Background: Loss of CD95 expression in tumour cells occurs frequently in colon carcinoma and may be associated with disease progression. On the other hand, neo-expression of CD95L in tumour cells may ...contribute to immune evasion. Aims: We aimed at further exploring the functional role and prognostic significance of the CD95/CD95L death inducing system in colon carcinomas. Patients and methods: CD95 and CD95L expression was examined by immunohistochemistry in 128 R0 resected UICC (International Union against Cancer) stage II/III colon carcinomas and correlated with disease free survival. Results: CD95 expression in tumour cells was observed in only 30 carcinomas (23.4%) whereas the others had at least a minor subpopulation of CD95 negative cells. Loss of CD95 in tumour cells was related to adverse prognosis in uni- and multivariate analysis (p = 0.046 and p = 0.036, respectively). Tumour infiltrating lymphocytes (TIL) were the major source of CD95L in colon carcinomas. CD95L+TIL were present in 83% of cases whereas CD95L was found in tumour cells in only 12% of cases. Moreover, a high rate of CD95L+TIL correlated with prolonged disease free survival in patients with UICC stage II (p = 0.05) but not in those with stage III. Conclusions: Loss of CD95 in tumour cells may be an independent prognostic factor in colon carcinomas. The CD95L counterattack is not a relevant feature in colon carcinoma but CD95L+TIL may contribute to tumour control in the early stages of the disease, exerting a concurrent selection pressure in the direction of CD95 abrogation/resistance.
Omni-stat®, a polysaccharide made by de-acetylation of chitin, is currently in use as a battlefield topical haemostat. This experimental study undertakes the first evaluation of Omni-stat in an in ...vivo porcine hepatectomy and liver trauma model.
A model of sequential liver resection was employed: following liver resection, further resections were undertaken in the same animal provided that there was cessation of bleeding from the earlier resection and that haemodynamic stability was maintained. An additional liver trauma injury was undertaken after completion of all resections. Data were collected on heart rate, blood pressure, haematocrit, resection volumes, blood loss and the efficacy of Omni-stat in haemostasis.
Eight minor resections and 12 major resections were undertaken. Topical application of Omni-stat to raw post-transection surfaces immediately upon completion of resection achieved complete haemostasis with a single application in 14 of 15 (93%) resections. There was no recurrence of bleeding during the 5-hour protocol. The median time for cessation of bleeding after resection in the Omni-stat group was 3 min (range 3-6). This was not significantly different from time to cessation of bleeding in 5 control resections. There was no difference in blood loss or haemodynamic parameters. Respiratory rate was significantly faster after application of Omni-stat. In 2 liver lacerations, Omni-stat was effective in achieving cessation of haemorrhage.
Omni-stat is an effective haemostat in experimental in vivo porcine liver resection and liver trauma. Further evaluation is required to assess its physiological absorption profile in man and its comparative efficacy against commercially established agents.
The utility of cancer whole genome and transcriptome sequencing (cWGTS) in oncology is increasingly recognized. However, implementation of cWGTS is challenged by the need to deliver results within ...clinically relevant timeframes, concerns about assay sensitivity, reporting and prioritization of findings. In a prospective research study we develop a workflow that reports comprehensive cWGTS results in 9 days. Comparison of cWGTS to diagnostic panel assays demonstrates the potential of cWGTS to capture all clinically reported mutations with comparable sensitivity in a single workflow. Benchmarking identifies a minimum of 80× as optimal depth for clinical WGS sequencing. Integration of germline, somatic DNA and RNA-seq data enable data-driven variant prioritization and reporting, with oncogenic findings reported in 54% more patients than standard of care. These results establish key technical considerations for the implementation of cWGTS as an integrated test in clinical oncology.
Abstract
BackgroundWe identified somatic PIK3CA mutations in 32.5% of 590 primary invasive breast cancers (BC) (manuscript in press: Clinical Cancer Research). Detected by massARRAY genotyping, ...PIK3CA mutations significantly associate with favorable clinicopathologic features and improved clinical outcome, including overall and breast cancer-specific survival. Given the strong association between PIK3CA mutations and hormone receptor (HR) positivity, one hypothesis is that PIK3CA mutations 'drive' HR positive BC and will be detected in pre-invasive breast tumors. As PIK3CA mutations offer a protective effect in BC, it has not been determined whether PIK3CA mutations are selected for in disease progression or whether additional collaborating mutations are required.MethodsTo determine the concordance of PIK3CA mutations and assess the acquisition of additional oncogene mutations, available matched tissue samples, from the previous database, were procured and underwent massARRAY genotyping (n = 83). Two mm cores were macro-dissected from matched formalin-fixed, paraffin embedded tissue, including normal breast tissue, benign lymph nodes (LN), ductal carcinoma-in-situ (DCIS), regional LN metastases (mets), and distant mets. MassARRAY (Sequenom) genotyping was performed on native DNA to identify rare and hotspot PIK3CA mutations, as well as AKT1 (E17K), RAS, and RET mutations.ResultsConcordance of PIK3CA mutations is noted between primary BC and DCIS, except for one rare PIK3CA mutation (Q546R) not detected in DCIS (4/5). No PIK3CA mutations are detected in normal breast tissue (0/8) or benign LN (0/6). Rare and hotspot PIK3CA mutations in primary BC are detected in 87.5% (7/8) matched regional LN met and 80 % (4/5) distant mets. For the patient with the disconcordant regional LN met, the rare PIK3CA mutation (H1047L) identified in primary BC is also present in the distant met site. Notably, for the single disconcordant PIK3CA met site, a rare PIK3CA mutation (E545A) is detected in a primary tumor, regional LN met, and bone met and is absent in a second bone met, in which a KRAS (G12C) mutation has been identified. One concomitant hotspot PIK3CA (E542K)/KRAS (G12C) mutation is present in both primary BC and paired DCIS. Complete concordance of AKT1 (E17K) mutations has been identified between in DCIS, primary BC, regional LN met, and distant mets (n=4).ConclusionsWe recently defined the positive prognostic significance of PIK3CA mutations in breast cancer. PIK3CA and AKT1 (E17K) mutations are early events in breast cancer, occurring in pre-invasive tumors. Despite the protective effect of PIK3CA mutations on clinical outcome, they persist and are selected for in disease progression, as they are detected in regional LN and distant mets. Complete concordance is identified between hotspot PIK3CA mutated primary BC and matched tumors samples, suggesting that PIK3CA mutations with higher oncogenic potency are maintained in tumor progression. These findings support that targeting the PI3K pathway may assist in tailoring therapy to appropriate patient populations. We are expanding matched tissue collection from a separate patient cohort to further assess genomic and functional genomic change with disease progression.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5164.
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