Prognostic factors in patients with symptomatic spinal metastases and normal neurological function.

AIMS: To evaluate potential prognostic factors for predicting survival after radiotherapy in patients with painful spinal metastases and normal neurological function. MATERIALS AND METHODS: In total, 173 patients were included. The following prognostic factors were assessed: primary cancer site, age, gender, albumin and haemoglobin levels, Karnofsky performance status (KPS), analgesic use, pain intensity, number of extraspinal bone metastases and visceral metastases, presence of tumour-conditioned spinal canal stenosis and metastatic spinal cord compression, and extension of spinal metastatic disease on magnetic resonance imaging (MRI). Ongoing systemic treatment, use of bisphosphonates and response to radiotherapy were also evaluated. A simple scoring system for predicting survival was used. RESULTS: The following predictive factors were found to be significant in multivariate analysis: primary cancer site, KPS, albumin level, number of visceral metastases and analgesic use. Three survival groups were proposed. The overall survival probabilities for groups 1-3 were 13, 46 and 94% at 6 months; 4, 28 and 79% at 12 months, respectively. The median survival times for groups 1-3 were 2.1, 5.5 and 24.9 months, respectively (P < 0.001). CONCLUSION: The pretreatment albumin level was a significant prognostic indicator for survival. Similarly, the primary cancer site, KPS and number of visceral metastases were associated with survival; these findings were consistent with the results of previous studies. The pretreatment analgesic use was significant using the univariate and multivariate analyses and this factor can be verified in future trials. Self-reported pain intensity, pain response to radiotherapy and MRI findings did not influence survival times.

MRI and neurological findings in patients with spinal metastases.

BACKGROUND: Magnetic resonance imaging (MRI) is the recommended primary investigation method for metastatic spinal cord compression (MSCC). Initiating treatment before the development of motor deficits is essential to preserve neurological function. However, the relationship between MRI-assessed grades of spinal metastatic disease and neurological status has not been widely investigated. PURPOSE: To analyze the association between neurological function and MRI-based assessment of the extent of spinal metastases using two different grading systems. MATERIAL AND METHODS: A total of 284 patients admitted to our institution for initial radiotherapy or surgery for symptomatic spinal metastases were included in the study. Motor and sensory deficits were categorized according to the Frankel classification system. Pre-treatment MRI evaluations of the entire spine were scored for the extent of spinal metastases, presence and severity of spinal cord compression, and nerve root compression. Two MRI-based scales were used to evaluate the degree of cord compression and spinal canal narrowing and relate these findings to neurological function. RESULTS: Of the patients included in the study, 28 were non-ambulatory, 49 were ambulatory with minor motor deficits, and 207 had normal motor function. Spinal cord compression was present in all patients with Frankel scores of B or C, 23 of 35 patients with a Frankel score of D (66%), and 48 of 152 patients with a Frankel score of E (32%). The percentage of patients with severe spinal canal narrowing increased with increasing Frankel grades. The grading according to the scales showed a significant association with the symptoms according to the Frankel scale (P < 0.001). CONCLUSION: In patients with neurological dysfunction, the presence and severity of impairment was associated with the epidural tumor burden. A significant number of patients had radiological spinal cord compression and normal motor function (occult MSCC).

Why do patients with radiation-induced sarcomas have a poor sarcoma-related survival?

BACKGROUND: This study aims to provide reasons for the poor sarcoma-related survival in patients with radiation-induced sarcoma (RIS). METHODS: We performed a case-control study comparing sarcoma-related survival of 98 patients with RIS to that of 239 sporadic high-grade malignant sarcomas. RESULTS: The cumulative sarcoma-related 5-year survival was 32% (95% confidence interval (CI): 22-42) for patients with RIS vs 51% (95% CI: 44-58) for controls (P<0.001). Female gender, central tumour site and incomplete surgical remission were significantly more frequent among RIS patients than in controls. In multivariate analysis incomplete surgical remission (hazard ratio (HR) 4.48, 95% CI: 3.08-6.52), metastases at presentation (HR 2.93, 95% CI: 1.95-4.41), microscopic tumour necrosis (HR 1.88, 95% CI: 1.27-2.78) and central tumour site (HR 1.71, 95% CI: 1.18-2.47) remained significant adverse prognostic factors, but not sarcoma category (RIS vs sporadic). CONCLUSION: The poor prognosis of RIS patients are not due to the previous radiotherapy per se, but related to the unfavourable factors - central tumour site, incomplete surgical remission, microscopic tumour necrosis and the presence of metastases, the two former factors overrepresented in RIS.

Pain after palliative radiotherapy for spine metastases.

AIMS: The purpose of the study was to evaluate the response to palliative radiotherapy in patients with painful spinal metastatic disease (SMD). MATERIALS AND METHODS: Three hundred and fifty-five patients admitted to the Norwegian Radium Hospital for radiotherapy for painful SMD were included in a prospective study and were followed up 2 months later. The Brief Pain Inventory was used to assess pain. Analgesic consumption was recalculated into the daily oral morphine-equivalent dose. The radiotherapy-related response rates were calculated using the criteria of the International Bone Metastases Consensus Group (IBMCG), taking into account the use of concomitant analgesics. The response to radiotherapy was assessed as complete or partial and non-response as stable pain, pain progression or 'other'. RESULTS: Brief Pain Inventory forms were obtained at follow-up from 229 of the 355 patients. Two months after radiotherapy, the median self-reported worst pain decreased significantly, but the median oral morphine-equivalent dose increased from 40 to 60 mg (P<0.001). Forty-three per cent of the patients reported pain relief, but a radiotherapy-related response was found in 37% of the patients. Overall correspondence between the patients' self-reported changes in pain experience and the IBMCG-based response categories was obtained in 63% of the patients. CONCLUSIONS: The radiotherapy-related response rates in our study were lower than those reported previously in patients with bone metastases in general, which possibly indicates the presence of more complex pathophysiological mechanisms of pain in SMD.

A population-based study of spinal metastatic disease in South-East Norway.

AIMS: Spinal metastatic disease (SMD) is a serious complication of cancer. To our knowledge, only one population-based study of metastatic spinal cord compression (MSCC) has been carried out. The purpose of the present study was to describe population-based incidences of SMD that required local treatment, such as radiotherapy, surgery or vertebroplasty, including patients with or without cord compression, and to characterise the neurological status of these patients. MATERIALS AND METHODS: During 18 months, all patients with SMD who received local treatment in the South-Eastern Health Region of Norway (population 2.6 million inhabitants) were identified and their medical records were reviewed. RESULTS: In total, 1002 patients were included; 83% had multiple lesions in the spine; 39% had SMD at the time of the primary cancer diagnosis. At the start of local treatment, 31% had MSCC and 11% were not able to walk. The prevalence of MSCC at the time of cancer diagnosis was 0.36%. The annual incidences per 100,000 inhabitants were 26.0 for SMD and 8.1 for MSCC. CONCLUSION: Population-based incidences of SMD requiring local treatment have been reported for the first time. The prevalence of MSCC at the time of cancer diagnosis was higher than previously reported. A more precise definition of MSCC and more population-based studies are needed to reduce selection bias when comparing different studies.

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.

Carvedilol reduces ischaemic skeletal muscle necrosis.

Carvedilol is an alpha1 and nonselective beta-adrenergic receptor antagonist with antioxidative properties known to protect against reperfusion injury in the heart, brain, and kidneys. The aim of this study was to test the hypothesis that carvedilol improves postischaemic reperfusion and tissue survival in skeletal muscle. Sixteen Wistar rats underwent tourniquet ischaemia of the left hindlimb for 3 hours and 15 minutes at 27 degrees C. Single-fiber laser Doppler probes were inserted in the left and right anterior tibial muscles, and microvascular perfusion was measured until 2 hours after removal of the tourniquet. Perfusion indices for each 15-minute interval were calculated for the left hindlimb (tourniquet ischaemia) by dividing the postischaemic by the pre-ischaemic laser Doppler flowmetry values, and the geometrical areas under the curves representing a plot of perfusion index relative to time, measured in arbitrary units, were compared. Laser Doppler flowmetry values for the right anterior tibial muscle were compared. Tissue damage was measured by histomorphometry of necrotic areas and no-reflow zones in cross sections from the anterior tibial muscle 72 hours after ischaemia. Neutrophils were counted in the same sections. The treatment group received 1 mg carvedilol/kg body weight before ischaemia and 1 mg/kg immediately before removal of the tourniquets. The areas under the curves representing the plot of perfusion index relative to time were larger for the rats treated with carvedilol: 9.5 compared with 3.0 arbitrary units (p = 0.0003). Treatment did not change the laser Doppler flowmetry values for the right hindlimbs. The histomorphometric areas of necrosis in cross sections from the muscles were reduced from 88% (38-96%) in the control animals to 41% (7-85%) in those treated with carvedilol (p = 0.01), and the area of no-reflow was reduced from 20% (2-52%) to 0% (0-7%) (p = 0.006). The number of neutrophils did not differ between groups. The study supports the hypothesis that carvedilol improves early reperfusion and protects skeletal muscle subjected to 3 hours and 15 minutes of ischaemia.

Protective effect of the endothelin antagonist Bosentan against ischemic skeletal muscle necrosis.

We tested the hypothesis that blocking of the endothelin system by Bosentan, a combined endothelin-A and -B receptor antagonist (Hoffmann La Roche, Basel, Switzerland), improves postischemic skeletal muscle reperfusion and reduces tissue damage. 16 Wistar rats were subjected to 3 h and 15 min hindlimb tourniquet ischemia at 27 degrees C. Perfusion was continuously measured with Laser Doppler Flowmetry (LDF) in the anterior tibial muscle during ischemia and the first 2 h of reperfusion. Perfusion indices were calculated for each 15 min, by dividing each LDF value by the preischemic LDF value of the leg. The areas under the perfusion index curves were compared. 72 h after ischemia, histomorphometry of necrosis and no-reflow zones, and counting of neutrophils were done in cross-sections of the muscles. The animals were randomized into two groups. The treatment group received an injection of Bosentan 15 mg/kg 10 min before ischemia, and this dose was repeated 5 min before reperfusion of the hindlimbs. The treatment group obtained an improved reperfusion (4.48 vs. 1.72, p = 0.02). The median cross-sectional area of necrosis was smaller in the treatment group, 70% vs. 93% (p = 0.02), while neither the areas of no-reflow nor the neutrophil counts in reperfused necrotic areas were different. This study supports the hypothesis that Bosentan seems to improve reperfusion and reduces postischemic skeletal muscle damage.

Compartment pressure in nailed tibial fractures. A threshold of 30 mmHg for decompression gives 29% fasciotomies.

During the past few years we have monitored tissue pressure in patients treated with intramedullary nailing of tibial shaft fractures. A value of 30 mmHg has been used as the threshold for fasciotomy. The purpose of this study was to evaluate this practice. Sixty-three patients were included in the series. Forty-three fractures were closed, 18 grade I (Gustilo) and two grade II. Tissue pressure measurements were performed in 43 patients. Eighteen legs were treated with decompressive fasciotomy, three on clinical findings alone, and 15 after measurement of a pressure higher than 30 mmHg. This gives a fasciotomy rate of 29%. At follow-up two patients were dead. All fractures were healed, and there were no major complications such as deep infection, extensive muscle necrosis, paresis or short-foot syndrome. Three fasciotomized patients had significantly reduced muscle strength compared with the contralateral leg.

Endothelin-1 is upregulated during skeletal muscle ischemia and reperfusion.

The aim of the present study was to test the hypothesis that the vasoconstrictive peptide endothelin-1 is upregulated in ischemia and reperfusion in skeletal muscle. Sixty-eight Wistar rats were included in the series: 12 served as controls that did not undergo the procedure, 16 underwent sham operations, and 40 were subjected to a modified tourniquet ischemia for 3 hours and 20 minutes. Of the 40 rats, 16 were killed at the end of the ischemic period, 16 underwent reperfusion for 2 hours, and eight underwent reperfusion for 72 hours. Areas of necrosis were measured by morphometry in hematoxylin and eosin-stained cross sections of the anterior tibial muscles that had been reperfused for 72 hours. Sections from the controls, the muscles that had not been reperfused, and the reperfused muscles were immunostained for endothelin-1. Serum endothelin-1 levels in blood samples from the aorta were determined with a commercial enzyme immunoassay kit. The anterior tibial muscle was harvested for preproendothelin-1 mRNA analysis with RNase protection assay. The hematoxylin and eosin-stained sections showed extensive necrosis with an acellular core of no reperfusion. The muscular core demonstrated weak immunostaining for endothelin-1 in all sections, a subfascial narrow brim of fibers showed enhanced immunoreactivity at the end of ischemia, and all fibers outside the core stained by 2 hours after the start of reperfusion. After 72 hours of reperfusion, the fibers outside the core stained positive in a checkerboard-like pattern. There were no differences in serum endothelin-1 levels between the groups. Preproendothelin-1 mRNA analysis with RNase protection assay showed 2-fold upregulation at the end of ischemia and 4-fold upregulation after 2 hours of reperfusion (p = 0.001). This study supports the hypothesis that both ischemia and reperfusion upregulate endothelin-1 in skeletal muscle.

Healing of tibial fractures is not impaired after acute hindlimb ischemia in rats.

The influence of transient circulatory arrest on the healing of closed tibial fractures was investigated in rats by the use of a hindlimb tourniquet technique. Twenty-four animals were randomly divided into three groups. In all animals, the left lower leg was fractured and fixed with an intramedullary nail system. In the ischemic group, complete acute transient ischemia for 4.5 h and neurapraxia of the sciatic and femoral nerves were induced prior to fracture. In the neurapraxia group, the sciatic and femoral nerves were crushed with forceps before fracture. In the control group, no other intervention than fracture was made. The rats of the control group ambulated normally 3-4 days after the operation. The animals of the ischemic and neurapraxia groups resumed normal weight-bearing after about 3 weeks. After 6 weeks, all animals were killed, and mechanical strength and bone mineral turnover of the healing tibia as well as blood flow of the bone and musculature were evaluated. The weight of the tibia and the corresponding anterior tibial muscle in the ischemic and neurapraxia animals were reduced compared with the control rats. Bone mineral turnover was found to be lower in the ischemic group. There were no differences between the groups in mechanical strength nor in blood circulation of bone and muscle. In conclusion, complete, acute hindlimb ischemia for 4.5 h in rats did not cause delayed healing of closed tibial fractures.

Anterior cruciate ligament strength. Can it be estimated by non-destructive testing?

For structural and material bone strength, non-destructive tests exist, while no such tests have been developed for ligaments. In the present study we compared the geometry and bone mineral content (BMC) of the rat tibia with the tensile strength of the anterior cruciate ligament (ACL). A significant correlation was found between the mediolateral diameter of the tibial condyle and ACL load to failure (r=0.83). Calculating the area of the condyle as an ellipse increased this correlation to r=0.93. No significant correlation was found to BMC. If this correlation is also found in humans, the mediolateral tibial head diameter may be used to estimate the strength of the ACL non-destructively.

Severe hindlimb ischemia causes periosteal proliferation in the rat tibia.

In this rat study, we found tibial periosteal hyperplasia and hypertrophy, and appositional new bone formation 3 days after transient hindlimb ischemia. This response was positively correlated to the extent of muscle necrosis, which was increased either by raising the environmental temperature during ischemia or by prolonging the period of ischemia. By changing the temperature from 21 degrees C to 34 degrees C, the area periost in percent of the total tibial area was increased from 5 to 17, and by changing the duration of ischemia from 3 to 5 hours, it increased from 8 to 18.

[Transiliacal screw fixation of the sacrum in unstable pelvic ring fractures]. / Transiliakal skruefiksasjon av sacrum ved ustabile bekkenringbrudd.

This article presents our experiences from fixation of the sacrum by transiliacal screw in 13 patients with unstable fractures of the pelvic ring. Early mobilization, with no secondary dislocation or postoperative complications, was achieved in all patients. Sagittal instability in unstable pelvic ring fractures must be acknowledged. The transiliac screw offers the possibility of early mobilization of patients with this fracture. The procedure is demanding and patients selected for this treatment should be referred to hospitals with experience in the treatment of pelvic fractures.

No increasing injury during early reperfusion of skeletal muscle.

Early reperfusion is thought to contribute to the final parenchymal and microvascular injury after transient ischaemia of skeletal muscle. Albumin, a large molecule which is not found in intact cells, can be used as an early marker of extensive membrane injury. In the present study, staining of intracellular albumin was used to test the hypothesis that muscle cell injury increases during early reperfusion. Complete ischaemia was induced for 3 h 15 min in rat hindlimbs. A total of 16 animals were randomized into two groups. The anterior tibial muscles were dissected and fixed in formaldehyde without reperfusion in one group, while circulation was re-established in the hindlimbs for 3 h in the other group. Cross-sections from the muscles were stained with antisera against rat albumin, using fast red as chromogen. This immunostaining showed a central zone of injured cells in each cross-section. The albumin-positive areas, calculated as a percentage of the total cross-sectional areas were 76 and 77% in the two groups respectively. This difference was not significant, suggesting that ischaemia and not reperfusion was the major trauma.

Cardiovascular response to blood loss during high intracranial pressure.

The authors hypothesized that the combination of hemorrhage and increased intracranial pressure (ICP) has deleterious effects on cardiovascular function. The effect of blood loss during normal and increased ICP was studied in eight pigs. The mean arterial pressure (MAP), pulmonary arterial pressure, pulmonary capillary wedge pressure, cardiac output, and cerebrospinal fluid (CSF) pressure were measured. The regional tissue blood flow was determined with radioactive microspheres labeled with four different nuclides. High ICP (80% of MAP) was induced by infusion of artificial CSF into the cisterna magna. The response to rapid arterial bleeding of 25% of blood volume was measured. The decrease in blood flow to the intestine, skeletal muscle, and the kidneys after blood loss was significantly greater during high ICP. The decrease in blood flow to the spleen and pancreas tended to be greater during high ICP, whereas the changes in blood flow to the liver, adrenal glands, and heart muscle showed no such tendency. The fall in cardiac output and heart stroke volume after blood loss were more pronounced when the ICP was high, and the increase in systemic vascular resistance was considerably greater. These observations suggest that during high ICP the physiological protective mechanisms against blood loss are impaired in the systemic circulation, and a loss of 25% of the blood volume, normally well compensated for, may induce a state of shock.

The repair of a ruptured deltoid ligament is not necessary in ankle fractures.

We randomised 50 patients with ankle fractures of Weber types B and C and a ruptured deltoid ligament treated by open reduction and internal fixation to two treatment groups to examine the influence of the repair of a ruptured deltoid ligament. No differences were found except for a longer duration of surgery in the repair group. Our findings suggest that a ruptured deltoid ligament can be left unexplored without any effect either on early mobilisation or on the long-term result.

Cerebral blood flow measured with intracerebral laser-Dopplerflow probes and radioactive microspheres.

We have measured cerebral blood flow with intracerebral laser-Doppler microprobes in pentobarbital-anesthetized pigs. We compared the results with measurements from laser-Doppler probes placed on the surface of the brain and with blood flow estimation by the radioactive microsphere method. The cerebral blood flow was varied by alterations in inspired carbon dioxide, hemorrhagic hypotension, and high cerebrospinal fluid pressure. The intracerebral probes and the surface probes showed parallel responses to variations in cerebral blood flow. The correlation was closest between surface probes and the intracerebral probes measuring from the cerebral cortex (r = 0.46; P < 0.005). The r value between laser-Doppler flowmetry and radioactive microspheres was 0.41 (P < 0.0005) for all measurements. The correlation to microspheres was best for the probes located 3 or 10 mm into the brain and poorest for the surface probe. In conclusion, intracerebral laser-Doppler flow measurements reflect changes in blood flow, and the technique appears useful for continuous estimates of cerebral blood flow.

Periosteal response to transient ischemia. Histological studies on the rat tibia.

Complete arrest of blood flow was induced for 4.5 hours in the left hindlimb of Wistar rats by a tourniquet applied proximally to the thigh. Histologically the periost of the tibial bone after 3 days showed marked hypertrophy and hyperplasia of the periosteal cells with an osteogen differentiation. This response is similar to the initial formation of external callus during fracture healing. Transient ischemia may be an important factor in initiating fracture healing.