Carbon sources of Antarctic nematodes as revealed by natural carbon isotope ratios and a pulse-chase experiment

δ13C of nematode communities in 27 sites was analyzed, spanning a large depth range (from 130 to 2,021 m) in five Antarctic regions, and compared to isotopic signatures of sediment organic matter. Sediment organic matter δ13C ranged from −24.4 to −21.9‰ without significant differences between regions, substrate types or depths. Nematode δ13C showed a larger range, from −34.6 to −19.3‰, and was more depleted than sediment organic matter typically by 1‰ and by up to 3‰ in silty substrata. These, and the isotopically heavy meiofauna at some stations, suggest substantial selectivity of some meiofauna for specific components of the sedimenting plankton. However, 13C-depletion in lipids and a potential contribution of chemoautotrophic carbon in the diet of the abundant genus Sabatieria may confound this interpretation. Carbon sources for Antarctic nematodes were also explored by means of an experiment in which the fate of a fresh pulse of labile carbon to the benthos was followed. This organic carbon was remineralized at a rate (11–20 mg C m−2 day−1) comparable to mineralization rates in continental slope sediments. There was no lag between sedimentation and mineralization; uptake by nematodes, however, did show such a lag. Nematodes contributed negligibly to benthic carbon mineralization

Combination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer

PURPOSE: To assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC). METHODS:Thirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers. RESULTS:Adequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by (18)FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively).CONCLUSIONS:The LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active

Prognostic gene expression signature for high-grade serous ovarian cancer.

BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches

A combination of the immunohistochemical markers CK7 and SATB2 is highly sensitive and specific for distinguishing primary ovarian mucinous tumors from colorectal and appendiceal metastases

This study is supported by research funds from Cancer Research Society of Canada (19319). NSM is supported by the NSW Ministry of Health and UNSW Sydney under the NSW Health PhD Scholarship Program, and the Translational Cancer Research Network, a translational cancer research center program funded by the Cancer Institute NSW. The Gynaecological Oncology Biobank at Westmead was funded by Cancer Institute NSW (12/RIG/1–17 and 15/RIG/1–16) and the National Health and Medical Research Council of Australia (ID310670, ID628903). FM is funded by University of Pittsburgh School of Medicine Dean's Faculty Advancement Award. The HOPE study is funded by: US National Cancer Institute (K07-CA80668, P50-CA159981, R01CA095023), US Army Medical Research and Materiel Command (DAMD17–02–1–0669) and NIH/National Center for Research Resources/General Clinical Research Center (MO1- RR000056). KS is funded by the Swedish Cancer foundation. The Generations Study thank Breast Cancer Now, the Institute of Cancer Research and Ovarian Cancer Action for support and funding. The ICR acknowledge NHS funding to the NIHR Biomedical Research Centre. Tissue samples for GER were provided by the tissue bank of the National Center for Tumor Diseases (NCT, Heidelberg, Germany) in accordance with the regulations of the tissue bank and the approval of the ethics committee of the University of Heidelberg. The Health Science Alliance (HSA) Biobank acknowledges the UNSW Biorepository, UNSW Sydney, Australia. We thank Shuhong Liu, Young Ou, and Deon Richards for immunohistochemical stains, and Thomas Kryton, BFA, digital imaging specialist for Alberta Public Lab for creating the figures. We especially thank all the study participants, health care staff and data providers internationally who have made this research possible

The role of preoperative lymphoscintigraphy in surgery planning for sentinel lymph node biopsy in malignant melanoma

AIM: To evaluate four years of preoperative lymphoscintigraphy experience and the accuracy of sentinel lymph node biopsy in our institution in melanoma patients with various tumor thicknesses. An additional aim was to evaluate the recurrence rate related to pathohistological findings. - - - - - METHODS AND PATIENTS: During the period from February 2002 to November 2005, 201 patients underwent sentinel node biopsy. Lymphoscintigraphy for identification of sentinel nodes was performed four to six hours prior to operation of the patient. Sentinel lymph node biopsy using an intraoperative hand-held gamma probe was performed in all patients, together with wide local excision of biopsy wound or primary lesion (N=56). Immediate complete basin dissection was performed in patients with sentinel node metastases. In four patients delayed complete lymph node dissection was performed after definitive histopathologic examination of sentinel nodes. The accuracy of sentinel node biopsy was determined by comparing the intraoperative rates of sentinel node identification and the subsequent development of nodal metastases in regional nodal basins in patients with tumor-negative sentinel nodes and in those with tumorpositive sentinel nodes. - - - - - RESULTS: Using preoperative lymphoscintigraphy, we identified sentinel nodes in all but one of the 201 patients (99.0%), and in 248 nodal basins (1.2/patient) we observed 372 sentinel nodes (1.52 sentinels/basin; 1.8 sentinels/patient). The highest number of sentinel nodes was noticed in the groin of patients with melanoma on the lower extremities (1.5/patient), followed by the axilla (1.3/patient). Anomalous lymphatic drainage patterns were observed in 15.0% of all patients. The identification rate of sentinel nodes was 99.0% overall: 100% for the groin basins, and 98.0% for the axilla and head and neck basin. Forty-two patients (20.8%) had tumor-positive sentinel nodes. Ten patients (5.0%) had local or distant recurrences during a median follow-up of 23.1 months (range 2-46). The rate of false-negative lymphatic mapping and sentinel node biopsy as measured by nodal recurrence in patients with tumor-negative sentinel nodes was 1.3%. During the follow-up period, three of 201 patients died from other diseases and three patients died as the result of melanoma metastases, with a median follow-up of 13.5 months (range 12-22). - - - - - CONCLUSION: Preoperative lymphoscintigraphy is a sensitive, inexpensive and essential method for the identification of drainage basins, determination of the number and position of sentinel nodes and their location outside the usual nodal basins. Scintigraphic findings may lead to changes in surgical management due to the unpredictability of lymphatic drainage. The low incidence of regional disease recurrence in patients with tumor-negative sentinel nodes supports the use of preoperative lymphoscintigraphy and sentinel node biopsy as a safe and accurate procedure for staging the regional nodal basin in patients with malignant melanoma