Decreased Serum Level of Sclerostin in Older Adults with Sarcopenia

Background@#Although muscles and bones interact with each other through various secretory factors, the role of sclerostin, an osteocyte-secreted factor, on muscle metabolism has not been well studied. We investigated the levels of serum sclerostin in Korean older adults with sarcopenia. @*Methods@#Blood samples were collected from 129 participants who underwent evaluation of muscle mass and function in an outpatient geriatric clinic of a teaching hospital. Sarcopenia and related parameters were determined using cutoff values for the Asian population. Serum sclerostin levels were measured using an enzyme-linked immunosorbent assay. @*Results@#The mean age of the participants was 69.6 years, and 20 participants (15.5%) were classified as having sarcopenia. After adjusting for age, sex, and body mass index, serum sclerostin levels were significantly lower in participants with sarcopenia, low muscle mass, or weak muscle strength (P=0.003 to 0.045). Serum sclerostin levels were positively associated with skeletal muscle index and grip strength after adjusting for confounders (P=0.001 and P=0.003), whereas sarcopenic phenotype score showed a negative association (P=0.006). These increases in muscle mass and strength were also dose dependent as serum sclerostin levels increased (P for trends=0.003 and P for trends=0.015). Higher serum sclerostin levels were associated with lower odds ratio (ORs) for sarcopenia, low muscle mass, and weak muscle strength after adjusting for confounders (OR, 0.27 to 0.50; P<0.001 to 0.025). @*Conclusion@#Higher serum sclerostin levels were associated with a lower risk of sarcopenia, low muscle mass, and weak muscle strength in Korean older adults.

Benefits of lumican on human bone health: clinical evidence using bone marrow aspirates

Background/Aims@#Lumican, a small leucine-rich proteoglycan, has shown osteoprotective effects by synchronously stimulating bone formation and suppressing bone resorption. To clarify the role of lumican in human bone metabolism, the association between lumican concentrations and osteoporosis-related phenotypes was evaluated using bone marrow (BM) samples directly reflecting local microenvironments. @*Methods@#BM aspirates were obtained from 77 patients during hip surgery for either fragility hip fractures (HF) (n = 29) or osteoarthritis (n = 48) and centrifuged. Concentrations of lumican and biochemical bone markers in BM supernatants were measured using enzyme linked immunosorbent assays. @*Results@#After considering confounders, lumican concentrations in BM supernatants were 16.9% lower in patients with HF than in controls, with each increase in the standard deviation of lumican concentration being associated with a 61% lower likelihood of HF. The odds ratios for HF decreased linearly with increasing lumican tertiles in BM, with the odds of having fragility HF markedly lower in participants in the highest than in the lowest lumican tertile. Higher lumican level correlated significantly with higher femur neck bone mineral density and higher bone-specific alkaline phosphatase levels, but not with tartrate-resistant acid phosphatase 5b concentrations, in BM supernatants. @*Conclusions@#These data clinically validate previous in vitro and animal experiments showing the beneficial roles of lumican for bone homeostasis and suggest that lumican may contribute to a reduction in fracture risk in humans mainly through its stimulation of bone formation.

Aldosterone Inhibits In Vitro Myogenesis by Increasing Intracellular Oxidative Stress via Mineralocorticoid Receptor

Background@#Despite clinical evidence indicating poor muscle health in subjects with primary aldosteronism (PA), it is still unclear whether the role of aldosterone in muscle metabolism is direct or mediated indirectly via factors, such as electrolyte imbalance or impaired glucose uptake. As one approach to clarify this issue, we investigated the effect of aldosterone on in vitro myogenesis and the potential mechanism explaining it. @*Methods@#Myogenesis was induced in mouse C2C12 myoblasts with 2% horse serum. Immunofluorescence, quantitative reversetranscription polymerase chain reaction, Western blot, viability, and migration analyses were performed for experimental research. @*Results@#Recombinant aldosterone treatment suppressed muscle differentiation from mouse C2C12 myoblasts in a dose-dependent manner, and consistently reduced the expression of myogenic differentiation markers. Furthermore, aldosterone significantly increased intracellular reactive oxygen species (ROS) levels in myotubes, and treatment with N-acetyl cysteine, a potent biological thiol antioxidant, reversed the decrease of myotube area, myotube area per myotube, nucleus number per myotube, and fusion index due to aldosterone through decreasing oxidative stress. A binding enzyme-linked immunosorbent assay confirmed that mineralocorticoid receptor (MR) interacted with aldosterone in C2C12 myoblasts, while eplerenone, an MR inhibitor, blocked aldosterone-stimulated intracellular ROS generation during myogenesis and markedly attenuated the suppression of in vitro myogenesis by aldosterone. @*Conclusion@#These findings support the hypothesis that hypersecretion of aldosterone, like PA, directly contributes to muscular deterioration and suggest that antioxidants and/or MR antagonists could be effective therapeutic options to reduce the risk of sarcopenia in these patients.

Aldosterone Inhibits In Vitro Myogenesis by Increasing Intracellular Oxidative Stress via Mineralocorticoid Receptor

Background@#Despite clinical evidence indicating poor muscle health in subjects with primary aldosteronism (PA), it is still unclear whether the role of aldosterone in muscle metabolism is direct or mediated indirectly via factors, such as electrolyte imbalance or impaired glucose uptake. As one approach to clarify this issue, we investigated the effect of aldosterone on in vitro myogenesis and the potential mechanism explaining it. @*Methods@#Myogenesis was induced in mouse C2C12 myoblasts with 2% horse serum. Immunofluorescence, quantitative reversetranscription polymerase chain reaction, Western blot, viability, and migration analyses were performed for experimental research. @*Results@#Recombinant aldosterone treatment suppressed muscle differentiation from mouse C2C12 myoblasts in a dose-dependent manner, and consistently reduced the expression of myogenic differentiation markers. Furthermore, aldosterone significantly increased intracellular reactive oxygen species (ROS) levels in myotubes, and treatment with N-acetyl cysteine, a potent biological thiol antioxidant, reversed the decrease of myotube area, myotube area per myotube, nucleus number per myotube, and fusion index due to aldosterone through decreasing oxidative stress. A binding enzyme-linked immunosorbent assay confirmed that mineralocorticoid receptor (MR) interacted with aldosterone in C2C12 myoblasts, while eplerenone, an MR inhibitor, blocked aldosterone-stimulated intracellular ROS generation during myogenesis and markedly attenuated the suppression of in vitro myogenesis by aldosterone. @*Conclusion@#These findings support the hypothesis that hypersecretion of aldosterone, like PA, directly contributes to muscular deterioration and suggest that antioxidants and/or MR antagonists could be effective therapeutic options to reduce the risk of sarcopenia in these patients.

Establishing a colorectal cancer liver metastasis patient-derived tumor xenograft model for the evaluation of personalized chemotherapy

PURPOSE: In order to suggest optimal anticancer drugs for patient-tailored chemotherapy, we developed a colorectal cancer (CRC)-liver metastasis patient-derived tumor xenograft (PDTX) model. METHODS: Tissue obtained from a patient with CRC-liver metastasis (F0) was transplanted in a nonobese female mouse with diabetic/severe combined immune deficiency (F1) and the tumor tissue was retransplanted into nude mice (F2). When tumor volumes reached ~500 mm³, the F2 mice were randomly divided into 4 groups (n = 4/group) of doxorubicin, cisplatin, docetaxel, and nontreated control groups. The tumor tissues were investigated using H&E staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assays, and immunohistochemistry. To determine where the mutant allele frequencies varied across the different passages, we isolated genomic DNA from the primary tumor, liver metastasis, and PDTX models (F1/F2). RESULTS: The physiological properties of the tumor were in accord with those of the patient's tumors. Anticancer drugs delayed tumor growth, inhibited proliferation, and caused apoptosis. Histological assessments revealed no observable heterogeneity among the intragenerational PDTX models. Target exon sequencing analysis without high-quality filter conditions revealed some genetic variations in the 83 cancer-related genes across the generations. However, when de novo mutations were defined as a total count of zero in F0 and ≥5 in F2, exactly prognostic impact of clone cancer profiling (EGFR, KRAS, BRAF, PIK3CA, NRAS, APC and TP53) were detected in the paired. CONCLUSION: A CRC liver metastasis PDTX model was established for the evaluation of chemotherapeutic efficacy. This model retained the physiological characters of the patient tumors and potentially provides a powerful means of assessing chemotherapeutic efficacy.

Gemcitabine Plus Vinorelbine as Second-line Chemotherapy of the Patients of Previously Treated Non-small Cell lung Cancer: Phase II Trial / 결핵및호흡기질환

BACKGROUND: Both gemcitabine and vinorelbine are effective anticancer drugs with mild toxicity on non-small cell lung cancer, and monotherapy of these drugs are effective as a second-line chemotherapy. The aim of this trial was to assess the response and toxicity of a combination of gemcitabine and vinorelbine in patients of previously treated for non-small cell lung cancer. MATERIALS AND METHODS: 24 patients, initial stage III A/B,IV and previously treated with platinium and taxane based regimens, were enrolled from June 2000 to March 2004. The regimens consisted of vinorelbine 25mg/m2 followed by an infusion of gemcitabine 1000mg/m2 on day 1 and day 8 every three weeks. This course was repeated more than twice. RESULTS: Twenty-four patients were analyzed for the response, survival rate, and toxicities. The overall response was 17% with a complete remission rate of 4%. The median time-to progression (TTP) was 3.1 months (95%, CI 1-10months), and the survival time was 8.2 months (95%, CI 1-23 months). The grade 3/4 toxicities encountered were neutropenia (12.5%), anemia (0%), thrombocytopenia (0%). Non-hematological 3/4 toxicities were not observed. CONCLUSION: A combination of gemcitabine and vinorelbine in patients previously treated for non-small cell lung cancer provides a relatively good response rate, and a low toxicity profile. However, further study will be needed to confirm its effectiveness.

Docetaxel as Second-line Monotherapy for Advanced Non-small Cell Lung Cancer / 결핵및호흡기질환

BACKGROUND: The survival benefit associated with first-line chemotherapy in lung cancer has led to the need for second-line chemotherapy, for which Docetaxel (Taxotere(R)) has proven efficacy in both settings. This study evaluated the safety and efficacy of docetaxel in patients with non-small cell lung cancer who had failed first-line platinum- based chemotherapy. METHODS: Thirty one patients with non-small-cell lung cancer, who had failed first-line platinum-based chemotherapy, between March 1999 and August 2003, were enrolled in this study. Patients received intravenous docetaxel, either 75 mg/m2 or 100 mg/m2, with routine premedication every three weeks. RESULTS: Fourteen patients (45.2%) had a partial response. The median survival and progression-free survival times were 12.5 months (95% CI 7.3-17.6) and 3.0 months (95% CI 1.6-4.5), respectively. This study showed 2 factors gave different survival benefits; the age ( or = 60 years: 6.6 months, p = 0.0105) and the histological type (adenocarcinoma: 25.6 months vs. others: 7.9 months, p=0.0055). The predominant toxicity was neutropenia, which occurred as WHO grade 3 or 4 in 38.7 % of patients. One treatment-related death was also reported. Non-hematological toxicity was minor and easily controlled. There were no significant statistical differences in the survival benefit and toxicity between the two doses. CONCLUSION: Docetaxel, as second-line monotherapy, was well tolerated and effective in patients with non-small- cell lung cancer who failed first-line platinum-based chemotherapy.

Factors Predicting the Development of Radiation Pneumonitis in the Patients Receiving Radiation Therapy for Lung Cancer / 결핵

BACKGROUND: Radiation pneumonitis(RP) is the major serious complication of thoracic irradiation treatment. In this study, we attempted to retrospectively evaluate the long-term prognosis of patients who experienced acute RP and to identify factor that might allow prediction of RP. METHODS: Of the 114 lung cancer patients who underwent thoracic radiotherapy between December 2000 and December 2002, We performed analysis using a database of 90 patients who were capable of being evaluated. RESULTS: Of the 44 patients(48.9%) who experienced clinical RP in this study, the RP was mild in 33(36.6%) and severe in 11(12.3%). All of severe RP were treated with corticosteroids. The median starting corticosteroids dose was 34 mg(30~40) and median treatment duration was 68 days(8~97). The median survival time of the 11 patients who experienced severe RP was significantly poorer than the mild RP group. (p=0.046) The higher total radiation dose(>or=60 Gy) was significantly associated with developing in RP.(p=0.001) The incidence of RP did not correlate with any of the ECOG performance, pulmonary function test, age, cell type, history of smoking, radiotherapy combined with chemotherapy, once-daily radiotherapy dose fraction. Also, serum albumin level, uric acid level at onset of RP did not influence the risk of severe RP in our study. CONCLUSION: Only the higher total radiation dose(>or=60 Gy) was a significant risk factor predictive of RP. Also severe RP was an adverse prognostic factor.

The Prognosis of Ocular-adnexal Lymphoproliferative Lesions

PURPOSE: Lymphoproliferative lesions of the ocular adnexa were analyzed to examine the final outcome, recurrence and extraorbital spread. METHODS: The biopsies and clinical follow up data for 55 patients (68 eyes) with ocular adnexal lymphoproliferative lesions were reviewed retrospectively and analyzed according to the WHO classification. RESULTS: The ocular-adnexal lymphoproliferative lesions were located as follows: orbit in 49 eyes, conjunctiva in 18 eyes, eyelid in 1 eye. The three main subtypes of lymphoma according to the WHO classification were extranodal marginal zone B-cell lymphoma of mucosa- associated lymphoid tissue (MALT-lymphoma) (62 eyes), diffuse large B-cell lymphoma (2 eyes), and benign lymphoid hyperplasia (4 eyes). Remission was achieved at 60eyes. Recurrence was occurred in 7eyes (orbit: 4, conjunctiva: 3) of MALT-lymphoma cases. Location of lymphoma at presentation was not a predictor for recurrence (conjunctiva 16.7%, orbit 8.2%; p>0.05), but bilaterality at presentation was predictive values for recurrence by a statistically significant difference(bilateral 23.1%, unilateral 4.8%; p=0.045). CONCLUSIONS: Most common ocular adnexal lymphoma in Korea was MALT- lymphoma (91.2%). Bilaterality has a predictive values on recurrence, and extraorbital spread was found only in orbital MALT-lymphoma. It is suggested that orbital MALT- lymphoma should be treated with excisional biopsy and subsequent low dose radiotherapy and followed up indefinity.

Detection of Brain Metastatses Using Limited Brain MR Imaging ; Usefulness of Limited Contrast-Enhanced MR Imaging in Brain Metastasis / 결핵

BACKGROUND: The brain is a common site of a metastasis in lung cancer patients. If left untreated, the patients succumb to progressive neurological deterioration with a lower survival rate than with other metastases sites. Contrast-enhanced MR imaging in the absence of symptoms or clinical signs is not recommended for identifying a cerebral metastasis in lung cancer patients because of management effectiveness. This pilot study was performed to estimate whether or not limited brain MR imaging, which has a lower cost, could be used to replace conventional brain MR imaging. METHOD: Between April 1999 and March 2001, 43 patients with a primary lung cancer and the others (breast cancer, stomach cancer, colon cancer, malignant melanoma etc), who had neurological symptoms and signs, were examined using conventional brain MR imaging to examine brain metastases. The control group involved four patients who had no evidence of brain metastases the sensitivity, specificity and correlation of limited brain MR imaging were compared with conventional brain MR imaging. RESULTS: All the 43 patients who were examined with conventional brain MR imaging showed evidence of brain metastases, whereas limited brain MR imaging indicated that 42 patients had brain metastases(sensitivity=97.67%). One patient in whom limited brain MR imaging showed no brain metastasis had a metastasis in the cerebellum, as shown by the contrast-enhanced T1 weighted axial view using conventional brain MR imaging. The conventional brain MR imaging and the limited brain MI imaging of the 4 control patients both indicated no brain metastases (specificity=100 %). The Pearson Correlation of the two groups was 0.884(Confidence Interval : 99%) observed. CONCLUSION: Limited brain MR imaging can detect a brain metastasis with the same accuracy. In addition, it is cost-effective (229,000 won, 180$) compared to conventional brain MR imaging(529,000 won, 480$) when patients had neurological symptoms and signs or staging.

Prognostic Factors for Survival in Patients with Stage IV Non-small Cell Lung Cancer / 결핵

BACKGROUND: Although patients with stage IV non-small cell lung cancer areknown to have a poor prognosis, the prognostic factors for survival have not been well evaluated. Such factors may be different from those for overall survival. This study was performed to analyze the prognostic factors for survival and the variation of survival according to metastatic organ, in patients with stage IV non-small cell lung cancer. MATERIALS AND METHODS: From January 1997 to December 2000, 151 patients with confirmed stage IV non-small cell lung cancer were enrolled into this study retrospectively. The clinical and laboratory data were analyzed using univariate Kaplan-Meier and Multivariate Cox regression models. RESULTS: On univariate analysis, age, performance status, serum albumin level, weight loss, forced expiratory volume in one second (FEV1), systemic chemotherapy, the number of metastatic organs and serum lactate dehydrogenase (LDH) level were significant factors (p<0.05). In multivariate analysis, important factors for survival were ECOG performance (relative risk of death [RR]: 2.709), systemic chemotherapy (RR: 1.944), serum LDH level (RR: 1.819) and FEV1 (RR: 1.774) (p<0.05). Metastasis to the brain and liver was also a significant factor on univariate analysis). The presence of single lung metastasis was associated with better survival than that of other metastatic organs (p=0.000). CONCLUSION: We confirmed that performance status and systemic chemotherapy were independent prognostic factors, as has been recognized. The survival of stage IV non-small cell lung cancer patients was different according to the metastatic organs. Among the metastatic sites, only patients with metastasis to the lung showed better survival than that of other sites, while metastasis of the brain or liver was associated with worse survival than that of other sites.

Vinorelbine Monotherapy on Advanced Non-small Cell Lung Cancer / 결핵

BACKGROUND: Unresectable non-small cell lung cancer has a poor response to chemotherapy and has an unfortunate prognosis. More effective and less toxic cytotoxic agents are needed to improve the outcome of these pa tients. The efficacy and safety of vinorelbine monotherapy in these advanced lung cancer patients was evaluated. METHODS: Sixteen patients with non-small cell lung cancer in stage III or IV, who received vinorelbine alone as an intial anticancer chemotherapy from June 1996 to December 2000 were enrolled in this study. Vinorelbine was given intravenously at a dose 30mg/m2 every weel. RESULTS: Among the sixteen patients, six had a partial response (38%) and the median survival was 16 weeks. The median response duration was 27 weeks (95% CI 6-47), and the time to progression was 16 weeks (95% CI 6-26). Among a ttal of 112 cycles, neutropenia (WHO grade 3 or 4) and anemia (grade 3) occurred in 9% and 3%, respectively. Only 1 patients required hospitalization for neutropenic fever. Non-hematologic toxicity was monor and was easily controlled. CONCLUSION: Vinorelbine monotherapy was well tolerated, and moderatly effective in patients with advanced non-small cell lung cancer.