Evaluation of the inflammation-based modified Glasgow Prognostic Score (mGPS) as a prognostic and predictive biomarker in patients with metastatic colorectal cancer receiving first-line chemotherapy: a post hoc analysis of the randomized phase III XELAVIRI trial (AIO KRK0110).

BACKGROUND: The inflammation-based modified Glasgow Prognostic Score (mGPS) combines serum levels of C-reactive protein and albumin and was shown to predict survival in advanced cancer. We aimed to elucidate the prognostic impact of mGPS on survival as well as its predictive value when combined with gender in unselected metastatic colorectal cancer (mCRC) patients receiving first-line chemotherapy in the randomized phase III XELAVIRI trial. PATIENTS AND METHODS: In XELAVIRI, mCRC patients were treated with either fluoropyrimidine/bevacizumab followed by additional irinotecan at first progression (sequential treatment arm; Arm A) or upfront combination of fluoropyrimidine/bevacizumab/irinotecan (intensive treatment arm; Arm B). In the present post hoc analysis, survival was evaluated with respect to the assorted mGPS categories 0, 1 or 2. Interaction between mGPS and gender was analyzed. RESULTS: Out of 421 mCRC patients treated in XELAVIRI, 362 [119 women (32.9%) and 243 men (67.1%)] were assessable. For the entire study population a significant association between mGPS and overall survival (OS) was observed [mGPS = 0: median 28.9 months, 95% confidence interval (CI) 25.9-33.6 months; mGPS = 1: median 21.4 months, 95% CI 17.6-26.1 months; mGPS = 2: median 16.8 months, 95% CI 14.3-21.2 months; P < 0.00001]. Similar results were found when comparing progression-free survival between groups. The effect of mGPS on survival did not depend on the applied treatment regimen (P = 0.21). In female patients, a trend towards longer OS was observed in Arm A versus Arm B, with this effect being clearly more pronounced in the mGPS cohort 0 (41.6 versus 25.5 months; P = 0.056). By contrast, median OS was longer in male patients with an mGPS of 1-2 treated in Arm B versus Arm A (20.8 versus 17.4 months; P = 0.022). CONCLUSION: We demonstrate the role of mGPS as an independent predictor of OS regardless of the treatment regimen in mCRC patients receiving first-line treatment. mGPS may help identify gender-specific subgroups that benefit more or less from upfront intensive therapy.

Quantitative analysis of apparent diffusion coefficients to predict neurological prognosis in cardiac arrest survivors: an observational derivation and internal-external validation study.

BACKGROUND: This study aimed to validate apparent diffusion coefficient (ADC) values and thresholds to predict poor neurological outcomes in out-of-hospital cardiac arrest (OHCA) survivors by quantitatively analysing the ADC values via brain magnetic resonance imaging (MRI). METHODS: This observational study used prospectively collected data from two tertiary academic hospitals. The derivation cohort comprised 70% of the patients randomly selected from one hospital, whereas the internal validation cohort comprised the remaining 30%. The external validation cohort used the data from another hospital, and the MRI data were restricted to scans conducted at 3 T within 72-96 h after an OHCA experience. We analysed the percentage of brain volume below a specific ADC value at 50-step intervals ranging from 200 to 1200 × 10-6 mm2/s, identifying thresholds that differentiate between good and poor outcomes. Poor neurological outcomes were defined as cerebral performance categories 3-5, 6 months after experiencing an OHCA. RESULTS: A total of 448 brain MRI scans were evaluated, including a derivation cohort (n = 224) and internal/external validation cohorts (n = 96/128, respectively). The proportion of brain volume with ADC values below 450, 500, 550, 600, and 650 × 10-6 mm2/s demonstrated good to excellent performance in predicting poor neurological outcomes in the derivation group (area under the curve [AUC] 0.89-0.91), and there were no statistically significant differences in performances among the derivation, internal validation, and external validation groups (all P > 0.5). Among these, the proportion of brain volume with an ADC below 600 × 10-6 mm2/s predicted a poor outcome with a 0% false-positive rate (FPR) and 76% (95% confidence interval [CI] 68-83) sensitivity at a threshold of > 13.2% in the derivation cohort. In both the internal and external validation cohorts, when using the same threshold, a specificity of 100% corresponded to sensitivities of 71% (95% CI 58-81) and 78% (95% CI 66-87), respectively. CONCLUSIONS: In this validation study, by consistently restricting the MRI types and timing during quantitative analysis of ADC values in brain MRI, we observed high reproducibility and sensitivity at a 0% FPR. Prospective multicentre studies are necessary to validate these findings.

A consortium of Hordeum vulgare and gut microbiota against non-alcoholic fatty liver disease via data-driven analysis.

Despite many recent studies on non-alcoholic fatty liver disease (NAFLD) therapeutics, the optimal treatment has yet to be determined. In this unfinished project, we combined secondary metabolites (SMs) from the gut microbiota (GM) and Hordeum vulgare (HV) to investigate their combinatorial effects via network pharmacology (NP). Additionally, we analyzed GM or barley - signalling pathways - targets - metabolites (GBSTMs) in combinatorial perspectives (HV, and GM). A total of 31 key targets were analysed via a protein-protein interaction (PPI) network, and JUN was identified as the uppermost target in NAFLD. On a bubble plot, we revealed that apelin signalling pathway, which had the lowest enrichment factor antagonize NAFLD. Holistically, we scrutinized GBSTM to identify key components (GM, signalling pathways, targets, and metabolites) associated with the Apelin signalling pathway. Consequently, we found that the primary GMs (Eubacterium limosum, Eggerthella sp. SDG-2, Alistipes indistinctus YIT 12060, Odoribacter laneus YIT 12061, Paraprevotella clara YIT 11840, Paraprevotella xylaniphila YIT 11841) to ameliorate NAFLD. The molecular docking test (MDT) suggested that tryptanthrin-JUN is an agonist, conversely, dihydroglycitein-HDAC5, 1,3-diphenylpropan-2-ol-NOS1, and (10[(Acetyloxy)methyl]-9-anthryl)methyl acetate-NOS2, which are antagonistic conformers in the apelin signalling pathway. Overall, these results suggest that combination therapy could be an effective strategy for treating NAFLD.

Enhanced prokaryotic expression, purification, and biological activities of human keratinocyte growth factor.

Keratinocyte growth factor (KGF), also known as fibroblast growth factor 7 (FGF7), plays a critical role in embryonic development, cell proliferation, and differentiation. However, efficient production of recombinant KGF remains a challenge due to its low expression levels and high tendency for aggregation in Escherichia coli. This study aimed to enhance the expression and solubility of KGF by employing different protein tags-PDIb'a', MBP, and His-fused to the N-terminus of KGF. Among these, H-PDIb'a'-KGF demonstrated superior stability and was selected for large-scale production and purification. The purified KGF was confirmed through liquid chromatography with tandem mass spectrometry analysis, which showed an 81% fragment mass identification coverage. Biological activity assessments using human breast cancer MCF-7 cells indicated that purified KGF significantly increased cell proliferation, with an EC50 of 6.4 ± 0.5 pM. Interestingly, PDIb'a' alone also exhibited a stimulatory effect on MCF-7 cells. Furthermore, the purified KGF enhanced the wound healing of HaCaT keratinocytes in a dose-dependent manner. These findings provide valuable insights into the efficient production and functional characterization of recombinant KGF for potential applications in therapeutic interventions.

Unlocking the Promise of Decellularized Pancreatic Tissue: A Novel Approach to Support Angiogenesis in Engineered Tissue.

Advancements in regenerative medicine have highlighted the potential of decellularized extracellular matrix (ECM) as a scaffold for organ bioengineering. Although the potential of ECM in major organ systems is well-recognized, studies focusing on the angiogenic effects of pancreatic ECM are limited. This study investigates the capabilities of pancreatic ECM, particularly its role in promoting angiogenesis. Using a Triton-X-100 solution, porcine pancreas was successfully decellularized, resulting in a significant reduction in DNA content (97.1% removal) while preserving key pancreatic ECM components. A three-dimensional ECM hydrogel was then created from this decellularized tissue and used for cell culture. Biocompatibility tests demonstrated enhanced adhesion and proliferation of mouse embryonic stem cell-derived endothelial cells (mES-ECs) and human umbilical vein endothelial cells (HUVECs) in this hydrogel compared to conventional scaffolds. The angiogenic potential was evaluated through tube formation assays, wherein the cells showed superior tube formation capabilities in ECM hydrogel compared to rat tail collagen. The RT-PCR analysis further confirmed the upregulation of pro-angiogenic genes in HUVECs cultured within the ECM hydrogel. Specifically, HUVECs cultured in the ECM hydrogel exhibited a significant upregulation in the expression of MMP2, VEGF and PAR-1, compared to those cultured in collagen hydrogel or in a monolayer condition. The identification of ECM proteins, specifically PRSS2 and Decorin, further supports the efficacy of pancreatic ECM hydrogel as an angiogenic scaffold. These findings highlight the therapeutic promise of pancreatic ECM hydrogel as a candidate for vascularized tissue engineering application.

Gut microbiota-derived indole compounds attenuate metabolic dysfunction-associated steatotic liver disease by improving fat metabolism and inflammation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, and its prevalence has increased worldwide in recent years. Additionally, there is a close relationship between MASLD and gut microbiota-derived metabolites. However, the mechanisms of MASLD and its metabolites are still unclear. We demonstrated decreased indole-3-propionic acid (IPA) and indole-3-acetic acid (IAA) in the feces of patients with hepatic steatosis compared to healthy controls. Here, IPA and IAA administration ameliorated hepatic steatosis and inflammation in an animal model of WD-induced MASLD by suppressing the NF-κB signaling pathway through a reduction in endotoxin levels and inactivation of macrophages. Bifidobacterium bifidum metabolizes tryptophan to produce IAA, and B. bifidum effectively prevents hepatic steatosis and inflammation through the production of IAA. Our study demonstrates that IPA and IAA derived from the gut microbiota have novel preventive or therapeutic potential for MASLD treatment.

Application of UV-Vis-NIR and FTIR spectroscopy coupled with chemometrics for quality prediction of katsuobushi based on the number of smoking treatments.

Katsuobushi, a smoked, dried skipjack tuna, is a traditional Japanese food additive with a unique flavor and taste. Gas chromatography mass spectrometry (GC-MS), fourier transform infrared (FTIR), and ultraviolet-visible-near infrared spectroscopy (UV-Vis-NIR) combined with chemometric methods were evaluated the quality of katsuobushi according to the number of smoking treatments. Using GC-MS, 46 metabolites were identified and five metabolites were selected as key compounds. All samples were classified according to their smoking number via principal component analysis (PCA), partial least squares-discriminate analysis (PLS-DA) and hierarchical cluster analysis (HCA) of the FTIR and NIR spectra. Partial least squares regression (PLSR) analysis revealed that the FTIR and NIR spectra were highly correlated with the metabolites by GC-MS. These results demonstrated the potential of using the FTIR and NIR spectroscopy combined with chemometrics to assess the quality of katsuobushi based on the smoking treatments, with NIR spectroscopy showed particularly promising.

ECFS standards of care on CFTR-related disorders: Towards a comprehensive program for affected individuals.

After three publications defining an updated guidance on the diagnostic criteria for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (pwCFTR-RDs), establishing its relationship to CFTR-dysfunction and describing the individual disorders, this fourth and last paper in the series addresses some critical challenges facing health care providers and pwCFTR-RD. Topics included are: 1) benefits and obstacles to collect data from pwCFTR-RD are discussed, together with the opportunity to integrate them into established CF-registries; 2) the potential of infants designated CRMS/CFSPID to develop a CFTR-RD and how to communicate this information; 3) a description of the challenges in genetic counseling, with particular regard to phenotypic variability, unknown long-term evolution, CFTR testing and pregnancy termination 4) a proposal for the assessment of potential barriers to the implementation and dissemination of the produced documents to health care professionals involved in the care of pwCFTR-RD and a process to monitor the implementation of the CFTR-RD recommendations; 5) clinical trials investigating the efficacy of CFTR modulators in CFTR-RD and how endpoints and outcomes might be adapted to the heterogeneity of these disorders.

Injectable Peptide Hydrogels Loaded with Murine Embryonic Stem Cells Relieve Ischemia In Vivo after Myocardial Infarction.

Myocardial infarction (MI) is a major cause of morbidity and mortality worldwide, especially in aging and metabolically unhealthy populations. A major target of regenerative tissue engineering is the restoration of viable cardiomyocytes to preserve cardiac function and circumvent the progression to heart failure post-MI. Amelioration of ischemia is a crucial component of such restorative strategies. Angiogenic ß-sheet peptides can self-assemble into thixotropic nanofibrous hydrogels. These syringe aspiratable cytocompatible gels were loaded with stem cells and showed excellent cytocompatibility and minimal impact on the storage and loss moduli of hydrogels. Gels with and without cells were delivered into the myocardium of a mouse MI model (LAD ligation). Cardiac function and tissue remodeling were evaluated up to 4 weeks in vivo. Injectable peptide hydrogels synergized with loaded murine embryonic stem cells to demonstrate enhanced survival after intracardiac delivery during the acute phase post-MI, especially at 7 days. This approach shows promise for post-MI treatment and potentially functional cardiac tissue regeneration and warrants large-scale animal testing prior to clinical translation.

Innate Immune-Enhancing Effect of Pinus densiflora Pollen Extract via NF-κB Pathway Activation.

Considering the emergence of various infectious diseases, including the coronavirus disease 2019 (COVID-19), people's attention has shifted towards immune health. Consequently, immune-enhancing functional foods have been increasingly consumed. Hence, developing new immune-enhancing functional food products is needed. Pinus densiflora pollen can be collected from the male red pine tree, which is commonly found in Korea. P. densiflora pollen extract (PDE), obtained by water extraction, contained polyphenols (216.29 ± 0.22 mg GAE/100 g) and flavonoids (35.14 ± 0.04 mg CE/100 g). PDE significantly increased the production of nitric oxide (NO) and reactive oxygen species (ROS) but, did not exhibit cytotoxicity in RAW 264.7 cells. Western blot results indicated that PDE induced the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2. PDE also significantly increased the mRNA and protein levels of cytokines and the phosphorylation of IKKα/ß and p65, as well as the activation and degradation of IκBα. Additionally, western blot analysis of cytosolic and nuclear fractions and immunofluorescence assay confirmed that the translocation of p65 to the nucleus after PDE treatment. These results confirmed that PDE increases the production of cytokines, NO, and ROS by activating NF-κB. Therefore, PDE is a promising nutraceutical candidate for immune-enhancing functional foods.

Effect of rice milling, washing, and cooking on reducing pesticide residues.

The effects of milling, washing, and cooking on etofenprox, flubendiamide, and tebufenozide levels in brown and polished rice were investigated by HPLC using a UV detector. The reduction rates of etofenprox, flubendiamide, and tebufenozide after milling were 68.74-93.16%, 64.49-90.25%, and 69.74-92.58%, respectively, 11.64-41.44%, 31.36-65.37%, and 31.61-73.79%, respectively, after washing brown rice, and 30.85-82.08%, 52.13-83.05%, and 43.04-83.89%, respectively, after washing polished rice. The residue levels of the three pesticides in brown rice decreased after electric and pressure cooking by 56.49 and 54.41%, 75.80 and 73.42%, and 70.01 and 71.27%, respectively, and the corresponding levels in polished rice decreased after electric and pressure cooking by 85.58 and 85.82%, 86.70 and 87.06%, and 89.89 and 89.68%, respectively. In conclusion, various processing methods decrease the residual levels of etofenprox, flubendiamide, and tebufenozide in rice.

The multifaceted functions of ß-arrestins and their therapeutic potential in neurodegenerative diseases.

Arrestins are multifunctional proteins that regulate G-protein-coupled receptor (GPCR) desensitization, signaling, and internalization. The arrestin family consists of four subtypes: visual arrestin1, ß-arrestin1, ß-arrestin2, and visual arrestin-4. Recent studies have revealed the multifunctional roles of ß-arrestins beyond GPCR signaling, including scaffolding and adapter functions, and physically interacting with non-GPCR receptors. Increasing evidence suggests that ß-arrestins are involved in the pathogenesis of a variety of neurodegenerative diseases, including Alzheimer's disease (AD), frontotemporal dementia (FTD), and Parkinson's disease (PD). ß-arrestins physically interact with γ-secretase, leading to increased production and accumulation of amyloid-beta in AD. Furthermore, ß-arrestin oligomers inhibit the autophagy cargo receptor p62/SQSTM1, resulting in tau accumulation and aggregation in FTD. In PD, ß-arrestins are upregulated in postmortem brain tissue and an MPTP model, and the ß2AR regulates SNCA gene expression. In this review, we aim to provide an overview of ß-arrestin1 and ß-arrestin2, and describe their physiological functions and roles in neurodegenerative diseases. The multifaceted roles of ß-arrestins and their involvement in neurodegenerative diseases suggest that they may serve as promising therapeutic targets.

The association of nursing home infection preventionists' training and credentialing with resident COVID 19 deaths.

BACKGROUND: Nursing home (NH) residents' vulnerability to COVID-19 underscores the importance of infection preventionists (IPs) within NHs. Our study aimed to determine whether training and credentialing of NH IPs were associated with resident COVID-19 deaths. METHODS: This retrospective observational study utilized data from the Centers for Disease Control and Prevention's National Healthcare Safety Network NH COVID-19 Module and USAFacts, from May 2020 to February 2021, linked to a 2018 national NH survey. We categorized IP personnel training and credentialing into four groups: (1) LPN without training; (2) RN/advanced clinician without training; (3) LPN with training; and (4) RN/advanced clinician with training. Multivariable linear regression models of facility-level weekly deaths per 1000 residents as a function of facility characteristics, and county-level COVID-19 burden (i.e., weekly cases or deaths per 10,000 population) were estimated. RESULTS: Our study included 857 NHs (weighted n = 14,840) across 489 counties and 50 states. Most NHs had over 100 beds, were for profit, part of chain organizations, and located in urban areas. Approximately 53% of NH IPs had infection control training and 82% were RNs/advanced clinicians. Compared with NHs employing IPs who were LPNs without training, NHs employing IPs who were RNs/advanced clinicians without training had lower weekly COVID-19 death rates (-1.04 deaths per 1000 residents; 95% CI -1.90, -0.18), and NHs employing IPs who were LPNs with training had lower COVID-19 death rates (-1.09 deaths per 1000 residents; 95% CI -2.07, -0.11) in adjusted models. CONCLUSIONS: NHs with LPN IPs without training in infection control had higher death rates than NHs with LPN IPs with training in infection control, or NHs with RN/advanced clinicians in the IP role, regardless of IP training. IP training of RN/advanced clinician IPs was not associated with death rates. These findings suggest that efforts to standardize and improve IP training may be warranted.

Co-enrichment of cancer-associated bacterial taxa is correlated with immune cell infiltrates in esophageal tumor tissue.

Esophageal carcinoma (ESCA) is a leading cause of cancer-related death worldwide, and certain oral and intestinal pathogens have been associated with cancer development and progression. We asked if esophageal microbiomes had shared alterations that could provide novel biomarkers for ESCA risk. We extracted DNA from tumor and non-tumor tissue of 212 patients in the NCI-MD case control study and sequenced the 16S rRNA gene (V3-4), with TCGA ESCA RNA-seq (n = 172) and WGS (n = 123) non-human reads used as validation. We identified four taxa, Campylobacter, Prevotella, Streptococcus, and Fusobacterium as highly enriched in esophageal cancer across all cohorts. Using SparCC, we discovered that Fusobacterium and Prevotella were also co-enriched across all cohorts. We then analyzed immune cell infiltration to determine if these dysbiotic taxa were associated with immune signatures. Using xCell to obtain predicted immune infiltrates, we identified a depletion of megakaryocyte-erythroid progenitor (MEP) cells in tumors with presence of any of the four taxa, along with enrichment of platelets in tumors with Campylobactor or Fusobacterium. Taken together, our results suggest that intratumoral presence of these co-occurring bacterial genera may confer tumor promoting immune alterations that allow disease progression in esophageal cancer.

Quality evaluation and storage test for capsaicin-fortified yogurt based on the multilayer nanoemulsion system.

Capsaicin has many benefits, such as pain relief, cancer prevention, and weight reduction. However, the application of capsaicin has been limited in the food industry due to its strong pungency, odor, and low solubility in water. Therefore, a multilayer nanoemulsion with chitosan and hyaluronic acid was developed for masking its odor and taste and improving the physicochemical stability against the surrounding environment. The capsaicin-fortified yogurts were prepared by blending various concentration levels of multilayer nanoemulsion (0-15%, w/v). The quality of yogurt was determined as a function of pH, acidity, viscosity, and total lactic acid bacteria population in an extended storage period (21 days). The multivariate statistical analysis was used to compare the quality of yogurts supplemented with capsaicin nanoemulsion. As a result, this study demonstrated the potential of capsaicin-loaded multilayer emulsion-supplemented yogurt as a novel nutrition-fortified food.

Eighth Cervical Nerve Root Block During Interscalene Brachial Plexus Block Decreases Pain Caused by Posterior Portal Placement but Increases Horner Syndrome in Patients Undergoing Arthroscopic Shoulder Surgery: A Randomized Controlled Trial.

PURPOSE: To compare the intensity of pain on posterior portal placement between a C5-C7 root block (conventional interscalene brachial plexus block [ISBPB]) and a C5-C8 root block in patients undergoing arthroscopic shoulder surgery. METHODS: In this prospective, single-blinded, parallel-group randomized controlled trial, patients were randomized to receive either a C5-C7 root block (C5-C7 group, n = 37) or a C5-C8 root block (C5-C8 group, n = 36) with 25 mL of 0.75% ropivacaine. The primary outcome was the pain intensity on posterior portal placement, which was graded as 0 (no pain), 1 (mild pain), or 2 (severe pain). The secondary outcomes were the bilateral pupil diameters measured 30 minutes after ISBPB placement; the incidence of Horner syndrome, defined as a difference in pupil diameter (ipsilateral - contralateral) of less than -0.5 mm; the onset of postoperative pain; and the postoperative numerical rating pain score, where 0 and 10 represent no pain and the worst pain imaginable, respectively. RESULTS: Fewer patients reported mild or severe pain on posterior portal placement in the C5-C8 group than in the C5-C7 group (9 of 36 [25.0%] vs 24 of 37 [64.9%], P = .003). Less pain on posterior portal placement was reported in the C5-C8 group than in the C5-C7 group (median [interquartile range], 0 [0-0.75] vs 1 [0-1]; median difference [95% confidence interval], 1 [0-1]; P = .001). The incidence of Horner syndrome was higher in the C5-C8 group than in the C5-C7 group (33 of 36 [91.7%] vs 22 of 37 [59.5%], P = .001). No significant differences in postoperative numerical rating pain scores and onset of postoperative pain were found between the 2 groups. CONCLUSIONS: A C5-C8 root block during an ISBPB reduces the pain intensity on posterior portal placement. However, it increases the incidence of Horner syndrome with no improvement in postoperative pain compared with the conventional ISBPB (C5-C7 root block). LEVEL OF EVIDENCE: Level I, randomized controlled trial.

The effects of fucoidan-rich polysaccharides extracted from Sargassum horneri on enhancing collagen-related skin barrier function as a potential cosmetic product.

BACKGROUND: Sargassum horneri came ashore after flowing from the South China Sea to Jeju Island a few years ago. This caused a significant environmental impact on coastal areas where S. horneri has accumulated because of decomposition and the release of toxic substances, such as hydrogen sulfide. AIMS: In this study, we evaluated a biological ingredient prepared from fucoidan-rich S. horneri and demonstrated its antiwrinkle effects on ultraviolet B (UVB)-induced fibroblast cells. MATERIALS AND METHODS: Fucoidan samples from S. horneri were prepared according to a previously published process with modifications. The compositional analysis of S. horneri fucoidan extract (SHFE) as well as its effects on antiaging were examined to determine its utility as a functional material. RESULTS: SHFE exhibited antioxidant properties using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay. Treatment of UVB-induced fibroblasts with SHFE significantly increased the synthesis of procollagen compared with adenosine treatment and inhibited MMP-1 and MMP-3 expression. In a clinical study, SHFE lotion improved skin barrier effects in forearms and transepidermal water loss (TEWL) values were reduced after 3 weeks of use compared with a placebo. CONCLUSION: SHFE has utility as an additive with functional antiaging effects for a range of cosmetic products as it restores skin hydration in the epidermal barrier.

Three-year follow-up analysis of axicabtagene ciloleucel in relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5).

ABSTRACT: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Approval was supported by the phase 2, multicenter, single-arm ZUMA-5 study of axi-cel for patients with R/R indolent non-Hodgkin lymphoma (iNHL; N = 104), including FL and marginal zone lymphoma (MZL). In the primary analysis (median follow-up, 17.5 months), the overall response rate (ORR) was 92% (complete response rate, 74%). Here, we report long-term outcomes from ZUMA-5. Eligible patients with R/R iNHL after ≥2 lines of therapy underwent leukapheresis, followed by lymphodepleting chemotherapy and axi-cel infusion (2 × 106 CAR T cells per kg). The primary end point was ORR, assessed in this analysis by investigators in all enrolled patients (intent-to-treat). After median follow-up of 41.7 months in FL (n = 127) and 31.8 months in MZL (n = 31), ORR was comparable with that of the primary analysis (FL, 94%; MZL, 77%). Median progression-free survival was 40.2 months in FL and not reached in MZL. Medians of overall survival were not reached in either disease type. Grade ≥3 adverse events of interest that occurred after the prior analyses were largely in recently treated patients. Clinical and pharmacokinetic outcomes correlated negatively with recent exposure to bendamustine and high metabolic tumor volume. After 3 years of follow-up in ZUMA-5, axi-cel demonstrated continued durable responses, with very few relapses beyond 2 years, and manageable safety in patients with R/R iNHL. The ZUMA-5 study was registered at www.clinicaltrials.gov as #NCT03105336.