Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial.

BACKGROUND: For many years, first-line treatment for locally advanced or metastatic soft-tissue sarcoma has been doxorubicin. This study compared gemcitabine and docetaxel versus doxorubicin as first-line treatment for advanced or metastatic soft-tissue sarcoma. METHODS: The GeDDiS trial was a randomised controlled phase 3 trial done in 24 UK hospitals and one Swiss Group for Clinical Cancer Research (SAKK) hospital. Eligible patients had histologically confirmed locally advanced or metastatic soft-tissue sarcoma of Trojani grade 2 or 3, disease progression before enrolment, and no previous chemotherapy for sarcoma or previous doxorubicin for any cancer. Patients were randomly assigned 1:1 to receive six cycles of intravenous doxorubicin 75 mg/m(2) on day 1 every 3 weeks, or intravenous gemcitabine 675 mg/m(2) on days 1 and 8 and intravenous docetaxel 75 mg/m(2) on day 8 every 3 weeks. Treatment was assigned using a minimisation algorithm incorporating a random element. Randomisation was stratified by age (≤18 years vs >18 years) and histological subtype. The primary endpoint was the proportion of patients alive and progression free at 24 weeks in the intention-to-treat population. Adherence to treatment and toxicity were analysed in the safety population, consisting of all patients who received at least one dose of their randomised treatment. The trial was registered with the European Clinical Trials (EudraCT) database (no 2009-014907-29) and with the International Standard Randomised Controlled Trial registry (ISRCTN07742377), and is now closed to patient entry. FINDINGS: Between Dec 3, 2010, and Jan 20, 2014, 257 patients were enrolled and randomly assigned to the two treatment groups (129 to doxorubicin and 128 to gemcitabine and docetaxel). Median follow-up was 22 months (IQR 15·7-29·3). The proportion of patients alive and progression free at 24 weeks did not differ between those who received doxorubicin versus those who received gemcitabine and docetaxel (46·3% [95% CI 37·5-54·6] vs 46·4% [37·5-54·8]); median progression-free survival (23·3 weeks [95% CI 19·6-30·4] vs 23·7 weeks [18·1-20·0]; hazard ratio [HR] for progression-free survival 1·28, 95% CI 0·99-1·65, p=0·06). The most common grade 3 and 4 adverse events were neutropenia (32 [25%] of 128 patients who received doxorubicin and 25 [20%] of 126 patients who received gemcitabine and docetaxel), febrile neutropenia (26 [20%] and 15 [12%]), fatigue (eight [6%] and 17 [14%]), oral mucositis (18 [14%] and two [2%]), and pain (ten [8%] and 13 [10%]). The three most common serious adverse events, representing 111 (39%) of all 285 serious adverse events recorded, were febrile neutropenia (27 [17%] of 155 serious adverse events in patients who received doxorubicin and 15 [12%] of 130 serious adverse events in patients who received gemcitabine and docetaxel, fever (18 [12%] and 19 [15%]), and neutropenia (22 [14%] and ten [8%]). 154 (60%) of 257 patients died in the intention-to-treat population: 74 (57%) of 129 patients in the doxorubicin group and 80 (63%) of 128 in the gemcitabine and docetaxel group. No deaths were related to the treatment, but two deaths were due to a combination of disease progression and treatment. INTERPRETATION: Doxorubicin should remain the standard first-line treatment for most patients with advanced soft-tissue sarcoma. These results provide evidence for clinicians to consider with their patients when selecting first-line treatment for locally advanced or metastatic soft-tissue sarcoma. FUNDING: Cancer Research UK, Sarcoma UK, and Clinical Trial Unit Kantonsspital St Gallen

Sensors in the stream: the high-frequency wave of the present

New scientific understanding is catalysed by novel technologies that enhance measurement precision, resolution or type, and that provide new tools to test and develop theory. Over the last 50 years, technology has transformed the hydrologic sciences by enabling direct measurements of watershed fluxes (evapotranspiration, streamflow) at time scales and spatial extents aligned with variation in physical drivers. High frequency water quality measurements, increasingly obtained by in-situ water quality sensors, are extending that transformation. Widely available sensors for some physical (temperature) and chemical (conductivity, dissolved oxygen) attributes have become integral to aquatic science, and emerging sensors for nutrients, dissolved CO2, turbidity, algal pigments, and dissolved organic matter are now enabling observations of watersheds and streams at timescales commensurate with their fundamental hydrological, energetic, elemental, and biological drivers. Here we synthesize insights from emerging technologies across a suite of applications, and envision future advances, enabled by sensors, in our ability to understand, predict, and restore watershed and stream systems

Resolved observations at 31 GHz of spinning dust emissivity variations in ρ\rho Oph

The $\rho$ Oph molecular cloud is one of the best examples of spinning dust emission, first detected by the Cosmic Background Imager (CBI). Here we present 4.5 arcmin observations with CBI 2 that confirm 31 GHz emission from $\rho$ Oph W, the PDR exposed to B-type star HD 147889, and highlight the absence of signal from S1, the brightest IR nebula in the complex. In order to quantify an association with dust-related emission mechanisms, we calculated correlations at different angular resolutions between the 31 GHz map and proxies for the column density of IR emitters, dust radiance and optical depth templates. We found that the 31 GHz emission correlates best with the PAH column density tracers, while the correlation with the dust radiance improves when considering emission that is more extended (from the shorter baselines), suggesting that the angular resolution of the observations affects the correlation results. A proxy for the spinning dust emissivity reveals large variations within the complex, with a dynamic range of 25 at 3$\sigma$ and a variation by a factor of at least 23, at 3$\sigma$, between the peak in $\rho$ Oph W and the location of S1, which means that environmental factors are responsible for boosting spinning dust emissivities locally.Comment: 12 pages, 7 figures, 8 tables. Accepted for publication in MNRA

Resolved spectral variations of the centimetre-wavelength continuum from the ρ Oph W photodissociation region

Centimetre-wavelength radio continuum emission in excess of free–free, synchrotron, and Rayleigh–Jeans dust emission (excess microwave emission, EME), and often called ‘anomalous microwave emission’, is bright in molecular cloud regions exposed to UV radiation, i.e. in photodissociation regions (PDRs). The EME correlates with infrared (IR) dust emission on degree angular scales. Resolved observations of well-studied PDRs are needed to compare the spectral variations of the cm-continuum with tracers of physical conditions and of the dust grain population. The EME is particularly bright in the regions of the ρ Ophiuchi molecular cloud (ρ Oph) that surround the earliest type star in the complex, HD 147889, where the peak signal stems from the filament known as the ρ Oph W PDR. Here, we report on Australia Telescope Compact Array observations of ρ Oph W that resolve the width of the filament. We recover extended emission using a variant of non-parametric image synthesis performed in the sky plane. The multifrequency 17–39 GHz mosaics reveal spectral variations in the centimetre-wavelength continuum. At ∼30 arcsec resolutions, the 17–20 GHz intensities tightly follow the mid-IR, $I_\mathrm{cm} \propto I(8\, \mu$m), despite the breakdown of this correlation on larger scales. However, while the 33–39 GHz filament is parallel to Infrared Array Camera 8 μm, it is offset by 15–20 arcsec towards the UV source. Such morphological differences in frequency reflect spectral variations, which we quantify spectroscopically as a sharp and steepening high-frequency cutoff, interpreted in terms of the spinning dust emission mechanism as a minimum grain size $a_\mathrm{cutoff} \sim 6 \pm 1\,$Å that increases deeper into the PDR

Genetic regulatory signatures underlying islet gene expression and type 2 diabetes

The majority of genetic variants associated with type 2 diabetes (T2D) are located outside of genes in noncoding regions that may regulate gene expression in disease-relevant tissues, like pancreatic islets. Here, we present the largest integrated analysis to date of high-resolution, high-throughput human islet molecular profiling data to characterize the genome (DNA), epigenome (DNA packaging), and transcriptome (gene expression). We find that T2D genetic variants are enriched in regions of the genome where transcription Regulatory Factor X (RFX) is predicted to bind in an islet-specific manner. Genetic variants that increase T2D risk are predicted to disrupt RFX binding, providing a molecular mechanism to explain how the genome can influence the epigenome, modulating gene expression and ultimately T2D risk

Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma

BACKGROUND: We wished to evaluate the clinical response following ATP-Tumor Chemosensitivity Assay (ATP-TCA) directed salvage chemotherapy in a series of UK patients with advanced ovarian cancer. The results are compared with that of a similar assay used in a different country in terms of evaluability and clinical endpoints. METHODS: From November 1998 to November 2001, 46 patients with pre-treated, advanced ovarian cancer were given a total of 56 courses of chemotherapy based on in-vitro ATP-TCA responses obtained from fresh tumor samples or ascites. Forty-four patients were evaluable for results. Of these, 18 patients had clinically platinum resistant disease (relapse < 6 months after first course of chemotherapy). There was evidence of cisplatin resistance in 31 patients from their first ATP-TCA. Response to treatment was assessed by radiology, clinical assessment and tumor marker level (CA 125). RESULTS: The overall response rate was 59% (33/56) per course of chemotherapy, including 12 complete responses, 21 partial responses, 6 with stable disease, and 15 with progressive disease. Two patients were not evaluable for response having received just one cycle of chemotherapy: if these were excluded the response rate is 61%. Fifteen patients are still alive. Median progression free survival (PFS) was 6.6 months per course of chemotherapy; median overall survival (OAS) for each patient following the start of TCA-directed therapy was 10.4 months (95% confidence interval 7.9-12.8 months). CONCLUSION: The results show similar response rates to previous studies using ATP-TCA directed therapy in recurrent ovarian cancer. The assay shows high evaluability and this study adds weight to the reproducibility of results from different centre

Correlation of solute partitioning into isooctane from water and from the gas phase based on updated Abraham equations

This article discusses the correlation of solute partitioning into isooctane from water and from the gas phase based on updated Abraham equations