Richard W. Nicholas

Bone metastasis: mechanisms and therapeutic opportunities

The skeleton is one of the most common sites for metastatic cancer, and tumors arising from the breast or prostate possess an increased propensity to spread to this site. The growth of disseminated tumor cells in the skeleton requires tumor cells to inhabit the bone marrow, from which they stimulate local bone cell activity. Crosstalk between tumor cells and resident bone and bone marrow cells disrupts normal bone homeostasis, which leads to tumor growth in bone. The metastatic tumor cells have the ability to elicit responses that stimulate bone resorption, bone formation or both. The net result of these activities is profound skeletal destruction that can have dire consequences for patients. The molecular mechanisms that underlie these painful and often incurable consequences of tumor metastasis to bone are beginning to be recognized, and they represent promising new molecular targets for therapy.

Intensive Therapy With Growth Factor Support for Patients With Ewing Tumor Metastatic at Diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457—A Report From the Children's Oncology Group

PURPOSE Prognosis is poor for Ewing sarcoma patients with metastasis at diagnosis. We intensified a five-drug therapy (ifosfamide, etoposide alternated with vincristine, doxorubicin, and cyclophosphamide) using filgrastim but not stem-cell support. We studied topotecan alone and combined with cyclophosphamide in therapeutic windows before the five-drug therapy. A randomly assigned proportion of patients received amifostine as a cytoprotective agent. PATIENTS AND METHODS Eligible patients were < or = 30 years old and had histologically proven Ewing sarcoma or primitive neuroectodermal tumor (PNET) and metastasis at diagnosis. Chemotherapeutic cycles began every 21 days, after recovery from toxicities. RESULTS One hundred ten of the 117 patients enrolled were eligible. Thirty-six patients received initial topotecan. Three had partial responses (PRs), and 17 had progressive disease (PD). Thirty-seven patients were administered topotecan and cyclophosphamide; 21 of these patients achieved PR, and one patient had PD. In a randomly assigned group of 69 patients, amifostine did not provide myeloprotection, which was measured by absolute neutrophil count, platelet count, or cycle intervals. The best responses to the overall therapy included 45 complete responses, 41 PRs, stable disease in 14 patients, and PD in five patients. For all patients, the 2-year event-free survival (EFS) rate was 24% (+/- 4%), and the overall survival rate was 46% (+/- 5%). For the 39 patients with isolated pulmonary metastases, the 2-year EFS rate was 31% (+/- 7%) compared with 20% (+/- 5%) for patients with more widespread disease. CONCLUSION Topotecan had limited activity in patients with Ewing sarcoma or PNET metastatic at diagnosis. The topotecan-cyclophosphamide combination was active. Amifostine was not myeloprotective. Overall results showed no improvement compared with previous studies.

Biomechanical Analysis of Patellar Tendon Allografts as a Function of Donor Age

We evaluated the biomechanical properties of patellar tendon allografts from donors aged 18 to 55 years. Bone-patellar tendon-bone complexes were harvested from acceptable donors and processed. Fat and soft tissue were removed, and the tendons were sectioned lengthwise leaving the central third. Area measure ments were taken, and mechanical testing was per formed. Specimens were pulled to failure at a rate of 10% of the initial length per second. The force at failure, tensile stress, modulus of elasticity, and percent elon gation were determined for each specimen. There was no significant correlation (P > 0.05) between age and any of the mechanical properties. Load at failure ranged from 2110 to 4650 N, with a mean of 3424 N. Regres sion analysis showed slightly decreasing tensile stress with increasing age, but the correlation was not signifi cant. It appears that patellar tendon allografts from do nors up to age 55 have similar mechanical properties.

The effects of resection of the proximal part of the fibula on stability of the knee and on gait.

We studied six patients to determine the effects of unilateral marginal resection of the proximal part of the fibula on stability of the knee and on gait. At the time of the operation, the fibular collateral ligament and the tendon of the biceps femoris were reattached, but no attempt was made to stabilize the fibula otherwise. The patients were tested an average of sixty-one months after operation. Stability of the knee was measured with an instrumented system. Gait was evaluated with an optical electronic three-dimensional digitizing system and a multicomponent force-platform. The gait of six healthy control subjects of similar age was also studied, and the reproducibility of measurements of stability of the knee was investigated in four healthy adults. There were significant differences between the side on which an operation had been done and the contralateral side with regard to the extent of anterior translation and of total anterior-posterior translation of the tibia at both 20 and 90 degrees of flexion of the knee, and in total varus and valgus rotation of the knee (the number of degrees from a position of maximum varus to one of maximum valgus angulation) at 20 degrees of flexion. The measurements of gait and of motion of the knee were found to be normal when compared with those in the control subjects. In the ground-reaction measurements, there were some significant differences from normal in the medial-lateral plane, but they were clinically unimportant. Resection of the proximal part of the fibula can lead to instability of the knee.

Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children's Oncology Group.

Patients with Ewing sarcoma require local primary tumor control with surgery, radiation, or both. The optimal choice of local control for overall and local disease control remains unclear.

Pullout strength of fixation screws from polymethylmethacrylate bone cement

Polymethylmethacrylate bone cement is often used to fill voids and increase the strength of osteoporotic and pathological bone. However, it is unclear as to which method of cement augmentation provides optimal screw fixation. This study was conducted to determine which of the current cement augmentation techniques provides the strongest construct when used in association with orthopaedic fixation screws. Pullout strength was determined for screws placed in sawbones with no cement, soft cement, doughy cement and hard cement after drilling and tapping. All cement-screw constructs were significantly stronger than the no cement group. Screws placed in doughy cement had a significantly higher pullout force than those placed in hard cement. Pullout strength of screws placed in soft cement was intermediate between the other cement techniques but not significantly different from either group.

Local progression after operative treatment of metastatic kidney cancer.

The cases of 78 patients with osseous metastases from kidney cancer were reviewed to determine the rate of local progression after operative resection as compared with more traditional intralesional procedures. Group I consisted of 41 (53%) patients who were treated with intralesional procedures involving internal fixation with or without curettage or polymethylmethacrylate. Of the 41 patients, additional operations were recommended for 17 (41%) of the patients who had local osseous progression. Fourteen additional procedures including nine wide resections with reconstruction, three amputations, and two mass excisions were done. Group II consisted of 37 (47%) patients who were treated with marginal or wide resection with or without reconstruction. In this group, only one patient required additional operative intervention for local osseous progression. Median survival of patients in Group I was 20 months compared with 35 months for patients in Group II. This study shows that despite shorter average survival, patients who undergo intralesional surgery are at high risk of reoperation for local progression. Resectional surgery should be considered in patients with skeletal metastases from kidney cancer to lessen the risk of reoperation for local progression.

Effect of methotrexate on distraction osteogenesis.

To assess the potential of using distraction osteogenesis to reconstruct bone deficient limbs after limb salvage for musculoskeletal sarcomas, the authors examined the effect of methotrexate on distraction osteogenesis in a rabbit tibial lengthening model. Eighteen rabbits underwent tibial corticotomy and application of a ring external fixator. Rabbits were assigned randomly to one of two groups in which either methotrexate (n = 12) or placebo (n = 6) was administered during a 21-day distraction period. Serum methotrexate levels and complete blood cell counts were monitored during distraction, and radiographs of the tibia were obtained weekly. Half of the animals from each group were sacrificed at the end of distraction, and the remaining animals were sacrificed after 6 weeks of neutral fixation when bone normally bridges the gap. Using methotrexate at serum concentrations similar to those used clinically for the treatment of human osteosarcomas, the authors were unable to show significant radiographic, histologic, or chemical differences in the effect of this antineoplastic drug on distraction osteogenesis in the rabbit model.

Case report 800

In summary, intramuscular myxoma associated with fibrous dysplasia of bone represents a benign disorder of uncertain etiology. Magnetic resonance imaging has proved to be a useful diagnostic tool in the evaluation of this benign disorder. In addition, MR is a valuable aid in the preoperative planning process.

The promise of bone cancer proteomics.

Mass spectrometric analysis of the low‐molecular‐weight (LMW) range of the serum/plasma proteome is revealing the existence of large numbers of previously unknown peptides and protein fragments, predicted to be derived from circulating low‐abundance proteins. While genomics and proteomics are the primary discovery research tool, recent innovations in high‐throughput proteomics are now standard practice for biomarker and target discovery. Surface‐enhanced laser desorption/ionization time‐of‐flight (SELDI‐TOF) mass spectrometry (MS) is the current mainstay for serum or plasma analysis, although other methods are emerging as alternative high‐throughput approaches. From a proteomics perspective, the bone cancers, such as myeloma, breast and prostate cancer bony metastases, and osteosarcoma, are likely among the least studied. As recent advances in proteomic technology have thrust the bone cancer field into the era of proteomics, a review of the current status of the proteome as it relates to the skeletal consequences of malignancy seems reasonable.