Session 6: Tumor

Katja Maretty-Nielsen, Ninna Aggerholm-Pedersen, Johnny Keller, Akmal Safwat, Steen Baerentzen, Alma Pedersen
Department of Experimental Clinical Oncology, Aarhus University Hospital; Department of Orthopaedic Surgery, Aarhus University Hospital; Department of Oncology, Aarhus University Hospital; Department of Pathology, Aarhus University Hospital; Department of Clinical Epidemiology, Aarhus University Hospital

Background: To assess the excess mortality caused by soft tissue sarcoma (STS), sarcoma-specific estimates are often reported; however, these rely on precise and correct data on the cause of death, which can be difficult to acquire. Another, more precise, method is to assess the relative mortality, i.e., mortality in sarcoma patients compared to the general population.
Purpose / Aim of Study: The aims of this study were to assess the relative mortality in STS patients, and to compare this with the sarcoma-specific mortality.
Materials and Methods: We included 1246 patients treated for STS at the Aarhus Sarcoma Centre between 1979 and 2008, and 6230 individually age- and sex-matched individuals from the general population. The relative mortality was estimated as rates and rate ratios, using the Cox proportional hazard model. The sarcoma-specific mortality was compared to the corresponding relative mortality.
Findings / Results: The overall 5- and 10-year relative mortality was 32.8% and 36.0% Overall, STS patients had a 4.4 times higher risk of dying within the first five years after diagnosis and a 1.6 times higher risk between five and ten years compared with the general comparison cohort. Patients with low-grade STS did not have increased mortality compared with the general population. The relative mortality was highest in younger patients and in patients without comorbidity. The overall 5- year sarcoma-specific mortality was underestimated by 3.1 percentage points compared to the relative mortality.
Conclusions: Patients with low-grade STS did not have increased mortality compared with the general population. A tendency towards underestimating mortality due to STS was seen when sarcoma-specific mortality using death certificates was reported.

Michala Skovlund Sørensen, Klaus Hindsø, Kristine Grubbe Gregersen, Michael Mørk Petersen
Ortopædkirurgisk klinik, Rigshospitalet

Background: Estimation of patient survival is important when planning surgical treatment of metastatic bone disease (MBD) of the extremities. We have done a single centre study evaluating prognostic preoperative parameters for patient survival after joint replacement (JR) surgery in patients with MDB of the appendicular bones.
Purpose / Aim of Study: To estimate prognostic preoperative parameters for patient survival, in patients receiving JR, due to MBD in the appendicular skeleton.
Materials and Methods: We included 130 patients that received a JR due to MBD during the period Jan '03 to Dec '08 at the Department of Orthopaedic Surgery, Rigshospitalet, Copenhagen. The cohort was followed with regard for survival until death or marts 29th '11. The following data were registered: age, gender, pathological fracture/impending fracture, number of bony metastases, visceral metastases, erythrocyte sedimentation rate (SR), C reactive protein (CRP), haemoglobin (HGB), Karnofsky score, ASA score, and primary type of cancer. Statistics: Kaplan-Meier survival analysis with logrank test and Cox proportional hazard regression analysis.
Findings / Results: The calculated probability of survival after surgery was 51% and 39% at 6 months and 1 years of follow-up. The median survival time was 7 (0.03–96) months. Univariate analysis showed that all preoperative parameters were statistical significant predictors for survival except gender and pathological fracture/impending fracture. Multivariate analysis showed that visceral metastasis, Karnofsky score < 7, ASA group 3 or 4, HGB < 8 and primary type of cancer remained statistical significant predictors of survival.
Conclusions: We have been able to identify preoperative parameters that correlate to patient survival in patients operated on, with a JR, because of MDB in the appendicular skeleton.

Andrea Thorn, Lise Hanne Christiansen, Søren Daugaard, Michael Mørk Petersen
Musculoskeletal Tumor Section, Department of Orthopedic Surgery, Rigshospitalet, University of Copenhagen, Denmark; Department of Pathology, Rigshospitalet, University of Copenhagen, Denmark

Background: YKL-40 is a glycoprotein that has showed increased expression in several other types of cells such as cancer cells, macrophages and leukocytes, embryonic cells, fetal cells, and cartilage cells. Previous studies have shown that elevated serum concentrations of YKL-40 in patients with various types of cancer constitute an independent prognostic variable for both short recurrence-free interval and short overall survival.
Purpose / Aim of Study: The aim of this study is to identify if ykl-40 can serve as a surrogate marker for prediction of the outcomes in patients with high-grade osteosarcoma.
Materials and Methods: All patients diagnosed with a high-malignant osteosarcoma of the extremities, spine or trunk wall at the Department of Pathology, Rigshospitalet during the years 2000-2010 were identified (n=86). Of these 48 patients (mean age 26 (6-88) years, F/M= 29/19) met criteria for inclusion in the study based on data availability and biopsy sample size. The biopsies were analysed by immunohistochemical analysis in order to determent the degree of YKL-40 staining intensity in tumour tissue
Findings / Results: All 48 biopsies were positive for YKL-40 staining with various staining intensities. If the mean staining intensity of 24% was used to divide the material, we found a better survival in patients with high staining intensity (p=0.05), and the 5 and 10 years survival was 80% for patients with a staining intensity over the mean intensity of 24% (n=15), and 48% and 43% respectively, for patients with an intensity below the mean (n=33)
Conclusions: Data indicates that a higher YKL-40 expression is connected to a longer overall survival.

Andrea Thorn, Søren Daugaard, Michael Mørk Petersen
Musculoskeletal Tumor Section, Department of Orthopedic Surgery, Rigshospitalet, University of Copenhagen, Denmark; Department of Pathology, Rigshospitalet, University of Copenhagen, Denmark

Background: Osteosarcoma is the most common histological type of bone sarcomas.
Purpose / Aim of Study: To examine the overall survival for all osteosarcoma patients diagnosed in East Denmark and treated at Rigshospitalet from 2000-2010.
Materials and Methods: All patients diagnosed with a high-malignant osteosarcoma at the Department of Pathology, Rigshospitalet during the years 2000-2010 were identified (n=86). Sixteen patients were excluded because it was consultation biopsies from other hospitals and 9 patients were excluded because the diagnosis was later changed (chondrosarcoma/giant cell sarcoma/osteoblastoma/myeloma/ desmoid fibromatose = 3/1/1/1/1), or was from before 2000 (n=2). A total of 61 patients (mean age 31 (6-88) years, F/M=34/27) were then analyzed for survival. Survival data were obtained from the CPR register. Statistics: Kaplan Meier survival analysis and log-rank test.
Findings / Results: The probability of 5 and 10-year survival for all patients (n=61) was 57% and 52% years respectively. The probability of survival in young individuals (age ≤20 years) was not different from patients aged >20 years (p=0.14) and no difference between sexes (p= 0.19) was found. In patients treated with preoperative chemotherapy (n=46) the survival was higher (p=0.002), if the degree of tumor cell necrosis was ≥90%. Both the probability of 5 and 10 years survival in patients with ≥90% necrosis (n=20) was 90%, while in patients with <90% necrosis (n=26) survival was 46% and 41% respectively.
Conclusions: The overall survival for patients with high- malignant osteosarcoma in East Denmark is consistent with the international average overall survival for this patient group.

Katja Maretty-Nielsen, Ninna Aggerholm-Pedersen, Johnny Keller, Alma Pedersen, Steen Baerentzen, Akmal Safwat
Department of Experimental Clinical Oncology, Aarhus University Hospital; Department of Orthopaedic Surgery, Aarhus University Hospital; Department of Clinical Epidemiology, Aarhus University Hospital; Department of Pathology, Aarhus University Hospital; Department of Oncology, Aarhus University Hospital

Background: The existing literature on biomarkers and mortality in soft tissue sarcoma (STS) is limited in both number and size, lacking the data on important confounders.
Purpose / Aim of Study: The aim of this study was to determine the prognostic value of pre-treatment biomarkers for mortality in a large population-based series of adult patients with localized STS.
Materials and Methods: Pre-treatment levels of albumin, C-reactive protein (CRP), hemoglobin, neutrophil to lymphocyte ratio (NLR), and sodium were analysed in 614 consecutive STS patients treated at the Aarhus Sarcoma Centre between 1994 and 2008. The prognostic value of biomarkers on sarcoma-specific mortality was estimated as hazard ratios (HR) using Cox proportional hazard models adjusted for important confounders including age and comorbidity.
Findings / Results: Hypoalbuminemia (HR 1.85 [95% CI 1.14- 2.99]), anemia (HR 1.66 [95% CI 1.07- 2.56]), and elevated NLR (HR 1.72 [95% CI 1.10-2.70]) were independently associated with a statistical significant increased mortality, while there where a clear tendency towards CRP (HR 1.46 [95% CI 0.98-2.19]) being associated as well. Patients with abnormal values in all important biomarkers had a significant additional risk of dying, compared to patients with only some abnormal values (HR 3.91 [95% CI 1.68-910]). The median survival was 95.8 months in patients with normal values compared to 30.7 and 7.2 in patients with only some abnormal values, and patients with abnormal values in all important biomarkers, respectively.
Conclusions: Hypoalbuminemia, anemia, and elevated NLR were independent prognosticators for early death in patients with localized STS. The measurement of these can be used as an additional diagnostic tool to identify high-risk patients that could be candidates for possible intensive therapy.

Morten Tange Kristensen, Gitte Holm, Michael Krasheninnikoff, Peter Gebuhr
Physical Medicine and Rehabilitation Research - Copenhagen, Depertments of Physiotherapy and Orthopa, Hvidovre University Hospital; Department of Orthopaedic Surgery, Hvidovre University Hospital

Background: Historically high 30-days and 1-year mortality rates of respectively 30% and 54% were reported in a Danish 2009 consecutive series of 93 patients with a non-traumatic lower limb amputation.
Purpose / Aim of Study: To evaluate if allocation of staff expertise and instituting an optimized program could reduce the number of these fatal events.
Materials and Methods: A consecutive series of 129 amputations (median age of 75 (IQR, 65-84) years, 53% below knee (BKA) and 47% amputated at a higher level or bilateral (AKA), admitted to an orthopaedic ward. The program instigated within a 2-year period included standards for fluid and transfusion, supplemental oxygen when supine, pain management, early mobilization and physiotherapy, weekly multidisciplinary meetings, and monthly audits of standards.
Findings / Results: Twenty (16%) and 48 (37%) patients respectively, died within 30-days and 1-year. Cox regression demonstrated that a patient from a nursing home (n=26) and/or an ASA-rating of 4 (n = 12) respectively, was 3 and 5 times more likely to die within 30 days, compared to a patient with an rating of 2 (n = 41), when adjusted for age, gender, cause of and amputation level. Length of stay was reduced with a mean of 6 days.
Conclusions: Allocating people with expertise and instituting an optimized program seem to reduce the short and long-term mortality rates markedly in patients with a major lower limb amputation.

Heidi Buvarp Dyrop, Peter Vedsted, Katja Maretty-Nielsen, Bjarne Hauge Hansen, Peter Holmberg Jørgensen, Johnny Keller
Department of Experimental Clinical Oncology, Aarhus University Hospital; The Research Unit for General Practice, Aarhus University; Department of Orthopaedics, Sarcoma Centre of Aarhus University Hospital

Background: Some sarcomas are referred after surgery on suspected benign tumors. This can affect patient prognosis and cause large re- excisions. Knowledge about diagnostic pathways of these patients is uncertain and must be reviewed.
Purpose / Aim of Study: To investigate patient and tumor characteristics, patient reported symptoms, suspected and final diagnosis, and explore reasons for referral, in sarcoma patients referred after surgery in non-specialist institutions.
Materials and Methods: Retrospective review of medical files. From a previous study on 258 sarcoma patients referred over 4 years, we identified 64 (24.8%) referred with a confirmed histological sarcoma. Medical files were reviewed for patient reported symptoms, suspected diagnosis and reasons for referral. Patient and tumor characteristics were previously collected.
Findings / Results: 27 (42.2 %) tumors were low grade, 37 (57.8 %) high grade. Lipoma and fibroma/dermatofibroma were most reported suspected diagnoses. 7 patients were suspected of other malignancies due to location (breast, testicles, kidney). For 23 (35.9%) patients, initial presence of alarm symptoms were described in the referral text. 9 tumors were >5cm, 10 subfascial and 9 were both. 32 (50%) had superficial small tumors, of which 21 (65.6%) were suspected skin conditions. 8 (12.5%) of 64 patients stated that it was a second removal of a tumor in the same area. 3 patients reported changes in a tumor that had been present for years.
Conclusions: 1/4 of sarcoma patients had surgery on suspected benign tumors. For 1/3, alarm symptoms had been reported, the remaining fell outside referral guidelines or alarm symptoms were not discovered. Sarcoma should be considered even in unusual or superficial locations, also when the tumor is <5 cm. Recurring benign tumors and changes in dormant tumors should cause re- evaluation of diagnosis.

Morten Tange Kristensen, Anni Østergaard Nielsen, Ulla Madsen Topp, Peter Gebuhr
Physical Medicine and Rehabilitation Research – Copenhagen, Departments of Physiotherapy and Orthopa, Hvidovre University Hospital; Department og Physiotherapy, Hvidovre University Hospital; Department of Orthopaedic Surgery, Hvidovre University Hospital

Background: Prosthetic fitting is the long term goal for most patients following a major lower limb amputation. However, this is not possible in every dysvascular amputee and not the primary focus of today’s acute in-patient rehabilitation programmes. On the contrary, independence in transfers and wheelchair skills is considered mandatory for all, but knowledge regarding who achieve this, and factors influencing are limited.
Purpose / Aim of Study: To examine factors predicting the basic amputee mobility outcome in an acute orthopaedic ward following a dysvascular major lower limb amputation.
Materials and Methods: Ninety-one out of 103 (12 died in- hospital) consecutive patients (32 women and 59 men, 57 below knee and 34 above knee or bilateral index amputations) with a mean age of 71.6 (SD, 12) years, admitted from their own home. The outcome variables were independency in bed- and bed to chair transfers, and indoor wheelchair manoeuvring.
Findings / Results: Patients who achieved independency (n=64) stayed in the ward a mean of 23.2 (9.3) days as compared to 30.2 (20.2) for those not (30%). Multiple logistic regression revealed that a patient with no preamputation walking ability was 6 times more likely not to achieve independency in basic activities during admittance, while odds increased with 8% per each additional year a patient got older, when adjusted for gender, ASA-score, diabetes (n=39) and the final amputation level. Correspondingly, odds was 4 times (P=0.06) higher for patients who experienced a major revision or reamputation (n=19).
Conclusions: The preamputation function and age were independent predictors of the in- hospital amputee mobility outcome, while having a reamputation also seem to influence. Clinicians, have the possibility to spot patients who may benefit from more intensive training, while number of reamputations should be reduced.