Artificial Intelligence for Real-Time Prediction of the Histology of Colorectal Polyps by General Endoscopists.

BACKGROUND: Real-time prediction of histologic features of small colorectal polyps may prevent resection and/or pathologic evaluation and therefore decrease colonoscopy costs. Previous studies showed that computer-aided diagnosis (CADx) was highly accurate, though it did not outperform expert endoscopists. OBJECTIVE: To assess the diagnostic performance of histologic predictions by general endoscopists before and after assistance from CADx in a real-life setting. DESIGN: Prospective, multicenter, single-group study. (ClinicalTrials.gov: NCT04437615). SETTING: 6 centers across the United States. PARTICIPANTS: 1252 consecutive patients undergoing colonoscopy and 49 general endoscopists with variable experience in real-time prediction of polyp histologic features. INTERVENTION: Real-time use of CADx during routine colonoscopy. MEASUREMENTS: The primary end points were the sensitivity and specificity of CADx-unassisted and CADx-assisted histologic predictions for adenomas measuring 5 mm or less. For clinical purposes, additional estimates according to location and confidence level were provided. RESULTS: The CADx device made a diagnosis for 2695 polyps measuring 5 mm or less (96%) in 1252 patients. There was no difference in sensitivity between the unassisted and assisted groups (90.7% vs. 90.8%; P = 0.52). Specificity was higher in the CADx-assisted group (59.5% vs. 64.7%; P < 0.001). Among all 2695 polyps measuring 5 mm or less, 88.2% and 86.1% (P < 0.001) in the CADx-assisted and unassisted groups, respectively, could be resected and discarded without pathologic evaluation. Among 743 rectosigmoid polyps measuring 5 mm or less, 49.5% and 47.9% (P < 0.001) in the CADx-assisted and unassisted groups, respectively, could be left in situ without resection. LIMITATION: Decision making based on CADx might differ outside a clinical trial. CONCLUSION: CADx assistance did not result in increased sensitivity of optical diagnosis. Despite a slight increase, the specificity of CADx-assisted diagnosis remained suboptimal. PRIMARY FUNDING SOURCE: Olympus America Corporation served as the clinical study sponsor.

Immune Landscape of Epstein-Barr Virus-Associated Gastric Cancer: Analysis From a Western Academic Institution.

INTRODUCTION: Epstein-Barr virus-associated gastric cancer (EBVaGC) may be a meaningful biomarker for potential benefit from immunotherapy. Further investigation is needed to characterize the immune landscape of EBVaGC. We assessed our institutional frequency of surgically treated EBVaGC and analyzed the immunologic biomarker profile and tumor-infiltrating lymphocyte (TIL) phenotypes of a series of EBVaGC compared to non-EBVaGC cases. METHODS: Available tissue samples from all patients with biopsy-confirmed gastric adenocarcinoma who underwent resection with curative intent from 2012 to 2020 at our institution were collected. In situ hybridization was used to assess EBV status; multiplex immunohistochemistry was performed to assess mismatch repair status, Programmed Death-Ligand 1 (PD-L1) expression, and phenotypic characterization of TILs. RESULTS: Sixty-eight samples were included in this study. EBVaGC was present in 3/68 (4%) patients. Among all patients, 27/68 (40%) had positive PD-L1 expression; two of three (67%) EBVaGC patients exhibited positive PD-L1 expression. Compared to non-EBVaGC, EBV-positive tumors showed 5-fold to 10-fold higher density of TILs in both tumor and stroma and substantially elevated CD8+ T cell to Tregulatory cell ratio. The memory subtypes of CD8+ and CD4+ T cells were upregulated in EBVaGC tumors and stromal tissue compared to non-EBVaGC. CONCLUSIONS: The incidence of surgically resected EBVaGC at our center was 4%. EBVaGC tumors harbor elevated levels of TILs, including memory subtypes, within both tumor and tumor-related stroma. Robust TIL presence and upregulated PD-L1 positivity in EBVaGC may portend promising responses to immunotherapy agents. Further investigation into routine EBV testing and TIL phenotype of patients with gastric cancer to predict response to immunotherapy may be warranted.

Novel histologic score predicts recurrent intestinal metaplasia after successful endoscopic eradication therapy.

Endoscopic eradication therapy (EET) is an effective treatment for Barrett's esophagus (BE); however, disease recurrence remains problematic requiring surveillance post-treatment. While data regarding predictors of recurrence are limited, uncontrolled reflux may play a significant role. Our aim was to develop a scoring system based on histopathologic reflux in surveillance biopsies following EET to identify patients at high risk for recurrence of BE. Patients were identified from two centers in the treatment with resection and endoscopic ablation techniques for BE consortium. Hematoxylin and eosin-stained slides of surveillance biopsies post-EET were assessed for histologic changes associated with reflux from a cohort of patients who also underwent pH-metry (derivation cohort). We developed a novel scoring system (Recurrent Epithelial Changes from Uncontrolled Reflux [RECUR]) composed of dilated intercellular spaces, epithelial ballooning, basal cell hyperplasia, and parakeratosis, to identify patients with abnormal esophageal acid exposure. This scoring system was then used to grade surveillance biopsies from patients with or without recurrence of BE following EET (validation cohort). Of 41 patients in the derivation cohort, 19.5% had abnormal acid exposure times (AET) while on proton pump inhibitor therapy. The mean (SD) RECUR score for patients with AET <4% was 4.0 (1.6), compared with 5.5 (0.9) for AET ≥4% (P = 0.015). In the validation cohort consisting of 72 patients without recurrence and 64 patients with recurrence following EET, the RECUR score was the only significant predictor of recurrence (odds ratio: 1.36, 95% confidence interval: 1.10-1.69, P = 0.005). Histologic grading of surveillance biopsies using the RECUR scoring system correlates with BE recurrence following EET.

Histopathological tumour response scoring in resected pancreatic cancer following neoadjuvant therapy: international interobserver study (ISGPP-1).

BACKGROUND: Most tumour response scoring systems for resected pancreatic cancer after neoadjuvant therapy score tumour regression. However, whether treatment-induced changes, including tumour regression, can be identified reliably on haematoxylin and eosin-stained slides remains unclear. Moreover, no large study of the interobserver agreement of current tumour response scoring systems for pancreatic cancer exists. This study aimed to investigate whether gastrointestinal/pancreatic pathologists can reliably identify treatment effect on tumour by histology, and to determine the interobserver agreement for current tumour response scoring systems. METHODS: Overall, 23 gastrointestinal/pancreatic pathologists reviewed digital haematoxylin and eosin-stained slides of pancreatic cancer or treated tumour bed. The accuracy in identifying the treatment effect was investigated in 60 patients (30 treatment-naive, 30 after neoadjuvant therapy (NAT)). The interobserver agreement for the College of American Pathologists (CAP) and MD Anderson Cancer Center (MDACC) tumour response scoring systems was assessed in 50 patients using intraclass correlation coefficients (ICCs). An ICC value below 0.50 indicated poor reliability, 0.50 or more and less than 0.75 indicated moderate reliability, 0.75 or more and below 0.90 indicated good reliability, and above 0.90 indicated excellent reliability. RESULTS: The sensitivity and specificity for identifying NAT effect were 76.2 and 49.0 per cent respectively. After NAT in 50 patients, ICC values for both tumour response scoring systems were moderate: 0.66 for CAP and 0.71 for MDACC. CONCLUSION: Identification of the effect of NAT in resected pancreatic cancer proved unreliable, and interobserver agreement for the current tumour response scoring systems was suboptimal. These findings support the recently published International Study Group of Pancreatic Pathologists recommendations to score residual tumour burden rather than tumour regression after NAT.

Amsterdam International Consensus Meeting: tumor response scoring in the pathology assessment of resected pancreatic cancer after neoadjuvant therapy.

Histopathologically scoring the response of pancreatic ductal adenocarcinoma (PDAC) to neoadjuvant treatment can guide the selection of adjuvant therapy and improve prognostic stratification. However, several tumor response scoring (TRS) systems exist, and consensus is lacking as to which system represents best practice. An international consensus meeting on TRS took place in November 2019 in Amsterdam, The Netherlands. Here, we provide an overview of the outcomes and consensus statements that originated from this meeting. Consensus (≥80% agreement) was reached on a total of seven statements: (1) TRS is important because it provides information about the effect of neoadjuvant treatment that is not provided by other histopathology-based descriptors. (2) TRS for resected PDAC following neoadjuvant therapy should assess residual (viable) tumor burden instead of tumor regression. (3) The CAP scoring system is considered the most adequate scoring system to date because it is based on the presence and amount of residual cancer cells instead of tumor regression. (4) The defining criteria of the categories in the CAP scoring system should be improved by replacing subjective terms including "minimal" or "extensive" with objective criteria to evaluate the extent of viable tumor. (5) The improved, consensus-based system should be validated retrospectively and prospectively. (6) Prospective studies should determine the extent of tissue sampling that is required to ensure adequate assessment of the residual cancer burden, taking into account the heterogeneity of tumor response. (7) In future scientific publications, the extent of tissue sampling should be described in detail in the "Materials and methods" section.

Technical feasibility, diagnostic yield, and safety of microforceps biopsies during EUS evaluation of pancreatic cystic lesions (with video).

BACKGROUND AND AIMS: Through-the-needle microforceps are a recent addition to the EUS armamentarium for evaluation of pancreatic cystic lesions (PCLs). The main aim of this study was to assess the technical feasibility, diagnostic yield, and safety of EUS-guided microforceps biopsy for PCLs. METHODS: Our electronic endoscopy database was queried to identify patients who underwent EUS-guided FNA (EUS-FNA) of PCLs and microforceps biopsies during the same procedure. A biopsy was done on the wall of the cyst with the microforceps through the 19-gauge needle, and cyst fluid was collected for cytology and carcinoembryonic antigen (CEA) levels. Adverse events were recorded per published American Society for Gastrointestinal Endoscopy criteria. RESULTS: Twenty-seven patients underwent EUS-FNA and microforceps biopsy of PCLs from February 2016 to July 2017. Fourteen cysts were located in the pancreatic head and/or uncinate, and 13 were located in the body and/or tail region. Microforceps biopsies were technically successful in all cases and provided a pathology diagnosis in 24 of 27 cases (yield 88.9%). Microforceps biopsies diagnosed mucinous cyst in 9 patients (33.3%), serous cystadenoma in 4 (14.8%), neuroendocrine tumor in 1 (3.7%), and benign and/or inflammatory cyst in 10 (37.1%). In 7 patients (26%), microforceps biopsy results drastically changed the diagnosis, providing diagnoses otherwise not suggested by cytology or cyst fluid CEA levels. However, cytology provided a diagnosis of mucinous cyst in 4 cases (14.8%) not detected by microforceps biopsies. No adverse events were noted. CONCLUSION: Microforceps biopsies were associated with high technical success, and an excellent safety profile and may be a useful adjunctive tool, complementing existing EUS-FNA sampling protocols for PCLs.

Dual compartmental targeting of cell cycle and angiogenic kinases in colorectal cancer models.

Cancer is a disease caused by several factors characterized by uncontrolled cell division, growth, and survival. ENMD-2076, is a novel orally active small molecule multikinase inhibitor targeting angiogenesis, proliferation, and the cell cycle. It is selectively active against the mitotic kinases aurora A and B, and kinases responsible for angiogenesis including VEGFR2/KDR and FGFR1 and 2. ENMD-2076 has been shown to inhibit tumor growth and prevent angiogenesis in vitro and in vivo in preclinical cancer models. Moreover, in a phase I trial, ENMD-2076 was well tolerated, exhibited a linear pharmacokinetic profile, and showed a promising antitumor activity in a number of solid tumors. In this study, we show that ENMD-2076 has antiproliferative effects, causes cell cycle arrest, and has activity in preclinical models of colorectal cancer (CRC), including patient-derived xenograft (PDX) models. Forty-seven human CRC cell lines were exposed in vitro to ENMD-2076 and analyzed for effects on cell cycle, apoptosis, and downstream effector proteins. The drug was then tested against 20 human CRC PDX models to further evaluate in-vivo antitumor activity. We show that ENMD-2076 exhibits a broad range of activity against a large panel of CRC cell lines with varying molecular characteristics. Mechanistically, ENMD-2076 exposure resulted in a G2/M cell cycle arrest, an increase in aneuploidy, and cell death in responsive cell lines. In addition, ENMD-2076 treatment resulted in a promising antitumor activity in CRC PDX models. These results support the continued development of ENMD-2076 in CRC including further exploration of rational combinations.

Effects of Low-Dose Amoxicillin on Staphylococcus aureus USA300 Biofilms.

Previous studies showed that sub-MIC levels of ß-lactam antibiotics stimulate biofilm formation in most methicillin-resistant Staphylococcus aureus (MRSA) strains. Here, we investigated this process by measuring the effects of sub-MIC amoxicillin on biofilm formation by the epidemic community-associated MRSA strain USA300. We found that sub-MIC amoxicillin increased the ability of USA300 cells to attach to surfaces and form biofilms under both static and flow conditions. We also found that USA300 biofilms cultured in sub-MIC amoxicillin were thicker, contained more pillar and channel structures, and were less porous than biofilms cultured without antibiotic. Biofilm formation in sub-MIC amoxicillin correlated with the production of extracellular DNA (eDNA). However, eDNA released by amoxicillin-induced cell lysis alone was evidently not sufficient to stimulate biofilm. Sub-MIC levels of two other cell wall-active agents with different mechanisms of action-d-cycloserine and fosfomycin-also stimulated eDNA-dependent biofilm, suggesting that biofilm formation may be a mechanistic adaptation to cell wall stress. Screening a USA300 mariner transposon library for mutants deficient in biofilm formation in sub-MIC amoxicillin identified numerous known mediators of S. aureus ß-lactam resistance and biofilm formation, as well as novel genes not previously associated with these phenotypes. Our results link cell wall stress and biofilm formation in MRSA and suggest that eDNA-dependent biofilm formation by strain USA300 in low-dose amoxicillin is an inducible phenotype that can be used to identify novel genes impacting MRSA ß-lactam resistance and biofilm formation.

Potent antitumor activity of cabozantinib, a c-MET and VEGFR2 inhibitor, in a colorectal cancer patient-derived tumor explant model.

Antiangiogenic therapy is commonly used for the treatment of colorectal cancer (CRC). Although patients derive some clinical benefit, treatment resistance inevitably occurs. The MET signaling pathway has been proposed to be a major contributor of resistance to antiangiogenic therapy. MET is upregulated in response to vascular endothelial growth factor pathway inhibition and plays an essential role in tumorigenesis and progression of tumors. In this study, we set out to determine the efficacy of cabozantinib in a preclinical CRC patient-derived tumor xenograft model. We demonstrate potent inhibitory effects on tumor growth in 80% of tumors treated. The greatest antitumor effects were observed in tumors that possess a mutation in the PIK3CA gene. The underlying antitumor mechanisms of cabozantinib consisted of inhibition of angiogenesis and Akt activation and significantly decreased expression of genes involved in the PI3K pathway. These findings support further evaluation of cabozantinib in patients with CRC. PIK3CA mutation as a predictive biomarker of sensitivity is intriguing and warrants further elucidation. A clinical trial of cabozantinib in refractory metastatic CRC is being activated.

Expression of the Novel Costimulatory Molecule B7-H5 in Pancreatic Cancer.

BACKGROUND: This study investigated how the B7-H5 protein, a new member of the B7 family, is expressed in normal human pancreas tissues and examined its expression changes in pancreatic cancer. METHODS: In this analysis, B7-H5 expression was examined by immunohistochemical staining of frozen specimens from patients undergoing pancreatic resection. RESULTS: Membranous B7-H5 protein was expressed on normal ductal epithelium within the pancreas. Other cell types from the normal pancreas, such as acinar cells and islet cells, did not express B7-H5. In adenocarcinoma, B7-H5 staining was decreased or absent. Interestingly, B7-H5 expression in intraductal papillary mucinous neoplasms varied with grade. No B7-H5 expression was found with other cancer types such as neuroendocrine tumors, but normal ducts adjacent to tumors were highly positive. CONCLUSIONS: The findings showed that B7-H5 expression was restricted to ductal cells in the normal pancreas and the expression was downregulated in pancreatic adenocarcinomas. In addition, the findings showed that B7-H5 expression changes within different stages of dysplasia. The study suggests that loss of the B7-H5 signal may contribute to immune evasion of pancreatic adenocarcinoma. However future studies are needed.

Micrococcal nuclease regulates biofilm formation and dispersal in methicillin-resistant Staphylococcus aureus USA300.

Biofilm formation is an important virulence factor for methicillin-resistant Staphylococcus aureus (MRSA). The extracellular matrix of MRSA biofilms contains significant amounts of double-stranded DNA that hold the biofilm together. MRSA cells secrete micrococcal nuclease (Nuc1), which degrades double-stranded DNA. In this study, we used standard methodologies to investigate the role of Nuc1 in MRSA biofilm formation and dispersal. We quantified biofilm formation and extracellular DNA (eDNA) levels in broth and agar cultures. In some experiments, cultures were supplemented with sub-MIC amoxicillin to induce biofilm formation. Biofilm erosion was quantitated by culturing biofilms on rods and enumerating detached colony-forming units (CFUs), and biofilm sloughing was investigated by perfusing biofilms cultured in glass tubes with fresh broth and measuring the sizes of the detached cell aggregates. We found that an MRSA nuc1- mutant strain produced significantly more biofilm and more eDNA than a wild-type strain, both in the absence and presence of sub-MIC amoxicillin. nuc1- mutant biofilms grown on rods detached significantly less than wild-type biofilms. Detachment was restored by exogenous DNase or complementing the nuc1- mutant. In the sloughing assay, nuc1- mutant biofilms released cell aggregates that were significantly larger than those released by wild-type biofilms. Our results suggest that Nuc1 modulates biofilm formation, biofilm detachment, and the sizes of detached cell aggregates. These processes may play a role in the spread and subsequent survival of MRSA biofilms during biofilm-related infections.IMPORTANCEInfections caused by antibiotic-resistant bacteria known as methicillin-resistant Staphylococcus aureus (MRSA) are a significant problem in hospitals. MRSA forms adherent biofilms on implanted medical devices such as catheters and breathing tubes. Bacteria can detach from biofilms on these devices and spread to other parts of the body such as the blood or lungs, where they can cause life-threatening infections. In this article, researchers show that MRSA secretes an enzyme known as thermonuclease that causes bacteria to detach from the biofilm. This is important because understanding the mechanism by which MRSA detaches from biofilms could lead to the development of procedures to mitigate the problem.

Effect of Neoadjuvant Chemotherapy on Tumor-Infiltrating Lymphocytes in Resectable Gastric Cancer: Analysis from a Western Academic Center.

Tumor-infiltrating lymphocytes (TILs) are an emerging biomarker predictive of response to immunotherapy across a spectrum of solid organ malignancies. The characterization of TILs in gastric cancer (GC) treated with contemporary, multiagent neoadjuvant chemotherapy (NAC) is understudied. In this retrospective investigation, we analyzed the degree of infiltration, phenotype, and spatial distribution of TILs via immunohistochemistry within resected GC specimens treated with or without NAC at a Western center. We hypothesized that NAC executes immunostimulatory roles, as evidenced by an increased number of anti-tumor TILs in the tumor microenvironment. We found significantly elevated levels of conventional and memory CD8+ T cells, as well as total TILs (CD4+, CD8+, Treg, B cells), within chemotherapy-treated tumors compared with chemotherapy-naïve specimens. We also revealed important associations between survival and pathologic responses with enhanced TIL infiltration. Taken together, our findings advocate for an immunostimulatory role of chemotherapy and underscore the potential synergistic effect of combining chemotherapy with immunotherapy in resectable gastric cancer.

Poly-ß-(1→6)-N-acetyl-D-glucosamine mediates surface attachment, biofilm formation, and biocide resistance in Cutibacterium acnes.

Background: The commensal skin bacterium Cutibacterium acnes plays a role in the pathogenesis of acne vulgaris and also causes opportunistic infections of implanted medical devices due to its ability to form biofilms on biomaterial surfaces. Poly-ß-(1→6)-N-acetyl-D-glucosamine (PNAG) is an extracellular polysaccharide that mediates biofilm formation and biocide resistance in a wide range of bacterial pathogens. The objective of this study was to determine whether C. acnes produces PNAG, and whether PNAG contributes to C. acnes biofilm formation and biocide resistance in vitro. Methods: PNAG was detected on the surface of C. acnes cells by fluorescence confocal microscopy using the antigen-specific human IgG1 monoclonal antibody F598. PNAG was detected in C. acnes biofilms by measuring the ability of the PNAG-specific glycosidase dispersin B to inhibit biofilm formation and sensitize biofilms to biocide killing. Results: Monoclonal antibody F598 bound to the surface of C. acnes cells. Dispersin B inhibited attachment of C. acnes cells to polystyrene rods, inhibited biofilm formation by C. acnes in glass and polypropylene tubes, and sensitized C. acnes biofilms to killing by benzoyl peroxide and tetracycline. Conclusion: C. acnes produces PNAG, and PNAG contributes to C. acnes biofilm formation and biocide resistance in vitro. PNAG may play a role in C. acnes skin colonization, biocide resistance, and virulence in vivo.

Cladribine tablets after treatment with natalizumab (CLADRINA) - rationale and design.

Background: Individual disease modifying therapies approved for multiple sclerosis (MS) have limited effectiveness and potentially serious side effects, especially when administered over long periods. Sequential combination therapy is a plausible alternative approach. Natalizumab is a monoclonal therapeutic antibody that reduces leukocyte access to the central nervous system that is associated with an increased risk of progressive multifocal leukoencephalopathy and disease reactivation after its discontinuation. Cladribine tablets act as a synthetic adenosine analog, disrupting DNA synthesis and repair, thereby reducing the number of lymphocytes. The generation of prospective, rigorous safety, and efficacy data in transitioning from natalizumab to cladribine is an unmet clinical need. Objectives: To test the feasibility of transitioning patients with relapsing forms of MS natalizumab to cladribine tablets. Design: Cladribine tablets after treatment with natalizumab (CLADRINA) is an open-label, single-arm, multicenter, collaborative phase IV, research study that will generate hypothesis regarding the safety, efficacy, and immunological impact of transition from natalizumab to cladribine tablets in patients with relapsing forms of MS. Methods and analysis: Participants will be recruited from three different sites. The primary endpoint is the absolute and percent change from baseline of lymphocytes and myeloid cell subsets, as well as blood neurofilament light levels. The secondary endpoint is the annualized relapse rate over the 12- and 24-month trial periods. Exploratory endpoints include the expanded disability status scale, and magnetic resonance imaging outcomes. Discussion: The CLADRINA trial will generate data regarding the safety, efficacy, and immunological impact of the transition from natalizumab to cladribine. As the pace of immunological knowledge of MS continues, insight into disease modifying therapy transition strategies is needed.

Characterization of TEM-1 ß-Lactamase-Producing Kingella kingae Clinical Isolates.

Kingella kingae is a human pathogen that causes pediatric osteoarticular infections and infective endocarditis in children and adults. The bacterium is usually susceptible to ß-lactam antibiotics, although ß-lactam resistance has been reported in rare isolates. This study was conducted to identify ß-lactam-resistant strains and to characterize the resistance mechanism. Screening of a set of 90 K. kingae clinical isolates obtained from different geographic locations revealed high-level resistance to penicillins among 25% of the strains isolated from Minnesota and Iceland. These strains produced TEM-1 ß-lactamase and were shown to contain additional ≥50-kb plasmids. Ion Torrent sequencing of extrachromosomal DNA from a ß-lactamase-producing strain confirmed the plasmid location of the blaTEM gene. An identical plasmid pattern was demonstrated by multiplex PCR in all ß-lactamase producers. The porin gene's fragments were analyzed to investigate the relatedness of bacterial strains. Phylogenetic analysis revealed 27 single-nucleotide polymorphisms (SNPs) in the por gene fragment, resulting in two major clusters with 11 allele types forming bacterial-strain subclusters. ß-Lactamase producers were grouped together based on por genotyping. Our results suggest that the ß-lactamase-producing strains likely originate from a single plasmid-bearing K. kingae isolate that traveled from Europe to the United States, or vice versa. This study highlights the prevalence of penicillin resistance among K. kingae strains in some regions and emphasizes the importance of surveillance for antibiotic resistance of the pathogen.

Antibiofilm polysaccharides.

Bacterial extracellular polysaccharides have been shown to mediate many of the cell-to-cell and cell-to-surface interactions that are required for the formation, cohesion and stabilization of bacterial biofilms. However, recent studies have identified several bacterial polysaccharides that inhibit biofilm formation by a wide spectrum of bacteria and fungi both in vitro and in vivo. This review discusses the composition, modes of action and potential biological roles of antibiofilm polysaccharides recently identified in bacteria and eukarya. Some of these molecules may have technological applications as antibiofilm agents in industry and medicine.

Acthar® Gel Treatment for Patients with Autoimmune and Inflammatory Diseases: An Historical Perspective and Characterization of Clinical Evidence.

Acthar® Gel (repository corticotropin injection) is a naturally sourced complex mixture of adrenocorticotropic hormone analogs and other pituitary peptides that is believed to have both steroidogenic and nonsteroidogenic immunomodulatory effects via activation of melanocortin receptors in various cells throughout the body. Since 1952, Acthar has been approved by the US Food and Drug Administration to treat a variety of autoimmune and inflammatory diseases. Since 2014, Mallinckrodt Pharmaceuticals has conducted a large number of preclinical, clinical, and real-world-evidence studies of Acthar for the treatment of rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis and polymyositis, multiple sclerosis relapse, ophthalmic disorders, sarcoidosis, and nephrotic syndrome. To date, Acthar has been the subject of more than 500 publications, many of which demonstrate the safety and efficacy of Acthar in patients with inflammatory diseases for whom standard treatments were ineffective or intolerable. Here, we review the history of Acthar and the findings of studies that have investigated the mechanism of action, safety, efficacy, and real-world effectiveness of Acthar for the treatment of inflammatory diseases.

Acthar^® Gel is an anti-inflammatory drug that directly affects the immune system in a manner that differs from other anti-inflammatory drugs, such as corticosteroids. Since 1952, Acthar has been approved by the U.S. Food and Drug Administration to treat a variety of diseases involving inflammation. The commercial rights to produce Acthar have changed hands several times over the years, beginning with Armour Pharmaceuticals and most recently ending with Mallinckrodt Pharmaceuticals in 2014. Since then, Mallinckrodt has conducted multiple studies in animals to demonstrate the function of Acthar compared with other anti-inflammatory drugs. Further, several clinical trials in humans and studies of hospital or clinical practice records have confirmed the safety and effectiveness of Acthar as a treatment for many inflammatory diseases. INFOGRAPHIC: A podcast discussion by the authors on Acthar^® Gel treatment for patients with autoimmune and inflammatory diseases, including their own personal reflections and experiences with Acthar^® Gel. For a transcript of the podcast see the electronic supplementary material. (MP4 177883 kb).

Micrococcal nuclease regulates biofilm formation and dispersal in methicillin-resistant Staphylococcus aureus USA300.

Biofilm formation is an important virulence factor for methicillin-resistant Staphylococcus aureus (MRSA). The extracellular matrix of MRSA biofilms contains significant amounts of double-stranded DNA. MRSA cells also secrete micrococcal nuclease (Nuc1) which degrades double-stranded DNA. In this study we used a nuc1 mutant strain to investigate the role of Nuc1 in MRSA biofilm formation and dispersal. Biofilm was quantitated in microplates using a crystal violet binding assay. Extracellular DNA (eDNA) was isolated from colony biofilms and analyzed by agarose gel electrophoresis. In some experiments, broth or agar was supplemented with sub-MIC amoxicillin to induce biofilm formation. Biofilm erosion was quantitated by culturing biofilms on rods, transferring the rods to fresh broth, and enumerating CFUs that detached from the rods. Biofilm sloughing was investigated by culturing biofilms in glass tubes perfused with broth and measuring the sizes of the detached cell aggregates. We found that a nuc1 mutant strain produced significantly more biofilm and more eDNA than a wild-type strain in both the absence and presence of sub-MIC amoxicillin, nuc1 mutant biofilms grown on rods detached significantly less than wild-type biofilms. Detachment was restored by exogenous DNase or a wild-type nuc1 gene on a plasmid. In the sloughing assay, nuc1 mutant biofilms released cell aggregates that were significantly larger than those released by wild-type biofilms. Our results suggest that Nuc1 modulates biofilm formation, biofilm detachment, and the sizes of detached cell aggregates. These processes may play a role in the spread and subsequent survival of MRSA biofilms during biofilm-related infections.

Genome sequence of Kingella kingae septic arthritis isolate PYKK081.

Kingella kingae is a human oral bacterium that can cause infections of the skeletal system in children. The bacterium is also a cardiovascular pathogen causing infective endocarditis in children and adults. We report herein the draft genome sequence of septic arthritis K. kingae strain PYKK081.

Overexpression of CXCL5 is associated with poor survival in patients with pancreatic cancer.

Epithelial neutrophil-activating peptide-78 (CXCL5), a member of the CXC chemokine family, has been shown to be involved in angiogenesis, tumor growth, and metastasis. The objective of this study was to determine the relationship between CXCL5 expression and tumor progression in human pancreatic cancer and to elucidate the mechanism underlying CXCL5-mediated tumor angiogenesis and cancer growth. We report herein that CXCL5 is overexpressed in human pancreatic cancer compared with paired normal pancreas tissue. Overexpression of CXCL5 is significantly correlated with poorer tumor differentiation, advanced clinical stage, and shorter patient survival. Patients with pancreatic cancer and CXCL5 overexpression who underwent resection of cancer had a mean survival time 25.5 months shorter than that of patients who did not overexpress CXCL5. Blockade of CXCL5 or its receptor CXCR2 by small-interfering RNA knockdown or antibody neutralization attenuated human pancreatic cancer growth in a nude mouse model. Finally, we demonstrated that CXCL5 mediates pancreatic cancer-derived angiogenesis through activation of several signaling pathways, including protein kinase B (Akt), extracellular signal-regulated kinase (ERK), and signal transducer and activator of transcription (STAT) in human endothelial cells. These data suggest that CXCL5 is an important mediator of tumor-derived angiogenesis and that it may serve as a survival factor for pancreatic cancer. Blockade of either CXCL5 or CXCR2 may be a critical adjunct antiangiogenic therapy against pancreatic cancer.