text:
\section{INTRODUCTION}

Quantum degenerate gases of neutral atoms not only provide platforms for studying few- or many-body quantum systems~\cite{bloch2008many,bloch2012quantum}, but are also promising candidates for high-precision quantum metrology~\cite{peters2001high} and scalable quantum computation~\cite{trotzky2008time}. In the past few decades, tremendous experimental efforts have been devoted to achieving quantum degenerate gases with alkali~\cite{anderson1995observation}, alkaline-earth~\cite{stellmer2009bose}, and rare-earth metals~\cite{lu2011strongly}. Due to the existence of both fermionic and bosonic isotopes, a dilute gas of potassium is of particular interest for studying Bose-Fermi and Fermi-Fermi mixtures with tunable interactions. For instance, a mixture of $^{40}$K and $^{41}$K represents an ideal test bed for exploring impurity problems~\cite{schirotzek2009observation} and strongly interacting Bose-Fermi mixtures~\cite{wu2011strongly}.

A Bose-Einstein condensate (BEC) of $^{41}$K was first achieved by sympathetic cooling with $^{87}$Rb~\cite{modugno2001bose} in 2001. With a positive background scattering length, $^{41}$K could be directly evaporatively cooled into a Bose-Einstein condensate~\cite{falke2008potassium,kishimoto2009direct}. Moreover, $^{41}$K has proven to be an efficient coolant for $^{6}$Li and $^{40}$K, due to their favorable interspecies background scattering lengths~\cite{tiemann2009coupled,wu2011strongly}. For most alkali-metal atoms, the temperature can be easily reduced below the Doppler limit through Sisyphus cooling in optical molasses. However, the D2 excited hyperfine splitting of $^{41}$K is only 17 MHz, which is unresolved in comparison to its natural linewidth ($\Gamma$=6 MHz) (see Fig.~\ref{Fig1}). Therefore, conventional sub-Doppler cooling techniques are ineffective, making direct evaporative cooling of $^{41}$K an arduous task. In order to overcome this obstacle, different laser-cooling techniques have been developed in recent years~\cite{landini2011sub,mckay2011low}. For example, using the narrower 4s-5p transition of potassium, temperatures around 60 $\mu$K have been observed, equivalent to half of the D2 transition Doppler-cooling limit~\cite{mckay2011low}. However, additional laser sources at 405 nm and optical setup are required for the implementation of this scheme, increasing its experimental complexity. Recently, a so-called gray molasses sub-Doppler cooling technique has been intensively exploited; this method takes advantage of Sisyphus cooling~\cite{dalibard1989laser} and velocity selective coherent population trapping (VSCPT)~\cite{aspect1988laser} to cool atoms well below the Doppler limit. To date, gray molasses has become a well-established method for achieving sub-Doppler cooling of $^{6}$Li~\cite{sievers2015simultaneous,burchianti2014efficient}, $^{7}$Li~\cite{grier2013lambda}, $^{23}$Na~\cite{PhysRevA.93.023421}, $^{39}$K~\cite{nath2013quantum,salomon2014gray}, and $^{40}$K~\cite{sievers2015simultaneous,fernandes2012sub}; however, to the best of our knowledge, the application of the gray molasses technique to $^{41}$K has yet to be reported.

\begin{figure}[htbp]
\includegraphics[width=\columnwidth]{Fig1.pdf}
\caption{(Color Online) The energy-level diagram of $^{41}$K atoms. The natural linewidth of the D2-transition of $^{41}$K is 6 MHz, which is comparable to its excited hyperfine splitting. The laser detuning for gray molasses is defined as $\delta$ for both cooling and repumping transitions.}
\label{Fig1}
\end{figure}

In this letter, we report sub-Doppler cooling of $^{41}$K by using D1 gray molasses. This technique allows us to lower the initial temperature of $2.4\times10^9$ atoms from 418 $\mu$K to 42 $\mu$K. With the help of two-stage evaporative cooling, we are able to produce a $^{41}$K BEC of up to $1.2\times10^6$ atoms in optical dipole trap without a discernible thermal fraction. Furthermore, we investigate the collisional properties of $^{41}$K theoretically and experimentally.

\section{EXPERIMENTAL SET-UP}

The experimental setup for potassium consists of three main parts: a 2D MOT chamber, a 3D MOT chamber, and a science chamber (Fig.~\ref{Fig2}). The shadow region is to be used for double-species experiments in the future. The 2D MOT chamber is a 4.5 cm$\times$4.5 cm$\times$9.5 cm full-glass cell. A customized absorptive-type polarizer and full-reflecting mirror with a hole in the center are glued to the differential tube between the 2D and 3D MOT chambers. Fifteen pairs of coils are applied to transfer the atomic cloud over a distance of 54 cm to the UHV science chamber for better vacuum and optical access. The achieved vacuum pressure in the full-glass dodecagonal cell is $5\times10^{-12}$ mbar, which greatly increases the lifetime of the atoms.

\begin{figure}[htbp]
\includegraphics[width=\columnwidth]{Fig2.pdf}
\caption{(Color Online) Schematics of the vacuum assembly. The shadowing represents the vacuum manifold for future double-species experiments. In the inset, we zoom-in on the 2D MOT chamber to illustrate the optics for our longitudinal molasses. The red and blue optics represent the absorptive polarizer and mirror, respectively.}
\label{Fig2}
\end{figure}

\section{2D$+$ MOT \& 3D MOT}

Our experimental procedure starts with pre-cooling and confinement of a $^{41}$K atomic vapor using an enhanced 2D$+$ MOT. In a standard 2D$+$ MOT, a pair of counter-propagating beams are applied to the longitudinal molasses. The intensity ratio between incident and retro-reflected beams strongly affect the performance of the 2D$+$ MOT. Thanks to the polarizer and mirror inside the chamber (see Fig.~\ref{Fig2}), we can easily tune the intensity ratio by changing the polarization of an incident laser beam. In our case, the intensity ratio is about 4:1, which is optimized for atomic fluorescence signals. Moreover, an additional blue-detuned laser beam with a 1/e$^{2}$ radius of 0.6 mm is applied in the axial direction to push the atoms into the 3D MOT chamber. We find this push beam to be particularly efficient for achieving a further 50\% enhancement of the atomic flux beyond that allowed by the standard 2D$+$ MOT. Special care is required to slightly misalign the push beam with the captured atomic cloud in the 3D MOT. We also install two UV LED arrays around the 2D MOT chamber, which serve to increase the loading efficiency due to light-induced atom desorption~\cite{klempt2006ultraviolet}. In a 3D MOT chamber, the atomic clouds are captured by six independent laser beams with 1/e$^{2}$ radii of 9 mm. The total intensity of each beam is $I\simeq29\ I_{sat}$, where $I_{sat}$=1.75 mW/cm$^2$ is the saturation intensity of the $^{41}$K D2 transition. We can load more than $4\times10^9$ atoms at a temperature of 5.6 mK in 2 s.

\section{GRAY MOLASSES}

\begin{figure*}[htbp]
\includegraphics[width=\textwidth]{Fig3.pdf}
\caption{(Color Online) (a) Simplified layout of the optical setup for gray molasses. (b) Atom number (blue squares) and temperature (red circles) varying with the final cooling intensity of a D1 laser. The power ratio between the cooler and repumper is fixed at 5:1. Atom temperature scales linearly with the final cooling intensity from $1.5\ I_{sat}$ (42 $\mu$K) to $12\ I_{sat}$ (160 $\mu$K). (c) Atom number (blue squares) and temperature (red circles) as a function of the duration, $\tau_m$. The lowest temperature of 47 $\mu$K is observed with a 1/e cooling time constant of $\tau$=3.84 ms. (d) Atom number (blue squares) and temperature (red circles) as a function of the detuning, $\delta$. Gray Molasses is found to work best for $\delta\in[4\ \Gamma,6\ \Gamma]$.}
\label{Fig3}
\end{figure*}

Gray molasses makes use of both Sisyphus cooling and VSCPT, which is capable of cooling atoms near the single-photon recoil energy. It is composed of two frequencies, which are each blue-detuned by either the $^{41}$K D1 cooling transition $|F=2\rangle\rightarrow |F^\prime=2\rangle$ or the repumping transition $|F=1\rangle\rightarrow |F^\prime=2\rangle$. When the detunings of the two lasers fulfill the Raman condition, a set of long-lived dressed dark states are generated. Dark states and bright states vary throughout real space because of the polarization gradient created by the radiation field. The atoms that are initially in the bright states consume their kinetic energy by climbing the potential hill before being pumped back into dark states, whereas the atoms in dark states that are not sufficiently cold turn into bright states and reenter the cooling circles. This procedure terminates when the atoms in the dark states have a sufficiently long lifetime, leading to a narrow peak in the momentum distribution.

A simplified layout of the D1 laser setup employed for gray molasses is presented in Fig.~\ref{Fig3}(a). A commercial diode laser (Toptica: DL pro) provides the laser at 770 nm, which is locked to the D1 transition of $^{39}$K. The laser passes through a resonant electro-optical modulator (EOM: Qubig EO-K41L3) operating at 254 MHz for generation of the required repumper frequency. The laser beams of the D1 and D2 transitions are superimposed using a customized dichroic mirror before being injected into a tapered amplifier (New Focus: TA 7613-H). Two individual acoustic-optical modulators (AOMs) serve as fast switches, allowing us to rapidly change the output frequency for different cooling phases. With this scheme, the same optical setup is used for both D1 gray molasses and D2 MOT, greatly reducing the experimental complexity.

Before the gray molasses phase, a novel hybrid D1-D2 compressed-MOT (CMOT) technique is implemented to increase the density of the atomic cloud, in a similar manner to that described in G. Salomon's work in Ref~\cite{salomon2014gray}. Compared with a conventional CMOT, the D1 cooling transition $|F=2\rangle\rightarrow |F^\prime=2\rangle$ is used instead of the D2 cooling transition. During this stage, we shut off the input signal of the EOM immediately and ramp up the magnetic gradient from 13 G/cm to 21 G/cm over 10 ms. In order to suppress light-assisted collision, cooling (repumping) intensity is linearly reduced from $11.4\ I_{sat}$ ($1\ I_{sat}$) to $0.1\ I_{sat}$ ($0.5\ I_{sat}$) and detuning is increased from $3.6\ \Gamma$ (-$5.6\ \Gamma$) to $4.5\ \Gamma$ (-$8.4\ \Gamma$). During this process, the RMS radius of the cloud is greatly reduced, yielding an eightfold increase in the peak density. Meanwhile, atom temperature is lowered from 5.6 mK to 418 $\mu$K.

\begin{table*}[htbp]
\begin{tabular*}{\textwidth}{@{\extracolsep\fill}ccccccccccccc}
\toprule
Sequence & $\delta_{2c}$ & $I_{2c}$ & $\delta_{2r}$ & $I_{2r}$ & $\delta_{1c}$ & $I_{1c}$ & $\delta_{1r}$ & $I_{1r}$ & B(G/cm) & T($\mu$K) & N & $\rho$ \\\hline
Loading (2 s) & -8.9 & 11.5 & -5 & 17.5 & - & - & - & - & 13 & 5600 & $4\times10^9$ & $9\times10^{-10}$\\
D1-D2 CMOT (10 ms) & - & - & -5.6$\rightarrow$-8.4 & 1$\rightarrow$0.5 & 3.6$\rightarrow$4.5 & 11.4$\rightarrow$0.1 & - & - & 13$\rightarrow$21 & 418 & $2.6\times10^9$ & $9.4\times10^{-8}$\\
Molasses Holding (2 ms) & - & - & - & - & 5.3 & 12.5 & 5.3 & 2.5 & - & - & - & -\\
Molasses Ramping (15 ms) & - & - & - & - & 5.3 & 12.5$\rightarrow$1.5 & 5.3 & 2.5$\rightarrow$0.3 & - & 42 & $2.4\times10^9$ & $5.4\times10^{-6}$\\
\toprule
\end{tabular*}
\caption{Optimal experimental parameters before the optical pumping stage. The unit of $\delta$ is the natural linewidth of the D2 transition of $^{41}$K ($\Gamma$=6 MHz) and the unit of I is its saturation intensity ($I_{sat}$=1.75 mW/cm$^2$). The subscripts 1 and 2 refer to D1 and D2 transitions, while c and r refer to cooling and repumping, respectively. We also present the time sequence, magnetic field gradient B, temperature T, atom number N, and phase-space density $\rho$ at each stage.}
\label{tab.1}
\end{table*}

In the gray molasses stage, the D2 repumping laser and magnetic field are switched off while the input signal of the EOM is switched on. In the following analysis, we use the same global detuning, $\delta$, for both D1 cooling and repumping transitions to fulfill the Raman condition shown in Fig.~\ref{Fig1}. As the capture efficiency is strongly affected by the laser intensity~\cite{sievers2015simultaneous}, we set the laser power to its maximum at the beginning of gray molasses phase, yielding a temperature of 160 $\mu$K. With an initial atom number of $2.6\times10^9$ in the CMOT, a maximum of $2.4\times10^9$ atoms can be captured by the gray molasses, corresponding to a capture efficiency of 92\%. We observe a further cooling of atoms when the laser intensity is ramped down to a lower value. Moreover, the lowered intensity is still capable of capturing almost all of the atoms in the gray molasses. Thus, we first measure the atom number and temperature of gray molasses by varying the final the D1 laser intensity. The loading time is fixed at 2 ms as gray molasses reaches its maximum capture rate, and then the laser intensity is linearly ramped down over the following 15 ms. The cooling/repumping intensity ratio is fixed at a constant ($\sim 5:1$) and the global detuning, $\delta$, is $4\ \Gamma$. As shown in Fig.~\ref{Fig3}(b), the atom temperature scales linearly with the final cooling intensity from $1.5\ I_{sat}$ to $12\ I_{sat}$. We observe a minimum temperature (42 $\mu$K) that occurs at $I_{cool}=1.5\ I_{sat}$. Both atom loss and inefficient cooling occur when the final intensity is below this value. Thus, we make use of this piecewise time sequence in our following measurements.

Then, we study the efficiency of gray molasses as a function of its duration, $\tau_m$, see Fig.~\ref{Fig3}(c). Though the initial atom temperature is 418 $\mu$K, it rapidly decreases over the first 10 ms and reaches an asymptotic temperature of 47 $\mu$K with a 1/e cooling time constant of $\tau$=3.84 ms.

Finally, we study the influence of global detuning, $\delta$, which is presented in Fig.~\ref{Fig3}(d). From the data, we observe that the atom number shows a weak dependence upon the global detuning from $2\ \Gamma$ to $6\ \Gamma$. For $\delta\in[2\ \Gamma,4\ \Gamma]$, the temperature decreases from 60 $\mu$K to 49 $\mu$K. Then, the temperature remains minimal for $\delta\in[4\ \Gamma,6\ \Gamma]$ and increases rapidly when $\delta\geq6\ \Gamma$.

A typical temperature after the gray molasses phase is 42 $\mu$K, and the obtained phase-space density is $5.4\times10^{-6}$. The optimized parameters before the optical pumping stage and the time sequence are presented in Table.~\ref{tab.1}.

\section{MAGNETIC TRANSPORT}

At the end of the gray molasses phase, atoms are depolarized and randomly distributed into hyperfine ground states. Hence, optical pumping is required to prepare atoms in the low-field seeking state $|F=2,m_F=2\rangle$ for magnetic trapping. In order to minimize the absorption-emission cycles during optical pumping, we use D1 line optical pumping, which causes the target state behave like a dark state in the presence of a bias magnetic field. Furthermore, we apply a pair of balanced retro-reflecting optical pumping beams to decrease the displacement of the atoms. With an optimized optical pumping phase, we achieve a loading efficiency of 70\% for the magnetic trap. Then, we adiabatically transfer the atoms a distance of 54 cm over 3 s from the MOT chamber to the science chamber. The magnetic transport consists of fifteen pairs of overlapping quadrupole coils which generate a moving trapping potential by applying time-varying currents. The transfer path has an angle of 45$^{\circ}$, such that the science cell is out of the line-of-sight of the potassium oven (see Fig.~\ref{Fig2}). We finally obtain $7\times10^8$ atoms with a temperature of 200 $\mu$K at a 115 G/cm magnetic gradient in the glass cell.

\section{EVAPORATIVE COOLING}

Although a $^{41}$K BEC has already been achieved in the magnetic trap, the fact that only the low-field seeking state can be magnetically confined limits its further applications. In contrast to magnetic traps, the trapping potential of optical traps is independent of magnetic substates, making the latter well-suited to investigating of spin-mixture~\cite{o2002observation,jochim2003bose} and Feshbach resonance~\cite{chin2010feshbach}. Therefore, it is desirable to achieve a $^{41}$K BEC in the optical dipole trap. In our experiment, due to heating and atom loss in the magnetic transport phase, directly loading atoms into an optical dipole trap is inefficient. To solve this problem, we adopt a two-stage evaporative cooling strategy. Atoms are first evaporatively cooled in the optically plugged magnetic trap, and then transferred into the optical dipole trap for subsequent evaporation.

In order to avoid Majorana spin-flip, a tightly focused 532 nm laser is used to plug the center of the quadrupole trap. The laser power is 11 W with a 1/e$^{2}$ radius of 34 $\mu $m, which provides a potential barrier of 360 $\mu$K. Evaporation is performed by driving the $|F=2,m_F=2\rangle\rightarrow|F=1,m_F=1\rangle$ transition, which is 254 MHz under zero magnetic field. In the first trail, we ramp up the magnetic gradient from 115 G/cm to 198 G/cm over 200 ms to increase the collision rate and then scan the RF-knife from 340 MHz to 265 MHz linearly over 11 s. In the second trail, in order to suppress three-body loss, we decompress the trap back to 110 G/cm over 160 ms. Afterwards, the RF-knife is further reduced from 261.5 MHz to 257 MHz over 2 s. Finally, we obtain a cloud of $1.5\times10^7$ atoms at 6.5 $\mu$K with an achieved phase-space density of 0.26. The evolution of phase-space density as a function of atom number is plotted in Fig.~\ref{Fig4}. The total efficiency, $\Gamma$, of evaporative cooling is $2.97\pm0.05$, where $\Gamma=-d(lnPSD)/d(lnN)$.

After evaporative cooling is performed in the optically plugged magnetic trap, we transfer the cold sample into a single beam dipole trap. Our trapping potential is generated by a 170 mW, 1064 nm laser with a single spatial and longitudinal mode. The beam is focused into a 1/e$^{2}$ radius of 24 $\mu$m, which corresponds to a 23 $\mu$K trap depth for $^{41}$K. Experimentally, we adiabatically ramp down the magnetic gradient and increase the laser intensity simultaneously over 100 ms. With optimized parameters, the total atom number transferred into the optical trap is $1.2\times10^7$ at 12.2 $\mu$K. Then, we immediately transfer atoms into the hyperfine ground state $|F=1,m_F=1\rangle$ by performing a Landau-Zener sweep. The forced evaporation is accomplished by exponentially decreasing the laser power by a factor of 24 in 3 s. Additional axial confinement is provided by the magnetic curvature under a 300 G bias field, which becomes dominant near the end of evaporation. Finally, we observe a $^{41}$K BEC of up to $1.2\times10^6$ atoms without a discernible thermal fraction (see the inset of Fig.~\ref{Fig4}). The calculated axial and radial trapping frequencies are about $2\pi\times3.7$ Hz and $2\pi\times190$ Hz, respectively.

\begin{figure}[htbp]
\includegraphics[width=\columnwidth]{Fig4.pdf}
\caption{(Color Online) Phase-space density as a function of atom number during two-stage evaporative cooling. The blue squares (red circles) represent evaporation in the optically plugged magnetic trap (optical dipole trap). The inset shows the false-color absorption image and the 1D-integrated density profile of a BEC after a 25 ms time-of-flight.}
\label{Fig4}
\end{figure}

\section{DETECTION OF FESHBACH RESONANCE}

Feshbach resonance is an essential ingredient for controlling interatomic interactions. Different theoretical approaches for predicting two-body collisional behaviors have been developed in recent years and shown good agreement with experiment results~\cite{stoof1988spin,wille2008exploring,houbiers1998elastic,hanna2009prediction}. Coupled-Channel calculation is a numerical solution method of the coupled Schr\"{o}dinger equations which can directly obtain the scattering length as a function of the bias field~\cite{stoof1988spin}.

Here, s-wave Feshbach resonances of $^{41}$K in the state $|F=1,m_F=1\rangle$ are theoretically simulated using a Coupled-Channel calculation, based on well-established singlet $X^1\Sigma$ and triplet $a^3\Sigma$ potentials~\cite{falke2008potassium}. The theoretical predictions of resonance locations (409.3 G \& 660.6 G) serve as a guide for the experiment. We perform inelastic loss spectroscopy to detect Feshbach resonances where enhanced atom losses occur due to three-body decay. In the following measurements, the initial status of $^{41}$K is $N=3.3\times10^6$ and $T=300$ nK. We first ramp the magnetic field to the desired value and then hold it there for a period of time before measuring the residual atom number in the trap. In order to avoid measurement fluctuations during fast deactivation of the magnetic field, the atom number is directly measured by high-field absorption imaging. Reproducible loss features are observed around 409.2 G and 660.6 G, as shown in Fig.~\ref{Fig5}; the blue dashed lines are theoretical predictions of the scattering length based on the Coupled-Channel calculation. The inelastic loss spectra are fitted with Lorentz functions, which satisfactorily agree with simulation results. The accuracy of the magnetic field is calibrated by RF spectroscopy between the two lowest hyperfine states of $^{41}$K for several points between 400 G and 700 G, and found to be better than 50 mG.

\begin{figure}[htbp]
\includegraphics[width=\columnwidth]{Fig5.pdf}
\caption{(Color Online) Inelastic loss spectra in the lowest hyperfine channel of $^{41}$K. The measurement data (red circles) are fitted by Lorentz functions. The resonance points are located at 409.2 G (a) and 660.6 G (b), respectively. The blue dashed lines represent the theoretical predictions of scattering length in the units of Bohr radius according to a Coupled-Channel calculation; these predictions are in good agreement with the experimental results.}
\label{Fig5}
\end{figure}

\section{CONCLUSION}

In summary, we have achieved a large production of a $^{41}$K BEC in an optical dipole trap. Our method is based on the a combination of enhanced 2D$+$ MOT, D1-D2 CMOT, D1 gray molasses, and a two-stage evaporation strategy. D1 gray molasses provides an effective sub-Doppler cooling mechanism for $^{41}$K. We make use of two successive cooling phases, yielding a high capture rate (92\%) as well as a low temperature (42 $\mu$K). After magnetically transferring the cloud into the science chamber, evaporative cooling is first performed in an optically plugged magnetic trap with an overall efficiency of $2.97\pm0.05$. This procedure allows us to enhance the phase-space density of atoms by more than four orders of magnitude. The subsequent evaporative cooling is performed in a single beam optical dipole trap, producing a pure BEC of more than $1.2\times10^6$ atoms, which is four times larger than that in any previous experiment~\cite{kishimoto2009direct}. The collisional properties of $^{41}$K in the state $|F=1,m_F=1\rangle$ are studied both theoretically and experimentally. Two resonance positions are observed at 409.2 G and 660.6 G, as has been predicted theoretically. These results set a new benchmark for generation of a BEC with $^{41}$K atoms.

We thank useful discussions with Jue Nan for Coupled-Channel calculations. This work has been supported by the NSFC of China, the CAS, and the National Fundamental Research Program (under Grant No. 2013CB922001). X.-C. Yao acknowledges support from the Alexander von Humboldt Foundation.

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Public Health and Drinking Water News Briefs
The drinking water in some Ontario communities has been found to contain high levels of trichlorethelene (TCE), a toxic industrial solvent, provincial water quality disclosure records show. Tens of thousands of people have been exposed to the compound in recent years at levels considered risky in the United States.
TCE is commonly used to degrease metals. Exposure to high levels of it is associated with leukemia and cancers of the cervix, prostate and colon, among others. It's dangerous to drink water containing TCE and risky even to bathe or shower in it because of the vapour.
The town of Beckwith, near Ottawa, had the worst results: TCE levels last year exceeded outdated provincial standards. Barrie, Cambridge, Fergus, Orangeville and Orillia were among towns whose water levels of TCE were near or exceeded the US TCE safety standard in 1998 and 1999 tests.
Ontario's TCE safety standard allows 10 times the amount permitted in the US. There, the deaths of 12 children were blamed on the chemical in a tragedy that inspired the novel and Hollywood film, A Civil Action. The Sierra Legal Defence Fund is demanding Ontario adopt the US standard of five parts per billion of TCE in drinking water.
--Globe and Mail, March 21, 2001
Questioning Water Safety
by author Rick de Vries
Studies undertaken in Europe, the United States and Canada have detected a wide range of pharmaceuticals and personal care products (PPCPs) in surface water, groundwater and even drinking water systems. PPCPs are basically all drugs such as antibiotics, steroids, antidepressants, narcotics, painkillers and tranquilizers. They also include oral contraceptives, antiseptics, fragrances, shampoos, sunscreens, insect repellents, food supplements, caffeine and nicotine, to name a few.
There are several ways this form of water contamination occurs. When you take a drug, a large percentage of it passes through the body unchanged. The body also converts some of that drug into other compounds called metabolites, which may be even more bioactive than the original drug. The combined result is excreted through urine and feces and ultimately ends up in waste treatment plants along with other personal care products that have been washed off the body. Most treatment plants are unable to remove PPCPs, so they pass into either surface waters (from the liquid portion) or groundwater (from the solid waste portion). Runoff from farm animal operations also contributes a significant amount of PPCPs to the environment, as do hospital discharges and the aquaculture industry.
The range of contaminants is staggering. German researchers have found up to 60 different drugs in their water samples. In their 30-state water sampling, the US Geological Survey has found 31 kinds of antibiotics and antibacterial chemicals, as well as a variety of hormones and birth control compounds.
We're not talking just small amounts of chemicals either. Thousands of tonnes are released into water annually, which is similar to the amount of fertilizers used by the agriculture industry. One startling example involves clofibric acid, a drug for reducing cholesterol levels. Estimates put the clofibric acid content in the North Sea at 43 to 66 tonnes, with an additional 50 to 100 tonnes flowing through every year!
Should We Be Concerned?
Yes. Little is known about how each component of this complex mix reacts with each other or the environment. There are simply too many chemicals to be able to predict what happens.
We don't know the long-term effects on humans and aquatic ecosystems. Some effects could be profound and readily visible; however, others could be so subtle that they may not be detectable for years.
At present, we have a long list of questions rather than facts. Consider the PPCPs found in drinking water samples. What are the long-term effects of drinking this chemical mixture every day? Musk (a fragrance used in detergents and perfumes) is fat-soluble and therefore accumulates in the fatty tissues of fish. What are the long-term effects of eating this fish? A pregnant woman risks the health of her developing fetus when she ingests chemicals. What are the effects on the fetus from the consumption of PPCPs in food or drinking water?
Hormones have also been detected in water samples. Could their continual ingestion be thecause of decreased fertility, cancers and other diseases? Some studies have indicated this may indeed be the case. In addition, the increased appearance of antibiotic-resistant bacteria is a matter of great concern among health-care professionals. Could the significant levels of antibiotics in water systems be a contributing factor? Some researchers say it is possible. The answer to all of these questions above and many more is that we simply do not know.
What We Do Know
Generations of aquatic organisms have lived and continue to live in this chemical soup. For them, there is no escape. Toxic exposure is constant and even low concentrations of PPCPs can have very significant effects on many species. The following are some examples:
· Synthetic estrogen in oral contraceptives can lead to the feminization of male fish and deformed sex organs in other species.
· Antidepressants can disrupt spawning behaviour in shellfish.
· Musk accumulates in the fatty tissues of aquatic organisms, which leads to bioaccumulation as it moves up the food chain.
· Certain cardiac drugs can prevent aquatic organisms from expelling contaminants from their systems, thus increasing the toxic effects of all the PPCPs they are exposed to.
The issue of PPCP contamination of water systems has only been recognized in the last 10 years. More extensive sampling programs have recently begun, and some effects on human and environmental health are beginning to be examined.
The magnitude of this problem and potential negative impacts definitely warrant further investigation. Contamination is extensive and exposure is continual. As long as wastewater treatment plants continue to pump out PPCPs, contaminants will always be present in water systems. Natural degradation of these chemicals can occur; however, new PPCPs continually flowing in results in no decrease in concentration and renders the existing treatment process ineffective. Perhaps before seeking an answer to the question of what PPCPs are doing to the environment, and us, we should look at how we can keep them out in the first place.
For more information, go the US Environmental Protection Agency's Web site at epa.gov/nerlesd1/chemistry/pharma/.
Rick de Vries is the co-publisher and editor of Fresh Outlook Magazine, which explores water and wastewater issues as well as related environmental topics. He has a background in biological sciences technology, specializing in pollution and environmental sciences.
by author Curtis Foreman
Water sustains life. The water you drink replenishes your body's cells and flushes out waste to keep you healthy and vibrant. In fact, at any given time, almost two-thirds of your body is composed of the water you've consumed in the previous few days.
Now picture this: a friend offers you a glass of water and presents you with something that smells strongly of chlorine. When you pull a face, she laughs and says she knows it smells, but thinks it's okay to drink.
In a way, she's right; chlorine is the very reason that most municipally treated water is "okay." Ever since the disinfecting properties of chlorine were discovered in the 19th century, cities have been adding it to drinking water to kill harmful micro-organisms and pathogens.
But the benefits of chlorination come at a cost. Although scientists and health officials generally agree that chlorine levels in municipally treated water are too low to pose a significant health risk to humans, the use of chlorine actually creates byproducts that can cause serious harm.
When chlorine reacts with organic material, such as leaves and twigs in source water, it produces chlorinated organic compounds called trihalomethanes, which include such toxic substances as chloroform. Several studies have shown these substances to be carcinogenic even in extremely low doses, and other studies have implicated them in problems during pregnancy.
Chlorine and its byproducts aren't the only hazards. Lead from pipes can leach into water supplies. If your drinking water comes from an untreated source such as a private well, the groundwater supply can become tainted with diseases such as Giardia or Cryptosporidium, fecal coliform from animal waste, or chemicals such as pesticides.
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Explore the surrealist universe of Salvador Dali with this enchanting picture! You will spend hours looking at every single detail that makes this work of art so unique! This poster will be right at home in your living room, bedroom or kitchen! Donoet forget to frame it to showcase it all the more!


Time: Thursday, April 9, 2:00p.m.
Location: On the mall outside the Natural History Museum...that's up next!
Status: Needing a break. Loving the warmth and the grass.
Look at Tim's face and look at Zach's face.
This picture has excellent symmetry.
Well, clearly, our Capital Contraband Snack got us about as far as it took us to eat it. So, still needing a little more, we decided to rest on the mall and have some dogs and fries.
I was fifth in line and waited TWENTY minutes for these tasty goodies. I'm convinced the salespeople were trying to TICK ME OFF. Seriously...they moved in slow motion. For those of you budgeting a trip to D.C. in the future, a (kosher Hebrew) hot dog, a cup of fries and a med. pop cost around $8! We got four meals and shared.
Notice Tim with the guidebook in the back right. This tome became such an integral part of Tim and the trip that Timmy fanatically insisted it come home with us as a lifelong souvineer. We may dip its dog-eared pages in gold.
It's a good old fashioned pile-on!
She's saying, "I can't believe you are letting us act this way in a public place!"
She pulls a last minute change-up! "BULLSEYE!" Nailed him!
Here it is up close! Those are some wet lips, I can assure you!
And up for air...... she's thinking...."that was great! I really grossed him out good! whew!...hard work, though."


text:
Radiomics to predict outcomes and abscopal response of patients with cancer treated with immunotherapy combined with radiotherapy using a validated signature of CD8 cells
Immunotherapy biomarkers
http://orcid.org/0000-0001-9866-6449Roger Sun1,2,3,
Nora Sundahl4,
http://orcid.org/0000-0003-2082-216XMarkus Hecht5,
Florian Putz5,
Andrea Lancia6,
Angela Rouyar2,
Marina Milic2,
Alexandre Carré1,2,
Enzo Battistella2,
Emilie Alvarez Andres2,7,
Stéphane Niyoteka2,
Edouard Romano1,
Guillaume Louvel1,
Jérôme Durand-Labrunie1,
Sophie Bockel1,2,3,
Rastilav Bahleda8,
http://orcid.org/0000-0001-8838-1343Charlotte Robert1,2,
http://orcid.org/0000-0001-5659-8791Celine Boutros9,
Maria Vakalopoulou10,
Nikos Paragios7,10,
http://orcid.org/0000-0001-6743-3351Benjamin Frey5,
Jean-Charles Soria9,
Christophe Massard3,8,
Charles Ferté9,
Rainer Fietkau5,
Piet Ost4,
http://orcid.org/0000-0001-6375-5476Udo Gaipl5 and
Eric Deutsch1,2,3
1 Department of Radiation Oncology, Gustave Roussy, Villejuif, Île-de-France, France
2 Institut Gustave Roussy, Inserm, Radiothérapie Moléculaire et Innovation Thérapeutique, Paris-Saclay University, Villejuif, Île-de-France, France
3 Paris-Saclay University Faculty of Medicine, Le Kremlin-Bicetre, Île-de-France, France
4 Department of Radiation Oncology, University Hospital Ghent, Gent, Oost-Vlaanderen, Belgium
5 Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
6 Department of Radiation Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Lombardia, Italy
7 TheraPanacea, Paris, France
8 Drug Development Department, Gustave Roussy, Villejuif, Île-de-France, France
9 Departement of Medicine, Gustave Roussy, Villejuif, Île-de-France, France
10 CentraleSupélec, Gif-sur-Yvette, Île-de-France, France
Correspondence to Prof. Eric Deutsch; eric.deutsch{at}gustaveroussy.fr
Background Combining radiotherapy (RT) with immuno-oncology (IO) therapy (IORT) may enhance IO-induced antitumor response. Quantitative imaging biomarkers can be used to provide prognosis, predict tumor response in a non-invasive fashion and improve patient selection for IORT. A biologically inspired CD8 T-cells-associated radiomics signature has been developed on previous cohorts. We evaluated here whether this CD8 radiomic signature is associated with lesion response, whether it may help to assess disease spatial heterogeneity for predicting outcomes of patients treated with IORT. We also evaluated differences between irradiated and non-irradiated lesions.
Methods Clinical data from patients with advanced solid tumors in six independent clinical studies of IORT were investigated. Immunotherapy consisted of 4 different drugs (antiprogrammed death-ligand 1 or anticytotoxic T-lymphocyte-associated protein 4 in monotherapy). Most patients received stereotactic RT to one lesion. Irradiated and non-irradiated lesions were delineated from baseline and the first evaluation CT scans. Radiomic features were extracted from contrast-enhanced CT images and the CD8 radiomics signature was applied. A responding lesion was defined by a decrease in lesion size of at least 30%. Dispersion metrices of the radiomics signature were estimated to evaluate the impact of tumor heterogeneity in patient's response.
Results A total of 94 patients involving multiple lesions (100 irradiated and 189 non-irradiated lesions) were considered for a statistical interpretation. Lesions with high CD8 radiomics score at baseline were associated with significantly higher tumor response (area under the receiving operating characteristic curve (AUC)=0.63, p=0.0020). Entropy of the radiomics scores distribution on all lesions was shown to be associated with progression-free survival (HR=1.67, p=0.040), out-of-field abscopal response (AUC=0.70, p=0.014) and overall survival (HR=2.08, p=0.023), which remained significant in a multivariate analysis including clinical and biological variables.
Conclusions These results enhance the predictive value of the biologically inspired CD8 radiomics score and suggests that tumor heterogeneity should be systematically considered in patients treated with IORT. This CD8 radiomics signature may help select patients who are most likely to benefit from IORT.
radioimmunotherapy
translational medical research
tumor biomarkers
This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.
http://dx.doi.org/10.1136/jitc-2020-001429
The introduction of immune-checkpoint inhibitors has profoundly changed the immuno-oncology (IO) and the treatment of patients with metastatic cancers.1 2 Unfortunately, despite the use of patients stratification criteria, the average response rate (RR) remains low while being significantly volatile (20%–50%).3 Strong evidence indicates that radiotherapy (RT) can invoke both local and systemic immunostimulatory effects that could synergize with immunotherapy in systemic tumor control.4–8 However, open questions about modalities to improve IORT efficacy, such as the choice and number of lesions to irradiate,9 10 are still pending. Patient's stratification becomes a necessity and the development of innovative biomarkers to optimize IORT paves the way to precision medicine in cancer care and improved clinical outcomes.
Quantitative imaging biomarkers are of great interest. Medical images are non-invasive, part of standard clinical protocol and reflect the whole tumor burden for which every single lesion can be analyzed, contrary to traditional biopsy.11 This is of crucial importance with IORT, where disease and treatment encompass and have to account for intrapatient heterogeneity. Lesions have different microenvironments and may receive either local and/or systemic treatment effects leading to heterogeneous patterns of global response.12
Evidence-based radiomic biomarkers have shown promising results to predict response to immunotherapy,13–18 but to the best of our knowledge, there is no evidence yet in IORT. Our team previously validated a biologically inspired radiomics-signature trained to estimate from conventional contrast-enhanced CT scans the abundance of CD8 T-cells and demonstrated correlations with outcomes of patients treated with immunotherapy.13 Here, we aimed to evaluate in a cohort of patients treated with IORT whether this tool can predict tumor response at a lesion-based level. We evaluated also whether this radiomics signature could help to assess disease spatial heterogeneity at a patient-level for clinical outcome prediction, and finally evaluated the impact of irradiation on the lesion radiomic scores.
Data and study design
Patients with metastatic solid tumors from three centers included in clinical trials of IORT were retrospectively screened for inclusion.
Patients for whom contrast-enhanced CT scans were available at both baseline and after start of treatment (first follow-up) were included for analysis.
Six clinical trials were considered for this study (SABR-PDL1: NCT02992912, MEL-IPI-RX: NCT01557114, 'ghent-nivo': NCT02821182,19 'ghent-ipi: NCT02406183,20 'ghent-pembro': NCT02826564,21 ST-ICI: NCT03453892). Immunotherapy consisted of anticytotoxic T-lymphocyte-associated protein 4 (ipilimumab), antiprogrammed cell death protein 1 (anti-PD-1) (pembrolizumab, nivolumab) or antiprogrammed death-ligand 1 (anti-PD-L1) (atezolizumab) in monotherapy. The main RT regimen was stereotactic RT delivered in three fractions after the start of immunotherapy. Clinical, biological and imaging data at baseline and follow-up, and PD-L1 expression were retrieved when available.
The primary objective was to evaluate the association between the previously validated biologically inspired radiomics score of CD8 T-cells of a lesion and its response at the first follow-up CT.13 Secondary objectives were (1) to evaluate the association between the radiomics scores of the analyzed lesions (see Definition of analyzed lesions) and patients' clinical outcomes at the first evaluation, progression-free survival (PFS) and overall survival (OS) and (2) to assess differences between irradiated and non-irradiated lesions. Potential clinical and biological confounding predictors of response (PFS, OS) and of abscopal response were analyzed.
Definition of analyzed lesions
Analyzed lesions were any tumor (primary or secondary) that was identifiable on both baseline and follow-up CTs, with diameter ≥5 mm at baseline. Lesions that could not be accurately discriminated from surrounding tissues (ie, lung nodule adjacent or within atelectasis) or from other adjacent lesions at baseline or follow-up CTs (ie, confluent metastases) were not delineated and excluded. Irradiated and non-irradiated lesions were labeled.
Feature extraction and CD8 T-cells radiomics score computation
Radiomic features were extracted from contrast-enhanced CTs. All images had slice-thickness ≤5 mm and were reconstructed using soft or standard convolution kernels. Experienced physicians from one center (RS, AL) delineated lesions on baseline and follow-up scans. All the segmentations were reviewed by one physician (RS) to ensure a homogeneous segmentation method in accordance with the published signature. Two volumes of interest (VOIs) were segmented for each lesion: (1) the lesion itself and (2) a peripheral ring, created following the method published in the original study13 to compute the radiomics signature. The ring was created using automated dilatation and shrinkage of the tumor boundaries by 2 mm on each side, namely outside and inside the boundary, resulted in a ring with a thickness of 4 mm (online supplementary figure S1). Radiomic feature extraction was performed using LIFEx software V.3.44 (Local Image Feature Extraction, freeware, www.lifexsoft.org).22 Images were resized to 1×1×1 mm3 voxels using three-dimensional Lagrangian polygon interpolation. Hounsfield-units (HU) values in the VOIs were then resampled into 400 discrete values using absolute discretisation.23 The minimum and maximum bounds of the resampling interval were set to −1000 and 3000 HU, leading to a bin size of 10 HU.
[jitc-2020-001429supp001.pdf]
The previously validated radiomics score of CD8 T-cells consists of a linear interpolation on the basis of eight variables: five radiomic features extracted from each lesion, two discrete labels about lesion location and one imaging acquisition-related variable—the peak kilovoltage (kVp).13 The five features from the radiomics signature were extracted and normalized in the range 0–1. VOI location was labeled as adenopathy, head and neck, lung, liver or other (subcutaneous or abdominal lesions) and the kVp was retrieved from CT metadata. Coefficients from the validated signature were applied to these eight variables to obtain the radiomics score of each analyzed lesion (figure 1).
Radiomics workflow. Irradiated and non-irradiated lesions were delineated. After image preprocessing to discretise the voxel intensity and to resample the voxel size, features from the radiomics signature of CD8 T-cells published in Sun et al, Lancet Oncol 2018, were extracted, allowing the estimation of CD8 T-cells. Associations with outcomes were evaluated.
Response evaluation
A lesion-wise evaluation of relative change in diameter between baseline and follow-up was carried out using RECIST V.1.1 criteria. A responding lesion was defined by a decrease in lesion size of >30%. A progressive lesion was defined by an increase in lesion size of >20%. To take into account the overall tumor burden and to assess the different patterns of response on a patient basis, mixed response was defined as the presence of both progressive and responding lesions, as opposed to patients presenting only responding (uniform response) or progressive lesions (uniform progression), irrespective of stable lesions or only stable lesions (stable disease (SD)). To compare patterns of response of non-irradiated lesions, occurrence of response in any non-irradiated lesion was defined as lesion-based abscopal response, while a decrease of >30% in the sum of the largest diameter of non-irradiated lesion was defined as a RECIST-based abscopal response.
Spatial heterogeneity evaluation
To assess the impact of intrapatient interlesion CD8 radiomics score heterogeneity, minimum value, maximal value, mean value, SD and entropy of the lesion scores distribution were retrieved. For subgroup analysis of irradiated and non-irradiated lesions, when the number of lesions was >1, the minimum value was kept. Median value was used to separate patients into two groups. Patients with extreme values (<first quartile or >third quartile) regarding the minimum value of their lesions were also compared in a post hoc analysis.24 False discovery rate (FDR) was at 0.2 to correct for multiple comparisons.
Comparisons between variables were performed using Wilcoxon signed-rank test or Kruskal-Wallis test for continuous variables, and Fisher's exact test for categorical variables. Clustering of patients into two distinct groups was done on the basis of the median value, unless there was a validated cut-off (ie, biological variables). A threshold of <0.05 was defined for double-tailed p value's significance. Statistical analyses were performed using R software V.3.6.0 (https://www.r-project.org/).25 OS and PFS were computed according to the Kaplan-Meier method and Cox proportional-hazards survival estimates. End points were death from any cause for OS, and any recurrence or death for PFS. Multivariate models included the clinically relevant variables that were significant in univariate analysis. No imputation was made for the missing data.
Role of the funding sources
The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. ED and RS had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Patient characteristics and analyzed lesions
Ninety-four patients were included from 1 July 2011 to 31 March 2019. Baseline characteristics of the patients are presented in table 1. All patients were diagnosed with advanced or metastatic solid tumors. Median age at baseline was 60.38 (IQR 50.68–69.04).
Two patients (2.1%) with irradiated brain metastases had no contrast-enhanced brain CTs available for imaging analysis of the irradiated lesion but were kept for the analysis of non-irradiated lesions response. Conversely, three patients (3.2%) had no identifiable non-irradiated analyzed lesion but were considered for the irradiated lesion response. Overall, 100 irradiated lesions and 189 non-irradiated lesions were analyzed at baseline and follow-up, leading to a total of 578 lesions. At baseline, median size of irradiated lesions was larger than non-irradiated lesions (26.9 mm, IQR (17.6–37.7) vs 21.5 mm, IQR (15.2–31.9), respectively, difference in location=3.6, 95% CI (0.3 to 6.8), p=0.034) (table 2).
Characteristics of lesions analyzed at baseline
Nearly all patients underwent hypofractionated RT (n=91 of 94; 96.9%). Six patients had two irradiated metastases (6.4%), and one had three irradiated metastases (1.1%). Median number of fractions and dose by fraction given were three fractions (IQR (3–3)) of 8 Gy (IQR (6–12)). Median number of IO therapy cycles given was 4 (IQR (3–10)). Median time between the start of IO therapy and the start of RT was 21 days (IQR (8–24)). Sixteen patients started RT before IO therapy (median interval: −5.5, IQR (−7–−1.75)). Median follow-up was 14.8 months (IQR (8.4–20.8)). Median time between baseline and follow-up CT was 2.8 months (IQR (2.0–3.4)).
Patient outcomes description
Lesion response
The median per cent change in lesion diameter was −13.0% (IQR (−28.9–+10.1)) for irradiated metastases versus +11.2% (IQR (−11.0–+40.5)) for non-irradiated metastases (p<0.0001), with respectively 16% progressive lesions (n=16 of 100 lesions) and 23% responding lesions (n=23 of 100) for irradiated metastases and 38% progressive lesions (n=72 of 189) and 17% responding lesions (n=32 of 189) for non-irradiated metastases.
Patient response
Regarding patient response at the first follow-up CT, 6 complete responses, 22 partial responses, 24 SD and 42 progressive disease were observed according to RECIST V.1.1, yielding an objective RR of 29.9% (28 of 94 patients). More precisely, 24.5% (n=23) showed uniform response, 38.3% (n=36) showed uniform progression, 12.8% (n=12) showed mixed response and 24.5% (n=23) presented only stable lesions.
Median OS was 25.2 months (95% CI (17.3–NA)) and median PFS was 4.7 months (95% CI (3.5–6.7)) (online supplementary figure S2). Patients with uniform responses had significantly higher OS (HR=0.20, 95% CI (0.08 to 0.53), p=0.0011), while OS of patients with mixed response was not significantly different from that of patients with uniform progression (p=0.84) (figure 2A).
(A) Response kinetics curve depicting individual lesion responses (red dots corresponding to irradiated lesions, blue dots corresponding to non-irradiated lesions) on a patient-to-patient basis. (B) Kaplan-Meier curves of overall survival according to patients' patterns of response. (C) Kaplan-Meier curves of overall survival according to out-of-field response (OOF). Out-of-field response which fulfilled RECIST V.1.1 criteria (30% decrease in the sum of the aggregate diameters of the non-irradiated lesions) showed higher overall survival (OS) than the rest of the population. (D, E) Kaplan-Meier curves of overall survival according to aggregate diameter changes of irradiated lesions (D) or non-irradiated lesions (E).
Out-of-field response
For the 91 patients with non-irradiated lesions available for analysis, out-of-field response using aggregate diameter of non-irradiated lesions according to RECIST (RECIST-based abscopal response) at the first follow-up CT was 16.5% (n=15). Using response defined by 30% reduction in any single non-irradiated lesions (lesion-based abscopal response), the non-irradiated RR was 26.4% (n=24). While both definitions were significantly associated with OS (p=0.011 and p=0.041, respectively), only patients with RECIST-based abscopal response had significantly higher OS than those with no out-of-field response (HR=0.31, 95% CI (0.11 to 0.88), p=0.027), contrary to the six patients with lesion-based abscopal response who did not achieve the criteria for RECIST-based abscopal response (p=0.89) (figure 2C). For irradiated lesions, diameter changes according to RECIST were not associated with OS (p=0.72) (figures 2D–E and 3).
Figure 3A
Lesion response according to baseline radiomics score. Responding lesions corresponded to lesions with a decrease in tumor size >30% (partial response and complete response). (B) Scatter plot of changes in tumor size (%) according to baseline radiomics score. (C, D) Associations between distribution metrices of the radiomics score of CD8 T-cells and clinical outcomes (progression-free survival (PFS), overall survival (OS)).
CD8 radiomics score and association with patient outcomes
At baseline, median value of the CD8 radiomics score was not significantly different between the two groups of lesions (irradiated and non-irradiated) (1.75, IQR (1.55–1.97) vs 1.74, IQR (1.54–1.97), respectively, difference in location=0.005, 95% CI (−0.03 to 0.04), p=0.76). Radiomics score of CD8 T-cells was not correlated with lesion size (Spearman's rho=−0.005, p=0.93).
Association between the CD8 radiomics score of a lesion at baseline and its response according to RECIST was significant (p=0.0066) with responding lesion having a higher CD8 radiomics score (median (IQR)=1.95 (1.64–1.98) and 1.72 (1.53–1.97) for stable or progressive lesions (area under the receiving operating characteristic curve (AUC)=0.63, 95% CI (0.56 to 0.71), p=0.0020) (figure 3A–B).
Several metrices were evaluated to decipher whether heterogeneity of the CD8 score at baseline was associated with clinical outcomes (figure 3C–D and online supplementary table S1).
Patients with uniform progression had lower CD8 radiomics scores at baseline (based on the minimal value across their lesions) than those with uniform response (p=0.012) and mixed response (p=0.0073), but patients with either mixed response or uniform progression had more heterogeneous CD8 radiomics scores across their lesions (higher entropy of the distribution of CD8 T-cells radiomics score) than patients with SD or uniform response (online supplementary figure S4).
Entropy of the distribution of the CD8 radiomics scores, was associated with PFS, patients with higher value than the median having poorer PFS (HR=1.67, 95% CI (1.02 to 2.75), p=0.040, FDR=0.080), and remained significantly associated with OS (HR=2.08, 95% CI (1.09 to 3.96), p=0.023, FDR=0.17).
Minimal value, maximal value, mean and SD of the lesion scores were not significantly associated with PFS or OS. However, a statistical trend was identified between PFS and the minimal value of the CD8 radiomics score across all lesions (p=0.07), and significance was reached when looking only at patients with extreme values (HR=0.34, 95% CI (0.17 to 0.68), p=0.0021) (online supplementary table S1).
CD8 radiomics scores on the follow-up CT were not significantly different from baseline CT.
Irradiated and non-irradiated lesions subgroup analysis
On a lesion level, for both irradiated and non-irradiated lesions, the radiomics scores of responding lesions were higher than those of progressive lesions (AUC=0.75, 95% CI (0.58 to 0.92), p=0.0090 and AUC=0.75, 95% CI (0.51 to 0.74), p=0.040, respectively). There was no difference in tumor size at baseline between responding and progressive lesions (online supplementary figure S5).
On a patient level, minimum value of the CD8 radiomics score across non-irradiated lesions was significantly associated with PFS (HR=0.37, 95% CI (0.18 to 0.76), p=0.0067, FDR=0.022). For the irradiated lesions, this value was not significantly associated with PFS (HR=0.62, 95% CI (0.38 to 1.02), p=0.059, FDR=0.10). When looking at the extreme values, the minimum values of both non-irradiated and irradiated lesions were associated with PFS (p=0.0011 and p=0.0067, respectively).
Regarding out-of-field response, heterogeneous CD8 radiomics scores based on entropy of the distribution were associated with RECIST-based abscopal response (AUC=0.70, 95% CI (0.56 to 0.84), p=0.014).
Clinical and biological predictors of outcomes and multivariate analysis
Univariate analysis of OS and PFS are summarized in supplemental data (online supplementary table S2, S3). A performance status (PS) >0, an interval between IO therapy and RT start >14 days, high level of lactate dehydrogenase (>250 UI/L), high level of C reactive protein (CRP) (>10 mg/L) and high entropy of the CD8 T-cells radiomics scores distribution were significantly associated with both poorer OS and PFS. In the multivariate analysis of OS including these factors, only CRP (HR=3.34; 95% CI (1.48 to 7.52), p=0.0036) and the entropy of the CD8 T-cells radiomics scores distribution remained significant (HR=2.64; 95% CI (1.21 to 5.75), p=0.015) (online supplementary table S4). For PFS, only the PS remained significant in multivariate analysis (HR=4.6; 95% CI (2.28 to 9.28), p<0.0001) (online supplementary table S4). Center of inclusion was not a significant confounding factor when included in the multivariate analyses (online supplementary table S5). In this cohort, we did not identify a prognostic role of PD-L1 either for PFS or OS (online supplementary table S2, S3). Royal Marsden Hospital score and Gustave Roussy Immune Score were associated with PFS, but not with OS.14 26–29
IORT is becoming widely used to potentiate immune response. Imaging biomarkers would be very valuable as they could assess the ensemble of the disease extent and its spatial heterogeneity, and may help in the choice of the target lesion(s) to irradiate in order to optimize synergistic effects.10 30 Some authors hypothesized that interlesion heterogeneity of bulky disease may limit the probability of RT-induced systemic antitumor immune response, especially in single-site abscopal approach.9 Moreover, some studies suggested that the location of irradiation may impact how the immune response is elicited, but there is still no evidence regarding the optimal strategy.31
In this study, we demonstrated that the predictive value of a radiomics score of CD8 T-cells previously validated in a cohort of patients treated with IO monotherapy could still be informative in a context of radio-immunotherapy combination.13 Indeed, lesions with high radiomics score at baseline were associated with decrease in the lesion size at the follow-up CT, irrespective of irradiation. Moreover, our results suggest that this tool could also be used to assess tumor heterogeneity, which was associated with patient outcome. On a per-patient basis, the lowest radiomics score of the patient's non-irradiated lesions was associated with PFS. This index was concordant with the observation that outcomes of non-irradiated lesions (vs irradiated lesion) were more predictive of the patient outcome (figures 2D–E and online supplementary figure S4). Therefore, this radiomics score of CD8 T-cells could be used to identify the lesions with the lowest CD8 tumor infiltration. Such lesions could benefit from local treatment since irradiation was associated with more responding lesions. On the contrary, the non-irradiated lesions with the highest radiomics scores would be more likely to present out-of-field response to IO therapy. Indeed, association with PFS and OS was even more important when considering patients with extreme values (although not significant for OS in this study). Entropy of the distribution of the radiomics scores of CD8 T-cells was associated with both PFS and OS and could discriminate patients who will present uniform response from those with uniform PD and mixed response. A high entropy indicated heterogeneous scores of CD8 infiltration and was associated with poorer outcomes. This index highlighted the impact of tumor heterogeneity on the prognosis of the patient and the importance of assessing the whole disease instead of only one lesion.
These results confirm the potential of radiomics to assess spatial heterogeneity as a non-invasive 'multiple virtual biopsies'.14 Korpics et al recently presented similar preliminary results in a population of patients treated with IORT, adding further external validation, although they only evaluated irradiated lesions.24 They analyzed 68 patients and 139 irradiated tumors and showed associations between the CD8 radiomics score and local tumor response (OR=10.21, 95% CI (1.76 to 59.17); p=0.010), OS (HR=0.39, 95% CI (0.20 to 0.75); p=0.005) and PFS (HR=0.47, 95% CI (0.26 to 0.85); p=0.013), using a 25% percentile cut-off for dichotomization of patients.
To the best of our knowledge, this previously published radiomics signature of CD8 T-cells predicting response to IO is the first to be validated by several subsequent independent studies.13 24 We acknowledge however that this study had some limitations. The magnitude of the association between the CD8 radiomics score and the lesion response, although significant, was limited with overlaps between the different groups of response. However, considering that the radiomic signature has not been retrained in this cohort, it was interesting to note that results seemed concordant with those published in the original study (radiomics score between patients with Complete Response or Partial Response (CRPR) and Stable Disease or Progressive Disease (SDPD) at 3 months 'Wilcoxon's difference in location 0.12, 95% CI 9.9×10−⁶ to 2.3; p=0.049', corresponding to an AUC of 0.62 in the immunotherapy cohort).13 Therefore, these results comfort further the reliability of the validated signature. Given the relatively low number of patients and the number of lesions evaluated per patient, we acknowledge that the analysis of the spatial heterogeneity should be interpreted with caution and should be only considered as exploratory. Overall, validation of these data still needs to be done in prospective and, if possible, randomized trials with homogeneous patients to refine and improve the performance of the signature in specific indications. Moreover, the association between the IORT protocol and the primitive tumor type inherent to the different clinical trials may have brought potential confounding factors limiting the analysis of the predictive factors. Still, this study addressed several pending questions regarding IORT. Tumor heterogeneity has shown to be important and correlates to certain extent with outcomes. However, the 'abscopal' out-of-field response should not be based only on the response of one non-irradiated lesion, as frequently reported.32 OS of patients who do not fulfill out-of-field RECIST criteria may not be different from patients without out-of-field response. Rather, we should stick with RECIST V.1.1. criteria which recommend not to use irradiated lesions as RECIST-target lesions to assess treatment response, and analyze several non-irradiated RECIST-target lesions to have information about the whole disease and the response heterogeneity.19 33 34 Regarding RT modalities, an interval between RT and IO therapy of <2 weeks was associated with better PFS and OS, although not significant in multivariate analysis. Interestingly, some variables such as liver metastasis, or scores like the Royal Marsden Hospital score and the Gustave Roussy Immune Score known to be prognostic factors with IO therapy,14 26–29 were only associated with PFS and not with OS in this cohort of patients treated with IORT. This may reflect potential long-lasting RT-induced immune response for which new biomarkers specifically validated for IORT strategies should be identified.
Our findings confirm the predictive value of the previously published CD8 radiomics score in patients with solid tumors treated with IORT combinations.13 Moreover, the results suggest that global spatial reasoning on this signature through a statistical analysis of the distribution of this score across patient's lesions could be a promising method to assess tumor heterogeneity and to predict clinical outcomes. Overall, this study asserts the potential of radiomics to help clinicians characterize the whole disease and to move toward in precision medicine.
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Twitter @rgrsun
Contributors RS, MV and ED had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: RS, NP, MV, ED. Acquisition, analysis or interpretation of data: RS, NS, MH, FP, AL, AR, MM, ER, GL, JD-L, SB, RB, CB. Drafting of the manuscript: RS, ED. Critical revision of the manuscript for important intellectual content: NS, MH, FP, AL, NP, BF, J-CS, CM, CF, RF, PO, UG. Statistical analysis: RS, MV, EB. Obtained funding: RS, CF, FP, CM, ED. Administrative, technical or material support: BF, CM, RF, PO, J-CS, UG, ED, CR, AC, Estienne, Alvarez-Andres, Niyoteka. Study supervision: ED.
Funding Fondation pour la Recherche Médicale (grant DIC20161236437), Fondation ARC pour la recherche contre le cancer (grant SIGN'IT20181007805), SIRIC-SOCRATE 2.0 (grant INCa-DGOS-INSERM_12551) and Amazon AWS grant provided funding to INSERM U1030 Radiomics team—Gustave Roussy. Fondation ARC pour la recherche contre le cancer and Paris-Saclay University provided support to RS with a grant for international mobility. RS has received the support of INSERM, in partnership with Fondation Bettencourt Schueller, within the program of CCA-INSERM-BETTENCOURT.
Competing interests RS received travel and accommodation expenses from AstraZeneca. NS reports travel grants from Merck Sharpe & Dohme, Astellas, Bayer and Bristol-Myers Squibb. MH declares consulting fees, research grants and travel expenses from Merck Serono, MSD, Novartis, BMS and Teva. PO reports research grants from Merck Sharpe & Dohme, Astellas and Janssen; travel grants from Ipsen and Ferring Pharmaceuticals and honorarium from Ferring and Bayer. CR received research grants from Therapanacea and Elekta. CF is a full-time employee of AstraZeneca since September 2017. NP reports grants from GE, Biogen and consulting fees from AstraZeneca and Ipsen. J-CS reports consultancy fees from AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche-Genentech, Sanofi, Servier, Symphogen, Takeda. J-CS has been Full time employee for AstraZeneca (September 2017–December 2019) and is a shareholder of AstraZeneca, Gritstone. CF received travel, accommodations, expenses from Amgen; Genentech; GlaxoSmithKline; MedImmune. CM is an advisory board member, speaker, investigator at Amgen, Astellas, AstraZeneca, Bayer, Celgene, Genentech, Ipsen, Janssen, Eli Lilly, Novartis, Pfizer, Roche, Sanofi, Orion. USG received support for presentation activities for Dr Sennewald Medizintechnik GmbH, has received support for investigator initiated clinical studies (IITs) from MSD and AstraZeneca and contributed at Advisory Boards Meetings of AstraZeneca and Bristol-Myers Squibb. RF received grants/research support from MSD; AstraZeneca; Merck (Germany/Darmstadt); Novocure; honoraria/consultation fees: MSD; AstraZeneca; Merck (Germany/Darmstadt); Novocure; Fresenius and reports participation in a company sponsered speakers bureau: AstraZeneca; MSD; Merck (Germany/Darmstadt); Sennewald; Novocure; Brainlab; Roche. ED has declared consulting fees and support from Roche, BMS, Boehringer, AstraZeneca, Lilly Amgen and Merck-Serono.
Ethics approval The study protocol was approved by the Medical Ethics Committee of each center. Patients provided informed consent in accordance with their respective trial protocols.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.


Indianapolis, IN (August 26, 2014) - Following Breaking Bad's 5 Emmy Award wins last night, GreenLight is excited to announce our new licensing agreement with Sony Pictures. GreenLight will be creating a series of vehicle replicas from the cultural phenomenon television show.
Breaking Bad won 5 Emmy Awards last night including Outstanding Drama Series, Outstanding Writing for a Drama Series, Outstanding Lead Actor in a Drama Series, Outstanding Supporting Actor in a Drama Series, and Outstanding Supporting Actress in a Drama Series for the final season of the show. Widely considered one of the greatest television shows of all time, Breaking Bad has won a total of 16 Emmy Awards, 8 Satellite Awards, 2 Golden Globes, and a People's Choice Award.


Complete line of parts and accessories for sale for Dynamo foosball tables including replacement parts for both coin operated and home foosball tables. Dynamo foosball tables stopped being produced shortly after the merge between Valley and Dynamo in late 1990's. Some Valley Tornado foosball parts are compatible with many Dynamo foosball tables. We still have many dynamo foosball table accessories and parts available for both old and new style tables including foosball balls, men, bearings, handles and more.
Dynamo foosball men are made out of hard plastic and come in four colors including red, blue, black and yellow. These foosball men also fit Great American Recreation games and others. These playing men are attached to standard 5/8″ steel rods with a nut and bolt or a roll pin depending on the model of the table. We sell the men individually or in sets of 11.


1.5 Litre Petrol Swirl pot with bulkhead stlye bracket fixing. 3 x Dash 6 and 1 x Dash 8 connections..
2.5L modular surge tank, universal. Fits 1 or 2 DW250il fuel pumps, PN 9-250. No fuel pumps includedModular Design allowing the use of one, two, or mounted externally utilizing the tank as a reservoir..
3.5L modular surge tank, universal. Fits 1 or 2 DW350il fuel pumps, PN 9-350. No fuel pumps includedModular Design allowing the use of one, two, or mounted externally utilizing the tank as a reservoir..


The guys did the webchat at the supercity 30 minutes ago and they talked about the next UK Tour, the new improvements on the site, Harry on Strictly.. below you have a brief resume with the most important things they said.
Thanks to @sc_pioneers, @mcflyaholic and @zoeibbotson for the info as I missed the webchat and Im going to watch it now if it's up at the supercity.
– Updates start in October.
– See email or news section.
– POINTS SYSTEMS IS GOING! You have 3 weeks to SPEND your points!!
– 27 date UK Theater tour.
– Tweet or message the guys on SC with your idea for a name of the tour as they can't think of one.
– Details to be released in next month about dates.
The guys are going to spend the day today with Tom Leishman doing a photoshoot for the 2012 calendar. Let's hope we can see some of this photoshoot soon!
@LoveLeishman Morning! Day 1 of the McFly calendar shoot. Here we go!!
@mcflyharry Opened Dougs arm rest. Look what I found……..such a perve.
I know all the McFly fans would love to help on this cause, no matter if they win or not. So let's show to the world how amazing the mcfly army is and donate as much as you can to this good cause that Georgia, Danny's girlfriend, is supporting. You don't have to be rich, you can donate as much as you want or can and be a part of this amazing cause. I already made a donation and i hope that all of you who are reading this right now made one too and tell other people mcfly fans or not to donate too.
@georgiahorsley1 As I'm sure some of you may know one of my good friends Natalie died last year and her wonderful sister @CristieatCiCi is raising money for a charity close to their hearts @CRY_UK by walking up Mount Snowdon on the 10th Sept. Unfortunately I can't take part as I will be at my sisters wedding. I've come up with an idea with a lot of help from the McFly boys to auction off two tickets for a McFly show next year. Plus a signed never seen before photo of the boys! The winning bid will be donated to the wonderful charity. Remember you must say who you are and and that your a McFly fan. The chance to win the McFly tickets and signed photo will end on Friday at 8:30pm the winner will be picked at random (so it doesn't matter if you don't have much money!) Winner will be announced on my twitter. So here's what you are bidding for: two tickets to see one *theatre date show early next year (you can choose which you would like to go to) (venue restrictions may apply) AND a never seen before photo of the boys signed by them all.


China Great Wall Industry Corporation LongMarch-3B/E launch vehicle has successfully delivered APStar-9 communication satellite to the target orbit.
An ILSLaunch Proton/Beeze-M launch vehicle has successfully delivered Turksat-4B communication satellite to the target orbit.
An Arianespace Ariane-5ECA launch vehicle has successfully delivered Sky Muster (NBN-Co 1A) and ARSAT-2 communication satellite to the target orbit.
An International Launch Services (ILS) Proton Breeze M launch vehicle has successfully delivered Inmarsat-5 F3 (I-5 F3) communication satellite to the target super-synchronous transfer orbit (SSTO). This marks the third Proton launch of the year and the 5th SSTO mission for ILS, a leader in providing launch services to the global commercial satellite industry.
Indian GSLV-D6 launch vehicle has successfully delivered GSat-6 communication satellite to the target orbit. GSLV-D6 was launched from the Second Launch Pad at Satish Dhawan Space Centre SHAR (SDSC SHAR), Sriharikota.


text:
Taliban don't believe in a peaceful solution to war: 2nd VP Danish
KABUL: Second Vice President Sarwar Danish on Monday blamed the Taliban for inordinate delays in the ongoing Doha peace talks.
At a press conference here in Kabul, he said the Taliban were "the main obstacle" for progress in the peace negotiations in Doha while lashing out at the group for their lack of dedication to a peaceful solution to the war in the country.
Danish blamed the Taliban for the stalemate in the talks, saying the group had shown no flexibility in its position.
Danish also called on the soon-to-be US administration to review and evaluate the country's decisions regarding the Afghan peace process, stressing there was a need for support to the process from all sides.
This comes as there has been no significant progress made in the intra-Afghan talks that were launched on Sept. 12 in Doha of Qatar because the negotiating sides are still bogged down in finalizing the technicalities.
It remains to be seen whether the new government, led by Joe Biden, will accept the US-Taliban deal signed in February or make a new decision in this regard.
Meanwhile, the Taliban have called on Biden to abide by the Doha accord and withdraw its forces from Afghanistan.