Logarithmic spin, logarithmic rate and material frame-indifferent generalized plasticity

In this work we present a new rate type formulation of large deformation generalized plasticity which is based on the consistent use of the logarithmic rate concept. For this purpose, the basic constitutive equations are initially established in a local rotationally neutralized configuration which is defined by the logarithmic spin. These are then rephrased in their spatial form, by employing some standard concepts from the tensor analysis on manifolds. Such an approach, besides being compatible with the notion of (hyper)elasticity, offers three basic advantages, namely:(i) The principle of material frame-indifference is trivially satisfied ; (ii) The structure of the infinitesimal theory remains essentially unaltered ; (iii) The formulation does not preclude anisotropic response. A general integration scheme for the computational implementation of generalized plasticity models which are based on the logarithmic rate is also discussed. The performance of the scheme is tested by two representative numerical examples

Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer

background: The present study aimed to examine the relationship between tumour invasiveness (T stage), the local and systemic environment and cancer-specific survival (CSS) of patients with primary operable colorectal cancer. methods: The tumour microenvironment was examined using measures of the inflammatory infiltrate (Klintrup-Makinen (KM) grade and Immunoscore), tumour stroma percentage (TSP) and tumour budding. The systemic inflammatory environment was examined using modified Glasgow Prognostic Score (mGPS) and neutrophil:lymphocyte ratio (NLR). A 5-year CSS was examined. results: A total of 331 patients were included. Increasing T stage was associated with colonic primary, N stage, poor differentiation, margin involvement and venous invasion (P<0.05). T stage was significantly associated with KM grade (P=0.001), Immunoscore (P=0.016), TSP (P=0.006), tumour budding (P<0.001), and elevated mGPS and NLR (both P<0.05). In patients with T3 cancer, N stage stratified survival from 88 to 64%, whereas Immunoscore and budding stratified survival from 100 to 70% and from 91 to 56%, respectively. The Glasgow Microenvironment Score, a score based on KM grade and TSP, stratified survival from 93 to 58%. conclusions: Although associated with increasing T stage, local and systemic tumour environment characteristics, and in particular Immunoscore, budding, TSP and mGPS, are stage-independent determinants of survival and may be utilised in the staging of patients with primary operable colorectal cancer

Metachronous peritoneal metastases in patients with pT4b colon cancer: An international multicenter analysis of intraperitoneal versus retroperitoneal tumor invasion

It was hypothesized that colon cancer with only retroperitoneal invasion is associated with a low risk of peritoneal dissemination. This study aimed to compare the risk of metachronous peritoneal metastases (mPM) between intraperitoneal and retroperitoneal invasion

Can we <i>S</i>ave the rectum by watchful waiting or <i>T</i>rans<i>A</i>nal microsurgery following (chemo) <i>R</i>adiotherapy versus total mesorectal excision for early <i>RE</i>ctal <i>C</i>ancer (STAR-TREC study)?::protocol for a multicentre, randomised feasibility study

Introduction Total mesorectal excision (TME) is the highly effective standard treatment for rectal cancer but is associated with significant morbidity and may be overtreatment for low-risk cancers. This study is designed to determine the feasibility of international recruitment in a study comparing organ-saving approaches versus standard TME surgery. Methods and analysis STAR-TREC trial is a multicentre international randomised, three-arm parallel, phase II feasibility study in patients with biopsy-proven adenocarcinoma of the rectum. The trial is coordinated from Birmingham, UK with national hubs in Radboudumc (the Netherlands) and Odense University Hospital Svendborg UMC (Denmark). Patients with rectal cancer, staged by CT and MRI as ≤cT3b (up to 5 mm of extramural spread) N0 M0 can be included. Patients will be randomised to either standard TME surgery (control), organ-saving treatment using long-course concurrent chemoradiation or organ-saving treatment using short-course radiotherapy. For patients treated with an organ-saving strategy, clinical response to (chemo)radiotherapy determines the next treatment step. An active surveillance regime will be performed in the case of a complete clinical regression. In the case of incomplete clinical regression, patients will proceed to local excision using an optimised platform such as transanal endoscopic microsurgery or other transanal techniques (eg, transanal endoscopic operation or transanal minimally invasive surgery). The primary endpoint of this phase II study is to demonstrate sufficient international recruitment in order to sustain a phase III study incorporating pelvic failure as the primary endpoint. Success in phase II is defined as randomisation of at least four cases per month internationally in year 1, rising to at least six cases per month internationally during year 2

Tumor-infiltrating macrophages and dendritic cells in human colorectal cancer: relation to local regulatory T cells, systemic T-cell response against tumor-associated antigens and survival

<p>Abstract</p> <p>Introduction</p> <p>Although systemic T-cell responses against tumor antigens and tumor infiltration by T cells have been investigated in colorectal cancer (CRC), the initiation of spontaneous immune responses <it>in situ </it>is not well understood. Macrophages and dendritic cells (DC) play an important role as a link between innate and adaptive immune response. The aim of the present study was to analyze macrophage and DC infiltration in CRC and to investigate whether there is a correlation to systemic T-cell response, regulatory T cell (Treg) infiltration, and survival.</p> <p>Methods</p> <p>Immunohistological staining was performed with nine markers for macrophages and DC (CD68, CD163, S100, CD11c, CD208, CD209, CD123, CD1a, Langerin) in 40 colorectal cancer samples from patients, in whom the state of systemic T-cell responses against tumor-associated antigens (TAA) and Treg infiltration had previously been determined.</p> <p>Results</p> <p>All specimens contained cells positive for CD68, CD163, S100 and CD1a in epithelial tumor tissue and tumor stroma. Only a very few (less than median 3/HPF) CD123+, CD1a+, CD11c+, CD 208+, CD209+, or Langerin+ cells were detected in the specimens. Overall, we found a trend towards increased infiltration by S100-positive DC and a significantly increased number of stromal S100-positive DC in patients without T-cell response. There was an increase of stromal S100 DC and CD163 macrophages in limited disease (S100: 11.1/HPF vs. 7.3/HPF, p = 0.046; CD163: 11.0/HPF vs. 8.1/HPF, p = 0.06). We found a significant, positive correlation between S100-positive DC and FOXP3-positive Tregs. Survival in patients with high DC infiltration was significantly better than that in those with low DC infiltration (p < 0.05). Furthermore, we found a trend towards better survival for increased infiltration with CD163-positive macrophages (p = 0.07).</p> <p>Conclusion</p> <p>The present <it>in situ </it>study adds new data to the discussion on the interaction between the innate and adoptive immune system. Our data strongly support the hypothesis that tumor-infiltrating DC are a key factor at the interface between innate and adaptive immune response in malignant disease. Tumor infiltrating S100-positive DC show an inverse relationship with the systemic antigen-specific T-cell response, a positive correlation with regulatory T cells, and a positive association with survival in CRC. These data put tumor-infiltrating DC at the center of the relevant immune response in CRC.</p

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity

Clinicopathological features and outcome in advanced colorectal cancer patients with synchronous vs metachronous metastases

Contains fulltext : 88999.pdf (publisher's version ) (Open Access)BACKGROUND: Synchronous metastases of colorectal cancer (CRC) are considered to be of worse prognostic value compared with metachronous metastases, but only few and conflicting data have been reported on this issue. METHODS: We retrospectively investigated patient demographics, primary tumour characteristics and overall survival (OS) in 550 advanced CRC patients with metachronous vs synchronous metastases, who participated in the phase III CAIRO study. For this purpose only patients with a prior resection of the primary tumour were considered. RESULTS: The clinical and pathological characteristics associated with poor prognosis that we observed more often in patients with synchronous metastases (n=280) concerned an abnormal serum lactate dehydrogenase (LDH) concentration (P=0.01), a worse WHO performance status (P=0.02), primary tumour localisation in the colon (P=0.002) and a higher T stage (P=0.0006). No significant difference in median OS was observed between patients with synchronous metastases and metachronous metastases (17.6 vs 18.5 months, respectively, P=0.24). CONCLUSION: Despite unfavourable clinicopathological features in patients with synchronous metastases with a resected primary tumour compared to patients with metachronous metastases, no difference in the median OS was observed. Possible explanations include a (partial) chemoresistance in patients with metachronous disease because of previous adjuvant treatment, whereas differences between the two groups in screening procedures resulting in a lead time bias to diagnosis or in prognostic molecular markers remain speculative

KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients

Contains fulltext : 96042.pdf (publisher's version ) (Open Access)BACKGROUND: KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor antibody in metastatic colorectal cancer (CRC). KRAS mutation analysis is usually performed on primary tumour tissue because metastatic tissue is often not available. However, controversial data are available on the concordance of test results between primary tumours and corresponding metastases. We assessed the concordance of KRAS mutation status in a study of 305 primary colorectal tumours and their corresponding liver metastases. METHODS: Patients with histologically confirmed CRC who underwent surgical resection of the primary tumour and biopsy or surgical resection of the corresponding liver metastasis were included. KRAS mutation analysis was performed for codons 12 and 13. RESULTS: KRAS mutation was detected in 108 out of 305 primary tumours (35.4%). In 11 cases (3.6%), we found a discordance between primary tumour and metastasis: 5 primary tumours had a KRAS mutation with a wild-type metastasis, 1 primary tumour was wild type with a KRAS mutation in the metastasis, and in 5 cases the primary tumour and the metastasis had a different KRAS mutation. CONCLUSION: We observed a high concordance of KRAS mutation status of 96.4% (95% CI 93.6-98.2%) between primary colorectal tumours and their corresponding liver metastases. In only six patients (2.0%; 95% CI 0.7-4.2%), the discordance was clinically relevant. In this largest and most homogenous study to date, we conclude that both primary tumours and liver metastases can be used for KRAS mutation analysis

The accuracy of Multi-detector row CT for the assessment of tumor invasion of the mesorectal fascia in primary rectal cancer

PURPOSE: To evaluate the accuracy of Multi-detector row CT (MDCT) for the prediction of tumor invasion of the mesorectal fascia (MRF). MATERIALS AND METHODS: A total of 35 patients with primary rectal cancer underwent preoperative staging magnetic resonance imaging (MRI) and MDCT. The tumor relationship to the MRF, expressed in 3 categories (1--tumor free MRF = tumor distance > or = 1 mm; 2--threatened = distance < 1 mm; 3--invasion = distance 0 mm) was determined on CT by two observers at patient level and at different anatomical locations. A third expert reader evaluated the MRF tumor relationship on MRI, which served as reference standard. Receiver operating characteristic curves (ROC-curves) and areas under these curves (AUC) were calculated. The inter-observer agreement of CT was determined by using linear weighted kappa statistics. RESULTS: The AUC of CT for MRF invasion was 0.71 for observer 1 and 0.62 for observer 2. The inter-observer agreement was kappa = 0.34. The performance of CT at mid-high rectal levels was statistically significant better compared to low anterior (obs.1: AUC = 0.88 vs. 0.50; obs 2: AUC = 0.84 vs. 0.31; P < or = 0.040). CONCLUSION: Multi-detector row CT has a poor accuracy for predicting MRF invasion in low-anterior located tumors.The accuracy of CT significantly improves for tumors in the mid-high rectum. There is a high inconsistency among readers