Warfarin induced spontaneous gastric intramural haematoma presenting with palpitations.

Spontaneous gastric intramural haematoma is an uncommon complication associated with anticoagulant therapy. A patient receiving chronic warfarin for paroxysmal atrial fibrillation was admitted due to atrial fibrillation with rapid ventricular response (RVR). An incidental intra-abdominal mass was detected on a CT scan. Following the initiation of the amiodarone infusion, the patient experienced bleeding attributed to warfarin-amiodarone-induced coagulopathy, with no identifiable bleeding source. Subsequent CT scans revealed an enlargement of the intra-abdominal mass, suggesting gastric intramural haematoma. After coagulopathy reversal, the haematoma is managed conservatively. Our case underscores the potential for incidental bleeding even when the international normalised ratio is within the normal range in patients on chronic warfarin therapy. When managing such patients with atrial fibrillation with RVR, physicians should maintain a high index of suspicion for bleeding, emphasising the importance of prompt coagulopathy reversal.

Prevalence of incidental colorectal cancer and polyps in autopsies of different populations: a systematic review with meta-regression analysis.

The colorectal cancer (CRC) and polyps incidentally found in autopsies represent the lesions that have not actually caused problems throughout the lifetime and thus may not need to be removed during screening. This study aimed to investigate the prevalence of incidental CRC (iCRC) and polyps in autopsies of different populations. A systematic search was performed on 19 August 2022 to identify autopsy studies that provided data on prevalence of iCRC, adenomatous polyps, hyperplastic polyps, and/or all polyps combined. The prevalence was pooled with the random-effects model. Subgroup and multivariable meta-regression analyses were conducted to investigate the heterogeneity. Forty-three eligible studies including 59,656 autopsies were identified, with 94% conducted before 1990 when CRC screening was uncommon or not available. The pooled prevalence was 0.7% (95% confidence interval [CI], 0.3-1.2%) for iCRC, 18.4% (95% CI, 13.3-24.1%) for adenomatous polyps, 16.4% (95% CI, 8.7-25.9%) for hyperplastic polyps, 26.3% (95% CI, 15.4-38.8%) for all polyps combined, and 29.9% (95% CI, 14.8-47.6%) for iCRC plus polyps. The prevalence of iCRC was higher (1.2%) in white-predominant populations but lower (0.4%) after excluding low-quality studies. Multivariable analyses showed that the prevalence of polyps was higher in white-predominant populations and higher-quality studies, increased with age, and showed a downward trend from "before 1975" through "after 1985". In conclusion, the prevalence of iCRC in autopsies was not low, considering the average lifetime risk of CRC, while incidental polyps were common. Both varied greatly in different populations. These findings may have implications when weighing the benefits and harms of screening.

Homozygous EXOSC3 c.395A>C Variants in Pontocerebellar Hypoplasia Type 1B: A Sibling Pair With Childhood Lethal Presentation and Literature Review.

Pontocerebellar hypoplasia type 1B (PCH1B) is an autosomal recessive neurodegenerative disorder that involves hypoplasia or atrophy of the cerebellum and pons. PCH1B is caused by mutations in EXOSC3, which encodes a subunit of the RNA exosome complex. The most frequently observed mutation in PCH1B patients is a c.395A>C (p.D132A) missense variant, for which the homozygous mutation typically results in milder symptoms compared to compound heterozygous mutations or homozygous mutations for other pathogenic variants. In the present study, we report on a sibling pair harboring homozygous EXOSC3 c.395A>C missense variants who deteriorated more rapidly than previously described. These cases expand the spectrum of clinical manifestations of PCH1B associated with this variant, highlighting the need for further research to determine predictive factors of PCH1B severity.

High-Fat Diet Promotes Colorectal Tumorigenesis Through Modulating Gut Microbiota and Metabolites.

BACKGROUND AND AIMS: Dietary fat intake is associated with increased risk of colorectal cancer (CRC). We examined the role of high-fat diet (HFD) in driving CRC through modulating gut microbiota and metabolites. METHODS: HFD or control diet was fed to mice littermates in CRC mouse models of an azoxymethane (AOM) model and Apcmin/+ model, with or without antibiotics cocktail treatment. Germ-free mice for fecal microbiota transplantation were used for validation. Gut microbiota and metabolites were detected using metagenomic sequencing and high-performance liquid chromatography-mass spectrometry, respectively. Gut barrier function was determined using lipopolysaccharides level and transmission electron microscopy. RESULTS: HFD promoted colorectal tumorigenesis in both AOM-treated mice and Apcmin/+ mice compared with control diet-fed mice. Gut microbiota depletion using antibiotics attenuated colon tumor formation in HFD-fed mice. A significant shift of gut microbiota composition with increased pathogenic bacteria Alistipessp.Marseille-P5997 and Alistipessp.5CPEGH6, and depleted probiotic Parabacteroides distasonis, along with impaired gut barrier function was exhibited in HFD-fed mice. Moreover, HFD-modulated gut microbiota promotes colorectal tumorigenesis in AOM-treated germ-free mice, indicating gut microbiota was essential in HFD-associated colorectal tumorigenesis. Gut metabolites alteration, including elevated lysophosphatidic acid, which was confirmed to promote CRC cell proliferation and impair cell junction, was also observed in HFD-fed mice. Moreover, transfer of stools from HFD-fed mice to germ-free mice without interference increased colonic cell proliferation, impaired gut barrier function, and induced oncogenic genes expression. CONCLUSIONS: HFD drives colorectal tumorigenesis through inducing gut microbial dysbiosis, metabolomic dysregulation with elevated lysophosphatidic acid, and gut barrier dysfunction in mice.

Neoadjuvant and Adjuvant Immunotherapy in Early-Stage Non-Small-Cell Lung Cancer, Past, Present, and Future.

Lung cancer is worldwide the most common malignancy. Standard of care treatments for early-stage non-small-cell lung cancer (NSCLC) include surgery and adjuvant chemotherapy. However, these patients continue to have poor prognosis due to systemic or local relapse. Immunotherapy has been considered as a novel approach to improve survival in patients with early-stage NSCLC. Since immune checkpoint inhibitors have transformed the treatment of advanced NSCLC, there is a growing interest in the role of immunotherapy in early-stage NSCLC. In this review, we summarize reported and ongoing clinical trials of immunotherapy in both neoadjuvant and adjuvant settings. We also highlight unaddressed issues in this field of research, such as the predictive markers, the optimal combination therapy, and the need for adjuvant immunotherapy. More studies are needed to optimize the treatment regimen of immunotherapy in patients with early-stage NSCLC.

Fecal microbial DNA markers serve for screening colorectal neoplasm in asymptomatic subjects.

BACKGROUND AND AIM: We have previously shown that fecal microbial markers might be useful for non-invasive diagnosis of colorectal cancer (CRC) and adenoma. Here, we assessed the application of microbial DNA markers, as compared with and in combination with fecal immunochemical test (FIT), in detecting CRC and adenoma in symptomatic patients and asymptomatic subjects. METHODS: We recruited 676 subjects [210 CRC, 115 advanced adenoma (AA), 86 non-advanced adenoma, and 265 non-neoplastic controls], including 241 symptomatic and 435 asymptomatic subjects. Fecal abundances of Fusobacterium nucleatum, a Lachnoclostridium sp. m3, Bacteroides clarus, and Clostridium hathewayi were quantified by quantitative PCR. Combining score of the four microbial markers (4Bac) and diagnostic prediction were determined using our previously established scoring model and cutoff values and FIT with a cutoff of 100 ng Hb/mL. RESULTS: 4Bac detected similar percentages of CRC [85.3% (95%CI: 79.2-90.2%) vs 84.9% (68.1-94.9%)] and AA [35.7% (12.8-64.9%) vs 38.6% (29.1-48.8%)], while FIT detected more CRC [72.1% (63.7-79.4%) vs 66.7% (48.2-82.0%)] and AA [28.6% (8.4-58.1%) vs 16.8% (10.1-25.6%)], in symptomatic vs asymptomatic subjects, respectively. Focusing on the asymptomatic cohort, 4Bac was more sensitive for diagnosing CRC and AA than FIT (P < 0.001), with lower specificity [83.3% (77.6-88.0%) vs 98.6% (96.0-99.7%)]. FIT failed to detect any non-advanced adenoma [0% (0.0-4.2%)] compared with 4Bac [41.9% (31.3-53.0%), P < 0.0001]. Combining 4Bac with FIT improved sensitivities for CRC [90.9% (75.7-98.1%)] and AA [48.5% (38.4-58.7%)] detection. CONCLUSION: Quantitation of fecal microbial DNA markers may serve as a new test, stand alone, or in combination with FIT for screening colorectal neoplasm in asymptomatic subjects.

Gastric microbes associated with gastric inflammation, atrophy and intestinal metaplasia 1 year after Helicobacter pylori eradication.

OBJECTIVE: Helicobacter pylori is associated with gastric inflammation, precancerous gastric atrophy (GA) and intestinal metaplasia (IM). We aimed to identify microbes that are associated with progressive inflammation, GA and IM 1 year after H. pylori eradication. DESIGN: A total of 587 H. pylori-positive patients were randomised to receive H. pylori eradication therapy (295 patients) or placebo (292 patients). Bacterial taxonomy was analysed on 404 gastric biopsy samples comprising 102 pairs before and after 1 year H. pylori eradication and 100 pairs before and after 1 year placebo by 16S rRNA sequencing. RESULTS: Analysis of microbial sequences confirmed the eradication of H. pylori in treated group after 1 year. Principal component analysis revealed distinct microbial clusters reflected by increase in bacterial diversity (p<0.00001) after H. pylori eradication. While microbial interactions remained largely unchanged after placebo treatment, microbial co-occurrence was less in treated group. Acinetobacter lwoffii, Streptococcus anginosus and Ralstonia were enriched while Roseburia and Sphingomonas were depleted in patients with persistent inflammation 1 year after H. pylori eradication. A distinct cluster of oral bacteria comprising Peptostreptococcus, Streptococcus, Parvimonas, Prevotella, Rothia and Granulicatella were associated with emergence and persistence of GA and IM. Probiotic Faecalibacterium praustznii was depleted in subjects who developed GA following H. pylori eradication. Functional pathways including amino acid metabolism and inositol phosphate metabolism were enriched while folate biosynthesis and NOD-like receptor signalling decreased in atrophy/IM-associated gastric microbiota. CONCLUSION: This study identified that gastric microbes contribute to the progression of gastric carcinogenesis after H. pylori eradication.

A novel faecal Lachnoclostridium marker for the non-invasive diagnosis of colorectal adenoma and cancer.

OBJECTIVE: There is a need for early detection of colorectal cancer (CRC) at precancerous-stage adenoma. Here, we identified novel faecal bacterial markers for diagnosing adenoma. DESIGN: This study included 1012 subjects (274 CRC, 353 adenoma and 385 controls) from two independent Asian groups. Candidate markers were identified by metagenomics and validated by targeted quantitative PCR. RESULTS: Metagenomic analysis identified 'm3' from a Lachnoclostridium sp., Fusobacterium nucleatum (Fn) and Clostridium hathewayi (Ch) to be significantly enriched in adenoma. Faecal m3 and Fn were significantly increased from normal to adenoma to CRC (p<0.0001, linear trend by one-way ANOVA) in group I (n=698), which was further confirmed in group II (n=313; p<0.0001). Faecal m3 may perform better than Fn in distinguishing adenoma from controls (areas under the receiver operating characteristic curve (AUROCs) m3=0.675 vs Fn=0.620, p=0.09), while Fn performed better in diagnosing CRC (AUROCs Fn=0.862 vs m3=0.741, p<0.0001). At 78.5% specificity, m3 and Fn showed sensitivities of 48.3% and 33.8% for adenoma, and 62.1% and 77.8% for CRC, respectively. In a subgroup tested with faecal immunochemical test (FIT; n=642), m3 performed better than FIT in detecting adenoma (sensitivities for non-advanced and advanced adenomas of 44.2% and 50.8% by m3 (specificity=79.6%) vs 0% and 16.1% by FIT (specificity=98.5%)). Combining with FIT improved sensitivity of m3 for advanced adenoma to 56.8%. The combination of m3 with Fn, Ch, Bacteroides clarus and FIT performed best for diagnosing CRC (specificity=81.2% and sensitivity=93.8%). CONCLUSION: This study identifies a novel bacterial marker m3 for the non-invasive diagnosis of colorectal adenoma.

Alterations in Enteric Virome Are Associated With Colorectal Cancer and Survival Outcomes.

BACKGROUND & AIMS: Patients with colorectal cancer (CRC) have a different gut microbiome signature than individuals without CRC. Little is known about the viral component of CRC-associated microbiome. We aimed to identify and validate viral taxonomic markers of CRC that might be used in detection of the disease or predicting outcome. METHODS: We performed shotgun metagenomic analyses of viromes of fecal samples from 74 patients with CRC (cases) and 92 individuals without CRC (controls) in Hong Kong (discovery cohort). Viral sequences were classified by taxonomic alignment against an integrated microbial reference genome database. Viral markers associated with CRC were validated using fecal samples from 3 separate cohorts: 111 patients with CRC and 112 controls in Hong Kong, 46 patients with CRC and 63 controls in Austria, and 91 patients with CRC and 66 controls in France and Germany. Using abundance profiles of CRC-associated virome genera, we constructed random survival forest models to identify those associated with patient survival times. RESULTS: The diversity of the gut bacteriophage community was significantly increased in patients with CRC compared with controls. Twenty-two viral taxa discriminated cases from controls with an area under the receiver operating characteristic curve of 0.802 in the discovery cohort. The viral markers were validated in 3 cohorts, with area under the receiver operating characteristic curves of 0.763, 0.736, and 0.715, respectively. Clinical subgroup analysis showed that dysbiosis of the gut virome was associated with early- and late-stage CRC. A combination of 4 taxonomic markers associated with reduced survival of patients with CRC (log-rank test, P = 8.1 × 10-6) independently of tumor stage, lymph node metastases, or clinical parameters. We found altered interactions between bacteriophages and oral bacterial commensals in fecal samples from patients with CRC compared with controls. CONCLUSIONS: In a metagenomic analysis of fecal samples from patients and controls, we identified virome signatures associated with CRC. These data might be used to develop tools to identify individuals with CRC or predict outcomes.