Waist-to-thigh ratio is a predictor of internal organ cancers in humans: findings from a cohort study

ObjectiveStudies have shown that some specific body measures are associated with the occurrence of cancers. Few studies have demonstrated the relationship with more comprehensive approaches. This study aims to explore body measures and the combinations associated with internal organ cancers.MethodsThree-dimensional anthropometric body surface scanning data collected 10,215 participants from the health examination department in a medical center of Taiwan during 2000–2010. Follow-up was conducted for an average of 8 years, and 244 internal organ cancer cases were identified.ResultsAn increased risk of internal organ cancers was observed among the subjects with larger waist circumference/smaller thigh circumference, in which waist-to-thigh ratio (WTR) was constructed. Comparing the subjects in the fourth quartile for WTR to the subjects in the first quartile with multiple Cox regression analysis yielded a hazard ratio of 1.842 (95% confidence interval, 1.131～2.999). The association between WTR quartile and internal organ cancers was stronger among male participants, older participants, and participants with chronic conditions.ConclusionsThe study has revealed that WTR is the most significant predictor for the occurrence of cancer in Asian populations. Because it is easy to measure and open to modification, WTR may be more useful in clinical and preventive medicine in the future.     

Fibroblast growth factor 23 regulates renal 1,25‐dihydroxyvitamin D and phosphate metabolism via the MAP kinase signaling pathway in Hyp mice

In X‐linked hypophosphatemia (XLH) and in its murine homologue, the Hyp mouse, increased circulating concentrations of fibroblast growth factor 23 (FGF‐23) are critical to the pathogenesis of disordered metabolism of phosphate (P_i) and 1,25‐dihydroxyvitamin D [1,25(OH)₂D]. In this study, we hypothesized that in Hyp mice, FGF‐23‐mediated suppression of renal 1,25(OH)₂D production and P_i reabsorption depends on activation of mitogen‐activated protein kinase (MAPK) signaling. Wild‐type and Hyp mice were administered either vehicle or the MEK inhibitor PD0325901 (12.5 mg/kg) orally daily for 4 days. At baseline, the renal abundance of early growth response 1 (egr1) mRNA was approximately 2‐fold greater in Hyp mice than in wild‐type mice. Treatment with PD0325901 greatly suppressed egr1 mRNA abundance in both wild‐type and Hyp mice. In Hyp mice, PD0325901 induced an 8‐fold increase in renal 1α‐hydroxylase mRNA expression and a 4‐fold increase in serum 1,25(OH)₂D concentrations compared with vehicle‐treated Hyp mice. Serum P_i levels in Hyp mice increased significantly after treatment with PD0325901, and the increase was associated with increased renal Npt2a mRNA abundance and brush‐border membrane Npt2a protein expression. These findings provide evidence that in Hyp mice, MAPK signaling is constitutively activated in the kidney and support the hypothesis that the FGF‐23‐mediated suppression of renal 1,25(OH)₂D production and P_i reabsorption depends on activation of MAPK signaling via MEK/ERK1/2. These findings demonstrate the physiologic importance of MAPK signaling in the actions of FGF‐23 in regulating renal 1,25(OH)₂D and P_i metabolism. © 2011 American Society for Bone and Mineral Research     

Papillary tubal hyperplasia: the putative precursor of ovarian atypical proliferative (borderline) serous tumors, noninvasive implants, and endosalpingiosis

In contrast to the controversy regarding the terminology and behavior of ovarian noninvasive low-grade serous tumors [atypical proliferative serous tumor (APST) and serous borderline tumor], little attention has been directed to their origin. Similarly, until recently, proliferative lesions in the fallopian tube had not been extensively studied. The recent proposal that ovarian high-grade serous carcinomas are derived from intraepithelial carcinoma in the fallopian tube prompted us to evaluate the possible role of fallopian tube in the genesis of low-grade serous tumors. We have identified a lesion, designated "papillary tubal hyperplasia (PTH)," characterized by small rounded clusters of tubal epithelial cells and small papillae, with or without associated psammoma bodies, that are present within the tubal lumen and which are frequently associated with APSTs. Twenty-two cases in this study were selected from a population-based study in Denmark of approximately 1000 patients with low-grade ovarian serous tumors in whom implants were identified on the fallopian tube. Seven additional cases were seen recently in consultation at The Johns Hopkins Hospital (JHH). These 7 cases were not associated with an ovarian tumor. PTH was found in 20 (91%) of the 22 cases in the Danish study. On the basis of this association of PTH with APSTs with implants and the close morphologic resemblance of PTH, not only to primary ovarian APSTs but also to noninvasive epithelial implants and endosalpingiosis, we speculate that the small papillae and clusters of cells from the fallopian tube implant on ovarian and peritoneal surfaces to produce these lesions. The 7 JHH cases of PTH that were not associated with an ovarian tumor support the view that PTH is the likely precursor lesion. We propose a model for the development of ovarian and extraovarian low-grade serous proliferations (APST, noninvasive epithelial implants, and endosalpingiosis) that postulates that all of these lesions are derived from PTH, which appears to be induced by chronic inflammation. If this hypothesis is confirmed, it can be concluded that low-grade and high-grade ovarian tumors develop from tubal epithelium and involve the ovary secondarily.     

The role of reactive oxygen species scavenging enzymes in the development of septic loosening after total hip replacement

In this study of 41 patients, we used proteomic, Western blot and immunohistochemical analyses to show that several reactive oxygen species scavenging enzymes are expressed differentially in patients with primary osteoarthritis and those with non-loosening and aseptic loosening after total hip replacement (THR). The patients were grouped as A (n = 16, primary THR), B (n = 10, fixed THR but requiring revision for polyethylene wear) and C (n = 15, requiring revision due to aseptic loosening) to verify the involvement of the identified targets in aseptic loosening. When compared with Groups A and B, Group C patients exhibited significant up-regulation of transthyretin and superoxide dismutase 3, but down-regulation of glutathione peroxidase 2 in their hip synovial fluids. Also, higher levels of superoxide dismutase 2 and peroxiredoxin 2, but not superoxide dismutase 1, catalase and glutathione perioxidase 1, were consistently detected in the hip capsules of Group C patients. We propose that dysregulated reactive oxygen species-related enzymes may play an important role in the pathogenesis and progression of aseptic loosening after THR.     

Testicular lymphoma with bone/bone marrow metastases illustrated by scrotal sonography, spinal MRI, and total body Tc-99m HMDP and Tc-99m MIBI imagines

An 83-year-old man with testicular lymphoma demonstrated progressive scrotal enlargement with non-homogeneity sonographically and abnormally increased uptake in the scrotum of Tc-99m HMDP and Tc-99m MIBI scintigraphically. Extensive bone/bone marrow metastases were exhibited by Tc-99m MIBI and Tc-99m HMDP scintigraphies and MRI of the spine. In addition, focal/tubular activity of the femoral bone marrow on Tc-99m MIBI imaging was consistent with skeletal scintigraphic findings. It is emphasized that Tc-99m MIBI total body imaging enabled the demonstration of testicular lymphoma as increased uptake and the illustration of skeletal/bone marrow metastases as diffuse and/or focal increased uptake, especially focal/tubular MIBI activity of the femoral marrow.     

Solitary vertebral collapse: distinction between benign and malignant causes using MR patterns.

Differentiation of benign from malignant causes of vertebral compression fracture can be difficult at a single location. We studied 37 patients with solitary vertebral collapse (SVC) in the spine using magnetic resonance imaging (MRI). Sixteen of them were found to have a benign cause of SVC, while the remaining 21 were found to have malignancy. The following four MRI characteristics were investigated: ill- or well-defined margin of the intravertebral lesion (P < 0.005); pedicle involvement (P < 0.05); MR enhancement pattern (P < 0.005); and paravertebral soft tissue lesion (PSL) (P < 0.025). It was found that cases of malignant SVC tended to have an ill-defined margin, abnormal signal involvement of the pedicle, a marked and heterogenous MR enhancement pattern, and irregular nodular-type PSL. Pedicle change with expansile lesion totally excluded a benign cause. By using these criteria, we were able to differentiate benign or malignant causes of SVC accurately.     

The development of high-grade serous carcinoma from atypical proliferative (borderline) serous tumors and low-grade micropapillary serous carcinoma: a morphologic and molecular genetic analysis

Recently, we have proposed a model for the development of ovarian surface epithelial tumors. In this model, all histologic types of surface epithelial tumors are divided into 2 categories designated type I and type II which correspond to 2 pathways of tumorigenesis. Type I tumors include low-grade serous carcinoma, mucinous carcinoma, endometrioid carcinoma, malignant Brenner tumor, and clear cell carcinoma which develop slowly in a stepwise fashion from well-recognized precursors, namely atypical proliferative (borderline) tumors. Type II tumors are high-grade, rapidly growing tumors that typically have spread beyond the ovaries at presentation. They include high-grade serous carcinoma ("moderately" and "poorly" differentiated), malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinoma. These tumors are rarely associated with morphologically recognizable precursor lesions and it has been proposed that they develop "de novo" from ovarian inclusion cysts. This model implies that the pathogenesis of type I and type II tumors are separate and independent but it is not clear whether some type II tumors develop from type I tumors. In this study, we attempted to address this issue by determining the clonality of 6 cases of high-grade serous carcinomas that were closely associated with atypical proliferative serous (borderline) tumors and invasive low-grade micropapillary serous carcinomas. We reviewed 210 ovarian serous tumors from the surgical pathology files of the Johns Hopkins Hospital and identified 3 high-grade serous carcinoma that were directly associated with atypical proliferative serous (borderline) tumors and 3 that were associated with invasive low-grade micropapillary serous carcinomas. A morphologic continuum between the high-grade carcinoma and the low-grade tumors was observed in 4 cases whereas in the remaining 2 cases the high-grade and low-grade components were separate. Mutational analyses for KRAS, BRAF, and p53 genes were performed on microdissected samples from the high-grade and low-grade tumor areas for each case. All 6 tumors demonstrated wild-type BRAF and p53 genes. Only 2 of the 6 cases were informative from a molecular genetic standpoint. In those 2 cases we found the same mutations of KRAS in both the atypical proliferative serous (borderline) tumor and the high-grade serous carcinoma component of the tumor, indicating a clonal relationship. The above results suggest that the majority of high-grade and low-grade carcinomas develop independently but in rare cases, a high-grade serous carcinoma may arise from an atypical proliferative serous (borderline) tumor.     

Anti-inflammation effects of naloxone involve phosphoinositide 3-kinase delta and gamma

Background

Phosphoinositide 3-kinase (PI3K) delta and gamma (the p110δ and p110γ isoforms of PI3K) actively participate in the process of inflammation. We sought to elucidate the possible roles of PI3Kδ and PI3Kγ in mediating the anti-inflammation effects of naloxone.

Materials and methods

Murine macrophages were treated with endotoxin, endotoxin plus naloxone, or endotoxin plus naloxone plus the PI3K inhibitors (the PI3Kδ inhibitor IC87114, the PI3Kγ inhibitor AS252424, or IC87114 plus AS252424) and denoted as the LPS, LPS + N, LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS group, respectively. Differences in inflammatory molecules and levels of nuclear factor-κB (NF-κB) activation and Akt activation (indicator of PI3K activity) among these groups were compared.

Results

The concentrations of inflammatory molecules (macrophage inflammatory protein 2, tumor necrosis factor-α, interleukin-1β, and cyclooxygenase-2/prostaglandin E₂) and the levels of NF-κB activation (p-NF-κB p65 and p-inhibitor-κB concentrations and NF-κB-DNA binding activity) of the LPS + N group were significantly lower than those of the LPS group (all P < 0.001). These data confirmed the anti-inflammation effects of naloxone. Moreover, the anti-inflammation effects of naloxone could be counteracted by the inhibitors of PI3Kδ and PI3Kγ, as the concentrations of inflammatory molecules and the levels of NF-κB activation of the LPS + N group were significantly lower than those of the LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS groups (all P < 0.05). In contrast, the concentration of phosphorylated Akt of the LPS + N group was significantly higher than those of the LPS, LPS + N + IC, LPS + N + AS, and LPS + N + IC + AS groups (all P < 0.05).

Conclusions

PI3Kδ and PI3Kγ play crucial roles in mediating the anti-inflammation effects of naloxone.