� � � � � � � � � � � � � � � � Musculoskeletal sarcomas call for multidisciplinary management by a “tumor team” of specialized orthopedic surgeons, radiologists, pathologists, tumor biologists (e.g. molecular and cytogenetics, DNA cytometry), cytologists, radiotherapists, and oncologists (Figure 1). Only a few such teams existed in Scandinavia during the 1970s. With the inception of the Scandinavian Sarcoma Group (SSG) in 1979, several new teams were started, each with regional responsibility for centralized treatment of sarcoma patients. Together, Denmark, Finland, Iceland, Norway and Sweden have a population of 25 million. These countries have similar social structures, with modern medical services covering all inhabitants and an effective registration of all cancer patients. The similarity of the
Both osteosarcoma and Ewingʼs sarcoma are highly malignant tumors, usually affecting children and adolescents. Before chemotherapy was introduced in the treatment of these tumors the prognosis was poor, but by intensified pre- and postoperative chemotherapy regimens the prognosis has improved dramatically. It soon became obvious that the tumor response to preoperative chemotherapy also served as a prognostic marker and today the postoperative chemotherapy treatment modality is based on the response rate. Those with a good tumor response receive a less intensive postoperative treatment than those whose tumor response has been poor (Picci 1997 et al., Bacci 2000 et al.). The Scandinavian sarcoma group (SSG), has since 25 years carried out several studies on both osteosarcoma and Ewingʼs sarcoma, some of them in collaboration with the Italian sarcoma group (ISG). The protocols for osteosarcoma SSG II, SSG VIII, ISG/SSG I, ISG/SSG II and SSG XIV, as well as the protocols for Ewingʼs sarcoma SSG IV, SSG IX, ISG/SSG III and ISG/SSG IV are described elsewhere (http://www.ssg-org.net/). In these protocols different methods of assessing the chemotherapy response have been used. Here, we will present and discuss the different methods.
Meniscectomy is recognized as an important risk factor for the development of knee osteoarthritis (OA), a disease that traditionally has been considered as a simple "wear and tear" phenomenon. However, despite numerous reports, little evidence has been presented that a limited meniscal resection, compared with a more extensive resection, reduces the risk of OA by preserving meniscal function. Why? This thesis provides one possible answer to that question. Patients, who had undergone isolated meniscal resection in 1973, 1978, or between 1983 and 1985 at Lund University Hospital, Sweden, were reviewed clinically and radiographically 15-22 years after the surgical procedure. Of the subjects (n = 317) almost 50% had developed radiographic OA in their operated knee, but just over half of these patients were symptomatic. An additional 20% of the patients had knee symptoms, but did not have radiographic knee OA. These results confirm a limited correlation between radiographic features of the disorder and symptoms. A degenerative type of meniscal tear and obesity were the factors most strongly associated with both radiographic knee OA and symptomatic radiographic knee OA. Partial meniscal resection induced less radiographic changes related to knee OA compared with total meniscectomy, but the patient-relevant outcomes remained essentially the same. If radiographic hand OA was present there was an increased likelihood of the patient also having knee OA following meniscectomy. This finding was independent of age, and therefore an inherited susceptibility to the disease contributes to the risk of knee OA after meniscal tear. Genetic and environmental risk factors interact in OA development. A degenerative meniscal lesion is often associated with early-stage knee OA, a disorder also involving the meniscal tissue. The tear may thus represent the first "signal" feature of OA. The challenge for the health professional is to discriminate between symptoms caused by a meniscal tear and those caused by OA. Meniscal resection may not benefit the patient with early-stage knee OA. The intervention merely removes evidence of the disorder, while the OA joint degradation proceeds.
The tissue microarray (TMA) technology was introduced in 1998 as a tissue preserving, highthroughput technique that allows studies of multiple markers in large sample sets. TMA slides can be analyzed using techniques such as immunohistochemistry and in situ hybridization and represents a powerful tool for the investigation of potential diagnostic and prognostic markers identified in DNA microarray studies. We review the TMA method, its reproducibility, advantages, limitations and future perspectives with specific focus on soft tissue sarcomas.
During the past 15 years the Scandinavian Sarcoma Group has treated 140 patients with Ewing's sarcoma. Two protocols have been used. SSG IV included 52 patients between 1984 and 1990 and SSG IX, 88 patients since 1990. After 5 years of treatment, local recurrences occurred in 19% of the patients (M0 + M1) in the SSG IV group and 10% in the SSG IX group. Distant metastases developed in 57% of the M0-patients in the SSG IV group and in 33% in the SSG IX group. Tumor-related survival (overall) of M0-patients was 49% in SSG IV and 70% in SSG IX, and the metastasis-free survival rate 45% and 58%, respectively. Patients having a localized extremity tumor had a survival rate of 90% (SSG IX). In both treatment groups, good responders to chemotherapy had a better survival rate than poor ones (SSG IV, p < 0.02, GI-II vs. G II-IV and SSG IX, p < 0.003, GI-III vs. G IV). In conclusions local control and survival rates were better with SSG IX than SSG IV.
In adult soft tissue sarcoma (STS) of the extremities and trunk wall, improved prognostic factors are needed to identify patients at high-risk for metastasis. Various factors are included in the many prognostic systems currently in use and the prognostic value of immunohistochemical (IHC) expression of biological markers is unclear. The tissue-preserving, high throughput tissue microarray (TMA) technique for analysis of immunohistochemical expression of biological markers was validated for Ki-67, and was found to yield results comparable to conventional staining methods. TMA was used to study the IHC expression of multiple markers (Ki-67, p53, cyclin A, bcl-2, beta-catenin, CD44, and Pgp) in 218 malignant fibrous histiocytomas (MFH) and in 140 mixed STS. In the MFH series, tumor size and Ki-67, as the only IHC marker, provided independent prognostic information. In the mixed STS series whole-tumor sections were used and TMA was performed in the peripheral tumor growth zone. Whole-tumor sections facilitated assessment of the strong independent prognostic factors for metastasis vascular invasion, hazard ratio (HR) 3.5, tumor necrosis (HR 2.8), and tumor growth pattern (HR 3.2), and the latter also correlated with local recurrence (LR). In comparison, histological malignancy grade, tumor size, and depth were not of independent prognostic value. When TMA was performed from the peripheral tumor growth zone, the IHC expression of Ki-67 (HR 1.9), beta-catenin (HR 2.7), CD44 (HR 2.1) and Pgp (HR 2.4) were independent prognostic factors. Finally, prognostic factors were found to be time-dependent, and most had lost their prognostic value after 2 years, whereas LR was a strong prognostic factor for metastasis whenever it occurred.
Soft tissue sarcomas represent a heterogeneous group of tumors and include over 50 histotypes. Some of these tumor types are characterized by specific chromosomal translocations, whereas other types show complex genetic aberrations. The recent developments within gene expression technologies have now been applied to studies of soft tissue sarcomas (STS) and the first results indicate that genetic signatures are useful for classification and diagnosis. Distinctive expression profiles have been found in e.g. gastrointestinal stromal tumors (GISTs), synovial sarcomas, malignant peripheral nerve sheath tumors (MPNSTs), and in subsets of liposarcomas. The more pleomorphic tumor types, such as high-grade variants of leiomyosarcomas, malignant fibrous histiocytomas (MFHs), fibrosarcomas, and subtypes of liposarcomas, show a greater variability among the expression profiles, but interestingly subsets with distinctive expression profiles can be identified also among these tumors. The data available place many of the genes hypothesized to be involved in the development of a certain type of STS, such as the KIT gene in GIST development, among the top discriminating genes. Thereby expression profiling provides novel insights into the pathogenesis of STS. Although much work remains to be done to validate the data and to define optimal discriminating gene lists, the current lessons from gene expression studies in STS are encouraging and imply that genetic signatures may serve as diagnostic and prognostic markers and may help identify novel therapeutic strategies.
In 1986, the Scandinavian Sarcoma Group initiated a Register of sarcoma patients who had been referred to tumor centers in Finland, Norway and Sweden. The Southern Sweden Sarcoma Register served as a model for the SSG Register (Rydholm 1983). All sarcoma centers in Norway (Bergen, Oslo, and Trondheim) and Sweden (Gothenburg, Linkoping, Lund, Stockholm, Umea) have continuously reported patients to the SSG Register. In these countries patients with sarcoma of the trunk wall and extremities are not treated outside of these referral centers except by mistake. Comparisons with the respective National Cancer Reg
INTRODUCTIONThe 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 METHODS460 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.RESULTSThe 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.
21 During the last 20 years, genetic analyses of bone and soft tissue tumors (BSTT) have revealed that most histopathologic entities investigated in sufficient detail are characterized by acquired, clonal chromosome aberrations. Many of these rearrangements are nonrandom and several of them are strongly associated with specific histo pathologic tumor subtypes. Cytogenetic studies using chromosome banding techniques have been an important first mapping step that has guided further efforts to identify mutations at the gene level by fluorescence in situ hybridization (FISH), reverse-transcriptase polymerase chain reaction (RT-PCR) and other molecular techniques. Chromosomal comparative genomic hybridization (CGH), and more recently CGH microarray techniques, have revealed many specific ampli cons in various sarcomas. The strong association between chromosome or gene rearrangements and tumor subtype has more and more been exploited to aid the diagnostic work. Less conclusive data are available as regards the role of genetic aberrations for disease progression, but there are reports indicating that some genetic changes may provide prognostically important information. Even less is known about the origin of chromosome mutations and the relation between genetic aberrations and abnormal cellular processes associated with tumorigenesis.
Gastrointestinal stromal tumors (GISTs) may be defined as intraabdominal nonepithelial (mesenchymal) tumors that express the KIT protein or have an activating mutation in a class III receptor tyrosine kinase gene (KITor PDGFRA). GISTs are diagnosed at a frequency of about 15 new cases annually per million, though small indolent GISTs are likely to occur more frequently in the general population. The clinical behavior is variable, and assessment of the malignancy potential is usually based mainly on the size and the proliferation characteristics of the tumor. The overwhelming majority of GISTs express the KIT protein, the transmembrane receptor tyrosine kinase for the stem cell factor. The majority of GISTs harbor a mutation in the KITproto-oncogene that translates into constitutively activated KIT protein kinase, and a minority have mutated PDGFRAgene resulting in activated platelet-derived growth factor alpha receptor tyrosine kinase. Most GISTs respond to imatinib mesylate, which selectively inhibits both KIT and PDGFRA, and is now considered as the standard systemic therapy for advanced GIST. In contrast, responses to conventional chemotherapy are infrequent (generally less than 10%), but combination therapies with imatinib have not been explored. Research on adjuvant imatinib and novel targeted therapies is ongoing.
Chronic low back pain (CLBP) has become one of the most common causes of disability in adults under 45 years of age and is consequently one of the most common reasons for early retirement in industrialised societies. Accordingly, CLBP represents an expensive drain on society's resources and is a very challenging area for which a consensus for rational therapy is yet to be established. The spinal fusion procedure was introduced as a treatment option for CLBP more than 70 years ago. However, few areas of spinal surgery have caused so much controversy as spinal fusion. The literature reveals divergent opinions about when fusion is indicated and how it should be performed. Furthermore, the significance of the role of postoperative rehabilitation following spinal fusion may be underestimated. There exists no consensus on the design of a program specific for rehabilitation. Ideally, for any given surgical procedure, it should be possible to identify not only possible complications relative to a surgical procedure, but also what symptoms may be expected, and what pain behaviour may be expected of a particular patient. The overall aims of the current studies were: 1) to introduce patient-based functional outcome evaluation into spinal fusion treatment; 2) to evaluate radiological assessment of different spinal fusion procedures; 3) to investigate the effect of titanium versus stainless steel pedicle screws on mechanical fixation and bone ingrowth in lumbar spinal fusion; 4) to analyse the clinical and radiological outcome of different lumbar spinal fusion techniques; 5) to evaluate complications and re-operation rates following different surgical procedures; and 6) to analyse the effect of different rehabilitation strategies for lumbar spinal fusion patients. The present thesis comprises 9 studies: 2 clinical retrospective studies, 1 clinical prospective case/reference study, 5 clinical randomised prospective studies and 1 animal study (Mini-pigs). In total, 594 patients were included in the investigation from 1979 to 1999. Each had prior to inclusion at least 2 years of CLBP and had therefore been subjected to most of the conservative treatment leg pain, due to localized isthmic spondylolisthesis grades I-II or primary or secondary degeneration. PATIENT-BASED FUNCTIONAL OUTCOME: Patients' self-reported parameters should include the impact of CLBP on daily activity, work and leisure time activities, anxiety/depression, social interests and intensity of back and leg pain. Between 1993 and 2003 approximately 1400 lumbar spinal fusion patients completed the Dallas Pain Questionnaire under prospective design studies. In 1996, the Low Back Pain Rating scale was added to the standard questionnaire packet distributed among spinal fusion patients. In our experience, these tools are valid instruments for clinical assessment of candidates for spinal fusion procedures. RADIOLOGICAL ASSESSMENT:It is extremely difficult to interpret radiographs of both lumbar posterolateral fusion and anterior interbody fusion. Plain radiographs are clearly not the perfect media for analysis of spinal fusion, but until new and better diagnostic methods are available for clinical use, radiographs will remain the golden standard. Therefore, the development of a detailed reliable radiographic classification system is highly desirable. The classification used in the present thesis for the evaluation of posteroalteral spinal fusion, both with and without instrumentation, demonstrated good interobserver and intraobserver agreement. The classification showed acceptable reliability and may be one way to improve interstudy and intrastudy correlation of radiologic outcomes after posterolateral spinal fusion. Radiology-based evaluation of anterior lumbar interbody fusion is further complicated when cages are employed. The use of different cage designs and materials makes it almost impossible to establish a standard radiological classification system for anterior fusions. BONE-SCREW INTERFACE: Mechanical binding at the bone-screw interface was significantly greater for titanium pedicle screws than it was for stainless steel. This could be explained by the fact that the titanium screws had superior bone on-growth. There was no correlation between screw removal torques and pull-out strength. Clinically, the use of titanium and titanium-alloy pedicle screws may be preferable for osteoporotic patients and those with decreased osteogenesis. OUTCOME:The present series of studies observed significant long-term functional improvement for approximately 70% of patients who had undergone lumbar spinal fusion procedure. Solid fusion as determined from radiographs ranged from 52% to 92% depending on the choice of surgical procedure. The choice of surgical procedure should relate to the diagnosis, as patients with isthmic spondylolisthesis (Grades I and II) are best served with posterolateral fusion without instrumentation, and patients with disc degeneration seem to gain most from instrumented posterolateral fusion or circumferential fusion. COMPLICATIONS:The number of perioperative complications increased with the use of pedicle screw systems to support posterolateral fusions and increased further with the use of circumferential fusions. There was no significant association between outcome result and perioperative complications. The risk of reoperation within 2 years after the spinal fusion procedure was, however, significantly lower for those who had received circumferential fusion in comparison to posterolateral fusion with instrumentation. Furthermore, the risk of non-union was found to be significantly lower for patients who had received circumferential fusion as compared to posterolateral fusion with and without instrumentation. The complications of sexual dysfunction and fusion at non-intended levels were found to be significant but without influence on the overall outcome. REHABILITATION:The patients in the Back-café group performed a succession of many daily tasks significantly better and moreover had less pain compared with both the Video and Training groups 2 years after lumbar spinal fusion. The Video group had significantly greater treatment demands outside the hospital system. This study demonstrates the importance of the inclusion of coping schemes and questions the role of intensive exercises in a rehabilitation program for spinal fusion patients.
17 Incidence Soft tisssue sarcoma (SST) represents a heterogenous group of tumor diseases orginating from connective tissue accounting for less than 1 % of all malignant tumors in Sweden. With increasing age there is an increase in incidence (National Board of Health). Comprehensive reviews of the epidemiology of soft tissue sarcoma have previously been published (Tucker et al. 1982, Zahm and Fraumeni 1997 and Olsson 1999). The heterogenity of sarcoma types and the rarity of cases have hampered etiologically oriented studies. When excluding Kaposi sarcoma the incidence of other soft tissue sarcomas have not dramatically increased in developed western countries. Becasue of the inherent difficulty in classifying SST inter national variations and geographic patterns have not been evaluated in a meaningful way. Risk factors of SST are thus only partly known. Risk factors include a family history of cancer/ soft tissue sarcoma, certain genetic syndromes, exposure to ionizing irradiation, and exposure to certain chemicals such as vinyl chloride. Other factors associated with SST development include longstanding lymphedema, exposure to Thorotrast, arsenical pesticides and medications, herbicides, immunosuppressive drugs, alkylating agents, androgen-anabolic steroids, human immunodefi ciency virus, and exposure to human herpes virus type 8 (Zahm and Fraumeni 1997 and Olsson 1999). Further a tissue trauma has been discussed as a possible risk factor. Studies from our own group has suggested that oral contraceptive use is partly protective for STS in women (Olsson et al.
The worldwide increase in hip fractures is a major challenge to the health care system and society. The proper treatment of femoral neck fractures in the elderly is still controversial, and even more so from an international perspective. Optimising the treatment for improved outcomes and a reduced need for secondary surgery is mandatory for humanitarian and economical reasons. The importance of incorporating the patient's perspective of the outcome in clinical trials has been acknowledged and there are now numerous instruments for assessing the quality of life. We evaluated two quality of life instruments, the EQ-5D and the SF-36, in patients with femoral neck fractures and also measured the quality of life two years after different interventions. The EQ-5D was validated in two prospective studies and it appeared to be an appropriate quality of life instrument in elderly patients with femoral neck fractures. There was a good correlation between the quality of life (EQ-5D index scores) and other outcome measures such as pain, mobility and independence in activities of daily living (ADL). The results also showed high responsiveness, i.e., ability to capture clinically important changes, for both the EQ-5D and the SF-36. The questionnaire response rate for both instruments was high. The rated prefracture EQ-5D index scores showed good correspondence with the scores of an age-matched Swedish reference population. The quality of life in patients with femoral neck fractures treated with internal fixation (IF) decreased, particularly in patients with fracture healing complications. The fracture healing complications rate at two years in patients with displaced femoral neck fractures treated with IF was 36% compared with 7% in patients with undisplaced fractures. The quality of life of patients with uneventfully healed fractures at two year was lower in patients with primary displaced fractures than in patients with primary undisplaced fractures. In a prospective randomised trial, patients with displaced femoral neck fractures were randomised to IF or total hip replacement (THR). IF resulted in more complications than THR, 36% versus 4%, and necessitated more reoperations, 42% versus 4%. Hip function and quality of life (EQ-5D) were generally better in the THR group. In summary, THR yielded a better outcome than IF for an elderly, relatively healthy, lucid patient with a displaced femoral neck fracture. In a study of elderly women with femoral neck fractures, nearly half of the patients displayed signs of protein-energy malnutrition. Underweight was associated with muscle fatigue, cognitive dysfunction and a low quality of life (Nottingham Health Profile). In a prospective randomised trial, protein-rich liquid supplementation in combination with an anabolic steroid given for 6 months to lean elderly women after a femoral neck fracture was shown to positively affect lean body mass, ADL and quality of life (EQ-5D). Fracture healing complications had a negative impact on body weight, lean body mass and quality of life.
It has been generally accepted that residual cartilage and subchondral bone has to be removed in order to get bony fusion in arthrodeses. In 1998 we reported successful fusion of 11 rheumatoid ankles, all treated with percutaneous fixation only. In at least one of these ankle joint there was cartilage left. This was confirmed by arthrotomy in order to remove an osteophyte, which hindered dorsiflexion. More than 25 rheumatoid patients with functional alignment in the ankle joint have subsequently been operated on with the percutaneous technique, and so far we have had only one failure. Patients with rheumatoid arthritis are known to sometimes fuse at least their subtalar joints spontaneously, and the destructive effect of the synovitis on the cartilage could contribute to fusion when using the percutaneous technique. In a rabbit study we therefore tested the hypothesis that even a normal joint can fuse merely by percutaneous fixation. The patella was fixated to the femur with lag screw technique without removal of cartilage, and in 5 of 6 arthrodeses with stable fixation bony fusion followed. Depletion of synovial fluid seemed to be the mechanism behind cartilage disappearance. The stability of the fixation achieved at arthrodesis surgery is an important factor in determining success or failure. Dowel arthrodesis without additional fixation proved to be deleterious. A good fit of the bone surfaces appears necessary. In the ankle joint, it would be technically demanding to retain the arch-shaped geometry of the joint after resection of the cartilage. Normally the joint surfaces are resected to produce flat osteotomy surfaces that are thus easier to fit together, encouraging healing to occur. On the other hand it is considered an advantage to preserve as much subchondral bone as possible, as the strong subchondral bone plate can contribute to the stability of the arthrodesis. Ankle arthrodesis can be successfully performed in patients with rheumatoid arthritis by percutaneous screw fixation without resection of the joint surfaces. This procedure has two advantages: first, it is less surgically traumatic, second, both the arch-shaped geometry and the subchondral bone are preserved, and thus both could contribute to the postoperative stability of the construct. Intuitively, preservation of the arch-shape should increase rotational stability. The results of our experimental sawbone study indicate that the arch shape and the subchondral bone should be preserved when ankle arthrodesis is performed. The importance of this is likely to increase in weak rheumatoid bone. In a finite element study the initial stability provided by two different methods of joint preparation and different screw configurations in ankle arthrodesis, was compared. Better initial stability is predicted for ankle arthrodesis when joint contours are preserved rather than resected. Overall, inserting the two screws at a 30-degree angle with respect to the long axis of the tibia and crossing them above the fusion site improved stability for both joint preparation techniques. The question rose as to whether patients with osteoarthritis could also be operated on solely by percutaneous fixation technique. The first metatarsophalangeal joint in patients with hallux rigidus was chosen as an appropriate joint to test the percutaneous technique. In this small series we have shown that it is possible to achieve bony fusion with a percutaneous technique in an osteoarthrotic joint in humans, but failed to say anything about the fusion rate.
We wanted to improve tendon healing by adding a growth factor. Bone Morphogenetic Proteins (BMPs) are well known to stimulate bone healing and bone formation. The local environment is of major importance for cell differentiation after a BMP has been added. Cartilage Derived Morphogenetic Proteins (CDMPs) -1, -2 and -3 (BMP 14, 13 and 12 or GDF 5, 6 and 7) form a subgroup in the BMP-family and are closely related to OP-1 (BMP 7). CDMP implants have been shown to induce bone and cartilage as well as tendon and ligament-like tissue. Our hypothesis has therefore been that if a BMP were added in a tendon environment, a tendon-like tissue would be induced. We have developed models in rats and rabbits where the Achilles tendon is transsected. To influence tendon healing, different BMPs (OP-1, CDMP-1. -2 and -3) were added, either on a collagen carrier, or as a local injection into the tendon defect. The tendons were evaluated by histology and mechanical testing at different time-points after transection. The results show that also when the mechanical environment would favour the formation of a tendon-like tissue, OP-1 reduced tendon strength in aid of bone formation. In contrast, CDMP-1, -2 and -3 had a beneficial effect upon tendon healing in rats. More callus tissue was produced than in controls, and strength and stiffness were improved, although minor amounts of bone and cartilage were detected in the tendon callus. Cartilage and bone formation sometimes occur normally during Achilles tendon healing in rats. In the rabbit model, where the healing situation is more similar to the clinical situation, the positive result with CDMP-2 was repeated. Moreover, in rabbits no bone or cartilage was found. The results suggest that conservative treatment of Achilles tendon ruptures with injection of a CDMP in combination with early rehabilitation might afford a good alternative to surgical treatment.
