乳腺癌骨转移疼痛的综合治疗

目的　探讨缓解乳腺癌骨转移疼痛 ,恢复患者活动能力的方法。方法　 31例乳腺癌骨转移患者采用以CMFP或CAFP方案化疗为主 ,辅以放射性同位素或双磷酸盐类药物综合治疗 ,观察治疗后疼痛缓解、活动能力恢复及骨外转移灶的变化情况。结果　全组骨痛缓解率为 87.1 % (2 7/ 31 ) ,功能活动恢复 85 .7% (6/ 7) ,骨外转移灶的有效率为 67.9% (1 9/ 2 8)。结论　以化疗为主的综合治疗 ,不仅能较好地控制骨外转移灶的发展 ,而且能显著地缓解骨痛 ,恢复患者的活动能力     

A Prospective Study of Bone Tumor Response Assessment in Metastatic Breast Cancer

BackgroundIn our previous study, new MD Anderson (MDA) bone tumor response criteria (based on computed tomography [CT], plain radiography [XR], and skeletal scintigraphy [SS]) predicted progression-free survival (PFS) better than did World Health Organization (WHO) bone tumor response criteria (plain radiography [XR] and SS) among patients with breast cancer and bone-only metastases. In this pilot study, we tested whether MDA criteria could reveal bone metastasis response earlier than WHO criteria in patients with newly diagnosed breast cancer with osseous and measurable nonosseous metastases.MethodsWe prospectively analyzed bone metastasis response using each imaging modality and set of bone response criteria to distinguish progressive disease (PD) from non-PD and their association with PFS and overall survival (OS). We also compared the response of osseous metastases assessed by both criteria with the response of nonosseous measurable lesions.ResultsThe median follow-up period was 26.7 months (range, 6.1-53.3 months) in 29 patients. PFS rates differed at 6 months based on the classification of PD or non-PD using either set of criteria (MDA, P = .002; WHO, P = .014), but these rates, as well as OS, did not differ at 3 months. Response in osseous metastases by either set of criteria did not correlate with the response in nonosseous metastases.ConclusionMDA and WHO criteria predicted PFS of patients with osseous metastases at 6 months but not at an earlier time point. We plan a well-powered study to determine the role of MDA criteria in predicting bone tumor response by incorporating 18-fluorodeoxyglucose (¹⁸F) positron emission tomography (FDG-PET)/CT to see if findings using this modality are earlier than those with WHO criteria.     

Improved diagnosis of advanced bone marrow metastases by means of radiolabeled antigranulocyte antibodies

Assessment of bone marrow metastases using Tc-99m-labeled antigranulocyte antibodies and Tc-99m-labeled nanocolloids is discussed in osseous metastasizing breast cancer. A 53-year-old patient with bone metastases of breast cancer (pT2 pN1biv cM1) developed leukocytopenia WHO Grade III following polychemotherapy. Bone marrow scintigraphy with Tc-99m labeled nanocolloids and Tc-99m-labeled antigranulocyte antibodies revealed pronounced bone marrow infiltration as the cause. Comparing both procedures, the images with antigranulocyte antibodies showed a clearly better bone marrow image, considerably higher contrast and almost no superimposition of the liver over the spine. In osseous metastasizing breast cancer, scintigraphy with Tc-99m-labeled antigranulocyte antibodies enables assessment of metastases in the entire bone marrow.     

全身骨显像联合血清骨型碱性磷酸酶诊断肺癌骨转移

 【摘要】　目的　探讨全身骨显像和血清骨型碱性磷酸酶（B-ALP）对肺癌骨转移的诊断价值。方法　对58例肺癌患者进行全身骨显像,同时测定血清碱性磷酸酶（ALP）、B-ALP 水平,对其结果进行比较分析。结果　58例患者中,骨转移33例,转移率56.90 %。其中肺腺癌的骨转移率为70.97 %（22／33）,肺鳞状细胞癌为42.86 %（9／21）,差异有统计学意义（χ2＝4.109,P＝0.0427）。血清B-ALP水平≥150 U／L者骨转移发生率为95.46 %（21／22）,血清B-ALP水平＜150 U／L者骨转移发生率为33.33 %（12／36）,差异有统计学意义（χ2＝21.487,P＝0.0000）。骨转移灶≤3处组与＞3处组B-ALP分别为（125.00±25.00）U／L和（176.14±49.09）U／L,两组间B-ALP水平差异有统计学意义（精确概率法,P＝0.0013）。在诊断敏感性和特异性的比较中,骨显像诊断的敏感度最高,达到93.94 %,但其特异度最低,为92.00 %;而骨显像+ B-ALP敏感度降低至57.58 %,但特异度可达到100.00 %。结论　诊断肺癌骨转移应首选骨显像。同时检测血清B-ALP有助于明确肺癌患者核素骨显像异常表现的病变性质,联合检测B-ALP+骨显像可以提高诊断特异度。血清B-ALP对肺癌骨转移诊断及病情判断有一定临床应用价值。     

胰腺癌骨转移

目的探讨胰腺癌骨转移的诊断与治疗。方法回顾性分析1999年至2003年间胰腺癌骨转移病例2例。结果经X线、B超、CT、ECT,淋巴细胞rDNA分析,肿瘤细胞学检查、肿瘤标记物检测等方法确诊。1例女性胰腺低分化腺癌,术后2年胸椎及右骶髂骨转移,接受放疗后半年后死亡;1例男性胰腺癌伴胸腰椎骨转移,在行梗阻性黄疸内引流术后1个月因肺部感染,呼吸衰竭死亡,尚未能接受对骨转移灶的治疗。结论影像学检查是发现骨转移瘤的主要方法。胰腺癌骨转移,预后差,除对原发肿瘤治疗外,应积极治疗骨转移灶以延长此类晚期患者的生存期及提高生活质量。     

Rhenium-188-HEDP therapy for the palliation of pain due to osseous metastases in lung cancer patients

Rhenium-188-hydroxyethylidine diphosphonate (188Re-HEDP) is a novel and attractive radiopharmaceutical that localizes in areas of osseous metastases and emits beta particles with energy sufficient to be therapeutically useful. The aim of this study is to evaluate the effectiveness of 188Re-HEDP in patients with lung cancer for the palliation of painful osseous metastases. Intravenous administration of activities ranging between 1.15 GBq (31 mCi) and 4.6 GBq (124 mCi) of 188Re-HEDP was given to each of 30 patients with painful osseous metastases from lung cancer. The patients were clinically followed at weekly intervals for the first 2 months, and monthly thereafter up to 1 year. Hematologic testing was performed before treatment and thereafter for 6 weeks. Pain response was scored by a four-point pain-rating scale as complete, marked, mild, and no response. Prompt and significant relief of bone pain occurred in 80% with no significant side-effects or hematopoietic toxicity. Forty-six percent (46%) of the patients discontinued analgesics after treatment. This clinical study indicated that 188Re-HEDP can offer significant pain palliation and is a useful radiopharmaceutical for treating painful osseous metastases from lung cancer.     

骨显像诊断原发恶性肿瘤骨转移的临床价值（附120例报告）

全身骨显像对于早期发现原发恶性肿瘤骨转移具有重要价值。本文对120例经手术病理或x线片等确诊的原发恶性肿瘤进行了全身核素骨显像,并对骨转移的分布、图形特点、骨转移发生率及临床意义进行了讨论。指出全身骨显像对诊断骨转移癌比X线片敏感。它比x线早期发现骨转移灶3～6个月。常见的原发恶性肿瘤中以肺癌、乳腺癌、直肠癌、前列腺癌的骨转移发生率较高。     

Clinical approaches to osseous metastases in prostate cancer

BACKGROUND: Prostate cancer is unique among solid tumors in its proclivity to metastasize primarily to bone. Osseous metastases pose a formidable health threat to patients with metastatic disease, putting them at risk for pain, marrow crowding, fracture, and other sequelae. Treatments directed against bone disease have the potential both to palliate pain and to increase survival. CONCLUSIONS: A number of agents exist that have the potential to palliate the effects of osseous metastases and should be routinely applied in the clinical care of the patient with advanced prostate cancer. These include hormones, bone-seeking radiopharmaceuticals, chemotherapy, and bisphosphonates. Strategies under investigation aim to eradicate bone disease, and not merely palliate symptoms. These approaches combine those listed above with tumor-directed targeting of osseous disease and manipulation of the biology that underlies the cancer's relationship to bone.     

The role of bisphosphonates as adjuvant therapy for breast cancer

Bone is the most common site of distant recurrence in breast cancer. The development of skeletal metastases involves complex interactions between the cancer cells and the bone microenvironment. The presence of tumor in bone is associated with activation of osteoclasts, resulting in excessive bone resorption. Bisphosphonates are potent inhibitors of osteoclastic bone resorption with proven efficacy in reducing tumor-associated skeletal complications. Several studies have investigated the adjuvant, or preventive, use of these drugs in breast cancer. Laboratory experiments have shown that the development of bone metastases can be inhibited by bisphosphonates. Three randomized clinical trials of bisphosphonates in nonmetastatic breast cancer patients have yielded conflicting results with respect to development of osseous and visceral metastases and survival. Defining the potential role of these agents in adjuvant breast cancer treatment requires further investigation in randomized, large-scale, multicenter clinical trials. The data available to date provide a strong impetus for continued clinical and laboratory work with bisphosphonates in breast cancer.     

Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis

Although metastasis is a frequent event in breast cancer patients, insight into the clinical course, prognosis and therapy with respect to the site of the first metastases has been poor and contradictory in former investigations. Follow-up data from 648 patients with metastatic breast cancer were statistically analyzed. Patients with bone metastases at first relapse had better overall survival (median 71 vs. 48 months; p<0.001) and survival after first metastases (median 24 vs 12 months; p<0.001) than patients with visceral metastases at first relapse. Bone was the site of first metastasis in 46%, and 71% of patients with metastatic breast cancer developed bone metastases. The localization of the second metastatic site was of prognostic relevance in patients with first visceral metastases, but not in patients with first bone metastases. The presence of osseous metastases correlated significantly with estrogen and progesterone receptor positivity, tumor grading I/II and S-phase fraction <5%. The better prognosis of patients with bone metastases is not determined exclusively by hormone receptor status. The disease is significantly more stable in patients with first bone metastases than in those with first visceral metastases.     

Skeletal muscle metastases from lung cancer

Hematogenous metastases to the limb skeletal muscles are extremely rare. Better understanding of the mechanisms resulting in the relative resistance of skeletal muscle to metastases could have bearing on therapeutic interventions for prevention of metastases. Three patients with non-small cell lung cancer and metastases in the proximal limb muscles are presented. Skeletal muscle metastases may present as painful masses in the proximal skeletal muscles. Subcutaneous and osseous metastases which are more frequent must be excluded by careful physical examination, bone scan and x-rays. Computed tomography (CT) can confirm the location of the tumor within the fascial planes of skeletal muscles and may help in the accurate delineation of the radiation portal. The tumor can be diagnosed and more common causes, such as hematoma or abscess, can be excluded by thin needle aspiration with cytologic examination. Clinical recognition of metastases in this unusual site is important based on our report that total tumor dose of 3600 to 4200 cGy of radiation in fractions of 300 cGy, 5 days a week, is effective in palliation of swelling and pain.     

Radionuclide bone scan, radiographic bone survey, and alkaline phosphatase: studies of limited value in asymptomatic patients with ovarian carcinoma

Bone scans or skeletal surveys were obtained in 104 patients with ovarian carcinoma. No metastases were identified at staging in the 43 patients with Stage I or II disease. Four patients in the entire series had osseous metastases. Three of the 40 patients with Stage III epithelial ovarian carcinoma had osseous metastases at the time of staging. All of these were Grade III lesions. One Stage I, Grade III patient demonstrated osseous metastases two years after initial diagnosis. None of the four patients with osseous metastases had an elevated alkaline phosphatase; three of the four had bone pain. Based on these results, it is suggested that radiographic bone survey and radionuclide bone scans are not indicated as screening procedures in asymptomatic patients with ovarian carcinoma.     

Total and nondialyzable hydroxyproline excretion in Stage D2 prostate cancer

Hydroxyproline is excreted in urine as a breakdown product of normal bone turnover: A dialyzable (D) fraction (90% of total) reflects active bone destruction and a nondialyzable (ND) fraction reflects bone growth/regrowth. In metastatic prostate cancer where blastic osseous metastases predominate, disease progression on bone scan correlated with elevation of both total hydroxyproline excretion (7.84 + 1.28, P less than 0.001) and the ND urinary level (0.94 +/- 0.20, P less than 0.01). In patients with a serially stable/improving scan, urinary excretion of each fraction (2.18 + 0.27 and 0.27 +/- 0.01) was similar to that of men with no evidence of disease. For Stage D2 prostate cancer, these two markers satisfactorily monitor osseous activity in the intervals between serial bone scintigraphy.     

A case of multiple bone metastases from gastric cancer treated with combination chemotherapy of S-1 and CDDP

We report a case of multiple bone metastases from gastric cancer treated with combination chemotherapy of S-1 and CDDP. A 54-year-old man underwent distal gastrectomy for gastric cancer (Stage II) in March 2003. Multiple bone metastases complicated with DIC were diagnosed in September 2005. The patient was treated with combination chemotherapy of S-1 and CDDP. S-1 (80 mg/m2/day) was administered for 21 days followed by 14 days rest as one course. CDDP (60 mg/m2) administration was begun 8 days after the start of S-1. After one course of the treatment, DIC was resolved. The abnormal uptake at the bone metastases was found to have decreased by bone scintigraphy. Bone metastases recurred in April 2006. Although combination chemotherapy of S-1 and DOC was administered, the patient died of DIC in August 2006. Combination chemotherapy of S-1 and CDDP is considered effective treatment for prolonging survival in cases of gastric cancer with bone metastases.     

Risk of complications from bone metastases in breast cancer. implications for management

A retrospective analysis of 859 patients who developed bone metastases from breast cancer between 1975 and 1991 was performed in order to identify factors that predict for complications from skeletal disease. The patients were divided into four groups based on the sites of disease at diagnosis of skeletal metastases: bone disease only; bone and soft tissue disease; bone and pleuro-pulmonary disease; bone and liver disease. Patients with metastatic disease confined to the skeleton were most likely to develop a pathological fracture. The time to long bone fracture was similar for all groups, but the least number of such fractures occurred in patients with bone and liver metastases since their survival was shortest (median: 5.5 months; P<0.001). Patients with bone metastases only were most likely to require radiotherapy to painful osseous deposits (P=0.0001) and most rapidly developed spinal cord compression (P=0.01, data not shown). The results suggest that patients with disease confined to the skeleton at the diagnosis of bone metastases are most likely to develop skeletal-related complications from advanced breast cancer. Such patients may benefit most from treatment with bisphosphonates.     

A case of bone marrow carcinomatosis from breast cancer treated with weekly Paclitaxel

We report a case of bone marrow carcinomatosis originating from breast cancer that was treated with weekly paclitaxel (PTX). A 42-year-old female patient underwent mastectomy with axillary lymph node dissection for breast cancer in 2001. Multiple bone metastases were diagnosed in 2008, but she remained stable with chemotherapy and hormonal therapy for about two years. In 2010, thrombocytopenia occurred, and she was diagnosed with bone marrow carcinomatosis after bone marrow biopsy. She was treated with weekly PTX(80 mg/m2), and recovered successfully after treatment. About one year has elapsed since initiation of therapy, and there has been no recurrence. Bone marrow carcinomatosis originating from breast cancer is very rare, and is regarded as a disease with a poor prognosis. However, weekly PTX could be a valid treatment for prolonging survival of bone marrow carcinomatosis originating from breast cancer.     

Synchronous bilateral retinal metastases from lung adenocarcinoma

Hematogenous retinal metastases from non-small cell lung cancer are rare, and are even more uncommonly observed bilaterally. Non-small cell lung cancer usually metastasizes to the liver, adrenal glands, lung, bone, central nervous system, and kidney. We report the case of a 41-year-old male patient with advanced lung adenocarcinoma heavily pretreated with polychemotherapy and palliative radiotherapy up to June 2003, when synchronous bilateral retinal metastases were diagnosed. The patient's prognosis was worsened by the onset of the retinal metastases and he died three months later.     

Complimentary role of FDG-PET imaging and skeletal scintigraphy in the evaluation of patients of prostate carcinoma

Prostate cancer is one of the most common malignancies of elderly males. Management depends on the accurate estimation of disease both at initial diagnosis and in its subsequent course. In the present study, we evaluated the diagnostic utility of positron emission tomography with 18 F-fluorodeoxyglucose (FDG-PET) in patients having prostate cancer. The findings were compared with the results of bone scan (BS) for the detection of bone metastases. Sixteen patients (age range, 55-83 years) with confirmed diagnosis of prostate cancer were included in the prospective study. Three patients had undergone bilateral orchidectomy, 1 had hormonal therapy, 9 had undergone both, and 3 had no therapy. All the patients underwent wholebody BS and FDG-PET within 1 week. Interpretation of BS and FDG-PET were performed qualitatively. Osseous abnormalities detected by both methods were compared. Involvement of the disease in other sites as seen on FDG-PET was also noted. BS detected 197 osseous lesions, whereas FDG-PET could detect 97 (49%) bone lesions. However, in 3 patients without any prior therapeutic intervention, FDG-PET results were superior or equivalent to that of BS. FDG-PET also detected extensive involvement of the disease in the bone marrow in 4 patients, lymph node metastases at various sites in 8, liver metastases in 2, and lung metastases in 1 patient. FDG-PET could demonstrate less number of osseous metastases in comparison with BSs, but the results have to be interpreted in the background of prior treatment administered and the tumor biology of the lesion. It is evident that FDG-PET could detect the unknown soft tissue involvement of the disease with good sensitivity, which might play an important role in the management of prostate cancer. Overall, in the absence of novel PET tracers, both skeletal scintigraphy and FDG-PET imaging can play a complimentary role in the management of prostate cancer.     

Prognostic factors for skeletal relapse in breast cancer.

Bone metastases and the strong interaction between osseous and metastatic cell populations require interdisciplinary thought and actions. If it were possible to interrupt the malignant dialogue between tumour and bone at an early stage, this might not only reduce the amount of bone destruction, but could also reduce the incidence of osseous metastases and remove the source of secondary metastases to other organs.Studies into the preventive effects of bisphosphonates are currently running or are planned. Most of these studies are in breast cancer patients with involvement of the axillary lymph nodes. The prognostic factors of lymph node status, tumour size and grading are better than none, but do not select patients at a high risk of skeletal metastasis. This would be much better done by using immunohistochemical methods to investigate the primary tumour for bone sialoprotein and parathyroid hormone-related protein (PTHrP). However, these methods are complicated, have not been validated in large numbers of patients and are not standardized. Serum tests for bone sialoprotein, PTHrP and collagen fragments are currently still under development and cannot be recommended generally. The clinical importance of tumour cells in the bone marrow has been demonstrated but is still only used at a few centres.     

ABCC5 supports osteoclast formation and promotes breast cancer metastasis to bone

Introduction

Bone is the most common site of breast cancer metastasis, and complications associated with bone metastases can lead to a significantly decreased patient quality of life. Thus, it is essential to gain a better understanding of the molecular mechanisms that underlie the emergence and growth of breast cancer skeletal metastases.

Methods

To search for novel molecular mediators that influence breast cancer bone metastasis, we generated gene-expression profiles from laser-capture microdissected trephine biopsies of both breast cancer bone metastases and independent primary breast tumors that metastasized to bone. Bioinformatics analysis identified genes that are differentially expressed in breast cancer bone metastases compared with primary, bone-metastatic breast tumors.

Results

ABCC5, an ATP-dependent transporter, was found to be overexpressed in breast cancer osseous metastases relative to primary breast tumors. In addition, ABCC5 was significantly upregulated in human and mouse breast cancer cell lines with high bone-metastatic potential. Stable knockdown of ABCC5 substantially reduced bone metastatic burden and osteolytic bone destruction in mice. The decrease in osteolysis was further associated with diminished osteoclast numbers in vivo. Finally, conditioned media from breast cancer cells with reduced ABCC5 expression failed to induce in vitro osteoclastogenesis to the same extent as conditioned media from breast cancer cells expressing ABCC5.

Conclusions

Our data suggest that ABCC5 functions as a mediator of breast cancer skeletal metastasis. ABCC5 expression in breast cancer cells is important for efficient osteoclast-mediated bone resorption. Hence, ABCC5 may be a potential therapeutic target for breast cancer bone metastasis.