Improved diagnostic efficiency of CRC subgroups revealed using machine learning based on intestinal microbes.

BACKGROUND: Colorectal cancer (CRC) is a common cancer that causes millions of deaths worldwide each year. At present, numerous studies have confirmed that intestinal microbes play a crucial role in the process of CRC. Additionally, studies have shown that CRC can be divided into several consensus molecular subtypes (CMS) based on tumor gene expression, and CRC microbiomes have been reported related to CMS. However, most previous studies on intestinal microbiome of CRC have only compared patients with healthy controls, without classifying of CRC patients based on intestinal microbial composition. RESULTS: In this study, a CRC cohort including 339 CRC samples and 333 healthy controls was selected as the discovery set, and the CRC samples were divided into two subgroups (234 Subgroup1 and 105 Subgroup2) using PAM clustering algorithm based on the intestinal microbial composition. We found that not only the microbial diversity was significantly different (Shannon index, p-value < 0.05), but also 129 shared genera altered (p-value < 0.05) between the two CRC subgroups, including several marker genera in CRC, such as Fusobacterium and Bacteroides. A random forest algorithm was used to construct diagnostic models, which showed significantly higher efficiency when the CRC samples were divided into subgroups. Then an independent cohort including 187 CRC samples (divided into 153 Subgroup1 and 34 Subgroup2) and 123 healthy controls was chosen to validate the models, and confirmed the results. CONCLUSIONS: These results indicate that the divided CRC subgroups can improve the efficiency of disease diagnosis, with various microbial composition in the subgroups.

A Novel, Low-Cost Alternative to Traditional Glaucoma Surgeries.

Purpose: To investigate the real-world efficacy of a novel, low-cost glaucoma drainage device in canine and human patients. Methods: A retrospective case series of 17 eyes in 14 canines and one eye of a human patient who each underwent novel drainage device implantation is described. This device was constructed by insertion and advancement of a 24-gauge cannula (canine) or 23-gauge cannula (human) perpendicularly through five adjacent tubes of a 25-mm Yeates surgical drain. Results: Of the canine patients, the average follow-up period was 362 days (range, 27-863). The mean preoperative intraocular pressure (IOP) was 50.9 ± 17.9 mm Hg. Following tube surgery, IOP was maintained at <20 mm Hg in 81.3%, 100%, 100%, 85.7%, 100%, and 75.0% of eyes at 1, 2, 3, 6, 9, and 12 months, respectively. Bleb needling and/or revisions were required in five eyes. Enucleations and/or device explantations were performed in five eyes at mean day 140. In the human case, the device was implanted in the right eye of a 64-year-old male with refractory raised IOP (55 mm Hg) despite maximum medical therapy. IOP was well controlled until day 818, when eventual tissue breakdown necessitated device removal. Conclusions: This design represents a novel, low-cost, effective alternative to traditional glaucoma tube devices. Translational Relevance: This device has great potential for use in regions where the needs for glaucoma drainage devices and surgical alternatives to trabeculectomy have not been met. Further development may include tube crimping or fenestration and preoperative loading of slow-release antibiotics and/or anti-metabolite medications within the non-draining lumens.

The past, present, and future of tumour deposits in colorectal cancer: Advancing staging for improved prognosis and treatment decision-making.

Tumour deposits (TDs) significantly impact colorectal cancer (CRC) prognosis. Integrating TDs into the TNM staging system can enhance individualized disease management. Keeping abreast of evolving TDs research is pivotal for clinical advancement. We comprehensively reviewed both recent and popular literature to grasp the field's essence. Subsequently, a data retrieval sourced articles on TDs in CRC for bibliometric analysis, spanning from 1 January 1935 to 30 April 2023. Bibliometrix software facilitated paper analysis and visualization. Bibliometric indicators, the trends and hotspots were determined. A total of 2147 articles were successfully retrieved. Brown G emerged as the most productive author, and the USA as the most prolific country. Central South University and Memorial Sloan Kettering Cancer Center led productivity. Bradford's law categorized 48 journals into zone 1. Keywords co-occurrence analysis identified three main clusters: the application of TDs in TNM staging, the pathogenesis of TDs, and the assessment of TDs. The trend topic analysis highlighted research focused on refining TDs incorporation into tumour staging. TDs wield enduring medical significance, shaping ongoing research. Much literature focused on confirming TD's prognostic value and optimizing TNM integration. Additionally, it is worth highlighting that TD's enigmatic pathogenesis demands research priority, as it holds the potential to unveil concealed knowledge regarding their development.

Diagnostic utility of in vivo confocal microscopy in Acanthamoeba keratitis following corneal crosslinking.

Acanthamoeba keratitis (AK) is a rare but potentially sight-threatening complication of corneal collagen crosslinking (CXL) for keratoconus. In this report, we describe an early adolescent male who underwent routine CXL for progressive keratoconus in his left eye. Preprocedural left visual acuity (VA) was 6/9. At day 5 postprocedure, multifocal corneal infiltrates were identified. Corneal scrape, bandage contact lens cultures and herpetic and Acanthamoeba PCR were negative. In vivo, confocal microscopy (IVCM) identified Acanthamoeba cysts within the corneal stroma. Intensive amoebicidal therapy was initiated, but recovery was complicated by significant inflammation, resulting in widespread aggressive corneal vascularisation necessitating topical steroids and steroid-sparing agents. At 10 months, his left VA was 6/24. This report emphasises the importance of maintaining a high index of suspicion for AK in cases of post-CXL microbial keratitis and highlights the diagnostic value of IVCM, particularly in culture-negative and PCR-negative cases.

Fusobacterium nucleatum promotes tumor progression in KRAS p.G12D-mutant colorectal cancer by binding to DHX15.

Fusobacterium nucleatum (F. nucleatum) promotes intestinal tumor growth and its relative abundance varies greatly among patients with CRC, suggesting the presence of unknown, individual-specific effectors in F. nucleatum-dependent carcinogenesis. Here, we identify that F. nucleatum is enriched preferentially in KRAS p.G12D mutant CRC tumor tissues and contributes to colorectal tumorigenesis in Villin-Cre/KrasG12D+/- mice. Additionally, Parabacteroides distasonis (P. distasonis) competes with F. nucleatum in the G12D mouse model and human CRC tissues with the KRAS mutation. Orally gavaged P. distasonis in mice alleviates the F. nucleatum-dependent CRC progression. F. nucleatum invades intestinal epithelial cells and binds to DHX15, a protein of RNA helicase family expressed on CRC tumor cells, mechanistically involving ERK/STAT3 signaling. Knock out of Dhx15 in Villin-Cre/KrasG12D+/- mice attenuates the CRC phenotype. These findings reveal that the oncogenic effect of F. nucleatum depends on somatic genetics and gut microbial ecology and indicate that personalized modulation of the gut microbiota may provide a more targeted strategy for CRC treatment.

Short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab for locally advanced esophageal squamous cell carcinoma (SCALE-1): a single-arm phase Ib clinical trial.

BACKGROUND: The optimal dosages, timing, and treatment sequencing for standard-of-care neoadjuvant chemoradiotherapy necessitate re-evaluation when used in conjunction with immune checkpoint inhibitors for patients with resectable, locally advanced esophageal squamous cell carcinoma (RLaESCC). The SCALE-1 phase Ib study aimed to evaluate the safety and efficacy of short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab in this patient population. METHODS: RLaESCC patients with clinical stages cT3-4aN0M0/cT1-4aN+M0 received neoadjuvant paclitaxel (135 mg/m2), carboplatin (area under the curve=5), and toripalimab (240 mg) every 3 weeks for two cycles. Short-course neoadjuvant radiotherapy (30 Gy in 12 fractions; 5 days per week) was administered between neoadjuvant immune-chemotherapy (nICT) doses. Esophagectomies were scheduled 4-6 weeks after completing neoadjuvant treatment. The primary endpoint was safety, with secondary endpoints including pathological complete response (pCR) rate, postoperative complications, progression-free survival (PFS), and overall survival (OS). Exploratory biomarker analysis used gene expression profiles via the nCounter platform. RESULTS: Of the 23 patients enrolled, all completed neoadjuvant radiotherapy, while 21 cases finished full nICT doses and cycles. Common grade 3/4 adverse events included neutropenia (57%), leukopenia (39%), and skin rash (30%). No grade 3 or higher esophagitis or pneumonitis occured. Twenty patients underwent surgery, and 11 achieved pCR (55%). Two patients (10%) experienced grade IIIb surgical complications. At the database lock, a 2-year PFS rate of 63.8% (95% CI 43.4% to 84.2%) and 2-year OS rate was 78% (95% CI 64.9% to 91.1%) were achieved. Tumor immune microenvironment analysis indicated that tumors with pCR exhibited significantly higher pretreatment T-cell-inflamed score and post-treatment reshaping of antitumor immunity. CONCLUSIONS: Combining short-course neoadjuvant radiotherapy with chemotherapy and toripalimab demonstrated favorable safety and promising efficacy in RLaESCC patients. TRIAL REGISTRATION NUMBER: ChiCTR2100045104.

Anlotinib combined with whole-brain radiotherapy in non-small cell lung cancer with multiple brain metastases that progressed or developed after at least one lines of prior treatment.

Background: Intracranial metastasis that failed standard systematic treatment is common in advanced non-small cell lung cancer (NSCLC), contributing significantly to morbidity and mortality. The aim of this study was to evaluate the efficacy and safety of anlotinib combined with whole-brain radiotherapy (WBRT) for NSCLC with brain metastases (BMs) that progressed or developed after at least one line of prior treatment and compare the outcomes with that of the contemporary institutional control. Methods: NSCLC patients with multiple BMs that progressed or developed after at least one line of prior systematic treatment and treated with WBRT subsequently between 2019 and 2021 were selected retrospectively for analysis. Based on whether concurrent anlotinib had been used in combination with WBRT, the cases were divided into the anlotinib group and control group. The primary endpoints were intracranial progression-free survival (iPFS) and safety. Results: A total of 76 patients met the inclusion criteria of the study. Of the 76 patients, 34 received concurrent WBRT and anlotinib followed by anlotinib maintenance and 42 were treated with WBRT alone or in combination with other systemic agents at the physicians' discretion. The median follow-up for the entire cohort was 21 months. The median iPFS for the anlotinib and control group was 6.7 months (95% CI, 4.6-9.9) and 5.3 months (95% CI, 4.0-6.5), respectively (log-rank P = 0.04). There was no difference in overall survival between the two groups (log-rank P = 0.38). In the anlotinib group, treatment-related adverse events were reported in 15 patients (44.1%), with acute or late grade 3-5 adverse events identified in 14.7% of patients (n = 5). Conclusions: WBRT plus anlotinib, as a convenient chemo-free regimen, may represent an overall safe and effective procedure in advanced NSCLC with multiple BMs that progressed or developed after standard systematic treatment.

Distribution pattern of medial group retropharyngeal lymph nodes and its implication in optimizing clinical target volume in nasopharyngeal carcinoma.

Purpose: This study aimed to determine the diagnostic value of diffusion-weighted imaging (DWI) and to elucidate the clinical characteristics of medial group retropharyngeal lymph nodes (RLNs) based on multi-modal imaging. Also, we intended to explore the feasibility of optimizing the CTV60 boundary based on the characteristics of medial group RLNs. Methods: A total of 549 patients with nasopharyngeal carcinoma received magnetic resonance imaging (MRI), DWI, and contrast-enhanced computed tomography (CT) to detect and evaluate clinical characteristics of medial group RLNs. [18F]Fluorodeoxyglucose positron emission tomography/computed tomography was utilized to identify fluorodeoxyglucose uptaking and contrast-enhanced CT to ensure the reliability of CTV optimization during radiotherapy. The DESdC (Drinking, Eating, Swallowing Difficulties, and Coughing while Eating or Drinking) score was utilized to evaluate swallowing disability. Results: Fourteen of 549 patients had medial group RLNs with a transverse diameter of 2.0-19.0 mm, which distributed between the upper margin of 1st cervical vertebra (C1) and the upper one-third of C3. Lasso regression and Pearson chi-square test suggested that its occurrence was associated with stage N, bilateral cervical lymph node metastases, especially when the transverse diameter of cervical lymph nodes was > 3 cm. The sensitivity of DWI, T2 STIR, and contrast-enhanced CT was 100%, 57.1%, and 21.4%, respectively. We optimized CTV60 of medial group RLNs from the base of skull to the upper edge of C2 excluding specific cases. For patients with CTV60 optimization, radiation dose and volume of swallowing structures decreased obviously. Based on our radiotherapy strategy on CTV60, acute toxicities of enrolled patients were well tolerated. Ninety-six of 549 patients had scores with DESdC score. Eighty-three patients scored 1, seven patients scored 2, one patient scored 3, and three patients scored 4. The median interval from the onset of symptoms was 72 (4-114) months. The 5-year overall survival, progression-free survival, local recurrence-free survival, and distant metastasis-free survival were 87%, 80%, 93%, and 85%, respectively. None of the patients with regional recurrence happened in the optimized region. Conclusion: DWI possesses superiorities in displaying lymph nodes. Based on the low incidence of the medial RLNs, CTV60 of medial group RLNs from the base of skull to the upper edge of C2 is feasible and has dosimetric advantages for protecting swallowing structures.

Long-term outcomes in patients with central and ultracentral non-small cell lung cancer treated with stereotactic body radiotherapy: single-institution experience.

OBJECTIVE: Treatment-related toxicity following stereotactic ablative radiotherapy (SABR) in patients with central and ultracentral non-small cell lung cancer (NSCLC) is of potential concern, and the best regimens are still being explored. This study aimed to evaluate the clinical outcomes and toxicities of the patients with ultracentral and central NSCLC treated with SABR at our institution. METHOD: This retrospective study included patients with central and ultracentral NSCLC treated with SABR to prescription doses of 50 Gy in five fractions, 56 Gy in seven fractions, or 60 Gy in ten fractionsat Jiangsu Cancer Hospital between May 2013 and October 2018. The patients were grouped as central or ultracentral tumors.Overall survival (OS), progression-free survival (PFS), and grade ≥3 toxicities were analyzed. RESULTS: Forty patients (31 male, nine female) were included. Median follow-up was 41 (5-81) months. The 1-, 2-, and 3-year OS rates were 90.0%, 83.6%, and 66.0%, respectively, and the 1-, 2-, and 3-year PFS rates were 82.5%, 62.9%, and 54.2%, respectively. OS in the ultracentral group was inferior compared with the central group (median, 52.0 months, 95%CI: 43.0-61.0 vs. not reached, P=0.03).The median PFS was 38.0 months in the ultracentral group (95%CI: 19.8-56.2) vs. not reached in the central group, although this difference was not statistically significant (P= 0.06). The overall incidence of grade ≥3 toxicity was five (12.5%) patients, (5 in the ultracentralgroup vs. 0 in the central group; P=0. 11), including one patient with grade 3 pneumonitis, two with grade 3 bronchial obstruction, one with grade 5 bronchial obstruction, and one with grade 5 esophageal perforation. CONCLUSION: Worse outcomes were obseverd in patients with ultracentral NSCLC than those with central tumors after SABR. Higher rate of treatment-related grade 3 or more toxicity was observed in the ultracentral group.

Association of red cell distribution width with the risk of 3-month readmission in patients with heart failure: A retrospective cohort study.

Background: In recent years, red cell distribution width (RDW) has been found to be associated with the prognosis of patients with heart failure (HF) in Western countries. However, evidence from Asia is limited. We aimed to investigate the relationship between RDW and the risk of 3-month readmission in hospitalized Chinese HF patients. Methods: We retrospectively analyzed HF data from the Fourth Hospital of Zigong, Sichuan, China, involving 1,978 patients admitted for HF between December 2016 and June 2019. The independent variable in our study was RDW, and the endpoint was the risk of readmission within 3 months. This study mainly used a multivariable Cox proportional hazards regression analysis. Smoothed curve fitting was then used to assess the dose-response relationship between RDW and the risk of 3-month readmission. Results: In the original cohort of 1,978 patients with HF (42% male and 73.1% aged ≥70 years), 495 patients (25.0%) were readmitted within 3 months after discharge. Smoothed curve fitting showed a linear correlation between RDW and the risk of readmission within 3 months. In the multivariable-adjusted model, every 1% increase in RDW was associated with a 9% increased risk of readmission within 3 months (hazard ratio = 1.09, 95% confidence interval: 1.00-1.15; P < 0.005). Conclusions: A higher RDW value was significantly associated with a greater risk of 3-months readmission in hospitalized patients with HF.

Dysbiosis of the stool DNA and RNA virome in Crohn's disease.

Pathogenesis of Crohn's disease (CD) relates to gut microbiome dysbiosis. However, less is known about the viral microbiome, consisting of bacteriophages and eukaryotic viruses, in CD. Here, we profiled the stool virome, viral functions, and viral-bacterial correlations that involved in CD pathogenesis. Metagenomics and metaviromics with novel viral identification and data analysis workflow were performed on stool of non-CD household controls, CD flare and remission patients. Both bacteriome and DNA/RNA virome alterations were characterized and correlated with disease status. There was a decreased diversity and extreme heterogeneity in both DNA and RNA virome in CD. We observed CD-specific dysbiosis in virome, particularly the prominent DNA eukaryotic Torque teno virus (TTV), disease-associated Faecalibacterium phage and Escherichia phage, and RNA tomato diet-related virus in CD, while some diverse prokaryotic viruses were more abundant in healthy subjects. Compared with the remission, inflammation-associated eukaryotic TTV and prokaryotic Staphylococcus phages were predominated in the flare, and displayed a link with complications and multiple therapeutic approaches. Multiple viral functions, particularly functions of viral DNA replication, integration and modification as well as the eukaryotic TTV-related capsid protein, were markedly enriched in CD. Furthermore, the virus-bacteria interactions became more specialized in CD, and the combination of bacteriome and virome composition provided better classification between CD and health. Our study presents a global view of the comprehensive viral component change in the CD patients' gut microbiome, and highlights the great potential of virome biomarkers in pathogenesis and accurate diagnostics of CD risk and disease status.

Integrated metagenomic and metabolomic analysis reveals distinct gut-microbiome-derived phenotypes in early-onset colorectal cancer.

OBJECTIVE: The incidence of early-onset colorectal cancer (EO-CRC) is steadily increasing. Here, we aimed to characterise the interactions between gut microbiome, metabolites and microbial enzymes in EO-CRC patients and evaluate their potential as non-invasive biomarkers for EO-CRC. DESIGN: We performed metagenomic and metabolomic analyses, identified multiomics markers and constructed CRC classifiers for the discovery cohort with 130 late-onset CRC (LO-CRC), 114 EO-CRC subjects and age-matched healthy controls (97 LO-Control and 100 EO-Control). An independent cohort of 38 LO-CRC, 24 EO-CRC, 22 LO-Controls and 24 EO-Controls was analysed to validate the results. RESULTS: Compared with controls, reduced alpha-diversity was apparent in both, LO-CRC and EO-CRC subjects. Although common variations existed, integrative analyses identified distinct microbiome-metabolome associations in LO-CRC and EO-CRC. Fusobacterium nucleatum enrichment and short-chain fatty acid depletion, including reduced microbial GABA biosynthesis and a shift in acetate/acetaldehyde metabolism towards acetyl-CoA production characterises LO-CRC. In comparison, multiomics signatures of EO-CRC tended to be associated with enriched Flavonifractor plauti and increased tryptophan, bile acid and choline metabolism. Notably, elevated red meat intake-related species, choline metabolites and KEGG orthology (KO) pldB and cbh gene axis may be potential tumour stimulators in EO-CRC. The predictive model based on metagenomic, metabolomic and KO gene markers achieved a powerful classification performance for distinguishing EO-CRC from controls. CONCLUSION: Our large-sample multiomics data suggest that altered microbiome-metabolome interplay helps explain the pathogenesis of EO-CRC and LO-CRC. The potential of microbiome-derived biomarkers as promising non-invasive tools could be used for the accurate detection and distinction of individuals with EO-CRC.

Integrated Analysis of Colorectal Cancer Reveals Cross-Cohort Gut Microbial Signatures and Associated Serum Metabolites.

BACKGROUND & AIMS: Studies have reported abnormal gut microbiota or circulating metabolome associated with colorectal cancer (CRC), but it remains a challenge to capture the CRC-relevant features consistent across geographic regions. This is particularly the problem for metabolic traits of CRC because the analyses generally use different platforms and laboratory methods, which poses a barrier to cross-dataset examination. In light of this, we sought to elucidate the microbial and metabolic signatures of CRC with broad population relevance. METHODS: In this integrated metagenomic (healthy controls [HC], n = 91; colorectal adenoma [CRA], n = 63; CRC, n = 71) and metabolomic (HC, n = 34; CRA, n = 31; CRC, n = 35) analysis, CRC-associated features and microbe-metabolite correlations were first identified from a Shanghai cohort. A gut microbial panel was trained in the in-house cohort and cross-validated in 7 published metagenomic datasets of CRC. The in-house metabolic connections to the cross-cohort microbial signatures were used as evidence to infer serum metabolites with potentially external relevance. In addition, a combined microbe-metabolite panel was produced for diagnosing CRC or adenoma. RESULTS: CRC-associated alterations were identified in the gut microbiome and serum metabolome. A composite microbe-metabolite diagnostic panel was developed and yielded an area under the curve of 0.912 for adenoma and 0.994 for CRC. We showed that many CRC-associated metabolites were linked to cross-cohort gut microbiome signatures of the disease, including CRC-enriched leucylalanine, serotonin, and imidazole propionate; and CRC-depleted perfluorooctane sulfonate, 2-linoleoylglycerol (18:2), and sphingadienine. CONCLUSIONS: We generated cross-cohort metagenomic signatures of CRC, some of which linked to in-house CRC-associated serum metabolites. The microbial and metabolic shifts may have wide population relevance.

Probiotic Cocktail Alleviates Intestinal Inflammation Through Improving Gut Microbiota and Metabolites in Colitis Mice.

The modulation of the gut microbiome has been widely suggested as a promising therapeutic strategy for inflammatory bowel disease (IBD). Here, we established a novel probiotic cocktail to investigate its therapeutic role in acute colitis mice. During dextran sulfate sodium (DSS)-induced colitis, the mice were treated with the probiotic cocktail, fecal microbiota transplantation (FMT) from a healthy mice donor, or 5-aminosalicylic acid (5-ASA), respectively. The inflammatory responses were assessed by symptoms, serum inflammatory factors, and histological scoring. The intestinal barrier function was assessed by detecting tight junction proteins. Gut microbiota and its metabolites were further identified using 16S rDNA sequencing and a liquid chromatograph mass spectrometer (LC-MS/MS). Compared with FMT and 5-ASA treatment, the probiotic cocktail performed better in alleviating symptoms of colitis and decreasing disease activity score and mucosal inflammation. The probiotic cocktail also significantly decreased serum IL-17 level and increased JAM-1 expression in colon. The gut microbiota analysis confirmed that the beneficial effects of the probiotic cocktail were attributed to increasing anti-inflammatory bacteria Akkermansia, Bifidobacterium, and Blautia, while decreasing pro-inflammatory bacteria Parasutterella. The targeted metabolome analysis further indicated a rise in the production of Bifidobacterium-related short-chain fatty acids (SCFAs) such as propanoic acid and isobutyric acid after probiotics treatment. Taken together, the probiotic cocktail effectively alleviated intestinal inflammation through improving gut microbiota and metabolites in colitis mice, suggesting its great potential to be a novel therapeutic approach for IBD patients.

Association of Blood Biochemical Indexes and Antibiotic Exposure With Severe Immune-related Adverse Events in Patients With Advanced Cancers Receiving PD-1 Inhibitors.

Some patients with cancer treated with programmed death 1 (PD-1) inhibitors experience immune-related severe adverse events (ir-SAEs), however, predictors are limited. The objective was to identify clinicopathologic features that may be associated with a higher ir-SAE risk. This was a nested case-control study. After screening a total of 832 PD-1 inhibitor-treated patients, we identified 42 ir-SAE cases. According to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, ir-SAEs were defined as grade ≥3 toxic effects associated with immunotherapy. A total of 126 controls were matched. The crude and adjusted risks of ir-SAEs were estimated by odds ratio (ORs) and 95% CIs using multivariate logistic regression models. Baseline neutrophil-to-lymphocyte ratio (NLR) [per SD increment-adjusted (aOR): 1.16], lactate dehydrogenase (LDH) ≥245 U/L (aOR: 2.39), and antibiotic exposure (aOR: 4.39) were associated with a higher risk of ir-SAEs. When NLR was categorized in 3 groups, significantly higher risks of ir-SAEs (aOR: 4.95) were found in participants in group 3 (>6) than in those in group 1 (<3). Furthermore, NLR (per SD increment-adjusted hazard ratio:1.08) were also significantly associated with shorter overall survival (OS). Baseline LDH ≥245 U/L and antibiotic exposure were no significant association with OS. In conclusion, ir-SAEs were associated between baseline NLR, LDH ≥245 U/L and antibiotic exposure. Lower NLR was correlated with longer OS for cancer.

Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations.

The ketogenic diet (KD) is a high-fat, adequate-protein, and very-low-carbohydrate diet regimen that mimics the metabolism of the fasting state to induce the production of ketone bodies. The KD has long been established as a remarkably successful dietary approach for the treatment of intractable epilepsy and has increasingly garnered research attention rapidly in the past decade, subject to emerging evidence of the promising therapeutic potential of the KD for various diseases, besides epilepsy, from obesity to malignancies. In this review, we summarize the experimental and/or clinical evidence of the efficacy and safety of the KD in different diseases, and discuss the possible mechanisms of action based on recent advances in understanding the influence of the KD at the cellular and molecular levels. We emphasize that the KD may function through multiple mechanisms, which remain to be further elucidated. The challenges and future directions for the clinical implementation of the KD in the treatment of a spectrum of diseases have been discussed. We suggest that, with encouraging evidence of therapeutic effects and increasing insights into the mechanisms of action, randomized controlled trials should be conducted to elucidate a foundation for the clinical use of the KD.

Dysbiosis of human gut microbiome in young-onset colorectal cancer.

The incidence of sporadic young-onset colorectal cancer (yCRC) is increasing. A significant knowledge gap exists in the gut microbiota and its diagnostic value for yCRC patients. Through 16S rRNA gene sequencing, 728 samples are collected to identify microbial markers, and an independent cohort of 310 samples is used to validate the results. Furthermore, species-level and functional analysis are performed by metagenome sequencing using 200 samples. Gut microbial diversity is increased in yCRC. Flavonifractor plautii is an important bacterial species in yCRC, while genus Streptococcus contains the key phylotype in the old-onset colorectal cancer. Functional analysis reveals that yCRC has unique characteristics of bacterial metabolism characterized by the dominance of DNA binding and RNA-dependent DNA biosynthetic process. The random forest classifier model achieves a powerful classification potential. This study highlights the potential of the gut microbiota biomarkers as a promising non-invasive tool for the accurate detection and distinction of individuals with yCRC.

Corticosteroid administration for cancer-related indications is an unfavorable prognostic factor in solid cancer patients receiving immune checkpoint inhibitor treatment.

OBJECTIVE: Immunotherapies targeting immune checkpoints have achieved encouraging survival benefits in patients with various solid cancers. Corticosteroids are frequently administrated for cancer/non-cancer related indications and immune-related adverse events (irAEs). This study aimed to clarify the prognostic significance of corticosteroid administration in solid cancer patients receiving immune checkpoint inhibitor (ICI) treatment. METHOD: First, a meta-analysis was performed using the literatures searched from PubMed, Cochrane Library, Web of Science, Embase, and Clinicaltrials.gov before January 2021. The Hazard ratios (HRs) coupled with 95% confidence intervals (CIs) were used to evaluate the correlation of corticosteroid administration with overall survival (OS) and progression-free survival (PFS). Then, a retrospective analysis enrolling 118 ICI-treated cancer patients was performed for validation, among which 26 patients received corticosteroids for cancer-related indications. RESULT: In the meta-analysis, corticosteroid administration for cancer-related indications was significantly correlated with worse PFS (HR = 1.735(1.381-2.180)) and OS (HR = 1.936(1.587-2.361)) of the ICI-treated patients. However, corticosteroid administration for non-cancer-related indications and irAEs was unrelated with PFS (non-cancer-related indications: HR = 0.830(0.645-1.067); irAEs: HR = 1.302(0.628-2.696)) and OS (non-cancer-related indications: HR = 0.786(0.512-1.206); irAEs: HR = 1.107(0.832-1.474)) of the ICI-treated patients. The following retrospective analysis identified corticosteroid administration for cancer-related indications was an independent unfavorable predictor for PFS (P = 0.006) and OS (P = 0.044) of the ICI-treated patients. The subgroup analysis based on non-small cell lung cancer (NSCLC) demonstrated the similar results (P = 0.002 for PFS and P = 0.047 for OS). CONCLUSION: Our study demonstrated corticosteroid administration for cancer-related indications is an unfavorable prognostic factor in solid cancer patients receiving ICI treatment. Therefore, careful selection of corticosteroid-treated patients for ICI therapy is quite necessary in individualized clinical management.

Alterations, Interactions, and Diagnostic Potential of Gut Bacteria and Viruses in Colorectal Cancer.

Gut microbiome alteration was closely associated with colorectal cancer (CRC). Previous studies had demonstrated the bacteria composition changes but lacked virome profiles, trans-kindom interactions, and reliable diagnostic model explorations in CRC. Hence, we performed metagenomic sequencing to investigate the gut microbiome and microbial interactions in adenoma and CRC patients. We found the decreased microbial diversity in CRC and revealed the taxonomic alterations of bacteria and viruses were highly associated with CRC at the species level. The relative abundance of oral-derived species, such as Fusobacterium nucleatum, Fusobacterium hwasookii, Porphyromonas gingivalis, and Bacteroides fragilis, increased. At the same time, butyrate-producing and anti-inflammatory microbes decreased in adenoma and CRC by non-parametric Kruskal-Wallis test. Despite that, the relative abundance of Escherichia viruses and Salmonella viruses increased, whereas some phages, including Enterobacteria phages and Uncultured crAssphage, decreased along with CRC development. Gut bacteria was negatively associated with viruses in CRC and healthy control by correlation analysis (P=0.017 and 0.002, respectively). Viruses were much more dynamic than the bacteria as the disease progressed, and the altered microbial interactions were distinctively stage-dependent. The degree centrality of microbial interactions decreased while closeness centrality increased along with the adenoma to cancer development. Uncultured crAssphage was the key bacteriophage that enriched in healthy controls and positively associated with butyrate-producing bacteria. Diagnostic tests based on bacteria by random forest confirmed in independent cohorts showed better performance than viruses for CRC. In conclusion, our study revealed the novel CRC-associated bacteria and viruses that exhibited specific differences and intensive microbial correlations, which provided a reliable diagnostic panel for CRC.