domain: chim sde

text:
Rasesh Pokharel

Qinzhi Li

Lian Zhou

Khalil Hanna
email: khalil.hanna@ensc-rennes.fr

Water flow and dissolved Mn II alter transformation of pipemidic acid by manganese oxide

Manganese oxides have been proposed as a promising geomedia to remove trace organic contaminants in both natural soils and artificial infiltration systems. Although MnO x -based redox processes have been largely investigated, little is known on the effects of water flow and dissolved Mn II on manganese-mediated redox reactions in saturated porous media. Here, we have demonstrated that the reactive transport of a widely used quinolone antibiotic, pipemidic acid (PIP), in MnO 2 -coated sand (MCS) columns is altered by the presence of dissolved Mn II , in situ generated as reduced ions or present in inflow solution. Decreasing flow rate or flow interruption facilitated oxidation reaction and generated redox byproducts (Mn II and PIP ox ). However, preloading of MCS columns with dissolved Mn II led to suppressed reactivity with PIP. When PIP and Mn II are simultaneously injected, competition between PIP and Mn II for binding at the edge sites takes place during the initial kinetic phase of reaction, while at later breakthrough time Mn II will occupy both edge and vacancy sites due to continuous supply of Mn II . We also developed a reactive transport model that accounts for adsorption kinetics to predict changes in transport behavior of antibiotics in presence of different doses of dissolved Mn II . This work has strong implications for an accurate assessment of reactivity of manganese oxides used as an engineered geomedia for quinolones remediation and in developing transport models of antibiotics in natural systems.

Introduction

The widespread occurrence of pharmaceuticals (e.g. quinolone antibiotics) in nature is an emerging global threat with alarming consequences on public health (e.g. multiple antimicrobial resistance has emerged as one of the serious health threats of the 21st century) [START_REF] Weist | ECDC publishes 2015 surveillance data on antimicrobial resistance and antimicrobial consumption in Europe[END_REF] and water resources quality. [START_REF] Ma | Occurrences and regional distributions of 20 antibiotics in water bodies during groundwater recharge[END_REF][START_REF] Lindberg | Behavior of Fluoroquinolones and Trimethoprim during Mechanical, Chemical, and Active Sludge Treatment of Sewage Water and Digestion of Sludge[END_REF][START_REF]WHO Pharmaceuticals in Drinking-water[END_REF] The use of recycled sewage sludge (which contain antibiotics up to several mg/L) [START_REF] Golet | Environmental Exposure Assessment of Fluoroquinolone Antibacterial Agents from Sewage to Soil[END_REF] by farmers globally as fertilizers for agricultural practices, further increases the chances of their reentry to humans/animals through soil-groundwater route. As a result, antibiotics have been detected in food and different water reservoirs such as surface, ground and drinking water at concentration levels ranging from ng/L to mg/L. [START_REF] Golet | Environmental Exposure and Risk Assessment of Fluoroquinolone Antibacterial Agents in Wastewater and River Water of the Glatt Valley Watershed, Switzerland[END_REF] The fate and transport of quinolones in aquatic and terrestrial systems are strongly related to their interactions with environmental mineral surfaces. Among redox-sensitive minerals, manganese species can be found as oxides and/or hydroxides in the form of coatings on other particles and/or as nodules of various diameters. [START_REF] Post | Manganese oxide minerals: Crystal structures and economic and environmental significance[END_REF] Manganese oxides are less abundant in comparison to Fe-oxyhydroxides but have higher redox potential. [START_REF] Sims | The Distribution of Micronutrient Cations in Soil Under Conditions of Varying Redox Potential and pH1[END_REF] Studies have shown that layered manganese oxide (also known as birnessite), one of the most common manganese oxides mineral in both terrestrial and marine settings [START_REF] Johnson | Towards a mechanistic understanding of carbon stabilization in manganese oxides[END_REF] , play an important role in the sorption and transformation of antibiotics. [START_REF] Jiang | Removal of ciprofloxacin from water by birnessite[END_REF][START_REF] Remucal | A critical review of the reactivity of manganese oxides with organic contaminants[END_REF][START_REF] Li | Oxidative transformation of levofloxacin by δ-MnO2: Products, pathways and toxicity assessment[END_REF][START_REF] Zhang | Oxidative Transformation of Fluoroquinolone Antibacterial Agents and Structurally Related Amines by Manganese Oxide[END_REF] Few studies have proposed birnessite coated sand as a potential geomedia in engineered infiltration systems to prevent quinolone from percolating into the groundwater sources. [START_REF] Charbonnet | Chemical Regeneration of Manganese Oxide-Coated Sand for Oxidation of Organic Stormwater Contaminants[END_REF][START_REF] Grebel | Oxidation of organic contaminants by manganese oxide geomedia for passive urban stormwater treatment systems[END_REF][START_REF] Balgooyen | Impact of bisphenol A influent concentration and reaction time on MnO2 transformation in a stirred flow reactor[END_REF] Although manganese oxides are of great interest from both natural and engineering points of view, most of available studies were limited to static batch experiments. [START_REF] Jiang | Removal of ciprofloxacin from water by birnessite[END_REF][START_REF] Remucal | A critical review of the reactivity of manganese oxides with organic contaminants[END_REF][START_REF] Li | Oxidative transformation of levofloxacin by δ-MnO2: Products, pathways and toxicity assessment[END_REF][START_REF] Zhang | Oxidative Transformation of Fluoroquinolone Antibacterial Agents and Structurally Related Amines by Manganese Oxide[END_REF][START_REF] Deng | Degradation of ciprofloxacin using α-MnO2 activated peroxymonosulfate process: Effect of water constituents, degradation intermediates and toxicity evaluation[END_REF] , and little is known about the assessment of redox transformation of antibiotics under flow-through conditions. Only two recent column studies have demonstrated the high reactivity of birnessite coated sand towards organic contaminants together with a progressive loss of reactivity over A c c e p t e d M a n u s c r i p t breakthrough time [START_REF] Charbonnet | Chemical Regeneration of Manganese Oxide-Coated Sand for Oxidation of Organic Stormwater Contaminants[END_REF][START_REF] Grebel | Oxidation of organic contaminants by manganese oxide geomedia for passive urban stormwater treatment systems[END_REF] , but mechanistic insights on the competitive adsorption of Mn II and organic compounds on MnO 2 surfaces and reactivity suppression under flow-through conditions is still missing. Furthermore, no data exist on how water flow variability influences the interactions of organic compounds and Mn II with birnessite surfaces. This is particularly relevant when solutes and redox byproducts (e.g. dissolved Mn II ) concurrently affect surface reactivity and thus mobility of compounds in environmental settings. Indeed, dissolved Mn II can interact with hexagonal birnessite (δ-MnO 2 and acid birnessite) and then transfer electron to lattice Mn IV producing Mn III , which induce changes in mineral structure and composition, e.g. conversion of birnessite into lower-valence Mn phases and/or modification of birnessite through adsorption or incorporation of Mn III into the mineral sheets. [START_REF] Lefkowitz | Influence of pH on the Reductive Transformation of Birnessite by Aqueous Mn(II)[END_REF][START_REF] Zhao | Redox Reactions between Mn(II) and Hexagonal Birnessite Change Its Layer Symmetry[END_REF][START_REF] Bargar | Biotic and abiotic products of Mn(II) oxidation by spores of the marine Bacillus sp. strain SG-1[END_REF][START_REF] Zhu | Decolorization of methylene blue by δ-MnO2-coated montmorillonite complexes: Emphasizing redox reactivity of Mn-oxide coatings[END_REF][START_REF] Lefkowitz | Impacts of Aqueous Mn(II) on the Sorption of Zn(II) by Hexagonal Birnessite[END_REF][START_REF] Elzinga | A Mn-54 Radiotracer Study of Mn Isotope Solid-Liquid Exchange during Reductive Transformation of Vernadite (δ-MnO2) by Aqueous Mn(II)[END_REF][START_REF] Hinkle | Impact of Mn(II)-Manganese Oxide Reactions on Ni and Zn Speciation[END_REF][START_REF] Elzinga | Reductive Transformation of Birnessite by Aqueous Mn(II)[END_REF][START_REF] Johnson | Real-Time Manganese Phase Dynamics during Biological and Abiotic Manganese Oxide Reduction[END_REF][START_REF] Ehlert | Impact of Birnessite on Arsenic and Iron Speciation during Microbial Reduction of Arsenic-Bearing Ferrihydrite[END_REF] This reductive transformation of hexagonal birnessite depends on several factors, including pH and the ratio of dissolved Mn II to structural Mn IV . [START_REF] Lefkowitz | Influence of pH on the Reductive Transformation of Birnessite by Aqueous Mn(II)[END_REF][START_REF] Elzinga | Reductive Transformation of Birnessite by Aqueous Mn(II)[END_REF] In this study, we investigate the adsorption and redox transformation of a model quinolone antibiotic, pipemidic acid (PIP), in water saturated MnO 2 -coated sand columns. Acid birnessite was used as it is structurally similar (layers with hexagonal sheet symmetry comprising of edgesharing Mn IV O 6 octahedra and nanoscale particle size distribution) to biogenic birnessite found in soils. [START_REF] Zhao | Redox Reactions between Mn(II) and Hexagonal Birnessite Change Its Layer Symmetry[END_REF][START_REF] Villalobos | Structural model for the biogenic Mn oxide produced by Pseudomonas putida[END_REF] Pipemidic acid, commonly used to treat urinary tract infections in humans and animals [START_REF] Shimizu | Pipemidic Acid: Absorption, Distribution, and Excretion[END_REF] , was chosen as a model quinolone compound. In order to mimic natural conditions where water movement is discontinuous, we employed the 'intermittent flow/no-flow' method in the column experiments. This technique allowed also to assess changes in reactivity of manganese oxides upon modification of the residence time in column. Furthermore, we also examined the impact of two contrasting concentrations of dissolved Mn II in the reactivity of MnO 2 -coated sand with PIP. The dissolved Mn II concentration range was chosen in order to cover a wide variety of relevant concentration found in shallow groundwater, soil pore waters and surface waters. [START_REF] Doula | Simultaneous removal of Cu, Mn and Zn from drinking water with the use of clinoptilolite and its Fe-modified form[END_REF][START_REF] Manzano | The impact of the Aznalcóllar mine tailing spill on groundwater[END_REF][32] Finally, a

Materials and Methods

Preparation and characterization of acid birnessite and manganese oxide-coated quartz

Acid birnessite (AB) was prepared following the procedure of McKenzie (1971). More details are provided in the Supporting Information. The solid was characterized using X-ray powder diffraction (XRD) using the Bruker AXS D8 Advance diffractometer (θ-2θ Bragg-Brentano geometry) using monochromatized CuKα1 radiation. X-ray diffraction (XRD) confirmed that the only product of the synthesis was poorly-crystalline hexagonal birnessite (Fig. S1). The Mn average oxidation state (AOS) was measured to be 3.98 ± 0.02 (SD) using the back-titration method with KMnO 4 solution. [START_REF] Kijima | Preparation and Characterization of Open Tunnel Oxide α-MnO2 Precipitated by Ozone Oxidation[END_REF] Scanning electron microscope (SEM; JEOL JSM-7100F) and High-resolution transmission electron microscope (HRTEM; JEOL 2100 LaB 6 ) were used for the ultrastructure examination of AB. SEM images showed that acid birnessite exhibits sheet stacked nanoflower spheres with a diameter of ∼400 nm (Fig. S2). HRTEM images showed aggregation of small crystalline domains surrounded by poorly-crystalline material. The surface area of AB was 57 ± 4.5 (SD) m 2 /g measured by N 2 adsorption BET method.

The prepared birnessite was coated with Fontainebleau quartz sand (150 -200 µm). Prior to coating, trace metal impurities from the pure quartz were removed (see the Supporting Information for details). The clean dried quartz was then mixed with AB suspension (quartz to AB ratio of 3). The ionic strength of the suspension was adjusted to 10mM using NaCl stock solution.

The suspension was then placed in a shaker at 130 rpm for 48 h. The excess solution was decanted, The coating density was within the previously reported range. [START_REF] Georgiadis | A simple method to produce birnessiteâcoated quartz sand[END_REF] Scanning electron microscope / Energy dispersive X-Ray spectroscopy (SEM/EDS) was applied to study the surface morphology and elemental composition of the MCS. Samples were examined with a JSM JEOL 7100 F with a field emission gun and OXFORD Genesis energy-dispersive X-ray spectrometer at 20kV at a working distance of 5-10 mm and magnifications from 10,000x to 20,000x. The SEM/EDAS imaging of MCS showed clusters/aggregates of AB inhomogenously distributed over the surface of MCS (Fig. S2). Aggregates tend to accumulate in surface depressions and cracks of the quartz surface. Examination using the highest SEM magnification showed particles in AB aggregates in coated sand were similar in morphology as uncoated AB, suggesting no significant modification in morphology occurred during the coating process. The quantitative EDAS spectra of MCS showed Mn, Si, and O as the main constituents (Fig. S8). Due to extremely low Mn amount in the MCS, XRD and AOS techniques could not be used for MCS characterization.

Dynamic column breakthrough experiments

The experimental setup used for dynamic column tests is described in Zhou et al. (2019).

Briefly, column experiments were conducted under ambient conditions and water-saturated conditions. Fifteen grams of MCS (containing 131 µmol MnO 2 ) was packed into a glass column with an internal diameter of 1.6 cm and a bed length of 4.7 cm. The uniform bulk density after packing was (1.59 ± 0.05 g/cm [START_REF] Lindberg | Behavior of Fluoroquinolones and Trimethoprim during Mechanical, Chemical, and Active Sludge Treatment of Sewage Water and Digestion of Sludge[END_REF] ). The pore volume (PV or V p ) of the column was 4 ± 0.1 mL. The

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A c c e p t e d M a n u s c r i p t column was saturated with a background solution of 10 mM NaCl (previously purged with N 2 ) at pH 6 with a constant flow-rate of 0.5 mL/min (residence time of 8 min). After saturation, bromide tracer experiments were performed to determine column transport properties using 10 mM sodium bromide (NaBr) solution at pH 6 as input solution and ionic chromatography to determine Br - breakthrough curve (Fig. S3). Details on calculation and interpretation of hydrodynamic parameters obtained from the bromide tracer experiments are provided in the Supporting Information. During water saturation and tracer experiments, total dissolved Mn in outflow was below the detection limit (<0.02 µM), and therefore possibility of mobilization of Mn particles was excluded from the column. Blank tests conducted also confirmed no adsorption of Mn II ions to the quartz sand (≤ 0.06 m 2 /g) used in this study.

Different column experiments were performed by injecting input solutions consisting of a constant amount of 10 mM NaCl and 10 µM pipemidic acid but with variable concentrations of Mn II . All input solutions were adjusted to pH 6 ± 0.1 and injected with a constant flow-rate of 0.5 mL/min, conditions close to or within range of natural soil pore water. [START_REF] Padilla | The effect of water content on solute transport in unsaturated porous media[END_REF][START_REF] Tye | Predicting the activity of Cd2+ and Zn2+ in soil pore water from the radio-labile metal fraction[END_REF] The input solution was purged with N 2 to avoid CO 2 contamination and maintain the experimental pH throughout the course of the experiment. Flow-interruption for 24 h (single or double) was done in some columns to assess the effect of residence time. After complete PIP breakthrough in some columns, desorption was done by injecting 10 mM NaCl at pH 6 at 0.5 mL/min. All effluent solutions were passed through a 0.2 µm filter and were collected in 7.5 mL -15 mL increments using a fractional collector. The pH of the effluent solution was determined by using an online pH meter. The effluent solution was also analyzed for PIP and by-products with High performance liquid chromatography (HPLC) and Ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) system. Details on experimental set-up for these techniques are provided in the Supporting Information. Because the adsorption of target compounds is negligible at pH higher than 10,

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A c c e p t e d M a n u s c r i p t desorption tests were conducted at pH 11 as a means to check the mass balance. After the column experiment, the solid bed was freeze-dried. The total Mn content in MCS before and after flow experiments was determined by ascorbic acid reductive dissolution [START_REF] Charbonnet | Chemical Regeneration of Manganese Oxide-Coated Sand for Oxidation of Organic Stormwater Contaminants[END_REF] and AAS measurement. SEM-EDS microscopy was performed to monitor morphological changes in the reacted MCS. All experiments were conducted in duplicates and showed a good reproducibility within 5% of average standard deviation.

Model approach

The transport of PIP through MCS columns both in the presence and absence of Mn II was simulated using a one-dimensional advection-dispersion model coupled with a two-site nonequilibrium adsorption model. [START_REF] Van Genuchten | Two-Site/Two-Region Models for Pesticide Transport and Degradation: Theoretical Development and Analytical Solutions[END_REF] Hydrus-1D program was used to obtain the model parameters for the two-site non-equilibrium model. The modeling approach used is explained in detail in the Supporting Information.

Results and Discussion

Adsorption and oxidation of PIP in MCS column

The breakthrough curve (BTC) of PIP exhibited sigmoidal-like shape but with an extensive tailing when PIP was injected in pristine MCS column (Fig. 1a). The first breakthrough point of PIP was at around 20 PV (pore volume) and later achieved a steady state breakthrough at around C/C 0 ~ 0.95 after injection of 600 PV. This partial breakthrough continued to be observed until the end of the column experiment (more than 1000 PV). Increasing the residence time in the column by interrupting flow did not influence the incomplete breakthrough, as the same partial breakthrough (C/C 0 ~ 0.95) was still observed upon flow resumption (Fig. 1a). This flow interruption period allowed species to react over a longer period during flow-through conditions.

Because the BTC of Br -used as a tracer showed no change upon flow interruption, we conclude Over the course of the experiment, the pH of the output solution increased only slightly (~0.6 units), but regained the original value of the input solution (pH 6 ± 0.1) when steady state breakthrough was attained (Fig. 1b). At our experimental pH range, the PIP molecule exists in a zwitterionic form (pK a1 and pK a2 values are 5.20 and 6.38, respectively). It is previously observed that quinolones binding to negatively charged Mn-oxide surfaces possibly through a metal-bound complex may involve proton co-binding. [START_REF] Zhang | Oxidative Transformation of Fluoroquinolone Antibacterial Agents and Structurally Related Amines by Manganese Oxide[END_REF] This binding can be associated with a heterogeneous redox reaction where two one-electron transfer steps or a single two-electron step resulting in the concomitant oxidation of PIP and reduction of surface-bound metal. One electron is transferred from ligand to the surface-bound Mn IV to yield radical intermediate and Mn III that can be further reduced to give Mn II . Subsequently, the formed radical intermediate may undergo several different reaction pathways to yield a range of by-products as shown by equation 1. A detailed step-wise reaction mechanism is provided in the Supporting Information.

A c c e p t e d M a n u s c r i p t ≡Mn IV + PIP→ ≡Mn IV -PIP ad → ≡Mn III /Mn II -PIP + → Mn II + PIP ox (1) To check the PIP heterogeneous reaction with MnO 2 , kinetic batch experiments were performed using 0.25 g MCS (2.2 µmol MnO 2 ) reacted with 10 µM PIP and 10mM NaCl solution at pH 6. As suggested by the mass balance, both adsorption and transformation processes may occur (Fig. 2). As an initial kinetic stage, the adsorbed amount increased to reach a maximum and then decreased. Once the PIP adsorbed reached a sufficient amount to trigger oxidation reaction, the oxidized amount increased to reach a steady-state (or plateau-like) (Fig. 2). However, Mn II aqueous concentration was below the detection limit (0.02 µM), most likely due to strong binding of Mn II to MCS surfaces at the working pH (i.e. pH 6). Indeed, adsorption isotherm determined at pH 6 showed great affinity of Mn II to MCS at the first stage, followed by an almost linear increase of adsorbed amount with increasing equilibrated Mn II concentration (Fig. S4). Since our experiments were performed under air ambient conditions, surface-catalyzed oxidation of Mn II by molecular oxygen could enable more Mn II sorption under oxic conditions relative to anoxic systems through the formation of new phases such as feitknechtite and/or manganite, as previously reported. [START_REF] Lefkowitz | Influence of pH on the Reductive Transformation of Birnessite by Aqueous Mn(II)[END_REF] However, it was also reported that formation of these lower valence Mn phases prevails at pH values higher than the working pH here (pH >7) and for high ratio of dissolved Mn II /MnO 2 . [START_REF] Lefkowitz | Influence of pH on the Reductive Transformation of Birnessite by Aqueous Mn(II)[END_REF][START_REF] Elzinga | Reductive Transformation of Birnessite by Aqueous Mn(II)[END_REF] Only a disturbance of stacking of MnO 2 sheets with no mineralogical transformation has been observed at pH 6. [START_REF] Lefkowitz | Influence of pH on the Reductive Transformation of Birnessite by Aqueous Mn(II)[END_REF] We verified this by conducting Mn II isotherm experiments with uncoated acid birnessite at pH 6 (±0.1) under both oxic and anoxic conditions.

Both isotherms overlapped at low range of Mn II /MnO 2 ratio, indicating no influence of O 2 at the experimental conditions of column tests. Only at higher Mn II /MnO 2 ratio (≥1.38), sharp removal in dissolved Mn II was observed under oxic conditions relative to anoxic systems (Fig. S5a), yet no new Mn-phase was detected by ATR-FTIR at pH 6 (Fig. S5b). The experimental setup as well as the results of all isotherm experiments is provided in the Supporting Information. The incomplete PIP breakthrough observed here (Fig. 1) suggests that both adsorption and transformation of PIP may also occur in the column system. The drop in PIP concentration under no-flow condition can result from rate-limited sorption/redox processes. Redox byproducts were then monitored in column effluent throughout the whole breakthrough time. Dissolved Mn II concentration was below the AAS detection limit (<0.02 µM), most likely because of the high tendency of manganese ions to be adsorbed at the oxide surface at the working pH. Dissolved Mn II (up to 1.5 µM) was only detected in column effluent after 24 h flow interruption and then flow resumption (Fig. 1b), probably because of generation of higher amount of Mn II . Indeed, flow interruption provided additional time for the PIP oxidation reaction to occur (eq. 1), resulting in accumulation of Mn II as redox byproduct in the column. Sorption of Mn II to MnO 2 surfaces may continue to proceed during the flow-interruption period, but was not able to entirely remove all accumulated Mn II . When flow was recommenced, elution of the interrupt-period resident solution caused a decrease in PIP concentration and an increase in Mn II concentration (Fig. 1b). Continuous injection of inflow solution led to an increase of PIP aqueous concentration up to reach the initial value and a decrease of Mn II concentration below the detection limit.

In order to assess the PIP oxidation reaction, all possible byproducts previously detected for analogous quinolone compounds [START_REF] Zhang | Oxidative Transformation of Fluoroquinolone Antibacterial Agents and Structurally Related Amines by Manganese Oxide[END_REF][START_REF] Wang | Oxidation of fluoroquinolone antibiotics and structurally related amines by chlorine dioxide: Reaction kinetics, product and pathway evaluation[END_REF] were searched by LC/MS. Consistently with past observations, PIP can be oxidized by MnO 2 through two one-electron transfers from the N atom of piperazine ring to Mn IV , generating Mn II and PIP cation radical. Further changes on the PIP cation radical can happen through C-hydroxylation and/or N-dealkylation that cause ring opening and subsequently forming several byproducts, as typically observed for other quinolones. [START_REF] Remucal | A critical review of the reactivity of manganese oxides with organic contaminants[END_REF][START_REF] Zhang | Oxidative Transformation of Fluoroquinolone Antibacterial Agents and Structurally Related Amines by Manganese Oxide[END_REF] However, only one predominant species of mass-to-charge ratio of m/z=227 can be detected using LC/MS (Fig. S6). The peak area of the LC/MS data of this species corresponding to M-26 (hereafter called PIP ox ) followed PIP breakthrough to reach a steady state (Fig. 1a). Because standards are not commercially available, an accurate quantification of formed species cannot be performed.

PIP ox broke out at the same time as the mother compound, reached a maximum and then decreased after ~100 PV to have a plateau (Fig. 1a). When the flow is resumed after 24 primary byproduct is highly expected. This primary byproduct reached a steady state concentration, thereby suggesting that a sorption/desorption equilibrium was reached.

The generation of redox byproducts (e.g. Mn II ) which in turn interact with MnO 2 surfaces may influence the ongoing oxidation reaction in the column, and thus affect the transport behavior of PIP in the column system. Furthermore, redox byproducts are flushing out of the column or moving up toward further zones, while they remained in contact with the reacted solid under static batch conditions. In order to test this hypothesis, the impact of dissolved Mn II on the MnO 2 reactivity was investigated under two situations: (i) PIP injection in Mn II -preloaded column and

(ii) simultaneous injection of PIP and dissolved Mn II in pristine columns.

Effects of dissolved Mn II on the MnO 2 reactivity and PIP oxidation in column

In the Mn II -preloaded column experiment, Mn II and PIP were injected in column after injection of ~346 PV with Mn II solution (10 µM), i.e. ~14 µmol of Mn II was reacted with 7.2 mg (131 µmol) of MnO 2 in the MCS column during preloading. Preloading of MCS column with 14 µmol of Mn II dramatically changed the transport behavior of PIP in terms of both retardation factor and breakthrough curve shape, as compared to no-preloading experiment (Fig. 3a and1a). The BTC of PIP became more sigmoidal/steeper, with an early breakthrough occurring at ~10PV and then a complete breakthrough at ~60 PV. No extensive tailing in both adsorption and desorption fronts (curve symmetry) was observed here relative to the BTC of PIP in no-preloading column. curve. This amount was considerably lower than that of the total PIP removed (adsorbed + oxidized) in no-preloading column (~2.6 µmol).

The complete PIP breakthrough and an incomplete Mn II breakthrough suggested preferential adsorption of Mn II over PIP in the Mn II preloaded MCS (Fig. 3). A total of ~22 µmol of Mn II was injected over the whole course of experiment, but only 8.2 µmol of total Mn II was removed (adsorbed + oxidized) as calculated by integrating breakthrough curve. This low Mn II /MnO 2 ratio (0.17) may explain why complete breakthrough of Mn II was never attained in the MCS column.

During Mn II preloading the solution pH rapidly decreased by ~1.5 units, most likely because of release of H + in the solution upon binding of Mn II ions to MnO 2 surfaces. Afterwards, outflow pH gradually increased to regain the inflow value, even after simultaneous injection of Mn II and PIP. Desorption front suggests that not all Mn II previously removed was released during desorption with 10 mM NaCl. Previous work indicates that monovalent cations like Na + cannot completely displace Mn II from the MnO 2 structures. [START_REF] Lafferty | Arsenite Oxidation by a Poorly-Crystalline Manganese Oxide. 3. Arsenic and Manganese Desorption[END_REF] Additional desorption tests in batch using 25 mM of Ca II as a desorption agent of solid-bound Mn II 16 did not allow more than 10% of previously adsorbed Mn II . We cannot rule out the possibility that comproportionation of Mn II to Mn III might have occurred under our experimental conditions, even if adsorption of Ca II on vacant sites is much weaker than Mn II and only high pH favors comproportionation reaction forming Mn III . [START_REF] Zhu | Cation Effects on the Layer Structure of Biogenic Mn-Oxides[END_REF] Indeed, infrared spectroscopic investigations (Fig. S5b) for uncoated MnO 2 in batch confirmed that transformation of hexagonal birnessite to manganite (γ-Mn III OOH) only occurred at high pH (i.e.

8) and high ratio of Mn II to MnO 2 (2.3).

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A c c e p t e d M a n u s c r i p t

Simultaneous injection of Mn II and PIP in pristine MCS column altered PIP mobility relative to injection of PIP alone in pristine MCS column or in Mn II -preloaded column. When low amount of Mn II (10 μM) was used, higher amount of PIP ox was detected in the column effluent resulting in a partial breakthrough of PIP (Fig. 4a). Complete breakthrough of PIP was only achieved after two interruption events through generation of more redox byproducts and thus by complete passivation of MnO 2 (Fig. 4a). At each flow interruption event, PIP concentration decreased and PIP ox and Mn II concentration increased, and then approached constant steady-state value (Fig. 4a and4b). The PIP ox became negligible after the second interruption event, as complete breakthrough was achieved for PIP.

Higher Mn II loading (117 µM) led to a steeper BTC and earlier breakthrough as compared to the BTC of PIP injected alone or with 10 µM of Mn II (Fig. 4a, 4c, and1a). The sharp decrease in pH during Mn II adsorption followed by a gradual increase to regain the original input value was observed here for both Mn II doses (Fig. 4b and4d). However, the decrease in pH was more

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A c c e p t e d M a n u s c r i p t pronounced during the high Mn II dose, indicating more Mn II adsorption. As expected, reacted Mn II amount (~6.4 µmol) estimated at the breakthrough point of PIP was higher than in the low Mn II dose column (~0.7 µmol). Furthermore, a complete PIP breakthrough was attained in the high Mn II dose and very low amount of PIP ox detected in column effluent, suggesting very low to negligible oxidation rate in this column. The desorption front of both PIP and Mn II indicated no significant tailing and an incomplete Mn II removal, similar to that observed in the Mn II preloaded column.

When 10 µM of Mn II was used as an inflow concentration, the amount of removed Mn II estimated before PIP breakthrough point (0.7 µmol) was much lower than 8.2 µmol removed in the Mn II preloaded column over the whole course of the experiment. This may explain why complete suppression of MnO 2 oxidative ability was only observed in the Mn II preloaded column. However, injection of higher amount of Mn II together with PIP, led to higher amount of removed Mn II (6.3 µmol), and thus complete suppression of MnO 2 oxidative ability. This falls in line with the very low amount of PIP ox observed in both high Mn II dose and Mn II preloading experiments.

A complete breakthrough of Mn II was also achieved after the second flow interruption (Fig. 4b). The C/C 0 of Mn II greater than 1 indicates the generation of dissolved Mn II from reductive dissolution of MnO 2 . This reductive dissolution has been confirmed by measuring the total Mn amount in the reacted MCS column. Around 44% decrease in total Mn content was observed as compared to the unreacted MCS. For other column experiments, only 15 % decrease in total Mn content was measured in the reacted MCS after breakthrough experiment. Taken together, the results showed that injection of high amount of Mn II or in situ generation of dissolved Mn II , for instance through flow interruption, may suppress PIP oxidation in the MCS columns.

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A c c e p t e d M a n u s c r i p t

PIP oxidation mechanisms in Mn II /MnO 2 systems

The structure of acid birnessite consists of two adsorption sites within its Mn IV O 6 octahedra layers: 1) edge sites at the edge of Mn IV octahedral sheets and 2) vacancy sites within the Mn IV octahedral sheets. [START_REF] Drits | Structure of synthetic monoclinic Na-rich birnessite and hexagonal birnessite: I. Results from X-ray diffraction and selected-area electron diffraction[END_REF] Because of their high density of negative charge, vacancies sites could be the primary location for cationic species (e.g. heavy metals), while high electronegative species (e.g. anionic species) would prefer edges sites. [START_REF] Villalobos | The Role of Surface Edge Sites in Metal(loid) Sorption to Poorly-Crystalline Birnessites[END_REF] As observed for oxyanions (e.g. As III and As V ) [START_REF] Lafferty | Arsenite Oxidation by a Poorly Crystalline Manganese-Oxide 1. Stirred-Flow Experiments[END_REF][START_REF] Tournassat | Arsenic(III) Oxidation by Birnessite and Precipitation of Manganese(II) Arsenate[END_REF][START_REF] Lafferty | Arsenite Oxidation by a Poorly Crystalline Manganese-Oxide. 2. Results from X-ray Absorption Spectroscopy and X-ray Diffraction[END_REF] or anionic ligands (e.g. phosphate) [START_REF] Villalobos | The Role of Surface Edge Sites in Metal(loid) Sorption to Poorly-Crystalline Birnessites[END_REF][START_REF] Yao | Adsorption of Phosphate on Manganese Dioxide in Seawater[END_REF] , it is likely that organic ligands such as pipemidic acid can be probably sorbed at edge sites. On the other hand, numerous studies reported that binding of cationic metals (e.g. Ni II , Zn II , Mn II ) likely occurs on edge sites as well as vacancy sites of hexagonal birnessite. [START_REF] Manceau | Natural speciation of Ni, Zn, Ba, and As in ferromanganese coatings on quartz using X-ray fluorescence, absorption, and diffraction[END_REF][START_REF] Peacock | Sorption of Ni by birnessite: Equilibrium controls on Ni in seawater[END_REF] For example, some reports showed that Mn II is preferentially sorbed at vacancy sites (higher thermodynamic stability forming triple corner-sharing complexes by sharing corners of its octahedral shell with Mn IV octahedral corners) until they are all occupied, and when all vacancy sites are occupied, Mn II will bind for the edge sites. [START_REF] Lafferty | Arsenite Oxidation by a Poorly Crystalline Manganese-Oxide 1. Stirred-Flow Experiments[END_REF][START_REF] Lafferty | Arsenite Oxidation by a Poorly Crystalline Manganese-Oxide. 2. Results from X-ray Absorption Spectroscopy and X-ray Diffraction[END_REF][START_REF] Manceau | Structure of heavy metal sorbed birnessite. Part III: Results from powder and polarized extended X-ray absorption fine structure spectroscopy[END_REF] However, a recent work reported that binding mechanisms of some cations (e.g. Co II ) are time dependent, i.e. they react first with edge sites within the first 10 min, and then diffuse to the vacancy sites at longer reaction times. [START_REF] Simanova | Time-Resolved Investigation of Cobalt Oxidation by Mn(III)-Rich δ-MnO2 Using Quick X-ray Absorption Spectroscopy[END_REF][START_REF] Wang | Diffusion-and pH-Dependent Reactivity of Layer-Type MnO2: Reactions at Particle Edges versus Vacancy Sites[END_REF] Collectively, we can assume that vacancies sites are the long-term adsorption and oxidation sites for cationic metals (e.g. Mn II ), whereas edges sites tend to interact with anionic species (e.g. PIP). At the first kinetic phase, competition between PIP and Mn II to edges sites can be expected.

ACS
When PIP is injected in pristine MCS column, PIP molecule will preferentially bind at the edge sites of MnO 2 , followed by electron-transfer reactions from ligand to surface-bound Mn IV resulting in the concomitant generation of PIP ox and Mn II , which can in turn interact with MnO 2 surfaces. The suppression of the oxidative ability of MnO 2 or the decrease in oxidation rate observed in the PIP/MnO 2 system under both batch and flow-through conditions, may result from competition of PIP and Mn II to interact with reactive surface sites and/or aqueous complexation of PIP with Mn II . The latter can be easily excluded because of weaker aqueous complexation of quinolones with divalent cations such as Mn II . [START_REF] Cuprys | Fluoroquinolones metal complexation and its environmental impacts[END_REF] However, more favorable electrostatic interactions exist between cationic metals and the negatively charged MnO 2 surface, thereby suggesting competition of PIP and Mn II for surface sites. Furthermore, the generated Mn II can exchange electrons with Mn IV to form two Mn III centers and, conversely, two Mn III centers can disproportionate to form Mn II and Mn IV centers. [START_REF] Balgooyen | Impact of bisphenol A influent concentration and reaction time on MnO2 transformation in a stirred flow reactor[END_REF] When Mn II is first injected in MCS column (i.e. preloading experiment), Mn II will interact first with edge sites and later diffuse to the vacancy sites (if we assume a similar behavior like Co II ). The vacancy content ranges from 6% (lowest) to 20 % (highest) of total Mn content (131 µmol here), corresponds to 8 and 26 µmol of vacancies, respectively. [START_REF] Villalobos | Structural model for the biogenic Mn oxide produced by Pseudomonas putida[END_REF][START_REF] Holguera | Contaminant loading and competitive access of Pb, Zn and Mn(III) to vacancy sites in biogenic MnO2[END_REF] In Mn II preloading, 14 µmol of Mn II was reacted before PIP injection, being within the range of the estimated vacancy content. If the diffusion-limited transport to vacancy sites makes the edges sites free again (potential binding sites for PIP), no competition between PIP and Mn II is expected here. However, the total adsorbed amount of PIP (~0.65 µmol) was much lower in the preloaded column than in other columns (e.g. pristine column). This observation can be explained if Mn II still occupied edges sites and compete with PIP, which could also depend on the amount of dissolved Mn II . Indeed, previous spectroscopic investigations of Co binding at hexagonal birnessite (δ-MnO 2 ) surfaces suggested that at longer time scale (t > 10 min) the adsorbed amount at vacancy sites keep increasing, while the amount at particle edges remained constant or decreased depending on the absence or presence of aqueous Co II . [START_REF] Wang | Diffusion-and pH-Dependent Reactivity of Layer-Type MnO2: Reactions at Particle Edges versus Vacancy Sites[END_REF] Unlike static batch reactors where the aqueous concentration of species tend to deplete, continuous supply of Mn II into MCS column enabled more competition for both edge and vacancy sites. This observation was supported by our batch data (Fig. S7 and2)

where adsorption of PIP remained constant with or without adding Mn II at longer reaction times i.e. 24 h, but lower oxidation rate was observed in presence of dissolved Mn II . Since all Mn II was removed within the first 10 minutes in batch, PIP may compete with Mn II as a first step (Fig. S7).

When diffusion of Mn II to vacancy sites take place, edge sites became free because of depleted aqueous Mn II in batch and thus competition became less pronounced.

When PIP and Mn II are simultaneously injected, PIP and Mn II will compete to bind at the edge sites as a first kinetic stage. Later when the edge sites are filled, Mn II will diffuse to the vacancy sites. Since most of PIP adsorption takes place in the first injected PV, there is probably competition between PIP and Mn II to bind at the edge sites, particularly for a short residence time in the column (i.e. 8 min). The amount of PIP removed was higher than in the preloading experiment where edges sites were mostly pre-occupied by Mn II . On the other hand, the amount of PIP removed (adsorbed + oxidized) determined by integrating the BTC decreased with increasing in Mn II dose (1.65 µmol at 10 µM of Mn II vs 0.78 µmol for 117 µM of Mn II ). When Mn II is in situ generated through flow interruption events, the binding and oxidative abilities of MnO 2 are further suppressed. Since high amount of Mn II is required to completely passivate MCS, several flowinterruptions events are needed to achieve complete breakthrough of PIP. This is also the case when low amount of Mn II was used (Fig 4a).

As mentioned previously, the incomplete desorption of adsorbed Mn II in column could also suggest the formation of Mn III species through comproportionation reaction of bound Mn II with structural Mn IV . However, no further adsorption of PIP is observed throughout all breakthrough experiment (i.e. C/C 0 remained constant), unlike As III and As V binding to newly formed Mn III species previously reported. [START_REF] Lafferty | Arsenite Oxidation by a Poorly Crystalline Manganese-Oxide 1. Stirred-Flow Experiments[END_REF][START_REF] Lafferty | Arsenite Oxidation by a Poorly Crystalline Manganese-Oxide. 2. Results from X-ray Absorption Spectroscopy and X-ray Diffraction[END_REF] Additionally, both ATR-FTIR and SEM/EDAS results showed no substantial differences in terms of composition or morphology between unreacted and reacted solids (Fig. S8), further ruling out significant mineral transformation under our experimental conditions.

The impact of dissolved Mn II on MCS reactivity and PIP mobility was further evaluated using a two-site non-equilibrium model in order to describe the breakthrough curves of PIP in nopreloaded and preloaded columns. Lower values for adsorption and oxidation parameters (R f or K d and µ s respectively; Table S1; Fig. 5) are required to accurately fit the experimental BTC in presence of Mn II . In simultaneous injection experiments, high dose of Mn II led to lower adsorption extent (K d or R f ), as expected from the experimental BTC. It is worth noting that fitted values of K d and µ s in Mn II preloaded and high Mn II dose column are close, confirming extensive suppression of MnO 2 reactivity in these columns. Indeed, complete breakthrough of PIP was observed upon adsorption of high amount of Mn II in MCS through preloading or injection of higher amount of dissolved Mn II .

Environmental Implications

Manganese oxides have the potential to be applied as a geomedia to prevent organic contaminants from percolating into the groundwater sources in both natural soils and artificial infiltration systems. We notably demonstrated that the reactivity of MCS can be strongly affected through reductive dissolution of birnessite and binding of reduced ions to MnO 2 surfaces. The presence of dissolved Mn II frequently found in shallow groundwater, soil pore waters and surface waters, can also alter surface reactivity and ultimately suppress the oxidative ability of birnessite.

The amount of dissolved Mn II available to compete with PIP for binding at the edge sites is the driving factor, but this effect depends on the experimental setup (static batch vs continuous dynamic flow). When a high amount of Mn II is contacted with MnO 2 surfaces through preloading or by increasing the inflow concentration, Mn II will interact first with edge sites and later diffuse to the vacancy sites, but both sites will be occupied due to continuous supply of Mn II in column experiments. Under these dynamic flow conditions, competition between PIP and Mn II to edges sites take place over the whole reaction time. However, under static batch conditions where the aqueous concentration of species depletes over time, competition between PIP and Mn II to edges sites is supposed to take place only during the first kinetic stage. Using reactive transport modeling, the estimated parameters are changed when column is previously loaded with Mn II , suggesting the modification of adsorption/oxidation mechanisms of PIP. Taken together, this work sheds light on an overlooked aspect of manganese-mediated redox reactions in presence of reduced ions and under flow-through conditions.

The implication of this work for environmental processes is twofold. First, the outcomes of this investigation will help in developing fate and transport models of quinolones in natural systems (e.g. groundwater and subsurface environments). Second, they are also pertinent for applications of MCS in engineered infiltration systems of contaminated waters (wastewater, stormwater, agricultural runoff, etc.). Our efforts aid to show various scenarios on how the feasibility and longevity of using MCS as a geomedia in such systems may fail. For example, contacting a high amount of Mn II with MCS before or simultaneously with target compound leads

A c c e

  p t e d M a n u s c r i p t transport model that accounts for oxidation and adsorption kinetics was used to help us in understanding adsorption/oxidation changes of PIP in presence of dissolved Mn II .

A c c e

  p t e d M a n u s c r i p t and the solid was washed several times with 10 mM NaCl solution until the runoff was clear. Then the AB coated quartz, hereafter referred as MnO 2 -coated sand (MCS), was dried at room temperature. Mn content in the MCS was determined by dissolving in 30 mM Ascorbic acid following the protocol of Charbonnet et al. (2018) and analyzed with Atomic absorption spectroscopy (AAS). The measured amount was 0.48 ± 0.02 (SD) mg Mn in one gram of MCS.

A c c e 41 Fig. 1 :

 411 Fig. 1: Breakthrough curves of (a) PIP and PIP ox (peak area of PIP byproduct; M-26) and (b) pH and Mn II . The dashed lines indicate the theoretical complete breakthrough of PIP (C/C 0 = 1) in (a) and detection limit of Mn II (0.02 µM) in (b). The arrow indicates the moment of flow-interruption (duration 24 h; V/V p = 876). Inflow conditions: 10 µM PIP, pH: 6.1 ± 0.1, 10 mM NaCl, PV: 4 mL, flowrate: 0.5 mL/min.

Fig. 2 :

 2 Fig. 2: Removal kinetics of PIP (aqueous residual PIP concentration, red circles in primary Y-axis) and evolution of PIP removed by adsorption and oxidation (black and white squares in secondary Y-axis) over reaction time. Adsorbed amount was determined as the difference between the total aqueous concentration after desorption and the residual concentration, and oxidized amount was determined as the difference between the initial concentration and the total aqueous concentration. Experimental conditions: 10 µM PIP; 10 mM NaCl; pH: 6 ±0.1; MCS amount: 0.25 g (~2.2 µmol MnO 2 ).

A c c e p t e d M a n u s c r i p t

  h flow interruption period, PIP ox concentration spiked up before reaching plateau again, suggesting the occurrence of kinetically limited redox process in the column system. Both sorption/desorption and oxidation reactions are expected during the flow interruption event, PIP concentration decreased and byproduct concentration increased, and then approached constant steady-state values. Because of a constant partial breakthrough (i.e. C/C 0 < 1) observed, ongoing oxidation and formation of ACS Paragon Plus Environment Environmental Science & Technology A c c e p t e d M a n u s c r i p t

Furthermore, complete

  breakthrough (i.e. C/C 0 =1) of PIP was achieved, suggesting very low to negligible oxidation extent under these experimental conditions. This was confirmed by the very low amount of PIP ox detected in the column effluent (Fig.3b). Since the oxidation was almost absent, the total removed amount of PIP in column should correspond to the adsorbed amount, determined as ~0.65 µmol of PIP bound to Mn II preloaded MCS by integrating the breakthrough ACS Paragon Plus Environment Environmental Science & TechnologyA c c e p t e d M a n u s c r i p t

Fig. 5 :

 5 Fig. 5: Experimental and modeling BTCs of PIP for all experiments. Solid line represents the calculated BTCs. Dashed line indicate theoretical complete breakthrough (C/C 0 = 1).

  to faster suppression of the MCS oxidative ability. Furthermore, flow interruption (or extremely low pore-water velocities and low Péclet number where diffusion dominates over advection) could trigger accelerated heterogeneous redox reactions to transform quinolones with MCS, but simultaneously generate large amounts of Mn II to progressively diminish MCS reactivity. These observations could help to design MCS based treatment systems with great longevity. For instance, (electro)coagulation or oxidation and filtration systems prior to treatment with the MCS geomedia could be proposed as a potential solution to remove the dissolved Mn II . Second, coupling water flow interruption with an in situ regeneration (e.g. using chlorine based oxidant or manganeseoxidizing microbes) of passivated MCS geomedia could increase both efficiency and longevity of manganese oxides based treatment systems. Finally, increasing the number of available reactive sites of MCS by increasing the coating density could further aid in developing effective systems for remediation of organic contamination. Synthesis of acid birnessite, procedure to clean quartz sand, bromide tracer experiments, oxalic acid-permanganate back-titration method, detection of pipemidic acid and byproducts by chromatographic analysis, batch experiments, isotherm experiments, model approach, and reaction mechanism of PIP and MnO 2 . Figures: XRD of AB, SEM and TEM images of AB and MCS, experimental and calculated bromide tracer breakthrough curve, sorption isotherm with MCS, sorption isotherm and ATR-FTIR with acid birnessite, PIP and PIP ox molecular structure, batch kinetic study, and SEM/EDAS imaging of MCS. Table: Parameters of PIP transport under step-injection conditions.

	Environmental Science & Technology Environmental Science & Technology
	M a n u s c r i p t
	ACS Paragon Plus Environment A c c e p t e d Supporting Information Methods: ACS Paragon Plus Environment

Acknowledgements

This work was supported by the Institut Universitaire de France (IUF) and Région Bretagne (SAD). We gratefully acknowledge Valerie Courousse for assistance in AAS measurements and Isabelle Soutrel for LC/MS measurements. We are also thankful to Francis Gouttefangeas, Mathieu Pasturel, and Vincent Dorcet for SEM, XRD, and TEM measurements respectively. Finally, we thank the three anonymous reviewers for their constructive comments.


MD Martin Bordet

Jean-François Bretagne
email: jf.bretagne@gmail.com

MD Christine Piette

BS Chloé Rousseau

MD Thomas Grainville

MD Mathilde Cosson

MD, PhD Astrid Lièvre

MD Jean-François Bretagne

J.-F Bretagne

Reappraisal of the characteristics, management, and prognosis of intramucosal colorectal cancers and their comparison with T1 carcinomas

Keywords: colorectal cancer, intramucosal cancer, T1 colorectal cancer, endoscopic

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

therapy, surgical treatment, colorectal cancer prognosis, colorectal cancer screening INTRODUCTION European guidelines for colorectal cancer (CRC) screening have used the revised Vienna classification [START_REF] Dixon | Gastrointestinal epithelial neoplasia: Vienna revisited[END_REF] in a simplified form for the characterization of colorectal neoplastic lesions. [START_REF] Quirke | European guidelines for quality assurance in colorectal cancer screening and diagnosis. First Edition -Quality assurance in pathology in colorectal cancer screening and diagnosis[END_REF] Thus, after removing indefinite neoplasia, colorectal lesions are classified into 4 pathological categories: negative for neoplasia, low-grade neoplasia, high-grade neoplasia, and invasive carcinoma. [START_REF] Quirke | European guidelines for quality assurance in colorectal cancer screening and diagnosis. First Edition -Quality assurance in pathology in colorectal cancer screening and diagnosis[END_REF] The term intramucosal carcinoma (IMC) was not retained and was substituted with mucosal high-grade neoplasia, whereas invasive carcinomas were characterized by the invasion of neoplastic cells into the submucosa or beyond. This dichotomy was based on patients with IMCs being considered at negligible risk of lymph node metastases, in connection with the lymphatic vessels present in the mucosal layer perhaps being immature or not communicating with the deeper lymphatic network. [START_REF] Fogt | Identification of lymphatic vessels in malignant, adenomatous and normal colonic mucosa using the novel immunostain D2-40[END_REF] However, the concept of invasive IMC has recently emerged from studies demonstrating the occurrence of lymphovascular invasion in cases of IMC, although the potential for lymph node metastasis in such cases has yet to be established. [START_REF] Hashimoto | Intramucosal colorectal carcinoma with lymphovascular invasion: clinicopathological characteristics of nine cases[END_REF] All of these considerations have led to various problems: first, the actual incidence of screen-detected carcinomas has been underestimated in most studies of CRC screening programs excluding IMC, whereas in France, IMC were included in the evaluation of the performance of the national screening program and where they represented 27.7% of all of the carcinomas detected with the guaiac test in 2008 to 2009; [START_REF] Leuraud | Colorectal cancer screening by guaiac faecal occult blood test in France: Evaluation of the programme two years after launching[END_REF] second, the management and prognosis of screen-detected IMCs are unknown because these carcinomas are only part of the lesions included in the high-grade neoplasia category; and third, little is known about the characteristics, management and prognosis of IMC compared with early invasive carcinomas, ie, those limited to the submucosa, also called T1 carcinomas. In this article, IMCs correspond to Tis cancers in the current International Union Against Cancer (UICC) tumor-nodes-metastasis (TNM) classification, [START_REF] Brierley | The TNM classification of malignant tumors[END_REF] ie, cancers with invasion of the lamina propria and eventually into the muscularis mucosae, but not beyond, which excludes intraepithelial cancers, the latter being indistinguishable from what many pathologists call high-grade dysplasia. As for T1 cancers, they invade the submucosa, but not the muscularis propria. [START_REF] Brierley | The TNM classification of malignant tumors[END_REF] It was stated that the management of screen-detected carcinomas should not differ, stage for stage, from that required for symptomatic disease. [START_REF] Steele | European guidelines for quality assurance in colorectal cancer screening and diagnosis. First Edition -Management of lesions detected in colorectal cancer screening[END_REF] However, because screening detects a higher proportion of early disease compared with that diagnosed in the symptomatic population, it is important to check that early cancers are properly managed. We and others have reported the existence of variations in the treatment of significant polyps and early CRC and have pointed out a specialist tribalism continuing to dominate the management of such lesions. [START_REF] Roy | Frequency of and risk factors for the surgical resection of nonmalignant colorectal polyps: a population-based study[END_REF][START_REF] Dattani | Variations in the management of significant polyps and early colorectal cancer: results from a multicentre observational study of 383 patients[END_REF][START_REF] Dattani | Understanding variations in the treatment of significant polyps and early colorectal cancer[END_REF] Although endoscopic therapeutic management can be expected in the vast majority of IMC cases, little is known about the actual conditions for resection of IMC in the literature. [START_REF] Mounzer | Endoscopic and surgical treatment of malignant colorectal polyps: a population-based comparative study[END_REF] Therefore, the primary aim of this study was to use a population-based approach to assess the characteristics of all screen-detected IMCs in one district in France over a 13-year period and to examine the management strategies used and the outcomes of these patients. The secondary purposes of our study were to compare these data with those recently reported for screen-detected T1 carcinoma in the same district at the same time [START_REF] Grainville | Management of T1 colorectal cancers detected at screening colonoscopy: A study from the French national screening programme[END_REF] and to assess the factors associated with therapeutic strategies for superficial cancers, ie, the summation of IMC and T1 cancers.

POPULATION AND METHODS

Study population

This study was a retrospective analysis of a prospective, multicentric cohort including all patients with IMC and T1 adenocarcinomas diagnosed after a positive fecal blood test through the national screening program in the Ille et Vilaine district from 2003 to 2015. Data were prospectively and regularly collected by the ADECI 35 (Association du Dépistage des Cancers en Ille et Vilaine) staff. There were 14,215 (2.5%) positive tests followed by 13,245 colonoscopies (93.2%). The switch from guaiac to immunochemical testing occurred in 2015. [START_REF] Bretagne | Switching from guaiac to immunochemical faecal occult blood test increases participation and diagnostic yield of colorectal cancer screening[END_REF] Every patient with screening-detected IMC was included in the study. According to the French recommendations [START_REF] Selves | Guidelines for the management of malignant colorectal polyps (pTis and pT1) treated by endoscopic resection[END_REF] based on the data from the current UICC/TNM classification 6 , intraepithelial carcinomas were excluded from the study. Demographic and baseline clinical data and details on the treatment and follow-up were recorded. The CRC screening program was declared and approved by the CNIL (Commission Nationale de l'Informatique et des Libertés) on August 30, 2002 (no. 812571). This research was approved by the CCTIRS (Comité Consultatif pour le Traitement de l'Information en Matière de Recherche dans le Domaine de la Santé).

Colonoscopy data

The date of the colonoscopy, the details of the gastroenterologist who performed the colonoscopy and of the endoscopy center where the colonoscopy was performed, the macroscopic features of colorectal neoplasias, and histological data were recorded. We investigated whether complex polyps were referred to a skilled endoscopist in distinguishing between simultaneous or delayed endoscopic resection, compared with diagnostic colonoscopy. The size of the malignant polyps, assessed by the endoscopists by using an open biopsy forceps as a standard, was categorized as <20 mm, 20 to 29 mm, or ≥30 mm. Malignant polyps located in the cecum, the right colon segment, the hepatic flexure or the transverse colon were considered proximal, whereas polyps adjacent or distal to the splenic flexure were considered distal, except for polyps of the rectum, which were isolated in a single category. According to their appearance, polyps were defined as pedunculated or sessile. The rare polyps described as flat were defined as sessile for the study. When 2 IMC were found by the same colonoscopy, the index case was that with the worse pathological features or the larger when the pathological severity was the same. Nonmalignant polyps were also recorded, and polyposis was defined as the presence of 10 polyps or more.

The endoscopic resection techniques used, such as snare polypectomy, endoscopic mucosal resection (EMR), and monobloc or piecemeal resection, were recorded. Postendoscopic adverse events and their severity grades as defined by ASGE were recorded. [START_REF] Cotton | A lexicon for endoscopic adverse events: report of an ASGE workshop[END_REF]

Surgery characteristics

The date of surgery, the details of the surgeon and surgery center, modalities (type and indications), postoperative adverse events as defined by the Clavien-Dindo classification, [START_REF] Dindo | Classification of Surgical Complications: A New Proposal With Evaluation in a Cohort of 6336 Patients and Results of a Survey[END_REF] and pathology analysis of surgical specimen were collected. Severe postoperative adverse events were those rated ≥IIIa. Surgery was called primary when the cancer was surgically resected after a diagnostic colonoscopy and secondary when the cancer had been primarily endoscopically resected, but there was an indication for complementary surgery. Data about the lymph nodes (number, invasion) were collected except for transanal resection because lymph nodes were not removed with this technique.

Histological features

Histological features were retrospectively assessed by reviewing the patient files. The following parameters were recorded: differentiation, depth of invasion, budding, presence of vascular or lymphatic invasion, perineural neoplastic invasion, and the surgical margins. If a feature was not mentioned in the histopathology report, we did not assume it was absent.

Follow-up

The close follow-up of patients aimed to assess mortality related or not related to tumor progression and local or metastatic recurrence. Data were collected until last followup or date of last medical record.

Statistical analysis

Quantitative variables are expressed as the means and standard deviations and were compared with the t-test or the Mann-Whitney Wilcoxon test. Qualitative variables are expressed as numbers or percentages and were compared with X² test or the Fisher test.

Factors associated with the therapeutic strategy were investigated using univariate logistic regression. Potential covariates (p ≤ 0.20) were placed into a multivariable logistic regression model that was performed using stepwise backward elimination. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were used to express the association between the studied features and outcomes. By considering patients with IMC or T1 carcinomas as a single group of superficial cancers, we assessed the factors associated with the choice of primary treatment, ie, endoscopic or surgical resection. For this analysis, we selected the gastroenterologists who performed 10 colonoscopies or more harboring one superficial cancer, whereas those contributing less than 10 cases of IMC/T1 cancer polyps were all combined together and considered as one gastroenterologist.

All of the analyses were performed using the SAS statistical software program SAS, version 9.4 (SAS Institute, Inc, Cary, NC, USA). A test was interpreted as significant if p was less than 0.05.

RESULTS

Characteristics of the IMC cohort

Over the 13-year period, 1060 cases of CRC were diagnosed, including 282 (26.6%) IMCs and 207 (19.5%) T1 adenocarcinomas, ie, 46.1% of all CRC cases were superficial cancers. The detailed characteristics of the T1 CRC cohort already published are not presented here. [START_REF] Grainville | Management of T1 colorectal cancers detected at screening colonoscopy: A study from the French national screening programme[END_REF] Here, we present the data concerning the IMC population and the comparative analysis between IMCs and T1 CRCs. There were 176 (62.4%) men and 106 (37.6%) women. The mean time between the positive fecal blood test and the diagnostic colonoscopy was 61.4 ± 63.4 days. The colonoscopies were performed by 51 various gastroenterologists in 21 endoscopy centers. The colonoscopies were performed in private centers in 247 (87.6%) cases and in public centers in 35 (12.4%) cases. The number of colonoscopies harboring IMC ranged from 1 to 18 (mean 5.4) per gastroenterologist. Twelve gastroenterologists performed 10 colonoscopies or more. The characteristics of the IMC cohort are reported in Table 1.

Characteristics of IMC and associated lesions

The mean size of IMCs was 22.5 ± 11.2 mm. IMCs were preferentially located in the distal colon and particularly in the sigmoid colon (n=174, 61.7%). Most of the malignant polyps were pedunculated. In 58.1% of the cases, IMC was associated with at least another polyp (mean 2.4 ± 1.6), and polyposis was diagnosed in 8 (2.8%) patients. A second IMC coexisted in 10 (3.5%) patients.

Management of IMC

Among the 282 patients with IMC, 227 (80.5%) underwent endoscopic resection, and 55 (19.5%) underwent primary surgical resection.

Endoscopic resection

The characteristics of patients and malignant polyps among those endoscopically resected are reported in Table 1. The treatment was performed during the diagnostic colonoscopy in 213 cases (93.8%) and was postponed in the others for various reasons. In only 1 (0.4%) case, the patient was referred to an expert in a tertiary endoscopy center. A snare polypectomy was performed in 180 (79.3%) cases and EMR in 47 (20.7%) cases. En bloc resection was performed in 213 (93.8%) cases, whereas 14 (6.2%) were piecemeal, mainly in cases of EMR. Severe bleeding occurred in 4 (1.8%) patients requiring emergency colonoscopy (n=3) or colectomy (n=1) for hemostasis. None of the patients with endoscopically resected IMCs required subsequent surgical resection, except one with residual adenoma and high-grade dysplasia at the time of a close follow-up colonoscopy.

Surgical resection

The characteristics of the patients and malignant polyps among those surgically resected are reported in Table 1. The main types of surgery were sigmoidectomy in 18 (32.7%) cases, right colectomy in 14 (25.5%) cases and left colectomy in 9 (16.4%) cases, whereas transanal resection and anterior rectal resection were each performed in 5 cases (9.1%). Two other (3.6%) patients underwent proctectomy, 1 (1.8%) patient a total colectomy and 1 (1.8%) patient a cecal resection. The mean number of resected lymph nodes was 14.1 ± 10.8, but 24 (48%) patients had fewer than 12 lymph nodes resected. No lymph nodes metastases were observed in any of the surgically resected cases. Postoperative adverse events were noted in 6 (10.9%) patients, including 2 grade I adverse events and 4 grade III adverse events: peritonitis due to anastomotic leakage requiring emergency surgery and stoma (n=2); and severe bleeding (n=2) requiring one radiologic drainage and one surgical drainage. Among the 55 patients directly operated on, none required reoperation for cancer-related reasons.

Factors associated with surgical resection rather than endoscopic resection

In both univariate and multivariate analyses, factors significantly associated with surgical resection were found to be the characteristics of the malignant polyp (proximal localization, size ≥20 mm, sessile morphology) (Table 2). The parameter with the greatest statistical weight was a size ≥30 mm. By univariate analysis, the endoscopists did not seem to be associated with the decision for surgery rather than endoscopic resection (p=0.20).

Histopathological data for IMCs

The lamina propria was invaded in all cases and the muscularis mucosae in two cases. IMCs were reported to be well differentiated in 196 (69.5%) cases and moderately differentiated in 4 cases (1.4%), whereas differentiation was not mentioned in 82 (29.1%) cases. No vascular or lymphatic invasion was reported, and tumor budding was found in 1 (0.35%) case, but these features were not mentioned in approximately half of the pathology reports.

Margins were superior to 1 mm in the 55 (100%) IMCs in the surgical group, and 200 patients (88.1%) in the endoscopic treatment group.

IMC prognosis

Among the 282 patients with IMCs, follow-up data were available for 268 (95.0%) with a median follow-up of 6.1 ± 3.8 years. All 268 patients were followed up clinically and 259 had colonoscopic follow-up. In addition 47 patients had at least one ultrasound examination and 33 at least one CT scan. Death occurred in 14

Comparative analysis of IMC and T1 CRC cohorts

There were no differences in the patient and malignant polyp characteristics between the groups, except for a higher proportion of pedunculated polyps in the IMC group than in the T1 group (68.4% vs 50.2%, p<0.0001). The therapeutic strategies were quite different between the groups with a greater proportion of endoscopic resection as first line treatment (80.5% vs 60.9%, p<0.0001) and ultimate treatment (80.1% vs 21.3%, p<0.0001) in the IMC group. Patients with T1 cancers were referred more frequently to expert endoscopists than those with IMC (2.4% vs 0.4%, p=0.045). Among patients undergoing surgical resection with lymph node dissection the rate of lymph node metastasis was higher in T1 cancers than IMCs (9.5% vs 0%, p<0.05).

After endoscopic resection, the rate of adverse events, particularly that of bleedings, was significantly higher for T1 than for IMC (8.7% vs 1.8%, p=0.001). After surgical resection, the rate of nonsevere adverse events was significantly higher for T1 than for IMC (20.0% vs 3.6%, p=0.006), but there were no differences for severe adverse events (3.9% vs 7.3%, p=0.45).

Finally, as expected, the rates of cancer recurrence and cancer-related death were significantly higher for T1 patients than for IMC patients (5.6% vs 0%, p<0.0001, and 2.5% vs 0%, p=0.013).

Analysis of factors associated with first line surgery rather than endoscopic resection in the whole cohort of superficial cancers (n=489) By univariate and multivariate analyses, the factors significantly associated with first line surgery were the malignant polyps' characteristics (location, morphology, size) and the gastroenterologist having performed the index colonoscopy (Table 3). The factor having the greatest statistical weight was a polyp size ≥30 mm (OR, 66.67; 95% CI, 22.02 -201.89).

Compared with the endoscopist who had endoscopically resected 31 of 32 superficial cancers, the odds ratios for first-line surgery ranged from 1.1 to 159.1 (median=7.2) for the other endoscopists. The lower limit of the CI was greater than 1 for 11 of them by univariate analysis and 4 of them by multivariate analysis.

DISCUSSION

The main outcome of this 13-year population-based study was to determine the characteristics, management and prognosis of IMC. We focused on screen-detected superficial cancers because such lesions are increasingly being detected in screening programs and because their treatment should reduce CRC mortality and morbidity. [START_REF] Zauber | Colonoscopic Polypectomy and Long-Term Prevention of Colorectal-Cancer Deaths[END_REF][START_REF] Brenner | Reduced Risk of Colorectal Cancer Up to 10 Years After Screening, Surveillance, or Diagnostic Colonoscopy[END_REF][START_REF] Levin | Effects of Organized Colorectal Cancer Screening on Cancer Incidence and Mortality in a Large Community-Based Population[END_REF] In France, unlike other European countries, 2 screen-detected IMC are considered actual CRCs and not high-grade neoplasias. Of course, that fact must be considered when comparing the performance of screening tests and programs between various countries. Thus, the positive predictive value of a positive fecal blood test, which we reported to be 8.5% for CRC with the OC-Sensor test and a cut-off of 30 µg of hemoglobin per gram of feces used for FIT positivity, [START_REF] Bretagne | Switching from guaiac to immunochemical faecal occult blood test increases participation and diagnostic yield of colorectal cancer screening[END_REF] would become 6.7% after excluding IMCs and considering only invasive cancers.

Little is known about the characteristics, management and prognosis of IMCs, mainly because these lesions are included in the mucosal high-grade neoplasia category. 2 Some authors have even included IMCs in the advanced adenoma category, [START_REF] Quintero | Equivalency of fecal immunochemical tests and colonoscopy in familial colorectal cancer screening[END_REF] which from our point of view is questionable because the latter category usually includes adenomas that either are 1 cm or larger in size, have tubulovillous or villous components, or are high-grade dysplasias. [START_REF] Zorzi | Impact on colorectal cancer mortality of screening programmes based on the faecal immunochemical test[END_REF] In contrast to Hashimoto et al, who reported 9 cases of invasive IMC, [START_REF] Hashimoto | Intramucosal colorectal carcinoma with lymphovascular invasion: clinicopathological characteristics of nine cases[END_REF] we did not observe in the present study any cases of IMC with lymphovascular invasion. This finding, however, must be interpreted cautiously because our study suffered from a large proportion of missing histological data and from the absence of pathology reassessments.

Nevertheless, by demonstrating the absence of lymph node metastasis on surgical specimens and the absence of any cancer recurrence after endoscopic or surgical resection with a median follow-up of more than 6 years in almost 300 patients, our study confirmed the excellent prognosis of IMC and therefore the exceptional nature of metastatic IMC occurrence. [START_REF] Bracey | Metastatic intramucosal colorectal adenocarcinoma: a case to support review of current concepts (and staging) of early colorectal cancer[END_REF] The present study showed that the majority of IMCs were in the form of pedunculated polyps located in the distal colon. The proportion of distal polyps was higher in our study than in previous reports, [START_REF] Hassan | Efficacy and safety of endoscopic resection of large colorectal polyps: a systematic review and meta-analysis[END_REF] but this study was not devoted exclusively to IMCs. Here, we report a high rate (19.5%) of first-line surgical management for IMCs, whereas no patients needed surgery after direct endoscopic resection, except for one patient because of a residual tumor detected by close follow-up colonoscopy. Thus, the fears of the European panel 2 that the use of the term IMC instead of high-grade neoplasia by pathologists could lead to surgical resections after a first endoscopic resection were unfounded. Nevertheless, the question arises as to why there was such a high rate of direct surgical resection, even if, in a U.S. population-based study from 1998 to 2009, a much higher rate of surgery (56.4%) was reported for T0 CRCs, including not solely IMCs but also intraepithelial carcinomas. [START_REF] Mounzer | Endoscopic and surgical treatment of malignant colorectal polyps: a population-based comparative study[END_REF] By both univariate and multivariate analyses, we demonstrated that the factors significantly associated with surgical resection of IMC were the characteristics of the malignant polyps (proximal localization, size ≥20 mm, sessile morphology), knowing that the factor with the greatest statistical weight was a size ≥30 mm. The gastroenterologist who performed the colonoscopy leading to the diagnosis of IMC was not found to be a factor significantly associated with the choice of treatment --a result identical to that observed for the T1 CRC cohort but quite different from that observed for nonmalignant polyps. [START_REF] Roy | Frequency of and risk factors for the surgical resection of nonmalignant colorectal polyps: a population-based study[END_REF] However, both studies of IMCs and T1 carcinomas lacked statistical power, given the relatively small number of colonoscopies harboring such neoplastic lesions performed by each gastroenterologist. In fact, by pooling the two cohorts, the present study demonstrated that the gastroenterologist was a significant factor associated with the referral to surgery for superficial CRC. One could speculate that the rate of primary surgery for the IMC cohort would have decreased if patients had been referred to endoscopists with more expertise for the characterization and treatment of complex polyps. The lack of use of the Kudo pit pattern classification [START_REF] Kudo | Colorectal tumours and pit pattern[END_REF][START_REF] Kudo | Pit pattern in colorectal neoplasia: endoscopic magnifying view[END_REF] by French gastroenterologists is to be deplored because these data were not present in any of the colonoscopy reports in the period under review. The subjective impression left by the polyp to the endoscopist and the endoscopist's confidence in his(her) own ability to resect a probably malignant polyp are nonmeasurable factors which probably play an important role in the therapeutic decision. In other words, we suspect that the comfort level of the endoscopist with resection has an important impact on the management of malignant polyps. It is hoped that the appropriation of tools, such as the recently developed JNET [START_REF] Sumimoto | Diagnostic performance of Japan NBI Expert Team classification for differentiation among noninvasive, superficially invasive, and deeply invasive colorectal neoplasia[END_REF] and CONNECT [START_REF] Fabritius | A simplified table using validated diagnostic criteria is effective to improve characterization of colorectal polyps: the CONECCT teaching program[END_REF] classifications, for the characterization and the training of gastroenterologists in the various endoscopic resection techniques, including submucosal dissection not used in this series, will in the future reduce the rate of referral to surgeons for IMC. Our study shows that piecemeal removal of sessile IMCs exposes to the risk of residual or recurrent disease, but in every case it was nonmalignant disease. The rate of residual or recurrent disease we found in this study for sessile IMCs (15.5%) was rather lower than that observed in other series of malignant polyps. [START_REF] Seo | Recurrence after endoscopic piecemeal mucosal resection for large sessile colorectal polyps[END_REF] Nevertheless, we agree with the justification for performing a second-look colonoscopy in these cases of piecemeal resection. [START_REF] Seo | Recurrence after endoscopic piecemeal mucosal resection for large sessile colorectal polyps[END_REF] We are not aware of any studies in the literature comparing IMCs and T1 CRCs. The present study showed first that there were no significant differences between the characteristics of both cohorts' patients (age, sex). There were also no significant differences between the two cohorts in the morphology of the malignant polyps (size, localization), except for the morphology with a higher rate of sessile polyps for T1 than IMC (49.8% vs 31.6%, p<0.0001).

The latter result, in agreement with another study [START_REF] Kurome | Risk factors for high-grade dysplasia or carcinoma in colorectal adenoma cases treated with endoscopic polypectomy[END_REF] , argues in favor of the transformation of pedunculated polyps into sessile polyps during colorectal carcinogenesis. Sessile morphology of malignant polyps was a factor significantly associated with surgical treatment in both the IMC and T1 cohorts, partly explained the higher direct surgical referral rate observed in the T1 cohort, compared with the IMC cohort (39.1% vs 19.5%, p<0.0001). Of course, the rate of second-line surgery after primary endoscopic resection was higher for the T1 cohort than the IMC cohort (65.0% vs 0.44%, p<0.0001) due to the presence of high-risk pathological features of lymph node metastasis for T1 carcinomas. Similarly, the higher rate of lymph node metastasis found in patients operated on for T1 CRCs compared with IMCs (9.5% vs 0%, p=0.0409) was expected. Thus, our study highlights the excellent prognosis of patients with IMCs with the absence of any cancer recurrence and cancer-related mortality for IMCs, in contrast to TI CRCs (5.6% and 2.5%, respectively). Finally, we must emphasize the large difference in the rate of postendoscopic bleeding that we observed between the IMC and T1 CRC cohorts (1.8% vs 8.7%, p=0.001). The rate of postendoscopic bleeding in the IMC cohort is in agreement with that of other studies, [START_REF] Reumkens | Post-Colonoscopy Complications: A Systematic Review, Time Trends, and Meta-Analysis of Population-Based Studies[END_REF][START_REF] Saraste | Complications after colonoscopy and surgery in a population-based colorectal cancer screening programme[END_REF] whereas the relatively high rate of postendoscopic adverse events that we registered for the T1 carcinoma cohort was a topic of debate for us. [START_REF] Grainville | Management of T1 colorectal cancers detected at screening colonoscopy: A study from the French national screening programme[END_REF] We previously evoked the possible inexperience of some endoscopists in the endoscopic treatment of T1 carcinomas, but this hypothesis no longer holds because it was the same endoscopists who performed the endoscopic treatment of malignant polyps in both cohorts. In their meta-analysis including 50 studies of endoscopic resection of large (≥20 mm) colorectal polyps, including 58% invasive cancers, Hassan et al [START_REF] Hassan | Efficacy and safety of endoscopic resection of large colorectal polyps: a systematic review and meta-analysis[END_REF] reported a mean rate of 6.5% for bleeding. A recent Dutch study including T1 CRCs reported rates of 3.7% and 1.2% for bleeding and perforation, respectively. [START_REF] Van De Ven | Periprocedural adverse events after endoscopic resection of T1 colorectal carcinomas[END_REF] In accordance with these data, our findings raise questions about the safety of endoscopic resection for T1 CRC, which should be explored more extensively.

The main limitations of the present study were its retrospective nature and the suboptimal collection of data regarding some histopathological items. A reassessment of histological specimens by a gastrointestinal pathologist could have confirmed or not the poor interobserver agreement of the diagnosis of lamina propria invasion, which was reported in a short Japanese series. 33 Furthermore, it cannot be ruled out that such an analysis could have revealed signs of lymphovascular invasion in some cases of IMC. But this relative pathological weakness is largely compensated by the quality and duration of the follow-up never reported to date, which is one of the strengths of the study.

CONCLUSION

This long-term population-based study of 282 screening-detected IMCs highlights the excellent prognosis of these CRCs, which did not result in any specific mortality or long-term cancer recurrence regardless of the endoscopic or surgical treatment performed. Surgical patients had more right-sided, more sessile and larger lesions. We speculate that the rate of surgery of 19.6% could be decreased by referring patients to expert endoscopists. The comparison between IMCs and T1 CRCs showed that they are different cancers in terms of their management and prognosis. In addition, the much higher rate of bleeding observed after endoscopic resection of T1 CRCs compared with IMCs raises questions about the safety of endoscopic resection for T1 carcinomas.

  cases, but none was cancer related. No local or distant cancer recurrence was found during follow-up. Conversely, metachronous CRC was observed in 2 patients. Of the 49 patients with sessile endoscopically resected IMCs, 45 (91.8%) were followed by colonoscopy, and tumor residue or local recurrence was diagnosed in 7 cases (15.5%). Compared with en bloc resection, piecemeal removal was more frequently associated with residual/recurrent disease (3/36 [8.3%] vs 4/9 [44.4%], OR=8.8 [95% CI, 1.5 -51.6]; p=0.016). Residual or recurrent disease which corresponded to lowgrade dysplasia or high-grade dysplasia adenoma in 4 and 3 cases, respectively, was successfully treated by further endoscopic resection in 6 cases and by surgical resection in one case.

TABLE 1 .

 1 Characteristics of patients, colonoscopies, and polyps according to the treatment of

	intramucosal carcinomas
	Variable	Total IMC	Endoscopic	Surgical resection P value
		cohort	resection
	PATIENTS'	282 (100%)	227 (80.5%)	55 (19.5%)	< 0.0001
	CHARACTERISTICS
	Age (years)
	Median age	63.81 ± 7.11	63.81 ± 7.00	63.80 ± 7.60	0.992
	50-54	42 (14.9%)	31 (13.7%)	11 (20.0%)	0.581
	55-59	34 (12.1%)	30 (30.2%)	4 (7.3%)
	60-64	62 (22.0%)	51 (22.5%)	11 (20.0%)
	65-69	74 (26.2%)	58 (25.6%)	16 (29.1%)
	70-74	70 (24.8%)	57 (25.1%)	13 (23.6%)
	Sex
	Male	176 (62.4%)	141 (62.1%)	35 (63.6%)	0.834
	Female	106 (37.6%)	86 (37.9%)	20 (36.4%)

Distribution of patients according to the number of associated polyps (excluding the index case)

	No associated	118 (41.8%)	93 (41.0%)	25 (45.5%)	0.253
	polyps
		156 (55.3%)	129 (56.8%)	27 (49.1%)
	1 to 9 polyps
		8 (2.8%)	5 (2.2%)	3 (5.5%)
	Polyposis (⩾10)
	Year of the colonoscopy
	Before 2007	163 (57.8%)	133 (81.6%)	30 (18.4%)	0.586
	After 2007	119 (42.2%)	94 (79.0%)	25 (21.0%)

TABLE 2 .

 2 Factors associated with surgical resection rather than endoscopic resection of

	intramucosal carcinomas
	Variable	Univariate analysis		Multivariate analysis
	PATIENTS	Odd	95% CI	P value	Odd	95% CI	P value
	CHARACTERISTICS	ratio			ratio
	Age (years)	1.00	[0.96 -1.04]	0.992
	Sex
	Men	1 (ref)
				0.834
	Women	0.94	[0.51 -1.73]
	POLYPS
	CHARACTERISTICS
	Localization
	Rectum	1 (ref)			1 (ref)
	Proximal colon	5.37	[2.04 -14.19]		4.45	[1.25; 15.89]
				< 0.0001			0.0461
	Distal colon	0.52	[0.24 -1.12]		3.10	[0.98; 9.74]
	Size

TABLE 3 .

 3 Analysis of factors associated with first line surgery rather than endoscopic resection in the whole cohort of superficial cancers (n=489)

	Variable	Univariate analysis		Multivariate analysis
		OR	95% CI	P value	OR	95% CI	P value
	POLYPS CHARACTERISTICS
	Localization
	Rectum	1 (ref)		< 0.0001	1 (ref)		0.026
	Proximal	3.90	[1.9 -8.2]		3.97	[1.42 -
	Distal	0.49	[0.3 -0.8]		1.97	11.1]
						[0.90 -
						4.31]
	Size
	<20 mm	1 (ref)		< 0.0001	1 (ref)		< 0.0001
	20-29 mm	9.68	[4.3 -22.1]		19.37	[6.62 -
	≥30 mm	42.14	[18.27 -		66.67	56.63]
			97.21]			[22.02 -
						201.9]
	Morphology
	Pedunculated	1 (ref)		< 0.0001	1 (ref)		< 0.0001
	Sessile	8.31	[5.28 -		10.80	[5.4 -
			13.06]			21.67]
	INDIVIDUAL

ENDOSCOPISTS WHO PERFORMED AT LEAST 10 COLONOSCOPIES

ACKNOWLEDGEMENTS

The authors acknowledge the contributions of the general practitioners, gastroenterologists and surgeons in the district of Ille-et-Vilaine. They also acknowledge the staff in charge of the database at the screening centre, particularly Samuel Foucrit, a computer scientist.

List of abbreviations