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Critical Reviews in Oncology/hematology Aug 2023Aflibercept; a decoy receptor for vascular endothelial growth factors (VEGFs) and placental growth factor (PLGF), in combination with FOLFIRI (leucovorin calcium,... (Meta-Analysis)
Meta-Analysis Review
A systemic review and meta-analysis of Aflibercept plus FOLFIRI regimen as a second-line treatment for metastatic colorectal cancer: A PRISMA compliant pooled analysis of randomized controlled trials and single arm studies to assess efficacy and safety.
BACKGROUND AND OBJECTIVE
Aflibercept; a decoy receptor for vascular endothelial growth factors (VEGFs) and placental growth factor (PLGF), in combination with FOLFIRI (leucovorin calcium, fluorouracil, irinotecan hydrochloride) chemotherapy regime, was FDA approved in 2012 as second-line salvage chemotherapy for metastatic colorectal cancer (mCRC). This is the first systematic review, and meta-analysis-based evidence to determine the efficacy and safety of Aflibercept plus FOLFIRI regimen pooling randomized controlled trials and single-arm studies.
METHOD
PubMed, Cochrane library, Embase, and Clinical trial.gov were systematically searched for published randomized controlled trials, single-arm studies, and national patient programs on aflibercept plus FOLFIRI chemotherapy for the treatment of mCRC till 11/10/2022.
RESULT
Ten studies met the inclusion criteria comprising 1075 patients for efficacy studies and 2027 patients for safety studies. The pooled prevalences were 18% (95% CI, 5%-37%, p = 0.00) for 12 m PFS and 61% (95% CI, 53-68%, p = 0.00) for 12 m OS. The pooled prevalences were 69% (95% CI, 55-82%, p = 0.00) for any grade 3-4 toxicities, 10% (95% CI, 5-16%, p = 0.00) for grade 3-4 diarrhea, 13% (95% CI, 5-24%, p = 0.00) for grade 3-4 hypertension, 31% (95% CI, 22-40%, p = 0.00) for grade 3-4 neutropenia and 5% (95% CI, 2-7%, p = 0.00) for grade 3-4 venous thromboembolic event.
CONCLUSION
Our meta-analysis shows that the aflibercept plus FOLFIRI combination shows better survival efficacies however; it is also associated with more high-grade adverse events.
Topics: Humans; Female; Colorectal Neoplasms; Camptothecin; Placenta Growth Factor; Randomized Controlled Trials as Topic; Colonic Neoplasms; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Rectal Neoplasms; Fluorouracil; Leucovorin; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37257732
DOI: 10.1016/j.critrevonc.2023.104034 -
Frontiers in Immunology 2021Recombinant antibodies such as nanobodies are progressively demonstrating to be a valid alternative to conventional monoclonal antibodies also for clinical applications....
Recombinant antibodies such as nanobodies are progressively demonstrating to be a valid alternative to conventional monoclonal antibodies also for clinical applications. Furthermore, they do not solely represent a substitute for monoclonal antibodies but their unique features allow expanding the applications of biotherapeutics and changes the pattern of disease treatment. Nanobodies possess the double advantage of being small and simple to engineer. This combination has promoted extremely diversified approaches to design nanobody-based constructs suitable for particular applications. Both the format geometry possibilities and the functionalization strategies have been widely explored to provide macromolecules with better efficacy with respect to single nanobodies or their combination. Nanobody multimers and nanobody-derived reagents were developed to image and contrast several cancer diseases and have shown their effectiveness in animal models. Their capacity to block more independent signaling pathways simultaneously is considered a critical advantage to avoid tumor resistance, whereas the mass of these multimeric compounds still remains significantly smaller than that of an IgG, enabling deeper penetration in solid tumors. When applied to CAR-T cell therapy, nanobodies can effectively improve the specificity by targeting multiple epitopes and consequently reduce the side effects. This represents a great potential in treating malignant lymphomas, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma and solid tumors. Apart from cancer treatment, multispecific drugs and imaging reagents built with nanobody blocks have demonstrated their value also for detecting and tackling neurodegenerative, autoimmune, metabolic, and infectious diseases and as antidotes for toxins. In particular, multi-paratopic nanobody-based constructs have been developed recently as drugs for passive immunization against SARS-CoV-2 with the goal of impairing variant survival due to resistance to antibodies targeting single epitopes. Given the enormous research activity in the field, it can be expected that more and more multimeric nanobody molecules will undergo late clinical trials in the next future. Systematic Review Registration.
Topics: Animals; Autoimmune Diseases; Communicable Diseases; Humans; Immunomodulation; Molecular Imaging; Molecular Targeted Therapy; Neoplasms; Recombinant Proteins; Single-Domain Antibodies
PubMed: 35116045
DOI: 10.3389/fimmu.2021.838082 -
Cancer Treatment Reviews Mar 2022In pancreatic ductal adenocarcinoma cytoreduction can be curative, or palliative. FOLFIRINOX and GEM-NAB are the two FDA/EMA approved regimens for advanced disease. We... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
In pancreatic ductal adenocarcinoma cytoreduction can be curative, or palliative. FOLFIRINOX and GEM-NAB are the two FDA/EMA approved regimens for advanced disease. We aim to identified the most cytoreductive regimen on the basis of current literature.
MATERIAL AND METHODS
PUBMED was searched for studies published to April 2021. Abstracts of annual meetings ASCO 2009-2021, and ESMO 2015-2020, were searched as well. Phase II, phase III clinical trials, prospective, observational and retrospective studies, reporting overall response rate (complete + partial response) (ORR) in patients treated either with FOLFIRINOX or GEM-NAB were included. The meta-analysis was performed using a randomized-effects model. Main outcome was cytoreduction with each regimen reported as ORR according to RECIST.
RESULTS
Among 2183 studies identified, 40 fulfilled the selection criteria (22 FOLFIRINOX, 18 GEM-NAB), totaling 2883 patients. Pooling of data found similar ORR between regimens: FOLFIRINOX [30% (95 CI 26-34%)] and GEM-NAB [30% (95 CI 26-35%),] P = 0.928. Disease control rate (DCR) was significantly higher with FOLFIRINOX [85% (95CI 82-88%)] compared to GEM-NAB [80% (95CI 77-84%)], P = 0.012. A significantly higher ORR irrespective of the regimen was observed in stage IV [36% (95CI 32-40%)] versus stage II-III [25% (95CI 20-31%)], P = 0.002.
CONCLUSIONS AND RELEVANCE
Our meta-analysis did not find significant superiority of one regimen over the other in terms of RECIST-based cytoreduction both in palliative and curative setting of patients with pancreatic adenocarcinoma. The significantly better DCR with FOLFIRINOX compared with GEM-NAB deserves further investigation including waterfall plot and correlations with potential predictive factors.
Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Cytoreduction Surgical Procedures; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Paclitaxel; Pancreatic Neoplasms; Prospective Studies; Retrospective Studies
PubMed: 35114498
DOI: 10.1016/j.ctrv.2022.102338 -
Clinical Toxicology (Philadelphia, Pa.) Dec 2020Paracetamol (acetaminophen) remains a leading cause of poisoning in Europe, North America, and Australia. For over four decades, acetylcysteine has been the antidote of...
BACKGROUND
Paracetamol (acetaminophen) remains a leading cause of poisoning in Europe, North America, and Australia. For over four decades, acetylcysteine has been the antidote of choice. However, despite the use of acetylcysteine, some patients who ingest very large doses of paracetamol or who reach hospital late in the course of their poisoning, develop acute liver failure. Some will develop metabolic acidosis indicating mitochondrial toxicity.
OBJECTIVE
We review the experimental and clinical data reported with the use of cimetidine, fomepizole, and calmangafodipir in the treatment of paracetamol toxicity to determine if these treatments alone or in combination with acetylcysteine might be of benefit.
METHODS
We searched Ovid Medline 1946-2020, Embase 1947-2020, Scopus 2004-2020, Cochrane Databases of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov 1997-2020 for records including the concepts of paracetamol poisoning and cimetidine, fomepizole, calmangafodipir, and acetylcysteine. We included basic science studies in animals and all available study types in humans. We reviewed the reference lists of included articles to search for references missed in the original search. We registered the protocol in PROSPERO.
RESULTS
We completed all search strategies on 20 August 2019, 27 January 2020, and 15 June 2020. These produced 6,826 citations. We identified and deleted 2,843 duplicate resulting in a total of 3,856 unique citations. After applying inclusion and exclusion criteria, 89 studies remained. The largest numbers of studies described the past use of cimetidine, and the more recent use of fomepizole. There is good animal evidence that cimetidine blocks CYP 2E1 with the potential to inhibit the toxic metabolism of paracetamol. Early case reports were inconclusive regarding the benefit to humans in paracetamol poisoning. Two comparative trials found no benefit of cimetidine in paracetamol poisoning, but few patients had severe poisoning. There is good animal evidence that fomepizole blocks CYP 2E1 with the potential to inhibit the toxic metabolism of paracetamol. There are no comparative trials of fomepizole for acute paracetamol poisoning. Case reports are inconclusive due to multiple other interventions including the use of acetylcysteine in all cases. The benefit of fomepizole as adjunct treatment has not been demonstrated. Calmangafodipir, a drug mimicking superoxide dismutase, has emerged as a potential treatment for severe paracetamol toxicity because the formation of superoxide free radicals appears to explain part of the mitochondrial toxicity of extremely large paracetamol overdoses. Calmangafodipir has reached Phase I/II trial of safety in humans with acute paracetamol overdose. Planning for a Phase III study of efficacy is currently underway.
CONCLUSIONS
The vast majority of patients with acute paracetamol overdose enjoy excellent outcomes with acetylcysteine alone. Although cimetidine and fomepizole inhibit CYP 2E1 in animals, there is insufficient evidence to recommend their use either as a primary treatment or adjunct therapy in paracetamol poisoning. Calmangafodipir remains investigational.
Topics: Acetaminophen; Acetylcysteine; Acidosis; Animals; Antidotes; Cimetidine; Drug Overdose; Edetic Acid; Fomepizole; Humans; Mitochondria; Pyridoxal Phosphate
PubMed: 32762579
DOI: 10.1080/15563650.2020.1798979 -
World Journal of Gastroenterology Nov 2021The use of proton pump inhibitors (PPI) is common worldwide, with reports suggesting that they may be overused. Several studies have found that PPI may affect colorectal...
BACKGROUND
The use of proton pump inhibitors (PPI) is common worldwide, with reports suggesting that they may be overused. Several studies have found that PPI may affect colorectal cancer (CRC) risk.
AIM
To summarize current knowledge on the relationship between PPI and CRC from basic research, epidemiological and clinical studies.
METHODS
This systematic review was based on the patients, interventions, comparisons, outcome models and performed according to PRISMA guidelines. MEDLINE, EMBASE, Scopus, and Web of Science databases were searched from inception until May 17, 2021. The initial search returned 2591 articles, of which, 28 studies met the inclusion criteria for this review. The studies were categorized as basic research studies ( = 12), epidemiological studies ( = 11), and CRC treatment studies ( = 5). The quality of the included studies was assessed using the Newcastle-Ottawa Scale or Cochrane Risk of Bias 2.0 tool depending on the study design.
RESULTS
Data from basic research indicates that PPI do not stimulate CRC development the trophic effect of gastrin but instead may paradoxically inhibit it. These studies also suggest that PPI may have properties beneficial for CRC treatment. PPI appear to have anti-tumor properties (omeprazole, pantoprazole), and are potential T lymphokine-activated killer cell-originated protein kinase inhibitors (pantoprazole, ilaprazole), and chemosensitizing agents (pantoprazole). However, these mechanisms have not been confirmed in human trials. Current epidemiological studies suggest that there is no causal association between PPI use and increased CRC risk. Treatment studies show that concomitant PPI and capecitabine use may reduce the efficacy of chemotherapy resulting in poorer oncological outcomes, while also suggesting that pantoprazole may have a chemosensitizing effect with the fluorouracil, leucovorin, oxaliplatin (FOLFOX) regimen.
CONCLUSION
An unexpected inhibitory effect of PPI on CRC carcinogenesis by way of several potential mechanisms is noted. This review identifies that different PPI agents may have differential effects on CRC treatment, with practical implications. Prospective studies are warranted to delineate this relationship and assess the role of individual PPI agents.
Topics: Capecitabine; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Proton Pump Inhibitors
PubMed: 34908809
DOI: 10.3748/wjg.v27.i44.7716 -
Journal of Medical Toxicology :... Jul 2023Activated charcoal is a decontaminating agent used for acute intoxication. It can be mixed with taste additives to overcome its poor palatability. Our purpose was to... (Review)
Review
INTRODUCTION
Activated charcoal is a decontaminating agent used for acute intoxication. It can be mixed with taste additives to overcome its poor palatability. Our purpose was to evaluate the taste additives used to improve activated charcoal's palatability.
METHODS
We conducted a systematic review of comparative studies on taste additives used to improve activated charcoal's palatability. We searched PubMed, Embase, Web of Science, Cochrane, and CINAHL. We included controlled trials and observational studies that evaluate the effect of at least one taste additive, compared with activated charcoal alone. Our primary outcome was palatability. Our secondary outcomes included treatment adherence, adsorption efficacy, and adverse events. The risk of bias was assessed using the Quality Assessment Tool for Quantitative Studies.
RESULTS
Among 38 eligible articles, seven observational studies and three crossover clinical trials met our inclusion criteria. The risk of bias was found to be high for seven studies and intermediate for three others. The preferred flavoring agents were cola and chocolate milk for children, and sweetening agents for adults. All taste additives studied seemed to improve activated charcoal's palatability, except for yogurt (n = 1). The addition of bentonite, sorbitol, carboxymethylcellulose, or yogurt showed no impact on the in-vivo adsorption capacity of activated charcoal, whereas the results were inconclusive for chocolate. No meta-analysis was performed due to insufficient data.
CONCLUSION
Strategies to improve activated charcoal's palatability seem to enhance the taste. Descriptive data are in favor of a limited impact on activated charcoal's adsorption capacity when adding binding agents or sweeteners.
TRIAL REGISTRATION ON PROSPERO
This review is registered as PROSPERO CRD42019135092.
Topics: Child; Adult; Humans; Charcoal; Taste; Flavoring Agents; Sorbitol
PubMed: 37000410
DOI: 10.1007/s13181-023-00934-6 -
Clinical Journal of the American... Apr 2022Methotrexate is used in the treatment of many malignancies, rheumatological diseases, and inflammatory bowel disease. Toxicity from use is associated with severe...
Methotrexate is used in the treatment of many malignancies, rheumatological diseases, and inflammatory bowel disease. Toxicity from use is associated with severe morbidity and mortality. Rescue treatments include intravenous hydration, folinic acid, and, in some centers, glucarpidase. We conducted systematic reviews of the literature following published EXtracorporeal TReatments In Poisoning (EXTRIP) methods to determine the utility of extracorporeal treatments in the management of methotrexate toxicity. The quality of the evidence and the strength of recommendations (either "strong" or "weak/conditional") were graded according to the GRADE approach. A formal voting process using a modified Delphi method assessed the level of agreement between panelists on the final recommendations. A total of 92 articles met inclusion criteria. Toxicokinetic data were available on 90 patients (89 with impaired kidney function). Methotrexate was considered to be moderately dialyzable by intermittent hemodialysis. Data were available for clinical analysis on 109 patients (high-dose methotrexate [>0.5 g/m]: 91 patients; low-dose [≤0.5 g/m]: 18). Overall mortality in these publications was 19.5% and 26.7% in those with high-dose and low-dose methotrexate-related toxicity, respectively. Although one observational study reported lower mortality in patients treated with glucarpidase compared with those treated with hemodialysis, there were important limitations in the study. For patients with severe methotrexate toxicity receiving standard care, the EXTRIP workgroup: () suggested against extracorporeal treatments when glucarpidase is not administered; () recommended against extracorporeal treatments when glucarpidase is administered; and () recommended against extracorporeal treatments instead of administering glucarpidase. The quality of evidence for these recommendations was very low. Rationales for these recommendations included: () extracorporeal treatments mainly remove drugs in the intravascular compartment, whereas methotrexate rapidly distributes into cells; () extracorporeal treatments remove folinic acid; () in rare cases where fast removal of methotrexate is required, glucarpidase will outperform any extracorporeal treatment; and () extracorporeal treatments do not appear to reduce the incidence and magnitude of methotrexate toxicity.
Topics: Drug Overdose; Drug-Related Side Effects and Adverse Reactions; Humans; Leucovorin; Methotrexate; Observational Studies as Topic; Poisoning; Renal Dialysis
PubMed: 35236714
DOI: 10.2215/CJN.08030621 -
Current Reviews in Clinical and... May 2024There is a lack of evidence on the effectiveness of antidotes in the management of organophosphate and carbamate (OPC) poisoning. We aimed to review the efficacy and...
OBJECTIVE
There is a lack of evidence on the effectiveness of antidotes in the management of organophosphate and carbamate (OPC) poisoning. We aimed to review the efficacy and safety of glycopyrrolate in the management of OPC poisoning.
METHODOLOGY
Databases such as PubMed, Scopus, Embase, and Cochrane Library were extensively searched from inception to November 2022 and updated till October 2023. Interventional, observational, and descriptive studies assessing the efficacy and safety of glycopyrrolate administered in any dose, route, and duration for the management of OPC poisoning published in the English language were considered for this review. The treatment with any other regimen that did not include glycopyrrolate was regarded as the comparator. The survival, intensive care unit (ICU) days and ventilatory outcomes were considered efficacy outcomes, and adverse effects were considered safety outcomes. Suitable quality assessment tools were used to assess the risk of bias in the included studies. Two independent reviewers were involved in the study selection, data extraction, and quality assessment and any discrepancies were resolved through mutual discussion or consultation with a third reviewer.
RESULTS
A total of 9 studies (2 RCTs, 4 cohorts, 1 case series, and 2 case reports) out of 591 nonduplicate records were considered for this review. Overall, the RCTs were observed to have a moderate quality, and observational studies and descriptive studies were found to have good quality. All the included studies used atropine administration as a standard treatment option along with glycopyrrolate. The OPC patients treated with glycopyrrolate had a fewer hospitalization days with comparable recovery and ventilatory outcomes than those that had not been treated with glycopyrrolate. The occurrence of adverse events and complications was lower in the glycopyrrolate group than in the control group.
CONCLUSION
Currently, there is a lack of comparative studies to recommend the use of glycopyrrolate in OPC poisoning, and further interventional studies are required to make an evidencebased recommendation on this topic.
PubMed: 38797902
DOI: 10.2174/0127724328290595240509051331 -
Journal of Environmental Management Nov 2023The use of pesticides is intense in agriculture and has caused contamination in water, air and soil. This fact led to the need to study strategies that can minimize the... (Meta-Analysis)
Meta-Analysis
The use of pesticides is intense in agriculture and has caused contamination in water, air and soil. This fact led to the need to study strategies that can minimize the effects that these pesticides have caused to the environment. In this context, biochar appears, as a type of material that has the ability to remove chemical substances, and because they can be activated with different chemical agents, they are extremely effective in the adsorption of toxic substances. Therefore, the aim of the study was to evaluate the use of biochar as a bioadsorbent for pesticides. This is a systematic review with meta-analysis and meta-regression, as the PRISMA protocol recommendations. Studies from the last 20 years were included, with at least the abstract available and considering preferentially experimental studies. Qualitative studies or studies with high risk of bias, other reviews and duplicates were excluded. The variables analyzed were the presence of factors that prove the effectiveness or not of pesticide adsorption. Studies with a superficial approach or those that do not show positivity or negativity in relation to the outcome were excluded. The search was conducted on the sources: Scopus, Web of Science electronic databases, PubMed (of the US National Library of Medicine, National Institutes of Health) and ScienceDirect (Elsevier). For better investigative determination, the data were searched separately. The descriptors used for the search were the following: Agrochemicals AND Activated Carbon AND Adsorption. Initially, 2431 references were found, from which 14 were selected to compose the meta-analysis review. With the joint analysis of the data, it was possible to verify using the random model (since the studies assess different contexts) that there is a proportion of effectiveness of the intervention of 81% (with a 95% confidence interval), ranging from 75 to 88%, which is represented by the meta-analysis diamond that is the final result of the statistical analysis. Biochar is effective in removing impurities, even including features such as low cost. There is a considerable lack of studies on the topic of pesticide adsorption with the use of biochar. The studies approach a very heterogeneous perspective on the subject, exposing different contexts.
Topics: Pesticides; Charcoal; Soil; Agriculture
PubMed: 37536127
DOI: 10.1016/j.jenvman.2023.118719 -
JAMA Network Open Jan 2022Various first-line chemotherapy treatment regimens for patients with metastatic pancreatic cancer have been approved in Japan, including gemcitabine (GEM); fluorouracil,... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Various first-line chemotherapy treatment regimens for patients with metastatic pancreatic cancer have been approved in Japan, including gemcitabine (GEM); fluorouracil, leucovorin, irinotecan, and oxaliplatin combination (FOLFIRINOX); GEM plus albumin-bound paclitaxel (GEM+NPTX), and S-1 (tegafur + gimeracil + oteracil). However, direct comparisons of these chemotherapy regimens are limited.
OBJECTIVE
To assess the short-term and long-term outcomes associated with first-line chemotherapy regimens for metastatic pancreatic cancer compared with chemotherapy regimens recommended in Japanese guidelines.
DATA SOURCES
In this systematic review and network meta-analysis, the bibliographic databases PubMed, Cochrane Library, and Web of Science, as well as medical journals published between January 1, 2002, and December 31, 2018, were searched for clinical trials comparing chemotherapy regimens.
STUDY SELECTION
Randomized 2-arm clinical trials evaluating first-line chemotherapy for advanced or metastatic pancreatic cancer were included.
DATA EXTRACTION AND SYNTHESIS
The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions was followed for data abstractions. Data were pooled using a random-effects model. The SIGN 50 Quality Assessment Instrument was used to assess the risk of bias and overall study quality of the selected trials.
MAIN OUTCOMES AND MEASURES
The primary end point was overall survival (OS), and the secondary end point was progression-free survival (PFS) compared with GEM for first-line chemotherapy for metastatic pancreatic cancer. The Kaplan-Meier curve of GEM from the literature and the estimated hazard ratios (HRs) were used to model the long-term associations to calculate the area under the curve (AUC) (person-months) for OS and PFS of each chemotherapy. Sensitivity analyses with multiple functional models were conducted to confirm the long-term estimations.
RESULTS
A total of 22 regimens (25 studies) for OS and a total of 18 regimens (21 studies) for PFS were identified from literature. The total number of participants was 10 186, with 5856 male (57.5%) and 4330 female (42.5%). The FOLFIRINOX and GEM+NPTX regimens were associated with reduction in the risk of death, with an HR of 0.57 (95% CI, 0.41-0.79) and 0.72 (95% CI, 0.55-0.95) compared with GEM, respectively. The curve estimation also showed that FOLFIRINOX had the largest AUC for survival at 15.49 person-months (range, 13.84-15.51 person-months), followed by GEM+NPTX with 12.36 person-months (range, 10.98-12.59 person-months), GEM+ERLO with 10.84 person-months (range, 9.66-11.23 person-months), S-1 with 8.44 person-months (range, 8.26-9.74 person-months), and GEM with 8.10 person-months (range, 7.93-9.38 person-months).
CONCLUSIONS AND RELEVANCE
The results of this network meta-analysis support the relative short-term and long-term outcomes associated with first-line chemotherapy for metastatic pancreatic cancer used clinically in Japan.
Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Comparative Effectiveness Research; Deoxycytidine; Drug Combinations; Fluorouracil; Humans; Irinotecan; Japan; Kaplan-Meier Estimate; Leucovorin; Neoplasm Metastasis; Network Meta-Analysis; Oxaliplatin; Oxonic Acid; Paclitaxel; Pancreatic Neoplasms; Progression-Free Survival; Proportional Hazards Models; Pyridines; Survival Rate; Tegafur; Treatment Outcome; Gemcitabine
PubMed: 35099549
DOI: 10.1001/jamanetworkopen.2021.45515