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JAMA Oncology Jun 2024Efficacy of second-line chemotherapy in advanced gastric or gastrooesphageal junction (GEJ) adenocarcinoma remains limited. (Randomized Controlled Trial)
Randomized Controlled Trial
FOLFIRI Plus Durvalumab With or Without Tremelimumab in Second-Line Treatment of Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: The PRODIGE 59-FFCD 1707-DURIGAST Randomized Clinical Trial.
IMPORTANCE
Efficacy of second-line chemotherapy in advanced gastric or gastrooesphageal junction (GEJ) adenocarcinoma remains limited.
OJECTIVES
To determine the efficacy of 1 or 2 immune checkpoint inhibitors combined with FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) in the treatment of advanced gastric/GEJ adenocarcinoma.
DESIGN, SETTING, AND PARTICIPANTS
The PRODIGE 59-FFCD 1707-DURIGAST trial is a randomized, multicenter, noncomparative, phase 2 trial, conducted from August 27, 2020, and June 4, 2021, at 37 centers in France that included patients with advanced gastric/GEJ adenocarcinoma who had disease progression after platinum-based first-line chemotherapy.
INTERVENTION
Patients were randomized to receive FOLFIRI plus durvalumab (anti-programmed cell death 1 [PD-L1]) (FD arm) or FOLFIRI plus durvalumab and tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4 [CTLA-4]) (FDT arm). The efficacy analyses used a clinical cutoff date of January 9, 2023.
MAIN OUTCOME AND MEASURES
The primary end point was progression-free survival (PFS) at 4 months according to RECIST 1.1 criteria evaluated by investigators.
RESULTS
Overall, between August 27, 2020, and June 4, 2021, 96 patients were randomized (48 in each arm). The median age was 59.7 years, 28 patients (30.4%) were women and 49 (53.3%) had GEJ tumors. Four month PFS was 44.7% (90% CI, 32.3-57.7) and 55.6% (90% CI, 42.3-68.3) in the FD and FDT arms, respectively. The primary end point was not met. Median PFS was 3.8 and 5.4 months, objective response rates were 34.7% and 37.7%, and median overall survival was 13.2 and 9.5 months in the FD and FDT arms, respectively. Disease control beyond 1 year was 14.9% in the FD arm and 24.4% in the FDT arm. Grade 3 to 4 treatment-related adverse events were observed in 22 (47.8%) patients in each arm. A combined positive score (CPS) PD-L1 of 5 or higher was observed in 18 tumors (34.0%) and a tumor proportion score (TPS) PD-L1 of 1% or higher in 13 tumors (24.5%). Median PFS according to CPS PD-L1 was similar (3.6 months for PD-L1 CPS ≥5 vs 5.4 months for PD-L1 CPS <5) by contrast for TPS PD-L1 (6.0 months for PD-L1 TPS ≥1% vs 3.8 months for PD-L1 TPS <1%).
CONCLUSIONS AND RELEVANCE
Combination of immune checkpoint inhibitors with FOLFIRI in second-line treatment for advanced gastric/GEJ adenocarcinoma showed an acceptable safety profile but antitumor activity only in a subgroup of patients.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03959293.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Stomach Neoplasms; Leucovorin; Male; Female; Middle Aged; Adenocarcinoma; Fluorouracil; Aged; Esophagogastric Junction; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Camptothecin; Adult; Esophageal Neoplasms; Progression-Free Survival
PubMed: 38573643
DOI: 10.1001/jamaoncol.2024.0207 -
Scientific Reports Jan 2024In this study, biochar (BC) and hydrochar (HC) composites were synthesized with natural kaolinite clay and their properties, stability, carbon (C) sequestration...
In this study, biochar (BC) and hydrochar (HC) composites were synthesized with natural kaolinite clay and their properties, stability, carbon (C) sequestration potential, polycyclic aromatic hydrocarbons (PAHs) toxicity, and impacts on maize germination and growth were explored. Conocarpus waste was pretreated with 0%, 10%, and 20% kaolinite and pyrolyzed to produce BCs (BC, BCK10, and BCK20, respectively), while hydrothermalized to produce HCs (HC, HCK10, and HCK20, respectively). The synthesized materials were characterized using X-ray diffraction, scanning electron microscope analyses, Fourier transform infrared, thermogravimetric analysis, surface area, proximate analyses, and chemical analysis to investigate the distinction in physiochemical and structural characteristics. The BCs showed higher C contents (85.73-92.50%) as compared to HCs (58.81-61.11%). The BCs demonstrated a higher thermal stability, aromaticity, and C sequestration potential than HCs. Kaolinite enriched-BCs showed the highest cation exchange capacity than pristine BC (34.97% higher in BCK10 and 38.04% higher in BCK20 than pristine BC), while surface area was the highest in kaolinite composited HCs (202.8% higher in HCK10 and 190.2% higher in HCK20 than pristine HC). The recalcitrance index (R) speculated a higher recalcitrance for BC, BCK10, and BCK20 (R > 0.7), minimal degradability for HCK10 and HCK20 (0.5 < R < 0.7), and higher degradability for biomass and HC (R < 0.5). Overall, increasing the kaolinite enrichment percentage significantly enhanced the thermal stability and C sequestration potential of charred materials, which may be attributed to changes in the structural arrangements. The ∑ total PAHs concentration in the synthesized materials were below the USEPA's suggested limits, indicating their safe use as soil amendments. Germination indices reflected positive impacts of synthesized charred materials on maize germination and growth. Therefore, we propose that kaolinite-composited BCs and HCs could be considered as efficient and cost-effective soil amendments for improving plant growth.
Topics: Kaolin; Zea mays; Charcoal; Soil
PubMed: 38218904
DOI: 10.1038/s41598-024-51786-1 -
Radiation and Environmental Biophysics Nov 2023A major challenge in modelling the decorporation of actinides (An), such as americium (Am), with DTPA (diethylenetriaminepentaacetic acid) is the fact that standard...
A major challenge in modelling the decorporation of actinides (An), such as americium (Am), with DTPA (diethylenetriaminepentaacetic acid) is the fact that standard biokinetic models become inadequate for assessing radionuclide intake and estimating the resulting dose, as DTPA perturbs the regular biokinetics of the radionuclide. At present, most attempts existing in the literature are empirical and developed mainly for the interpretation of one or a limited number of specific incorporation cases. Recently, several approaches have been presented with the aim of developing a generic model, one of which reported the unperturbed biokinetics of plutonium (Pu), the chelation process and the behaviour of the chelated compound An-DTPA with a single model structure. The aim of the approach described in this present work is the development of a generic model that is able to describe the biokinetics of Am, DTPA and the chelate Am-DTPA simultaneously. Since accidental intakes in humans present many unknowns and large uncertainties, data from controlled studies in animals were used. In these studies, different amounts of DTPA were administered at different times after contamination with known quantities of Am. To account for the enhancement of faecal excretion and reduction in liver retention, DTPA is assumed to chelate Am not only in extracellular fluids, but also in hepatocytes. A good agreement was found between the predictions of the proposed model and the experimental results for urinary and faecal excretion and accumulation and retention in the liver. However, the decorporation from the skeletal compartment could not be reproduced satisfactorily under these simple assumptions.
Topics: Humans; Rats; Animals; Pentetic Acid; Americium; Models, Biological; Chelating Agents; Plutonium
PubMed: 37831188
DOI: 10.1007/s00411-023-01046-z -
Annals of Surgery Dec 2023A high systemic immune-inflammation index (SIII) at diagnosis of various cancers, including pancreatic cancer, is associated with poor prognosis. The impact of...
Increasing Systemic Immune-inflammation Index During Treatment in Patients With Advanced Pancreatic Cancer is Associated With Poor Survival: A Retrospective, Multicenter, Cohort Study.
BACKGROUND AND OBJECTIVES
A high systemic immune-inflammation index (SIII) at diagnosis of various cancers, including pancreatic cancer, is associated with poor prognosis. The impact of FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) chemotherapy or stereotactic body radiotherapy on this index is unknown. In addition, the prognostic value of changes in the SIII during treatment is unclear. In this retrospective analysis, we aimed to find answers regarding patients with advanced pancreatic cancer.
METHODS
Patients with advanced pancreatic cancer treated with FOLFIRINOX chemotherapy alone or with FOLFIRINOX chemotherapy followed by stereotactic body radiotherapy between 2015 and 2021 in 2 tertiary referral centers were included. Baseline characteristics, laboratory values at 3 time points during treatment, and survival outcomes were collected. The patient-specific evolutions of SIII and their association with mortality were assessed with joint models for longitudinal and time-to-event data.
RESULTS
Data of 141 patients were analyzed. At a median follow-up time of 23.0 months (95% CI: 14.6-31.3), 97 (69%) patients had died. Median overall survival was 13.2 months (95% CI: 11.0-15.5). During treatment with FOLFIRINOX, the log (SIII) was reduced by -0.588 (95% CI: -0.0978, -0.197; P = 0.003). One unit increase in log (SIII) increased the hazard ratio of dying by 1.604 (95% CI: 1.068-2.409; P = 0.023).
CONCLUSIONS
In addition to carbohydrate antigen 19-9, the SIII is a reliable biomarker in patients with advanced pancreatic cancer.
Topics: Humans; Pancreatic Neoplasms; Cohort Studies; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Leucovorin; Inflammation
PubMed: 37010512
DOI: 10.1097/SLA.0000000000005865 -
Journal of Medical Case Reports Jul 2023Apixaban is a non-vitamin K antagonist oral anticoagulant (NOACs) recently emerged as an effective alternative to conventional vitamin K antagonists (VKAs) in the...
BACKGROUND
Apixaban is a non-vitamin K antagonist oral anticoagulant (NOACs) recently emerged as an effective alternative to conventional vitamin K antagonists (VKAs) in the treatment of several thromboembolic disorders. However, in case of overdose or in patients requiring emergency surgery there is a high bleeding rate and severe adverse side effects due to the absence of an antidote. There is promising data from in vitro and clinical studies, that certain antithrombotic agents (that is Rivaroxaban and Ticagrelor) have been successfully removed by the extracorporeal hemoadsorption therapy CytoSorb. Here, we present the case of a patient successfully treated with CytoSorb as a kind of antidote to enable emergency surgery for bilateral nephrostomy.
CASE PRESENTATION
A 82-year-old Caucasian man was admitted to the Emergency Room with acute kidney injury (AKI) in the context of severe bilateral hydroureteronephrosis. The patient's medical history included chronic obstructive pulmonary disease, arterial hypertension, atrial fibrillation (anticoagulated with Apixaban) and a locally advanced prostate adenocarcinoma treated with trans-ureteral resection of the bladder and radiotherapy in the previous months. The indication for a bilateral nephrostomy could not be considered immediately given the major bleeding risk due to Apixaban, which was discontinued and replaced with calciparin. After 36 hours of continuous renal replacement therapy (CRRT), the Apixaban blood level was still elevated and it was decided to install CytoSorb into the running CRRT to accelerate the drug clearance. After 2 hours 30 minutes, there was good reduction of Apixaban from 139 to 72 ng/ml (reduction rate of 48.2%) registered, and this allowed for an easy placement of bilateral nephrostomies without complications. Four days after surgery renal function parameters further normalized, the patient did not require additional dialysis treatments and Apixaban therapy was prescribed again once the patient returned home.
CONCLUSIONS
In this case we report the findings of a patient with post-renal AKI requiring emergency nephrostomy placement while on chronic anticoagulation with Apixaban therapy. Combined treatment with CRRT and CytoSorb was associated with the rapid and effective removal of Apixaban allowing for prompt and urgent surgery while simultaneously ensuring the low risk of bleeding as well as an uneventful post-operative course.
Topics: Male; Humans; Aged, 80 and over; Anticoagulants; Dabigatran; Administration, Oral; Antidotes; Hemorrhage; Pyridones; Atrial Fibrillation; Acute Kidney Injury
PubMed: 37415195
DOI: 10.1186/s13256-023-03949-3 -
Advanced Science (Weinheim,... Apr 2024Abnormal activation of the intestinal mucosal immune system, resulting from damage to the intestinal mucosal barrier and extensive invasion by pathogens, contributes to...
Abnormal activation of the intestinal mucosal immune system, resulting from damage to the intestinal mucosal barrier and extensive invasion by pathogens, contributes to the pathogenesis of inflammatory bowel disease (IBD). Current first-line treatments for IBD have limited efficacy and significant side effects. An innovative HS-releasing montmorillonite nanoformulation (DPs@MMT) capable of remodeling intestinal mucosal immune homeostasis, repairing the mucosal barrier, and modulating gut microbiota is developed by electrostatically adsorbing diallyl trisulfide-loaded peptide dendrimer nanogels (DATS@PDNs, abbreviated as DPs) onto the montmorillonite (MMT) surface. Upon rectal administration, DPs@MMT specifically binds to and covers the damaged mucosa, promoting the accumulation and subsequent internalization of DPs by activated immune cells in the IBD site. DPs release HS intracellularly in response to glutathione, initiating multiple therapeutic effects. In vitro and in vivo studies have shown that DPs@MMT effectively alleviates colitis by eliminating reactive oxygen species (ROS), inhibiting inflammation, repairing the mucosal barrier, and eradicating pathogens. RNA sequencing revealed that DPs@MMT exerts significant immunoregulatory and mucosal barrier repair effects, by activating pathways such as Nrf2/HO-1, PI3K-AKT, and RAS/MAPK/AP-1, and inhibiting the p38/ERK MAPK, p65 NF-κB, and JAK-STAT3 pathways, as well as glycolysis. 16S rRNA sequencing demonstrated that DPs@MMT remodels the gut microbiota by eliminating pathogens and increasing probiotics. This study develops a promising nanoformulation for IBD management.
Topics: Humans; Bentonite; Phosphatidylinositol 3-Kinases; RNA, Ribosomal, 16S; Inflammatory Bowel Diseases; Intestinal Mucosa
PubMed: 38308198
DOI: 10.1002/advs.202308092 -
Journal of Nanobiotechnology Aug 2023Organophosphate (OP)-induced delayed neurological damage is attributed to permanent neuropathological lesions caused by irreversible OP-neurocyte interactions, without...
BACKGROUND
Organophosphate (OP)-induced delayed neurological damage is attributed to permanent neuropathological lesions caused by irreversible OP-neurocyte interactions, without potent brain-targeted etiological antidotes to date. The development of alternative therapies to achieve intracerebral OP detoxification is urgently needed.
METHODS
We designed a brain-targeted nanoreactor by integrating enzyme immobilization and biomimetic membrane camouflaging protocols with careful characterization, and then examined its blood-brain barrier (BBB) permeability both in vitro and in vivo. Subsequently, the oxidative stress parameters, neuroinflammatory factors, apoptotic proteins and histopathological changes were measured and neurobehavioral tests were performed.
RESULTS
The well-characterized nanoreactors exerted favourable BBB penetration capability both in vitro and in vivo, significantly inhibiting OP-induced intracerebral damage. At the cellular and tissue levels, nanoreactors obviously blocked oxidative stress, cellular apoptosis, inflammatory reactions and brain histopathological damage. Furthermore, nanoreactors radically prevented the occurrence of OP-induced delayed cognitive deficits and psychiatric abnormality.
CONCLUSION
The nanoreactors significantly prevented the development of OP-induced delayed neurological damage, suggesting a potential brain-targeted etiological strategy to attenuate OP-related delayed neurological and neurobehavioral disorders.
Topics: Humans; Organophosphates; Organophosphate Poisoning; Brain; Antidotes; Nanotechnology
PubMed: 37550745
DOI: 10.1186/s12951-023-02039-2 -
Scientific Reports Nov 2023Biomass and its interactions for heat generation have received little attention. In this study, the woody biomass materials were Prosopis africana (PA), Harungana...
Biomass and its interactions for heat generation have received little attention. In this study, the woody biomass materials were Prosopis africana (PA), Harungana madascariences (HM), Vitrllaria paradoxa (VP), and Afzelia africana (AA). The composition (extractives, carbohydrate, and lignin) of the biomass was determined. The biomass was converted to charcoal in a traditional kiln. A thermo-kinetic examination of the charcoal samples was carried out. The kinetic parameters and potential reaction mechanisms involved in the decomposition process were both obtained using the integral (Flynn-Wall Ozawa) isoconversional methods in conjunction with the Coats-Redfern approach. The activation energy profiles for the charcoal samples in oxidizing atmospheres were 548 kJ/mol for AA, 274 kJ/mol for VP, 548 kJ/mol for PA, and 274 kJ/mol for HM. All charcoal samples underwent comprehensive, multi-step, complex reaction pathways for thermal degradation. The charcoal samples exhibit not only great potential for biochemical extraction but also for bioenergy applications. The significant amount of combustion characteristics in the raw biomass and charcoal samples indicates that each type of wood charcoal produced has more fixed carbon, less ash, and less volatile matter, all of which are desirable for the thermo-chemical conversion of biomass for the production of heat.
Topics: Charcoal; Hot Temperature; Biomass; Wood; Kinetics; Thermogravimetry
PubMed: 37935802
DOI: 10.1038/s41598-023-46054-7 -
Ecotoxicology and Environmental Safety Jan 2024Mercury (Hg) contamination is acknowledged as a global issue and has generated concerns globally due to its toxicity and persistence. Tunable surface-active sites (SASs)... (Review)
Review
Mercury (Hg) contamination is acknowledged as a global issue and has generated concerns globally due to its toxicity and persistence. Tunable surface-active sites (SASs) are one of the key features of efficient BCs for Hg remediation, and detailed documentation of their interactions with metal ions in soil medium is essential to support the applications of functionalized BC for Hg remediation. Although a specific active site exhibits identical behavior during the adsorption process, a systematic documentation of their syntheses and interactions with various metal ions in soil medium is crucial to promote the applications of functionalized biochars in Hg remediation. Hence, we summarized the BC's impact on Hg mobility in soils and discussed the potential mechanisms and role of various SASs of BC for Hg remediation, including oxygen-, nitrogen-, sulfur-, and X (chlorine, bromine, iodine)- functional groups (FGs), surface area, pores and pH. The review also categorized synthesis routes to introduce oxygen, nitrogen, and sulfur to BC surfaces to enhance their Hg adsorptive properties. Last but not the least, the direct mechanisms (e.g., Hg- BC binding) and indirect mechanisms (i.e., BC has a significant impact on the cycling of sulfur and thus the Hg-soil binding) that can be used to explain the adverse effects of BC on plants and microorganisms, as well as other related consequences and risk reduction strategies were highlighted. The future perspective will focus on functional BC for multiple heavy metal remediation and other potential applications; hence, future work should focus on designing intelligent/artificial BC for multiple purposes.
Topics: Mercury; Catalytic Domain; Soil Pollutants; Charcoal; Soil; Sulfur; Ions; Nitrogen; Oxygen; Environmental Restoration and Remediation
PubMed: 38171108
DOI: 10.1016/j.ecoenv.2023.115916 -
Journal of Environmental Management Jul 2023More people globally are now using on-site sanitation technologies than sewered connections. The management of faecal sludge generated by on-site facilities is still...
More people globally are now using on-site sanitation technologies than sewered connections. The management of faecal sludge generated by on-site facilities is still challenging and requires an understanding of all sanitation service chain components and their interactions; from source conditions to treatment and resource recovery. This study aimed to improve the current lack of knowledge regarding these interactions, by establishing a quantifiable relationship between human excreta source separation and resource recovery via pyrolysis. The effects of source separation of faeces and urine on biochar quality were investigated for different pyrolysis temperatures (450 °C, 550 °C, 650 °C) and this information was used to assess energy and nutrient recovery. Results quantify the benefits of urine diversion for nitrogen recovery (70% of total N losses during thermal treatment avoided) and show an increase in the liming potential of the produced faecal-based biochars. The quality of produced solid fuels is also improved when source-separated faeces (SSF) are used as a feedstock for pyrolysis, including a 50% increase in char calorific value. On the other hand, biochars from mixed urine and faeces (MUF) are more rich in phosphorus and potassium, and surface morphology investigation indicates higher porosity compared to SSF biochars. The high salinity of MUF biochars should be considered before agricultural applications. For both biochar types (SSF, MUF), the presence of phosphate compounds of high fertiliser value was confirmed by X-ray diffraction analysis, and temperatures around 500 °C are recommended to optimise nutrient and carbon behaviour when pyrolysing human excreta. These findings can be used for the design of circular faecal sludge management systems, linking resource recovery objectives to source conditions, and vice-versa. Ultimately, achieving consistent resource recovery from human excreta can act as an incentive for universal access to safe and sustainable sanitation.
Topics: Humans; Sewage; Pyrolysis; Charcoal; Carbon
PubMed: 37015142
DOI: 10.1016/j.jenvman.2023.117782