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Fracture liaison services often perform laboratory testing, but these results may be altered by surgery. In 40 hip arthroplasty patients, many laboratory parameters of bone health relevance were reduced by 8-22% on the first post-operative day. Laboratory results obtained in the immediate post-surgery interval do not reliably ascertain baseline status.As secondary causes of osteoporosis are common, fracture liaison services often perform laboratory testing in the immediate post-fracture interval. We hypothesized that laboratory results obtained shortly after surgery may not accurately ascertain baseline status. If true, such alterations might confound subsequent fracture prevention efforts.Patients undergoing elective total hip arthroplasty were studied as a surrogate for hip fracture patients. Blood and urine were obtained 2 weeks before surgery, before anesthetic induction, on post-operative day one, and 6 weeks after surgery. Serum total and free 25-hydroxyvitamin D (25(OH)D), vitamin D-binding protein (DBP), calcium, creatinine, albumin (Alb), alkaline phosphatase (ALP), plasma hemoglobin (Hgb) and urinary DBP/creatinine ratio (UDBP/Cr) were measured.Forty volunteers (28 women; 12 men) with mean age of 65.7 [8.7] years were studied. Laboratory results were stable from 2 weeks before to the day of surgery. On the first day after surgery, total 25(OH)D, DBP, calcium, creatinine, ALP, and Alb declined 8-22% (p 0.0001); free 25(OH)D and Hgb declined by 8 and 15% (p 0.01), respectively; and UDBP/Cr increased 32% (p 0.01). Using a 25(OH)D30 ng/mL threshold, vitamin D inadequacy prevalence increased from 38% before surgery to 68% the day after (p 0.001). All laboratory values returned to baseline at 6 weeks after surgery.Laboratory values are reduced immediately following elective total hip arthroplasty. Testing at that time does not accurately ascertain baseline status and may lead to elevated estimates of vitamin D inadequacy, incorrect interventions, and misallocation of healthcare resources.

Increased activation of epidermal growth factor receptor (EGFR) family members such as HER2/Erbb2 can result in more aggressive disease, resistance to chemotherapy and reduced survival of head and neck squamous cell carcinoma (HNSCC) patients. In order to identify mechanisms through which these receptor tyrosine kinases accelerate tumor progression, the regulation of metalloprotease expression by EGFR family members was investigated in 11 squamous cell carcinoma (SCC) cell lines. HER2 expression was significantly correlated with ADAM12 (A Disintegrin And Metalloprotease 12) expression in these cell lines and was co-expressed in human head and neck cancers. Inhibition of HER2 or EGFR decreased ADAM12 transcripts whereas HER2 transfection upregulated ADAM12 expression. To understand the molecular mechanisms underlying HER2 regulation of ADAM12, we investigated the signaling pathways directing ADAM12 production in SCC cells. Inhibition of phosphatidyl inositol-3-kinase or mammalian target of rapamycin decreased ADAM12 transcripts in HER2-expressing SCC cells, whereas transfection with AKT increased ADAM12 mRNA. Experiments utilizing ADAM12 transfection or siRNA targeting of ADAM12 revealed that the protease increased both the migration and invasiveness of oral SCC cells. Surprisingly, ADAM12 also increased HER2 message, protein levels and activity through an Ets1-dependent mechanism. Collectively, these results reveal a novel positive activation loop between ADAM12 and HER2 that may contribute to HNSCC progression.

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.

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.

BRCA-1 mutations predispose women to early onset breast cancer, but approximately 20% never develop cancer. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) profiling can differentiate protein signatures of cancer and normal subjects. Our objective was to distinguish women with BRCA-1 mutations who developed breast cancer (BRCA-1 Ca) from those who did not (Carrier), normal volunteers (NL), and women with sporadic breast cancer (SBC), using SELDI-TOF.Baseline serum specimens were obtained from women with BRCA-1 mutations without cancer, SBC, and NL. BRCA-1 women were later divided into two cohorts, pending cancer development. The sera were spotted onto protein chips for SELDI-TOF analysis and analyzed with classification algorithm software.BRCA-1 Ca patients (n = 15) developed cancer within 3 years of baseline, while BRCA-1 carriers (n = 15) were cancer-free in 7 years of follow-up. SELDI-TOF analysis revealed differentially expressed proteins (P.05) between BRCA-1 Ca, Carrier, and SBC patients (n = 16), such that 13/15 BRCA-1 Ca vs. Carrier women were correctly identified (sensitivity/specificity of 87%/87%) and 14/15 BRCA-1 Ca vs. SBC patients were correctly identified (sensitivity/specificity 94%/100%). Profiles of Carriers resembled NL profiles (n = 16).SELDI-TOF protein profiles from this small pilot study distinguished between women with BRCA-1 Ca, Carriers, and women with SBC. Whether BRCA-1 Ca represents earlier detection of occult cancer or other risk factors is unknown. Follow-up studies with larger numbers and longer follow-up are required to validate these findings but may allow more timely prophylactic or therapeutic strategies.

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.

A male member of a large HNPCC kindred, affected by primary malignancies of the breast and colon, was identified. This individual was found to harbor a germline mutation of the MLH1 mismatch repair gene previously shown to segregate with disease in this kindred. The breast tumor exhibited somatic reduction to homozygosity for the MLH1 mutation, and microsatellite instability was evident in the breast tumor. We conclude that hereditary male breast cancer can occur as an integral tumor in the HNPCC syndrome.

The FAMMM syndrome consists of the familial occurrence of cutaneous malignant melanoma and atypical nevi (dysplastic nevi), and is inherited as an autosomal dominant trait. Conflicting results have been reported on the question of whether the syndrome includes increased susceptibility to non-melanoma cancers. We have studied cancer of all anatomic sites and histologies in nine FAMMM families which were ascertained in a pigmented lesions clinic in the Netherlands. We evaluated two hypotheses: that the number of systemic cancers observed in the families was excessive, compared to expected incidence, based on Dutch incidence data, and that there was variation (or heterogeneity) among families in the frequency of systemic cancer. A significant excess of systemic cancer (especially digestive tract cancer) was observed. Significant heterogeneity was also found among the families; three of the nine families had marked excess in numbers of systemic cancers, and the remaining families had normal numbers of cancers among the known FAMMM gene carriers and their first degree relatives. Thus, we provide evidence of increased susceptibility to systemic cancer occurring in conjunction with the FAMMM syndrome in a subset of this resource.

This study is the first to examine the genetic risk in a breast cancer-prone family wherein two of three triplet sisters and their mother manifested breast cancer. The unaffected triplet, the proband, was found to be monozygotic with her deceased sister through DNA testing of tumor blocks and dizygotic to her living affected sister. Genetic counseling implications are discussed.

A device is described which automatically measures barpresses reinforced by short opportunities to attack male mice. Data on barpress rates indicate rapid and reliable acquisition of preferences for reinforcer bars and rapid abolition of this preference when the reinforcement contingency is subsequently eliminated. The data are less reliable for reversal learning.

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.