A prognostic profile of hypoxia-induced genes for localised high-grade soft tissue sarcoma.

BACKGROUND: For decades, tumour hypoxia has been pursued as a cancer treatment target. However, prognostic and predictive biomarkers are essential for the use of this target in the clinic. This study investigates the prognostic value of a hypoxia-induced gene profile in localised soft tissue sarcoma (STS). METHODS: The hypoxia-induced gene quantification was performed by real-time quantitative PCR (RT-qPCR) of formalin-fixed, paraffin-embedded tissue samples. The gene expression cut-points were determined in a test cohort of 55 STS patients and used to allocate each patient into a more or a less hypoxic group. The cut-points found in the test cohort were applied to a cohort of 77 STS patients for validation. RESULTS: For patients with localised high-grade STS treated with surgery with or without postoperative radiation therapy, the prognostic value of the hypoxia-induced gene profile was proved in the test cohort and confirmed in the validation cohort. After adjustment for confounders, the hazard ratio (HR) was 3.2 (95% CI: 1.5; 7.0) for patients with more hypoxic tumours compared with patients with less hypoxic tumours regarding disease-specific survival. Moreover, for the development of metastatic disease, the HR was 2.61 (95% CI: 1.27; 5.33). CONCLUSIONS: The hypoxia-induced gene profile is a validated independent prognostic marker that may help identify STS patients needing more aggressive or different adjuvant treatment.

The importance of standardized treatment in high-grade osteosarcoma: 30 years of experience from a hospital-based database.

BACKGROUND: Treatment of high-grade osteosarcoma remains a major challenge in orthopedic oncology as no major breakthrough in overall survival has occurred in the past 20 years. Due to the rarity of the disease, comparing the results of a single institution to best standard practice needs the establishment of clinical databases. The aim of this study was to report the cumulative 30-years' experience of a single institution and to assess the incidence, survival and prognostic factors of high-grade osteosarcoma using a recently validated, hospital-based database, representing all citizens living in western Denmark, the Aarhus Sarcoma Registry. MATERIAL AND METHODS: Between 1979 and 2008, 169 patients were treated at the Sarcoma Centre of Aarhus University Hospital for high-grade osteosarcoma. The incidence was calculated as a WHO age-standardized incidence per million per year. The endpoint was overall survival, analyzed by the Kaplan-Meier method and log-rank. Possible prognostic factors were analyzed by the uni- and multivariate Cox proportional hazard method. RESULTS: The incidence of high-grade osteosarcoma in western Denmark from 1979 to 2008 was 2.7/million inhabitants/year. The five-year overall survival was 42% (95% CI 34; 49) for the whole cohort of patients with high-grade osteosarcoma and 54% (95% CI 43; 64) for patients with localized disease treated with wide excision and chemotherapy. For patients treated with curative intent, no soft tissue extension, treatment with sufficient surgical margin and standard chemotherapy, as well as a high degree of necrosis after chemotherapy were all independent prognostic factors for overall survival. CONCLUSION: The data from this hospital-based, validated database confirms the relevance of the known prognostic factors of high-grade osteosarcoma and emphasizes the importance of adequate surgical margins and chemotherapy.

The importance of reference gene analysis of formalin-fixed, paraffin-embedded samples from sarcoma patients - an often underestimated problem.

OBJECTIVE: Reverse transcription quantitative real-time polymerase chain reaction is efficient for quantification of gene expression, but the choice of reference genes is of paramount importance as it is essential for correct interpretation of data. This is complicated by the fact that the materials often available are routinely collected formalin-fixed, paraffin-embedded (FFPE) samples in which the mRNA is known to be highly degraded. The purpose of this study was to investigate 22 potential reference genes in sarcoma FFPE samples and to study the variation in expression level within different samples taken from the same tumor and between different histologic types. METHODS: Twenty-nine patients treated for sarcoma were enrolled. The samples encompassed 82 (FFPE) specimens. Extraction of total RNA from 7-µm FFPE sections was performed using a fully automated, bead-base RNA isolation procedure, and 22 potential reference genes were analyzed by reverse transcription quantitative real-time polymerase chain reaction. The stability of the genes was analyzed by RealTime Statminer. The intrasamples variation and the interclass correlation coefficients were calculated. The linear regression model was used to calculate the degradation of the mRNA over time. RESULTS: The quality of RNA was sufficient for analysis in 84% of the samples. Recommended reference genes differed with histologic types. However, PPIA, SF3A1, and MRPL19 were stably expressed regardless of the histologic type included. The variation in ∆Cq value for samples from the same patients was similar to the variation between patients. It was possible to compensate for the time-dependent degradation of the mRNA when normalization was made using the selected reference genes. CONCLUSION: PPIA, SF3A1, and MRPL19 are suitable reference genes for normalization in gene expression studies of FFPE samples from sarcoma regardless of the histology.

High frequency of MYC gene amplification is a common feature of radiation-induced sarcomas. Further results from EORTC STBSG TL 01/01.

Irradiation is a major causative factor among the small subgroup of sarcomas with a known etiology. The prognosis of radiation-induced sarcomas (RIS) is significantly worse than that of their spontaneous counterparts. The most frequent histological subtypes include undifferentiated pleomorphic sarcomas, angiosarcomas, and leiomyosarcomas. A high frequency of MYC amplifications in radiation-induced angiosarcomas, but not in primary angiosarcomas, has recently been described. To investigate whether MYC amplifications are also frequent in RIS other than angiosarcomas, we analyzed the MYC amplification status of 83 RIS and 192 sporadic sarcomas by fluorescence in situ hybridization. We found significantly higher numbers of MYC amplifications in RIS than in sporadic sarcomas (P < 0.0001), especially in angiosarcomas, undifferentiated pleomorphic sarcomas, and leiomyosarcomas. Angiosarcomas were special in that MYC amplifications were particularly frequent and always high level, while other RIS showed low-level amplifications. We conclude that MYC amplifications are a frequent feature of RIS as a group and may contribute to the biology of these tumors.

Serum Natrium Determines Outcome of Treatment of Advanced GIST with Imatinib: A Retrospective Study of 80 Patients from a Single Institution.

Treatment with tyrosine kinase inhibitors (TKIs) has drastically improved overall survival (OS) of patients with advanced GIST. The aim of this study is to evaluate the results of treatment with different TKIs on advanced GIST and identify prognostic factors for OS. The medical records of all patients treated at the Department of Oncology, Aarhus University Hospital were retrospectively reviewed. Between 2001 and 2009, 80 patients with advanced GIST were treated with imatinib as first-line therapy. The median OS was 44 months (95% CI 31-56), and the 5-year OS was 40%. Since 2005, 32 patients were treated with sunitinib as 2nd-line therapy. The median time to progression was 9 months (95% CI: 3-13 months), and the 3-year OS was 30%. The data illustrate that data from large multicenter studies are reproducible in a single sarcoma centre. This retrospective study pointed to low serum sodium at the start of imatinib as a possible prognostic factor affecting OS.

Chemotherapy-induced changes of CA 125 in patients with epithelial ovarian cancer.

OBJECTIVES: CA 125 is a tumor marker widely used to diagnose, monitor, and follow-up women with epithelial ovarian cancer, as the marker is well related to the amount of vital tumor cells. However, CA 125 before the operation or during the first 2 courses of chemotherapy does not provide enough information concerning survival to serve as a prognostic marker. The present investigation was inspired by studies describing a paradoxical increase of tumor markers (CEA, CA 125, and CA 15-3) in the days after chemotherapy of women with breast cancer. If CA 125 increases within days after chemotherapy, the increase may be caused by death of the cancer cells. It was therefore speculated if a CA 125 spike may serve as an early prognostic parameter. The aim of the present investigation was to evaluate if CA 125 increases within days after the first course of chemotherapy of women with ovarian cancer. PATIENTS: Twenty women with epithelial ovarian cancer were included in the study. CA 125 was measured in each woman on day 0 (the day of, but before initiation of chemotherapy) and 1, 3, 5, 7, 9, and 14 days after chemotherapy. RESULTS: One woman was excluded due to normal CA 125 values. The remaining 19 patients displayed a significant decrease in CA 125 during the 14-day period after chemotherapy. CONCLUSION: In the present study, no chemotherapy-induced increase of CA 125 within the first 14 days after chemotherapy could be demonstrated.

Quality of life in patients with skeletal metastases of prostate cancer and status prior to start of endocrine therapy: results from the Scandinavian Prostate Cancer Group Study 5.

OBJECTIVES: Prostate cancer (PC) is a highly lethal neoplastic disease affecting the physical, mental and social well-being of patients, i.e. their quality of life (QOL). Patients suffering from metastatic PC are faced with serious decisions regarding treatment strategies. Therefore, QOL information has become a crucial element of decision making in this group of patients. The first objective of this study was to describe QOL in a group of patients diagnosed with metastatic PC and skeletal metastases. At the time of evaluation the patients had not received any treatment but were evaluated before entering a study of androgen-modulating therapy (the Scandinavian Prostate Cancer Group study 5). The second objective was to identify demographic and disease-related factors affecting QOL. MATERIAL AND METHODS: A total of 917 patients with metastatic PC were evaluated using a well-described and validated questionnaire [European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-C30 (EORTC QLQ-C30)]. The characteristics of the PC were noted, and simultaneously patients were evaluated with respect to use of analgesics, pain and performance status using a scoring system. Biochemical tests were performed when patients entered the study. A multivariate regression analysis was performed to analyse the correlations between QOL scores, patient demographics and disease-related data. RESULTS: The patients reported QOL scores significantly lower than those in the background population. Pain and fatigue were pronounced, whereas dyspnoea, insomnia, loss of appetite, constipation and diarrhoea were less prominent. Patients with high tumour grades, high PSPA scores (the sum of the pain score, the performance status and the use of analgesics) and those using analgesics had significantly lower QOL scores than the other patients. CONCLUSIONS: Patients with metastatic PC have reduced QOL. Our findings are in line with those of other studies of QOL among patients with this disease as evaluated by means of the EORTC QLQ-C30 questionnaire. Baseline data from studies like this provide important information when treatment modalities for PC are evaluated.

[Surgical treatment of giant cell tumor of bone]. / Kirurgisk behandling af kaempecelletumorer i knogler.

INTRODUCTION: This study analyses a 5-year follow-up after treatment of giant cell tumour of bone during a 31-year period. MATERIAL AND METHODS: Sixty patients with giant cell tumours of bone had been treated at the Centre for Musculoskeletal Tumours at Aarhus University Hospital. All patients were followed at regular intervals for 5-35 years, median = 11 years. RESULTS: There were 54 benign giant cell tumours of bone, whereas six were classified as malignant. The most common location was around the knee. There were nine cases of recurrence. The 5-year recurrence-free survival was 77%. The lowest frequency of recurrence appeared after resection (6%) and the highest after bone-transplantation (22%). DISCUSSION: The classical microscopic and macroscopic criteria for malignancy are not applicable for this rare tumour. All giant cell tumours of bone should be considered as potentially malignant, and therefore patients should be referred to a Centre for Musculoskeletal Tumours.

Neoadjuvant chemotherapy with cisplatin and methotrexate in patients with muscle-invasive bladder tumours.

This prospective, randomized study based on two associated trials was designed to evaluate the effect of neoadjuvant chemotherapy with cisplatin and methotrexate with folinic acid rescue or no chemotherapy prior to local treatment in patients with T2-T4b, NX-3, MO transitional cell carcinoma of the bladder. In the first trial, local treatment consisted of cystectomy (DAVECA 8901) and in the other trial the treatment was radiotherapy (DAVECA 8902); 153 eligible patients were randomized. The majority of the patients (89%) completed the protocol. The overall time to progression for all 153 patients was 12.9 months. Median time to progression was 14.2 months with chemotherapy and 11.4 months without chemotherapy. The actuarial 5-year overall survival rate for all 153 patients was 29%, and 29% for both treatment groups. Multivariate analyses showed that T-stage, tumour size and serum creatinine were independent prognostic factors for survival. The cystectomy trial included 33 patients. Median survival was 78.9 months, 82.5 months with chemotherapy and 45.8 months without chemotherapy (p = 0.76). The radiotherapy trial included 120 patients. The median survival was 17.6 months. Median survival was 19.2 months in the group receiving chemotherapy and 16.3 in the group not receiving chemotherapy. The 5-year survival rate was 19% in the group receiving chemotherapy and 24% in the groups not receiving chemotherapy (p = 0.98). Late toxicity grade 3 or 4 of the bladder was recorded in 25% of the patients (actuarial rate). Neoadjuvant chemotherapy with cisplatin and methotrexate did not significantly improve disease-free or overall survival in 153 randomized patients with invasive bladder cancer.