Role of TKI for Metastatic Osteogenic Sarcoma.

OPINION STATEMENT: Osteosarcomas (OS) belong to a large family of mesenchymal tumor entities which exhibit heterogenous histological, genetic, and molecular features. Current OS treatment regimen consists of the combination of surgery and intensive multi-agent chemotherapy. Ever since the introduction of chemotherapy, 5-year survival rate among OS patients has improved to 60-75%. However, 30-35% of OS patients are associated with pulmonary metastasis and relapse, which have significantly poor prognosis, with an overall 5-year survival rate of about 20%. The fact that OS are both rare forms of cancer and highly heterogeneous may explain why patients' survival has not improved in the past three decades, especially for metastatic/relapsed and unresectable osteosarcomas. Patients who experience relapse with metastatic disease have limited therapeutic options, often receiving additional cytotoxic therapy such as ifosfamide and etoposide and/or carboplatin or gemcitabine plus docetaxel. Novel precise OS-targeted thrapies are being developed with the hope of improving metastatic/relapsed OS prognosis. This review provides an overview of the most updated targeted therapies in relapsed/metastatic osteosarcoma and dicusses some clinical options in order to improve progression-free survival.

Perineural invasion by prostate adenocarcinoma in needle biopsies predicts bone metastasis: Ten year data from the TROG 03.04 RADAR Trial.

AIMS: Perineural invasion (PNI) by prostatic adenocarcinoma is debated as a prognostic parameter. This study investigates the prognostic predictive value of PNI in a series of patients with locally advanced prostate cancer treated with radiotherapy and androgen deprivation using 10 years outcome data from the TROG 03.04 RADAR trial. METHODS: Diagnostic prostate biopsies from 976 patients were reviewed and the presence of PNI noted. Patients were followed for 10 years according to the trial protocol or until death. The primary endpoint for the study was time to bone metastasis. Secondary endpoints included time to soft tissue metastasis, transition to castration resistance, prostate cancer-specific mortality and all-cause mortality. RESULTS: PNI was detected in 449 cases (46%), with 234 cases (24%) having PNI in more than one core. The presence of PNI was significantly associated with higher ISUP grade, clinical T staging category, National Comprehensive Cancer Network risk group, and percent positive biopsy cores. The cumulative probability of bone metastases according to PNI status was significant over the 10 years follow-up interval of the study (log-rank test P < 0.0001). PNI was associated with all endpoints on univariable analysis. After adjusting for baseline clinicopathological and treatment factors, bone metastasis was the only endpoint in which PNI retained its prognostic significance (hazard ratio 1.42, 95% confidence interval 1.05-1.92, P = 0.021). CONCLUSIONS: The association between PNI and the development of bone metastases supports the inclusion of this parameter as a component of the routine histology report. Further this association suggests that evaluation of PNI may assist in selecting those patients who should be monitored more closely during follow-up.

SAFETY AND TOXICITY OF AN ACCELERATED COARSELY FRACTIONATED RADIATION PROTOCOL FOR TREATMENT OF APPENDICULAR OSTEOSARCOMA IN 14 DOGS: 10 GY × 2 FRACTIONS.

Coarsely fractionated radiation is commonly used as a method for pain control in dogs with appendicular osteosarcoma, however there is little published information on optimal protocols. The aim of this retrospective, descriptive study was to report safety and toxicity findings in a sample of dogs with appendicular osteosarcoma that had been treated with a radiation scheme of 10 Gy delivered over two consecutive days for a total of 20 Gy. Dogs were included in the study if they had osteosarcoma that was treated with the aforementioned protocol. Dogs were excluded if treated with the same protocol for any other bone tumor besides osteosarcoma or inadequate follow-up. Thirteen of the 14 patients received adjuvant therapy with pamidronate and a nonsteroidal anti-inflammatory. Nine dogs received adjuvant chemotherapy with carboplatin after radiation was complete. Within a median of 14 days, 92.8% of dogs subjectively had improved pain control. Median duration of response (DOR) was 80 days (range 20-365). The majority of patients developed VRTOG grade one toxicity, primarily alopecia. Five dogs (35.7%) developed pathologic fracture postradiation treatment. Timing of fracture was variable ranging from 24 to 250 days. This radiation protocol was well tolerated, with minimal toxicity, subjectively improved survival time, and had the benefit of being completed in two consecutive days.

Brown tumours of the tibia and second metacarpal bone in a woman with severe vitamin D deficiency.

Brown tumours caused by vitamin D deficiency are rare. Most cases are caused by primary hyperparathyroidism, and are rarely caused by secondary hyperparathyroidism in cases of renal failure. We present a case of Brown tumours of the tibia and second metacarpal bone in a 50-year-old woman who had a low dietary intake of vitamin D and had worn a veil for most of her adult life. The Brown tumours were caused by vitamin D deficiency and secondary hyperparathyroidism. The patient improved on treatment with vitamin D3 and calcium supplements. This is a rare case and the first, to our knowledge, with a Brown tumour of the tibia caused by vitamin D deficiency due to decreased dietary intake and decreased exposure to sunlight. The course of treatment and investigations of the patient are described.

Surgical Treatments of Tumor-Induced Osteomalacia Lesions in Long Bones: Seventeen Cases with More Than One Year of Follow-up.

BACKGROUND: Tumor-induced osteomalacia is a rare and fascinating paraneoplastic syndrome usually caused by a small, benign phosphaturic mesenchymal tumor. Most tumors are treated surgically, but we are unaware of any reports that compare the results of curettage and segmental resection for lesions in long bones. METHODS: Seventeen patients (ten male and seven female) with tumor-induced osteomalacia lesions in long bones, who underwent surgical treatment from December 2004 to August 2013 in our hospital, were included in this retrospective study. The mean follow-up (and standard deviation) was 35 ± 27 months (range, twelve to 116 months). The characteristics of the tumor and the effects of different surgical treatments (curettage compared with segmental resection) were evaluated. RESULTS: All patients showed typical clinical characteristics of tumor-induced osteomalacia, including elevated serum fibroblast growth factor-23 (FGF-23); 82% of tumors were in the epiphysis, and 82% grew eccentrically. The mean maximum diameter of the tumors was 2.4 ± 2.0 cm. The complete resection rates were similar for curettage (67%) and segmental resection (80%). However, the recurrence rate after curettage (50%) was higher than that after segmental resection (0%). The complete resection rate for secondary segmental resection (75%) was not different from that for primary segmental resection (83%). All of our cases of tumor-induced osteomalacia were caused by phosphaturic mesenchymal tumors. After successful removal of tumors, serum FGF-23 returned to normal within twenty-four hours and serum phosphorus levels returned to normal at a mean of 6.5 ± 3.5 days. CONCLUSIONS: Most lesions in long bones are located in the epiphysis, so curettage is first suggested to maintain joint function. If curettage is incomplete or there is a recurrence, secondary segmental resection should be considered curative. Changes of serum FGF-23 and phosphorus levels before and after the operation may be of prognostic help.

Malignant fibrous histiocytoma at the site of an alumina-on-alumina-bearing total hip arthroplasty mimicking infected trochanteric bursitis.

Although the incidence of malignant tumors in patients undergoing total hip arthroplasties (THAs) is known to be lower than the general population, there exist several reports on the development of malignant tumors at the site of THAs. We report another case of malignant fibrous histiocytoma at the site of a THA, which was developed in an older patient who presented a cystic mass around the total hip prosthesis using a ceramic-on-ceramic bearing system, even without evidence of osteolysis or loosening of implants. This is the second case associated with an aluminum oxide prosthesis in English literature.

Current concepts on the molecular biology of osteosarcoma.

Despite the knowledge of many of the genetic alterations present in osteosarcoma, its complexity precludes placing its biology into a simple conceptual framework. In contrast to many other malignancies, multiple genetic and environmental factors can all lead to the development of osteosarcoma which is defined phenotypically rather than molecularly. Despite the many factors capable of leading to its development, osteosarcoma is a rare malignancy that is relatively homogeneous in its clinical behavior and chemotherapy response. It remains unknown whether the clinical features of osteosarcoma are defined by the cell of origin, the genetic events leading to transformation, the timing of those events or factors related to differentiation into an osteoblastic phenotype. Identifying new treatment approaches has generally been through empiric and screening approaches. In this presentation the genetic alterations present in osteosarcoma, issues related to the cell of origin and bone differentiation will be reviewed along with the recent results of preclinical drug screening.

Transcutaneous electrical nerve stimulation (TENS) for cancer bone pain.

In the cancer population, painful bony metastases are common, difficult to treat and significantly reduce quality of life. Common treatments include opioid analgesics, bisphosphonates, and radiotherapy; yet these have significant side effects and are not universally effective. Transcutaneous electrical nerve stimulation (TENS) is inexpensive, relatively free from side effects, and widely available. We present a case study of successful TENS therapy in a patient with cancer bone pain and discuss the rationale for using TENS in this setting.

Osteoid osteoma of the carpal bones. Two case reports.

Osteoid osteoma rarely develops in the wrist. The symptoms resemble atypical tenosynovitis, with variations according to the location of the tumor. As a result, diagnostic wanderings are common. In addition, the pain may seem related to an injury, as illustrated by two cases reported herein. Conventional investigations often fail to contribute to the diagnosis. The most specific investigation is thin-slice computed tomography (CT), which can be coupled to magnetic resonance imaging. CT typically visualizes a round lucency surrounded by a rim of sclerosis; in addition, CT shows the exact location of the tumor, particularly relative to neighboring joints. Complete excision of the nidus must be achieved to ensure a permanent cure. Same-stage carpal bone fusion may be required in patients with extensive joint involvement.

Postlymphoproliferative disorder affecting bone after a renal transplantation.

OBJECTIVE: To illustrate a posttransplant lymphoproliferative lymphoma presenting as a solitary osseous lesion situated in the rib. CLINICAL FEATURES: A 53-year-old man was referred to a surgical department because of persistent local pain over the lower part of his left posterior hemithorax. Due to a previous history of chronic glomerulonephritis, a renal transplant was performed 7 years previously, followed by immunosuppressive therapy with azathioprine cyclophosphamide. INTERVENTION AND OUTCOME: Surgical removal of the rib lesion was performed because of the patient's history of the organ transplant. The histological study of the surgically removed tissue revealed diffuse infiltration of the marrow by lymphoid-like cells. There was evidence of interstitial fibrosis, and further immunohistochemical examination showed the presence of B cells in the specimen confirming the diagnosis of B-cell lymphoma. CONCLUSION: This case report discusses an unusual presentation of a lymphoma induced by immunosuppressive therapy in a patient who had received an organ transplant. Such lesions may appear in any organ or system, although this is distinctively unusual to involve the skeletal system.

Metastatic bone disease: pathogenesis and new strategies for treatment.

Bone is the third leading site of metastatic disease, after the lung and liver. Pain, pathological fractures, neurological deficits, and forced immobilization significantly decrease the quality of life of patients with bone metastasis. The development of metastasis, from the migration of malignant cells from the primary tumor to their proliferation at a distant site, involves a series of sequential steps: angiogenesis, matrix degradation, cell motility, cell attachment, and cellular proliferation. A better understanding of the pathogenesis of metastasis may be expected to lead to the development of new treatment modalities for bone metastasis. Currently, antiangiogenic agents, matrix metalloproteinase (MMP) inhibitors, and hyperthermia are some of the newer therapeutic modalities that seem to hold promise for the treatment of metastatic bone disease.

Protracted treatment of C57B1 mice with Zn-DTPA after 241Am injection reduces the long-term radiation effects.

Repeated intraperitoneal injections of ZnNa3-diethylenetriaminepenta-acetate (ZnDTPA), once a week, during 8 successive weeks, and starting 4 days after injection of 58 and 373 kBq 241Am/kg to C57B1 mice, were an effective protection against long-term radiation damage. At both dose levels of 241Am, Zn-DTPA reduced the 241Am concentration in bones by between 33% and 45%, and in the liver by 97%. Mean survival with 241Am was shortened in Zn-DTPA-treated mice, by 17% at the lower dose level and by 70% at the higher dose level. After treatment with DTPA at the lower 241Am level, survival became equal to that of control mice without 241Am, while at the higher level life span was still shortened. After the lower 241Am dose the incidence of bone tumours, liver carcinomas and the total number of all malignant tumours were significantly reduced by chelation therapy. The decrease in bone tumour incidence was proportional to the decrease in 241Am concentration and reduction in cumulative radiation dose in bone after chelation therapy. The incidence of liver carcinomas was reduced to that in non-241Am-injected mice and the reduction was thus proportional to the 97% reduction in 241Am concentration of the liver at the end of chelation therapy. After the higher 241Am dose no tumours showed up in sham-treated mice, probably due to the overkill effect on the cells at risk. In the corresponding Zn-DTPA-treated mice, bone tumours and a few other malignant tumours were observed.

Cancer risk from the lifetime intake of Ra and U isotopes.

From extensive human data on the induction of skeletal cancers (bone sarcomas and carcinomas of the head sinuses) by 226Ra, 228Ra and 224Ra, the cumulative lifetime risk to 1 million people, each ingesting 5 pCi of a Ra isotope per day, was calculated to be nine bone sarcomas plus 12 head carcinomas for 226Ra, 22 bone sarcomas for 228Ra, and 1.6 bone sarcomas for 224Ra. Assuming that the risk per rad of average skeletal dose is equal for 226Ra and the U isotopes with half-lives exceeding 1000 yr and that the equilibrium skeletal content is 25 times the daily ingestion of 226Ra, but 11 times the daily ingestion of long-lived U, the cumulative life-span risk to 1 million persons, each ingesting 5 pCi per day of 233U, 234U, 235U, 236U or 238U, is estimated to be about 1.5 bone sarcomas. The U risk is not well established and additional research is needed on the metabolism of U in humans and its carcinogenicity in laboratory animals. These estimates assume linear dose responses. However, if incidence varies with the square of dose, virtually no induced cancers would be expected from these levels of radioactivity.

Metabolism of ingested U and Ra.

The literature on metabolism of U and Ra for man relevant to deriving drinking water standards has been reviewed and summarized. Radium is well understood, but significant gaps remain in our knowledge about U metabolism. Limits should be based on an equilibrium model where a constant relationship between intake and organ burden is established, using the best and most likely metabolic parameters. For the skeleton we conclude that the best estimate of skeletal burden expressed in days equivalent intake are 25 days for 226Ra, 10 days for 228Ra, and 0.3 days for 224Ra. For long-lived isotopes of U, we chose 11 days, with a range between 1 and 35 days. The committee believes that intake of natural U in water should be limited by considerations of toxicity to the kidney, and we believe that the metabolic model of Spoor and Hursh with a modified gastrointestinal (GI) absorption (1.4%) should be used to infer kidney content. Our review and analysis of the world literature leads us to believe the average human GI absorption of U is most likely 1-2% and is probably reasonably independent of age or the mass of U ingested. Using a safety factor of 50-150, the committee recommends a limit of U in water of 100 micrograms/l in order to limit toxic effects in the kidney. One hundred micrograms/liter is equivalent to 67 pCi/l of long-lived alpha-emitting natural U isotopes. Further research into the distribution of U in the human body is desirable, especially at natural levels in kidney and skeleton, the time-dependent pharmacokinetics of U in animals, the GI absorption of U in man from water and food, toxicological and U distribution studies in animals under conditions of chronic oral U intake, and metabolic model error propagation.