Predicting nodal metastases in squamous cell carcinoma of the oral tongue using artificial intelligence.

OBJECTIVE: The presence of occult nodal metastases in patients with squamous cell carcinoma (SCC) of the oral tongue has implications for treatment. Upwards of 30% of patients will have occult nodal metastases, yet a significant number of patients undergo unnecessary neck dissection to confirm nodal status. This study sought to predict the presence of nodal metastases in patients with SCC of the oral tongue using a convolutional neural network (CNN) that analyzed visual histopathology from the primary tumor alone. METHODS: Cases of SCC of the oral tongue were identified from the records of a single institution. Only patients with complete pathology data were included in the study. The primary tumors were randomized into 2 groups for training and testing, which was performed at 2 different levels of supervision. Board-certified pathologists annotated each slide. HALO-AI convolutional neural network and image software was used to perform training and testing. Receiver operator characteristic (ROC) curves and the Youden J statistic were used for primary analysis. RESULTS: Eighty-nine cases of SCC of the oral tongue were included in the study. The best performing algorithm had a high level of supervision and a sensitivity of 65% and specificity of 86% when identifying nodal metastases. The area under the curve (AUC) of the ROC curve for this algorithm was 0.729. CONCLUSION: A CNN can produce an algorithm that is able to predict nodal metastases in patients with squamous cell carcinoma of the oral tongue by analyzing the visual histopathology of the primary tumor alone.

It's "not black and white": Students' perceptions of "altruism" content in preclinical medical education.

OBJECTIVE: This study investigated how students as stakeholders viewed behavioral and social science (BSS) content in a preclinical longitudinal course entitled "Medicine, Body, and Society" (MBS) at UT Health San Antonio Long School of Medicine (LSOM). We present students' perceptions of successes and challenges tied to "altruism" and other non-biomedical objectives outlined by this institution. METHODS: We conducted a qualitative thematic analysis of MBS course evaluation data. Two researchers independently performed initial coding followed by interrater reliability checks to revise codes and a final MAXQDA lexical search to refine three themes. RESULTS: Three major themes emerged: (1) Students shared pedagogical preferences strongly favoring stories. (2) Students detected deficits in the module content tied to identities. (3) Students labelled BSS content as "soft," "subjective," and "siloed" which confounded its role in the course. CONCLUSIONS: Advancing altruism aligned with BSS content in preclinical medical education remains a challenge. A closer review of student evaluations framed as learner-centeredness is key to a greater understanding and resolution of competency issues in preclinical curriculum and its impact on mastery in subsequent clinical education and practice.

Revisiting Feed Forward: Promoting a Student-Centered Approach to Education Handoffs, Remediation, and Clerkship Success.

Issue: Throughout medical school, and especially during clerkships, students experience changing work and learning environments and are exposed to new academic, interpersonal, and professional challenges unique to clinical learning. Given the siloed nature of clinical rotations, students often "fall through the cracks" and may repeatedly struggle through clerkships without support and coaching from which they would otherwise benefit. Many institutions have grappled with creating feed forward processes, that is, educational handoffs in which information is shared among faculty about struggling students with the intention of providing longitudinal support to ensure their success, while protecting students from negative bias that may follow them throughout the remainder of their medical school tenure. Evidence: Here, the authors describe the feed forward processes of four medical schools. Each school's process relies on close collaboration between course directors and deans to identify students and develop intervention plans. Course leadership and administration are typically the primary drivers for long-term follow-up with students. The number of participants in the process varies, with only one school directly involving students. Two schools hold larger, regularly scheduled meetings with up to 12 faculty present in their institution's feed forward process. Across these institutions, students can "graduate" from the feed forward process once they achieve competency in the areas of concern. Implications: The authors believe the most important outcome achieved is the formalization and adherence to a feed forward process. Thus, risk to students in the form of negative bias is mitigated by the flow of information, the extent to which information is available, and permitting students to be part of the process. These exemplars give insight into variable approaches to feed forward systems adopted by medical schools and demonstrate highly visible methodologies by which educational leadership empower students and educators toward a shared goal of student progress and achievement.

The MK2 pathway is linked to G-CSF, cytokine production and metastasis in gastric cancer: a novel intercorrelation analysis approach.

BACKGROUND: Gastric cancer is associated with chronic inflammation, but there is still much to understand about the tumor microenvironment and the underlying tumor-promoting mechanisms. The Map kinase-activated protein kinase 2 (MK2) pathway is a regulator of inflammatory cytokine production that we have been studying in gastrointestinal cancers. Here, we set out to determine the significance of this gene in gastric cancer along with its downstream mediators and if there were differences in the primary tumors with and without metastasis. METHODS: Human gastric cancer tissues with and without metastasis were examined for MK2 expression and cytokine profile in organ culture supernatants. Advanced statistical methods including a lower triangular correlation matrix, novel rooted correlation network, linear and logistic regression modeling along with Kruskal-Wallis testing with Sidak correction for multiple testing were applied to gain understanding of cytokines/chemokines linked to metastasis. RESULTS: The MK2 pathway is strongly linked with metastasis and a panel of cytokines. Gene expression was able to classify gastric cancer metastasis 85.7% of the time. A significant association with a panel of cytokines was found, including G-CSF, GM-CSF, Mip-1ß, IFN-α, MCP-1, IL-1ß, IL-6, and TNF-α. Mip-1ß was found to have the strongest association with MK2 and metastasis after Sidak correction for multiple testing. CONCLUSIONS: MK2 gene expression and a novel associated cytokine panel are linked to gastric cancer metastasis. G-CSF is the strongest cytokine to differentiate between metastasis and non-metastasis patients and had the lowest P value, while Mip-1ß showed the strongest association with MK2 and metastasis after Sidak correction. MK2 and associated cytokines are potential biomarkers for gastric cancer metastasis. The novel intercorrelation analysis approach is a promising method for understanding the complex nature of cytokine/chemokine regulation and links to disease outcome.

Giant Gastric Ulcers: An Unusual Culprit.

Mycophenolate Mofetil (MMF) is routinely used immunosuppressant in solid organ transplantation is commonly associated with several gastrointestinal (GI) side effects. Here we present a case of giant gastric ulcer of 5 cm from MMF use post cardiac transplant. CASE DESCRIPTION: A 56-year-old male with history of severe ischemic cardiomyopathy post heart transplant was on immunosuppression with MMF, tacrolimus and prednisone for 5 months. He presented with severe epigastric pain and intermittent episodes of melena for 1 month. His pain radiated to back that is worsened with eating. Associated with loss of appetite, vomiting and 16-pound weight loss in 3 months. He never smoked, drank alcohol or used over the counter pain medications. He was profoundly anemic requiring blood transfusions. EGD performed demonstrated very large clean-based ulcer of 5 cm diameter in the body, smaller ulcer of 8 mm diameter in pre-pyloric region and 5-10 small aphthous ulcers in the gastric body and fundus. Gastric biopsies taken from the ulcer were negative for Helicobacter pylori, cytomegalovirus and malignancy. Flexible sigmoidoscopy revealed non-bleeding inflamed internal hemorrhoids. Consequently, MMF was discontinued and switched to azathioprine. He was treated with twice daily proton pump inhibitor therapy with resolution of abdominal pain, improved appetite and weight gain. DISCUSSION: MMF is well known for common GI side-effects such as nausea, diarrhea, vomiting, ulcers, abdominal pain and rarely gastrointestinal bleeding. Few studies reported 3 to 8% incidence of ulcer perforation and GI bleeding within 6 months. Risk of gastroduodenal erosions is nearly 1.83 times for MMF, with the highest lesions associated with MMF-tacrolimus-corticosteroid combination treatment as seen in our patient. Hypothesis is that GI tract is vulnerable because of dependence of enterocytes on de novo synthesis of purines, which is disrupted by MMF. Typically, upper GI mucosal injuries of mucosal irritation leading to esophagitis, gastritis and/or ulcers are seen. Endoscopy is both diagnostic and therapeutic if bleeding gastric ulcers are noted. Minor complications improve with reduction of drug dose or use of enteric coated preparation if feasible. Discontinuation of the drug is main stay in the management of MMF related ulcer disease. Simple medical treatment with either H2-receptor antagonists, proton-pump inhibitors, coating agents, prostaglandins or combination has proven effective in most cases. Considering excellent results with medical management of ulcer, role of surgery is limited.

Phase II Trial Using a Combination of Oxaliplatin, Capecitabine, and Celecoxib with Concurrent Radiation for Newly Diagnosed Resectable Rectal Cancer.

LESSONS LEARNED: Colorectal cancers exhibit a high level of cyclooxygenase-2 (COX-2) expression with strong preclinical rationale for improved clinical outcomes with COX-2 inhibition. Celecoxib is a COX-2 inhibitor and we have shown that it can be safely combined with capecitabine and oxaliplatin as part of neoadjuvant treatment with radiation therapy (RT) in rectal cancer.There was a significant improvement in skin toxicity with this combination as compared with historical data. Considering the field has moved on to single-agent capecitabine, we believe future trials with capecitabine and celecoxib hold potential. BACKGROUND: Improved survival is seen among patients with rectal cancer who achieve pathologic complete response (pCR) after neoadjuvant therapy. Cyclooxygenase-2 (COX-2) expression is increased in gastrointestinal malignancies and it may serve as a target to enhance pathologic response. A trial combining chemoradiation and COX-2 inhibition was conducted to evaluate the pCR rate, surgical outcomes, survival, and treatment toxicity. METHODS: Patients with resectable (T3-4, N1-2) rectal cancer within 12 cm of the anal verge were included in this phase II clinical trial. The neoadjuvant treatment consisted of capecitabine 850 mg/m2 b.i.d. Monday through Friday for 5 weeks, weekly oxaliplatin 50 mg/m2 intravenous (IV), celecoxib 200 mg b.i.d. daily, along with concurrent 45 gray radiation therapy in 25 fractions. RESULTS: Thirty-two patients were included in the final analysis. The primary endpoint was pCR: 31% (95% confidence interval [CI]: 16%-50%). Secondary endpoints were surgical downstaging (SD): 75% (95% CI: 57%-89%) and sphincter-sparing surgery (SSS): 56% (95% CI: 38%-74%). Common grade >3 toxicities were diarrhea and abnormal liver function tests (9% each). Grade 0 and 1 toxicities included radiation dermatitis (59% and 34%, respectively) and proctitis (63% and 28%, respectively). At 3 years, disease-free survival and overall survival (OS) were 84% (95% CI: 65%-93%) and 94% (95% CI: 77%-98%), respectively. CONCLUSION: Chemoradiation with celecoxib in rectal cancer was well tolerated and demonstrated high rates of pCR, SD, and SSS. Improvement in skin toxicity (34% grade 1 and no grade 3/4) as compared with historical results (43%-78% grade 3/4) seems to be a significant improvement with addition of celecoxib to neoadjuvant chemotherapy.

Cholesterol-Enriched Domain Formation Induced by Viral-Encoded, Membrane-Active Amphipathic Peptide.

The α-helical (AH) domain of the hepatitis C virus nonstructural protein NS5A, anchored at the cytoplasmic leaflet of the endoplasmic reticulum, plays a role in viral replication. However, the peptides derived from this domain also exhibit remarkably broad-spectrum virocidal activity, raising questions about their modes of membrane association. Here, using giant lipid vesicles, we show that the AH peptide discriminates between membrane compositions. In cholesterol-containing membranes, peptide binding induces microdomain formation. By contrast, cholesterol-depleted membranes undergo global softening at elevated peptide concentrations. Furthermore, in mixed populations, the presence of ∼100 nm vesicles of viral dimensions suppresses these peptide-induced perturbations in giant unilamellar vesicles, suggesting size-dependent membrane association. These synergistic composition- and size-dependent interactions explain, in part, how the AH domain might on the one hand segregate molecules needed for viral assembly and on the other hand furnish peptides that exhibit broad-spectrum virocidal activity.

Blockade of MK2 is protective in inflammation-associated colorectal cancer development.

Chronic inflammation is a risk factor for colorectal cancer. The MAPK-activated protein kinase 2 (MK2) pathway controls multiple cellular processes including p38-dependent inflammation. This is the first study to investigate the role of MK2 in development of colitis-associated colon cancer (CAC). Herein, we demonstrate that MK2(-/-) mice are highly resistant to neoplasm development when exposed to AOM/DSS, while wild type (WT) C57BL/6 develop multiple neoplasms with the same treatment. MK2-specific cytokines IL-1, IL-6 and TNF-α were substantially decreased in AOM/DSS treated MK2(-/-) mouse colon tissues compared with WT mice, which coincided with a marked decrease in macrophage influx. Restoring MK2-competent macrophages by injecting WT bone marrow derived macrophages into MK2(-/-) mice led to partial restoration of inflammatory cytokine production with AOM/DSS treatment; however, macrophages were not sufficient to induce neoplasm development. These results indicate that MK2 functions as an inflammatory regulator to promote colonic neoplasm development and may be a potential target for CAC.

High priority for hepatitis C screening in safety net hospitals: Results from a prospective cohort of 4582 hospitalized baby boomers.

UNLABELLED: Low-income populations are disproportionately affected by hepatitis C virus (HCV) infection. Thus, implementing baby boomer screening (born 1945-1965) for HCV may be a high priority for safety net hospitals. We report the prevalence and predictors of HCV infection and advanced fibrosis or cirrhosis based on the Fibrosis-4 score plus imaging for a baby boomer cohort admitted to a safety net hospital over a 21-month interval with >9 months of follow-up. Anti-HCV antibody testing was performed for 4582, or 90%, of all never-screened patients, of whom 312 (6.7%) tested positive. Adjusted odds ratios of testing anti-HCV-positive were 2.66 for men versus women (P<0.001), 1.25 for uninsured versus insured (P=0.06), 0.70 for Hispanics versus non-Hispanic whites (P=0.005), and 0.93 per year of age (P<0.001). Among 287 patients tested for HCV RNA (91% of all anti-HCV-positive cases), 175 (61%) were viremic (3.8% overall prevalence in cohort), which was 5% less likely per year of age (P<0.03). Noninvasive staging of 148 (84.6%) chronic HCV patients identified advanced fibrosis or cirrhosis in 50 (33.8%), with higher adjusted odds ratios of 3.21 for Hispanics versus non-Hispanic whites/Asians (P=0.02) and 1.18 per year of age (P=0.001). Other factors associated with significantly higher adjusted odds ratios of advanced fibrosis or cirrhosis were alcohol abuse/dependence, obesity, and being uninsured. CONCLUSION: In this low-income, hospitalized cohort, 4% of 4582 screened baby boomers were diagnosed with chronic HCV, nearly twice the rate in the community; one-third had noninvasive testing that indicated advanced fibrosis or cirrhosis, which was significantly more likely for Hispanics, those of older age, those with obesity, those with alcohol abuse/dependence, and those who lacked insurance.

Eosinophilic Gastroenteritis: An Underdiagnosed Condition.

BACKGROUND: Eosinophilic gastroenteritis (EOGE) is a rare idiopathic disease characterized by eosinophil-predominant inflammation of the stomach and/or intestines. Our aims are to determine the epidemiology, clinical features and outcomes of EOGE cases in a tertiary-care hospital. METHODS: Retrospective cohort study of patients with gastrointestinal eosinophilic infiltration from 2004 through 2014. All relevant specimens were reviewed by an expert pathologist. Significant eosinophilic infiltrate was defined as >25 eosinophils/HPF in the stomach or small intestine and >50 eosinophils/HPF in the colon. RESULTS: Three hundred and sixty-one charts were reviewed and 13 EOGE cases were identified, including nine adults and four pediatric cases. The majority (78 %) of adult cases were females. Clinical presentation was variable; most patients (62 %) had abdominal pain, followed by diarrhea (31 %) and nausea/vomiting (31 %). Atopy and food allergies were present in 54 and 38 % of patients, respectively. Weight loss and failure to thrive were present only in pediatric cases (50 vs 0 %; P = .01). Most EOGE cases (69 %) had peripheral eosinophilia, which was more prominent in patients with ascites compared to patients without ascites (37.3 ± 25.4 vs 9.3 ± 5.4 %; P = .01). Among patients who had long-term follow-up; 30 % had spontaneous remission, 60 % responded to steroids and/or restriction diet, and 10 % had refractory disease. CONCLUSION: EOGE is an underdiagnosed condition. In contrast to eosinophilic esophagitis; the disease might be female-predominant in adults. High index of clinical suspicion is required for diagnosis. Further studies about the long-term outcomes and the efficacy of restriction diet in adult patients are required.

Natural History of Patients Presenting with Autoimmune Hepatitis and Coincident Nonalcoholic Fatty Liver Disease.

BACKGROUND: Given the increase of nonalcoholic fatty liver disease (NAFLD) in the general population, a similar rise might be expected in autoimmune hepatitis (AIH) patients. AIMS: We sought to determine the clinical outcome of patients with coincident AIH and NAFLD. METHODS: We identified all intradepartmental AIH cases, and those meeting study criteria were placed into one of three cohorts: AIH only, AIH and simple steatosis (SS), and AIH and nonalcoholic steatohepatitis (NASH). The following outcome and clinical data were analyzed: incidence of all-cause mortality, incidence of liver-related mortality, incidence of liver-related adverse outcomes, and prevalence of cirrhosis at index biopsy. RESULTS: Out of a total 73 study patients, 14 % classified as AIH with SS and 16 % as AIH and NASH. Fifty percent of AIH and NASH patients had cirrhosis at index biopsy as compared to 18 % of AIH-only patients (p = 0.032). Patients with AIH and NASH had a relative risk of 7.65 (95 % CI 1.43-40.8) for liver-related mortality and 2.55 (95 % CI 0.92-7.09) for liver-related adverse outcomes, as compared to the AIH-only cohort. No significant difference in outcome measures existed in comparing (AIH only) with (AIH and SS) cohorts. DISCUSSION: Patients with coincident AIH and NASH were more likely to present with cirrhosis and more likely to develop adverse clinical outcome with decreased survival as compared to AIH-only patients. These findings suggest that simultaneous exposure confers a clinically significant increased risk, which may warrant closer follow-up and surveillance.

On-demand self-assembly of supported membranes using sacrificial, anhydrobiotic sugar coats.

Borrowing principles of anhydrobiosis, we have developed a technique for self-assembling proteolipid-supported membranes on demand--simply by adding water. Intact lipid- and proteolipid vesicles dispersed in aqueous solutions of anhydrobiotic trehalose are vitrified on arbitrary substrates, producing glassy coats encapsulating biomolecules. Previous efforts establish that these carbohydrate coats arrest molecular mobilities and preserve native conformations and aggregative states of the embedded biomolecules, thereby enabling long-term storage. Subsequent rehydration, even after an extended period of time (e.g., weeks), devitrifies sugar--releasing the cargo and unmasking the substrate surface--thus triggering substrate-mediated vesicle fusion in real time, producing supported membranes. Using this method, arrays of membranes, including those functionalized with membrane proteins, can be readily produced in situ by spatially addressing vitrification using common patterning tools--useful for multiplexed or stochastic sensing and assaying of target interactions with the fluid and functional membrane surface.

A case of jaundice of obscure origin.

BACKGROUND: Idiopathic painless jaundice with significant elevations in serum transaminases, occurring in a previously healthy patient, invokes a circumscribed set of possibilities including viral hepatitis, auto-immune hepatitis (AIH) and drug-induced liver injury (DILI). METHODS: In this described case, common causes of cholestatic jaundice were considered including drug-induced liver injury, viral causes of hepatitis, and auto-immune antibodies. Biliary obstruction was excluded by appropriate imaging studies. Liver biopsy was obtained, though not definitive. RESULTS: After detailed investigation failed to reveal a cause of the jaundice, an empiric trial of steroids was initiated on the possibility that our patient had antibody-negative AIH and not DILI, with an associated grave prognosis. CONCLUSIONS: Empiric treatment with prednisone led to rapid resolution of jaundice and to the conclusion that the correct diagnosis was antibody-negative AIH.