Advanced enteropathy-associated T cell lymphoma (EATL) presenting with severe malabsorption and concomitantly diagnosed coeliac disease (CD).

Enteropathy-associated T cell lymphoma (EATL) is an aggressive subtype of non-Hodgkin's lymphoma often associated with coeliac disease (CD). We describe a previously healthy man in his 50 s who presented with a history of abdominal pain, failure to thrive and significant weight loss over a 3-month period. Investigations revealed a positive coeliac serology, diffuse duodenal atrophy with multiple duodenal and jejunal ulcers on endoscopy and mesenteric lymphadenopathy on CT imaging. Duodenal tissue biopsy confirmed a diagnosis of EATL Stage IVB. Chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone regimen was initiated. This case highlights the need for greater awareness and consideration of EATL in individuals with worsening malabsorption and abdominal pain, irrespective of coeliac history.

Practicing Digital Gastroenterology through Phonoenterography Leveraging Artificial Intelligence: Future Perspectives Using Microwave Systems.

Production of bowel sounds, established in the 1900s, has limited application in existing patient-care regimes and diagnostic modalities. We review the physiology of bowel sound production, the developments in recording technologies and the clinical application in various scenarios, to understand the potential of a bowel sound recording and analysis device-the phonoenterogram in future gastroenterological practice. Bowel sound production depends on but is not entirely limited to the type of food consumed, amount of air ingested and the type of intestinal contractions. Recording technologies for extraction and analysis of these include the wavelet-based filtering, autoregressive moving average model, multivariate empirical mode decompression, radial basis function network, two-dimensional positional mapping, neural network model and acoustic biosensor technique. Prior studies evaluate the application of bowel sounds in conditions such as intestinal obstruction, acute appendicitis, large bowel disorders such as inflammatory bowel disease and bowel polyps, ascites, post-operative ileus, sepsis, irritable bowel syndrome, diabetes mellitus, neurodegenerative disorders such as Parkinson's disease and neonatal conditions such as hypertrophic pyloric stenosis. Recording and analysis of bowel sounds using artificial intelligence is crucial for creating an accessible, inexpensive and safe device with a broad range of clinical applications. Microwave-based digital phonoenterography has huge potential for impacting GI practice and patient care.

Artificial intelligence-enabled screening strategy for drug repurposing in monoclonal gammopathy of undetermined significance.

Monoclonal gammopathy of undetermined significance (MGUS) is a benign hematological condition with the potential to progress to malignant conditions including multiple myeloma and Waldenstrom macroglobulinemia. Medications that modify progression risk have yet to be identified. To investigate, we leveraged machine-learning and electronic health record (EHR) data to screen for drug repurposing candidates. We extracted clinical and laboratory data from a manually curated MGUS database, containing 16,752 MGUS patients diagnosed from January 1, 2000 through December 31, 2021, prospectively maintained at Mayo Clinic. We merged this with comorbidity and medication data from the EHR. Medications were mapped to 21 drug classes of interest. The XGBoost module was then used to train a primary Cox survival model; sensitivity analyses were also performed limiting the study group to those with non-IgM MGUS and those with M-spikes >0.3 g/dl. The impact of explanatory features was quantified as hazard ratios after generating distributions using bootstrapping. Medication data were available for 12,253 patients; those without medications data were excluded. Our model achieved a good fit of the data with inverse probability of censoring weights concordance index of 0.883. The presence of multivitamins, immunosuppression, non-coronary NSAIDS, proton pump inhibitors, vitamin D supplementation, opioids, statins and beta-blockers were associated with significantly lower hazard ratio for MGUS progression in our primary model; multivitamins and non-coronary NSAIDs remained significant across both sensitivity analyses. This work could inform subsequent prospective studies, or similar studies in other disease states.

A Living, Interactive Systematic Review and Network Meta-analysis of First-line Treatment of Metastatic Renal Cell Carcinoma.

CONTEXT: Identifying the most effective first-line treatment for metastatic renal cell carcinoma (mRCC) is challenging as rapidly evolving data quickly outdate the existing body of evidence, and current approaches to presenting the evidence in user-friendly formats are fraught with limitations. OBJECTIVE: To maintain living evidence for contemporary first-line treatment for previously untreated mRCC. EVIDENCE ACQUISITION: We have created a living, interactive systematic review (LISR) and network meta-analysis for first-line treatment of mRCC using data from randomized controlled trials comparing contemporary treatment options with single-agent tyrosine kinase inhibitors. We applied an advanced programming and artificial intelligence-assisted framework for evidence synthesis to create a living search strategy, facilitate screening and data extraction using a graphical user interface, automate the frequentist network meta-analysis, and display results in an interactive manner. EVIDENCE SYNTHESIS: As of October 22, 2020, the LISR includes data from 14 clinical trials. Baseline characteristics are summarized in an interactive table. The cabozantinib + nivolumab combination (CaboNivo) is ranked the highest for the overall response rate, progression-free survival, and overall survival, whereas ipilimumab + nivolumab (NivoIpi) is ranked the highest for achieving a complete response (CR). NivoIpi, and atezolizumab + bevacizumab (AteBev) were ranked highest (lowest toxicity) and CaboNivo ranked lowest for treatment-related adverse events (AEs). Network meta-analysis results are summarized as interactive tables and plots, GRADE summary-of-findings tables, and evidence maps. CONCLUSIONS: This innovative living and interactive review provides the best current evidence on the comparative effectiveness of multiple treatment options for patients with untreated mRCC. Trial-level comparisons suggest that CaboNivo is likely to cause more AEs but is ranked best for all efficacy outcomes, except NivoIpi offers the best chance of CR. Pembrolizumab + axitinib and NivoIpi are acceptable alternatives, except NivoIpi may not be preferred for patients with favorable risk. Although network meta-analysis provides rankings with statistical adjustments, there are inherent biases in cross-trial comparisons with sparse direct evidence that does not replace randomized comparisons. PATIENT SUMMARY: It is challenging to decide the best option among the several treatment combinations of immunotherapy and targeted treatments for newly diagnosed metastatic kidney cancer. We have created interactive evidence summaries of multiple treatment options that present the benefits and harms and evidence certainty for patient-important outcomes. This evidence is updated as soon as new studies are published.

Systolic-to-diastolic myocardial volume ratio as a novel imaging marker of cardiomyopathy.

BACKGROUND: In patients with normal left ventricular ejection fraction, it may be difficult to distinguish between the normal and diseased heart. Novel assessments of ventricular function, such as extracellular volume imaging, myocardial perfusion imaging and myocardial contraction fraction are emerging to better assess disease burden in these cases. This study endeavored to determine whether the ratio of myocardial volume in systole to myocardial volume in diastole (MVs/MVd), differs between normal hearts and those with disease states characterized by normal ejection fraction. METHOD: Consecutive patients from 2008 to 2018 with hypertrophic cardiomyopathy (HCM), cardiac amyloidosis, and heart failure with preserved ejection fraction (HFpEF) who underwent cardiac magnetic resonance imaging (MRI) were selected for inclusion, along with a sex- and age-matched cohort of normal volunteers who also underwent cardiac MRI. Manual tracings were performed on each MRI to calculate MVs/MVd, which was then compared across subgroups. RESULTS: Included were 50 patients with HCM, 50 patients with cardiac amyloidosis, 26 patients with HFpEF, and 30 normal subjects. Age was 54.1 years (SD 16.7); mean MVs/MVd was 0.88 (SD 0.04) in the normal subgroup, 1.03 (SD 0.06) in HCM patients, 1.03 (SD 0.06) in cardiac amyloidosis patients, and 0.97 (SD 0.02) in HFpEF patients, with all pathology subgroups different from the normal subgroup (p < .0001 for each). The ratio of MVs/MVd discriminated diseased from normal with c statistic 0.989 (p < .001). CONCLUSIONS: This study suggests that a novel and easily-captured metric of ventricular function, MVs/MVd, can differentiate normal ventricular function from multiple cardiomyopathies with normal ejection fractions.

Clinico-radiologic Features of Lung Disease Associated With Aspiration Identified on Lung Biopsy.

BACKGROUND: Aspiration-related lung diseases are commonly diagnosed presumptively based on the clinical context and radiologic findings. Limited data exist on the spectrum of clinico-radiologic presentations associated with aspiration. METHODS: This study reviewed all cases of aspiration identified on lung biopsy encountered at the Mayo Clinic between 2003 and 2017. Demographic and clinical features, including risk factors for aspiration, diagnoses suspected prior to biopsy, imaging findings, and microbiologic data, were analyzed. RESULTS: A total of 52 consecutive adult cases of aspiration identified on lung biopsy (histologic presence of food or other particulate matter) were included; patients' median age was 59 years (range, 22 to 79 years), 38% were women, and there were five lung transplant recipients. Of these, 63% were diagnosed according to results of surgical biopsy (including four cases of lobectomy) and 37% according to results of transbronchial biopsy. Aspiration was clinically suspected prior to biopsy in 35% of the subjects. Ninety percent of subjects had at least one identifiable risk factor for aspiration; gastroesophageal reflux disease was the most common (62%), followed by a structurally abnormal esophagogastric tract and the use of consciousness-impairing medications. Only 27% of patients reported dysphagia or choking. Chest CT imaging revealed a variety of parenchymal patterns, including bronchiolitis (42%), patchy consolidation (19%), and mass (15%). Of 25 patients undergoing a video-swallow evaluation, 14 (56%) had abnormal results with laryngeal penetration with or without aspiration. Microbial cultures obtained in 21 lung biopsy specimens yielded no pathogens. CONCLUSIONS: Aspiration can occur in the absence of subjective or demonstrable swallowing difficulties and manifest a broad spectrum of clinico-radiologic presentations.

Spectrum of Chronic Complications Related to Silicone Leakage and Migration.

BACKGROUND: Medical silicone is widely used as implants and free injections, but the spectrum of complications related to migration or embolization of silicone remains unclear. METHODS: We retrospectively reviewed 79 patients with silicone migration as confirmed on pathology between January 1, 2001, and December 31, 2016. The presenting clinical and imaging features, diagnostic testing, treatment, and outcome were assessed. RESULTS: Nearly all patients were women, and 43% had a history of breast cancer. Sixty-three cases (80%) consisted of localized silicone granulomas, including 1 patient who developed severe hypercalcemia related to the granulomatous reaction. The remaining 16 cases (20%) involved migration of silicone to regional lymph nodes or distant tissue and included 1 case of chronic silicone pneumonitis. These complications were detected many years (median, 22 years; range, 1-40 years) after initial silicone placement. Only magnetic resonance imaging, dual-energy computed tomography (CT), and ultrasonography demonstrated specificity for detection of silicone in lymph nodes and soft tissues. Other modalities including positron emission tomography, single-energy CT, and mammography detected only nonspecific abnormalities. Excisional biopsy of symptomatic lymphadenopathy or masses usually led to resolution of symptoms. The patient with silicone pneumonitis improved with corticosteroid therapy. CONCLUSIONS: Chronic complications related to silicone extravasation and migration can present with local or distant manifestations, typically encountered many years after the original silicone placement. Magnetic resonance imaging, dual-energy CT, and ultrasonography are helpful for noninvasive diagnosis.

Caveolin-1 and force regulation in porcine airway smooth muscle.

Caveolae are specialized membrane microdomains expressing the scaffolding protein caveolin-1. We recently demonstrated the presence of caveolae in human airway smooth muscle (ASM) and the contribution of caveolin-1 to intracellular calcium ([Ca(2+)](i)) regulation. In the present study, we tested the hypothesis that caveolin-1 regulates ASM contractility. We examined the role of caveolins in force regulation of porcine ASM under control conditions as well as TNF-α-induced airway inflammation. In porcine ASM strips, exposure to 10 mM methyl-ß-cyclodextrin (CD) or 5 µM of the caveolin-1 specific scaffolding domain inhibitor peptide (CSD) resulted in time-dependent decrease in force responses to 1 µM ACh. Overnight exposure to the cytokine TNF-α (50 ng/ml) accelerated and increased caveolin-1 expression and enhanced force responses to ACh. Suppression of caveolin-1 with small interfering RNA mimicked the effects of CD or CSD. Regarding mechanisms by which caveolae contribute to contractile changes, inhibition of MAP kinase with 10 µM PD98059 did not alter control or TNF-α-induced increases in force responses to ACh. However, inhibiting RhoA with 100 µM fasudil or 10 µM Y27632 resulted in significant decreases in force responses, with lesser effects in TNF-α exposed samples. Furthermore, Ca(2+) sensitivity for force generation was substantially reduced by fasudil or Y27632, an effect even more enhanced in the absence of caveolin-1 signaling. Overall, these results indicate that caveolin-1 is a critical player in enhanced ASM contractility with airway inflammation.