Cell surface RNAs control neutrophil recruitment.

RNAs localizing to the outer cell surface have been recently identified in mammalian cells, including RNAs with glycan modifications known as glycoRNAs. However, the functional significance of cell surface RNAs and their production are poorly known. We report that cell surface RNAs are critical for neutrophil recruitment and that the mammalian homologs of the sid-1 RNA transporter are required for glycoRNA expression. Cell surface RNAs can be readily detected in murine neutrophils, the elimination of which substantially impairs neutrophil recruitment to inflammatory sites in vivo and reduces neutrophils' adhesion to and migration through endothelial cells. Neutrophil glycoRNAs are predominantly on cell surface, important for neutrophil-endothelial interactions, and can be recognized by P-selectin (Selp). Knockdown of the murine Sidt genes abolishes neutrophil glycoRNAs and functionally mimics the loss of cell surface RNAs. Our data demonstrate the biological importance of cell surface glycoRNAs and highlight a noncanonical dimension of RNA-mediated cellular functions.

Multi-omic analysis reveals metabolic pathways that characterize right-sided colon cancer liver metastasis.

There are well demonstrated differences in tumor cell metabolism between right sided (RCC) and left sided (LCC) colon cancer, which could underlie the robust differences observed in their clinical behavior, particularly in metastatic disease. As such, we utilized liquid chromatography-mass spectrometry to perform an untargeted metabolomics analysis comparing frozen liver metastasis (LM) biobank samples derived from patients with RCC (N = 32) and LCC (N = 58) to further elucidate the unique biology of each. We also performed an untargeted RNA-seq and subsequent network analysis on samples derived from an overlapping subset of patients (RCC: N = 10; LCC: N = 18). Our biobank redemonstrates the inferior survival of patients with RCC-derived LM (P = 0.04), a well-established finding. Our metabolomic results demonstrate increased reactive oxygen species associated metabolites and bile acids in RCC. Conversely, carnitines, indicators of fatty acid oxidation, are relatively increased in LCC. The transcriptomic analysis implicates increased MEK-ERK, PI3K-AKT and Transcription Growth Factor Beta signaling in RCC LM. Our multi-omic analysis reveals several key differences in cellular physiology which taken together may be relevant to clinical differences in tumor behavior between RCC and LCC liver metastasis.

How I Learned is How I Teach - Perspectives on How Faculty Surgeons Approach Informed Consent Education.

OBJECTIVE: To understand the variability of surgical attending experience and perspectives regarding informed consent and how it impacts resident education DESIGN: A novel survey was distributed electronically to explore faculty surgeon's personal learning experience, knowledge, clinical practice, teaching preferences and beliefs regarding informed consent. Chi-square and Kruskal-Wallis testing was performed to look for associations and a cluster analysis was performed to elucidate additional patterns among. SETTING: Single, tertiary, university-affiliated health care system (Yale New Haven Health in Connecticut), including 6 teaching hospitals. PARTICIPANTS: Clinical faculty within the Department of Surgery. RESULTS: A total of 85 surgeons responded (49% response rate), representing 17 specialties, both private practice and university and/or hospital-employed, with a range of years in practice. Across all ages, specialties, the most common method for both learning (86%) and teaching (82%) informed consent was observation of the attending. Respondents who stated they learned by observing attendings were more likely to report that they teach by having trainees observe them (OR 8.5, 95% CI 1.3-56.5) and participants who recalled learning by having attendings observe them were more likely to observe their trainees (OR 4.1, 95% CI 1.5-11.2).Cluster analysis revealed 5 different attending phenotypes with significant heterogeneity between groups. A cluster of younger attendings reported the least diverse learning experience and high levels of concern for legal liability and resident competency. They engaged in few strategies for teaching residents. By comparison, the cluster that reported the most diverse learning experience also reported the richest diversity of teaching strategies to residents but rarely allowed residents to perform consent with their patients. Meanwhile, 2 other cluster provided a more balanced experience with some opportunities for practice with patients and some diversity of teaching- these clusters, respectively, consist of older, experienced general surgeons and surgeons in trauma and/or critical care. CONCLUSIONS: Surgeon's demographics, personal experiences, and specialty appear to significantly influence their teaching styles and the educational experience residents receive regarding informed consent.

5-Fluorouracil efficacy requires anti-tumor immunity triggered by cancer-cell-intrinsic STING.

5-Fluorouracil (5-FU) is a widely used chemotherapeutic drug, but the mechanisms underlying 5-FU efficacy in immunocompetent hosts in vivo remain largely elusive. Through modeling 5-FU response of murine colon and melanoma tumors, we report that effective reduction of tumor burden by 5-FU is dependent on anti-tumor immunity triggered by the activation of cancer-cell-intrinsic STING. While the loss of STING does not induce 5-FU resistance in vitro, effective 5-FU responsiveness in vivo requires cancer-cell-intrinsic cGAS, STING, and subsequent type I interferon (IFN) production, as well as IFN-sensing by bone-marrow-derived cells. In the absence of cancer-cell-intrinsic STING, a much higher dose of 5-FU is needed to reduce tumor burden. 5-FU treatment leads to increased intratumoral T cells, and T-cell depletion significantly reduces the efficacy of 5-FU in vivo. In human colorectal specimens, higher STING expression is associated with better survival and responsiveness to chemotherapy. Our results support a model in which 5-FU triggers cancer-cell-initiated anti-tumor immunity to reduce tumor burden, and our findings could be harnessed to improve therapeutic effectiveness and toxicity for colon and other cancers.

Cellular Angiofibroma Presenting as a Subepithelial Rectal Mass.

A very rare case of cellular angiofibroma arising from the rectum in a 62-year-old man with a normal colonoscopy 2 years earlier is reported. To our knowledge, this is the first such case reported in the literature. The tumor was transanally excised with clear margins, and the patient had no postoperative complications. It is key to accurately differentiate this lesion from other subepithelial rectal tumors and more aggressive genital soft tissue tumors because clinical management varies. We performed a review of clinical records and pathology as well as an extensive literature review.

Liver-first approach to stage IV colon cancer with synchronous isolated liver metastases.

BACKGROUND: The only possibility for cure in patients with colon adenocarcinoma (CAC) with isolated liver metastases (ILM) is resection of both primary and metastatic tumors. Little is known about the implication of the sequence in which a colectomy and hepatectomy are performed on outcomes. This study analyzes whether resection sequence impacts clinical outcomes. METHODS: The National Cancer Database was queried for CAC cases with hepatic metastases from 2010-2015 with exclusion of extrahepatic metastases. We compared patients treated with a liver-first approach (LFA) to those treated with a colectomy-first or simultaneous approach using Kaplan Meier and multivariable Cox proportional hazards analysis. RESULTS: In 21,788 CAC patients identified, the LFA was uncommon (2%), but was associated with higher rates of completion resection of remaining tumor (41% vs. 22%, P<0.001). Patients selected for LFA were younger, less comorbid, and more commonly received upfront chemotherapy (P<0.05). The LFA was associated with increased median survival [34 months, 95% CI (30.5-39.6 months) vs. 24 months, 95% CI (23.7-24.6 months), logrank P<0.001] and decreased risk of death [HR 0.783; 95% CI (0.67-0.89), P=0.001]. CONCLUSIONS: The LFA to CAC with synchronous ILM is uncommon but is associated with greater likelihood of receiving chemotherapy prior to surgery and increased survival in selected candidates.

Application of Advanced Bioinformatics to Understand and Predict Burnout Among Surgical Trainees.

OBJECTIVE: Physician burnout, including surgical trainees, is multidimensional. Input variables used to predict burnout include grit, exhaustion, and financial stress. Each instrument has intrinsic limitations of scope and strength. We hypothesize that bioinformatics methods borrowed from oncogenetics may allow meta-analysis of existing predictive tools to improve identification of subpopulations at highest risk of burnout. DESIGN: A composite survey was created using widely accepted instruments: demographic factors, burnout using the Single-Item Maslach Burnout Inventory Emotional Exhaustion Measure, grit using the Duckworth Grit Scale, occupational fatigue using the Occupational Fatigue Exhaustion/Recovery Scale, financial well-being, perceptions of physician leadership, and attitudes towards robotic surgery. Surveys were analyzed using k-means analysis and supervised/unsupervised clustering. SETTING: Yale General Surgery Residency. PARTICIPANTS: Survey participants consisted of Yale General Surgery residents. Of 70 residents, 53 responded (75.7%). Males comprised 57.1% and each postgraduate year had majority representation, 68.8% to 100%. RESULTS: Unsupervised hierarchical clustering showed heterogeneous resident answer patterns and suggested clusters of responders. To define groups of dissimilar responders, we performed k-means clustering, testing 15 iterations with 50 attempts. The analysis revealed 3 discrete clusters of responders with differential risk for burnout (p = 0.021). The highest risk group demonstrated the lowest grit score, low interest in innovation and leadership, higher financial stress, and concordantly, the highest rates of anxiety, dread, and self-reported burnout. (p = 0.0004; 0.0014; 0.1217; 0.0625; 0.021; 0.0011; 0.0224) CONCLUSIONS: The limited scope of common tools aiming to predict burnout constrains their utility. The machine-learning technique of cluster analysis organizes compound data to describe complex outcomes such as oncologic risks. We apply this analysis technique to create a composite predictor of burnout among surgical residents. Our method determines subgroups of residents sharing unique traits predictive of burnout. Residencies can use this tool to allocate resources to best support resident well-being.

Gene Alterations of N6-Methyladenosine (m6A) Regulators in Colorectal Cancer: A TCGA Database Study.

N6-methyladenosine (m6A) plays an important role in many cancers. However, few studies have examined the role of m6A in colorectal CRC. To examine the effect of m6A on CRC, we studied the genome of 591 CRC cases from The Cancer Genome Atlas (TCGA). The relationship between the messenger RNA (mRNA) expression, copy number variation (CNVs), and mutations of m6A "Writers," "Readers," and "Erasers," prognosis, immune cell infiltration, and genetic mutations in CRC cases were analyzed. CNVs and mutations were found in thirteen m6A regulators. As expected, gain and amplification of m6A regulators increased the mRNA expression of these regulators, while deletion led to reduction in the mRNA expression. Moreover, CNVs and mutation of these regulators were significantly associated with APC, TP53, and microsatellite instability (MSI) status (p < 0.001, p < 0.001, and p = 0.029, respectively). CNVs of m6A regulators also correlated with inferred immune cell infiltration in CRC tissues, especially in colon tissues. Additionally, alterations of RBM15, YTHDF2, YTHDC1, YTHDC2, and METTL14 genes were related to the worse overall survival and disease-free survival (DFS) of CRC patients. Specifically, the deletion status of "Writers" was also correlated to the DFS of CRC patients (p = 0.02). Gene set enrichment analysis found that FTO was involved in mRNA 3' end processing, polyubiquitin binding, and RNA polymerase promoter elongation, while YTHDC1 was related to interferon-alpha and gamma response. In conclusion, a novel relationship was identified between CNVs and mutations of m6A regulators with prognosis and inferred immune function of CRC. These findings will improve the understanding of the relationship of m6A in CRC.

Digital Inference of Immune Microenvironment Reveals Low-Risk Subtype of Early Lung Adenocarcinoma.

BACKGROUND: Classification of lung adenocarcinoma (LUAD) currently relies on the TNM pathological staging system, which cannot fully account for the variability in postsurgery overall survival (OS). Despite the advances in immunotherapy and increased appreciation of the involvement of cancer immune microenvironment (IME) in cancer progression, the contribution of IME to postsurgery LUAD prognosis is not well understood. METHODS: We digitally inferred the contribution of 22 immune cell types or activation states to the tumor IME using CIBERSORT (Celltype Identification By Estimating Relative Subsets Of RNA Transcripts) analysis in an exploratory metadataset of 581 patients with early-stage LUAD. Patients were arranged based on similarity in IME using k-means clustering. Relationship to postsurgical OS was tested in univariable and multivariable models using Kaplan-Meier analysis and Cox proportional hazards modeling, respectively. To confirm survival relationships, a support vector machine classifier was constructed from a comparison of low-risk and high-risk IME groups. The classifier was applied to a the Cancer Genome Atlas LUAD validation dataset of 394 patients. RESULTS: Patients with an inferred IME enriched in resting mast cells and depleted of macrophages represented a low-clinical-risk group in both exploratory and validation cohorts. CONCLUSIONS: Variability in the digitally inferred composition of the tumor IME contributes to heterogeneity in postsurgical OS. Our data suggest that low inferred macrophage content and inferred resting activation state of intratumor mast cells are associated with improved clinical outcome. Computational inference can be used to define LUAD risk groups and help guide clinical decision making.

Privacy Concerns About Personal Health Information and Fear of Unintended Use of Biospecimens Impact Donations by African American Patients.

Biospecimen donation is essential for studies of cancer prevention, early detection, and treatment. Donations from minority groups, for whom the cancer burden is high, are infrequent and inadequate for research purposes. The obstacles to donation of biospecimens by African Americans and other minority groups must be identified. Patients aged 18-85 years were surveyed based on the clinic visited (group A: GI/primary care and group B: oncology with confirmed cancer diagnosis) and analyzed as separate groups. The validated biobanking attitudes and knowledge survey (BANKS) as well as pancreatic cancer questions were used. In group A, 278/292 surveys were completed (5/6 patients participated). In group B, 54/59 surveys were completed (4/5 patients participated). There were low mean scores on the BANKS knowledge sections, specifically in regard to specimen ownership and the separation of research and medical records. Also, two major concerns limited donation: (1) fear that personal, medical, and family medical information may be stolen from the biobank; and (2) mistrust that biospecimens could be used for unintended purposes. Low knowledge about biospecimen acquisition, added to mistrust, warrant community-based, and patient education in an effort to improve attitudes, increase participation, and regain healthy therapeutic alliances.

Robotic cholecystectomy and cholecystoenteric fistula closure in a female with remote cholangitis.

Cholecystocolic fistula (CCF), a connection between the gallbladder and neighboring colon, is a rare entity with little consensus as to the optimal surgical management. Existing case reports have described both open and laparoscopic repairs. We describe the first reported case of a successful robotic repair of a CCF in a 50-year-old woman diagnosed with cholangitis 5 years prior to surgery. The patient had a longitudinal follow-up by a single surgeon, allowing for early diagnosis and repair. This case also includes radiographic imaging over 5 years during the index hospitalization and preoperative workup. This allows for a glimpse into the natural pathogenesis of this disease. After robotic surgery, the patient made a complete recovery with no postoperative complications.

Practice Patterns and Guideline Non-Adherence in Surgical Management of Appendiceal Carcinoid Tumors.

BACKGROUND: Surgical management of appendiceal carcinoid tumors is heavily debated, despite National Comprehensive Cancer Network guidelines recommending aggressive resection of tumors >2 cm. We investigated national practice patterns and the predictors and impact of guideline non-adherence. STUDY DESIGN: The National Cancer Database was queried for cases of appendiceal carcinoids diagnosed from 2004 to 2015 treated with either appendectomy or hemicolectomy. Multivariable logistic regression, adjusted for demographic and clinical factors, identified associations with the procedure type among patients stratified by tumor size ≤2 cm and >2 cm. Cox Proportional Hazards then identified associations with overall survival among stratified patient groups. RESULTS: Of 3,198 cases of appendiceal carcinoids, 1,893 appendectomies and 1,305 hemicolectomies were identified. Contrary to National Comprehensive Cancer Network guidelines, 32.4% of tumors ≤2 cm were treated with hemicolectomy and 31.3% of tumors >2 cm were treated with definitive appendectomy. Hemicolectomy for small tumors was associated with age 65 years and older (odds ratio [OR] 2.4; 95% CI 1.7 to 3.3; reference group age 18 to 39 years), history of malignancy (OR 2.0; 95% CI 1.6 to 2.6), tumor size 1.1 to 2 cm (OR 2.8; 95% CI 2.3 to 3.4; reference group size ≤1 cm), and lymphovascular invasion (OR 2.2; 95% CI 1.6 to 3.2); appendectomy for large tumors was associated with age 65 years and older only (OR 2.2; 95% CI 1.1 to 4.2). Procedure type was not associated with survival for small or large tumors (hazard ratio 1.0; 95% CI 0.7 to 1.4 and hazard ratio 1.1; 95% CI 0.6 to 2.0, respectively). CONCLUSIONS: Despite well-known size-based treatment guidelines for appendiceal carcinoids, one-third of patients in the US undergo hemicolectomy for small tumors and appendectomy for large tumors. Guideline non-adherence, however, is not associated with overall survival. Reasons for these practice patterns should be explored, and guidelines revisited.

Regional Differences in Palliative Care Utilization Among Geriatric Colorectal Cancer Patients Needing Emergent Surgery.

BACKGROUND: The benefits of palliative care (PC) in critical illness are validated across a range of diseases, yet it remains underutilized in surgical patients. This study analyzed patient and hospital factors predictive of PC utilization for elderly patients with colorectal cancer (CRC) requiring emergent surgery. METHODS: The National Inpatient Sample was queried for patients aged ≥ 65 years admitted emergently with CRC from 2009 to 2014. Patients undergoing colectomy, enterectomy, or ostomy formation were included and stratified according to documentation of PC consultation during admission. Chi-squared testing identified unadjusted group differences, and multivariable logistic regression identified predictors of PC. RESULTS: Of 86,573 discharges meeting inclusion criteria, only 3598 (4.2%) had PC consultation. Colectomy (86.6%) and ostomy formation (30.4%) accounted for the operative majority. PC frequency increased over time (2.9% in 2009 to 6.2% in 2014, P < 0.001) and was nearly twice as likely to occur in the West compared with the Northeast (5.7 vs. 3.3%, P < 0.001) and in not-for-profit compared with proprietary hospitals (4.5 vs. 2.3%, P < 0.001). PC patients were more likely to have metastases (60.1 vs. 39.9%, P < 0.001) and die during admission (41.5 vs. 6.4%, P < 0.001). On multivariable logistic regression, PC predictors (P < 0.05) included region outside the Northeast, increasing age, more recent year, and metastatic disease. CONCLUSIONS: In the USA, PC consultation for geriatric patients with surgically managed complicated CRC is low. Regional variation appears to play an important role. With mounting evidence that PC improves quality of life and outcomes, understanding the barriers associated with its provision to surgical patients is paramount.

Defining Early-Onset Colon and Rectal Cancers.

Background: Colorectal cancer (CRC) incidence is rising in the young, yet the age of those affected is not clearly defined. In this study, we identify such cohorts and define clinicopathological features of early-onset colon and rectal cancers. Methods: The Surveillance, Epidemiology and End Results Program (SEER) database was queried to compare clinicopathological characteristics of colon and rectal cancers diagnosed during 1973-1995 with those diagnosed during 1995-2014. Results: We identified 430,886 patients with colon and rectal cancers. From 1973-1995 to 1995-2014, colon cancer incidence increased in patients aged 20-44 years, while rectal cancer incidence increased in patients aged ≤54 years. The percent change of cancer incidence was greatest for rectal cancer with a 41.5% (95% confidence interval (CI): 37.4-45.8%) increase compared to a 9.8% (CI: 6.2-13.6%) increase in colon cancer. Colon cancer has increased in tumors located in ascending, sigmoid, and rectosigmoid locations. Adenocarcinoma histology has increased in both colon and rectal cancers (P < 0.01), but mucinous and signet ring cell subtypes have not increased (P = 0.13 and 0.08, respectively). Incidence increases were race-specific, with rectal cancer seeing similar rises in white (38.4%, CI: 33.8-43.1%) and black populations (38.0%, CI: 26.2-51.2%), while colon cancer as a whole saw a rise in white (11.5%, CI: 7.2-15.9%) but not black populations (-6.8%, CI: -14.6-1.9%). Conclusions: Our study underscores the existence of key differences between early-onset colon (20-44 years) and rectal cancers (≤54 years) and provides evidence-based inclusion criteria for future investigations. We recommend that future research of CRC in the young should avoid investigating these cases as a single entity.

A rare case of splenic pseudoaneurysm in pediatric splenic blunt trauma patient: Review of diagnosis and management.

INTRODUCTION: Splenic pseudoaneurysms (SPA) are a rare but serious sequela of blunt traumatic injury to the spleen. Management of adult blunt splenic trauma is well-studied, however, in children, the management is much less well-defined. PRESENTATION OF CASE: A 15 year-old male presented with severe abdominal pain of acute onset after sustaining injury to his left side while playing football. FAST was positive for free fluid in the abdomen. Initial abdomen CT demonstrated a grade III/IV left splenic laceration with moderate to large hemoperitoneum with no active extravasation or injury to the splenic vessels noted. A follow-up CT angiography of the abdomen demonstrated a splenic hypervascular structure suspicious for a small pseudoaneurysm. Splenic arteriogram which demonstrated multiple pseudoaneurysms arising from the second order splenic artery branches which was angioembolized and treated. DISCUSSION & CONCLUSION: Questions still remain regarding the timing of repeat imaging for diagnosis of SPA following non-operative blunt splenic trauma, which patients should be imaged, and how to manage SPA upon diagnosis. More clinical study and basic science research is warranted to study the disease process of SPA in pediatric patient. We believe that our proposed management algorithm timely detect formation of delayed SPA formation and addresses the possible fatal disease course of pediatric SPA.

Curaxin CBL0137 eradicates drug resistant cancer stem cells and potentiates efficacy of gemcitabine in preclinical models of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) continues to be one of the deadliest cancers due to the absence of effective treatment. Curaxins are a class of small molecules with anti-cancer activity demonstrated in different models of cancer in mice. The lead curaxin compound, CBL0137, recently entered Phase I clinical trials. Curaxins modulate several important signaling pathways involved in the pathogenesis of PDA through inhibition of chromatin remodeling complex FACT. FACT is overexpressed in multiple types of tumor, with one of the highest rate of overexpression in PDA (59%). In this study, the efficacy of CBL0137 alone or in combination with current standard of care, gemcitabine, was tested against different models of PDA in vitro and in mouse models. It was found that CBL0137 alone is a potent inducer of apoptosis in pancreatic cancer cell lines and is toxic not only for proliferating bulk tumor cells, but also for pancreatic cancer stem cells. In mice, CBL0137 was effective against several PDA models, including orthotopic gemcitabine resistant PANC-1 model and patient derived xenografts, in which CBL0137 anti-tumor effect correlated with overexpression of FACT. Moreover, we observed synergy of CBL0137 with gemcitabine which may be explained by the ability of CBL0137 to inhibit several transcriptional programs induced by gemcitabine, including NF-kappaB response and expression of ribonucleotide reductase, one of the targets of gemcitabine in cells. This data suggest testing of CBL0137 efficacy in Phase II trial in PDA patients alone and in combination with gemcitabine.

Moderating laboratory adaptation with the use of a heart-rate variability biofeedback device (StressEraser).

Difficulty sleeping is a common problem with laboratory polysomnograms. This affects both polysomnograms that are used as a clinical tool to investigate sleep pathology or as an outcome variable in research. The goal of this study was to use a handheld biofeedback device (StressEraser) to improve sleep quality in the laboratory. Ten subjects without a history of sleep disorders were randomly assigned to either a StressEraser or no-treatment control condition. A sleep disturbance scale derived from sleep efficiency, REM latency, minutes of stage 1 sleep, and wake after sleep onset was created to evaluate the differences between these groups. Subjects in the StressEraser group had significantly lower scores on the sleep disturbance scale compared to the no-treatment control group (p = 0.003). Sleep latency was not improved. In conclusion, the StressEraser significantly improved sleep quality compared to a no-treatment control group. This suggests that the StressEraser may be an effective tool to help reduce the first-night effect in nighttime laboratory sleep studies.