Non-Spine Bone Metastasis as an Initial Manifestation of Cancer in Korea

Non-spine bone metastasis accounts for approximately 20% of all skeletal metastases, but little data have been published that focused on bone metastasis to the pelvis and extremities as an initial manifestation of cancer. We determined 1) clinicopathologic characteristics of patients who presented with non-spine bone metastasis of unknown primary malignancy, and 2) process by which the diagnosis of primary cancer was made. We retrospectively reviewed 84 patients with bone metastasis of unknown primary cancer site at the time of presentation. The study population consisted of 56 men and 28 women, with a mean age of 59.1 yr (17.5-85.6 yr). The average follow-up period was 20.8 months (1-120 mo). Primary cancer site was identified in 79 patients (94.0%), and was determined to be the lung (46.4%), kidney (13.1%), liver (9.5%), thyroid (8.3%), and prostate (4.8%). Five-year overall survival rate was 28.0%. Multiple bone metastases, distant organ metastasis, and multiple bone with organ metastases were the significant prognostic factors in univariate analysis. Multiple bone metastases remained significant after multivariate analysis (P = 0.008). Lung cancer is the most common site of primary cancer, and patients with multiple bone metastases have a poor prognosis, possibly due to disseminated cancer and a greater tumor burden.

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Near-infrared fluorescence imaging as an alternative to bioluminescent bacteria to monitor biomaterial-associated infections

Biomaterial-associated infection is one of the most common complications related to the implantation of any biomedical device. Several in vivo imaging platforms have emerged as powerful diagnostic tools to longitudinally monitor biomaterial-associated infections in small animal models. In this study, we directly compared two imaging approaches: bacteria engineered to produce luciferase to generate bioluminescence and reactive oxygen species (ROS) imaging of the inflammatory response associated with the infected implant. We performed longitudinal imaging of bioluminescence associated with bacteria strains expressing plasmid-integrated luciferase driven by different promoters or a strain with the luciferase gene integrated into the chromosome. These luminescent strains provided an adequate signal for acute (0–4 days) monitoring of the infection, but the bioluminescence signal decreased over time and leveled off at 7 days post-implantation. This loss in the bioluminescence signal was attributed to changes in the metabolic activity of the bacteria. In contrast, near-infrared fluorescence imaging of ROS associated with inflammation to the implant provided sensitive and dose-dependent signals of biomaterial-associated bacteria. ROS imaging exhibited higher sensitivity than the bioluminescence imaging and was independent of the bacteria strain. Near-infrared fluorescence imaging of inflammatory responses represents a powerful alternative to bioluminescence imaging for monitoring biomaterial-associated bacterial infections.     

骨组织工程中调节巨噬细胞行为促进骨愈合的策略

骨组织工程将材料作为骨再生支架植入缺损局部,帮助完成骨愈合。近年来随着骨免疫学的发展,人们意识到巨噬细胞的免疫应答决定着材料植入的成败。巨噬细胞具有多样性和可塑性,可以根据环境信号极化为M1样(促炎)和M2样(抑炎)表型,在骨愈合的不同阶段发挥作用。巨噬细胞的迁移、增殖、极化等行为对材料特性敏感。对目前在骨组织工程中,通过改变材料的物理特性、表面化学特性以及生物特性,设计能主动调节巨噬细胞行为的材料,从而促进骨愈合的策略进行了概括总结,相关策略包括：增加材料的粗糙度、大孔结合纳米结构、合适的电信号或机械信号、中性或阴离子表面、增加亲水性、利用免疫调节材料或向局部输送免疫活性物质等,以期为设计具有良好免疫调节性的骨组织工程材料提供思路。     

Using Cartilage to Repair Bone: An Alternative Approach in Tissue Engineering

Materials and techniques currently used for bone replacement/repair conform to the current paradigm, relying on bone or bone products to produce bone or induce bone formation. Yet, nature forms and heals most of the skeleton by ossification of a cartilaginous model. In this study, we cultured aggregates of E10.5 or E12 mouse embryonic limb cells in the bioreactor for 3 weeks, determined the stages of cartilage differentiation attained, and assessed the ossification and bone healing potential of the spheroids by implantation adjacent to, or directly in, a skull defect. Cultured spheroids had large cartilaginous areas, sometimes with cellular arrangements characteristic of growth plate zones. Aggregates implanted for 2 weeks adjacent to a defect mineralized and ossified (histology, micro-CT). Defects with implants had a central mass of differentiated and differentiating bone, with osteoclast activity, filling the defect. Controls had considerable remodeling on the bone edges demarcating the still present defect. This study shows that cartilage, grown in the bioreactor for 3 weeks, ossified when implanted adjacent to a bone defect, and when implanted directly in a defect, contributed to its healing. Our ability to grow differentiated bone-forming cartilage for implantation is an alternative approach in the field of bone repair.     

Long-term Outcome of Microscopic Transsphenoidal Surgery for Prolactinomas as an Alternative to Dopamine Agonists

BackgroundAlthough long-term dopamine agonist (DA) therapy is recommended as a first-line treatment for prolactinoma, some patients may prefer surgical treatment because of the potential adverse effects of long-term medication, or the desire to become pregnant. This study aimed to determine whether surgical treatment of prolactinomas could be an alternative to DA therapy.MethodsIn this retrospective study, 96 consecutive patients (74 female, 22 male) underwent primary pituitary surgery without long-term DA treatment for prolactinomas at a single institution from 1990 to 2010. All patients underwent primary surgical treatment in the microscopic transsphenoidal approach (TSA).ResultsThe median age and median follow-up period were 31 (16–73) years and 139.1 (12.2–319.6) months, respectively. An initial overall remission was accomplished in 47.9% (46 of 96 patients, 33 macroadenomas, and 13 microadenomas) of patients. DA dose reduction was achieved in all patients after TSA. A better remission rate was independently predicted by lower diagnostic prolactin levels and by a greater extent of surgical resection. Overall remission at the last follow-up was 33.3%, and the overall recurrence rate was 30.4%. The permanent complication rate was 3.1%, and there was no mortality.ConclusionTSA can be considered a safe and potentially curative treatment for selective microprolactinomas as an alternative to treatment with a long-term DA.     

Dried Blood as an Alternative to Plasma or Serum for Trypanosoma cruzi IgG Detection in Screening Programs

Trypanosoma cruzi serological screening is recommended for people potentially exposed to this parasite in countries where Trypanosoma cruzi is endemic and those where it is not endemic. Blood samples on filter paper may be a practical alternative to plasma/serum for antibody detection. Using the Architect Chagas assay, we detected the presence of IgG against T. cruzi in matched serum and dried blood spots (DBS) collected from 147 patients residing in Madrid, Spain, who had potential previous exposure to T. cruzi. The κ statistic for the DBS/serum proportion of agreement for the detection of antibodies against T. cruzi was 0.803, considering an S/CO (assay result unit; chemiluminescent signal from the sample [S] divided by the mean chemiluminescent signal for the three calibrators used in the test [CO]) cutoff value of ≥1.00. The relative sensitivity of the Architect test using DBS increased from 95.2% to 98.8% when the cutoff was lowered from ≥1.00 to ≥0.88, while the relative specificity decreased from 84.1% to 71.6%. Overall, the median S/CO values for DBS were significantly lower than those for serum (2.6 versus 6.5; P < 0.001). Discrepancies that occurred with the use of DBS included 10 false positives (with low S/CO values in 9 cases [median, 2.13]) and 4 false negatives, with mean S/CO values of 0.905 (gray zone). Using DBS plus a highly sensitive and specific enzyme-linked immunosorbent assay (ELISA) may be a simple and reliable method for detecting IgG against T. cruzi when blood sampling by venipuncture is not feasible. This method may also reduce the false-negative rates observed with some rapid diagnostic tests. The lower relative sensitivity compared to the reference method may be increased by lowering the optical density threshold.     

Detection of Echinococcus multilocularis in the Definitive Host: Coprodiagnosis by PCR as an Alternative to Necropsy

Recently, extensions of the range of Echinococcus multilocularis in Europe and North America and drastic increases in fox populations in Europe put an increasing proportion of the human population at risk of alveolar echinococcosis. To obtain data on the local infection pressure, studies of the prevalence of the parasite in the animals that transmit the parasite, foxes, dogs, and cats, are urgently required. Such investigations, however, have been hampered by the need for necropsy of the host animal to specifically diagnose infection with the parasite. In this study, a nested PCR and an improved method for DNA extraction were developed to allow the sensitive and specific diagnosis of E. multilocularis infections directly from diluted fecal samples from foxes. The target sequence for amplification is part of the E. multilocularis mitochondrial 12S rRNA gene. The specificity of the method was 100% when it was tested against 18 isolates (metacestodes and adult worms) of 11 cestode species, including E. granulosus. The sensitivity of the method was evaluated by adding egg suspensions and individual eggs to samples of diluted feces from uninfected foxes. The presence of one egg was sufficient to give a specific signal. To confirm the PCR results, an internal probe which hybridized only with E. multilocularis amplification products but not with the DNA of other cestodes was constructed. In order to investigate the applicability of this method for epidemiological studies, 250 wild foxes from a area in southern Germany where echinococcosis is highly endemic were examined by both necropsy and PCR of rectal contents. The sensitivity correlated with the parasites’ number and stage of maturity. It ranged from 100% (>1,000 gravid worms) to 70% (<10 nongravid worms). On the basis of positive PCR results for 165 foxes, the sensitivity of the traditional and widely used necropsy method was found to be not higher than 76%. We therefore present this PCR system as an alternative method for the routine diagnosis of E. multilocularis in carnivores.     

Adaptations of Trabecular Bone to Low Magnitude Vibrations Result in More Uniform Stress and Strain Under Load

Extremely low magnitude mechanical stimuli (<10 microstrain) induced at high frequencies are anabolic to trabecular bone. Here, we used finite element (FE) modeling to investigate the mechanical implications of a one year mechanical intervention. Adult female sheep stood with their hindlimbs either on a vibrating plate (30 Hz, 0.3 g) for 20 min/d, 5 d/wk or on an inactive plate. Microcomputed tomography data of 1 cm bone cubes extracted from the medial femoral condyles were transformed into FE meshes. Simulated compressive loads applied to the trabecular meshes in the three orthogonal directions indicated that the low level mechanical intervention significantly increased the apparent trabecular tissue stiffness of the femoral condyle in the longitudinal (+17%, p < 0.02), anterior–posterior (+29%, p < 0.01), and medial-lateral (+37%, p < 0.01) direction, thus reducing apparent strain magnitudes for a given applied load. For a given apparent input strain (or stress), the resultant stresses and strains within trabeculae were more uniformly distributed in the off-axis loading directions in cubes of mechanically loaded sheep. These data suggest that trabecular bone responds to low level mechanical loads with intricate adaptations beyond a simple reduction in apparent strain magnitude, producing a structure that is stiffer and less prone to fracture for a given load. © 2003 Biomedical Engineering Society.     

Evaluation of Royal Jelly as an Alternative to Fetal Bovine Serum in Cell Culture Using Cell Proliferation Assays and Live Cell Imaging

Background

Royal jelly is a nutritious substance produced by the young nurse bees and contains significant amounts of proteins which are important for cell growth and proliferation. The aim of this study was to evaluate the effect of royal jelly as an alternative to fetal bovine serum (FBS) in cell culture using cell proliferation assays and live cell imaging.

Materials and Methods

MRC-5 cells were treated with various concentrations of royal jelly extract in MTT assay. The control groups were comprised of Alpha-Minimal Essential Medium (α-MEM) alone and α-MEM with 10% FBS. Subsequently, the cell proliferation was studied for 10 days using Alamar Blue assay and live cell imaging from 48 to 72 h. The population doubling time (PDT) was determined using trypan blue assay after live cell imaging.

Results

In MTT assay, 0.156 and 0.078 mg/ml of royal jelly produced higher cell viability compared to positive control group but were not significantly different (P > 0.05). In the Alamar Blue assay, 0.156 and 0.078 mg/ml of royal jelly produced greater percentage of reduction at day 3 even though no significant difference was found (P > 0.05). Based on live cell imaging, the PDT for positive, negative, 0.156 and 0.078 mg/ml of royal jelly groups were 29.09, 62.50, 41.67 and 41.67 h respectively. No significant difference was found in the PDT between all the groups (P > 0.05).

Conclusion

Royal jelly does not exhibit similar ability like FBS to facilitate cell growth under the present test conditions.     

Evaluation of the Bio-Rad Multispot HIV-1/HIV-2 Rapid Test as an alternative to Western blot for confirmation of HIV infection

BackgroundIn the United States, a new HIV diagnostic algorithm has been proposed that uses an HIV-1/HIV-2 antibody differentiation immunoassay instead of Western blot or immunofluoresence for confirmatory testing.ObjectivesTo evaluate the Multispot HIV-1/HIV-2 Rapid Test (Multispot) as an alternative to Western blot analysis for confirmation of HIV infection.Study designA series of 205 serum and plasma specimens positive for HIV-1 or HIV-2 were used to compare the performance of Multispot to a standard HIV-1 Western blot. Positive samples included 63 specimens from patients > 18 months of age, 33 proficiency survey specimens, and 109 specimens from nine commercial seroconversion and performance panels. In addition, 63 specimens from 51 HIV-exposed, uninfected children ≤ 18 months of age in various stages of seroreversion and 192 HIV-negative samples were tested. Specimens were initially screened using a 4th generation HIV Ag/Ab Combo assay.ResultsMultispot readily discriminated between individuals with HIV-1 or HIV-2 infection and those who were uninfected. Of the 205 samples repeatedly reactive by the 4th generation screening assay, infection status was correctly confirmed by Multispot in 83.9% (172/205) compared to 68.8% (141/205) for Western blot. Multispot detected HIV-1 earlier in 27.6% of low-titer antibody specimens called indeterminate by Western blot, and effectively reduced the number of indeterminate results in seroreverting HIV-1 exposed, uninfected infants and for HIV-2 infections misinterpreted as indeterminate or positive by HIV-1 Western blot.ConclusionsMultispot offers speed and simplicity over Western blot and has an excellent performance for differentiation and confirmation of antibodies to HIV-1 and HIV-2.     

Assessing transmission risks and control strategy for monkeypox as an emerging zoonosis in a metropolitan area

To model the spread of monkeypox (MPX) in a metropolitan area for assessing the risk of possible outbreaks, and identifying essential public health measures to contain the virus spread. The animal reservoir is the key element in the modeling of zoonotic disease. Using a One Health approach, we model the spread of the MPX virus in humans considering potential animal hosts such as rodents (e.g., rats, mice, squirrels, chipmunks, etc.) and emphasize their role and transmission of the virus in a high-risk group, including gay and bisexual men-who-have-sex-with-men (gbMSM). From model and sensitivity analysis, we identify key public health factors and present scenarios under different transmission assumptions. We find that the MPX virus may spill over from gbMSM high-risk groups to broader populations if the efficiency of transmission increases in the higher-risk group. However, the risk of outbreak can be greatly reduced if at least 65% of symptomatic cases can be isolated and their contacts traced and quarantined. In addition, infections in an animal reservoir will exacerbate MPX transmission risk in the human population. Regions or communities with a higher proportion of gbMSM individuals need greater public health attention. Tracing and quarantine (or “effective quarantine” by postexposure vaccination) of contacts with MPX cases in high-risk groups would have a significant effect on controlling the spreading. Also, monitoring for animal infections would be prudent.     

Effect of Fatiguing Exercise on Longitudinal Bone Strain as Related to Stress Fracture in Humans

Muscular fatigue in the training athlete or military recruit has been hypothesized to cause increased bone strain that may contribute to the development of a stress fracture. Under normal circumstances, muscles exert a protective effect by contracting to reduce bending strains on cortical bone surfaces. In vivo strain studies in dogs show that muscle fatigue following strenuous exercise elevates bone strain and changes strain distribution. However, a similar experiment has yet to be performed in humans. The purpose of this work was to test the hypothesis in humans that strenuous fatiguing exercise causes an elevation in bone strain. It was also hypothesized that this elevation is greater in younger people than in older people due to the decline in muscle strength and endurance that normally occurs with age. To test these hypotheses, strain in the tibiae of seven human volunteers was measured during walking before and after a period of fatiguing exercise. Neither hypothesis was sustained. Post-hoc analysis of the strain data suggests that strain rate increases after fatigue with a greater increase in younger as opposed to older persons. Although not conclusive, this suggests that it is strain rate, rather than strain magnitude, that may be causal for stress fracture. © 1998 Biomedical Engineering Society. PAC98: 8745Dr, 8745Bp, 0180+b     

Circulating microRNA-339-5p and -21 in plasma as an early detection predictors of lung adenocarcinoma

Background

Many studies have shown that differentially expressed miRs in body fluids can serve as biomarkers in non-invasive detection of the cancers. However, the clinical significance of plasma miRs in the diagnosis of lung adenocarcinoma (LA) is still not clear. Therefore, we examined the LA-specific miRs in plasma, which could be utilized to diagnosis and monitor LA in routine clinical practice.

Assessing oral brushing technique as a source to collect DNA and its use in detecting human papillomavirus

Collecting buccal cell DNA has a number of advantages in terms of practicality and technical quality when employed for detecting human papillomavirus (HPV), arguably an important etiological factor for head and neck carcinomas. The objective of the present study was to assess oropharyngeal mucosa brushing as an effective method for collecting DNA samples and for detecting HPV. Forty-three female patients diagnosed with cervical intraepithelial neoplasia, and 21 of their spouses, both groups without clinically detectable oral lesions, were submitted to quantitative and qualitative DNA analysis obtained through buccal cell brushing, with spectrophotometry assessment and beta-globin PCR. DNA samples were also checked for the presence of HPV. Efficient collection of DNA was achieved in all the sample cases. Two samples, a male and a female (not sexual partners), showed HPV-positivity. The results revealed that the oral brushing technique is an effective method for DNA collection to detect HPV, confirming that it could usefully contribute to epidemiological studies undertaken in Brazil's Public Health System. HPV detection using PCR showed that only 3.12% of the cases were HPV-positive. Although the sample was small, our study nevertheless allowed the detection of HPV in DNA samples of oral biological material.     

Diagnostic Accuracy of Elisa Methods as an Alternative Screening Test to Indirect Immunofluorescence for the Detection of Antinuclear Antibodies. Evaluation of Five Commercial Kits

Detection of antinuclear antibodies (ANA) is a fundamental laboratory test for diagnosing systemic autoimmune diseases. Currently, the method of choice is indirect immunofluorescence (IIF) on a HEp-2 cell substrate. The goal of this study was to evaluate the diagnostic accuracy of five commercially available enzyme immunoassay (EIA) kits for ANA detection and to verify the possibility of using them as an alternative to the IIF method.

The study involved 1513 patients, 315 of whom were diagnosed with a systemic autoimmune disease and 1198 in whom an autoimmune disorder was excluded. For all sera, ANA detection was performed via IIF and with five different EIA kits. The results were evaluated in relation to clinical diagnosis and the presence of possible specific autoantibodies (anti-ENA or anti-dsDNA); lastly, they were compared with the results obtained using ANA-IIF as the method of reference.

The positive rate of the ANA-IIF test in subjects with systemic autoimmune diseases was 92%, whereas in the five ANA-EIA kits there was broad diversity in terms of response, with positive rates ranging from 74 to 94%. All the EIA kits correctly detected the presence of antibodies (anti-dsDNA, anti-RNP, anti-Ro/SSA) responsible for homogeneous and speckled fluorescence pattern, but at the same time they showed substantial inaccuracy with the nucleolar pattern, with a mean sensitivity of approximately 50% in this case. Instead, there was a large kit-to-kit difference in terms of identification of anti-Scl70 and centromere patterns, for which sensitivities ranged between 45 and 91%, and between 49 and 100%, respectively.

The results of the study demonstrate that the commercially available ANA-EIA kits show different levels of sensitivity and specificity. Some of them have a diagnostic accuracy that is comparable and, in some cases, even higher than the IIF method. Consequently, these could be used as an alternative screening test to IIF. However, others do not ensure acceptable results. Therefore, careful evaluation of the various kits on the market is advisable before including any of these methods in the clinical and diagnostic testing.     

Ionic liquids as an alternative to formalin in histopathological diagnosis

Asymmetry of cations and the type of anions play a key role in the properties of ionic liquids (ILs) as fixatives for tissue preservation. 1-Methyl-3-octyloxymethylimidazolium tetrafluoroborate has proven to be a very good fixative, with similar effects as formalin. Our study shows that it is applicable for both histological and immunohistochemical purposes. After treatment with 1-methyl-3-octyloxymethylimidazolium tetrafluoroborate, tissue sections are more intensely stained. With respect to expression patterns and staining intensity, immunohistochemical staining is comparable in tissues fixed in formalin and the selected ILs. The present study demonstrates the properties of 1-methyl-3-octyloxymethylimidazolium tetrafluoroborate for tissue preservation in histopathological procedures, eliminating the requirement of formalin.     

Recombinant cytokines as an approach to immune reconstitution in aging

Aging is characterized by a decreased humoral and cell-mediated immunity to a large variety of exogenous antigens and by an increased propensity to autoantibody production, suggesting an age-related disregulation of the immune system. The decline in immune responsiveness to exogenous antigens has been attributed to thymus involution, consisting of a fall in the capacity to induce intrathymic T-cell growth and differentiation, and also to export mature T cells to the periphery. T-cell activation and secretion of soluble factors have been reported to change with aging, but, as with cytokines, the results are conflicting. We investigated the production of IL-2 and IFN-γ (Th1 type) and IL-4 (Th2 type) cytokines by mitogen-activated spleen cells from young, adult and old mice and their regulation by the addition of a recombinant cytokine (IL-1β, IL-2, IL-3, IL-4, IL-12, IFN-γ) at varying concentrations. The results indicate that cytokine production can be enhanced only when it is deficient, suggesting the possible use of recombinant cytokines as efficient immunomodulators in age-associated immune disorders.