Exploring the use of pegylated liposomal doxorubicin (Caelyx®) as pressurized intraperitoneal aerosol chemotherapy

Background: Peritoneal carcinomatosis is a common metastatic pattern in ovarian, gastric, colorectal, and appendiceal cancer; systemic chemotherapy is the current standard of care for peritoneal metastatic disease; however, in a subset of patients its beneficial effect remains questionable. More effective perioperative chemotherapy is needed. Materials and methods: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new treatment that applies chemotherapeutic drugs into the peritoneal cavity as an aerosol under pressure. It's a safe and feasible approach that improves local bioavailability of chemotherapeutic drugs as compared with conventional intraperitoneal chemotherapy. Till now the drugs used in PIPAC for the treatment of the peritoneal carcinomatosis (PC) are cisplatin, doxorubicin, and oxaliplatin; as of yet, there are no in vivo data comparing different drug formulations and dosage schedules of PIPAC. Pegylated liposomal doxorubicin 1.5 mg/sm was aerosolized in PIPAC procedures. Results: Pharmacokinetics analysis of 10 procedures performed with conventional doxorubicin solution at the dose of 1.5 mg/m2 were compared to 15 procedures with the same dose of pegylated liposomal doxorubicin (PLD). Significant differences between experimental groups were detected by one-way ANOVA followed by Bonferroni correction; a p value < 0.05 was considered statistically significant. A statistically different doxorubicin tissue concentration was observed for the doxorubicin solution compared to pegylated liposomal doxorubicin in the right parietal peritoneum and right diaphragm. In the Caelyx\uae series a mean tissue concentration of 1.27 \ub1 1.33 mg/g was reported, while in the second one we registered a mean concentration of 3.1 \ub1 3.7 mg/g. Conclusions: The delivery of nano-particles in PIPAC was feasible, but pegylated liposomal concentrations are lower than standard doxorubicin formulation. Probably mechanical and physical properties of pressurized aerosol chemotherapy might alter their stability and cause structural disintegration

Fate of conjugated natural and synthetic steroid estrogens in crude sewage and activated sludge batch studies

This document is the unedited author's version of a Submitted Work that was subsequently accepted for publication in Environmental Science & Technology, copyright © American Chemical Society after peer review. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/es801952h.Steroids are excreted from the human body in the conjugated form but are present in sewage influent and effluent as the free steroid, the major source of estrogenic activity observed in water courses. The fate of sulfate and glucuronide conjugated steroid estrogens was investigated in batch studies using activated sludge grown on synthetic sewage in a laboratory-scale Husmann simulation and crude sewage from the field. A clear distinction between the fate of sulfate and glucuronide conjugates was observed in both matrices, with sulfated conjugates proving more recalcitrant and glucuronide deconjugation preferential in crude sewage. For each conjugate, the free steroid was observed in the biotic samples. The degree of free steroid formation was dependent on the conjugate moiety, favoring the glucuronide. Subsequent degradation of the free steroid (and sorption to the activated sludge solid phase) was evaluated. Deconjugation followed the first order reaction rate with rate constants for 17α-ethinylestradiol 3-glucuronide, estriol 16α-glucuronide, and estrone 3-glucuronide determined as 0.32, 0.24, and 0.35 h respectively. The activated sludge solid retention time over the range of 3−9 days had 74 to 94% of sulfate conjugates remaining after 8 h. In contrast, a correlation between increasing temperature and decreasing 17α-ethinylestradiol 3-glucuronide concentrations in the activated sludge observed no conjugate present in the AS following 8 h at 22 °C Based on these batch studies and literature excretion profiles, a hypothesis is presented on which steroids and what form (glucuronide, sulfate, or free) will likely enter the sewage treatment plant.EPSR

How old is the Tasmanian cultural landscape? a test of landscape openness using quantitative land-cover reconstructions

Aim: To test competing hypotheses about the timing and extent of Holocene landscape opening using pollen-based quantitative land-cover estimates. Location: Dove Lake, Tasmanian Wilderness World Heritage Area, Australia. Methods: Fossil pollen data were incorporated into pollen dispersal models and corrected for differences in pollen productivity among key plant taxa. Mechanistic models (REVEALS-Regional Estimates of VEgetation Abundance from Large Sites) employing different models for pollen dispersal (Gaussian plume and Lagrangian stochastic models) were evaluated and applied in the Southern Hemisphere for the first time. Results: Validation of the REVEALS model with vegetation cover data suggests an overall better performance of the Lagrangian stochastic model. Regional land-cover estimates for forest and non-forest plant taxa show persistent landscape openness throughout the Holocene (average landscape openness similar to 50%). Gymnoschoenus sphaerocephalus, an indicator of moorland vegetation, shows higher values during the early Holocene (11.7-9 ka) and declines slightly through the mid-Holocene (9-4.5 ka) during a phase of partial landscape afforestation. Rain forest cover reduced (from similar to 40% to similar to 20%) during the period between 4.2-3.5 ka. Main conclusions: Pollen percentages severely under-represent landscape openness in western Tasmania and this bias has fostered an over-estimation of Holocene forest cover from pollen data. Treeless vegetation dominated Holocene landscapes of the Dove Lake area, allowing us to reject models of landscape evolution that invoke late-Holocene replacement of a rain forest-dominated landscape by moorland. Instead, we confirm a model of Late Pleistocene inheritance of open vegetation. Rapid forest decline occurred after c.4 ka, likely in response to regional moisture decline.Australian Research Council; AINSE AWARD [ALNGRA16024]; AINSE PGRA scholarship [12039]info:eu-repo/semantics/publishedVersio

Simultaneous determination of natural and synthetic steroid estrogens and their conjugates in aqueous matrices by liquid chromatography / mass spectrometry

An analytical method for the simultaneous determination of nine free and conjugated steroid estrogens was developed with application to environmental aqueous matrices. Solid phase extraction (SPE) was employed for isolation and concentration, with detection by liquid chromatography/mass spectrometry (LC/MS) using electrospray ionisation (ESI) in the negative mode. Method recoveries for various aqueous matrices (wastewater, lake and drinking water) were determined, recoveries proving to be sample dependent. When spiked at 50 ng/l concentrations in sewage influent, recoveries ranged from 62-89 % with relative standard deviations (RSD) < 8.1 %. In comparison, drinking water spiked at the same concentrations had recoveries between 82-100 % with an RSD < 5%. Ion suppression is a known phenomenon when using ESI; hence its impact on method recovery was elucidated for raw sewage. Both ion suppression from matrix interferences and the extraction procedure has bearing on the overall method recovery. Analysis of municipal raw sewage identified several of the analytes of interest at ng/l concentrations, estriol (E3) being the most abundant. Only one conjugate, estrone 3-sulphate (E1-3S) was observe

Standard (8 weeks) vs long (12 weeks) timing to minimally-invasive surgery after NeoAdjuvant Chemoradiotherapy for rectal cancer: A multicenter randomized controlled parallel group trial (TiMiSNAR)

Background: The optimal timing of surgery in relation to chemoradiation is still controversial. Retrospective analysis has demonstrated in the recent decades that the regression of adenocarcinoma can be slow and not complete until after several months. More recently, increasing pathologic Complete Response rates have been demonstrated to be correlated with longer time interval. The purpose of the trial is to demonstrate if delayed timing of surgery after neoadjuvant chemoradiotherapy actually affects pathologic Complete Response and reflects on disease-free survival and overall survival rather than standard timing. Methods: The trial is a multicenter, prospective, randomized controlled, unblinded, parallel-group trial comparing standard and delayed surgery after neoadjuvant chemoradiotherapy for the curative treatment of rectal cancer. Three-hundred and forty patients will be randomized on an equal basis to either robotic-assisted/standard laparoscopic rectal cancer surgery after 8 weeks or robotic-assisted/standard laparoscopic rectal cancer surgery after 12 weeks. Discussion: To date, it is well-know that pathologic Complete Response is associated with excellent prognosis and an overall survival of 90%. In the Lyon trial the rate of pCR or near pathologic Complete Response increased from 10.3 to 26% and in retrospective studies the increase rate was about 23-30%. These results may be explained on the relationship between radiation therapy and tumor regression: DNA damage occurs during irradiation, but cellular lysis occurs within the next weeks. Study results, whether confirmed that performing surgery after 12 weeks from neoadjuvant treatment is advantageous from a technical and oncological point of view, may change the current pathway of the treatment in those patient suffering from rectal cancer. Trial registration: ClinicalTrials.gov NCT3465982

Standard (8&#8201;weeks) vs long (12&#8201;weeks) timing to minimally-invasive surgery after NeoAdjuvant Chemoradiotherapy for rectal cancer: a multicenter randomized controlled parallel group trial (TiMiSNAR)

BACKGROUND: The optimal timing of surgery in relation to chemoradiation is still controversial. Retrospective analysis has demonstrated in the recent decades that the regression of adenocarcinoma can be slow and not complete until after several months. More recently, increasing pathologic Complete Response rates have been demonstrated to be correlated with longer time interval. The purpose of the trial is to demonstrate if delayed timing of surgery after neoadjuvant chemoradiotherapy actually affects pathologic Complete Response and reflects on disease-free survival and overall survival rather than standard timing. METHODS: The trial is a multicenter, prospective, randomized controlled, unblinded, parallel-group trial comparing standard and delayed surgery after neoadjuvant chemoradiotherapy for the curative treatment of rectal cancer. Three-hundred and forty patients will be randomized on an equal basis to either robotic-assisted/standard laparoscopic rectal cancer surgery after 8\u2009weeks or robotic-assisted/standard laparoscopic rectal cancer surgery after 12\u2009weeks. DISCUSSION: To date, it is well-know that pathologic Complete Response is associated with excellent prognosis and an overall survival of 90%. In the Lyon trial the rate of pCR or near pathologic Complete Response increased from 10.3 to 26% and in retrospective studies the increase rate was about 23-30%. These results may be explained on the relationship between radiation therapy and tumor regression: DNA damage occurs during irradiation, but cellular lysis occurs within the next weeks. Study results, whether confirmed that performing surgery after 12\u2009weeks from neoadjuvant treatment is advantageous from a technical and oncological point of view, may change the current pathway of the treatment in those patient suffering from rectal cancer

Biogeochemical responses to Holocene catchment-lake dynamics in the Tasmanian World Heritage Area, Australia

Environmental changes such as climate, land use, and fire activity affect terrestrial and aquatic ecosystems at multiple scales of space and time. Due to the nature of the interactions between terrestrial and aquatic dynamics, an integrated study using multiple proxies is critical for a better understanding of climate- and fire-driven impacts on environmental change. Here we present a synthesis of biological and geochemical data (pollen, spores, diatoms, micro X-ray fluorescence scanning, CN content, and stable isotopes) from Dove Lake, Tasmania, allowing us to disentangle long-term terrestrial-aquatic dynamics through the last 12 kyear. We found that aquatic dynamics at Dove Lake are tightly linked to vegetation shifts dictated by regional hydroclimatic variability in western Tasmania. A major shift in the diatom composition was detected at ca. 6 ka, and it was likely mediated by changes in regional terrestrial vegetation, charcoal, and iron accumulation. High rainforest abundance prior ca. 6 ka is linked to increased terrestrially derived organic matter delivery into the lake, higher dystrophy, anoxic bottom conditions, and lower light penetration depths. The shift to a landscape with a higher proportion of sclerophyll species following the intensification of El Niño-Southern Oscillation since ca. 6 ka corresponds to a decline in terrestrial organic matter input into Dove Lake, lower dystrophy levels, higher oxygen availability, and higher light availability for algae and littoral macrophytes. This record provides new insights on terrestrial-aquatic dynamics that could contribute to the conservation management plans in the Tasmanian World Heritage Area and in temperate high-altitude dystrophic systems elsewhere