Survival and complications of skeletal reconstructions after surgical treatment of bony metastatic renal cell carcinoma.

Improvements in survival for patients with renal cell carcinoma have resulted in an increase in the burden of disease due to skeletal metastases, which are often solitary and resistant to radiotherapy. Surgical intervention remains a valid treatment to improve function and relieve pain, and replacement is able to achieve this and improve disease free implant survival. The aim of this study was identify prognostic factors for reconstruction survival of skeletal metastases in renal cell carcinoma and to characterise the nature of the reconstruction related complications. A retrospective analysis of all patients treated for metastatic renal cell carcinoma in three international bone tumour units between 2000 and 2014 identified 268 surgical interventions suitable for inclusion. Reconstruction survivorship was calculated using the Kaplan-Meier method whilst factors affecting reconstruction survival were assessed using Cox-regression multivariate analysis. Differences in proportions were assessed using Fisher's exact test. The overall rate of complications was 17%, which were classified as structural failure (7.1%), infection (4.9%) and tumour progression (3.7%). Endoprosthetic replacement when performed as the primary procedure demonstrate the best survivorship whilst factors associated with compromised reconstruction survival included previous surgical intervention and pre operative radiotherapy, and intralesional resection margins. We conclude that endoprosthetic replacement be considered as the index surgical intervention for skeletal metastases from renal cell carcinoma in certain locations as this carries the lowest incidence of complications. Revision of previous skeletal stabilisation, especially when combined with radiotherapy carries a high risk of complication, including infection, which often necessitates amputation.

Surgical treatment of skeletal metastatic lesions of the proximal femur: endoprosthesis or reconstruction nail?

We report positive and negative factors associated with the most commonly-used methods of reconstruction after pathological fracture of the proximal femur. The study was based on 142 patients treated surgically for 146 metastatic lesions between 1996 and 2003. The local rate of failure was 10.3% (15 of 146). Of 37 operations involving osteosynthetic devices, six failed (16.2%) compared with nine (8.3%) in 109 operations involving endoprostheses. Of nine cases of prosthetic failure, four were due to periprosthetic fractures and three to recurrent dislocation. In the osteosynthesis group, three (13.6%) of 22 reconstruction nails failed. The two-year risk of re-operation after any type of osteosynthesis was 0.35 compared with 0.18 after any type of endoprosthetic reconstruction (p = 0.07). Endoprosthetic reconstructions are preferable to the use of reconstruction nails and other osteosynthetic devices for the treatment of metastatic lesions in the proximal third of the femur.

The Scandinavian Sarcoma Group Skeletal Metastasis Register. Survival after surgery for bone metastases in the pelvis and extremities.

INTRODUCTION: The assessment of the prognosis for the individual patient is important for the choice of surgical treatment of skeletal metastases. In 1999 the Scandinavian Sarcoma Group (SSG) initiated the Skeletal Metastasis Register as a multicentric, prospective study to provide a scientific basis for treatment recommendations. To improve prognostication we analyzed the survival of patients with skeletal metastases surgically treated at 9 SSG centres. PATIENTS AND METHODS: 460 patients with an average age of 64 years underwent 501 operations for non-spinal skeletal metastases. 7% were operated for more than one metastasis. Carcinoma of the breast, prostate, kidney and lung were the dominating primary tumors. RESULTS: The survival rate was 0.4 at 1 year, 0.3 at 2 years and 0.2 at 3 years. Univariate analysis showed that survival was related to bone localization, skeletal metastatic load, presence of visceral metastases, Karnofsky performance score, primary tumor type, presence of a complete pathological fracture and preoperative hemoglobin content. Multivariate regression analysis showed that pathological fracture, visceral metastases, haemoglobin content < 7 mmol/L and lung cancer were negative prognostic factors for survival. Myeloma was the sole positive prognostic factor for survival.

Surgical treatment for pathologic fracture.

AIM: To evaluate epidemiology, prognosis and diagnostics in metastatic bone disease and identify risk factors for failure after operation for pathologic fracture. PATIENTS: The study was based on patients treated for skeletal metastases, myeloma or lymphoma between 1986 and 1998 at the Oncology Service, Department of Orthopedics, Karolinska Hospital and on patients diagnosed with symptomatic skeletal metastases 1989-1994 in the Stockholm Region. EPIDEMIOLOGY: 641 breast cancer patients were diagnosed with symptomatic skeletal metastases 1989-1994. Based upon 1100 new primary breast cancer cases yearly, the overall risk of developing symptomatic skeletal metastases was 10-15%. One out of 5 patients with skeletal metastases required surgical treatment for skeletal complications. PROGNOSIS: The survival rate after surgical treatment for skeletal complications was 0.3 at 1 year and 0.008 at 3 years. Multivariate analysis based on 619 patients showed that complete pathologic fracture and soft tissue metastases were negative prognostic variables for 1-year survival after operation. Solitary skeletal metastasis, breast, prostate, kidney cancer, myeloma, and lymphoma were positive variables. DIAGNOSIS: Fine Needle Aspiration Biopsy (FNAB) was assessed in 110 patients for diagnostic accuracy and to which extent information about primary site of the metastatic carcinoma could be gained. There were 80 patients with metastatic carcinoma, 14 with lymphoma, and 16 with myeloma. FNAB offered correct diagnosis in 9 of 10 patients and also provided guidance in the search for the primary lesions. Hence, 27 of 30 myeloma or lymphomas were diagnosed by FNAB and in half of the patients with metastatic carcinoma the site of the primary tumor could be ascertained. For patients with a suspected skeletal metastasis the search for the primary tumor may preferably start with FNAB. SURGICAL TREATMENT: Risk factors for failure after operation for pathologic fractures were identified in 192 patients treated for 228 metastatic lesions of the long bones. 26 out of 228 procedures (11%) lead to failures necessitating reoperation. Long survival after surgery was the most important risk factor for failure of the reconstruction. Kidney cancer was the primary tumor associated with the highest rate of reoperations. Reoperations were more common in the femur than in the humerus. Reconstructions based on prosthetic as opposed to osteosynthetic devices appeared safer. There was a tendency for a high reoperation rate in hospitals with few treated patients. CONCLUSION: To decrease the risk of reoperation, it is important to identify patients with a long expected survival. Patients with a good prognosis should be considered for wide resection and reconstruction as applied in primary malignant bone tumors.

Surgical treatment for skeletal breast cancer metastases: a population-based study of 641 patients.

BACKGROUND: The objective of this article was to assess the occurrence of symptomatic bone metastases in a defined population of patients with breast carcinoma and to characterize the clinical outcome with reference to surgical treatment for pathologic fracture or neurologic deficit. METHODS: The authors identified all patients in the Stockholm Breast Cancer Database (population base 1.8 million) with a diagnosis of bone metastases during 1989--1994. These cases were linked with the Stockholm County Council Hospital Discharge Diagnosis Registry that includes information on in-patient care and discharge diagnoses. This enabled us to identify patients who had undergone surgical treatment for their bony metastases at any of the six departments of orthopedics in the region, or who had been treated at the one department of neurosurgery. RESULTS: Six hundred forty-one patients with breast carcinoma presented with symptomatic skeletal metastasis during 1989--1994, and 107 (17%) were operated on. Metastases were located in long bones (77), spine (14), and pelvis (6). The median survival postoperatively was 6 months. The total reoperation rate was 0.12. Hip screws and glide-screw plates were associated more often with failure as was location in the distal femur. Pain decreased postoperatively in 77% of the patients, and function improved in 65%. CONCLUSIONS: One in 10 patients with breast carcinoma developed symptomatic bone metastases, and one-fifth of these patients required surgery for pathologic fracture or neurologic deficit. There was a high failure rate in those hospitals in which few patients were operated on.

Cytological diagnosis of skeletal lesions. Fine-needle aspiration biopsy in 110 tumours.

We have previously shown that cytological diagnosis based on fine-needle aspiration biopsy (FNAB) is a safe and efficient method for the discrimination between benign, primary malignant and metastatic bony lesions. We have now studied metastatic lesions to assess the diagnostic accuracy and to ascertain whether FNAB allows identification of the primary lesion. Between 1990 and 1997, 447 patients were referred for diagnosis of skeletal lesions of unknown type. Of these 119 proved to have metastatic disease, either myeloma or lymphoma. Nine were excluded leaving 110 consecutive patients with metastatic carcinoma (80), myeloma (16) or lymphoma (14). FNAB gave a correct diagnosis in 102 of the 110 patients (93%). In eight it was inconclusive. It correctly diagnosed 15 of 16 patients with myeloma, 12 of 14 with lymphoma, and 75 of 80 with metastatic carcinoma. Furthermore, the site and type of malignancy were correctly suggested in two-thirds of patients with metastatic carcinoma. Overall, only seven open biopsies were carried out. We conclude that time-consuming and costly investigations can be reduced by choosing FNAB as the initial diagnostic method for skeletal lesions of unknown origin. The choice of radiological examinations, laboratory tests and surgical biopsies can be determined by using FNAB.

Failures after operation for skeletal metastatic lesions of long bones.

This study was based on 192 patients treated surgically for 228 metastatic lesions of the long bones from 1986 through 1995. The survival rate was 0.3 at 1 year after surgery. The surgical treatment consisted of resection and reconstruction of the involved bone (18), intralesional curettage (133), or stabilization only (77). Reconstruction was achieved by an endoprosthesis in 54 cases, by an osteosynthetic device in 162, by cement only in 10. In two cases no reconstruction was performed. The local failure rate was 11% and the median time to failure was 8 months. Local failure was most frequent in patients with kidney cancer (24%) and in diaphyseal and distal femoral lesions (20%). Among 162 operations involving osteosynthetic devices, 22 (14%) were failures as compared with one of 54 (2%) endoprostheses. Sixty percent of the patients received preoperative or postoperative radiotherapy. Five of the six patients who had surgery for local tumor progression had not received radiotherapy. Eight of 10 nonunions and all five patients who developed a stress fracture had been treated with radiotherapy. It is concluded that endoprosthetic reconstructions are preferable to osteosynthetic devices. The skeletal complications associated with radiotherapy may be circumvented by the use of endoprostheses.

Survival after surgery for spinal and extremity metastases. Prognostication in 241 patients.

We assessed the survival after surgery in 153 patients with extremity metastases and 88 with spinal metastases. The survival rate for the whole series of 241 patients was 0.30 at 1 year, 0.15 at 2, and 0.08 at 3 years. The 1-year survival rate was the same for the extremity metastases group and the spinal group. Univariate analysis showed that 1-year survival was related to metastatic load, site of primary tumor, and presence of pathologic fracture. Multivariate regression analysis showed that pathologic fracture, visceral or brain metastases, and lung cancer were negative prognostic variables. Solitary skeletal metastases, breast and kidney cancer, myeloma, and lymphoma were positive variables. A prognostication model based on these variables stratified the patients into 3 groups with a 1-year survival ranging from 0.5 to 0.0. These prognostic variables can be used for differentiating the treatment of cancer patients with pathologic fracture or epidural compression.

Electrostatic effects and hydrogen exchange behaviour in proteins. The pH dependence of exchange rates in lysozyme.

The pH dependence of the exchange rates for a number of tryptophan and amide hydrogen atoms in hen egg-white lysozyme has been determined at temperatures well below the thermal denaturation temperature. The pH behaviour of each hydrogen is unique and can differ markedly from that of simple compounds. A model for electrostatic effects in proteins is described and used to explain a number of the features of the pH dependence of the exchange rates of certain hydrogens. The results indicate that exchange takes place from a conformation of the protein closely similar to that of the native protein, with local fluctuations providing the mechanism for exchange. For the more-buried hydrogens at low pH values there is a general increase in the exchange rates caused by the decreasing stability of the protein as calculated from the electrostatic model. The analysis shows how evidence from hydrogen exchange studies can be used to provide information about electrostatic interactions in localized regions of proteins. A description of the electrostatic model and some applications are given in the Appendix.

Exchange of individual hydrogens for a protein in a crystal and in solution.

A preliminary comparison of the solvent exchange of individual hydrogens of a protein in solution and in a crystal has been possible by using data for lysozyme from 1H nuclear magnetic resonance and neutron diffraction studies. It is suggested that this approach enables a direct comparison of local dynamical behaviour in the two states. The results indicate markedly similar behaviour for many residues, but significant differences are indicated in several regions of the protein.

Correlation of hydrogen exchange behaviour and thermal stability of lysozyme.

The solvent exchange rates of individual indole NH hydrogens of tryptophan residues of lysozyme have been measured, by using 1H nuclear magnetic resonance spectroscopy, as a function of temperature in the presence of urea and following chemical modification. The results have been interpreted in terms of a low activation energy process which is not dependent on the thermal stability of the protein, and a higher activation energy process that is directly correlated with the thermal stability. The significance of these observations for an understanding of the dynamics of the protein is discussed.

Mechanisms of hydrogen exchange in proteins from nuclear magnetic resonance studies of individual tryptophan indole NH hydrogens in lysozyme.

The individual rates of solvent exchange of the six tryptophan indole NH hydrogens of lysozyme in 2H2O have been measured over a wide range of temperatures by using 1H NMR. Two distinct mechanisms for exchange have been identified, one characterized by a high activation energy and the other by a much lower activation energy. The high-energy process has been shown to be associated directly with the cooperative thermal unfolding of the protein and is the dominant mechanism for exchange of the most slowly exchanging hydrogen even 15 degrees C below the denaturation temperature. Rate constants and activation for the folding and unfolding reactions were obtained from the experimental exchange rates. At low temperatures, a lower activation energy mechanism is dominant for all hydrogens, and this can be associated with local fluctuations in the protein structure which allows access of solvent. The relative exchange rates and activation energies can only qualitatively be related to the different environments of the residues in the crystal structure. There is provisional evidence that a mechanism intermediate between these two extremes may be significant for some hydrogens under restricted conditions.