Triplet chemotherapy with or without bevacizumab as first line treatment for metastatic colorectal cancer: An AGEO multicenter real-world study.

BACKGROUND: Prior trials validated triplet chemotherapy (Tri-CT) with bevacizumab as first line treatment for metastatic colorectal cancer (mCRC) but real-world data are scarce and practices remain heterogeneous. AIMS: To evaluate Tri-CT +/- bevacizumab efficacy and safety, and to identify factors influencing treatment decisions. METHODS: The COLOTRIP retrospective study enrolled mCRC patients treated from 2014 to 2019 in 14 French centers. RESULTS: Of 299 patients (81% PS 0-1, 58% RAS-mutated and 19% BRAF-mutated), 51% received Tri-CT and 49% Tri-CT + bevacizumab. Metastatic disease was classified as resectable (6.5%), potentially resectable (40%), and unresectable (54%). Bevacizumab use was associated with primary tumor location, mutational status and number of metastases. Median overall survival was 33.5 months in the Tri-CT group and 23.9 months in the Tri-CT + bevacizumab group, with median progression-free survival being 14.5 and 11.4 months. After adjusting for initial characteristics, no difference in survival was noted. Around 30% of patients experienced grade ≥3 adverse events. CONCLUSIONS: This study highlights several factors influencing Tri-CT use +/- bevacizumab decision and confirms the real-world good oncological outcomes and tolerability of these regimens in mCRC patients. Our results suggest that Tri-CT alone may by an appropriate option for specific subgroups of patients.

Feasibility study of a Great Lakes bioenergy system.

A bioenergy production and delivery system built around the Great Lakes St. Lawrence Seaway (GLSLS) transportation corridor was assessed for its ability to mitigate energy security and climate change risks. The land area within 100 km of the GLSLS and associated railway lines was estimated to be capable of producing at least 30 Mt(dry) yr(-1) of lignocellulosic biomass with minimal adverse impacts on food and fibre production. This was estimated to be sufficient to displace all of the coal-fired electricity in Ontario plus more than 620 million L of green diesel (equivalent to 5.3% of diesel consumption in GLSLS provinces). Lifecycle greenhouse gas emissions were 88% and 76% lower than coal-fired power and conventional diesel, respectively. Production costs of $120 MWh(-1) for power and up to $30 GJ(-1) ($1.1 L(-1)) for green diesel were higher than current market prices, but a value for low-carbon energy would narrow the price differential.

Examination of sludge accumulation rates and sludge characteristics for a decentralized community wastewater treatment systems with individual primary clarifier tanks located in Wardsville (Ontario, Canada).

In conventional septic systems, settling and partial treatment via anaerobic digestion occurs in the septic tank. One of the byproducts of solids separation in the septic tank is a semi-liquid material known as septage, which must be periodically pumped out. Septage includes the liquid portion within the tank, as well as the sludge that settles at the bottom of the tank and the scum that floats to the surface of the liquid layer. A number of factors can influence septage characteristics, as well as the sludge and scum accumulation rates within the tank. This paper presents the results of a 2007 field sampling study conducted in Wardsville (Ontario, Canada). The field study examined 29 individual residential two-chamber septic tanks in a community serviced by a decentralized wastewater treatment system in operation for approximately 7 years without septage removal. The field investigation provided a comprehensive data set that allowed for statistical analysis of the data to assess the more critical factors influencing solids accumulation rates within each of the clarifier chambers. With this data, a number of predictive models were developed using water usage data for each residence as an explanatory variable.

Factorial analysis of trihalomethanes formation in drinking water.

Disinfection of drinking water reduces pathogenic infection, but may pose risks to human health through the formation of disinfection byproducts. The effects of different factors on the formation of trihalomethanes were investigated using a statistically designed experimental program, and a predictive model for trihalomethanes formation was developed. Synthetic water samples with different factor levels were produced, and trihalomethanes concentrations were measured. A replicated fractional factorial design with center points was performed, and significant factors were identified through statistical analysis. A second-order trihalomethanes formation model was developed from 92 experiments, and the statistical adequacy was assessed through appropriate diagnostics. This model was validated using additional data from the Drinking Water Surveillance Program database and was applied to the Smiths Falls water supply system in Ontario, Canada. The model predictions were correlated strongly to the measured trihalomethanes, with correlations of 0.95 and 0.91, respectively. The resulting model can assist in analyzing risk-cost tradeoffs in the design and operation of water supply systems.

Production of bio-synthetic natural gas in Canada.

Large-scale production of renewable synthetic natural gas from biomass (bioSNG) in Canada was assessed for its ability to mitigate energy security and climate change risks. The land area within 100 km of Canada's network of natural gas pipelines was estimated to be capable of producing 67-210 Mt of dry lignocellulosic biomass per year with minimal adverse impacts on food and fiber production. Biomass gasification and subsequent methanation and upgrading were estimated to yield 16,000-61,000 Mm(3) of pipeline-quality gas (equivalent to 16-63% of Canada's current gas use). Life-cycle greenhouse gas emissions of bioSNG-based electricity were calculated to be only 8.2-10% of the emissions from coal-fired power. Although predicted production costs ($17-21 GJ(-1)) were much higher than current energy prices, a value for low-carbon energy would narrow the price differential. A bioSNG sector could infuse Canada's rural economy with $41-130 billion of investments and create 410,000-1,300,000 jobs while developing a nation-wide low-carbon energy system.

Investigating effects of bromide ions on trihalomethanes and developing model for predicting bromodichloromethane in drinking water.

Chlorination for drinking water can form brominated trihalomethanes (THMs) in the presence of bromide ions. Recent studies have reported that bromodichloromethane (BDCM) has a stronger association with stillbirths and neural tube defects than other THMs species. In this paper, the results of an experimental investigation into the factors forming THMs in the presence of bromide ions are presented. The experiments were conducted using synthetic water samples with different characteristics (e.g., pH, temperature, dissolve organic content). Different combinations of these characteristics were considered in the experimental program. The results showed that increased bromide ion concentrations led to increases in the formation of total THMs, with higher BDCM and dibromochloromethane (DBCM), and lower chloroform formation. By increasing the pH from 6 to 8.5, increased chloroform and decreased BDCM and DBCM formation were observed. Higher bromide ions to chlorine ratios increased BDCM and DBCM and decreased chloroform formation, while higher temperatures increased BDCM, DBCM and chloroform formation. In most cases, bromoform (CHBr(3)) concentrations were found to be below the detection limit. Significant factors influencing BDCM formation were identified using a statistical analysis. A model for BDCM formation was estimated from 44 experiments and statistical adequacy was assessed using appropriate diagnostics, including residual plots and an R(2) of 0.97. The model was validated using external data from 17 water supply systems in Newfoundland, Canada. The predictive performance of the model was found to be excellent, and the resulting model could be used to predict BDCM formation in drinking water and to perform risk-cost balance analyses for best management practices.

Models for predicting disinfection byproduct (DBP) formation in drinking waters: a chronological review.

Disinfection for the supply of safe drinking water forms a variety of known and unknown byproducts through reactions between the disinfectants and natural organic matter. Chronic exposure to disinfection byproducts through the ingestion of drinking water, inhalation and dermal contact during regular indoor activities (e.g., showering, bathing, cooking) may pose cancer and non-cancer risks to human health. Since their discovery in drinking water in 1974, numerous studies have presented models to predict DBP formation in drinking water. To date, more than 48 scientific publications have reported 118 models to predict DBP formation in drinking waters. These models were developed through laboratory and field-scale experiments using raw, pretreated and synthetic waters. This paper aims to review DBP predictive models, analyze the model variables, assess the model advantages and limitations, and to determine their applicability to different water supply systems. The paper identifies the current challenges and future research needs to better control DBP formation. Finally, important directions for future research are recommended to protect human health and to follow the best management practices.

Uncertainty characterization approaches for risk assessment of DBPs in drinking water: a review.

The management of risk from disinfection by-products (DBPs) in drinking water has become a critical issue over the last three decades. The areas of concern for risk management studies include (i) human health risk from DBPs, (ii) disinfection performance, (iii) technical feasibility (maintenance, management and operation) of treatment and disinfection approaches, and (iv) cost. Human health risk assessment is typically considered to be the most important phase of the risk-based decision-making or risk management studies. The factors associated with health risk assessment and other attributes are generally prone to considerable uncertainty. Probabilistic and non-probabilistic approaches have both been employed to characterize uncertainties associated with risk assessment. The probabilistic approaches include sampling-based methods (typically Monte Carlo simulation and stratified sampling) and asymptotic (approximate) reliability analysis (first- and second-order reliability methods). Non-probabilistic approaches include interval analysis, fuzzy set theory and possibility theory. However, it is generally accepted that no single method is suitable for the entire spectrum of problems encountered in uncertainty analyses for risk assessment. Each method has its own set of advantages and limitations. In this paper, the feasibility and limitations of different uncertainty analysis approaches are outlined for risk management studies of drinking water supply systems. The findings assist in the selection of suitable approaches for uncertainty analysis in risk management studies associated with DBPs and human health risk.

Benzene vapor treatment using a two-phase partitioning bioscrubber: an improved steady-state protocol to enhance long-term operation.

The performance and stability of a two-phase partitioning bioscrubber (TPPB) containing 33% (vol.) n-hexadecane as an immiscible phase was investigated during 30 days of continuous gaseous benzene treatment. Elimination capacities of 141 +/- 12 g/m(3) h were achieved by Achromobacter xylosoxidans Y234 while maintaining >99% removal throughout. A new steady-state operating strategy that limits excessive biomass production by directing substrate consumption to maintenance energy has eliminated the requirement for frequent exchange of liquid contents. Simplifying the operating protocols in this manner has dramatically reduced material costs and rendered the TPPB operational requirements as more comparable (in terms of frequency of required operator inputs) with other vapor-phase bioreactors. The practicality of the proposed simplification to the operating protocol was confirmed by demonstrating that intermediate metabolites were not accumulating in the TPPB, inorganic nutrient requirements were readily predictable, and that high culture viability could be sustained for prolonged cell retention times (30 days).

Direct estimation of the oxygen requirements of Achromobacter xylosoxidans for aerobic degradation of monoaromatic hydrocarbons (BTEX) in a bioscrubber.

The O2 requirements for biomass production and supplying maintenance energy demands during the degradation of both benzene and ethylbenzene by Achromobacter xylosoxidans Y234 were measured using a newly proposed technique involving a bioscrubber. Using this approach, relevant microbial parameter estimates were directly and simultaneously obtained via linear regression of pseudo steady-state data. For benzene and ethylbenzene, the biomass yield on O2, Y(X/O2), was estimated on a cell dry weight (CDW) basis as 1.96 +/- 0.25 mg CDW mgO2(-1) and 0.98 +/- 0.17 mg CDW mgO2(-1), while the specific rate of O2 consumption for maintenance, m(O2), was estimated as 0.041 +/- 0.008 mgO(2) mg CDW(-1) h(-1) and 0.053 +/- 0.022 mgO(2) mg CDW(-1) h(-1), respectively.

Transient performance of a two-phase partitioning bioscrubber treating a benzene-contaminated gas stream.

The dynamic performance of a prototype, two-phase partitioning bioscrubber in response to fluctuating benzene waste gas feeds has been characterized through a series of spike, step, and shutdown-restart experiments. From stable operation at a nominal loading capacity of 62 +/- 6 g/(m3 h) and removal efficiencies of over 99%, the bioscrubber was subjected to influent benzene concentration step changes and spikes as high as 10- and 20-fold, respectively. The bioscrubber responded rapidly and effectively to all feed concentration spikes and steps, as well as to step changes in the feed flow rate, maintaining nearly undisturbed performance. Although benzene absorption by the two liquid phases was found to dominate the early stages of each transient, Achromobacter xylosoxidans Y234 responded quickly to prolonged disturbances, readily consuming most of the excess absorbed substrate. The results demonstrate that the two-phase partitioning bioscrubber can rapidly acclimate to and recover from fluctuations, ensuring that stable performance can be maintained both during and aftertransients. The presence of n-hexadecane promotes benzene capture in the two-phase system by increasing the absorption driving force, an important characteristic during high intermittent loadings. Rapid recovery from two different shutdown scenarios further demonstrates the practical potential of the two-phase partitioning bioscrubber as a high-performance biotechnology alternative for the treatment of toxic waste gases.

A restructured framework for modeling oxygen transfer in two-phase partitioning bioreactors.

This communication proposes a mechanistic modification to a recently published method for analyzing oxygen mass transfer in two-phase partitioning bioreactors (Nielsen et al., 2003), and corrects an oversight in that paper. The newly proposed modification replaces the earlier empirical approach, which treated the two liquid phases as a single, homogeneous liquid phase, with a two-phase mass transfer model of greater fundamental rigor. Additionally, newly developed empirical models are presented that predict the mass transfer coefficient of oxygen absorption in both aqueous medium and an organic phase (n-hexadecane) as a function of bioreactor operating conditions. Experimental values and theoretical predictions of mass transfer coefficients in two-phase dispersions, k(L)a(TP), are compared. The revised approach more clearly demonstrates the potential for oxygen mass transfer enhancement by organic phase addition, one of the motivations for employing a distinct second phase in a partitioning bioreactor.

Quantifying maintenance requirements from the steady-state operation of a two-phase partitioning bioscrubber.

An innovative method for directly and explicitly quantifying the maintenance energy requirements of pure cultures growing on volatile organic compound (VOC) substrates in a two-phase partitioning bioscrubber is described. Direct evidence of maintenance energy requirements of Achromobacter xylosoxidans Y234 is provided both through observed reductions in the macroscopic biomass-to-substrate yield with decreasing specific growth rates, but more remarkably through achievement of steady-state operation. The data conclusively show that maintenance activities do occur in the two-phase partitioning bioscrubber and clearly illustrate the importance of this phenomenon to the operation of this process, and similar bioreactor systems. While benzene was selected as the principal, sole substrate of interest in this study, ethylbenzene degradation experiments were also subsequently performed to illustrate and confirm the general applicability of the proposed technique, as well as the potential capabilities of the two-phase partitioning bioscrubber for the continuous treatment of waste gases containing various VOCs. The proposed method has been shown to generate maintenance energy estimates that are consistent with those obtained while employing more widely recognized estimation strategies, further validating its capabilities. The proposed steady-state mode also offers key operational advantages in terms of decreased disposal requirements in two-phase partitioning bioscrubbers. (c) 2005 Wiley Periodicals, Inc.

A novel method of simulating oxygen mass transfer in two-phase partitioning bioreactors.

An empirical correlation, based on conventional forms, has been developed to represent the oxygen mass transfer coefficient as a function of operating conditions and organic fraction in two-phase, aqueous-organic dispersions. Such dispersions are characteristic of two-phase partitioning bioreactors, which have found increasing application for the biodegradation of toxic substrates. In this work, a critical distinction is made between the oxygen mass transfer coefficient, k(L)a, and the oxygen mass transfer rate. With an increasing organic fraction, the mass transfer coefficient decreases, whereas the oxygen transfer rate is predicted to increase to an optimal value. Use of the correlation assumes that the two-phase dispersion behaves as a single homogeneous phase with physical properties equivalent to the weighted volume-averaged values of the phases. The addition of a second, immiscible liquid phase with a high solubility of oxygen to an aqueous medium increases the oxygen solubility of the system. It is the increase in oxygen solubility that provides the potential for oxygen mass transfer rate enhancement. For the case studied in which n-hexadecane is selected as the second liquid phase, additions of up to 33% organic volume lead to significant increases in oxygen mass transfer rate, with an optimal increase of 58.5% predicted using a 27% organic phase volume. For this system, the predicted oxygen mass transfer enhancements due to organic-phase addition are found to be insensitive to the other operating variables, suggesting that organic-phase addition is always a viable option for oxygen mass transfer rate enhancement.

Dynamic modeling and optimal fed-batch feeding strategies for a two-phase partitioning bioreactor.

A dynamic model for the degradation of phenol in a two-phase partitioning bioreactor has been developed based on mechanistic balances around the bioreactor. The key process characteristics including substrate transfer between the organic and aqueous phases, substrate inhibition, oxygen limitation, and cell entrainment were incorporated into the model. The model predictions were validated against existing experimental data obtained for a 2-L bioreactor, and good correlation was observed for the time frames of the simulations, as well as for trends in cell and substrate concentrations. Optimal fed-batch, phenol feeding strategies were then developed based on two approaches: (1) maximization of phenol consumption in a fixed time interval and (2) consumption of a fixed amount of phenol in minimal time. The optimal feeding policies, determined using the Iterative Dynamic Programming algorithm, provided substantial improvements in the amount of phenol consumed when compared to a typical experimental heuristic approach. For example, 45.73 g of phenol was predicted to be consumed in 50 h (not including lag phase) using the optimal feeding profile compared to 10.26 g of phenol consumed in the simulated experimental approach. Oxygen limitation was predicted to be a recurring operational challenge in the partitioning bioreactor, and had a strong impact on the optimization results.

Experimental investigation and modeling of oscillatory behavior in the continuous culture of Zymomonas mobilis.

The mechanism causing oscillation in continuous ethanol fermentation by Zymomonas mobilis under certain operating conditions has been examined. A new term, "dynamic specific growth rate," which considers inhibitory culture conditions in the recent past affecting subsequent cell behavior, is proposed in this article. Based on this concept, a model was formulated to simulate the oscillatory behavior in continuous fermentation of Zymomonas mobilis. Forced oscillation fermentation experiments, in which exogenous ethanol was added at a controlled rate to generate oscillatory behavior, were performed in order to obtain estimates for the model parameters and to validate the proposed model. In addition, data from a literature example of a sustained oscillation were analyzed by means of the model, and excellent agreement between the model simulation and experimental results was obtained. The lag in the cells' response to a changing environment, i.e., ethanol concentration change rate experienced by the cells, was shown to be the major factor contributing to the oscillatory behavior in continuous fermentation of Zymomonas mobilis under certain operating conditions.

Mediastinal pancreatic pseudocyst.

Among previous cases of mediastinal pseudocyst requiring surgical decompression, all but one had been found at surgery to occupy a position both in the mediastinum and in the upper abdomen. In the present case, although preoperative ultrasound and CT scans suggested that the pseudocyst was straddling the diaphragm, an abdominal portion could not be found at surgery, and the pseudocyst was drained successfully through the diaphragm by a Roux-en-Y loop of jejunum. Because ultrasound and CT scan may not be able to determine the precise relationship of a mediastinal pseudocyst to the diaphragm and the availability of the lower portion of the pseudocyst for surgical decompression, an endoscopic retrograde cholangiopancreatography is strongly recommended as part of the preoperative evaluation.

Transcutaneous carbon dioxide monitoring.

We studied changes in transcutaneous PCO2 in healthy volunteers and patients to establish the accuracy and practicability of a new cutaneous capnometer (HP47201A). In 9 healthy volunteers, as many as 4 experiments each were performed during each laboratory session. After cutaneous electrode stabilization, a gas mixture of CO2 in O2 was rebreathed under "open-loop" conditions allowing a rapid progressive increase in alveolar PCO2. The electrode stabilized on the skin with a time constant of 2.87 +/- 0.72 min. During rebreathing, alveolar PCO2 increased 4.25 +/- 0.63mm Hg/min. The simultaneous rate of increase in transcutaneous PCO2 was 2.91 +/- 0.59 mm Hg of CO2/min. Electrode response was also studied during steady-state conditions after a step increase in alveolar PCO2 of 10 mm Hg more than the resting end-tidal PCO2. The time constant of the skin electrode's response under these conditions was 3.2 +/- 1.9 min. We compared the arterial PCO2 of 25 blood samples with simultaneous transcutaneous PCO2 measurements in hemodynamically and metabolically stable patients. The range of arterial PCO2 values varied between 24 and 98 mm Hg, and the electrode remained stable during each 12-h study. Observed values closely approximated arterial PCO2 measurements, with transcutaneous readings 4 mm Hg more than measured arterial values (r = 0.98). We conclude that the cutaneous capnometer accurately and consistently reflects arterial PCO2 and has delay and response characteristics that may allow its use in clinical monitoring of patients.