Early Detection Of Bone Metastases Research Articles

Urinary hydroxyproline and prognosis in human breast cancer.

The excretion of urinary hydroxyproline has been measured before mastectomy in 342 patients presenting with breast cancer for the first time to Guy's Hospital. The first 106 women were maintained on a gelatine-free diet whilst the remainder were on unrestricted diet. In both dietary groups hydroxyproline levels or the ratio of hydroxyproline to urinary creatinine were not related to pathological stage or histological grade. The time between initial presentation and subsequent bone metastases was negatively and significantly associated with hydroxyproline excretion (P less than 0.05) and the ratio of hydroxyproline to creatinine (P less than 0.01) in women on a gelatine-free diet. A similar, but not significant, trend was observed in patients on unrestricted diet. Although hydroxyproline excretion was related to the time to onset of bone metastases the amount of hydroxyproline excreted by these patients was not significantly different from patients who had recurrences at sites other than bone or patients who were disease-free up to 5 years after initial diagnosis. The conclusion is that hydroxyproline is of little value in the early detection of bone metastases.

Getting Small Is Suddenly Very Big: Review of the Proceedings of the Third Annual Meeting of the Society for Molecular Imaging

he field of molecular imaging, defined here as imaging that provides information on cellular processes and molecular pathways in vivo, is rapidly growing. In this context, the term “molecular imaging” has been used for barely a decade and, until recently, few radiologists were aware of the term. The remarkable progress occurring during this short interval is, quite literally, leading to a revolution in thought. Anatomic imaging is being replaced by functional imaging, in which the underlying biochemical pathways can be directly interrogated to confirm the presence or absence of pathology. It is clear that many new techniques and insights gained from molecular imaging in animal models will play a role in imaging of human disease processes. However, which applications will bear fruit, and when, remain unclear. In the past few years, many scientific societies have formed to advance molecular imaging techniques. One of the major ones, the Society for Molecular Imaging (SMI), founded in 2000, held its third annual meeting September 9–12, 2004, in St. Louis, MO. The mission of the SMI is “to advance our understanding of biology and medicine through noninvasive in vivo investigation of cellular molecular events involved in normal and pathologic processes” [1]. Attendance at SMI’s annual meetings has grown significantly during the society’s short history. The first meeting in 2002 drew approximately 550 attendees; in 2004, the meeting had approximately 850 registrants. The goal of the 2004 meeting, to highlight the increasing ability to view disease processes in vivo, was accomplished through six plenary sessions, 16 symposia, two seminars, and more than 100 oral presentations. In addition, more than 300 posters were presented during two sessions. The meeting was called to order by David Piwnica-Worms, Washington University School of Medicine, after which Britton Chance, University of Pennsylvania, delivered the keynote lecture. This review highlights the presentations that are likely to be of special interest to radiologists. Those seeking more information should visit SMI’s Web site [1]. In his presentation, “How to Integrate ‘Molecular Imaging’ into Clinical Radiology,” King Li, National Institutes of Health, addressed the misconception that molecular imaging is an esoteric topic that will not contribute significantly to radiologic imaging of humans. Li defined molecular imaging as “the practice of medical imaging in an era of molecular medicine,” a description that should arouse the interest of radiologists in the field. He outlined the preliminary steps radiologists can take while they await the transition of molecular imaging from the animalimaging environment to the clinical-human environment. The first step is to understand the molecular biology that underlies the morphologic features seen on conventional imaging studies. The next step is to combine imaging information with the molecular diagnostic information available through numerous sources. One of the more interesting presentations explained how molecular imaging can advance our understanding of a common disease process—bone metastases from a remote primary tumor. Because development of metastases in bone marrow is dependent on expression of various growth factors normally released during bone resorption, therapies aimed at pharmacologic interference with bone turnover would be expected to decrease the rate of formation of these metastases. Several investigators are examining methods for early detection of bone metastases and assessment of therapies aimed at slowing the rate of formation. In “Optical Imaging in Early De-

Current role of bone scan with phosphonates in the follow-up of breast cancer.

A number of studies have demonstrated that bone scintigraphy has high sensitivity and efficacy in the early detection of bone metastases from several tumours, including breast cancer. Bone scintigraphy is the most definitive tool for diagnosing and monitoring metastatic spread of breast cancer. However, in the past decade there has been a wide debate on its impact on survival time, morbidity and quality of life. Worldwide economic restrictions and these studies have led to the adoption of an almost minimalist policy for breast cancer follow-up using evidence-based guidelines. The recommended breast cancer surveillance testing includes only a few procedures (history, physical and breast self-examination, patient education on symptoms, pelvic examination). The routine use of additional tests, such as blood cell count, tumour markers, liver ultrasonography, bone scan and chest X-rays, is not recommended. Accordingly, scintigraphy should be reserved for a limited number of patients. On the other hand, early diagnosis of bone involvement may reduce the risk of skeletal related events, thus leading to a significant improvement in quality of life. Furthermore, new drugs (e.g. bisphosphonates) can now delay the onset of bone metastasis and reduce the number of patients who experience skeletal complications. In conclusion, the evidence of the clinical usefulness of bone scintigraphy (to allow early planning of new treatments in advanced disease) has to be re-evaluated, possibly by large randomised prospective trials.

Bone remodeling markers in the detection of bone metastases in prostate cancer

Background: Early detection of bone metastases in prostatic carcinoma is very useful in treatment and prognosis of the disease. The aim of this work was to evaluate the sensitivity and specificity of a group of bone markers in order to discriminate between prostate carcinoma patients without (M 0) and with (M 1) bone metastases. Methods: Sixty-seven non-treated patients with: benign prostate hyperplasia ( n=21), prostatic carcinoma in several stages without bone metastases (T X M 0) ( n=31) and with bone metastases (T X M 1) ( n=15) were studied. The following markers were studied: (A) bone formation: (1) serum bone alkaline phosphatase, IRMA (Tandem Ostase, Beckman); (2) serum procollagen I amino-terminal propeptide (PINP), RIA (Orion Diagnostica); (B) bone resorption: (1) urinary collagen I amino-terminal telopeptide (NTX), ELISA (Ostex); (2) collagen I carboxy terminal telopeptide (CTX): (2A) urinary α-CTX, RIA (Osteometer), (2B) serum β-CTX, Elecsys (Roche); (3) collagen I cross-linked carboxy terminal telopeptide (ICTP), RIA (Orion Diagnostica). Results: Levels of all bone markers were significantly higher in group M 1 than in group M 0. A complete separation of groups M 0 and M 1 was achieved with PINP and β-CTX (100% sensitivity and specificity). Conclusions: These results support the use of PINP or β-CTX as a tool to confirm the presence or absence of bone metastases in the first staging of prostatic carcinoma patients.

Treatment and prognosis in colorectal cancer patients with bone metastasis

We have reviewed the cases of every patient presenting with bone metastasis after colorectal surgery and tried to establish the features of this clinical entity and generate basic strategies to the therapeutic management of this condition. Of 928 primary tumor resected colorectal cancer patients, 12 (1.3%) were identified with bone metastasis and included in this study. The majority of primary tumors were located at the rectosigmoid portion of the colon. All cases were highly advanced at the time of diagnosis, including 8 cases of stage IV by TNM classification. Sites of metastatic tumors were concentrated in lumber or pelvic bones. At the onset of bone metastasis, 9 of the 12 cases had other metastatic sites, i.e., only 3 patients had bone metastasis alone. Survival after onset of bone metastasis was very poor, with a median survival of approximately 5 months and a 20% survival rate at 1 year. With regard to cause of death, seven patients died of pulmonary failure, one of liver failure, and one of DIC. Only 2 cases of solitary osseous metastasis have survived more than 1 year. In order to significantly improve prognosis, the early detection of bone metastases is important.

Early detection of bone metastases in a murine model using fluorescent human breast cancer cells: application to the use of the bisphosphonate zoledronic acid in the treatment of osteolytic lesions.

A very common metastatic site for human breast cancer is bone. The traditional bone metastasis model requires human MDA-MB-231 breast carcinoma cell inoculation into the left heart ventricle of nude mice. MDA-MB-231 cells usually develop osteolytic lesions 3-4 weeks after intracardiac inoculation in these animals. Here, we report a new approach to study the formation of bone metastasis in animals using breast carcinoma cells expressing the bioluminescent jellyfish protein (green fluorescent protein [GFP]). We first established a subclone of MDA-MB-231 cells by repeated in vivo passages in bone using the heart injection model. On stable transfection of this subclone with an expression vector for GFP and subsequent inoculation of GFP-expressing tumor cells (B02/GFP.2) in the mouse tail vein, B02/GFP.2 cells displayed a unique predilection for dissemination to bone. Externally fluorescence imaging of live animals allowed the detection of fluorescent bone metastases approximately 1 week before the occurrence of radiologically distinctive osteolytic lesions. The number, size, and intensity of fluorescent bone metastases increased progressively with time and was indicative of breast cancer cell progression within bone. Histological examination of fluorescent long bones from B02/GFP.2-bearing mice revealed the occurrence of profound bone destruction. Treatment of B02/GFP.2-bearing mice with the bisphosphonate zoledronic acid markedly inhibited the progression of established osteolytic lesions and the expansion of breast cancer cells within bone. Overall, this new bone metastasis model of breast cancer combining both fluorescence imaging and radiography should provide an invaluable tool to study the effectiveness of pharmaceutical agents that could suppress cancer colonization in bone.

Intérêt du dosage de la désoxypyridinoline urinaire dans le dépistage des métastases osseuses du mélanome

Urinary deoxypyridinoline as a marquer of bone metastases in patients with melanoma. We measured urinary deoxypyridinoline (DPD) in 168 melanoma bearing patients, by an chemiluminescence immunoassay. The results were expressed as ratio to creatinine (DPD/Cr in nmol/mmol). The patients were distributed in five groups: patients without any detectable metastases, patients with cutaneous metastases, with lymph nodes metastases, with visceral or bone metastases. The control group included 40 healthy volunteers. We calculated reference values and means of level DPD/Cr in each group. The mean DPD/Creatinine was significantly higher for women with bone metastases than for the control group (respectely 16.7 nmol/nmol and 4.96 nmol/mmol (p = 0.003)) with a sensitivity of 62 % and a specificity of 98 %. We determinated a cutoff level at 15 nmol/mmol. However, no significantly inter group difference was observed for men. Measurement of urinary DPD is not superior to bone scintigraphy in the early detection of bone metastases, but may provide an useful alternative tool to bone scintigraphy for diagnosis of bone metastases.

Impact of abnormal uptakes in bone scan on the prognosis of patients with lung cancer

The detection of bone metastases is important in the management of patients with lung cancer because bone metastasis has a major impact on the prognosis and choice of treatment modality. Bone scan has been widely used for early detection of bone metastases but its low specificity complicates confirmation of bone scan findings. To evaluate the effects of abnormal bone scan findings on the prognosis of patients with lung cancer, we retrospectively analyzed the effect of abnormal uptakes on the prognosis of patients with primary lung cancer. The overall survival of patients with abnormal bone uptake was not significantly different from those without abnormal uptake. However, the patients with more than two abnormal bone uptakes had significantly shorter survival than those with no abnormal uptake ( P<0.05). To confirm the effect of abnormal bone uptakes on survival, we compared the survival curves of three patient groups without knowledge of bone scan findings: group A, stage I–IIIB with more than two abnormal bone uptakes (potential stage IV); group B, stage IIIB with no abnormal bone uptake (true stage IIIB); and group C, stage IV with no abnormal bone uptake. Group A revealed shorter survival than group B ( P<0.05). But, there was no significant difference in survival times between group A and group C. In the Cox regression analysis, the presence of more than two abnormal bone uptakes was a significant prognostic factor ( P=0.0277), together with performance status, stage, and albumin. These results suggest that one or two abnormal bone uptake at diagnosis did not affect overall survival of the patients, and that the patients with more than two abnormal bone uptakes are considered as clinical stage IV because of high probability of bone metastases.

Osteoporosis After Orchiectomy for Prostate Cancer

The possibility of increased osteoporosis and osteoporotic fractures following therapeutic orchiectomy in men with prostate cancer was investigated. A total of 235 men with nonstage A prostate cancer diagnosed between 1983 and 1990 was analyzed for therapeutic orchiectomy, other osteoporotic risk factors and subsequent hospital treatment for osteoporotic fractures. The 17 castrated men alive in 1995 were interviewed, and femoral neck bone mineral density was compared to that of 23 controls of similar age. Risk factors for osteoporosis, including smoking, slender habitus and atrophic testes, were common among men treated with orchiectomy. Of the men in the study cohort 10 had osteoporotic fractures: 8 of 59 treated with and 2 of 176 without orchiectomy (13.6 versus 1.1%, p < 0.001). First fracture cumulative incidence rates 7 years after castration or diagnosis were 28 and 1%, respectively (p < 0.001). Osteoporotic fractures were much more common than pathological fractures or those due to major trauma (1 each). Bone mineral density averaged 0.91, 0.84, 0.79 and 0.66 gm./cm.2 in 9 controls without prostate cancer, 14 men with prostate cancer before orchiectomy, 9 men at 9 to 60 and 8 men at 60 to 115 months after orchiectomy, respectively. Of the 16 men surviving for longer than 60 months after orchiectomy 6 had osteoporotic fractures, as did 5 of 6 and 5 of 7 with a bone mineral density of less than 0.70 gm./cm.2 and less than 75% of normal for age, respectively. Orchiectomy for prostate cancer is frequently followed by severe osteoporosis, some of which had developed before castration. Appropriate therapy should be identified that does not diminish the antitumorigenic effectiveness of androgen ablation.

Biochemical evaluation of bone turnover in cancer patients with bone metastases: relationship with radiograph appearances and disease extension

Serum bone alkaline phosphatase (BALP), serum carboxy-terminal propeptide of type I procollagen (PICP) and serum bone gla protein (BGP) as markers of bone formation, serum carboxy-terminal telopeptide of type I collagen (ICTP) as a marker of collagen resorption and fasting molar ratio of urinary calcium to creatinine (CaCr) and serum parathyroid hormone (PTH) were determined in two groups of cancer patients: 48 with advanced or metastatic disease with negative bone scan and 174 with bone metastases categorised as having lytic, mixed or blastic lesions and with more or fewer than or equal to three sites involved. In patients without apparent bone involvement, bone formation markers were rarely elevated. Conversely, serum ICTP was frequently found to be supranormal, showing it to be a non-specific marker for early detection of bone metastases. As expected, values of bone formation markers progressively increased in patients with lytic, mixed and blastic lesions, but ICTP levels did not show any differences according to the types of bone appearances, confirming previous reports of elevated osteoclast activity also in patients with apparent blastic lesions. Serum PTH increased significantly in patients with lytic compared with patients with mixed and blastic appearances, paralleling the bone formation markers, but CaCr showed the opposite pattern. These data are compatible with calcium entrapment in the bone in patients with increased osteoblast activity. This so called 'bone hunger syndrome' is further confirmed by the finding that in the subgroup of blastic appearances CaCr diminished whereas both ICTP and PTH increased according to the extent of tumour load in the bone.

Superscan in patients with nasopharyngeal carcinoma.

Bone scintigraphy plays an important role in the early detection of bone metastases in patients with nasopharyngeal carcinoma and serial scans may aid the clinician to assess the therapeutic response. A superscan is a pattern described as abnormal bone scan, indicating extensive bony metastases associated with various neoplastic diseases. Bone scans from 407 patients with nasopharyngeal carcinoma were reviewed retrospectively. Only six superscans (1.5%) were found. The appearance of a superscan is frequently accompanied by an abnormal titer of serological markers IgG-VCA and IgA-VCA, liver metastases, and poor survival. Although a superscan rarely occurs in nasopharyngeal carcinoma, its appearance may represent a poor prognosis in these patients.

A glance at the history of nuclear medicine.

The development of nuclear medicine has resulted in several effective routine methods in diagnosis and therapy. There is an ongoing discussion about the future of activity based on the fast development of ultrasound, CT and MR. In such discussions, it is often forgotten that nuclear medicine is also a dynamic diagnostic tool under continuous progress. As seen from this historical review, nuclear medicine has grown from quite simple in vitro tests to very advanced methods to image organ function. This is the result of the development of radiopharmaceuticals and instrumentation. Today, development is moving towards what is called receptor scintigraphy, i.e., the use of radiopharmaceuticals which are very specific to certain diseases, for instance, tumours. Even at present there is no other method for early detection of bone metastases than bone scintigraphy. Also, there is no other method to determine the regional myocardial blood flow both at stress and at rest, than myocardial scintigraphy. Nuclear medicine will remain an important diagnostic tool as long as it employs people with engagement and interest. Such people will also guarantee that the hospital management will supply the activity with funds for the necessary investments.

神経芽腫の骨および骨髄腔転移における MRI の検討 : 早期発見と治療効果判定

神経芽腫の骨および骨髄腔転移における MRI の検討 : 早期発見と治療効果判定

腎癌骨転移に関する検討

Twenty-nine cases of bone metastases from renal cell carcinoma were examined. Eight had metastatic bone pain as the initial symptom and were diagnosed that the primary lesion was in a kidney. In eight cases bone metastases appeared after treatment of the primary site. Seven had only bone metastases and another 22 cases had multiple metastases in organs such as the lung and lymph node when the bone metastasis was found. Curable surgical treatment was performed in only 2 cases. The survival curve of these patients were: 1 year; 41 per cent, 2 year; 30 per cent and 3 year; 15 per cent. Bone scan used for detection of bone metastases of carcinoma frequently ends with false positive results. CT scan and angiography are available for differential diagnosis of bone metastasis. We examined 6 cases (9 lesions) of bone metastases from renal cell carcinoma (3 pelvic bones, 2 lumbar bones, 2 femurs and 2 humerus). All lesions were hypervascular by angiography and were easily diagnosed as bone metastases. For early detection of bone metastases from renal cell carcinoma, angiography is useful because hypervascularity and tumor stain are easily detected even in such small lesions as 2 cm. Angiography was also useful for chemoembolization.

Value of bone scanning in the follow-up of breast cancer patients

The aim of the study was to assess the value of routine bone scintigrams, independent of the primary tumor stage or the presence of symptoms, in the postsurgical follow-up of breast cancer patients for the early detection of bone metastases. For this purpose 1,000 patients with postsurgical breast cancer without previous documentation of metastatic disease, who were admitted to the special oncology hospital, Onkologische Klinik Bad Trissl, entered a prospective study in 1987-1988. The parameters followed were the TNM stage of the primary tumor, the presence of pain, bone pain as revealed by a thorough physical examination, and the patient's history for the assessment of risk factors. In addition, a whole-body skeletal scintigram, supplementary X-rays, and additional diagnostic measures were performed, if necessary, to detect bone metastases. It was shown that in 856 of 894 patients (groups 1-6) without clinical symptoms, the clinical examination and radiological and scintigraphic diagnostic measurements, demonstrating the absence of bone metastases, gave matching results, but in 12 of the 894 patients the results of all examinations remained questionable. In another 12 of the 894 patients (groups 1-3) radiological and/or scintigraphical evidence for the presence of bone metastases was found. In 14 of 79 cases (groups 7-10) with clinically suspicious symptoms these were proven to be signs of metastases by subsequent scintigrams, supplementary X-rays, and additional diagnostic measures. In 65 of the 79 patients with clinically suspicious symptoms, bone metastases could not be confirmed by obtaining bone scintigrams or X-rays while in the other 14 patients (groups 9 and 10) evidence for the presence of bone metastases was found in the scintigrams and/or X-rays. However, 10 of these 14 patients were high-risk patients for developing bone metastases as they had axillary lymph node infiltration. The other 4 patients were of the low-risk group as they had positive receptor status or no axillary lymph node infiltration at the time of primary diagnosis. In 13 of 27 patients (groups 11-14) with clinical symptoms indicating the presence of bone metastases this diagnosis was confirmed by scintigrams and/or X-rays (groups 11 and 12), while it was possible to exclude the presence of bone metastases in spite of the symptoms in 11 of the 27 patients. In the other 3 patients the results of the additional examinations remained questionable.(ABSTRACT TRUNCATED AT 400 WORDS)

Bone metastases of medulloblastoma in childhood; correlation with flow cytometric DNA analysis

Thirty children with medulloblastoma who were treated between 1980 and 1986 are presented. Flow cytometric DNA analysis using formalin-fixed and paraffin-embedded tissues showed that 15 were DNA aneuploid, 13 diploid and 2 tetraploid. After homogeneous treatment with a combination of radical resection and radiation therapy, patients with DNA aneuploid medulloblastoma showed significantly better outcome (p = 0.003). Among these 30 patients, 6 (20%) had bone metastases of medulloblastoma during a minimum of 2-year follow-up period. DNA ploidy of these patients was diploid in 5 and aneuploid in 1. Incidence of bone metastases appears to correlate with DNA ploidy (p = 0.046). At the time of discovery of bone metastases, 4 had no demonstrable recurrence in the central nervous system (CNS). Radionuclide bone scan was more sensitive in disclosing these lesions, while only one patient had positive results of bone marrow aspirates/biopsy. Three patients were treated with chemotherapy, two had a combination of regional irradiation and chemotherapy and one refused treatment. All treated bone metastases in 5 patients responded clinically and radiographically, but only one patient is alive 66 months after therapy. Four patients died due to either CNS recurrence of septic complication of chemotherapy. Early detection of bone metastases by use of frequent bone scans is important. Patients with diploid medulloblastoma should be treated with adjuvant chemotherapy in order to prevent recurrences and metastases.

The clinical reliability of 99mTc-polyphosphate skeletal scintigraphy in the early detection of bone metastases

A comparison between 99mTc-polyphosphate and pyrophosphate for the early detection of skeletal metastases demonstrated a significant difference between them. Of 71 lesions visualized by polyphosphate scintigrams only 54 were to be found on pyrophosphate scintigrams. The lesions not visualized by pyrophosphate were associated with bone with a high bone-marrow content. It has been suggested that polyphosphate should be the reagent of choice for the detection of skeletal malignancy. In a retrospective study of 118 patients the diagnostic reliability of positive polyphosphate scintigrams was found to be in excess of 90% in patients where skeletal associated pain was the only indication of metastasis.

Scintillation Scanning in Clinical Medicine: Based on a Symposium Sponsored by the Department of Radiology of the Bowman Gray School of Medicine

This new publication should be of great value to all engaged in nuclear medicine. For the neophyte it provides a good summary of many valuable scanning procedures and for the expert, sound basis for expanding present scanning services. The scope is broad, covering all of the current clinically useful scanning areas. The volume contains 19 sections, three on basic principles, the remainder on organ scanning. The routine scanning procedures are covered plus the newer applications in parathyroid and pancreatic tumors, early detection of bone metastases and early pulmonary infarction. Most subjects are presented from more than one aspect. The brain-scanning sections are particularly well done and should do much to extend this field. The data presented in the discussion should end the pre-scanning use of nonradioactive mercury as a blocking agent, shown here to be valueless. The consideration of pulmonary scanning, with the excellent illustrations and discussion, indicate a great