Automated Measurements of Body Composition in Abdominal CT Scans Using Artificial Intelligence Can Predict Mortality in Patients With Cirrhosis.

Body composition measures derived from already available electronic medical records (computed tomography [CT] scans) can have significant value, but automation of measurements is needed for clinical implementation. We sought to use artificial intelligence to develop an automated method to measure body composition and test the algorithm on a clinical cohort to predict mortality. We constructed a deep learning algorithm using Google's DeepLabv3+ on a cohort of de-identified CT scans (n = 12,067). To test for the accuracy and clinical usefulness of the algorithm, we used a unique cohort of prospectively followed patients with cirrhosis (n = 238) who had CT scans performed. To assess model performance, we used the confusion matrix and calculated the mean accuracy of 0.977 ± 0.02 (0.975 ± 0.018 for the training and test sets, respectively). To assess for spatial overlap, we measured the mean intersection over union and mean boundary contour scores and found excellent overlap between the manual and automated methods with mean scores of 0.954 ± 0.030, 0.987 ± 0.009, and 0.948 ± 0.039 (0.983 ± 0.013 for the training and test set, respectively). Using these automated measurements, we found that body composition features were predictive of mortality in patients with cirrhosis. On multivariate analysis, the addition of body composition measures significantly improved prediction of mortality for patients with cirrhosis over Model for End-Stage Liver Disease alone (P < 0.001). Conclusion: The measurement of body composition can be automated using artificial intelligence and add significant value for incidental CTs performed for other clinical indications. This is proof of concept that this methodology could allow for wider implementation into the clinical arena.

Risk of Hepatocellular Cancer Recurrence in Hepatitis C Virus+ Patients Treated with Direct-Acting Antiviral Agents.

BACKGROUND: With advent of direct-acting antiviral agents (DAA), hepatitis C virus (HCV) treatment is dramatically increasing. Although few studies reported rates of hepatocellular carcinoma (HCC) recurrence following DAA treatment, there have been no studies that followed sufficient number of DAA-treated patients after successful HCC treatment to examine HCC recurrence. METHODS: We conducted a cohort study of HCV+ patients who had successfully treated HCC before initiating DAAs. We conducted medical record reviews to confirm HCC diagnosis, treatment, and remission prior to DAA initiation, and subsequent HCC recurrence. We calculated HCC recurrence rate and examined the recurrent tumor characteristics. We used Cox proportional hazard model to identify factors associated with HCC recurrence. RESULTS: We identified 264 HCV+ patients who received DAAs after an average of 30.9 (20.6) months following HCC treatment. HCC recurred in 26.1% patients during 23.3 (9.8) months follow-up, at a rate of 0.38 [0.30, 0.48] per 1000 person-month. Most (82.3%) recurrent HCC were early stage. Receiving non-curative treatment for HCC was associated with a higher risk of recurrence than curative treatment (HRadj = 2.06, [1.24, 3.40]). The risk of HCC recurrence decreased with longer duration between HCC treatment completion and DAA initiation (HRadj = 0.97, [0.95, 0.99] per additional month). Compared with patients who achieved sustained virological response (SVR), those without SVR had significantly increased risk of HCC recurrence (HRadj = 4.17, [1.48, 11.75]). CONCLUSIONS: We conclude that most HCV+ patients with HCC benefit from DAA treatment; however, timing of DAA initiation after HCC treatment should be carefully considered.

Human Intestinal Enteroids: New Models to Study Gastrointestinal Virus Infections.

Human rotavirus (HRV) and human norovirus (HuNoV) infections are recognized as the most common causes of epidemic and sporadic cases of gastroenteritis worldwide. The study of these two human gastrointestinal viruses is important for understanding basic virus-host interactions and mechanisms of pathogenesis and to establish models to evaluate vaccines and treatments. Despite the introduction of live-attenuated vaccines to prevent life-threatening HRV-induced disease, the burden of HRV illness remains significant in low-income and less-industrialized countries, and small animal models or ex vivo models to study HRV infections efficiently are lacking. Similarly, HuNoVs remained non-cultivatable until recently. With the advent of non-transformed human intestinal enteroid (HIE) cultures, we are now able to culture and study both clinically relevant HRV and HuNoV in a biologically relevant human system. Methods described here will allow investigators to use these new culture techniques to grow HRV and HuNoV and analyze new aspects of virus replication and pathogenesis.

Guilt by association: intestinal metaplasia does not progress to gastric cancer.

PURPOSE OF REVIEW: This review integrates the new thinking about relationships between gastric cancer and intestinal metaplasia/pseudopyloric metaplasia (SPEM). We address whether recent studies have closed or widened the knowledge gap regarding gastric cancer pathogenesis in mice or humans. RECENT FINDINGS: Recent studies in mouse models have provided a variety of new insights into the cellular origin and progression of events resulting in gastric cancer. Many suggest a direct transformation from intestinal metaplasia/pseudopyloric metaplasia/SPEM to gastric cancer. However, results from different investigator and models are conflicting and often describe events not present in studies in humans. SUMMARY: Both Helicobacter pylori-associated and autoimmune gastritis may produce gastric atrophy with extensive intestinal metaplasia and an abnormal gastric microbiome. However, only H. pylori gastritis carries a risk for adenocarcinoma. The differences reported with mouse models can best be explained as the results of different models of regeneration and repair rather than as models of gastric cancer. Overall, the data remains consistent with the original hypothesis that gastric cancer results from increased genetic instability of gastric stem cells rather than a direct transition from metaplasia to cancer. Intestinal metaplasia, pseudopyloric metaplasia, and SPEM have all been falsely accused based on guilt by association.

Engineered Human Gastrointestinal Cultures to Study the Microbiome and Infectious Diseases.

New models to study the intestine are key to understanding intestinal diseases and developing novel treatments. Intestinal organ-like culture systems (organoids and enteroids) have substantially advanced the study of the human gastrointestinal tract. Stem cell-derived cultures produce self-organizing structures that contain the multiple differentiated intestinal epithelial cell types including enterocytes, goblet, Paneth, and enteroendocrine cells. Understanding host-microbial interactions is one area in which these cultures are expediting major advancements. This review discusses how organoid and enteroid cultures are biologically and physiologically relevant systems to investigate the effects of commensal organisms and study the pathogenesis of human infectious diseases. These cultures can be established from many donors and they retain the genetic and biologic properties of the donors, which can lead to the discovery of host-specific factors that affect susceptibility to infection and result in personalized approaches to treat individuals. The continued development of these cultures to incorporate more facets of the gastrointestinal tract, including neurons, immune cells, and the microbiome, will unravel new mechanisms regulating host-microbial interactions with the long-term goal of translating findings into novel preventive or therapeutic treatments for gastrointestinal infections.

Determinants and Outcomes of Hospice Utilization Among Patients with Advance-Staged Hepatocellular Carcinoma in a Veteran Affairs Population.

BACKGROUND: Hospice provides integrative palliative care for advance-staged hepatocellular carcinoma (HCC) patients, but hospice utilization in HCC patients in the USA is not clearly understood. AIMS: We examined hospice use and subsequent clinical course in advance-staged HCC patients. METHODS: We conducted a retrospective study on a national, Veterans Affairs cohort with stage C or D HCC. We evaluated demographics, clinical factors, treatment, and clinical course in relation to hospice use. RESULTS: We identified 814 patients with advanced HCC, of whom 597 (73.3%) used hospice. Oncologist management consistently predicted hospice use, irrespective of HCC treatment [no treatment: OR 2.25 (1.18-4.3), treatment: OR 1.80 (1.10-2.95)]. Among patients who received HCC treatment, hospice users were less likely to have insurance beyond VA benefits (47.2 vs. 60.0%, p = 0.01). Among patients without HCC treatment, hospice users were older (62.2 [17.2] vs. 60.2 [14.0] years, p = 0.05), white (62.1 vs. 52.9%, p = 0.01), resided in the Southern USA (39.5 vs. 31.8%, p = 0.05), and had a performance score ≥ 3 (41.9 vs. 31.8%, p = 0.01). The median time from hospice entry to death or end of study was 1.05 [2.96] months for stage C and 0.53 [1.18] months for stage D patients. CONCLUSIONS: 26.7% advance-staged HCC patients never entered hospice, representing potential missed opportunities for improving end-of-life care. Age, race, location, performance, insurance, and managing specialty can predict hospice use. Differences in managing specialty and short-term hospice use suggest that interventions to optimize early palliative care are necessary.

Epithelial WNT Ligands Are Essential Drivers of Intestinal Stem Cell Activation.

Intestinal stem cells (ISCs) maintain and repair the intestinal epithelium. While regeneration after ISC-targeted damage is increasingly understood, injury-repair mechanisms that direct regeneration following injuries to differentiated cells remain uncharacterized. The enteric pathogen, rotavirus, infects and damages differentiated cells while sparing all ISC populations, thus allowing the unique examination of the response of intact ISC compartments during injury-repair. Upon rotavirus infection in mice, ISC compartments robustly expand and proliferating cells rapidly migrate. Infection results specifically in stimulation of the active crypt-based columnar ISCs, but not alternative reserve ISC populations, as is observed after ISC-targeted damage. Conditional ablation of epithelial WNT secretion diminishes crypt expansion and ISC activation, demonstrating a previously unknown function of epithelial-secreted WNT during injury-repair. These findings indicate a hierarchical preference of crypt-based columnar cells (CBCs) over other potential ISC populations during epithelial restitution and the importance of epithelial-derived signals in regulating ISC behavior.

Direct regulation of GTP homeostasis by (p)ppGpp: a critical component of viability and stress resistance.

Cells constantly adjust their metabolism in response to environmental conditions, yet major mechanisms underlying survival remain poorly understood. We discover a posttranscriptional mechanism that integrates starvation response with GTP homeostasis to allow survival, enacted by the nucleotide (p)ppGpp, a key player in bacterial stress response and persistence. We reveal that (p)ppGpp activates global metabolic changes upon starvation, allowing survival by regulating GTP. Combining metabolomics with biochemical demonstrations, we find that (p)ppGpp directly inhibits the activities of multiple GTP biosynthesis enzymes. This inhibition results in robust and rapid GTP regulation in Bacillus subtilis, which we demonstrate is essential to maintaining GTP levels within a range that supports viability even in the absence of starvation. Correspondingly, without (p)ppGpp, gross GTP dysregulation occurs, revealing a vital housekeeping function of (p)ppGpp; in fact, loss of (p)ppGpp results in death from rising GTP, a severe and previously unknown consequence of GTP dysfunction.