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This paper presents the latest development of HyGenSys, a new sustainable process and technology for the conversion of natural gas to hydrogen and power. The concept combines a specific steam reforming reactor-exchanger with a gas turbine. The heat necessary for the steam reforming reaction comes from hot pressurized flue gases produced in a gas turbine instead of a conventional furnace. Thanks to this high level of heat integration, the overall efficiency is improved and the natural gas consumption is reduced which represents an advantage with regard to economics and CO2 emission reduction. In addition to the efficient HyGenSys process scheme itself, the technology of the reactorexchanger also offers a high level of heat integration for even more energy saving. Two main alternatives are examined in order to meet two different requirements. The first one, named HyGenSys-0, focuses on the hydrogen production for the refining and petrochemical application. The second one named HyGenSys-1, concerns the centralized power production with pre-combustion CO2capture. In that case, the produced hydrogen is fully used to fuel a power gas turbine. HyGenSys-1 has been developed and optimised in CACHET, a European Community funded project. The CACHET electrical power objective was 400 MW at the minimum. HyGenSys-0 and HyGenSys-1 are described in detail with challenges and advantages compared to existing technologies. For both alternatives, the heart of the technology is the reactor-exchanger. The reactor-exchanger design relies on an innovative arrangement of bayonet tubes that allows, at large scale, multiple heat exchanges between hot pressurized flue gas, natural gas feed and hydrogen rich stream produced. Cet article présente les développements récents d’HyGenSys, nouvel éco-procédé de conversion du gaz naturel en hydrogène et électricité. Le concept combine un réacteur-échangeur spécifique de reformage à la vapeur avec une turbine à gaz. En fait, la chaleur nécessaire pour la réaction de reformage à la vapeur provient des fumées pressurisées produites dans une turbine à gaz au lieu d’un four conventionnel. Grâce à cette intégration thermique poussée, l’efficacité globale est améliorée et la consommation de gaz naturel réduite, ce qui représente un avantage d’un point de vue économique et environnemental notamment vis-à-vis de la réduction des émissions de CO2. Deux déclinaisons du procédé sont détaillées, elles répondent chacune à des besoins différents. La première, appelée HyGenSys-0, correspond à la production d’hydrogène pour le raffinage et la pétrochimique. La deuxième, appelée HyGenSys-1, permet la production d’énergie centralisée avec la capture de CO2 en précombustion. Dans ce cas, l’hydrogène produit est entièrement utilisé pour alimenter une turbine de production d’électricité. HyGenSys-1 a été développé et optimisé au cours du projet CACHET, financé par la Communauté européenne, avec comme objectif de fournir une puissance de 400 MW minimum. Les versions HyGenSys-0 et HyGenSys-1 du procédé sont décrites en détail avec les défis et avantages comparés aux technologies existantes. Dans les deux cas, le coeur de la technologie est le réacteuréchangeur dont le développement est également présenté en détail. La conception de réacteur-échangeur est basée sur un arrangement innovant de tubes à baïonnette autorisant une conception à grande échelle, de l’échange thermique multiple entre la fumée pressurisée chaude, l’alimentation de gaz naturel et l’effluent riche en hydrogène.

Peritoneal metastases (PM) are common in metastatic colorectal cancer (mCRC). We aimed to characterize patients with mCRC and PM from a clinical and molecular perspective using the American Association of Cancer Research Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC) registry. Patients' tumor samples underwent targeted next-generation sequencing. Clinical characteristics and treatment outcomes were collected retrospectively. Overall survival (OS) from advanced disease and progression-free survival (PFS) from start of cancer-directed drug regimen were estimated and adjusted for the left truncation bias. A total of 1,281 patients were analyzed, 244 (19%) had PM at time of advanced disease. PM were associated with female sex [OR: 1.67; 95% confidence interval (CI): 1.11-2.54; P = 0.014] and higher histologic grade (OR: 1.72; 95% CI: 1.08-2.71; P = 0.022), while rectal primary tumors were less frequent in patients with PM (OR: 0.51; 95% CI: 0.29-0.88; P < 0.001). APC occurred less frequently in patients with PM (N = 151, 64% vs. N = 788, 79%) while MED12 alterations occurred more frequently in patients with PM (N = 20, 10% vs. N = 32, 4%); differences in MED12 were not significant when restricting to oncogenic and likely oncogenic variants according to OncoKB. Patients with PM had worse OS (HR: 1.45; 95% CI: 1.16-1.81) after adjustment for independently significant clinical and genomic predictors. PFS from initiation of first-line treatment did not differ by presence of PM. In conclusion, PM were more frequent in females and right-sided primary tumors. Differences in frequencies of MED12 and APC alterations were identified between patients with and without PM. PM were associated with shorter OS but not with PFS from first-line treatment., Significance: Utilizing the GENIE BPC registry, this study found that PM in patients with colorectal cancer occur more frequently in females and right-sided primary tumors and are associated with worse OS. In addition, we found a lower frequency of APC alterations and a higher frequency in MED12 alterations in patients with PM., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Background: Recent studies have demonstrated that T cells can induce vasodilation in a choline-acetyltransferase dependent manner, leading to an increase in T cell migration to infected tissues in response to viral infection, but its role in cancer is unclear. Choline acetyltransferase catalyzes the production of acetylcholine from choline and acetyl-CoA, however, acetylcholine is challenging to quantify due to its extremely short half-life while choline is stable. This study aims to correlate serum choline levels in patients with advanced solid tumors receiving pembrolizumab with treatment outcomes., Methods: Blood samples were collected at baseline and at week 7 (pre-cycle 3) in patients treated with pembrolizumab in the INvestigator-initiated Phase 2 Study of Pembrolizumab Immunological Response Evaluation phase II trial (NCT02644369). Samples were analyzed for choline and circulating tumor DNA (ctDNA). Multivariable Cox models were used to assess the association between choline and overall survival (OS) and progression-free survival (PFS) when including ΔctDNA C3 (the change in ctDNA from baseline to cycle 3), cohort, PD-L1 expression and tumor mutation burden (TMB). An independent validation cohort from the LIBERATE study (NCT03702309) included patients on early phase trials treated with a PD-1 inhibitor., Results: A total of 106 pts were included in the analysis. With a median follow-up of 12.6 months, median PFS and OS were 1.9 and 13.7 months, respectively. An increase in serum choline level at week 7 compared with baseline (Δcholine C3 ) in 81 pts was significantly associated with a better PFS (aHR 0.48, 95% CI 0.28 to 0.83, p=0.009), and a trend toward a better OS (aHR 0.64, 95% CI 0.37 to 1.12, p=0.119). A combination of ΔctDNA C3 and Δcholine C3 was prognostic for both OS and PFS. Multivariable analyses show Δcholine C3 was a prognostic factor for PFS independent of ΔctDNA C3 , cohort, PD-L1 and TMB. In the independent validation cohort (n=51), an increase in serum choline at cycle 2 was associated with a trend to improved PFS., Conclusions: This is the first exploratory report of serum choline levels in pan-cancer patients receiving pembrolizumab. The association between improved PFS and Δcholine C3 suggests a possible role for the cholinergic system in the regulation of antitumor immunity. Further pre-clinical and clinical studies are required to validate this finding., Trial Registration Number: NCT03702309., Competing Interests: Competing interests: ESG, W-JZ, ZAL, SCY, SL, SK, HB, SG, WX have no disclosures. GAW received travel grants from Bristol Myers Squibb and Abbvie, and honoraria from Pfizer. BW has received honoraria from AstraZeneca and Tessa Therapeutics. PLB: consulting/advisory (uncompensated) with Bristol-Myers Squibb, Seattle Genetics, Gilead, Merck, Pfizer, Amgen, Lilly; and institution receives clinical trials support from Novartis, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Roche/Genentech, AstraZeneca, Merck, Amgen, Zymeworks, Seattle Genetics, Nektar Therapeutics, Lilly, and Bicara Therapeutics. MOB Ad boards: Merck, BMS, Novartis, Adaptimmune, GSK, Sanofi, LaRoche Possey, Sun Pharma, Instil Bio, IOVANCE, Pfizer. Grant funding: Merck, Takara Bio, Novartis. Safety Review Committee: Adaptimmune, GSK. Honoraria for talks: BMS, Novartis, Merck, Sanofi, Pfizer. SL is principal investigator and co-investigators of different industry-sponsor or investigated initiated trials. I received honoraria from AZ, GSK, Roche, Merck, Eisai and Shattuck labs. DC: Consulting/Advisory Boards: AstraZeneca, Dynamo Therapeutics, Eisai, Exact Sciences, Gilead, GlaxoSmithKline, Merck, Novartis, Pfizer and Roche. Research funding to institution: GlaxoSmithKline, Inivata, Merck, Pfizer, and Roche. Patent (US62/675,228) for methods of treating cancers characterized by a high expression level of spindle and kinetochore associated complex subunit 3 (ska3) gene. ARH reports institutional support for clinical trials conduct from Novartis, Bristol-Myers Squibb, Pfizer, Boehringer-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Astellas and Bayer; and compensated consulting/advisory boards for AstraZeneca, Merck and GlaxoSmithKline. AAR has received research funding from Roche, Genentech, Eli Lilly, Merck, Boehringer Ingelheim, Novartis, AbbVie, Deciphera, Karyopharm, Astra Zeneca, Medimmune, Blueprint, Bristol Myers Squibb, GSK, Entremed/Casi Pharmaceuticals, Adaptimmune and BetaCat. He also has also served the advisory board for Eli Lilly, Merck, Adaptimmune, Boehringer Ingelheim. AS has served as an advisory board consultant for Merck (compensated), Bristol-Myers Squibb (compensated), Novartis (compensated), Oncorus (compensated), Janssen (compensated). She has also received research funding from Novartis, Bristol-Myers Squibb, Symphogen AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma, GSK. TWM Cofounder Treadwell Therapeutics. Stock ownership Agios Therapeutics Stock, Agios, Treadwell LS: consulting/advisory arrangements with Merck, Pfizer, Celgene, AstraZeneca, Morphosys, Roche, Oncorus, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi, Arvinas, Tessa, Navire, Relay, Rubius, Janpix, Daiichi Sanyko; stock ownership of Agios (spouse); leadership position in Treadwell Therapeutics (spouse); and institution receives clinical trials support from Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati Therapeutics, Shattucks, Avid. EC: honoria from Bayer and Taiho; institution receives clinical trials support from Novartis, Bristol-Myers Squibb, Roche, AstraZeneca, Merck, 1Globe, Mirati Therapetuics, Zymeworks and Amgen., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Circulating tumor DNA (ctDNA) has emerged as a biomarker with wide-ranging applications in cancer management. While its role in guiding precision medicine in certain tumors via noninvasive detection of susceptibility and resistance alterations is now well established, recent evidence has pointed to more generalizable use in treatment monitoring. Quantitative changes in ctDNA levels over time (i.e., ctDNA kinetics) have shown potential as an early indicator of therapeutic efficacy and could enable treatment adaptation. However, ctDNA kinetics are complex and heterogeneous, affected by tumor biology, host physiology, and treatment factors. This review outlines the current preclinical and clinical knowledge of ctDNA kinetics in cancer and how early on-treatment changes in ctDNA levels could be applied in clinical research to collect evidence to support implementation in daily practice.

Eligibility criteria restrict patient enrollment in clinical trials. A Nature paper applied a machine-learning algorithm in a real-world database to show that relaxing some criteria may not jeopardize efficacy and safety. This may enable more patients to have earlier access to new therapies and make results more generalizable to clinical practice., Competing Interests: Declaration of interests Enrique Sanz-Garcia declares no competing interests. Benjamin Haibe-Kains has consulting arrangements with Code Ocean Inc. Lillian L. Siu has consulting/advisory arrangements with Merck, Pfizer, Celgene, AstraZeneca, Morphosys, Roche, Oncorus, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi, Arvinas, Tessa, Navire, Relay, Rubius, Janpix, and Daiichi Sanyko; stock ownership of Agios (spouse); and a leadership position in Treadwell Therapeutics (spouse); and her institution receives clinical trials support from Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati Therapeutics, Shattucks, and Avid., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (MAFs, or the 'mutation dose') of a driver gene may reveal the genomic structure of tumors and influence response to targeted therapies. We performed a comprehensive analysis of MAFs of driver alterations in unpaired primary and metastatic colorectal cancer (CRC) at our institution from 2010 to 2015 and studied their potential clinical relevance. Of 763 CRC samples, 622 had detailed annotation on overall survival in the metastatic setting (OSmet) and 89 received targeted agents matched to KRAS (MEK inhibitors), BRAF (BRAF inhibitors), or PIK3CA mutations (PI3K pathway inhibitors). MAFs of each variant were normalized for tumor purity in the sample (adjMAFs). We found lower adjMAFs for BRAF V 600E and PIK3CA than for KRAS, NRAS, and BRAF non-V600 variants. TP53 and BRAF V 600E adjMAFs were higher in metastases as compared to primary tumors, and high KRAS adjMAFs were found in CRC metastases of patients with KRAS wild-type primary tumors previously exposed to EGFR antibodies. Patients with RAS- or BRAF V 600E -mutated tumors, irrespective of adjMAFs, had worse OSmet. There was no significant association between adjMAFs and time to progression on targeted therapies matched to KRAS, BRAF, or PIK3CA mutations, potentially related to the limited antitumor activity of the employed drugs (overall response rate of 4.5%). In conclusion, the lower BRAF V 600E and PIK3CA adjMAFs in subsets of primary CRC tumors indicate subclonality of these driver genes. Differences in adjMAFs between metastases and primary tumors suggest that approved therapies may result in selection of BRAF V 600E - and KRAS-resistant clones and an increase in genomic heterogeneity with acquired TP53 alterations. Despite significant differences in prognosis according to mutations in driver oncogenes, adjMAFs levels did not impact on survival and did not help predict benefit with matched targeted agents in the metastatic setting., (© 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)