Serum YKL-40 is increased in patients with hepatic fibrosis

BACKGROUND/AIMS: YKL-40, a mammalian member of the chitinase family, is a lectin that binds heparin and chitin. The function of YKL-40 is unknown, but it may function in tissue remodelling. The aims of this study were to assess the level of circulating YKL-40 in patients with various kinds and degree of chronic liver disease and its possible relation to liver fibrosis. METHODS: Serum YKL-40 levels were determined by radioimmunoassay in 129 patients with suspected liver disease and related to histological findings and immunohistochemical staining of YKL-40 in a liver biopsy taken simultaneously with the blood sample. RESULTS: The median serum YKL-40 was highest in patients with alcoholic cirrhosis (532 microg/l), in particular in patients with additional alcoholic hepatitis (740 microg/l). Patients with alcoholic cirrhosis, post-hepatitic cirrhosis (425 microg/l) and non-cirrhotic fibrosis (330 microg/l) had significantly higher serum YKL-40 than normal subjects (102 microg/l), patients with fatty liver (195 microg/l) or patients with viral hepatitis without fibrosis (174 microg/l). Serum YKL-40 was significantly (p<0.001) related to the degree of liver fibrosis with the highest levels in patients with moderate (466 microg/l) to severe (676 microg/l) fibrosis. Serum YKL-40 was also increased (p=0.018) in patients with slight fibrosis (270 microg/l) compared to patients without fibrosis. Immunohistochemical analysis demonstrated positive staining for YKL-40 antigen in areas with fibrosis, particularly areas with active fibrogenesis. YKL-40 staining was never found in hepatocytes. CONCLUSIONS: Our study indicates that the increased serum YKL-40 in patients with liver disease of various degree and aetiology seems to reflect fibrosis and fibrogenesis.     

Increased serum YKL-40 and C-reactive protein levels are associated with angiographic lesion progression in patients with coronary artery disease

Objective

YKL-40 is a pro-inflammatory protein highly expressed in atherosclerotic plaques, and is related to prognosis of patients with coronary artery disease (CAD). This study aimed to assess the possible association between YKL-40 and coronary lesion progression in CAD patients.

Methods

A total of 313 patients with CAD, who underwent percutaneous coronary intervention (PCI) and follow-up angiography (mean 13.2 ± 3.2 months) were recruited. Serum YKL-40 and high-sensitivity C-reactive protein (hsCRP) levels were measured using ELISA kits.

Results

Baseline serum YKL-40 and hsCRP levels were higher in those with lesion progression (all p < 0.001 vs. patients without lesion progression), and correlated significantly with change of lumen diameter stenosis and cumulative coronary obstruction score (all p < 0.01). Multivariable logistic regression analysis revealed that after adjusting for conventional risk factors, number of total coronary artery lesions, YKL-40 and hsCRP levels were independent determinants of lesion progression. An area under the curve of YKL-40 and hsCRP was 0.744 (CI 95% 0.685–0.804, p < 0.001) and 0.716 (CI 95% 0.657–0.776, p < 0.001), respectively. The optimal values of cut-off point were 74.98 ng/ml (sensitivity 70%, specificity 71%) for YKL-40 and 3.21 mg/l (sensitivity 66%, specificity 68%) for hsCRP to predict lesion progression.

Conclusion

Increased serum YKL-40 and hsCRP levels are independently associated with lesion progression in patients with CAD.     

Substratification of patients with newly diagnosed standard-risk multiple myeloma

Despite the absence of high-risk cytogenetics and lower International Staging System (ISS) stages, a subset of patients with multiple myeloma (MM) experience poor overall survival (OS). We studied 1461 patients with newly diagnosed MM to identify patient and disease characteristics that predict a high-risk phenotype among standard-risk patients. Fifty-six percent of all patients presented with standard-risk disease. Among them, advanced age, extremes of body mass index, non-hyperdiploid karyotype and abnormal lymphocyte counts were associated with worse OS. Standard-risk patients with 0–1 of these adverse factors (hazard ratio [HR] 0·32, 95% confidence interval [CI] 0·24–0·43, P < 0·001) and 2 adverse factors (HR 0·54, 95% CI 0·41–0·72, P < 0·001) experienced better OS than high-risk patients. Two or more adverse factors were present in 17% of standard-risk patients and were associated with OS comparable to high-risk patients (HR 0·91, 95% CI 0·67–1·24, P = 0·548). Predictive power among standard-risk patients was improved using score groups compared to ISS stages. Patients with standard-risk MM are a heterogeneous group with one in six patients experiencing OS comparable to high-risk disease. Patients at risk can be identified using readily available patient and disease characteristics. These findings emphasize the importance of accurate risk stratification and help explain part of the heterogeneity observed in clinical practice.     

Assessment of bone involvement in patients with multiple myeloma using bone densitometry

Abstract: To evaluate the use of dual energy X-ray absorptiometry (DXA) in multiple myeloma (MM) we performed a prospective study of 34 patients with newly diagnosed MM. Most patients had advanced disease and all but two patients had osteolytic bone destructions and/or pathological fractures. Bone mineral content (BMC) and bone mineral density (BMD) of the lumbar spine (L₁–L₄) and hip were measured using a Hologic QDR-1000 scanner. Collapsed vertebrae were not excluded from analysis. Data from 289 healthy Danish volunteers aged 21–79 yr were used for calculation of Z-scores. Lumbar spine BMC (Z-score –0.46±0.23, p=0.05) and lumbar spine BMD (Z-score –0.56±0.23, p=0.02) were significantly reduced in MM patients, whereas no reduction was seen in hip BMC or BMD. Collapsed vertebrae had marked reduced BMD (Z-score –1.34±0.22, p<0.001), as had non-fractured vertebrae in the same individuals (Z-score –1.42±0.25, p<0.001). Lumbar spine BMD correlated with radiologically assessed bone morbidity (r –0.37, p=0.03) and stronger with the incidence of vertebral fractures (r –0.64, p<0.001). Thus, osteopenia of the back is common in multiple myeloma and correlates with an increased incidence of fractures. DXA may identify subjects with increased risk of vertebral fractures for more intensive chemotherapeutic or anti-resorptive treatment.     

Psychosocial QOL is an independent predictor of overall survival in newly diagnosed patients with multiple myeloma

Only few studies have analyzed quality of life (QOL) and its association with prognosis in patients with multiple myeloma. We studied QOL at start of conventional treatment to evaluate the impact of symptomatic myeloma on QOL and to determine the prognostic significance of various dimensions of QOL. Our study provided further evidence of the significant impairment of QOL in patients with multiple myeloma at onset of therapy. Furthermore, our data showed a closer correlation between the more physical QOL scales such as pain, fatigue, physical functioning and global QOL with the activity of the disease than between psychosocial dimensions such as role, emotional, social, and cognitive functioning and the status of the disease. Multivariate analyses including each a QOL scale and known prognostic parameters (response to therapy, creatinine level, calcium, LDH, Hb, beta2-microglobulin, and albumin) revealed a marked difference in the prognostic significance between psychosocial and other QOL scales. All psychosocial dimensions of QOL were found to be independent prognostic factors, while physical QOL and global QOL were eliminated by disease-associated prognosticators. Taken together, QOL was found to be significantly impaired in myeloma patients at start of therapy. Psychosocial, but not physical dimensions of QOL were found to be independent prognostic factors.     

Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma

Objectives: Lytic bone disease is a hallmark of multiple myeloma (MM) and is caused by osteoclast activation and osteoblast inhibition. Secretion of Dickkopf (DKK)‐1 by myeloma cells is a major factor which causes inhibition of osteoblast precursors. So far, there is no study showing a significant difference in serum DKK‐1 levels in MM patients with or without lytic bone lesions. Methods: DKK‐1 serum levels were quantified in 184 untreated MM patients and 33 monoclonal gammopathy of undetermined significance (MGUS) patients by ELISA, using a monoclonal anti‐DKK‐1 antibody. Results: Serum DKK‐1 was elevated in MM as compared with MGUS (mean 11 963 pg/mL vs. 1993 pg/mL; P < 0.05). Serum DKK‐1 levels significantly correlated with myeloma stage according to Durie and Salmon (mean 2223 pg/mL vs. 15 209 pg/mL in stage I and II/III, respectively; P = 0.005). Importantly, myeloma patients without lytic lesions in conventional radiography had significantly lower DKK‐1 levels than patients with lytic bone disease (mean 3114 pg/mL vs. 17 915 pg/mL; P = 0.003). Of interest, serum DKK‐1 correlated with the number of bone lesions (0 vs. 1–3 vs. >3 lesions: 3114 pg/mL vs. 3559 pg/mL vs. 24 068 pg/mL; P = 0.002). Conclusion: Using a large series of myeloma patients, we could show for the first time a correlation between DKK‐1 serum concentration and the amount of lytic bone disease, indicating that DKK‐1 is an important factor for the extent of bone disease and supporting the hypothesis of DKK‐1 as a therapeutic target in myeloma bone disease.     

多发性骨髓瘤患者血清OPG检测及临床意义

目的：探讨OPG在多发性骨髓瘤（MM）患者血清中的表达水平及与骨病、预后的关系,初步探索其在MM骨病和预后判断中的作用。方法：采用双抗体夹心酶联免疫吸附试验（ELISA）技术分别检测28例MM患者和28例对照组的血清中OPG的水平。结果：MM患者的血清OPG水平为（222．4&#177;114．8）pg／ml,与对照组相比明显降低（P〈0．01）。0～1个骨损组血清OPG水平为（312．4&#177;129．6）pg／ml,而2～3个骨损组为（179．0&#177;59．4）pg／ml,0～1个骨损组明显高于2～3个骨损组（P〈0．01）。MM患者血清OPG水平与β2-微球蛋白相关（P〈0．01）,与球蛋白相关（P〈0．01）,与白蛋白无关（P〉0．05）,与临床分期、免疫学分型、血红蛋白、血钙未发现有相关性。结论：MM患者血清OPG水平明显低于正常对照,且其降低程度与骨损害的严重程度密切相关;同时,OPG水平与β2-微球蛋白呈负相关,提示血清OPG水平可能对MM的预后具有重要意义。     

Three-step high-dose sequential chemotherapy in patients with newly diagnosed multiple myeloma

BACKGROUND AND OBJECTIVES: High-dose chemotherapy (HDT) with autologous peripheral blood progenitor cell (PBPC) transplant has been increasingly used for newly diagnosed multiple myeloma (MM) in recent years. Presently available results suggest an improvement in the complete remission rate and survival as compared to conventional chemotherapy. However, there is no plateau in the survival curves, and experiments with new treatment schedules and conditioning regimens are warranted. DESIGN AND METHODS: In a non-randomised controlled trial, 20 patients underwent three-step HDT following conventional vincristine/doxorubicin/dexamethasone (VAD)-based induction. In the intensification phase patients received high-dose cyclophosphamide (HD-CY), high-dose etoposide (HD-VP), and mitoxantrone (NOV) plus melphalan (L-PAM) with haemopoietic rescue. Maintenance treatment with interferon was given until relapse. Actuarial overall survival (OS) and event-free survival (EFS) curves were plotted according to the method of Kaplan and Meier. In five of the eight patients achieving complete remission (CR), the molecular disease was monitored by polymerase chain reaction technique (PCR). RESULTS: Overall 18/20 (90%) patients responded, with a CR rate of 40%. After an average follow-up of 40 months, median EFS and OS are 25.5 and 44.6 months, respectively. Monoclonal cells were detectable in the post-treatment bone marrow and in the aphereses of the five CR patients monitored by PCR. CONCLUSION: The present three-step HDT regimen, including conditioning with mitoxantrone and melphalan, proved to be feasible and safe. Our results are in agreement with the hypothesis that HDT results in an increased remission rate and in prolonged survival in newly diagnosed MM, but a cure is unlikely.     

血清乳酸脱氢酶水平与初诊老年多发性骨髓瘤病人预后的相关性分析

目的探讨血清乳酸脱氢酶(LDH)与初诊老年多发性骨髓瘤(MM)临床指标的相关性及其预后意义。方法回顾性分析我院2009年7月至2016年1月年龄≥65岁的78例初诊老年MM病人的临床资料,并绘制病人的Kaplan-Meier生存曲线,分析初诊时血清LDH水平与病人预后的关系。根据病人的LDH水平分为LDH正常组和LDH升高组,并根据荧光原位杂交技术检测结果对60例资料完整的MM病人进行修正的国际分期系统(R-ISS)分期,比较其与国际分期系统(ISS)分期对预后判断的准确性。结果所有病人中位随访时间为16.5个月,初诊时LDH水平升高者占11.5%(9/78)。LDH正常组中位生存期(OS)和中位无进展生存期(PFS)分别为44.0个月、23.0个月,LDH升高组分别为14.0个月、12.0个月,2组间比较,差异有统计学意义(P<0.01)。COX多因素回归分析显示,LDH水平升高是老年MM病人OS的独立不良预后因素(HR=5.998,95%CI2.454~14.664,P<0.001)。另外,ISS分期Ⅱ期和Ⅲ期病人的中位OS差异无统计学意义(44.0个月比39.0个月,P=0.713),中位PFS差异也无统计学意义(26.0个月比20.0个月,P=0.569);而R-ISS分期Ⅱ期和Ⅲ期病人的中位OS差异有统计学意义(44.0个月比15.5个月,P<0.001),中位PFS差异无统计学意义(21.0个月比14.0个月,P=0.097)。结论LDH水平是判断老年MM病人预后的重要指标,基于其基础上的R-ISS分期在预后判断中要优于ISS分期。     

Bortezomib and thalidomide, a steroid free regimen in newly diagnosed patients with multiple myeloma

Despite their efficacy in myeloma, corticosteroids have acute and chronic toxicities. Newer agents with significant anti-myeloma activity permit the development of steroid-free regimens. We designed a Phase II clinical trial to study the toxicity and efficacy of a steroid-free combination of bortezomib and thalidomide as a first-line treatment in patients with symptomatic myeloma. Patients received bortezomib 1·3 mg/m(2) on days 1, 4, 8 and 11 every 21 d and thalidomide 150 mg/d for a maximum of eight cycles. Amongst 27 evaluable patients, the overall response was 81·5% with 25·8% near complete response or greater. The response rate was comparable to most other two drug combinations for upfront therapy but lower than that obtained with the use of three drugs. The most common grade 3 toxicities were peripheral neuropathy (22%), pneumonia (15%), fatigue (7%) and anaemia (7%). Peripheral neuropathy completely resolved in 80% of the patients upon completion of therapy, but not in the remaining 20% of patients. No venous thromboembolic events were observed even in the absence of prophylactic anticoagulation. The median progression-free survival was 16·8 months (95% confidence interval 8·7-21·6 months). Median overall survival has not yet been reached at a median follow up of 39 months. The 3-year overall survival was 74%. This study demonstrates: (i) the efficacy of a steroid-free regimen; (ii) mostly reversible treatment-related peripheral neuropathy; and (iii) the absence of venous thrombotic events.     

Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)-1alpha and MIP-1beta correlates with lytic bone lesions in patients with multiple myeloma

Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta have been identified as candidates for multiple myeloma (MM)-derived bone-resorbing factors. To validate the clinical relevance of these observations, we investigated correlations between the ability of MM cells to secrete these chemokines and the extent of MM bone lesions as well as levels of biochemical bone markers in patients with MM. Patients with multiple bone lesions exhibited higher MIP-1alpha and MIP-1beta secretion from MM cells along with elevated urinary deoxypyridinoline (Dpd), without significant elevation of serum bone-specific alkaline phosphatase (BALP) or osteocalcin compared with those with minimal bone lesions. MIP-1alpha and MIP-1beta levels correlated positively with urinary Dpd and serum BALP but not with serum osteocalcin. These results provide further evidence for a causal role of MIP-1alpha and MIP-1beta in the development of lytic bone lesions, and suggest that MM cells suppress osteoblastic bone formation to cause an imbalance of bone turnover and development of destructive bone lesions.     

YKL-40, a new biomarker of endothelial dysfunction, is independently associated with albuminuria in type 2 diabetic patients

The aim of this study was to examine the possible association between YKL-40, a new biomarker of endothelial dysfunction, and albuminuria in 180 type 2 diabetic patients. Multivariate logistic regression analyses demonstrated that serum YKL-40 level was a determinant of albuminuria independently of conventional risk factors.     

Sotatercept in patients with osteolytic lesions of multiple myeloma

This phase IIa study evaluated the safety and tolerability of sotatercept, and its effects on bone metabolism and haematopoiesis in newly diagnosed and relapsed multiple myeloma (MM) patients. Patients were randomized (4:1) to receive four 28‐d cycles of sotatercept (0·1, 0·3, or 0·5 mg/kg) or placebo. Patients also received six cycles of combination oral melphalan, prednisolone, and thalidomide (MPT). Thirty patients were enrolled; six received placebo and 24 received sotatercept. Overall, 25% of patients received all four sotatercept doses; 71% of sotatercept‐treated patients had ≥1 dose interruption mainly due to increases in haemoglobin levels. Grade ≥3 adverse events (AEs) were reported in 17% of patients receiving placebo and 58% receiving sotatercept. Grade 4 AEs in sotatercept‐treated patients were neutropenia, granulocytopenia, and atrial fibrillation (one patient each). In patients without bisphosphonate use, anabolic improvements in bone mineral density and in bone formation relative to placebo occurred, whereas bone resorption was minimally affected. Increases in haemoglobin levels, versus baseline, and the duration of the increases, were higher in the sotatercept‐treated patients, with a trend suggesting a dose‐related effect. Multiple doses of sotatercept plus MPT appear to be safe and generally well‐tolerated in MM patients.     

硼替佐米对多发性骨髓瘤骨病的作用及其机制探讨

目的观察硼替佐米联合地塞米松方案(BD方案)对多发性骨髓瘤(MM)骨痛的疗效并初步探讨其作用机制。方法观察2006年10月至2009年4月中山大学附属第一医院血液科收治的59例接受BD方案和33例接受VADM方案(长春新碱、阿霉素、地塞米松与马法兰联合)的MM患者骨痛缓解、活动能力改善及骨事件发生情况;用酶联免疫吸附试验(ELISA)检测其中25例患者治疗前后抗酒石酸酸性磷酸酶(TRACP-5b)、骨碱性磷酸酶(BALP)及Wnt信号通路抑制因子DKK1的浓度。结果BD组在骨痛缓解率、活动能力改善和骨相关事件发生率方面均优于VADM组[分别为75.7%对50.0%,64.9%对20.8%和13.8%对57.8%(P均<0.05)]。与化疗前相比,BD组患者化疗后BALP浓度升高[(15.90±11.88)U/L对(48.98±47.07)U/L],TRACP-5b水平下降[(4.04±1.92)U/L对(2.22±1.53)U/L],DKK1水平下降[(19.08±11.78)μg/L对(9.78±5.14)μg/L],差异有统计学意义(P均<0.05)。结论BD方案对MM患者骨病有显著疗效;可促进骨髓瘤患者...     

YKL-40和IL-6在评估慢阻肺患者预后中的应用

目的探讨血清人软骨糖蛋白39(YKL-40)和白细胞介素-6(IL-6)在评估慢性阻塞性肺疾病(简称慢阻肺)患者预后中的应用价值。方法选择慢阻肺急性加重期患者60例、缓解期患者50例及体检健康者20例,分别测定YKL-40、IL-6、FEV1%及慢阻肺评估测试分数(CAT),分析其水平变化及相关性。结果与对照组比较,慢阻肺缓解组和急性加重组YKL-40、IL-6及CAT水平均升高,FEV1%均降低(P0.05);与慢阻肺缓解组比较,急性加重组YKL-40、IL-6及CAT水平均升高,FEV1%均降低(P0.05)。慢阻肺缓解组和急性加重组血清YKL-40、IL-6水平与FEV1%间存在负相关(P均0.05),与CAT间存在正相关(P均0.05)。结论联合检测血清YKL-40和IL-6水平在评估慢阻肺患者预后中具有重要应用价值,但其临界值水平需要进一步研究。