Serum bone turnover markers may be involved in the metastatic potential of lung cancer patients

The aim of this study was to investigate several bone markers in Non-Small Cell Lung (NSCLC) and Small Cell Lung (SCLC) patients experiencing or not secondary bony disease. Fasting serum levels of bone formation, bone resorption, and osteoclastogenesis markers were determined in 22 NSCLC patients with bone metastases, 18 without bone metastasis, and 28 SCLC patients. A total of 29 healthy volunteers were also included in the study. Decreased osteocalcin (OC) serum levels and increased osteopontin and ligand of the receptor of nuclear factor kB (RANKL) serum levels were detected in NCSLC patients with bone metastases while increased C-terminal cross-linking telopeptide of type I collagen and increased RANKL/OPG (osteoprotegerin) ratio were detected in SCLC patients. Increased serum levels of OPG were observed in all lung cancer patients. OPG may be actively involved in the development of lung cancer metastasis. Furthermore, OC, OPN, and RANKL in NSCLC and CTX and RANKL in SCLC patients may also have a broader role in the pathogenesis and spread of lung cancer. They also provide useful information in identifying the group of patients that may benefit from a more rigorous treatment.     

骨转换标志物在非小细胞肺癌骨转移临床应用价值的研究

Objective  

The purpose of this study was to assess the clinical application value of bone turnover markers in non-small-cell lung cancer (NSCLC) patients with bone metastases. Including diagnosing bone metastases, detecting bone metastatic spread.     

Biochemical markers of bone turnover in breast cancer patients with bone metastases: a preliminary report

BACKGROUND: Some biochemical markers of bone turnover are expected to reflect the disease activity of metastatic bone tumor. In the present study six biochemical markers were evaluated to determine appropriate markers for the detection of metastatic bone tumors from breast cancer (BC). METHODS: A panel of bone turnover markers was assessed in 11 normocalcemic patients with bone metastases from BC and in 19 BC patients without clinical evidence of bone metastases. Bone formation was investigated by measuring serum bone isoenzyme of alkaline phosphatase (BALP), osteocalcin (OC) and carboxy-terminal propeptide of type I procollagen (PICP): Bone resorption was investigated by measuring serum carboxy-terminal telopeptide of type I collagen (ICTP), fasting urinary pyridinoline (Pyr) and deoxypyridinoline (D-Pyr). RESULTS: PICP was influenced by age and menopausal status. Significant correlations were observed between each of bone turnover markers except between BALP and OC. The mean levels of the six bone turnover markers were higher in patients with bone metastases than in those without them and significance was observed except for OC. The best diagnostic efficiency by receiver-operating characteristic (ROC) analysis was provided by ICTP followed by Pyr or D-Pyr, BALP, PICP and OC and significance was observed between ICTP and OC. Multiple logistic regression analysis adjusted by age revealed that the only significant marker related to bone metastases was ICTP. CONCLUSIONS: Serum ICTP appears to be the leading marker of bone metastases from BC. However, to reveal the clinical usefulness of these markers, further examination will be needed to account for the ease and cost-effectiveness of the measurements.     

Different patterns of change in bone turnover markers during treatment with bone-modifying agents for breast cancer patients with bone metastases

Background

Bone-modifying agents are effective for treatment of breast cancer patients with bone metastases. Since their action is mediated through suppression of the osteoclast function, their efficacy can be determined by monitoring bone turnover markers. However, the clinical significance of these markers is yet to be compared.

Methods

For this study, 52 breast cancer patients with bone metastases treated with zoledronic acid (n = 36) or denosumab (n = 22) were enrolled (6 patients were treated sequentially with both agents). Serum tartrate-resistant acid phosphatase-5b (TRACP-5b), pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (1CTP), N-terminal cross-linking telopeptides of type I collagen (NTX) and bone-specific alkaline phosphatase (BAP) were measured at pretreatment and 1, 3 and 6 months after treatment.

Results

Serum TRACP-5b (p < 0.0001), NTX (p = 0.0007) and BAP (p = 0.0032) decreased significantly after treatment. The baseline median value of TRACP-5b (457.5 mU/dL, range 173–1630 mU/dL) decreased to 137 mU/dL (91–795 mU/dL) 1 month after treatment. Reduction in serum NTX and BAP was greatest after 3 and 6 months, respectively. TRACP-5b, NTX and BAP were above normal levels at baseline in 62.5, 25 and 35.3 % of patients, respectively, and nearly 80 % of these patients attained normal levels during the treatment.

Conclusions

Although bone-modifying agents reduced the baseline levels of TRACP-5b, NTX and BAP significantly, the reduction patterns differed. TRACP-5b appears to affect levels most quickly and sensitively, possibly due to its direct link to the number and activity of osteoclasts. These findings suggest that the efficacy of TRACP-5b is clinically significant when considering which bone-modifying agents to use for breast cancer patients with bone metastases.

     

Clinical use of markers of bone turnover in metastatic bone disease

Bone metastases profoundly perturb normal bone remodeling. Biochemical markers of bone turnover have been shown to reflect these tumor-induced changes in bone remodeling and might therefore be useful in the diagnosis and follow-up of patients with malignant bone disease. Most markers of bone turnover, particularly those of bone resorption, are elevated in patients with established bone metastases. While this might indicate a role for bone markers as diagnostic tools in cancer patients, the available evidence does not provide any final conclusions as to the accuracy and validity of the markers presently used in the early diagnosis of bone metastases. Markers of bone resorption respond promptly and profoundly to bisphosphonate and antineoplastic therapy, and this response is associated with a favorable clinical outcome. Most markers, however, have been more useful in groups of patients monitored in clinical studies than in studies of individuals. While this makes them a good tool for drug development, it remains unknown whether the use of bone markers in a routine clinical setting has any defined beneficial effects on overall outcome in cancer patients. In particular, no study has addressed the question of whether patients with bone metastases should be treated according to their rate of bone turnover and what the treatment goals are in this respect. While it is unlikely that bone-turnover markers have sufficient diagnostic or prognostic value when used in isolation, the combination of these markers with other diagnostic techniques might be the way forward to improve the clinical assessment of patients with cancers of the bone.     

Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: diagnostic and prognostic implications

Our aim was to assess the diagnostic accuracy of bone markers in serum of patients with prostate cancer (PCa) for early detection of bone metastases and their usefulness as predictors of PCa-caused mortality. In sera of 117 PCa patients (pN0M0, n = 39; pN1M0, n = 34; M1, n = 44), 35 healthy men and 35 patients with benign prostatic hyperplasia, bone formation markers [total and bone-specific alkaline phosphatase (tALP, bALP), amino-terminal procollagen propeptides of type I collagen (P1NP), osteocalcin (OC)], bone resorption markers [bone sialoprotein (BSP), cross-linked C-terminal (CTX) and cross-linked N-terminal (NTX) telopeptides of type I collagen, tartrate-resistant acid phosphatase isoenzyme 5b (TRAP)] and osteoclastogenesis markers [osteoprotegerin (OPG), receptor activator of nuclear factor kappaB ligand (RANKL)] were measured. tALP, bALP, BSP, P1NP, TRAP, NTX and OPG were significantly increased in PCa patients with bone metastases compared to patients without metastases. OPG showed the best discriminatory power to differentiate between these patients. Logistic regression analysis resulted in a model with OPG and TRAP as variables that predicted bone metastasis with an overall correct classification of 93%. Patients with concentrations of OPG, P1NP, tALP, bALP, BSP, NTX, TRAP and CTX above cut-off levels showed significantly shorter survival than patients with low marker concentrations. Multivariate Cox proportional hazards regression revealed that only OPG and BSP were independent prognostic factors for PCa-related death. Thus, the importance of serum OPG in detecting bone metastatic spread, alone or in combination with other bone markers, and predicting survival in PCa patients has been clearly demonstrated.     

Gallium nitrate inhibits accelerated bone turnover in patients with bone metastases

Bone metastases are a major source of morbidity in patients with cancer. Previously, we found that gallium nitrate was a highly effective treatment for cancer-related hypercalcemia. Laboratory studies have shown that this drug inhibits bone resorption in vitro and that short-term treatment in vivo increases the calcium content of bone. We evaluated the clinical effects of gallium nitrate on biochemical parameters of increased bone turnover in 22 patients with bone metastases. Treatment with gallium nitrate for five to seven days caused a median reduction in 24-hour urinary calcium excretion of 66% relative to baseline measurements (P less than .01). Hydroxyproline (OHP) excretion was also significantly reduced (P less than .01). The greatest reduction in hydroxyprolinuria occurred in patients with high baseline excretion. Ionized serum calcium and serum phosphorous declined significantly after treatment (P less than .01 for each). Serum immunoreactive parathyroid hormone (PTH) increased significantly (P less than .01), as did serum levels of 1,25 (OH)2-vitamin D3 (P less than .05). Urinary phosphorous excretion and serum levels of 25-OH-vitamin D3 were not significantly changed. No major toxic reactions occurred as a result of this treatment. These results indicate that gallium nitrate significantly reduces biochemical parameters associated with accelerated bone turnover and that this agent may be useful for preventing pathologic conditions associated with bone metastases.     

Serum tumor markers in patients with breast cancer

Several serum tumor markers have been investigated in patients with breast cancer for assessing outcome, predicting recurrence and monitoring the therapeutic response. There is a general consensus concerning their limited application in diagnosing malignancy; however, serum tumor markers can be considered for the early detection of recurrence. The most effective markers for this indication are cancer antigens (CA)15-3 and 27.29, and c-erbB-2, although their efficacy in establishing disease progression has not been determined to date. In terms of evaluating prognosis and predicting response to therapy, only the expression of c-erbB-2 has clinical evidence. To conclude, at present, no serum tumor marker is cost effective, and none can be used with confidence in the decision making regarding breast cancer patients.     

Serum tumor markers in patients with breast cancer

Several serum tumor markers have been investigated in patients with breast cancer for assessing outcome, predicting recurrence and monitoring the therapeutic response. There is a general consensus concerning their limited application in diagnosing malignancy; however, serum tumor markers can be considered for the early detection of recurrence. The most effective markers for this indication are cancer antigens (CA)15-3 and 27.29, and c-erbB-2, although their efficacy in establishing disease progression has not been determined to date. In terms of evaluating prognosis and predicting response to therapy, only the expression of c-erbB-2 has clinical evidence. To conclude, at present, no serum tumor marker is cost effective, and none can be used with confidence in the decision making regarding breast cancer patients.     

骨生化指标在骨肿瘤中的临床应用进展

骨肿瘤是起源于间充质细胞,发生于骨组织及其附属结构的一类良、恶性肿瘤的总称,骨肿瘤的发病率女性约为1.060/10万,男性约为1.112/10万,虽属少见的肿瘤类型,但对人体的危害大,特别是恶性肿瘤,目前疗效虽然提高,但仍不令人满意,发病趋势呈年轻,在骨科领域中占有重要地位[1]。正常的骨代谢是骨生成和骨吸收的动态平衡,这种平衡主要有骨组织中成骨细胞或破骨细胞维持,当这种平衡被打破时就会表现出各种骨疾病。骨生成和骨吸收异常伴随的生化指标及导致骨生成和骨吸收变化的相关因素均可作为骨肿瘤的生物标记。随着分子生物学技术的发展,有望通过检测骨肿瘤患者体内的生化指标变化达到早期诊断和治疗的目的。现在就骨组织生化指标在骨肿瘤患者诊治中的研究作一综述,以探讨他们的临床应用价值。     

肿瘤切除术后肝动脉介入化疗栓塞术治疗原发性肝癌患者的血清肿瘤标志物和生存情况研究

目的探讨肿瘤切除术后肝动脉介入化疗栓塞术(TACE)治疗原发性肝癌患者的血清肿瘤标志物及生存情况。方法选取2014年1月至2016年7月间资阳市安岳县人民医院收治的行肿瘤切除术的64例原发性肝癌患者,采用随机数表法分为研究组和对照组,每组32例。两组患者均行常规肿瘤切除术,研究组患者术后2个月内行TACE治疗,比较两组患者治疗结束后血清肿瘤标志物水平,随访复发率和生存率。结果治疗后,研究组患者甲胎蛋白异质体(AFP-L3)、甲胎蛋白(AFP)、磷脂酰肌醇蛋白聚糖-3(GPC3)和高尔基体蛋白-73(GP73)含量均低于对照组,差异均有统计学意义(均P <0. 05)。研究组患者1年复发率和2年复发率均低于对照组,差异均有统计学意义(均P <0. 05);两组患者3年复发率比较,差异无统计学意义(P>0. 05)。研究组患者1年生存率和2年生存率均高于对照组,差异均有统计学意义(均P <0. 05);两组患者3年生存率比较,差异无统计学意义(P>0. 05)。结论肿瘤切除术后行TACE治疗原发性肝癌患者,能有效降低患者肿瘤标志物水平,短期内有效降低复发率,提高生存率。     

Serum bone sialoprotein in patients with primary breast cancer is a prognostic marker for subsequent bone metastasis.

Bone sialoprotein (BSP) is a noncoflagenous bone matrix protein that is important for both mineralization and cell-cell interactions. Tissue studies in primary breast cancers have shown that immunohistochemical expression of BSP is associated with a high incidence of bone metastases in the course of the disease. We used a RIA to investigate the importance of serum BSP as a marker for subsequent bone metastases. Between 1994 and 1996, preoperative blood samples were collected from 388 consecutive patients with nonmetastatic breast cancer and from 30 control patients with benign breast disease. Serum BSP concentrations were measured in a blinded fashion by RIA. The cutoff for elevated serum BSP values was 24 ng/ml, ie., two SDs above the normal mean value. Serum BSP was correlated with the risk of metastasis and analyzed with regard to its prognostic value. After a median follow-up period of only 20 months, 28 patients had developed metastases. Fourteen patients had bone metastases only, 9 visceral metastases only, and 5 a combination of osseous and visceral metastases. Of the 19 women with skeletal metastases, 17 had preoperative serum BSP values in excess of 24 ng/ml (median BSP values: 48.3 ng/ml for isolated metastatic bone disease, 30.6 ng/ml for combined metastases), whereas none of the women with visceral metastases only had elevated serum BSP concentrations (median BSP value: 12.3 ng/ml). The median serum BSP value in the control group (benign breast disease) was 8.8 ng/ml serum BSP; levels correlated with the size of the primary tumor, but not with any other prognostic factors. Using a multivariate regression analysis, serum BSP was found to be the most important independent prognostic factor for the development of skeletal metastasis (P < 0.001; relative risk, 94); its specificity was 96.7%, and its sensitivity was 89.5%. Our study shows that patients with preoperatively elevated serum BSP levels are at high risk of subsequent bone metastases in the first years after primary surgery. The mechanism of BSP in the pathogenesis of skeletal metastases is unclear. Because BSP contains an integrin recognition sequence, its expression in tumor cells may facilitate their adhesion to the bone surface. However, it is possible that a proportion of circulation BSP is derived from normal or tumor-induced bone turnover. Breast cancer patients with elevated serum BSP levels may benefit from osteoprotective adjuvant therapy with bisphosphonates.     

Clinical outcome of total scapulectomy in 10 patients with primary malignant bone and soft-tissue tumors

BACKGROUND AND OBJECTIVES: Limb reconstruction after total scapulectomy for malignant bone and soft-tissue tumors around the scapula is difficult. This study was undertaken to clarify the clinical results of total scapulectomy in patients with malignant bone and soft-tissue tumors around the shoulder girdle in our institute between 1984 and 1998. METHODS: Ten patients undergoing total scapulectomy had an age range of 12-82 years (average = 56 years). There were 5 cases of bone tumor and 5 cases of soft-tissue tumor. The follow-up period ranged from 8 months to 13 years 5 months. RESULTS: Seven patients are currently alive; the remaining 3 patients died of other diseases. One case of local recurrence was detected. The 2-year survival rate of all cases was 78.8%, and the 5-year survival rate was 52.5%. The average function evaluated by Enneking's criteria was 64.6%. Although the range of motion in the shoulder joint was seriously limited in all patients, the elbow and hand functions were almost normal. Recently, we have used a bone-anchoring system to suture between the clavicle and muscles, including the biceps, triceps, and deltoid muscles. CONCLUSIONS: Patients who undergo total scapulectomy may achieve much better upper limb function than those who undergo forequarter amputation (interscapulothoracic amputation).     

Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving zoledronic acid

BACKGROUND: For patients with bone metastases, high N-telopeptide of type I collagen (NTX) levels correlate with increased risks of skeletal-related events and death. However, the relation between NTX decreases and clinical benefits is unclear. METHODS: Correlations between NTX normalization during treatment and clinical outcome were retrospectively analyzed in 3 large, phase 3 trials. Urinary NTX levels were measured at baseline and at Month 3 in patients with bone metastases from breast cancer (BC; n = 578), hormone-refractory prostate cancer (HRPC; n = 472), or nonsmall-cell lung cancer and other solid tumors (NSCLC/OST; n = 291) who received zoledronic acid or control (pamidronate for BC; placebo for HRPC and NSCLC/OST) for up to 24 months. NTX levels were characterized as normal (N; <64 nmol/mmol creatinine) or elevated (E; > or =64 nmol/mmol creatinine). RESULTS: After 3 months of zoledronic acid, most N-group patients maintained normal levels; however, most E-group patients normalized their NTX levels (BC, 81%; HRPC, 70%; NSCLC/OST, 81%). In contrast, NTX levels normalized with pamidronate in 65% of BC, with placebo in 8% of HRPC, and in 17% of NSCLC/OST E-group patients. Normalized NTX correlated with improved overall survival versus persistently elevated NTX (significant for zoledronic acid-treated patients; trend for placebo-treated patients). Moreover, percentage reductions from baseline NTX levels correlated with benefits regardless of whether patients transitioned from E to N. CONCLUSIONS: Zoledronic acid normalizes or maintains normal NTX levels in most patients with bone metastases. Normalized NTX within 3 months of treatment, versus persistently elevated NTX, was associated with reduced risks of skeletal complications and death.     

Influence of adjuvant tamoxifen treatment on bone mineral density and bone turnover markers in postmenopausal breast cancer patients in Japan

Molecular prognostic and predictive factors have extensively been studied in different cancers during the past decades, some of which were found to be useful in diagnosis, follow up or even treatment of some malignant tumors. To assess the significance of c-erbB-1, c-erbB-2 and p53 expression in head and neck tumors among Iranian patients and their correlation with known prognostic factors, samples from 53 patients with squamous cell carcinomas of larynx and tongue were studied immunohistochemically. Strong immunoreactivity of c-erbB-1, c-erbB-2 and p53 was observed in 37 (70%), 40 (76%) and 37 (70%) of cases, respectively. The coexpression of these molecules was detected in 27 (50.9%) samples. Neither histological grading nor nodal involvement revealed correlation with c-erbB-1 and/or c-erbB-2 expression. No correlation was found between p53 expression and histological grade. However, a significant positive association was observed between p53 expression and nodal involvement. This data, which is the first report on head and neck squamous cell carcinomas (HNSCC) in Iran, indicates the significance of p53 protein expression which may result from p53 tumor suppressor gene inactivation in lymph node metastasis of HNSCC among Iranian patients.     

Adult Gaucher disease in association with primary malignant bone tumors

BACKGROUND: Malignant neoplastic disorders are more common in patients with Gaucher disease (GD) than in the general population. Very few cases of primary malignant bone tumors in association with GD have been reported to date. Thus, the recommendations for an adequate therapy are often based on limited professional experience. To their knowledge, the authors report the first case of a leiomyosarcoma of the bone in a patient with GD and report another patient with GD and an anaplastic large cell non-Hodgkin lymphoma with localized osseous manifestation. A review of the literature is included. METHODS: The clinical, radiologic, and histologic data of the authors' two patients who had GD and primary malignant bone tumor are presented. Epidemiologic data, clinical data, and treatment results from published reports of 18 patients who had GD and various malignancies and the authors' 2 patients were compared and evaluated. RESULTS: Radiographic examination showed a destructive osteolytic lesion in a case of a leiomyosarcoma of the bone and in a case of anaplastic, large-cell, non-Hodgkin lymphoma. In both cases, the bone marrow architecture was partially effaced by sheets of large histiocytic cells with striated or fibrillary cytoplasm. In both patients, chemotherapy was performed. Whereas the patient who had the leiomyosarcoma showed poor recovery of the bone marrow that necessitated withdrawal of aggressive chemotherapy, the patient who had non-Hodgkin lymphoma and enzyme therapy tolerated the chemotherapy well. In spite of local control after preoperative radiotherapy and hemipelvectomy, the first patient developed lung metastases and finally died. The second patient was continuously free of disease at a follow-up examination 32 months after chemotherapy and radiotherapy. In a total of 20 patients who had malignant disorders and GD, the numbers of males and females were equivalent, and the mean age was 55 years. Approximately 33% presented with a cancer originating in the bone. In 16 patients, follow-up data were available. Of these, after a mean follow-up of 36 months (range, few days-108 mos), only 2 patients were continuously free of disease, and one patient was alive with disease. The other patients had died of disease or hemorrhagic complications of GD. CONCLUSIONS: Because there is a relatively high incidence of malignant disorders of the bone, the study suggested that malignant disorders have to be included in the differential diagnosis of painful lytic lesions in patients who have GD. Evaluation of the expense and value of enzyme therapy to patients who have GD should be undertaken with regard to the incidence of malignant disorders and patient survival.