Occurrence Of Bone Metastases Research Articles

Alteration of bone sialoprotein expression in osseous metastasized renal cell carcinomas and the tumor surrounding tissue

Bone sialoprotein (BSP) regulates bone metabolism by directly influencing the activity of osteoblasts and osteoclasts. A significant correlation between the tissue expression of BSP in tumors and the occurrence of bone metastases was found in different cancers. Aim of this study was to identify the BSP expression in renal cell carcinomas (RCC) according to their stage of metastatic disease. Tissue samples of patients with RCC who underwent partial resection or nephrectomy were separated into three groups, each with 10 patients showing either no metastases (group I), only soft tissue metastases (group II) or bone metastases (group III) at date of surgery. Immunohistochemical analysis of BSP expression in tumor tissue and corresponding renal parenchyma was performed and evaluated with an established semiquantitative scoring system. BSP expression was detected both in tumor tissue and renal parenchyma. Concerning the expression in malignant tissue, no significant difference could be found between the three groups whereas the corresponding renal parenchyma showed a staining score of 164, 198 and 224 for group I, II and III (P=0.07). RCC staged T3 showed only a little higher BSP expression than those staged T1/2 (P<0.21), while the corresponding parenchyma of T3 tumors showed significantly higher expressions (P=0.02). This pilot study revealed a correlation between expression of BSP and tumor staging and type of metastases, especially for osseous metastases in RCC. Alternation of BSP expression could be detected particularly in renal parenchyma and linked to the type of metastases.

Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial

Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer. In this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen [PSA] ≥8·0 μg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. The primary endpoint was bone-metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov, number NCT00286091. 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 [95% CI 25·4-33·3] vs 25·2 [22·2-29·5] months; hazard ratio [HR] 0·85, 95% CI 0·73-0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 [95% CI 29·5-38·0] vs 29·5 [22·4-33·1] months; HR 0·84, 95% CI 0·71-0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 [95% CI 40·1-not estimable] months vs placebo, 44·8 [40·1-not estimable] months; HR 1·01, 95% CI 0·85-1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo. This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer. Amgen Inc.

Receptor activator for nuclear factor κ B expression predicts poor prognosis in breast cancer patients with bone metastasis but not in patients with visceral metastasis

BackgroundIt was recently reported that receptor activator for nuclear factor κ B ligand (RANKL)/receptor activator for nuclear factor κ B (RANK) pathway is critical for RANK-expressing cancer cells to home...

Receptor Activator of NF-kB (RANK) Expression in Primary Tumors Associates with Bone Metastasis Occurrence in Breast Cancer Patients

BackgroundReceptor activator of NFkB (RANK), its ligand (RANKL) and the decoy receptor of RANKL (osteoprotegerin, OPG) play a pivotal role in bone remodeling by regulating osteoclasts formation and activity. RANKL stimulates migration of RANK-expressing tumor cells in vitro, conversely inhibited by OPG.Materials and MethodsWe examined mRNA expression levels of RANKL/RANK/OPG in a publicly available microarray dataset of 295 primary breast cancer patients. We next analyzed RANK expression by immunohistochemistry in an independent series of 93 primary breast cancer specimens and investigated a possible association with clinicopathological parameters, bone recurrence and survival.ResultsMicroarray analysis showed that lower RANK and high OPG mRNA levels correlate with longer overall survival (P = 0.0078 and 0.0335, respectively) and disease-free survival (P = 0.059 and 0.0402, respectively). Immunohistochemical analysis of RANK showed a positive correlation with the development of bone metastases (P = 0.023) and a shorter skeletal disease-free survival (SDFS, P = 0.037). Specifically, univariate analysis of survival showed that “RANK-negative” and “RANK-positive” patients had a SDFS of 105.7 months (95% CI: 73.9–124.4) and 58.9 months (95% CI: 34.7–68.5), respectively. RANK protein expression was also associated with accelerated bone metastasis formation in a multivariate analysis (P = 0.029).ConclusionsThis is the first demonstration of the role of RANK expression in primary tumors as a predictive marker of bone metastasis occurrence and SDFS in a large population of breast cancer patients.

Abstract 3264: Preclinical multi-modal therapy of metastatic androgen independent prostate cancer using docetaxel, capecitabine, and a Lu-177-BB2r targeting peptide

Abstract Introduction: The Gastrin Releasing Peptide receptor (GRPr) also known as the bombesin receptor subtype 2 (BB2r) is currently of interest as a molecular target for the selective delivery of targeted radiation therapy for prostate cancer. We have previously demonstrated that 177Lu-177-DOTA-8-AOC-BBN(7-14)NH2, when administered concurrently with docetaxel, can achieve significant tumor control in flank xenograft models of androgen independent prostate cancer. We now present findings related to the use of 177Lu-177-DOTA-8-AOC-BBN(7-14)NH2 and chemotherapy for the treatment of systemic prostate cancer metastases using a SCID mouse model. Methods: DOTA-8-AOC-BBN(7-14)NH2 was synthesized in house and radiolabeled with Lu-177. 177Lu-DOTA-8-AOC-BBN(7-14)NH2 was purified using analytical HPLC, which resulted in obtaining a high specific activity preparation. Systemic prostate metastases in SCID mice were created following intracardiac administration of 1×106 PC-3 cells. Micro-CT scans were performed weekly, beginning on day 24, to determine initial presence and extent of bone metastases. Treatment evaluation compared a chemotherapy only arm (docetaxel/capecitabine) with a multi-modal arm consisting of chemotherapy and targeted radiation therapy (TRT). Multi-modal therapy, consisting of docetaxel (8mg/kg; administered weekly), capecitabine (100mg/kg; administered daily (M-F) for 14 days followed by 7 day rest), and 177Lu-DOTA-8-AOC-BBN(7-14)NH2 (37MBq/25g; administered weekly), was delivered in two consecutive 3 week rounds. Animals were removed from the study based on evidence of morbidity as a result of either skeletal fracture and/or low body condition score. Results: Survival analysis and Micro-CT evaluation at study endpoint (Day 84) revealed that 35% of the mice in the multi-modal therapy arm were responding to treatment (chemo + targeted Lu-177 radiation therapy) resulting in a mean survival of 57 +/- 5 d, whereas 100% of the chemotherapy only arm did not survive past Day 67, resulting in a Mean survival of 47 +/- 5d. Furthermore, Micro-CT analysis identified approximately 5 bony metastases per subject. Conclusions: Our preclinical data suggests that 177Lu-DOTA-8-AOC-BBN(7-14)NH2 when used concurrently with docetaxel and capecitabine to control a model of androgen independent prostate cancer metastases can enhance overall mean survival times. Based on the survival limitations identified as a result of mortality causing SRE's, our findings further suggest that the use of bisphosphonates, to decrease the risk of bone fracture and delay the occurrence of bone metastases, may be the next logical addition to enhance multimodal therapy regimens combining 177Lu-DOTA-8-AOC-BBN(7-14)NH2 with chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3264. doi:10.1158/1538-7445.AM2011-3264

Treatment of severe cancer pain by transdermal fentanyl.

The goal of research was to determine the frequency, intensity, time of occurrence, duration and causes of breakthrough pain (BTP) in patients whose carcinoma pain was treated by transdermal fentanyl. (TDF). A prospective study was conducted in a hospice for recumbent patients of the Centre for Palliative Care (hospice) University Clinical Centre Tuzla from October 2009 to December 2010. 33 patients in terminal stage of carcinoma, who had been treated by transdermal fentanyl due to their excruciating pain (7-10 mark on numerical scale) with initial dosage of 25 microg as a strong opiate analgesic, were monitored within the time period of 10 days. In the statistics we used the even T - test, the Wilcox test and Mann-Whitney test. The difference was seen to be significant at p < 0.05. Treatment by transdermal fentanyl significantly reduces the intensity of strong carcinoma pain (p < 0.0001), with a frequent requirement for dose increase with bone metastasis. The intensity of BTP is higher compared to the pain experienced upon reception. The frequency and intensity of BTP are significantly reduced already in the second day of treatment by transdermal fentanyl (p = 0.0024). The BTP is most intense in patients with neck and head tumours (9.26 +/- 0.66), and most frequent with abdomen and pelvic tumour. The biggest number of BTP (68.3 %) occurs within first three days of treatment. BTP most frequently occurs in the evening or at night (between 18:00 and 06:00 h in 62.2 % of the cases), with the duration of usually less than 15 minutes (65.2 % of the cases). In 61.6 % cases the occurrence of BTP is related to physical activities or psychosocial incidents, while the cause is undetermined in 38.4 % of examinees. BTP is most frequent within first three days of treatment by TDF. Using the optimal dosage a good control of carcinoma pain is enabled, regardless of the occurrence of bone metastasis, while it also helps reduce the frequency and intensity of BTP.

The application of bone collagen metabolism markers in bone metastases of breast carcinoma

Objective To evaluate the values of using specific osteolytic bone metabolic markers such as serum type Ⅰ collagen carboxyterminal telopeptide(sICTP),urinary nitrogen-terminal cross-linked telopeptides of type Ⅰ collagen(uNTx),urinary pyridinoline crosslinks(uPYD)in bone metastasis of breast cancer.Methods The levels of slCTP,uNTx and uPYD in 72 patients with breast cancer were measured using ELISA.The sensitivity and specificity of diagnostic value in bone metastasis of breast cancer were cal-culated.Seventy-two patients with breast carcinoma were divided into two groups depending on the presence of bone metastasis according to bone scan findings and confirmed by X-ray and/or CT.The level of bone markers was compared between the two groups.Further relation between bone metabolic marker and tumor behavior in the patients with bone metastases was studied detailedly.Results The levels of all bone mark-ers in patients with bone metastasis were significantly higher than those of in ones without bone metastasis(P＜0.05).A significant correlation was seen between each two markers(r＞0.5,P＜0.01).The sensitivity and specificity was 72.00% and 83.33% in uNTx; 80.56% and 80.56% in uPYD; 80.56% and 97.22% in sICTP,respectively.Evident differences were seen between the extent of skeletal infiltration and the levels of the three biomarkers(P＜0.05).The correlations were seen between the levels of the three biomarkers and the risk of occurrence of bone metastasis(P＜0.05).Conclusion The measurement of sICTP,uNTx and uPYD are of significant utility as biochemical markers of bone metastasis in patients with breast cancer and can be used to achieve a timely diagnosis for bone metastasis of breast cancer. Key words: Breast neoplasms; Bone neoplasms; Neoplasm metastasis; Biological markers; Collagen type Ⅰ

Spinal Metastasis From Lung Cancer Fifteen Years After Surgery Presenting a Pseudohemangioma Appearance of the Vertebra

Case report. To describe a case of solitary metastasis of the seventh thoracic vertebra (T7) from lung cancer 15 years after surgery. Late recurrence of the bone over 5 years after curative surgery for lung cancer is highly exceptional. In addition, bone metastasis from lung cancer showing a coarse trabecular pattern of the vertebra on computed tomography (CT) is quite unusual. A case of solitary metastasis of T7 from lung cancer 15 years after surgery showing a pseudohemangioma appearance of the vertebra on CT is presented. A 66-year-old man presented with a 2-month history of gradually progressed numbness and muscle weakness of the bilateral leg, with a more recently developed spastic gate. He had undergone a left lower lobectomy for lung cancer 15 years previously. Magnetic resonance imaging showed an ill-defined mass lesion involving the entire vertebral body of T7 with extension into the posterior element and surrounding soft tissue, which resulted in moderate spinal canal stenosis. CT showed a coarse trabecular pattern at T7 with a mild compression fracture. No other lesion was detected by whole-body CT and bone scintigraphy. Tumor resection and T5-T9 posterior spinal fusion had been performed, and a pathologic diagnosis of metastatic pulmonary adenocarcinoma of the bone was established. Additional radiation therapy (40 Gy) was added, and the patient recovered and continued to survive uneventfully at the 3-month follow-up. We have reported a rare case of solitary metastasis to T7 appearing 15 years after surgery for lung cancer. The incidence of lung cancer recurrence more than 5 years after surgery is exceedingly low; however, even in patients with lung cancer, late occurrence of bone metastasis should be considered and included in the differential diagnosis of a pseudohemangioma appearance of the vertebra.

Abstract A63: Inhibition of ROCK signaling prevents breast cancer metastasis to human bone

Abstract ROCK signaling plays a fundamental role in regulating cell morphology, adhesion and motility. Aberrant expression of ROCK is related to tumor metastases and correlates with poor clinical outcome. However, the molecular mechanisms responsible for ROCK-mediated effects and the potential utility of ROCK inhibition as a therapeutic target have not been fully investigated. Here, we show that ROCK expression is increased in metastatic human breast cancer (BrCa) cell lines and clinical mammary tumors compared to non-metastatic cell lines and tumors. Inhibition of ROCK activity, either by a specific ROCK inhibitor (Y27632) or ROCK-targeted siRNAs, reduces BrCa cell migration and proliferation in vitro. We evaluated the effect of ROCK inhibition on metastasis to bone in vivo using a novel “human BrCa metastasis to human bone” mouse model. Metastases to human bone cores (hBCs) were inhibited in Y27632-treated mice (5 out of 14, 36%) compared to control mice (8 out of 12, 67%), based on luminescent imaging. The overall frequency of metastasis to mouse skeleton in Y27632-treated mice was reduced by 36% compared to controls. Moreover, the mass of metastatic tumors in the mouse skeleton was diminished by 77% (P&amp;lt;0.05) in Y27632-treated mice. ROCK1 siRNAs also decrease the frequency of BrCa metastasis to hBCs and mouse skeleton, but to a lesser extent than Y27632. We demonstrate that ROCK's effects on tumor cell invasion/motility and growth may derive from regulating the actin-myosin cytoskeleton, modulating the c-Myc pathway by increasing the stabilization of c-Myc protein via phosphorylation, and targeting c-miRNAs. Coupled to increased c-Myc, expression of the c-Myc-regulated miR-17-92 cluster is shown here to be elevated in metastatic BrCa cells compared to non-metastatic cells, and diminished upon Y27632 treatment. Furthermore, blockade of miR-17 is shown to decrease BrCa cell invasion/migration in vitro and metastasis in vivo. Collectively, these findings suggest that augmented ROCK signaling contributes to BrCa metastasis in at least 3 ways, by 1) regulating the actin cytoskeleton and actin-myosin-dependent contractility; 2) targeting mRNAs controlled by the transcription factor c-Myc to potentiate cell growth and viability; and 3) modulating the expression of certain miRNAs, such as the c-Myc-regulated oncogenic miR-17-92 cluster. Inhibition of ROCK-mediated signaling appears to be a promising and potentially specific approach to suppress the occurrence of bone metastases in BrCa. Citation Information: Cancer Res 2009;69(23 Suppl):A63.

Reduced risk of bone metastases in breast cancer patients treated with Cox-2 inhibitors

526 Background: Approximately 40–70% of women diagnosed with breast cancer will develop bone metastases. The level of cyclooxygenase-2 (Cox-2) is overexpressed in human bone metastases and correlates with the occurrence of bone metastases in animal models. We hypothesize that the use of Cox-2 inhibitors in early phases of breast cancer could protect against the development of bone metastases. Methods: The medical charts of all patients treated for stage II and III breast cancer between 1999–2005 were reviewed. Patients were subsequently subdivided into those who took Cox-2 inhibitors (celecoxib, rofecoxib or valdecoxib) for at least 6 months following the diagnosis of breast cancer and those who did not. The diagnosis of bone metastases required conclusive radiologic imaging. Fisher's exact test and a multivariate logistic regression were used to analyze the data. Results: A total of 692 patients were included in this analysis. The patients’ mean age was 59 and the mean follow up was 3.9 years. Eleven percent (74/644) of patients who did not take Cox-2 inhibitors developed bone metastasis compared to two percent (1/48) of those who did (Fisher's exact test p = 0.05). Significant predictors for developing bone metastases using a multivariate logistic regression model were: 3 or more positive nodes (p<0.001; Odds Ratio = 3.19, 95% CI = 1.79 - 5.70), stage IIb-IIIc (p = 0.001; OR = 4.61, 95% CI = 2.19–9.72) and use of Cox-2 inhibitors (p = 0.025; OR = 0.10, 95% CI = 0.013–0.75). Adjusting for TNM stage, of the 327 patients in stages IIb-IIIc, 21.5% (63/293) had bone metastasis in the non-Cox-2 group vs. 3% (1/34) in the Cox-2 group (p = 0.006). In this high-risk group of patients, the calculated odds ratio for development of bone metastases associated with the use of Cox-2 inhibitors was 0.10 (95% CI = 0.014–0.78). There was no significant difference between the groups in the number of patients that received adjuvant radiotherapy, chemotherapy, or hormone therapy. Conclusions: This retrospective study suggests that the use of Cox-2 inhibitors can reduce the risk of bone metastases in patients with stage II and III breast cancer. Prospective randomized trials of adjuvant Cox-2 inhibitors in patients with high-risk breast cancer are needed to validate this conclusion. No significant financial relationships to disclose.

Can clinical factors be determinants of bone metastases in non-small cell lung cancer?

OBJECTIVE:The aim of this study was to investigate the correlations among symptoms, laboratory findings of bone metastasis and whole body bone scanning (WBBS) and the frequency of occurrence of bone metastasesMATERIALS AND METHODS:Hundred and six patients who were diagnosed with non-small cell lung cancer (NSCLC) between June 2001 and September 2005 were investigated retrospectively. Bone pain, detection of bone tenderness on physical examination, hypercalcemia and increased serum alkaline phosphatase were accepted clinical factors of bone metastases. Presence of multiple asymmetric lesions in WBBS was also accepted as bone metastases. Subjects whose clinical factors and WBBS indicated doubtful bone metastases were evaluated with magnetic resonance and/or biopsy.RESULTS:Occurrence of bone metastases was 31.1% among all patients. Bone metastases were determined in 21 (52.5%) of 40 patients who had at least one clinical factor. Asymptomatic bone metastases without any clinical factors were established in 11.3% of all NSCLC patients and 15.3% of 26 operable patients. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the clinical factors of bone metastases were 63.6, 73.9, 52.5, 81.8 and 70.7% respectively. There was no significant relationship between histologic type and bone metastases. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of WBBS in detection of bone metastases were 96.9, 86.3, 76.2, 98.4, 89.6% respectively.CONCLUSION:Sensitivity and specificity of the clinical factors of bone metastases are quite low. Routine WBBS prevented futile thoracotomies. Therefore, routine WBBS should be performed in all NSCLC patients, even in the absence of bone-specific clinical factors.

BONE METASTASIS AS THE FIRST MANIFESTATION OF LUNG CANCER

SUMMARYBone metastasis usually occurs late in the course of the disease, but in some patients it is the first manifestation of lung cancer. To evaluate the characteristics of patients with bone metastasis as a first manifestation of lung cancer, the medical records of 1063 patients with lung cancer between 1976 and 2001 were reviewed retrospectively. Twenty‐four (2.3%) lung cancer patients presented symptoms of bone metastasis as a first manifestation; 11 patients had bone metastasis as the only site of spread in lung cancer; 16 had adenocarcinoma; five had a primary lesion &lt;30 mm, and nine had N0‐1 disease. Patients with sole bone metastasis did not have a more favourable survival rate than patients with bone and other systemic metastases (p=0.2938). Whether metastasis is the first manifestation of lung cancer or not, the occurrence of bone metastasis generally means a poor prognosis.

Association of the Vitamin D Receptor Genotype with Bone Metastases in Breast Cancer Patients

This study was designed in order to evaluate specific vitamin D receptor (VDR) genotypes as indicators of the likelihood of developing osseous metastases in breast cancer patients. Therefore, we determined polymorphisms of the VDR gene in a study group comprising 183 breast cancer patients. Specific fragments spanning over intron 8 and exon 9 of the VDR gene were amplified by polymerase chain reaction. The fragments were then incubated with each of the specific endonucleases ApaI, BsmI or TaqI, respectively. The VDR gene polymorphisms were detected by the presence or absence of the particular restriction site using agarose gel electrophoresis. Statistical analyses revealed a significant correlation between both the VDR gene polymorphisms indicated as AA (absence of the ApaI restriction site in both alleles) or TT (absence of the TaqI restriction site in both alleles), respectively, and the occurrence of bone metastases. Patients with the AA genotype have a 1.7-fold increased risk of developing bone metastases, whereas patients with the TT genotype have a 0.5-fold risk. Neither other genotypes nor allelic combinations displayed any further correlation with the clinical stage. The data suggest that the AA genotype of the VDR gene might be useful to identify breast cancer patients with a high probability of forming occult bone metastases who are considered to benefit from an adjuvant bone-protective therapy.

Analysis of repeated events.

Events that may occur repeatedly for individual subjects are of interest in many medical studies. We review methods of analysis for repeated events, emphasizing that the approach taken in a given study should allow clinical questions to be addressed as directly as possible. Methods based on full models for event processes as well as on simpler 'marginal' assumptions are considered. The treatment of dependent terminating events related to the recurrent events is also discussed. We apply various methods of analysis to studies involving pulmonary exacerbations in persons with cystic fibrosis, and the occurrence of bone metastases and skeletal events in cancer patients, respectively. Most of the methodology considered can be implemented with existing software.

The parathyroid hormone-related protein (PTHrP) gene: use of downstream TATA promotor and PTHrP 1-139 coding pathways in primary breast cancers vary with the occurrence of bone metastasis.

We analyzed the use of different promoters and the splicing patterns of the exons encoding 5'- and 3'-untranslated sequence amounts of parathyroid hormone-related protein (PTHrP) gene products in breast cancers. Tumor samples from 74 cases of primary breast cancer that had been followed from 1 to 14 years were selected retrospectively according to the occurrence of metastasis: 18 patients developed no metastasis (NM), 56 developed metastases (M), 22 of whom developed metastases in soft tissues (MB-) and 34 of whom developed bone metastases (MB+). The amount of the 1-139 isoform mRNA was much higher in the tumors of patients who later developed metastases (M: 0.29 +/- 0.03) than in those of patients who developed no metastases (NM, 0.13 +/- 0.03; p < 0.01). This isoform mRNA was also more abundant in breast tumors from patients who developed bone metastases (MB+, 0.39 +/- 0.04) than in those of patients who developed metastases in soft tissues (MB-, 0.15 +/- 0.03; p < 0. 0001). By contrast, the amounts of the 1-141 isoform mRNA in these three groups of tumors were similar, but its concentration was higher in the tumors of premenopausal women than in those of postmenopausal women (p < 0.05). Analysis with 5' untranslated regions-specific primers showed transcription from all three putative transcription start sites of PTHrP (P1, P2, and P3). The P3-initiated transcripts were more abundant in patients who developed metastases (M, 0.31 +/- 0.03) than in the nonmetastatic tumors (NM, 0.13 +/- 0.03; p < 0.01). The amount of P3 element did not differ with the site of metastasis (BM+, 0.32 +/- 0.05; BM-, 0. 28 +/- 0.05; NS). The same trend was observed for the P2 element. However, the use of P2-initiated messages was strongly associated with the absence of estrogen receptors from the breast tumors (p < 0. 01). We thus find a close association between the pattern of PTHrP gene expression and the outcome of breast cancer. The P3-initiated start site and the presence of PTHrP 139 mRNA could help identify patients at risk of developing metastases.

Clear cell sarcoma of the kidney in children: A distinct entity

Four cases of clear cell sarcoma of the kidney in children are reported. The specificity of the tumor is examined. The pathologic features, the clinical presentation, and the occurrence of bone metastasis are reasons to distinguish clear cell sarcoma from the Wilms' tumor group. The poor prognosis may be improved in the future by radical resection associated with polyvalent chemotherapy.

Analysis of serial radionuclide bone images in osteosarcoma and breast carcinoma.

The authors first describe and illustrate didactically the use of the Kaplan-Meier actuarial technique for serial diagnostic studies. They then present an analysis of previously published data on the results of serial radionuclide bone images in patients with osteosarcoma or breast carcinoma, using this technique. The data indicate that patients with osteosarcoma show an almost linear increase in the occurrence of bone metastases between 5 and 29 months after diagnosis; the rate is approximately 1% per month. Patients with breast cancer, on the other hand, show a biphasic rate of development, averaging only 0.5% per month during the first year after diagnosis but increasing rapidly to approximately 2% per month after 15 months.

The Giant Cell Tumor, Appeared in the Sacrum Seven Years After the Amptuation of the Right Humerus

The occurrence of bone metastasis of the giant cell tumor is rarely reported. On the other hand, the concept of multicentric leison should be considered, although it is difficult to distinguish a multicentric giant cell tumor from a secondary giant cell tumor of metastatic spread, each at a different time.This paper reports an unusual case of 29 year old woman who had been well for seven years after the amputation of primary lesion, the right humerus, until December 1977, when examination and roentogenogram revealed destructively expansile lesion of the body of the sacrum.

Roentgen Therapy in Bone Metastasis of Carcinoma

Bone metastasis from carcinoma and its treatment have been discussed repeatedly in a general way (1, 2) and numerous case reports can be found in the literature (2, 3, 4, 5). Such publications have made it clear that bone metastasis may respond in a remarkable way to roentgen therapy and that the patient may be relieved from severe pain for relatively long periods. A more definite impression of what may be accomplished should be obtained from a report of all carcinoma patients treated for bone metastasis. In an attempt to do that we have gone over our treatment records of carcinoma of the breast, prostate, cervix and corpus uteri, and thyroid. Hypernephroma and melanoma have also been included in this survey. The records have been collected since July, 1926, when high voltage therapy was introduced at the University Hospital. It should be kept in mind that patients seldom come to a cancer institute until the disease is far advanced. A routine procedure to discover bone metastasis has not been carried out, as a rule, as it may occur in almost any bones of the body and a complete roentgenologic study would be impracticable. The pelvis is, however, almost always examined roentgenographically in carcinoma of the prostate. Pain is the most common symptom which leads to the diagnosis of bone metastasis. In three instances the diagnosis was made in spite of the fact that the X-ray films were negative and in four others the diagnosis was made without any X-ray film. On the other hand, in some instances, metastatic bone lesions causing neither pain nor other clinical symptoms have been discovered on X-ray films. It is, therefore, evident that many patients may have had bone metastases which were never discovered. In Table I the total number of patients who have been treated with high voltage roentgen rays is given and also the number of those with known bone metastasis. The occurrence of bone metastasis has not been expressed in percentages as the number of patients is too small to give reliable figures in this respect. The patients who are known to be dead are grouped separately; the others are referred to as alive, though some of them probably are dead by this time. It is well known that bone metastasis in carcinoma of the prostate is very common: Table I shows that more than one-half of our patients (22 out of 38) had bone involvement. Carcinoma of the breast comes next with almost one-third of the patients (49 out of 156) in the metastatic group. Bone metastasis in carcinoma of the body and cervix of the uterus has been recorded in only 3 out of 165 patients. The occurrence seems to be more frequent in carcinoma of the thyroid (1 out of 4), in hypernephroma (5 out of 16), and in melanoma (1 out of 12). This is in agreement with the statements of other authors.