safety and efficacy of trifluridine tipiracil ftd tpi in metastatic colorectal cancer mcrc patients according to previous treatment with regorafenib in the international phase iiib preconnect study

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Colorectal neuroendocrine carcinomas and adenocarcinomas share oncogenic pathways. A clinico-pathologic study of 12 cases

OBJECTIVE: Neuroendocrine carcinomas (NECs) are rare neoplasms with an increasing incidence. Oncogenetic pathways of colorectal NEC are still poorly understood, and no treatment standards are available for these rare tumors. METHODS: We analyzed retrospectively the clinical records and histology of 12 patients with colorectal NEC. KRAS and BRAF mutations were investigated after the dissection of exoendocrine and neuroendocrine components. ALK alterations and EML4-ALK transcripts were detected by in-situ hybridization and determination of fusion transcripts, respectively. RESULTS: At the time of diagnosis, the mean age of the patients was 60 years (40-79) and 10 patients had synchronous metastases. A transient response occurred in two patients and one patient treated with cisplatin-etoposide or fluoropyrimidine-oxaliplatin, respectively. Tumor progression-related death occurred in 11 of 12 patients. Ten tumors contained an exocrine component, accounting for 5-70% of the tumor, and the other two contained an amphicrine component. BRAF/KRAS mutations were found in six of 10 tumors, corresponding to BRAF(V600E) (n=2) or KRAS(G12D) (n=2), KRAS(G12V) or KRAS(G13D). DNA was obtained from both exocrine and endocrine components in seven cases, and the BRAF/KRAS status was identical in all cases. Split of the ALK locus was detected in a minority of tumor cells in two of eight cases, but EML4-ALK transcripts were absent. CONCLUSION: The association of an exocrine component in all cases and the similar profile of BRAF/KRAS mutations indicate that colorectal NEC may correspond to a high-grade transformation of colorectal carcinoma. New chemotherapy regimens using targeted therapies should be assessed in these tumors

Panitumumab-based maintenance after oxaliplatin discontinuation in metastatic colorectal cancer: A retrospective analysis of two randomised trials

Panitumumab is approved for RAS wild-type metastatic colorectal cancer and was evaluated in Phase III (PRIME, NCT00364013) and Phase II (PEAK, NCT00819780) first-line randomised studies. This retrospective analysis of these trials investigated efficacy and toxicity of panitumumab-based maintenance after oxaliplatin discontinuation in RAS wild-type patients. First-line regimens were FOLFOX4 \ub1 panitumumab in PRIME and mFOLFOX6 plus panitumumab or mFOLFOX6 plus bevacizumab in PEAK. Outcomes included median progression-free survival (PFS) and overall survival (OS), from randomisation and oxaliplatin discontinuation, and toxicity. Overall, median duration of panitumumab plus 5-fluorouracil/leucovorin (5-FU/LV) maintenance was 21 (interquartile range: 11-41) weeks; that of 5-FU/LV \ub1 bevacizumab maintenance was 16 (6-31) weeks. Median OS from randomisation was 40.2 (95% confidence interval: 30.3-50.4) and 39.1 (34.2-63.0) months for panitumumab plus 5-FU/LV maintenance and 24.1 (17.7-33.0) and 28.9 (21.0-32.0) months for 5-FU/LV \ub1 bevacizumab maintenance in PRIME and PEAK, respectively. Median PFS from randomisation was 16.6 (11.3-23.6) and 15.4 (11.6-18.4) months for panitumumab plus 5-FU/LV maintenance and 12.6 (9.4-16.2) and 13.1 (9.5-16.6) months for 5-FU/LV \ub1 bevacizumab maintenance in PRIME and PEAK, respectively. From oxaliplatin discontinuation, median OS was 33.9 (24.7-42.8) and 33.5 (24.5-54.9) months for panitumumab plus 5-FU/LV maintenance and 16.4 (12.4-24.1) and 23.3 (15.7-26.3) months for 5-FU/LV \ub1 bevacizumab maintenance in PRIME and PEAK, respectively; PFS was 11.7 (7.8-19.2) and 9.7 (5.8-14.8) months and 7.1 (5.6-10.2) and 7.0 (3.9-10.6) months, respectively. The most frequently reported adverse events were rash, fatigue and diarrhoea. Maintenance of panitumumab plus 5-FU/LV after oxaliplatin discontinuation was well tolerated and may be an acceptable treatment paradigm for patients demonstrating a good response to first-line treatment. Prospective studies are warranted

New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel

Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cell

The Science of Marine Protected Areas (3rd edition, Mediterranean)

The main purpose of the booklet is to present the latest scientific information about the effects of MPAs in the Mediterranean in order to inform current management dialogues. This is particularly relevant given the increasing legislative frameworks and political initiatives to implement networks of MPAs in countries across the Mediterranean Sea. Importantly, this Edition does much more than simply tailor the earlier content for the Mediterranean region. The edition update the basic content of the booklet, drawing on the wealth of new published scientific literature, highlighting case studies from the Mediterranean Sea

Brief review on systematic hypothermia for the protection of central nervous system during aortic arch surgery: a double-sword tool?

Antegrade selective cerebral perfusion in conjunction with hypothermia attenuate postoperative neurological injury, which in turn still remains the main cause of mortality and morbidity following aortic arch surgery. Hypothermic circulatory arrest however could be a useful tool during arch surgery, surgery for chronic thromboembolic disease, air on the arterial line during CPB, during cavotomy for extraction of renal cell carcinoma with level IV extension, or when dealing with difficult trauma to the SVC or IVC. Cerebral protective effects with hypothermic procedures including inhibition of neuron excitation, and discharge of excitable amino acids, and thereby, prevention of an increase in intercellular calcium ions, hyperoxidation of lipids in cell membranes, and free radical production

Totally biological composite aortic stentless valved conduit for aortic root replacement: 10-year experience

<p>Abstract</p> <p>Objectives</p> <p>To retrospectively analyze the clinical outcome of a totally biological composite stentless aortic valved conduit (No-React^®BioConduit) implanted using the Bentall procedure over ten years in a single centre.</p> <p>Methods</p> <p>Between 27/10/99 and 19/01/08, the No-React^®BioConduit composite graft was implanted in 67 patients. Data on these patients were collected from the in-hospital database, from patient notes and from questionnaires. A cohort of patients had 2D-echocardiogram with an average of 4.3 ± 0.45 years post-operatively to evaluate valve function, calcification, and the diameter of the conduit.</p> <p>Results</p> <p>Implantation in 67 patients represented a follow-up of 371.3 patient-year. Males were 60% of the operated population, with a mean age of 67.9 ± 1.3 years (range 34.1-83.8 years), 21 of them below the age of 65. After a mean follow-up of 7.1 ± 0.3 years (range of 2.2-10.5 years), more than 50% of the survivors were in NYHA I/II and more than 60% of the survivors were angina-free (CCS 0). The overall 10-year survival following replacement of the aortic valve and root was 51%. During this period, 88% of patients were free from valved-conduit related complications leading to mortality. Post-operative echocardiography studies showed no evidence of stenosis, dilatation, calcification or thrombosis. Importantly, during the 10-year follow-up period no failures of the valved conduit were reported, suggesting that the tissue of the conduit does not structurally change (histology of one explant showed normal cusp and conduit).</p> <p>Conclusions</p> <p>The No-React^®BioConduit composite stentless aortic valved conduit provides excellent long-term clinical results for aortic root replacement with few prosthesis-related complications in the first post-operative decade.</p

Cyclin H expression is increased in GIST with very-high risk of malignancy

<p>Abstract</p> <p>Background</p> <p>Risk estimation of gastrointestinal stromal tumours (GIST) is based on tumour size and mitotic rate according to the National Institutes of Health consensus classification. The indication for adjuvant treatment of patients with high risk GIST after R₀resection with small molecule inhibitors is still a controversial issue, since these patients represent a highly heterogeneous population. Therefore, additional prognostic indicators are needed. Here, we evaluated the prognostic value of cyclin H expression in GIST.</p> <p>Methods</p> <p>In order to identify prognostic factors of GIST we evaluated a single centre cohort of ninety-five GIST patients. First, GISTs were classified with regard to tumour size, mitotic rate and localisation according to the NIH consensus and to three additional suggested risk classifications. Second, Cyclin H expression was analysed.</p> <p>Results</p> <p>Of ninety-five patients with GIST (53 female/42 male; median age: 66.78a; range 17-94a) risk classification revealed: 42% high risk, 20% intermediate risk, 23% low risk and 15% very low risk GIST. In patients with high risk GIST, the expression of cyclin H was highly predictive for reduced disease-specific survival (p = 0.038). A combination of cyclin H expression level and high risk classification yielded the strongest prognostic indicator for disease-specific and disease-free survival (p ≤ 0.001). Moreover, in patients with tumour recurrence and/or metastases, cyclin H positivity was significantly associated with reduced disease-specific survival (p = 0.016) regardless of risk-classification.</p> <p>Conclusion</p> <p>Our data suggest that, in addition to high risk classification, cyclin H expression might be an indicator for "very-high risk" GIST.</p