vitro matrix mineralization by alizarin red staining, and mRNA expression of osteopontin and osteonectin was determined by quantitative reverse-transcriptase polymerase chain reaction. hPDLSCs were further assessed for osteocalcin mRNA expression. Stem cells cultured in osteogenic medium were employed as a standard positive control group. RESULTS: In none of the experimental groups were bone-related mRNAs detected subsequent to treatment with EMD for 5, 10, and 15 days. Alizarin red staining on day 21 was negative in EMD-treated BMSC and PDLSC cultures. In rhTGF-ß-supplemented BMSC culture, expression of osteonectin mRNA was demonstrated on day 15, which was statistically comparable to the positive control group. Nevertheless, extracellular matrix mineralization was inhibited in both groups of stem cells. CONCLUSIONS: Within the limitations of this study, it could be concluded that EMD with a concentration of 10, 50, or 100 µg/mL has no appreciable effect on osteoblastic differentiation of BMSCs and PDLSCs. Application of rhTGF-ß increased osteonectin mRNA expression in BMSCs. This finding corroborates the hypothesis that TGF-ß might be involved in early osteoblastic maturation.

Healing of extraction sockets and augmented alveolar defects following 1-year treatment with bisphosphonate.

To assess the effect of bisphosphonates on healing of extraction sockets and augmented alveolar defects, 12 adult female mongrel dogs were assigned to 2 experimental groups and a control group. The experimental groups received oral alendronate (ALN, 3.5 mg/kg/wk) or IV pamidronate (PAM, 1 mg/kg/wk) for 12 months. Animals were randomly tested for serum C-terminal telopeptide of collagen I (CTx). The right first and second premolars were extracted. After 8 weeks, extraction sites were evaluated for healing. Subsequently, 3-wall defects were created in ridges and filled with human mineralized cortical particulate bone. Two months post-augmentation, animals were sacrificed and mandibles were collected for cone-beam computed tomography (CBCT) and histomorphometric appraisal. The obtained data were compared using 1-way ANOVA test. CTx test results in both experimental groups were comparable (<10 pg/mL) but lower than that of the control group (minimum 159.2 pg/mL). Two months post-extraction, bone sequestra were noticed in extraction sites in BP-treated groups, involving the entire alveolar bone in the PAM group and the upper rim of the alveoli in the ALN group. Histologically, bone sequestra from the PAM group demonstrated empty osteocyte lacunae, while in the ALN group areas of necrotic bone along with evidence of active bone remodeling was distinguished. Eight weeks post-augmentation, the experimental groups showed no evidence of bone formation in the augmented area, while bone formation ratio was measured to be 18.32% in the control group. The mean amount of pixel intensity calculated from the CBCT images of the ALN, PAM, and control group was 113.69 ± 11.04, 124.94 ± 4.72, and 113.69 ± 6.63, respectively. Pixel intensity in PAM-treated group was significantly higher than both other groups. This study demonstrated that 1-year treatment with ALN/PAM was associated with impairment of post-extraction and post-augmentation bone healing in dogs.

Bone regeneration with a combination of nanocrystalline hydroxyapatite silica gel, platelet-rich growth factor, and mesenchymal stem cells: a histologic study in rabbit calvaria.

OBJECTIVE: This study aimed to assess NanoBone as a carrier construct for mesenchymal stem cells (MSCs) and platelet-rich growth factor (PRGF). STUDY DESIGN: In the calvarial bone of 8 mature New Zealand White male rabbits, four 8-mm defects were created. Each defect received one of the following treatments: Group 1, 0.2 mg Nano-hydroxyapatite (HA) granule + 2 mL culture medium; Group 2, 0.2 mg Nano-HA + 1 mL autologous PRGF + 2 mL acellular culture medium; Group 3, 0.2 mg Nano-HA + 2 mL culture medium containing 100,000 autogenous MSCs; Group 4, 0.2 mg Nano-HA + 2 mL culture medium containing 100,000 autogenous MSCs + 1 mL autologous PRGF. RESULT: Histomorphometric analysis at 6 and 12 weeks demonstrated significantly higher bone formation in group 4 (29.45% and 44.55%, respectively) (P < .05). Bone formation in groups 1, 2, and 3 were as follows: 11.35% and 32.53%, 29.10% and 39.74%, and 25.82% and 39.11%, respectively. CONCLUSIONS: NanoBone with MSCs and PRGF seems to be an effective combination for bone regeneration in a rabbit calvaria model.

Current trends in mesenchymal stem cell application in bone augmentation: a review of the literature.

PURPOSE: The literature regarding mesenchymal stem cell (MSC)-based bone reconstruction techniques are sparse and no comprehensive review of current methods has been performed. The aim of this article was to provide a discussion of clinical and experimental reports of MSC application in the reconstruction of bony defects in live models. MATERIALS AND METHODS: This search was executed using the PubMed database with various combinations of related keywords. Currently published English-language studies that had applied MSCs as a part of their treatment protocol for reconstruction of bony defects in rat, rabbit, dog, and human models were reviewed. The included studies had reported substantiation that the applied cells were of MSC origin as a part of the study design. Publications inclusive to February 1, 2010 were evaluated. Of review of 187 found abstracts and full texts, 25 articles met the inclusion criteria. RESULT: Based on this review, tremendous differences exist among investigators for the application of MSCs in bone augmentation procedures. These differences include not only species uniqueness but also a plethora of other variances, such as stem cell source, defect sites and sizes, carriers and constructs, use of additional growth factors, measured parameters, and methods of data collection. CONCLUSION: Because of the multitude of protocols, range of parameters, and data in the current English-language literature, this review did not reach any significant conclusion as to the "most predictable" model in stem cell reconstruction. However, it does "shed light" on the need for additional collaborated studies using similar homogenous designs and data analysis in advancing the science of bone reconstruction using MSCs.