Olga Zaikova

Insight opinion to surgically treated metastatic bone disease: Scandinavian Sarcoma Group Skeletal Metastasis Registry report of 1195 operated skeletal metastasis.

The number of cancer patients living with metastatic disease is growing. The increased survival has led to an increase in the number of cancer-induced complications, such as pathologic fractures due to bone metastases. Surgery is most commonly needed for mechanical complications, such as fractures and intractable pain. We determined survival, disease free interval and complications in surgically treated bone metastasis. Data were collected from the Scandinavian Skeletal Metastasis Registry for patients with extremity skeletal metastases surgically treated at eight major Scandinavian referral centres between 1999 and 2009 covering a total of 1195 skeletal metastases in 1107 patients. Primary breast, prostate, renal, lung, and myeloma tumors make up 78% of the tumors. Number of complications is tolerable and is affected by methods of surgery as well as preoperative radiation therapy. Overall 1-year patient survival was 36%; however, mean survival was influenced by the primary tumor type and the presence of additional visceral metastases. Patients with impending fracture had more systemic complications than those with complete fracture. Although surgery is usually only a palliative treatment, patients can survive for years after surgery. We developed a simple, useful and reliable scoring system to predict survival among these patients. This scoring system gives good aid in predicting the prognosis when selecting the surgical method. While it is important to avoid unnecessary operations, operating when necessary can provide benefit.

Liposarcoma : Outcome Based on the Scandinavian Sarcoma Group Register

The aim was to study the clinicopathological characteristics, treatment, and outcome of liposarcoma in an unselected, population‐based patient sample, and to establish whether treatment was according to the Scandinavian Sarcoma Group (SSG) treatment guidelines.BACKGROUND The aim was to study the clinicopathological characteristics, treatment, and outcome of liposarcoma in an unselected, population-based patient sample, and to establish whether treatment was according to the Scandinavian Sarcoma Group (SSG) treatment guidelines. METHODS The SSG Pathology Board reviewed 319 liposarcoma cases reported between 1986 and 1998. After the review, 237 patients without metastasis were analyzed for local recurrence rate in relation to surgical margins, radiotherapy, occurrence of metastasis, and survival. RESULTS Seventy-eight percent of the patients were primarily operated on at a sarcoma center, 45% with wide margins. All patients operated on outside the center had nonwide margins. Low-grade lesions constituted 67% of cases. Despite nonwide surgery, only 58% of high-grade lesions were treated with postoperative radiotherapy. The risk of local recurrence after nonwide surgery, without irradiation, was 47% for high-grade lesions. The estimated 10-year, local recurrence-free and metastasis-free survival in the low-grade group was 87% and 95%, respectively. In the high-grade group, it was 75% and 61%, respectively. Independent adverse prognostic factors for local recurrence were surgery outside a sarcoma center and histological type dedifferentiated liposarcoma. For metastases, they were old age, large tumor size, high grade, and histological type myxoid liposarcoma with a round cell component. Radiotherapy showed significant effect on local recurrence rate for the same grade and margin. CONCLUSIONS Patients with liposarcoma should be treated at specialized centers. Postoperative radiotherapy decreases the local recurrence rate. To maintain quality and provide support for further trials, reporting to quality registers is crucial.

Prognostic role of en-bloc resection and late onset of bone metastasis in patients with bone-seeking carcinomas of the kidney, breast, lung, and prostate: SSG study on 672 operated skeletal metastases.

In metastatic disease, decisions regarding potential surgery require reliable data about the patients survival. In this study, we evaluated different prognostic factors and their impact in four common primary tumors causing bone metastases.

Complications and survival after surgical treatment of 214 metastatic lesions of the humerus

BACKGROUND The humerus is the second most common long-bone site of metastatic bone disease. We report complications, risk factors for failure, and survival of a large series of patients operated on for skeletal metastases of the humerus. MATERIALS AND METHODS This study was based on 208 patients treated surgically for 214 metastatic lesions of the humerus. Reconstructions were achieved by intramedullary nails in 148, endoprostheses in 35, plate fixation in 21, and by other methods in 10. RESULTS The median age at surgery was 67 years (range, 29-87 years). Breast cancer was the primary tumor in 31%. The overall failure rate of the surgical reconstructions was 9%. The reoperation rate was 7% in the proximal humerus, 8% in the diaphysis, and 33% in the distal part of the bone. Among 36 operations involving an endoprosthesis, 2 were failures (6%) compared with 18 of 178 osteosynthetic devices (10%). In the osteosynthesis group, intramedullary nails failed in 7% and plate fixation failed in 22%. Multivariate Cox regression analysis showed that prostate cancer was associated with an increased risk of failure after surgery (hazard ratio, 7; P < 0.033). The cumulative survival after surgery was 40% (95% confidence interval [CI] 34-47) at 1 year, 21% (95% CI, 15-26) at 2 years, and 16% (95% CI, 12-19) at 3 years. CONCLUSIONS Our method of choice is the cemented hemiprosthesis for pathologic proximal humeral fractures and interlocked intramedullary nail for lesions in the diaphysis. Pathologic fractures in the distal humerus are uncommon and associated with a very high reoperation rate.

Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma

Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.

Prognostic factors and treatment results of high-grade osteosarcoma in norway: a scope beyond the "classical" patient.

Purpose. A retrospective study of prognostic factors and treatment outcome of osteosarcoma (OS) during modern chemotherapy era with focus on patients with primary metastatic disease, nonextremity localisation, or age >40 years (nonclassical OS). Methods. A nationwide cohort, comprising 424 high-grade Norwegian bone OS patients, was based on registry sources supplemented with clinical records from hospitals involved in sarcoma management between 1975 and 2009. Results. Only 48% were younger patients with tumour in the extremities and without metastasis at diagnosis (classical OS). A considerable discrepancy in survival between classical and nonclassical OS was observed: 61% versus 26% 10-year sarcoma specific survival. Twice as many of the former received both adequate surgery and chemotherapy compared to the latter. This could only partly explain the differences in survival due to inherent chemoresistance in primary metastatic disease and a higher rate of local relapse among patients with axial tumours. Metastasis at diagnosis, increased lactate dehydrogenase, age > 40 years, and tumour size above median value were all adverse prognostic factors for overall survival. Conclusion. We confirm a dramatic difference in outcome between classical and nonclassical high-grade OS patients, but treatment variables could only partly explain the dismal outcome of the latter.

Unscrambling the genomic chaos of osteosarcoma reveals extensive transcript fusion, recurrent rearrangements and frequent novel TP53 aberrations

In contrast to many other sarcoma subtypes, the chaotic karyotypes of osteosarcoma have precluded the identification of pathognomonic translocations. We here report hundreds of genomic rearrangements in osteosarcoma cell lines, showing clear characteristics of microhomology-mediated break-induced replication (MMBIR) and end-joining repair (MMEJ) mechanisms. However, at RNA level, the majority of the fused transcripts did not correspond to genomic rearrangements, suggesting the involvement of trans-splicing, which was further supported by typical trans-splicing characteristics. By combining genomic and transcriptomic analysis, certain recurrent rearrangements were identified and further validated in patient biopsies, including a PMP22-ELOVL5 gene fusion, genomic structural variations affecting RB1, MTAP/CDKN2A and MDM2, and, most frequently, rearrangements involving TP53. Most cell lines (7/11) and a large fraction of tumor samples (10/25) showed TP53 rearrangements, in addition to somatic point mutations (6 patient samples, 1 cell line) and MDM2 amplifications (2 patient samples, 2 cell lines). The resulting inactivation of p53 was demonstrated by a deficiency of the radiation-induced DNA damage response. Thus, TP53 rearrangements are the major mechanism of p53 inactivation in osteosarcoma. Together with active MMBIR and MMEJ, this inactivation probably contributes to the exceptional chromosomal instability in these tumors. Although rampant rearrangements appear to be a phenotype of osteosarcomas, we demonstrate that among the huge number of probable passenger rearrangements, specific recurrent, possibly oncogenic, events are present. For the first time the genomic chaos of osteosarcoma is characterized so thoroughly and delivered new insights in mechanisms involved in osteosarcoma development and may contribute to new diagnostic and therapeutic strategies.

Pathological subtrochanteric fractures in 194 patients: a comparison of outcome after surgical treatment of pathological and non-pathological fractures.

The surgical treatment of pathological subtrochanteric fractures has been associated with technical difficulties and frequent failures. We analyzed survival, risk factors for death, and outcome after surgical treatment.

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.

Radiotherapy or surgery for spine metastases

Background and purpose Radiotherapy (RT) remains the cornerstone of management of spine metastases (SM), even though surgery is a well-established treatment for selected patients. We compared the use of RT and surgery in a population-based cohort of patients with SM, investigated pre-treatment factors that were associated with use of these treatment modalities, and examined survival. Patients and methods 903 patients in the south-eastern Norway who were admitted for RT or surgery for SM for the first time during an 18-month period in 2007–2008 were identified and their medical records were reviewed. Results The primary treatment was surgery in 58 patients and RT in 845 patients, including 704 multiple-fraction (MF) and 141 single-fraction (SF) RT schedules. 11 of 607 patients without motor impairment (2%) and 47 of 274 patients with motor impairment (17%) underwent primary operations. 11 of 58 operated patients and 244 of 845 irradiated patients died within 2 months after the start of treatment. 26% of those who received multiple-fraction RT or surgery died within 2 months. Interpretation Motor impairment was the main indication for surgery. Better identification of patients with short survival is needed to avoid time-consuming treatment (major surgery and long-term RT).