Patterns of local recurrence and dose fractionation of adjuvant radiation therapy in 462 patients with soft tissue sarcoma of extremity and trunk wall

Purpose To study the impact of dose fractionation of adjuvant radiation therapy (RT) on local recurrence (LR) and the relation of LR to radiation fields. Methods and Materials LR rates were analyzed in 462 adult patients with soft tissue sarcoma who underwent surgical excision and adjuvant RT at five Scandinavian sarcoma centers from 1998 to 2009. Medical records were reviewed for dose fractionation parameters and to determine the location of the LR relative to the radiation portals. Results Fifty-five of 462 patients developed a LR (11.9%). Negative prognostic factors included intralesional surgical margin (hazard ratio [HR]: 7.83, 95% confidence interval [CI]: 3.08-20.0), high malignancy grade (HR: 5.82, 95% CI: 1.31-25.8), age at diagnosis (HR per 10 years: 1.27, 95% CI: 1.03-1.56), and malignant peripheral nerve sheath tumor histological subtype (HR: 6.66, 95% CI: 2.56-17.3). RT dose was tailored to margin status. No correlation between RT dose and LR rate was found in multiple Cox regression analysis. The majority (65%) of LRs occurred within the primary RT volume. Conclusions No significant dose–response effect of adjuvant RT was demonstrated. Interestingly, patients given 45-Gy accelerated RT (1.8 Gy twice daily/2.5 weeks) had the best local outcome. A total dose of 50 Gy in 25 fractions seemed adequate following wide margin surgery. The risk of LR was associated with histopathologic subtype, which should be included in the treatment algorithm of adjuvant RT in soft tissue sarcoma.publishedVersio

The effect of antecedent hypoglycaemia on β2-adrenergic sensitivity in healthy participants with the Arg16Gly polymorphism of the β2-adrenergic receptor

Contains fulltext : 96423.pdf (publisher's version ) (Closed access)AIMS/HYPOTHESIS: Homozygosity for glycine at codon 16 (GlyGly) of the beta(2)-adrenergic receptor may alter receptor sensitivity upon chronic stimulation and has been implicated in the pathogenesis of hypoglycaemia unawareness. We compared the effect of antecedent hypoglycaemia on beta(2)-adrenergic receptor sensitivity between GlyGly participants and those with arginine 16 homozygosity (ArgArg) for the beta(2)-adrenergic receptor. METHODS: We enrolled 16 healthy participants, who were either GlyGly (n = 8) or ArgArg (n = 8). They participated randomly in two 2 day experiments. Day 1 consisted of two 2-h hyperinsulinaemic hypoglycaemic (2.8 mmol/l) or euglycaemic (4.8 mmol/l) glucose clamps. On day 2, we measured the forearm vasodilator response to the beta(2)-adrenergic receptor agonist salbutamol and the dose of isoprenaline required to increase the heart rate by 25 bpm (IC(25)). RESULTS: The vasodilator response to salbutamol tended to be greater after antecedent hypoglycaemia than after euglycaemia (p = 0.078), consistent with increased beta(2)-adrenergic receptor sensitivity. This effect was driven by a significant increase in beta(2)-adrenergic receptor sensitivity following hypoglycaemia compared with euglycaemia in ArgArg participants (p = 0.019), whereas no such effect was observed in the GlyGly participants. Antecedent hypoglycaemia tended to decrease the IC(25) in ArgArg participants, whereas the reverse occurred in the GlyGly participants (GlyGly vs ArgArg group p = 0.047). CONCLUSION/INTERPRETATION: Antecedent hypoglycaemia did not affect beta(2)-adrenergic receptor sensitivity in healthy GlyGly participants, but increased it in ArgArg participants. If these results also hold for participants with type 1 diabetes, such an increase in beta(2)-adrenergic receptor sensitivity may potentially reduce the risk of repeated hypoglycaemia and the subsequent development of hypoglycaemia unawareness in ArgArg diabetic participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT00160056

The Scandinavian Sarcoma Group Central Register : 6,000 patients after 25 years of monitoring of referral and treatment of extremity and trunk wall soft-tissue sarcoma

Purpose - We wanted to examine the potential of the Scandinavian Sarcoma Group (SSG) Central Register, and evaluate referral and treatment practice for soft-tissue sarcomas in the extremities and trunk wall (STS) in the Nordic countries. Background - Based on incidence rates from the literature, 8,150 (7,000-9,300) cases of STS of the extremity and trunk wall should have been diagnosed in Norway, Finland, Iceland, and Sweden from 1987 through 2011. The SSG Register has 6,027 cases registered from this period, with 5,837 having complete registration of key variables. 10 centers have been reporting to the Register. The 5 centers that consistently report treat approximately 90% of the cases in their respective regions. The remaining centers have reported all the patients who were treated during certain time periods, but not for the entire 25-year period. Results - 59% of patients were referred to a sarcoma center untouched, i.e. before any attempt at open biopsy. There was an improvement from 52% during the first 5 years to 70% during the last 5 years. 50% had wide or better margins at surgery. Wide margins are now achieved less often than 20 years ago, in parallel with an increase in the use of radiotherapy. For the centers that consistently report, 97% of surviving patients are followed for more than 4 years. Metastasis-free survival (MFS) increased from 67% to 73% during the 25-year period. Interpretation - The Register is considered to be representative of extremity and trunk wall sarcoma disease in the population of Scandinavia, treated at the reporting centers. There were no clinically significant differences in treatment results at these centers.Peer reviewe

High incidence of metastatic disease in primary high grade and large extremity soft tissue sarcomas treated without chemotherapy

BACKGROUND: The risk of metastasis and the survival in patients with primary extremity soft tissue sarcomas is worse when tumour size is large and the grade of malignancy is high. Such tumours may receive chemotherapy and/or radiation therapy (RTX) for optimising local control. Irradiation can either be applied preoperatively or after tumour resection. The question arises if the kind of RTX in the absence of chemotherapy influences the outcome concerning local control, metastatic disease, survival and complications. METHODS: We retrospectively reviewed the clinical outcome of 233 patients with a primary extremity soft tissue sarcoma treated between 1990 – 2000 with a mean follow-up of 35.8 (4–120) months in our institute. 41 patients had high grade, deep and large tumours (>8 cm), an AJCC stage III (no evidence of metastasis prior to treatment) and were treated with limb salvage surgery and irradiation but stayed without additional chemotherapy. Two groups of patients were compared: the first group received postoperative RTX after tumour resection (n = 33); the second group was treated with preoperative RTX (n = 8). Both groups did not differ concerning clinical parameters. We analysed primary and secondary outcomes. RESULTS: 56% (23/41) of the population developed metastatic disease, 24% (10/41) local recurrence. The risk of metastasis was higher in the group with preoperative irradiation (p = 0.046). The overall (p = 0.0248) and relapse free survival (p = 0.104) were worse in this group. The delay to tumour resection amounted 8 weeks on average in the preoperative group. Local control was not different (p = 0.38) in both study groups. Wound infections and other combined therapy related complications were equally distributed (p = 0.22). CONCLUSION: Without chemotherapy there remains a high risk of metastasis in AJCC grade 3 patients. In high risk patients treated without chemotherapy the elapsed time to tumour resection after preoperative radiation might contribute to the development of metastasis. This outcome may support the thesis that a combination of RTX and offensive multimodal treatment protocols is advantageous in such a subset of patient

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression

Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer

Background: About 20% of patients diagnosed with endometrial cancer (EC) are considered high-risk with unfavorable prognosis. In the framework of the European Network for Individualized Treatment in EC (ENITEC), we investigated the presence and phenotypic features of Circulating Tumor Cells (CTC) in high-risk EC patients. Methods: CTC isolation was carried out in peripheral blood samples from 34 patients, ranging from Grade 3 Stage IB to Stage IV carcinomas and recurrences, and 27 healthy controls using two methodologies. Samples were subjected to EpCAM-based immunoisolation using the CELLection™ Epithelial Enrich kit (Invitrogen, Dynal) followed by RTqPCR analysis. The phenotypic determinants of endometrial CTC in terms of pathogenesis, hormone receptor pathways, stem cell markers and epithelial to mesenchymal transition (EMT) drivers were asked. Kruskal-Wallis analysis followed by Dunn's post-test was used for comparisons between groups. Statistical significance was set at p < 0.05. Results: EpCAM-based immunoisolation positively detected CTC in high-risk endometrial cancer patients. CTC characterization indicated a remarkable plasticity phenotype defined by the expression of the EMT markers ETV5, NOTCH1, SNAI1, TGFB1, ZEB1 and ZEB2. In addition, the expression of ALDH and CD44 pointed to an association with stemness, while the expression of CTNNB1, STS, GDF15, RELA, RUNX1, BRAF and PIK3CA suggested potential therapeutic targets. We further recapitulated the EMT phenotype found in endometrial CTC through the up-regulation of ETV5 in an EC cell line, and validated in an animal model of systemic dissemination the propensity of these CTC in the accomplishment of metastasis. Conclusions: Our results associate the presence of CTC with high-risk EC. Gene-expression profiling characterized a CTC-plasticity phenotype with stemness and EMT features. We finally recapitulated this CTC-phenotype by over-expressing ETV5 in the EC cell line Hec1A and demonstrated an advantage in the promotion of metastasis in an in vivo mouse model of CTC dissemination and homing