Dynamic three-dimensional structures of a metal-organic framework captured with femtosecond serial crystallography.

Crystalline systems consisting of small-molecule building blocks have emerged as promising materials with diverse applications. It is of great importance to characterize not only their static structures but also the conversion of their structures in response to external stimuli. Femtosecond time-resolved crystallography has the potential to probe the real-time dynamics of structural transitions, but, thus far, this has not been realized for chemical reactions in non-biological crystals. In this study, we applied time-resolved serial femtosecond crystallography (TR-SFX), a powerful technique for visualizing protein structural dynamics, to a metal-organic framework, consisting of Fe porphyrins and hexazirconium nodes, and elucidated its structural dynamics. The time-resolved electron density maps derived from the TR-SFX data unveil trifurcating structural pathways: coherent oscillatory movements of Zr and Fe atoms, a transient structure with the Fe porphyrins and Zr6 nodes undergoing doming and disordering movements, respectively, and a vibrationally hot structure with isotropic structural disorder. These findings demonstrate the feasibility of using TR-SFX to study chemical systems.

Determination of the Optimal Concentration of Natural Antimicrobial Agents in Marinade Sauce for Meal Kits.

This study aimed to determine the antimicrobial effectiveness of natural antimicrobial agents (NAAs) (yuzu juice, wasabi extract, and rosemary extract) against three target microorganisms (TMs) (Escherichia coli, Staphylococcus aureus, and Salmonella Typhimurium) and to determine the optimal concentration of these agents using response surface methodology (RSM) to ensure the safety of meal kits manufactured using marinade sauce. The three NAAs added to marinade sauce effectively inactivated TMs (P<0.05), in particular, yuzu juice had the greatest antimicrobial effect against TMs, followed by wasabi and rosemary extracts. To determine the optimal concentration of NAAs using RSM, 17 concentrations were tested with three TMs as dependent variables and three NAAs as independent variables. The results showed that E. coli was not present under any of the conditions tested, whereas S. aureus and S. Typhimurium exhibited different characteristics depending on the conditions. Through response surface analysis of the TMs except for E. coli, which was not detected, it was determined that S. aureus had a coefficient of determination (R2) of 0.928 and a lack of fit of 0.074, and the linear regression of [yuzu juice] (X1) and quadratic regression of [yuzu juice]2 (X12) were both significant (P<0.05). S. Typhimurium had an R2 of 0.8955 and a lack of fit of 0.051, and only the quadratic regression of [yuzu juice]2 (X12) was significant (P<0.05). Based on RSM and ridge analysis, the optimal mixed conditions were determined to be 3.92% (v/w) yuzu juice, 23.41% (v/w) wasabi extract, and 3.93% (v/w) rosemary extract. After investigating the antimicrobial effect under the optimal conditions, E. coli and S. Typhimurium were absent, and S. aureus was reduced to 2.50 ± 0.09 log colony-forming units/g after 24 h. The results indicated that mixed treatment with the three NAAs had a more significant antimicrobial effect due to their synergistic properties compared to when used in isolation.

Capturing the generation and structural transformations of molecular ions.

Molecular ions are ubiquitous and play pivotal roles1-3 in many reactions, particularly in the context of atmospheric and interstellar chemistry4-6. However, their structures and conformational transitions7,8, particularly in the gas phase, are less explored than those of neutral molecules owing to experimental difficulties. A case in point is the halonium ions9-11, whose highly reactive nature and ring strain make them short-lived intermediates that are readily attacked even by weak nucleophiles and thus challenging to isolate or capture before they undergo further reaction. Here we show that mega-electronvolt ultrafast electron diffraction (MeV-UED)12-14, used in conjunction with resonance-enhanced multiphoton ionization, can monitor the formation of 1,3-dibromopropane (DBP) cations and their subsequent structural dynamics forming a halonium ion. We find that the DBP+ cation remains for a substantial duration of 3.6 ps in aptly named 'dark states' that are structurally indistinguishable from the DBP electronic ground state. The structural data, supported by surface-hopping simulations15 and ab initio calculations16, reveal that the cation subsequently decays to iso-DBP+, an unusual intermediate with a four-membered ring containing a loosely bound17,18 bromine atom, and eventually loses the bromine atom and forms a bromonium ion with a three-membered-ring structure19. We anticipate that the approach used here can also be applied to examine the structural dynamics of other molecular ions and thereby deepen our understanding of ion chemistry.

A Phase 1b/2a Study of GC1118 with 5-Fluorouracil, Leucovorin and Irinotecan (FOLFIRI) in Patients with Recurrent or Metastatic Colorectal Cancer.

PURPOSE: GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a). MATERIALS AND METHODS: Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/week) in combination with biweekly FOLFIRI (irinotecan 180 mg/m2; leucovorin 400 mg/m2; 5-fluorouracil 400 mg/m2 bolus and 2,400 mg/m2 infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study. RESULTS: RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of ≥ grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0-8.0). CONCLUSION: GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC.

Treatment Patterns and Prognosis of Palliative Chemotherapy Combined With Targeting Agents in Patients With Unresectable Metastatic Colorectal Cancer: CHOICE, A Multicenter Longitudinal Observational Study.

BACKGROUND/AIM: This study investigated the treatment patterns and prognosis of patients with metastatic or unresectable colorectal cancer (mCRC) treated with chemotherapy with targeting agents. PATIENTS AND METHODS: This longitudinal multicenter study included 963 patients with mCRC who were treated in Korea between 2016 and 2020. Treatment patterns and efficacy were compared according to the mutation status and clinical factors. RESULTS: As first-line therapy, most of the patients (83.5%) received FOLFOX plus bevacizumab (35.4%), followed by FOLFIRI plus bevacizumab (18.8%), FOLFIRI plus cetuximab (17.0%), and FOLFOX plus cetuximab (12.3%). Bevacizumab was the most frequent agent (78.8%) combined with chemotherapy in RAS-mutated CRC, while cetuximab (57.2%) in RAS wild-type CRC. Cetuximab was frequently combined with a doublet regimen in patients with left-sided CRC than in those with right-sided CRC (34.4% vs. 16%). As second-line therapy, most patients (63.4%) also received doublet regimens with bevacizumab, and FOLFIRI plus aflibercept was administered in 15.1%. The objective response rate with FOLFIRI plus cetuximab was significantly higher in patients with left-sided CRC than in those with right-sided CRC (59.2% vs. 30.8%, p=0.008) and marginally higher in patients with RAS wild-type CRC than in those with RAS-mutated CRC (55.6% vs. 0.0%, p=0.092). Progression-free survival (PFS) with FOLFOX plus bevacizumab was significantly shorter than that with FOLFIRI plus bevacizumab (p=0.030) in RAS-mutated CRC, whereas there were no significant differences between regimens in RAS wild-type CRC. CONCLUSION: In patients with unresectable metastatic colorectal cancer, doublet chemotherapy with targeting agents is the most common therapy and efficacy depends on the mutation status as well as clinical factors.

Clinical Practice Recommendations for the Use of Next-Generation Sequencing in Patients with Solid Cancer: A Joint Report from KSMO and KSP.

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

Determination of Optimum Processing Condition of High Protein Laver Chip Using Air-Frying and Reaction Flavor Technologies.

This study aimed to develop a high-protein and gluten-free laver chip using air-frying and reaction flavor technologies via response surface methodology (RSM). The optimum processing condition (w/w) was determined with a batter composition of 20% dried laver, 21.3% hair tail surimi, and 58.7% rice flour. Additional ingredients included б-gluconolactone, NaHCO3, soybean oil, corn syrup, table salt, saccharin, and a mixture of distilled water and reaction flavor-inducing solution (RFIS). The laver pellet processed and dried (50 °C, 1-2 h) with air-frying (195 °C, 52.5 s) to process the laver chip. The values of brittleness and puffing ratio of the laver chip were 6.93 ± 0.33 N and 116.19 ± 0.48%, respectively, with an error within 10% of the predicted values of RSM. RFIS was prepared via RSM with the addition of precursor substances (w/v) of methionine 0.54%, threonine 3.30%, glycine 2.40%, glutamic acid 0.90%, and glucose 3% to distilled water and then heating reaction (121 °C, 90 min). The quantitatively descriptive analysis (QDA) of RFIS, baked potato-like and savory odor were 6.00 ± 0.78 and 4.00 ± 0.91, respectively, with an error within 10% of the predicted values. The laver chip exhibited high-protein (24.26 ± 0.10 g%) and low-calorie (371.56 kcal) contents.

Cerium Photocatalyst in Action: Structural Dynamics in the Presence of Substrate Visualized via Time-Resolved X-ray Liquidography.

[Ce(III)Cl6]3-, with its earth-abundant metal element, is a promising photocatalyst facilitating carbon-halogen bond activation. Still, the structure of the reaction intermediate has yet to be explored. Here, we applied time-resolved X-ray liquidography (TRXL), which allows for direct observation of the structural details of reaction intermediates, to investigate the photocatalytic reaction of [Ce(III)Cl6]3-. Structural analysis of the TRXL data revealed that the excited state of [Ce(III)Cl6]3- has Ce-Cl bonds that are shorter than those of the ground state and that the Ce-Cl bond further contracts upon oxidation. In addition, this study represents the first application of TRXL to both photocatalyst-only and photocatalyst-and-substrate samples, providing insights into the substrate's influence on the photocatalyst's reaction dynamics. This study demonstrates the capability of TRXL in elucidating the reaction dynamics of photocatalysts under various conditions and highlights the importance of experimental determination of the structures of reaction intermediates to advance our understanding of photocatalytic mechanisms.

Shelf Life Prediction of Vacuum-Packaged Grilled Mackerel.

The current study aimed to establish the shelf life of vacuum-packaged grilled mackerel stored at 5, -5, and -20°C for 70 days. To this end, physicochemical analyses, which involved determining the pH, volatile basic nitrogen, amino nitrogen, trimethylamine (TMA), and thiobarbituric acid levels; microbiological analyses (aerobic plate count and coliform); and sensory quality determination were performed. Regression analysis on the relationship between physicochemical properties and storage time at various temperatures revealed TMA level was the most suitable parameter (R2=0.9769) for predicting changes in the quality of grilled mackerel during storage, with a quality limit value of 8.74 mg/100 g. The shelf life of vacuum-packaged grilled mackerel according to temperature was 21, 53, 62, and 75 days for 5, -5, -15, and -20°C, respectively, with the use-by date being 23 days at 5°C and 74 days at -5°C. In conclusion, TMA was the most suitable parameter for predicting changes in the quality of grilled mackerel during storage.

Mutational evolution after chemotherapy-progression in metastatic colorectal cancer revealed by circulating tumor DNA analysis.

Emerging new mutations after treatment can provide clues to acquired resistant mechanisms. Circulating tumor DNA (ctDNA) sequencing has enabled noninvasive repeated tumor mutational profiling. We aimed to investigate newly emerging mutations in ctDNA after disease progression in metastatic colorectal cancer (mCRC). Blood samples were prospectively collected from mCRC patients receiving palliative chemotherapy before treatment and at radiological evaluations. ctDNA from pretreatment and progressive disease (PD) samples were sequenced with a next-generation sequencing panel targeting 106 genes. A total of 712 samples from 326 patients were analyzed, and 381 pretreatment and PD pairs (163 first-line, 85 second-line and 133 later-line [≥third-line]) were compared. New mutations in PD samples (mean 2.75 mutations/sample) were observed in 49.6% (189/381) of treatments. ctDNA samples from later-line had more baseline mutations (P = .002) and were more likely to have new PD mutations (adjusted odds ratio [OR] 2.27, 95% confidence interval [CI]: 1.40-3.69) compared to first-line. RAS/BRAF wild-type tumors were more likely to develop PD mutations (adjusted OR 1.87, 95% CI: 1.22-2.87), independent of cetuximab treatment. The majority of new PD mutations (68.5%) were minor clones, suggesting an increasing clonal heterogeneity after treatment. Pathways involved by PD mutations differed by the treatment received: MAPK cascade (Gene Ontology [GO]: 0000165) in cetuximab and regulation of kinase activity (GO: 0043549) in regorafenib. The number of mutations revealed by ctDNA sequencing increased during disease progression in mCRC. Clonal heterogeneity increased after chemotherapy progression, and pathways involved were affected by chemotherapy regimens.

Utilizing Plasma Circulating Tumor DNA Sequencing for Precision Medicine in the Management of Solid Cancers.

Plasma circulating tumor DNA (ctDNA) sequencing has demonstrated clinical utility for tumor molecular profiling at initial diagnosis or tumor progression in advanced solid cancers and is being rapidly incorporated into the clinical practice guidelines, including non-small cell lung and breast cancer. Despite relatively low sensitivity, plasma ctDNA sequencing has several advantages over tissue-based assays, including ease of sampling, rapid turnaround time, repeatability, and the ability to overcome spatial heterogeneity, which makes it ideal for investigating acquired resistance and monitoring tumor evolution and dynamics. With technological advancement and declining costs, the clinical application of plasma ctDNA is expanding, and numerous ongoing clinical trials are examining its potential to guide the management of advanced, localized, and even preclinical cancers of various tumor types. The ability of plasma ctDNA analysis to detect minimal residual disease following curative treatment in the absence of clinical disease is among its most promising attributes. Plasma ctDNA sequencing can also facilitate the conduct of clinical trials and drug development, particularly in immunotherapy. In order to incorporate plasma ctDNA sequencing for clinical decision-making, it is important to understand the preanalytical and analytical factors that may affect its sensitivity and reliability.

Comparison of training effects between underwater treadmill gait training and overground gait training on the walking ability and respiratory function in patients with chronic severe hemiplegic stroke: A randomized, controlled, preliminary trial.

BACKGROUND: The need to develop a more effective intervention to obtain a functional recovery of stroke patients who are unable to perform land-based treadmill gait training has been widely reported. Thus, this pilot study aimed to identify a gait training type that could lead to improved gait and respiratory functioning in adult patients with chronic severe hemiplegic stroke. OBJECTIVES: To examine whether underwater treadmill or/and overground gait training could be more effective in stroke patients. METHODS: In this single-blinded, randomized, controlled, comparative study, 22 patients with severe hemiplegic stroke in a rehabilitation hospital were randomly assigned to the experimental (underwater treadmill gait training) or control group (overground gait training). All participants performed a 60-min neurodevelopmental treatment (five times/week for 12 weeks). Each group performed 30-min underwater or overground gait training (two times/week for 12 weeks). Gait and respiratory function were measured before and after the 12-week training. RESULTS: For the walking variables, step-time difference changes post-training showed significant differences between the groups (-.06 vs. +.04 s, p < .05). Both groups showed significant increases in the maximal voluntary volume (MVV) at post compared to pre training (p < .05). The post-training MVV values were significantly different between the two groups (+23.35 vs. +4.76 L, p < .05). CONCLUSIONS: In severe stroke patients, underwater treadmill gait training can be more effective in improving gait and respiratory function than overground gait training and could be an effective clinical intervention tool for the training of such patients.

Recommendations for the Use of Next-Generation Sequencing and the Molecular Tumor Board for Patients with Advanced Cancer: A Report from KSMO and KCSG Precision Medicine Networking Group.

Next-generation sequencing (NGS) is becoming essential in the fields of precision oncology. With implementation of NGS in daily clinic, the needs for continued education, facilitated interpretation of NGS results and optimal treatment delivery based on NGS results have been addressed. Molecular tumor board (MTB) is multidisciplinary approach to keep pace with the growing knowledge of complex molecular alterations in patients with advanced solid cancer. Although guidelines for NGS use and MTB have been developed in western countries, there is limitation for reflection of Korea's public health environment and daily clinical practice. These recommendations provide a critical guidance from NGS panel testing to final treatment decision based on MTB discussion.

Retreatment of Irinotecan in Later Lines of Therapy for Metastatic Colorectal Cancer: A Retrospective Study.

BACKGROUND: Due to few efficacious options in later lines of therapy in metastatic colorectal cancer (mCRC), there has been considerable interest in the possibility of retreatment with previously administered agents. This study investigated the efficacy and safety of irinotecan retreatment (IRI2) in patients with refractory mCRC. METHODS: We performed a retrospective analysis of patients with mCRC who were retreated with irinotecan-based regimens. The retreatment regimens with anti-epidermal growth factor receptor therapies were excluded. RESULTS: A total of 64 patients were included. Patients had a median age of 56 years and were offered mainly in the setting of third- or fourth-line therapy with IRI2. The disease control rate was 78.2% including an objective response of 23.5%. Median progression-free survival and overall survival were 5.5 and 19.3 months, respectively. The most frequent grade 3 or higher toxicities were nausea/vomiting (27.9%) and neutropenia (25%). CONCLUSION: IRI2 might be a reasonable option for heavily pretreated patients with mCRC who achieved disease control with prior irinotecan therapy.

Cancer Patients' Willingness to Take COVID-19 Vaccination: A Nationwide Multicenter Survey in Korea.

Considering the high morbidity and mortality of Coronavirus disease 2019 (COVID-19) in patients with malignancy, they are regarded as a priority for COVID-19 vaccination. However, general vaccine uptake rates among cancer patients are known to be lower than in their healthy counterparts. Thus, we aimed to investigate the attitude and acceptance rates for the COVID-19 vaccine in cancer patients and identify predictive factors for vaccination that could be modified to increase vaccine uptake rates, via a paper-based survey (58 items over six domains). A total of 1001 cancer patients participated in this nationwide, multicenter survey between February and April 2021. We observed that 61.8% of respondents were willing to receive the COVID-19 vaccine. Positive predictive factors found to be independently associated with vaccination were male gender, older age, obesity, previous influenza vaccination history, absence of cancer recurrence, time since cancer diagnosis over 5 years, and higher EuroQol Visual Analogue Scale scores. Along with the well-known factors that are positively correlated with vaccination, here, we report that patients' disease status and current health status were also associated with their acceptance of the COVID-19 vaccination. Moreover, 91.2% of cancer patients were willing to be vaccinated if their attending physicians recommend it, indicating that almost 30% could change their decision upon physicians' recommendation. Unlike other factors, which are unmodifiable, physicians' recommendation is the single modifiable factor that could change patients' behavior. In conclusion, we firstly report that Korean cancer patients' acceptance rate of the COVID-19 vaccination was 61.8% and associated with disease status and current health status. Physicians should play a major role in aiding cancer patients' decision-making concerning COVID-19 vaccines.

Pelvic Belt Wearing during Exercise Improves Balance of Patients with Stroke: A Randomized, Controlled, Preliminary Trial.

OBJECTIVES: To investigate whether wearing a pelvic belt during a trunk stability exercise program positively affects balance in patients with stroke. MATERIALS AND METHODS: Twenty-four patients with stroke were randomly allocated to the experimental or control group and performed a 60-min general physical therapy and an additional 30-min trunk stability exercise (five times/week for 6 weeks). Those in the experimental and control groups performed the trunk stability exercises with and without wearing the pelvic belt, respectively. RESULTS: The experimental group showed a significantly greater magnitude of improvements in balance than the control group (Postural Assessment Scale for Stroke: +18.3%, F (1, 22)=14.350, p=.001, η2=.395; Berg Balance Scale: +11%, F (1, 22)=19.062, p=.000, η2=.464; Timed Up and Go Test: -10.5%, F (1, 22)=8.562, p=.008, η2=.280; center of pressure path length with eyes open: -15.1%, F (1, 22)=6.770, p=.016, η2=.235; center of pressure path length with eyes closed: -19.5%, F (1, 22)=9.256, p=.006, η2=.296; center of pressure path velocity with eyes open: -22.6%, F (1, 22)=37.747, p=.000, η2=.632; center of pressure path velocity with eyes closed: -13.9%, F (1, 22)=6.511, p=.018, η2=.228, respectively). CONCLUSIONS: Wearing a pelvic belt while performing trunk stability exercise programs could be a more effective approach for improving balance in patients with stroke.

Muscle activities of lower extremity and erector spinae muscles according to ankle joint position during squat exercise.

OBJECTIVE: The purpose of this study was to investigate the most effective ankle joint position for squat exercise by comparing muscle activities of lower extremity and erector spinae muscles in different ankle joint positions. METHODS: Thirty-seven normal healthy adults in their 20s participated in this study. Muscle activities of dominant vastus medialis oblique, vastus lateralis, biceps femoris, and erect spinae were measured in three ankle joint positions; dorsiflexion, neutral, and plantar flexion. RESULTS: Muscle activities of the vastus medialis oblique, vastus lateralis, and erector spinae muscles were statistically different in the three ankle joint positions during squat exercise (p< 0.05). Vastus medialis oblique muscles showed higher muscle activity in ankle plantar flexion than in the dorsiflexion or neutral positions (plantar flexion > neutral position, +3.3% of maximal voluntary isometric contraction (MVIC); plantar flexion > dorsiflexion, +12.2% of MVIC, respectively). Vastus lateralis muscles showed 7.1% of MVIC greater muscle activity in the neutral position than in dorsiflexion, and erector spinae muscles showed higher muscle activity in dorsiflexion than in plantar flexion or in the neutral position (dorsiflexion > neutral position, +4.3% of MVIC; dorsiflexion > plantar flexion, +7.1% of MVIC, respectively). CONCLUSION: In squat exercises designed to strengthen the vastus medialis oblique, ankle joint plantar flexion is probably the most effective ankle training position, and the dorsiflexion position might be the most effective exercise for strengthening the erector spinae muscle.

Cross training effects of non-paralytic dorsiflexion muscle strengthening exercise on paralytic dorsiflexor muscle activity, gait ability, and balancing ability in patients with chronic stroke: A randomized, controlled, pilot trial.

OBJECTIVE: To investigate the effects of non-paralytic dorsiflexion muscle strengthening exercise on functional abilities in chronic hemiplegic patients after stroke. METHODS: A total of 21 patients with chronic stroke underwent dorsiflexion muscle strengthening exercise (MST) 5 times a week for 6 weeks (the experimental group, MST to non-paralytic dorsiflexion muscles, n=11; the control group, MST to paralytic dorsiflexion muscles; n=10). Paralytic dorsiflexor muscle activities (DFA) and 10 m walking tests (10MWT) and timed up and go tests (TUG) were measured before and after intervention. RESULTS: A significant increase in DFA was observed after intervention in the experimental and control groups (p<0.05) (experimental 886.6% for reference voluntary contraction (RVC), control 931.6% for RVC). TUG and 10MWT results showed significant reductions post-intervention in the experimental and control groups (experimental group -5.6 sec, control -4.8 sec; experimental group -3.1 sec, control, -3.9 sec; respectively). No significant intergroup difference was observed between changes in DFA or between changes in TUG and 10MWT results after intervention (p>.05). CONCLUSION: Strengthening exercise performed on non-paralytic dorsiflexion muscles had positive cross-training effects on paralytic dorsiflexor muscle activities, balance abilities, and walking abilities in patients with chronic stroke.

Efficacy and Safety of Systemic Treatments Among Colorectal Cancer Patients: A Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Systemic treatments, namely, either monotherapy or combination therapy, are commonly administered to patients with advanced or metastatic colorectal cancer (CRC). This study aimed to provide the complete efficacy and safety profiles and ranking of systemic therapies for the treatment of unresectable advanced or metastatic CRC. METHODS: We searched PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov from inception until June 30, 2021, and also the bibliographies of relevant studies. Randomized controlled trials comparing two or more treatments, namely, at least capecitabine, 5-fluorouracil, leucovorin, irinotecan, bevacizumab, cetuximab, oxaliplatin, or panitumumab were investigated. A network meta-analysis using the Bayesian approach was performed to compare the efficacy and safety of treatments. The surface under the cumulative ranking curve (SUCRA) was calculated for the probability of each treatment as the most effective. The overall response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), adverse events (AEs) grade ≥3, and serious adverse events (SAEs) were evaluated. RESULTS: One hundred two publications with 36,147 participants were assigned to 39 different treatments. Among 11 treatments with full information on six outcomes, FOLFIRI/FOLFOX/FOLFOXIRI + bevacizumab significantly improved both the ORR and DCR, compared to FOLFIRI. Although FOLFOX and FOLFIRI/FOLFOX + cetuximab significantly prolonged both OS and PFS, treatments were comparable in terms of AEs grade ≥3 and SAEs. The top highest SUCRA values were observed in the FOLFOXIRI + panitumumab group for ORR (96%) and DCR (99%), FOLFIRI + bevacizumab + panitumumab group for OS (62%) and PFS (54%), and FOLFOXIRI + bevacizumab group for AEs grade ≥3 (59%) and SAEs (59%) outcomes. CONCLUSIONS: These findings suggest an available range of systemic treatment therapies with different efficacy and safety profiles with patients. Further investigations of the side effects and mutation status are required to confirm our findings. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD42019127772.