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.

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).

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.

Training increases the in vivo strength of the lower leg: an experimental study in the rat.

The effect of training on bone strength has been investigated in rats. After 7 weeks of training, fracture strength of the tibia in vivo during muscle contraction and after resection was assessed. A group of 30 male rats 11 weeks old were randomized to exercise on a treadmill, sedentary (ordinary caging), and inactivity (right-sided patellar tendonectomy) groups. The training group ran on a treadmill with a 10% inclination for 1 h per day. After 4 weeks the animals in all groups were anesthetized and the right lower legs loaded in three-point ventral bending until fracture during electrically induced muscle contraction. The contralateral tibiae were tested correspondingly after resection. Ultimate bending moment, energy absorption to failure, bending stiffness, and deflection were assessed for the in vivo and the resected tibiae. The body weight gain was 37% higher in the sedentary and 57% higher in the inactive animals than in the training group (P < 0.05), indicating a physiologic effect of the training. In the dissected tibiae there were no significant group differences in any of the mechanical parameters, indicating that neither training nor inactivity changed the structural capacity of the tibiae per se. In contrast, there were significant differences between the in vivo tibiae. Ultimate bending moment was 12% higher in the training group than in the sedentary and inactive groups (P = 0.03). Energy absorption in the training group was 11 and 12% higher (not significant) than in the sedentary and inactivity groups, respectively. Bending stiffness was 7 and 17% higher in the training group compared to sedentary and inactivity groups (P = 0.018).(ABSTRACT TRUNCATED AT 250 WORDS)

Muscle contraction increases the in vivo structural strength to the same degree in osteopenic and normal rat tibiae.

The increase in structural capacity due to muscle contraction in the lower leg was investigated in osteopenic and normal rats. Osteopenia was induced by ovariectomy combined with a low-calcium diet (0.01%). The control rats were sham operated and fed a diet containing 1.1% calcium. After 7 weeks the right lower leg of all animals were fractured in three-point ventral cantilever bending during muscle contraction induced by electrical stimulation of the ischiatic nerve. The left tibiae were resected and fractured as each animal's control. During muscle contraction in vivo, the ultimate bending moment, energy absorption, bending stiffness, and deflection were significantly lower in the osteopenic than in the sham-operated animals. However, the increase in mechanical parameters due to muscle contraction comparing the in vivo and resected tibiae in each animal were equally high in the osteopenic and sham-operated animals. Ultimate bending moment in the resected tibiae was 10% higher in the sham-operated animals compared with the ovariectomized, proving mechanically weaker tibiae in the osteopenic rats. In accordance with this, the medullary area of the osteopenic rats was 46% larger in the distal tibial diaphysis, and the ultimate stress the tibiae could withstand was 15% lower in the osteopenic compared with the sham-operated rats. The trabecular bone volume in the distal tibial metaphysis of the osteopenic rats was reduced by 70% compared with the sham operated. This study shows that muscle protection against fracture can be substantial in osteopenic tibia and that it is of the same magnitude as in rats with normal bone mass.

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.

Hamstrings and gastrocnemius co-contraction protects the anterior cruciate ligament against failure: an in vivo study in the rat.

An anesthetized rat model was used to study the effects of muscle contraction on the ultimate tensile load and the energy absorption at failure of the anterior cruciate ligament. In both knees, the joint capsule and ligaments, except for the anterior cruciate ligament, were divided, and the menisci were removed with the aid of a stereomicroscope. The cruciate ligament of the right knee was tested in tension until failure by femorotibial distraction during contraction of the hamstrings and calf muscles induced by electrical stimulation of the ischiatic nerve. The cruciate ligament of the left knee, which was loaded to failure with nonstimulated (relaxed) muscles, served as the control. The mean ultimate tensile load during muscle contraction was 86 N compared with 53 N when tested with relaxed muscles (p < 0.001). The energy absorption at failure was 0.41 and 0.19 J during contraction and relaxation, respectively (p < 0.05). This study suggests that previous investigations evaluating the force and energy necessary to rupture the anterior cruciate ligament (with use of a femur-anterior cruciate ligament-tibia complex stripped of all soft tissues and without gastrocnemius-hamstring muscle contractions) are incomplete and probably not representative of the in vivo situation.

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.

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.

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 clinical importance of DNA synthesis and aneuploidy in bone and soft tissue tumours.

DNA flow cytometric analysis including the analysis of S-phase fraction was performed on 46 bone and soft tissue tumours. Histologically, 24 lesions were benign, 11 were low grade and 11 were high grade malignant tumours. The percentages of aneuploidy in these groups were 29, 54 and 82, respectively. The S-phase fraction was smaller than 14% in all benign tumours. High S-phase fraction (> or = 14%) was found in 3 out of 11 low-grade tumours (27%) and in 9 out 11 high-grade tumours (82%). Seven of nine patients who died of metastatic disease during the average 5 year follow-up had aneuploid stemlines with S-phase fraction higher than 14%. Histologically, these were all high-grade tumours. Three patients with high S-phase in low-grade tumours survived. We conclude that high DNA synthetic activity in an aneuploid population, more than the DNA aneuploidy alone, has prognostic significance in musculoskeletal tumours.

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.

Mechanical effects of intramedullary reaming in pinned osteotomies in rats.

The biomechanical effects of intramedullary reaming on the healing of femoral osteotomies were studied. In rats, transverse osteotomies at the midshaft of both femurs were made. On the left side only, reaming of the medullary cavity was performed, and the osteotomies were then stabilized by intramedullary pinning. At 15, 30, 60, and 90 days after osteotomy, the production of callus, the bending moment, and the bending rigidity were evaluated. There were no significant differences in these biomechanical parameters between the right unreamed and the left reamed femurs during the experimental period. The results indicate that reaming of the medullary cavity of diaphyseal bone does not significantly impair or improve the healing of pinned osteotomies in rats.

Fracture weakens ipsilateral long bones: mechanical and metabolic changes after femoral or tibial injury in rats.

We have studied the effect of tibial osteotomy on mechanical and metabolic properties of the femur, and the effects of femoral osteotomy or fracture on mechanical properties of the tibia in rats. In the bone ipsilateral to the trauma, there was a significant reduction of mechanical strength and stiffness, both in bending and torsion, compared with the contralateral side. The ipsilateral bone lost weight and the blood flow was increased. The mineral incorporation rate was not affected. This may be due in part to disuse of the traumatized limb, but the fracture itself may affect the other bones in the extremity.

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.

Circulation in corticocancellous bone grafts measured with laser Doppler flowmetry. An experimental study in rats.

Laser Doppler flowmetry has been evaluated for measurement of the microcirculation (flux) in corticocancellous bone grafts. Corticocancellous tibial grafts were transplanted between four donor and eight recipients rats of two histocompatibility-mismatched strains. The microcirculations in the grafted and the intact tibias were measured after 12 weeks. Variation of the method in a single animal was 0.3-0.4 in both normal and grafted bone. The flux variation between the animals was of similar magnitude. The variation did not depend upon the magnitude of the flux values. Grafts had between 26% and 53% lower circulation than normal bone, but the graft bone interface, which contained callus, had a 56% higher flux than normal bone. We conclude that laser Doppler flowmetry might be useful in research into bone grafts.

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.

[Lack of sterility after vasectomy]. / Manglende sterilitet etter vasektomi.

PIP: In Norway, vasectomy is generally performed under local anesthesia; 1-2 cm of the vas deferens are resected and the ends are ligated. The most common complication is the development of sperm granulomata. Recanalisation occurs in 1-5% of the cases, depending on the technique used. The case of a 29-year-old man whose wife became pregnant 19 months after a vasectomy is reported; the patient had a sperm count of 30 million sperm/ml 19 months after the operation. It is recommended that some type of fascial barrier be provided by the vasectomy operation. A histological study of the resected material should be done, and regular postoperative sperm counts should be taken.^ieng

Interlocking medullary nails--radiation doses in distal targeting.

Distal interlocking of intramedullary nails involves the use of a fluoroscope and a targeting device. A specially designed awl makes the interlocking procedure simple and efficient. The 30-cm-long side arm of this awl protects the surgeon's hand from direct radiation, and measurements of X-ray exposure show that the protection against radiation is sufficient.