MGMT promoter hypermethylation is a frequent, early, and consistent event in astrocytoma progression, and not correlated with TP53 mutation

Hypermethylation of the MGMT gene promoter and mutation of the TP53 tumor-suppressor gene are frequently present in diffuse astrocytomas. However, there is only anecdotal information about MGMT methylation status and TP53 mutations during progression of low-grade diffuse astrocytoma (AII) to anaplastic astrocytoma (AIII) and secondary glioblastoma (sGB). In this study biopsy specimens from 51 patients with astrocytic tumors with radiologically proved progression from low to high-grade malignancy were investigated for the presence and consistency of MGMT promoter hypermethylation and TP53 mutations. For 27 patients biopsy samples both of primary tumors and their recurrences were available. For the other 24 patients histology of either the low-grade lesion or the high-grade recurrence was available. It was found that MGMT promoter hypermethylation and TP53 mutations are both frequent and early events in the progression of astrocytomas and that their status is consistent over time. No correlation was found between MGMT methylation status and the presence of TP53 mutations. In addition, no correlation was found between MGMT promoter hypermethylation and the type of TP53 mutations. These results argue against the putative TP53 G:C>A:T transition mutations suggested to occur preferentially in MGMT hypermethylated tumors

A randomized two arm phase III study in patients post radical resection of liver metastases of colorectal cancer to investigate bevacizumab in combination with capecitabine plus oxaliplatin (CAPOX) vs CAPOX alone as adjuvant treatment

<p>Abstract</p> <p>Background</p> <p>About 50% of patients with colorectal cancer are destined to develop hepatic metastases. Radical resection is the most effective treatment for patients with colorectal liver metastases offering five year survival rates between 36-60%. Unfortunately only 20% of patients are resectable at time of presentation. Radiofrequency ablation is an alternative treatment option for irresectable colorectal liver metastases with reported 5 year survival rates of 18-30%. Most patients will develop local or distant recurrences after surgery, possibly due to the outgrowth of micrometastases present at the time of liver surgery. This study aims to achieve an improved disease free survival for patients after resection or resection combined with RFA of colorectal liver metastases by adding the angiogenesis inhibitor bevacizumab to an adjuvant regimen of CAPOX.</p> <p>Methods/design</p> <p>The Hepatica study is a two-arm, multicenter, randomized, comparative efficacy and safety study. Patients are assessed no more than 8 weeks before surgery with CEA measurement and CT scanning of the chest and abdomen. Patients will be randomized after resection or resection combined with RFA to receive CAPOX and Bevacizumab or CAPOX alone. Adjuvant treatment will be initiated between 4 and 8 weeks after metastasectomy or resection in combination with RFA. In both arms patients will be assessed for recurrence/new occurrence of colorectal cancer by chest CT, abdominal CT and CEA measurement. Patients will be assessed after surgery but before randomization, thereafter every three months after surgery in the first two years and every 6 months until 5 years after surgery. In case of a confirmed recurrence/appearance of new colorectal cancer, patients can be treated with surgery or any subsequent line of chemotherapy and will be followed for survival until the end of study follow up period as well. The primary endpoint is disease free survival. Secondary endpoints are overall survival, safety and quality of life.</p> <p>Conclusion</p> <p>The HEPATICA study is designed to demonstrate a disease free survival benefit by adding bevacizumab to an adjuvant regime of CAPOX in patients with colorectal liver metastases undergoing a radical resection or resection in combination with RFA.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier NCT00394992</p

Are ipsilateral breast tumour invasive recurrences in young (⩽40 years) women more aggressive than their primary tumours?

The characteristics of ipsilateral breast tumour recurrences (IBTRs) relative to those of their primary tumours (PTs) remain scarcely studied. Of 70 young (⩽40 years) premenopausal women with IBTRs, we studied a series of 63 with paired histological data. Median follow-up since IBTR was 10 years. Rates of histological types, grades or hormonal receptors were not significantly different in PTs and in IBTRs. The concordance between IBTRs and their PTs was good for histological types. IBTRs with conserved histological types tended to occur more locally, but not significantly sooner than others. These IBTRs had good concordance for hormone receptors. In discordant cases there were as many losses as appearances of the receptors. The concordance was weak for grades, with equivalent numbers of IBTRs graded lower as higher than their PTs. The 10-year overall survival rate was 70%. Neither the conservation of histological type, location, nor of the two combined were associated with deaths. Early (<2 years) IBTRs, tended to be associated with poorer survival (HR=2.24 (0.92–5.41); P=0.08). IBTRs did not display features of higher aggressiveness than PTs. Neither clinical nor histological definition of a true recurrence could be established other than the conservation of the histological type

Proxy evidence for state-dependence of climate sensitivity in the Eocene greenhouse

Despite recent advances, the link between the evolution of atmospheric CO2 and climate during the Eocene greenhouse remains uncertain. In particular, modelling studies suggest that in order to achieve the global warmth that characterised the early Eocene, warmer climates must be more sensitive to CO2 forcing than colder climates. Here, we test this assertion in the geological record by combining a new high-resolution boron isotope-based CO2 record with novel estimates of Global Mean Temperature. We find that Equilibrium Climate Sensitivity (ECS) was indeed higher during the warmest intervals of the Eocene, agreeing well with recent model simulations, and declined through the Eocene as global climate cooled. These observations indicate that the canonical IPCC range of ECS (1.5 to 4.5 °C per doubling) is unlikely to be appropriate for high-CO2 warm climates of the past, and the state dependency of ECS may play an increasingly important role in determining the state of future climate as the Earth continues to warm

Is the meiofauna a good indicator for climate change and anthropogenic impacts?

Our planet is changing, and one of the most pressing challenges facing the scientific community revolves around understanding how ecological communities respond to global changes. From coastal to deep-sea ecosystems, ecologists are exploring new areas of research to find model organisms that help predict the future of life on our planet. Among the different categories of organisms, meiofauna offer several advantages for the study of marine benthic ecosystems. This paper reviews the advances in the study of meiofauna with regard to climate change and anthropogenic impacts. Four taxonomic groups are valuable for predicting global changes: foraminifers (especially calcareous forms), nematodes, copepods and ostracods. Environmental variables are fundamental in the interpretation of meiofaunal patterns and multistressor experiments are more informative than single stressor ones, revealing complex ecological and biological interactions. Global change has a general negative effect on meiofauna, with important consequences on benthic food webs. However, some meiofaunal species can be favoured by the extreme conditions induced by global change, as they can exhibit remarkable physiological adaptations. This review highlights the need to incorporate studies on taxonomy, genetics and function of meiofaunal taxa into global change impact research

Ferumoxide-enhanced magnetic resonance imaging techniques in pre-operative assessment for colorectal liver metastases

Aim:The objective was to evaluate whether contrast-enhanced magnetic resonance imaging (MRI) techniques used in a pre-operative assessment protocol for colorectal liver metastases are as accurate as spiral computer tomography during arterial portography (CTAP). Pre-operative accuracy and clinical consequences of MRI are described and compared with CTAP. Moreover, post-operative survival rate and tumour recurrence were studied. Methods: The study group comprised 84 patients which were possible candidates for a partial hepatectomy for colorectal liver metastases. Patients were pre-operatively evaluated by CT of the abdomen, CT of the thorax and spiral CTAP and ferumoxide-enhanced MRI was performed in routine way for all patients. Following this selection, 35 patients underwent a partial hepatectomy with curative intent. All patients were retrospectively evaluated. Results: Ferumoxide-enhanced MRI proved to be at least as accurate as spiral CTAP in 81% of patients. In nine patients (11%) spiral CTAP revealed more intrahepatic lesions than MRI; in only two patients (2%) did these foundings influenced the clinical decision. These patients were considered to have irresectable disease. In seven patients (8%) MRI detected more lesions than spiral CTAP and influenced the clinical decision in three patients (4%) and these did not undergo a laparotomy. The actuarial 3 year overall survival of operated patients was 41% and the actuarial 3 year disease-free survival was 19%. Conclusion: Evaluation of the clinical impact of a pre-operative assessment protocol extended with ferumoxide MRI techniques demonstrated that this non-invasive MRI technique is safe and at least as accurate as spiral CTAP. This MRI technique results in comparable clinical decisions and outcome after hepatectomy. We suggest that the performance of routine contrast-enhanced MRI should instead be used in the pre-operative evaluation of colorectal liver metastases.</p

Cosmetic outcome of breast conserving therapy after sentinel node biopsy versus axillary lymph node dissection

Introduction. Next to locoregional control, good cosmetic outcome is one of the main goals of breast conserving treatment (BCT) for breast cancer surgery. Factors affecting cosmetic outcome are well known. The sentinel node (SN) procedure avoids lymphedema in the breast, which might influence cosmetic outcome. The aim of this study was to evaluate the cosmetic outcome of BCT after the SN procedure compared to that after axillary lymph node dissection (ALND). Methods. The subjects were 20 patients who underwent ALND and 20 patients who underwent the SN procedure. After a minimum follow-up period of 43 months, we photographed each patient. Fifteen healthy women served as control subjects. We used the percentage breast retraction assessment index (pBRA=BRA/reference length × 100) to compare cosmetic outcome. Results. The median pBRAs of the ALND group and SN group (14.3 and 6.71, respectively) significantly differed (p = 0.001). The pBRA of the SN group was comparable to the pBRA (6.1) of the control group (p=0.317). Conclusion. Cosmetic outcome of BCT after the SN procedure was superior compared to the cosmetic outcome after ALND. This is an important additional reason to implement the SN procedure in routine daily practice

Wedge-shaped applicator for additional light delivery and dosimetry in the diaphragmal sinus during photodynamic therapy for malignant pleural mesothelioma

In situ light dosimetry during photodynamic therapy (PDT) of malignant pleural mesothelioma (MPM) after tumour resection facilitates the delivery of a controlled light distribution to the inner thoracic surface. Illumination of the diaphragm-induced sinus, however, remains difficult. Our aim was to develop a wedge-shaped light applicator with incorporated light dosimetry to deliver an additional fluence limited to the sinus. The wedge-shaped applicator contains a cylindrical diffuser for light delivery and two isotropic detectors for simultaneous light dosimetry. These detectors were placed at strategic positions where the fluence rate is maximal or minimal (middle and edge). Prior to its clinical use, the performance of the sinus light applicator was tested in several optical tissue phantoms with different optical properties. The fluence rate distribution over the surface of the applicator showed little change when the wedge was submerged in four different optical phantoms. During clinical PDT of MPM the applicator had to be re-located manually four times in order to give an additional fluence of approximately 2 J cm(-2) to the entire sinus. The light applicator enables dosimetry-control led light delivery for additional illumination of the sinus region that is often under-illuminated during thoracic integral illumination of MP