A randomised phase II study of extended pleurectomy/decortication preceded or followed by chemotherapy in patients with early-stage pleural mesothelioma:EORTC 1205

BACKGROUND: The role of surgery in pleural mesothelioma remains controversial. It may be appropriate in highly selected patients as part of a multimodality treatment including chemotherapy. Recent years have seen a shift from extrapleural pleuropneumonectomy toward extended pleurectomy/decortication. The most optimal sequence of surgery and chemotherapy remains unknown. METHODS: EORTC-1205-LCG was a multicentric, noncomparative phase 2 trial, 1:1 randomising between immediate (arm A) and deferred surgery (arm B), followed or preceded by chemotherapy. Eligible patients (Eastern Cooperative Oncology Group 0-1) had treatment-naïve, borderline resectable T1-3 N0-1 M0 mesothelioma of any histology. Primary outcome was rate of success at 20 weeks, a composite end-point including 1) successfully completing both treatments within 20 weeks; 2) being alive with no signs of progressive disease; and 3) no residual grade 3-4 toxicity. Secondary end-points were toxicity, overall survival, progression-free survival and process indicators of surgical quality. FINDINGS: 69 patients were included in this trial. 56 (81%) patients completed three cycles of chemotherapy and 58 (84%) patients underwent surgery. Of the 64 patients in the primary analysis, 21 out of 30 patients in arm A (70.0%; 80% CI 56.8-81.0%) and 17 out of 34 patients (50.0%; 80% CI 37.8-62.2%) in arm B reached the statistical end-point for rate of success. Median progression-free survival and overall survival were 10.8 (95% CI 8.5-17.2) months and 27.1 (95% CI 22.6-64.3) months in arm A, and 8.0 (95% CI 7.2-21.9) months and 33.8 (95% CI 23.8-44.6) months in arm B. Macroscopic complete resection was obtained in 82.8% of patients. 30- and 90-day mortality were both 1.7%. No new safety signals were found, but treatment-related morbidity was high. INTERPRETATION: EORTC 1205 did not succeed in selecting a preferred sequence of pre- or post-operative chemotherapy. Either procedure is feasible with a low mortality, albeit consistent morbidity. A shared informed decision between surgeon and patient remains essential.</p

Pathways of methane removal in the sediment and water column of a seasonally anoxic eutrophic marine basin

Methane (CH4) is a key greenhouse gas. Coastal areas account for a major proportion of marine CH4 emissions. Eutrophication and associated bottom water hypoxia enhance CH4 production in coastal sediments. Here, we assess the fate of CH4 produced in sediments at a site in a seasonally anoxic eutrophic coastal marine basin (Scharendijke, Lake Grevelingen, the Netherlands) in spring (March) and late summer (September) in 2020. Removal of CH4 in the sediment through anaerobic oxidation with sulfate (Formula presented.) is known to be incomplete in this system, as confirmed here by only slightly higher values of δ13C-CH4 and δD-CH4 in the porewater in the shallow sulfate-methane-transition zone (~5-15 cm sediment depth) when compared to deeper sediment layers. In March 2020, when the water column was fully oxygenated, CH4 that escaped from the sediment was at least partially removed in the bottom water through aerobic oxidation. In September 2020, when the water column was anoxic below ~35 m water depth, CH4 accumulated to high concentrations (up to 73 µmol L-1) in the waters below the oxycline. The sharp counter gradient in oxygen and CH4 concentrations at ~35 m depth and increase in δ13C-CH4 and δD-CH4 above the oxycline indicate mostly aerobic water column removal of CH4. Water column profiles of particulate and dissolved Fe and Mn suggest redox cycling of both metals at the oxycline, pointing towards a potential role of metal oxides in CH4 removal. Water column profiles of (Formula presented.) and (Formula presented.) indicate removal of both solutes near the oxycline. Analyses of 16S rRNA gene sequences retrieved from the water column reveal the presence of aerobic CH4 oxidizing bacteria (Methylomonadaceae) and anaerobic methanotrophic archaea (Methanoperedenaceae), with the latter potentially capable of (Formula presented.) and/or metal-oxide dependent CH4 oxidation, near the oxycline. Overall, our results indicate sediment and water column removal of CH4 through a combination of aerobic and anaerobic pathways, which vary seasonally. Some of the CH4 appears to escape from the surface waters to the atmosphere, however. We conclude that eutrophication may make coastal waters a more important source of CH4 to the atmosphere than commonly assumed

Seasonal dynamics of the microbial methane filter in the water column of a eutrophic coastal basin

In coastal waters, methane-oxidizing bacteria (MOB) can form a methane biofilter and mitigate methane emissions. The metabolism of these MOBs is versatile, and the resilience to changing oxygen concentrations is potentially high. It is still unclear how seasonal changes in oxygen availability and water column chemistry affect the functioning of the methane biofilter and MOB community composition. Here, we determined water column methane and oxygen depth profiles, the methanotrophic community structure, methane oxidation potential, and water–air methane fluxes of a eutrophic marine basin during summer stratification and in the mixed water in spring and autumn. In spring, the MOB diversity and relative abundance were low. Yet, MOB formed a methane biofilter with up to 9% relative abundance and vertical niche partitioning during summer stratification. The vertical distribution and potential methane oxidation of MOB did not follow the upward shift of the oxycline during summer, and water–air fluxes remained below 0.6 mmol m−2 d−1. Together, this suggests active methane removal by MOB in the anoxic water. Surprisingly, with a weaker stratification, and therefore potentially increased oxygen supply, methane oxidation rates decreased, and water–air methane fluxes increased. Thus, despite the potential resilience of the MOB community, seasonal water column dynamics significantly influence methane removal

A sequential extraction procedure for particulate manganese and its application to coastal marine sediments

An existing sequential extraction scheme for particulate iron (Fe) is evaluated for manganese (Mn) using a range of Mn standards. The scheme consists of 5 steps and quantifies 5 operationally defined Mn pools (1) poorly ordered Mn oxides and Mn phosphates (ascorbic acid extractable); (2) Mn carbonates and Mn sulfides (1 M HCl extractable), (3 and 4) crystalline Mn oxides (citrate buffered dithionite and ammonium oxalate extractable, respectively) and (5) Mn associated with pyrite (concentrated HNO3 extractable). Application of the extraction scheme to coastal sediments from six locations (Black Sea, Baltic Sea, Bothnian Sea, Gulf of Mexico and Chesapeake Bay) highlights the dependency of sediment Mn partitioning on bottom water redox conditions. In sediments deposited in anoxic and sulfidic (euxinic) bottom waters, Mn is mostly present in Mn carbonates, pyrite and in non-reactive Mn forms, in approximately equal amounts. We find that in sediments deposited in periodically euxinic and hypoxic (oxygen <63 μmol L−1) waters, Mn carbonates dominate over the two other fractions, and small amounts of Mn oxides are observed. In sediments deposited in oxygenated bottom waters, Mn oxides, Mn-rich vivianite-type minerals and Mn carbonates dominate and no pyrite-bound Mn is observed. A large advantage of the extraction scheme is that it quantifies sediment forms of Mn and Fe simultaneously. Given the role of Mn as a bottom water redox proxy, the separation of poorly ordered Mn oxides, carbonates and pyrite is of specific relevance

A sequential extraction procedure for particulate manganese and its application to coastal marine sediments

An existing sequential extraction scheme for particulate iron (Fe) is evaluated for manganese (Mn) using a range of Mn standards. The scheme consists of 5 steps and quantifies 5 operationally defined Mn pools (1) poorly ordered Mn oxides and Mn phosphates (ascorbic acid extractable); (2) Mn carbonates and Mn sulfides (1 M HCl extractable), (3 and 4) crystalline Mn oxides (citrate buffered dithionite and ammonium oxalate extractable, respectively) and (5) Mn associated with pyrite (concentrated HNO3 extractable). Application of the extraction scheme to coastal sediments from six locations (Black Sea, Baltic Sea, Bothnian Sea, Gulf of Mexico and Chesapeake Bay) highlights the dependency of sediment Mn partitioning on bottom water redox conditions. In sediments deposited in anoxic and sulfidic (euxinic) bottom waters, Mn is mostly present in Mn carbonates, pyrite and in non-reactive Mn forms, in approximately equal amounts. We find that in sediments deposited in periodically euxinic and hypoxic (oxygen <63 μmol L−1) waters, Mn carbonates dominate over the two other fractions, and small amounts of Mn oxides are observed. In sediments deposited in oxygenated bottom waters, Mn oxides, Mn-rich vivianite-type minerals and Mn carbonates dominate and no pyrite-bound Mn is observed. A large advantage of the extraction scheme is that it quantifies sediment forms of Mn and Fe simultaneously. Given the role of Mn as a bottom water redox proxy, the separation of poorly ordered Mn oxides, carbonates and pyrite is of specific relevance

Selective proton-observed, carbon-edited (selPOCE) MRS method for measurement of glutamate and glutamine 13C-labeling in the human frontal cortex

Purpose: 13C magnetic resonance spectroscopy (MRS) in combination with infusion of 13C-labeled substrates has led to unique insights into human brain metabolism and neurotransmitter cycling. However, the low sensitivity of direct 13C MRS and high radiofrequency power requirements has limited 13C MRS studies to predominantly data acquisition in large volumes of the occipital cortex. The purpose of this study is to develop an MRS technique for localized detection of 13C-labeling of glutamate and glutamine in the human frontal lobe. Methods: We used an indirect (1H-[13C]), proton-observed, carbon-edited MRS sequence (selPOCE) for detection of 13C-labeled metabolites in relatively small volumes located in the frontal lobe at 4 T. The SelPOCE method allows for selective and separate detection of glutamate and glutamine resonances, which significantly overlap at magnetic field strengths used for clinical MRI. Results: Phantom data illustrate how selPOCE can be tuned to selectively detect 13C labeling in different metabolites. Three-dimensional specific absorption rate simulations of radiofrequency power deposition show that the selPOCE method operates comfortably within the global and local Food and Drug Administration specific absorption rate guidelines. In vivo selPOCE data are presented, which were acquired from a 45-mL volume in the frontal lobe of healthy subjects. The in vivo data show the time-dependent 13C-labeling of glutamate and glutamine during intravenous infusion of [1-13C]-glucose. Metrics describing spectral fitting quality of the glutamate and glutamine resonances are reported. Conclusions: The SelPOCE sequence allows the detection of 13C-labeling in glutamate and glutamine from a relatively small volume in the human frontal lobe at low radiofrequency power requirements. Magn Reson Med 80:11–20, 2018

On the magnetic field dependence of deuterium metabolic imaging

\u3cp\u3eDeuterium metabolic imaging (DMI) is a novel MR-based method to spatially map metabolism of deuterated substrates such as [6,6'-\u3csup\u3e2\u3c/sup\u3eH\u3csub\u3e2\u3c/sub\u3e]-glucose in vivo. Compared with traditional \u3csup\u3e13\u3c/sup\u3eC-MR-based metabolic studies, the MR sensitivity of DMI is high due to the larger \u3csup\u3e2\u3c/sup\u3eH magnetic moment and favorable T\u3csub\u3e1\u3c/sub\u3e and T\u3csub\u3e2\u3c/sub\u3e relaxation times. Here, the magnetic field dependence of DMI sensitivity and transmit efficiency is studied on phantoms and rat brain postmortem at 4, 9.4 and 11.7 T. The sensitivity and spectral resolution on human brain in vivo are investigated at 4 and 7 T before and after an oral dose of [6,6'-\u3csup\u3e2\u3c/sup\u3eH\u3csub\u3e2\u3c/sub\u3e]-glucose. For small animal surface coils (Ø 30 mm), the experimentally measured sensitivity and transmit efficiency scale with the magnetic field to a power of +1.75 and −0.30, respectively. These are in excellent agreement with theoretical predictions made from the principle of reciprocity for a coil noise-dominant regime. For larger human surface coils (Ø 80 mm), the sensitivity scales as a +1.65 power. The spectral resolution increases linearly due to near-constant linewidths. With optimal multireceiver arrays the acquisition of DMI at a nominal 1 mL spatial resolution is feasible at 7 T.\u3c/p\u3