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We aimed to examine associations between the oral, fecal, and mucosal microbiome communities and adenoma formation.Data are limited regarding the relationships between microbiota and preneoplastic colorectal lesions.Individuals undergoing screening colonoscopy were prospectively enrolled and divided into adenoma and nonadenoma formers. Oral, fecal, non-adenoma and adenoma-adjacent mucosa were collected along with clinical and dietary information. 16S rRNA gene libraries were generated using V4 primers. DADA2 processed sequence reads and custom R-scripts quantified microbial diversity. Linear regression identified differential taxonomy and diversity in microbial communities and machine learning identified adenoma former microbial signatures.One hundred four subjects were included, 46% with adenomas. Mucosal and fecal samples were dominated by Firmicutes and Bacteroidetes whereas Firmicutes and Proteobacteria were most abundant in oral communities. Mucosal communities harbored significant microbial diversity that was not observed in fecal or oral communities. Random forest classifiers predicted adenoma formation using fecal, oral, and mucosal amplicon sequence variant (ASV) abundances. The mucosal classifier reliably diagnosed adenoma formation with an area under the curve (AUC) = 0.993 and an out-of-bag (OOB) error of 3.2%. Mucosal classifier accuracy was strongly influenced by five taxa associated with the family Lachnospiraceae, genera Bacteroides and Marvinbryantia, and Blautia obeum. In contrast, classifiers built using fecal and oral samples manifested high OOB error rates (47.3% and 51.1%, respectively) and poor diagnostic abilities (fecal and oral AUC = 0.53).Normal mucosa microbial abundances of adenoma formers manifest unique patterns of microbial diversity that may be predictive of adenoma formation.

Background Colorectal cancer is a leading cause of cancer-related death. Early onset colorectal cancer (age ≤45 y) is increasing and associated with advanced disease. Although distinct molecular subtypes of colorectal cancer have been characterized, it is unclear whether age-related molecular differences exist. Objective We sought to identify differences in gene expression between early and late-onset (age ≥65 y) colorectal cancer. Design We performed a review of our institution's colorectal cancer registry and identified patients with colorectal cancer with tissue specimens available for analysis. We used the Cancer Genome Atlas to initially identify differences in gene expression between early and late-onset colorectal cancer. In vitro experiments were performed on 2 colorectal cancer cell lines. Settings The study was conducted at a tertiary medical center. Patients Patients with early onset (n = 28) or late onset (age ≥65 y; n = 38) at time of diagnosis were included. Main outcome measures The primary outcome was differential gene expression in patients with early versus late-onset colorectal cancer. The secondary outcome was patient mortality. Results Seven genes had increased expression in younger patients using The Cancer Genome Atlas. Only PEG10 was sufficiently expressed with quantitative polymerase chain reaction and had increased expression in our early onset group. Multivariable linear regression analysis identified age as a significant independent predictor of increased PEG10 expression. Outcomes data from The Cancer Genome Atlas suggests that PEG10 is associated with poor overall survival. In vitro studies in HCT-116 and HT-29 cell lines showed that PEG10 contributes to cellular proliferation and invasion in colorectal cancer. Limitations Tissue samples were from formalin-fixed, paraffin-embedded sections. Many patients did not have mutational status for review. Conclusions PEG10 is differentially expressed in early onset colorectal cancer and may functionally contribute to tumor cell proliferation and invasion. An increase in PEG10 expression correlates with decreased overall survival. See Video Abstract at http://links.lww.com/DCR/B343. LA EXPRESION DIFERENCIAL DE PEG10 CONTRIBUYE A LA ENFERMEDAD AGRESIVA EN EL CANCER COLORRECTAL DE INICIO TEMPRANO VERSUS INICIO TARDIO: El cancer colorrectal es una de las principales causas de muerte relacionada con el cancer. El cancer colorrectal de inicio temprano (edad ≤45 anos) esta en aumento y asociado con enfermedad avanzada. Aunque se han caracterizado distintos subtipos moleculares del cancer colorrectal, no esta claro si existen diferencias moleculares relacionadas con la edad.Se busco identificar diferencias en la expresion genica entre el cancer colorrectal de inicio temprano y tardio (edad ≥ 65 anos).Realizamos una revision del registro de cancer colorrectal de nuestra institucion e identificamos pacientes con cancer colorrectal con muestras de tejido disponibles para su analisis. Utilizamos el Atlas del Genoma del Cancer para identificar inicialmente las diferencias en la expresion genica entre el cancer colorrectal de inicio temprano y de inicio tardio. Se realizaron experimentos in vitro en dos lineas celulares de cancer colorrectal.El estudio se realizo en un centro medico de tercer nivel.Se incluyeron pacientes con inicio temprano (n = 28) e inicio tardio (edad ≥65 anos, n = 38) al momento del diagnostico.El resultado primario fue la expresion diferencial de genes en pacientes con cancer colorrectal de inicio temprano versus tardio. El resultado secundario fue la mortalidad de los pacientes.Siete genes aumentaron su expresion en pacientes mas jovenes usando el Atlas del Genoma del Cancer. Solo PEG10 se expreso suficientemente con la reaccion en cadena de la polimerasa cuantitativa y tuvo una mayor expresion en nuestro grupo de inicio temprano. El analisis de regresion lineal multivariable identifico la edad como un predictor independiente significativo del aumento de la expresion de PEG10. Los datos de resultados de el Atlas del Genoma del Cancer sugieren que PEG10 esta asociado con una pobre supervivencia general. Los estudios in vitro en lineas celulares HCT-116 y HT-29 mostraron que PEG10 contribuye a la proliferacion e invasion celular en el cancer colorrectal.Las muestras de tejido fueron de portaobjetos embebidos en parafina fijados con formalina. Muchos pacientes no tenian el estado de mutacion para su revision.El PEG10 se expresa diferencialmente en el cancer colorrectal de inicio temprano y puede contribuir funcionalmente a la proliferacion e invasion de celulas tumorales. El aumento en la expresion de PEG10 se correlaciona con la disminucion de la supervivencia general. Consulte Video Resumen en http://links.lww.com/DCR/B343.

CASE SUMMARY A 61-year-old woman with ongoing tobacco use was referred to a colorectal surgery clinic after a screening colonoscopy found irregular lesions at the dentate line with biopsies revealing a high-grade squamous intraepithelial lesion. She reported scant bleeding and irregular bowel function, but no incontinence. She has a history of abnormal Papanicolaou tests, but has since undergone a hysterectomy and has no history of immunosuppressive treatment or HIV. She was taken for an examination under anesthesia that revealing a 2.5-cm mass in the anal canal and was biopsied. Pathological examination confirmed anal squamous cell carcinoma (ASCC) with strongly positive p16 staining. A CT of her chest, abdomen, and pelvis did not reveal metastatic disease. She was referred to medical and radiation oncology for radiation therapy with concurrent chemotherapy (5-fluorouracil (5-FU) and mitomycin C). Subsequent office examination with anoscopy 3 months after treatment demonstrated an anterior scar without residual tumor.

Despite a decrease in the incidence of colorectal cancer (CRC) over the last 40 years, the incidence of CRC in people under 50 years old is increasing around the globe. Early onset (≤50 years old) and late onset (≥65 years old) CRC appear to have differences in their clinicopathological and genetic features, but it is unclear if there are differences in the tumor microenvironment. We hypothesized that the immune microenvironment of early onset CRC is distinct from late onset CRC and promotes tumor progression. We used Nanostring immune profiling to analyze mRNA expression of immune genes in FFPE surgical specimens from patients with early (N=40) and late onset (N=39) CRC. We found three genes, SAA1, C7, and CFD, have increased expression in early onset colorectal cancer and distinct immune signatures based on the tumor location. After adjusting for clinicopathological features, increased expression of CFD and SAA1 were associated with worse progression free survival and increased expression of C7 was associated with worse overall survival. Our data demonstrate that the immune microenvironment in early onset CRC is unique, location dependent, and associated with worse outcomes.

Despite a decrease in the incidence of colorectal cancer (CRC) over the last 40 years, the incidence of CRC in people under 50 years old is increasing around the globe. Early onset (≤50 years old) and late onset (≥65 years old) CRC appear to have differences in their clinicopathological and genetic features, but it is unclear if there are differences in the tumor microenvironment. We hypothesized that the immune microenvironment of early onset CRC is distinct from late onset CRC and promotes tumor progression. We used Nanostring immune profiling to analyze mRNA expression of immune genes in FFPE surgical specimens from patients with early (N=40) and late onset (N=39) CRC. We found three genes, SAA1, C7, and CFD, have increased expression in early onset colorectal cancer and distinct immune signatures based on the tumor location. After adjusting for clinicopathological features, increased expression of CFD and SAA1 were associated with worse progression free survival and increased expression of C7 was associated with worse overall survival. Our data demonstrate that the immune microenvironment in early onset CRC is unique, location dependent, and associated with worse outcomes. We propose that age specific immune signatures in the colorectal immune microenvironment can be used as biomarkers for prognosis as well as the development of targeted immune modulatory agents. Citation Format: Ivy H. Gardner, Ragavan Siddarthan, Katherine Watson, Elizabeth Dewey, Rebecca Ruhl, Xiangnan Guan, Zheng Xia, Liana V. Tsikitis, Sudarshan Anand. Innate immune genes distinguish the immune microenvironment of early onset colorectal cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-031.

The factors that predispose one-tenth of reproductive-aged women to endometriosis are poorly understood. We determined that genetic deficiency in transforming growth factor β1 impairs endometriosis-like lesion growth in mice. Given that seminal plasma is an abundant source of transforming growth factor β, we evaluated the effect of exposure to seminal plasma on the growth of endometrial lesions. Human endometrial explants were exposed to seminal plasma or to control medium before transfer to Prkdc(scid)-mutant (severe combined immunodeficient) mice. Xenografts exposed to seminal plasma showed an eightfold increase in volume and a 4.3-fold increase in weight after 14 days. These increases were associated with increased proliferation of endometrial epithelial cells and enhanced survival and proliferation of human stromal cells compared with those in control lesions, in which human stromal cell persistence was negligible. Although the distribution of macrophages was altered, their number and activation status did not change in response to seminal plasma. Seminal plasma stimulated the production of a variety of cytokines in endometrial tissue, including growth-regulated oncogene, granulocyte macrophage colony-stimulating factor, and IL-1β. These data suggest that seminal plasma enhances the formation of endometriosis-like lesion via a direct effect on endometrial cell survival and proliferation, rather than via macrophage-mediated mechanisms. These findings raise the possibility that endometrial exposure to seminal plasma could contribute to endometriotic disease progression in women.

The international normalized ratio (INR) was developed to assess adequacy of Coumadin dosing. Its use has been generalized to guide fresh frozen plasma (FFP) therapy in stable patients. Thrombelastography (TEG) is a whole-blood assay measuring the viscoelastic properties of the clot in near real time. This study hypothesized that INR does not reflect coagulopathy and should not be used to guide FFP therapy in stable trauma and surgical patients.Prospective observational data were collected from stable trauma and surgical patients (n = 106) who received FFP transfusions. Pretransfusion and posttransfusion blood samples were obtained to assess complete blood count, standard coagulation parameters (INR, partial thromboplastin time, fibrinogen and D-dimer), soluble clotting factors (II, V, VII, VIII, IX, X, XI, XII, proteins C and S) and TEG. Data were analyzed using a Mann-Whitney U-test. Significance was defined as p0.05.A total of 262 U of FFP were transfused, with 78% of 106 patients receiving two or more units. Despite a reduction in INR, median TEG values remained within normal limits, while clotting factor levels retained adequate function to produce normal clotting before and following FFP transfusion.The use of FFP in this population did not affect coagulation status in a clinically relevant manner based on TEG values and coagulation factor function. INR is not a predictor of coagulopathy and should not be used to guide coagulation factor replacement in stable trauma and surgical patients.Diagnostic study, level III.

Background The purpose of this study was to determine the relationship between coagulopathy and outcome after traumatic brain injury. Methods Patients admitted with a traumatic brain injury were enrolled prospectively and admission blood samples were obtained for kaolin-activated thrombelastogram and standard coagulation assays. Demographic and clinical data were obtained for analysis. Results Sixty-nine patients were included in the analysis. A total of 8.7% of subjects showed hypocoagulability based on a prolonged time to clot formation (R time, > 9 min). The mortality rate was significantly higher in subjects with a prolonged R time at admission (50.0% vs 11.7%). Patients with a prolonged R time also had significantly fewer intensive care unit–free days (8 vs 27 d), hospital-free days (5 vs 24 d), and increased incidence of neurosurgical intervention (83.3% vs 34.9%). Conclusions Hypocoagulability as shown by thrombelastography after traumatic brain injury is associated with worse outcomes and an increased incidence of neurosurgical intervention.

Background The purpose of this study was to compare standard gauze (SG) and advanced hemostatic dressings in use by military personnel in a no-hold model. Methods A randomized, controlled trial was conducted using 36 swine. Animals underwent femoral arteriotomy, followed by 60 seconds of uncontrolled hemorrhage. After hemorrhage, packing with 1 of 3 dressings—SG, Combat Gauze (CG), or Celox Rapid gauze (XG)—and a 500-mL bolus of Hextend were initiated. Pressure was not held after packing, and animals were followed for 120 minutes. Physiologic parameters were monitored continuously, and electrolyte and hematologic laboratory assessments were performed before injury and 30 and 120 minutes after injury. Dressing failure was determined if bleeding occurred outside the wound. Results All animals survived to study end. Baseline characteristics were similar between groups. No statistical difference was seen in initial blood loss or dressing success rate (SG, 10 of 12; CG, 10 of 12; and XG, 12 of 12). Secondary blood loss was significantly less with XG (median, 12.8 mL; interquartile range, 8.8 to 39.7 mL) compared with SG (median, 44.7 mL; interquartile range, 17.8 to 85.3 mL; P = .02) and CG (median, 31.9 mL; interquartile range, 18.6 to 69.1 mL; P = .05). Packing time was significantly shorter with XG (mean, 37.1 ± 6.2 seconds) compared with SG (mean, 45.2 ± 6.0 seconds; P P = .01). Conclusions XG demonstrated shorter application time and decreased secondary blood loss in comparison with both SG and CG. These differences may be of potential benefit in a care-under-fire scenario.