Association between teriparatide treatment persistence and adherence, and fracture incidence in Taiwan: analysis using the National Health Insurance Research Database.

UNLABELLED: Medication persistence and adherence are critical for osteoporosis outcomes. Using the Taiwan National Health Insurance Research Database, we found that persistence and adherence to teriparatide were low in Taiwanese patients with osteoporosis and that greater persistence and adherence were associated with a lower incidence of hip and other nonvertebral fractures. INTRODUCTION: The purpose of this study was to determine the persistence and adherence to teriparatide treatment in Taiwanese patients with osteoporosis, and to examine the association between persistence and adherence to teriparatide with fracture risks. METHODS: Medical and pharmacy claims for 4,692 patients with vertebral or hip fractures and teriparatide prescriptions between 2005 and 2008 were identified (Taiwan National Health Insurance Research Database). Persistence was the time from the start of treatment to the first 90-day gap between two teriparatide prescriptions. Adherence was the number of teriparatide pens (each pen is used over 1 month) prescribed over 24 months. Association of persistence and adherence to teriparatide with fracture incidence was assessed using adjusted Cox proportional hazards models. RESULTS: The proportion of patients persisting with teriparatide for >6 months and >12 months was 44.6 and 24.9 %, respectively. Over 24 months, 53.6 % of patients were adherent for >6 months and 33.9 % were adherent for >12 months. Patients persisting for >12 months had a significantly lower incidence of hip (adjusted hazard ratio [HR], 0.61 [95 % confidence interval (CI), 0.40-0.93], P = 0.0229) and nonvertebral fracture (HR, 0.79 [95 % CI, 0.63-0.99], P = 0.0462) compared with those who persisted for ≤12 months. Patients adherent for >12 months had a lower incidence of hip (HR, 0.66 [95 % CI, 0.46-0.96], P = 0.0286) and nonvertebral fracture (HR, 0.81 [95 % CI, 0.66-0.99], P = 0.0377) compared with those adherent for ≤12 months. CONCLUSIONS: Persistence and adherence to teriparatide over 24 months were low in Taiwanese patients with osteoporosis; greater adherence and persistence were associated with a lower incidence of nonvertebral fractures.

Prognostic value of the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification in stage IB lung adenocarcinoma.

BACKGROUND: Patients with pathological stage IB lung adenocarcinoma have a variable prognosis, even if received the same treatment. This study investigated the prognostic value of the new International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) lung adenocarcinoma classification in resected stage IB lung adenocarcinoma. METHODS: We identified 276 patients with pathological stage IB adenocarcinoma who had undergone surgical resection at the Nanjing Chest Hospital between 2005 and 2010. The histological subtypes of all patients were classified according to the 2011 IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification. Kaplan-Meier and Cox regression analyses were used to analyze the correlation between the IASLC/ATS/ERS classification and patients' prognosis. RESULTS: Two hundred and seventy-six patients with pathological stage IB adenocarcinoma had an 86.2% 5-year overall survival (OS) and 80.4% 5-year disease-free survival (DFS). Patients with micropapillary and solid predominant tumors had a significantly worse OS and DFS as compared to those with other subtypes predominant tumors (p = 0.003 and 0.001). Multivariate analysis revealed that the new classification was an independent prognostic factor for both OS and DFS of pathological stage IB adenocarcinoma (p = 0.009 and 0.003). CONCLUSION: Our study revealed that the new IASLC/ATS/ERS classification was an independent prognostic factor of pathological stage IB adenocarcinoma. This new classification is valuable of screening out high risk patients to receive postoperative adjuvant therapy.

Simultaneous osteonecrosis and osteomyelitis in a patient with cancer of the breast.

Breast cancer is generally managed surgically with adjuvant agents which include hormone therapy, chemotherapy, radiotherapy and bisphosphonate therapy. However, some of these adjuvant therapies may cause adverse events, including wound infection, neutropenia, bone marrow suppression and fever. The simultaneous presentation of osteonecrosis and osteomyelitis has not previously been described in patients with breast cancer undergoing hormone therapy and chemotherapy. We report a patient with breast cancer who developed bone infarcts in both legs as well as osteomyelitis in the right distal tibia after treatment which included a modified radical mastectomy, hormone therapy and chemotherapy. Simultaneous osteonecrosis and osteomyelitis should be considered in patients with breast cancer who are receiving chemotherapy and hormone therapy who present with severe bone pain, especially if there have been infective episodes during treatment.

Water solution of onion crude powder inhibits RANKL-induced osteoclastogenesis through ERK, p38 and NF-kappaB pathways.

UNLABELLED: Onion powder has been reported to decrease the ovariectomy-induced bone resorption of rats. However, the molecular mechanism of onion powder on the bone cells has not been reported. Here, we report that water solution of onion crude powder decreases the osteoclastogenesis from co-cultures of bone marrow stromal cells and macrophage cells. Additionally, water solution of onion crude powder inhibits the RANKL-induced ERK, p38 and NF-kappaB activation in macrophages. In summary, our data showed that onion powder may benefit bone through an anti-resorption effect on the osteoclasts. INTRODUCTION: A nutritional approach is important for both prevention and treatment of osteoporosis. Onion has been reported to decrease the ovariectomy-induced bone resorption. However, the functional effects of onion on the cultured osteoclasts and osteoblasts remain largely unknown. Here, we found that water solution of onion crude powder markedly inhibited the receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis through ERK, p38 and NF-kappaB pathways. Other studies were also designed to investigate the potential signaling pathways involved in onion-induced decrease in osteoclastogenesis. METHODS: The osteoclastogenesis was examined using the TRAP staining method. The MAPKs and NF-kappaB pathways were measured using Western blot analysis. A transfection protocol was used to examine NF-kappaB activity. RESULTS: Water solution of onion crude powder inhibited the RANKL plus M-CSF-induced osteoclastic differentiation from either bone marrow stromal cells or from RAW264.7 macrophage cells. Treatment of RAW264.7 macrophages with RANKL could induce the activation of ERK, p38 and NF-kappaB that was inhibited by water solution of onion crude powder. On the other hand, it did not affect the cell proliferation and differentiation of human cultured osteoblasts. CONCLUSIONS: Our data suggest that water solution of onion crude powder inhibits osteoclastogenesis from co-cultures of bone marrow stromal cells and macrophage cells via attenuation of RANKL-induced ERK, p38 and NF-kappaB activation.

Hospital-based allogenic bone bank--10-year experience.

Bone banking in a hospital provides resources of allogenic bone grafts. However, they may transmit infection from donor to recipient. We found few reports discussing the infection rate and monitoring processes associated with bone banks. The discard rate using the screening test was 18.5% (309/1674) in this series. The leading cause was hepatitis B antigen (HBsAg) positive donor serum (67%), followed by Venereal Disease Research Laboratory (VDRL) positive donor serum (15%), and anti-hepatitis C virus (HCV) positive donor serum (12%). The overall infection rate in the recipients was 1.3% (17/1365). Among 1353 implanted allografts, 22 cases (1.6%) had a positive swab culture result after thawing. Only four out of these 22 cases (18.2%) developed infection. However, the wound cultures of the infected recipients were different from the swab culture of thawing allografts except in one case. Among the 1331 recipients with sterile allograft bones, 13 (1%) were found to have infection. In conclusion, our bone bank operates under a strict monitoring system which results in a low infection rate. The recipient's status, the aseptic technique and environment during operation is likely to be more critical in prevention of allograft-related infection.

Arsenic and benzo[a]pyrene differentially alter the capacity for differentiation and growth properties of primary human epidermal keratinocytes.

Normal human epidermal keratinocytes (NHEK) have been chosen as an in vitro model to test the hypothesis that chemicals which alter or interfere in cellular differentiation will concomitantly induce growth perturbations and are, thus, potential carcinogens. In these studies, we have focused on two known skin carcinogens, arsenic and benzo(a)pyrene (BaP). Our results demonstrated that BaP inhibits terminal differentiation in NHEK, as measured by cross-linked envelope (CLE) formation, up to 5.8-fold in control and 1.7-fold in calcium (Ca2+)-treated cells. In comparison, arsenic decreased CLE formation 20-fold in control cells and 5.5-fold in Ca2+-treated NHEK. To characterize the effects of these agents on the growth rate and cell cycle distributions of NHEK, flow cytometric analysis was used. BaP at 2 microM increased proliferation rates by 29%. Altered cell-cycle distribution in BaP-treated cells indicated a more rapid progression through the cell cycle, possibly by a shortened G2 phase. In contrast, arsenic at 5 microM inhibited proliferation by 25%; growth arrest (9%) was also observed in NHEK treated with 2 mM Ca2+. Our findings suggest that, although both BaP and arsenic inhibit CLE production in NHEK, different mechanisms may be involved. Studies in progress will attempt to identify molecular markers involved in the observed chemical effects. These markers will facilitate a mechanistic understanding of how an altered balance between growth and differentiation may play a role in the transformation process in NHEK.

A biologically based model of growth and senescence of Syrian hamster embryo (SHE) cells after exposure to arsenic.

We modified the two-stage Moolgavkar-Venzon-Knudson (MVK) model for use with Syrian hamster embryo (SHE) cell neoplastic progression. Five phenotypic stages are proposed in this model: Normal cells can either become senescent or mutate into immortal cells followed by anchorage-independent growth and tumorigenic stages. The growth of normal SHE cells was controlled by their division, death, and senescence rates, and all senescent cells were converted from normal cells. In this report, we tested the modeling of cell kinetics of the first two phenotypic stages against experimental data evaluating the effects of arsenic on SHE cells. We assessed cell division and death rates using flow cytometry and correlated cell division rates to the degree of confluence of cell cultures. The mean cell death rate was approximately equal to 1% of the average division rate. Arsenic did not induce immortalization or further mutations of SHE cells at concentrations of 2 microM and below, and chromium (3.6 microM) and lead (100 microM) had similar negative results. However, the growth of SHE cells was inhibited by 5.4 microM arsenic after a 2-day exposure, with cells becoming senescent after only 16 population doublings. In contrast, normal cells and cells exposed to lower arsenic concentrations grew normally for at least 30 population doublings. The biologically based model successfully predicted the growth of normal and arsenic-treated cells, as well as the senescence rates. Mechanisms responsible for inducing cellular senescence in SHE cells exposed to arsenic may help explain the apparent inability of arsenic to induce neoplasia in experimental animals.

Toxicological interactions among arsenic, cadmium, chromium, and lead in human keratinocytes.

To evaluate health effects of chemical mixtures, such as multiple heavy metals in drinking water, we have been developing efficient and accurate hazard identification strategies. Thus, in this study, we determine the cytotoxicity of arsenic, cadmium, chromium, and lead, and characterize interactions among these metals in human epidermal keratinocytes. Three immortal keratinocyte cell lines (RHEK-1, HaCaT, and NM1) and primary keratinocytes (NHEK) were used. A statistical approach applying an additivity response surface methodology was used to test the validity of the additivity concept for a 4-metal mixture. Responses of the 4 keratinocyte strains to the metal mixture were highly dose-dependent. A growth stimulatory effect (hormesis) was observed in RHEK-1, NM1, and NHEK cells with the metal mixture at low concentrations (low ppb range). This hormesis effect was not significant in HaCaT. As the mixture concentration increased, a trend of additivity changed to synergistic cytotoxicity in all 4 cell strains. However, in NHEK, RHEK-1, and HaCaT, at the highest mixture concentrations tested, the responses to the metal mixtures were antagonistic. In NM1, no significant antagonistic interaction among the metals was observed. To explore a mechanistic basis for these differential sensitivities, levels of glutathione and metallothioneins I and II were determined in the keratinocyte cell strains. Initial data are consistent with the suggestion that synergistic cytotoxicity turned to antagonistic effects because at highest mixture exposure concentrations cellular defense mechanisms were enhanced.

Assessing interaction thresholds for trichloroethylene in combination with tetrachloroethylene and 1,1,1-trichloroethane using gas uptake studies and PBPK modeling.

The volatile organic solvents trichloroethylene (TCE), tetrachloroethylene (perchloroethylene, PERC), and 1,1,1-trichloroethane (methylchloroform, MC) are widely distributed environmental pollutants and common contaminants of many chemical waste sites. To investigate the mode of pharmacokinetic interactions among TCE, PERC, and MC and to calculate defined "interaction thresholds", gas-uptake experiments were performed using a closed-chamber exposure system. In each experiment, two rats (Fischer 344, male, 8-9 weeks old) were exposed to different initial concentrations of TCE, PERC, and MC, applied singly or as a mixture, and their concentration in the gas phase of the chamber was monitored over a period of 6 h. A physiologically based pharmacokinetic (PBPK) model was developed to test multiple mechanisms of inhibitory interactions, i.e., competitive, non-competitive, or uncompetitive. All mixture exposure data were accurately described by a system of equations in which a PBPK model was provided for each chemical and each was regarded as an inhibitor of the others' metabolism. Sensitivity-analysis techniques were used to investigate the impact of key parameters on model output and optimize experimental design. Model simulations indicated that, among these three chemicals, the inhibition was competitive. The PBPK model was extended to assess occupationally relevant exposures at or below the current threshold-limit values (TLVs). Based on 10% elevation in TCE blood levels as a criterion for significant interaction and assuming TCE exposure is set at TLV of 50 ppm, the calculated interaction thresholds for PERC and MC were 25 and 135 ppm, respectively. TLV exposures to binary TCE/PERC mixture were below the 10% significance level. The interaction threshold for TCE and MC co-exposure would be reached at 50 and 175 ppm, respectively. Such interactive PBPK models should be of value in risk assessment of occupational and environmental exposure to solvent mixtures.

Contact stress on polyethylene components of a new rotating hinge with a spherical contact surface.

OBJECTIVE: To assess the nonlinear contact stress of a new rotating hinge of our knee prosthesis at various rotation angles. DESIGN: The contact surface between the metal tibial bearing and the ultra-high-molecular weight polyethylene plate of a conventional rotating hinge is of cylindrical design. We have designed a new type of rotating hinge with a congruous spherical contact surface. BACKGROUND: The endoprosthesis for reconstruction of limb after wide resection of malignant tumor around knee usually incorporates a rotating hinge. Our new rotating hinge with a spherical contact surface incorporates the benefits of an increased contact surface and potentially increased rotational stability during axial loading. METHODS: We utilized the ABAQUS finite element program to assess the nonlinear contact stress of this new rotating hinge at rotation angles of 0 degrees, 4 degrees and 8 degrees, based on a contact force of about 2800 N. RESULTS: The results show that von Mises stress for the finite element model of the polyethylene component of this rotating hinge ranges from 4.90 x 10(-6) to 8.22 MPa at the aforementioned rotational angles. The von Mises stress is about 1.31--1.82 MPa on the major parts of the ultra-high-molecular weight polyethylene plate, including both flanks. There is a mild stress concentration on the outer edge of polyethylene component, especially at 4 degrees and 8 degrees of rotation. The maximum values of von Mises stress at the contact surface at 0 degrees, 4 degrees and 8 degrees of rotation are 5.92, 7.49 and 8.22 MPa, respectively. These contact stresses are within the safety range of the ultra-high-molecular weight polyethylene (compressive yield strength, 14 MPa). CONCLUSIONS: This new rotating hinge has an evenly distributed contact stress during axial load because of congruous contact design.

Pharmacokinetics, metabolism, and carcinogenicity of arsenic.

The carcinogenicity of arsenic in humans has been unambiguously demonstrated in a variety of epidemiological studies encompassing geographically diverse study populations and multiple exposure scenarios. Despite the abundance of human data, our knowledge of the mechanism(s) responsible for the carcinogenic effects of arsenic remains incomplete. A deeper understanding of these mechanisms is highly dependent on the development of appropriate experimental models, both in vitro and in vivo, for future mechanistic investigations. Suitable in vitro models would facilitate further investigation of the critical chemical species (arsenate/arsenite/MMA/DMA) involved in the carcinogenic process, as well as the evaluation of the generation and role of ROS. Mechanisms underlying the clastogenic effects of arsenic, its role in modulating DNA methylation, and the phenomenon of inducible tolerance could all be more completely investigated using in vitro models. The mechanisms involved in arsenic's inhibition of ubiquitin-mediated proteolysis demand further attention, particularly with respect to its effects on cell proliferation and DNA repair. Exploration of the mechanisms responsible for the protective or anticarcinogenic effects of arsenic could also enhance our understanding of the cellular and molecular interactions that influence its carcinogenicity. In addition, appropriate in vivo models must be developed that consider the action of arsenic as a promoter and/or progressor. In vivo models that allow further investigation of the comutagenic effects of arsenic are also especially necessary. Such models may employ initiation-promotion-progression bioassays or transgenic animals. Both in vitro and in vivo models have the potential to greatly enhance our current understanding of the cellular and molecular interactions of arsenic and its metabolites in target tissues. However, refinement of our knowledge of the mechanistic aspects of arsenic carcinogenicity is not alone sufficient; an understanding of the pharmacokinetics and target tissue doses of the critical chemical species is essential. Additionally, a more thorough characterization of species differences in the tissue kinetics of arsenic and its methylated metabolites would facilitate the development of more accurate and relevant PBPK models. Improved models could be used to further investigate the existence of a methylation threshold for arsenic and its relevance to arsenic carcinogenicity in humans. The significance of alterations in relative tissue concentrations of SAM and SAH deserves further attention, particularly with respect to their role in modulating methyltransferases involved in arsenic metabolism and DNA methylation. The importance of genetic polymorphisms and nutrition in influencing methyltransferase activities must not be overlooked. In vivo models are necessary to evaluate these factors; transgenic or knockout models would be particularly useful in the investigation of methylation polymorphisms. Further evaluation of methylation polymorphisms in human populations is also warranted. Other in vivo models incorporating dietary manipulation could provide valuable insight into the role of nutrition in the carcinogenicity of arsenic. With more complete knowledge of the pharmacokinetics of arsenic metabolism and the mechanisms associated with its carcinogenic effects, development of more reliable risk assessment strategies are possible. Integration of data, both pharmacokinetic and mechanistic in nature, will lead to more accurate descriptions of the interactions that occur between the active chemical species and cellular constituents which lead to the development of cancer. This knowledge, in turn, will facilitate the development of more accurate and reliable risk assessment strategies for arsenic.

Rhodostomin, a snake venom disintegrin, inhibits angiogenesis elicited by basic fibroblast growth factor and suppresses tumor growth by a selective alpha(v)beta(3) blockade of endothelial cells.

Angiogenesis consists of the proliferation, migration, and differentiation of endothelial cells, although angiogenic factor and integrin-extracellular matrix interaction modulate this process. We report here that a snake venom-derived disintegrin, rhodostomin, inhibited distinct steps in angiogenesis elicited by basic fibroblast growth factor (bFGF), and also suppressed in vivo murine melanoma tumor growth. Rhodostomin dose-dependently inhibited bFGF-induced human umbilical vein endothelial cell (HUVEC) proliferation as examined by cell number count, metabolic activity, and BrdU incorporation assays with submicromolar IC(50) values. However, it apparently did not affect the viability of murine B16F10 melanoma cells, even up to 50 microM. Rhodostomin also inhibited HUVEC migration and invasion evoked by bFGF, and tube formation of bFGF-treated HUVECs in Matrigel. Moreover, rhodostomin selectively inhibited bFGF-, but not vascular endothelial growth factor-associated angiogenesis in the chick chorioallantoic membrane model. Furthermore, rhodostomin blocked both bFGF- and B16F10-induced neovascularization in murine Matrigel plug model and suppressed the growth of subcutaneously inoculated B16F10 solid tumor, leading to a prolonged survival of the rhodostomin-treated C57BL/6 mice. The antiangiogenic effect of rhodostomin on bFGF-treated HUVECs is related to the integrin alpha(v)beta(3) blockade, as evidenced by its selective inhibition on the binding of 7E3, a monoclonal antibody (mAb) raised against alpha(v)beta(3,) but not that of P1F6, an alpha(v)beta(5) mAb toward both naive and bFGF-primed HUVECs. Moreover, 7E3 specifically blocked fluorescein isothiocyanate-conjugated rhodostomin binding to HUVEC, whereas P1F6 and anti-integrin alpha(2), alpha(3), alpha(4), or alpha(5) mAbs did not.

A clonal growth model: time-course simulations of liver foci growth following penta- or hexachlorobenzene treatment in a medium-term bioassay.

A combination of experimental and simulation approaches were used to analyze the clonal growth of preneoplastic, enzyme-altered foci during liver carcinogenesis in an initiation-promotion regimen. Male Fisher 344 rats, 8 weeks of age, were initiated with a single dose (200 mg/kg, i.p.) of diethylnitrosamine (DEN). Beginning 2 weeks later, animals were exposed to daily gavage consisting of 0.1 mmol/kg pentachlorobenzene (PECB) or hexachlorobenzene (HCB) in corn oil vehicle for 6 weeks. Partial hepatectomy was performed 3 weeks after initiation. Experimental data including liver weight, hepatocyte density (number of hepatocytes/unit volume), 5-bromo-2'-deoxyuridine-labeling index for analysis of cell division rate, and number and volume of glutathione-S-transferase pi-positive foci were collected 23, 26, 28, 47, or 56 days after initiation. Model parameters describing liver growth were obtained directly from the experimental data. The probability of mutation/division of normal cells and the growth rate of initiated cells were inferred by a comparison of model outcomes with the observed time courses of foci development. To describe the time-dependent increases in foci volume and the concomitant reduction of foci number observed in all treatment groups, the calibrated model for the DEN controls incorporated the hypothesis of two initiated cell populations (referred to as A and B cells) within the framework of the two-stage model. The B cells are initiated cells that have a selective growth advantage under conditions that inhibit the growth of A cells and normal hepatocytes. The parameter values defined in the DEN controls were used to evaluate experiments involving the administration of PECB or HCB. Both PECB and HCB caused a significant increase in foci volume compared with the DEN controls. HCB treatments resulted in increased proliferation of normal hepatocytes, which was not observed for PECB under the same treatment regimen. The best description of the data resulted from the model incorporating the hypothesis that PECB and HCB promoted the growth of foci via increased net growth rates of B cells. We present here a biologically based clonal growth simulation platform to describe the growth of preneoplastic foci under experimental manipulations of initiation-promotion studies. This simulation work is an example of quantitative approaches that could be useful for the analysis of other initiation-promotion studies.

Theoretical study of convergent ultrasound hyperthermia for treating bone tumors.

This study investigates the optimal external parameters for using an ultrasound applicator for treating bone tumors. This system utilized spherically arranged applicators such as scanned focused ultrasound, and spherically focused multielement applicators. The power deposition pattern is modeled as geometric gain with exponential attenuation. The specific absorption rate ratio (SARR) criteria have been used to determine the proper heating domain of ultrasound driving frequency and therapeutic tumor diameter. The results demonstrate that the optimal driving frequency depends on tumor depth, ultrasound absorption of bone marrow, and diameter of bone, but it is independent of the acoustic window area and SARR. The treatable diameter of bone tumor increased when the absorption ratio of bone marrow to tumor, acoustic window of surface skin, and diameter of bone were elevated. However, the treatable diameter of bone tumor decreased when muscle thickness, SARR of bone tumor site to the surface skin, bone marrow, and bone declined. To deliver the ultrasound energy into the tumor site and to avoid the potential damage to the normal tissue as much as possible, the specific absorption rate (SAR) in the bone tumor site has to be three times higher than that in the surface skin, tumor/marrow, and marrow/bone interfaces. The temperature distributions can verify the SARR criteria in this model. This study provides the information for choosing the optimal operating frequency of the ultrasound transducer and the acoustic window on the skin surface, and for designing the ultrasound applicator for clinical implementation.

Rhodostomin inhibits the transforming growth factor-beta1-enhanced adhesion activity of ROS 17/2.8 osteosarcoma cells.

We have investigated the effect of transforming growth factor-beta1 (TGF-beta1) on the in vitro adhesion activity of the rat osteosarcoma cell lines (ROS 17/2.8) to extracellular matrix substrata, including fibronectin, type I and IV collagen, as well as laminin. The interaction of Arg-Gly-Asp (RGD) and rhodostomin, an RGD containing snake venom, with TGF-beta1 on the cell adhesion was also evaluated. The results showed that incubation with various concentration of TGF-beta1 (1-15 ng/ml) significantly increased the adhesion activity (1.4 to 2.5 folds) of ROS 17/2.8 to fibronectin and type I collagen (p<0.01), whereas the adhesion activity to laminin and type IV collagen was slightly elevated (1.1 to 1.5 folds). The peak effect of TGF-beta1 on the cell adhesion occurred after pretreatment of ROS 17/2.8 with TGF-beta1 for 6 hours. Treatment with Arg-Gly-Asp-Ser (RGDS) and rhodostomin effectively suppressed the TGF-beta1-enhanced adhesion activity to fibronectin and type I collagen. This study demonstrated that the up-regulated cell adhesion activity of ROS 17/2.8 cells by the TGF-beta1 can be inhibited by the rhodostomin.

Intracortical osteosarcoma: report of a case.

Intracortical osteosarcoma is the rarest anatomic variation of osteosarcoma. There have been only 12 cases reported in the English-language literature. We present a case of osteosarcoma in an 18-year-old Taiwanese man that originated within the cortex of the tibial diaphysis. The initial radiograph revealed a lytic mass confined to the cortex, mimicking a benign bone lesion. Histopathologic examination of the biopsy specimen showed an osteoblastic osteosarcoma mingled with some fibroblastic foci. He underwent en bloc resection, and a metallic prosthetic intercalary stem was used to replace the larger bone defect. Adjuvant chemotherapy was administered before and after the operation. He was free of disease during 40 months of follow-up. A review of all reported cases of intracortical osteosarcoma revealed that the initial method of treatment plays an important role in local recurrence and distant metastasis. Local excision and curettage leads to the worst results. The outcomes of more recently reported cases have improved because of early awareness of the possibility of malignancy and advances in chemotherapy. However, whether patients with intracortical osteosarcoma have a different prognosis from those with conventional osteosarcoma cannot be determined, because of the small number of intracortical osteosarcoma cases available for analysis.

Subungual squamous cell carcinoma: report of 2 cases.

Subungual squamous cell carcinoma (SCC) is a rare malignant tumor with an indolent course. Its etiology is unknown. It often involves the distal phalanx of the thumb or the index finger, and often presents as a chronic ulcer that is commonly misdiagnosed as chronic paronychia, pyogenic granuloma or verruca vulgaris. Approximately 150 cases of subungual SCC, including one in a Taiwanese patient, have been reported. Here, we report two cases of subungual SCC presenting as a chronic ulcer of the nail bed refractory to antibiotic treatment. One case involved the right thumb, while the other involved the right index finger. Radiographs of both cases showed an osteolytic bone lesion involving the distal phalanx. Excision biopsy revealed SCC in both cases. Both patients received amputation of the involved distal phalanx and showed no signs of reoccurrence during 5 years of follow-up. These findings suggest that all recalcitrant ulcers of the nail bed should be biopsied to facilitate early diagnosis and treatment of subungual SCC.

A physiologically based pharmacodynamic analysis of hepatic foci within a medium-term liver bioassay using pentachlorobenzene as a promoter and diethylnitrosamine as an initiator.

A stochastic clonal growth model for describing quantitative changes in size and number of putative preneoplastic lesions was modified to analyze the time-course information of cell proliferation and glutathione S-transferase pi (GST-P) foci within a medium-term bioassay. The study used F344 rats and a single initiating event using diethylnitrosamine (200 mg/kg ip) at Week 0. After a 2-week recovery period, chemical treatment began by gavage administration of pentachlorobenzene (PeCB; 100 micromol/kg/day, 7 days/week) in a corn oil vehicle and continued for 6 weeks. One week after beginning gavage dosing, a two-thirds partial hepatectomy was performed and the animals were serially euthanized at 48, 120, 168, 624, and 840 h postsurgery, which corresponds to 216, 288, 336, 792, and 1008 h following the beginning of PeCB treatment, respectively. For analysis, two types of models were evaluated for describing the time-course changes in GST-P foci. First, a sequential model describing the transformation of normal cells into a homogenous initiated cell population (i.e., one-cell model). Second, a two-cell model that describes a heterogeneous foci population by splitting the initiated cell population into two distinct types. In our study, the one-cell model was unable to adequately represent the time-course data for changes in both size and number of foci. In contrast, the two-cell model, which was parameterized to describe a negative selection mechanism, produced adequate simulations of both the size and number of foci. This model-based analysis suggested that the differences between PeCB-treated and untreated animals were primarily in parameters involving the rates of cell death.

Expandable endoprosthesis reconstruction in skeletally immature patients with tumors.

Between September 1984 and January 1996, 32 expandable endoprostheses were used for limb reconstruction after resection of malignant bone tumors in patients who were skeletally immature. The 20 boys and 12 girls ranged in age from 3 to 15 years (mean, 9.7 years). One patient had a Stage IIA tumor, 22 patients had Stage IIB tumors, and seven patients had Stage III tumors according to the classification of the Musculoskeletal Tumor Society. There also were two patients with parosteal osteosarcomas. The histologic diagnosis was osteosarcoma in 23 patients and Ewing's sarcoma in nine. All patients except the patients with parosteal osteosarcoma received standard neoadjuvant therapy. Twenty-two Lewis Expandable Adjustable Prostheses, four modular Wright Medical prostheses, four modular Howmedica prostheses, and two Techmedica expandable prostheses were used. Thirteen patients died, two have no evidence of disease, and 17 are continuously disease free. Sixteen of 32 patients (50%) have not had an expansion procedure because of early death in 10 and early amputation in three. Three patients are waiting to undergo an expansion procedure. Sixteen of the 32 patients (50%) have undergone 32 expansion procedures, to a maximum of 9 cm, without any infection. To maintain range of motion before the expansion procedure, a complete resection of the pseudocapsule was done routinely. Fourteen of the 32 patients did not have complications. Eighteen of the 32 patients had 27 complications. All Lewis Expandable Adjustable Prosthesis endoprostheses and the two nonmodular Techmedica prostheses were associated with a large amount of titanium debris. The children's functional results were similar to the results reported for adults with an average Musculoskeletal Tumor Society rating of good to excellent at the knee, fair to good at the hip, and fair about the shoulder. Rehabilitation of the knee in very young patients (5-8 years) remains problematic and careful selection of patient and family is necessary. The Lewis Expandable Adjustable Prosthesis probably should be reserved for very young patients (5-8 years) and modular systems should be used for large preadolescent and adolescent children.