Standardizing steroid protocols for newly diagnosed inflammatory bowel disease patients: A quality improvement initiative.

OBJECTIVES: Systemic steroids can be used for induction of inflammatory bowel disease (IBD), but are not recommended as long-term therapy. Steroid weaning requires rigorous monitoring of symptoms, which may be cumbersome and lead to missed opportunities. We aim to describe our local quality improvement (QI) initiative to improve and standardize the steroid weaning process. METHODS: After identifying drivers of steroid weaning, a protocol was developed and implemented for newly diagnosed IBD patients started on steroids and subsequently initiated on anti-TNF-α therapy. Interventions included development of a tapering schedule, and standardizing communication with patients and evaluation of symptoms. The primary aim was to increase the percent of patients called on a weekly basis by 20%; secondary aims were to decrease the median steroid days by 25% and to increase the number of our patients weaned off steroids at 8 weeks from 35% to 75% by 1 year after the initiative. RESULTS: The median percent of patients called on a weekly basis to assess clinical symptoms and to wean steroids increased to 80% after 1 year. The median number of systemic corticosteroid days decreased from 67.5 to 50.5 days post-protocol implementation with 61.1% patients weaned off by 8 weeks from discharge. Zero patients were admitted for flares with the protocol implementation. CONCLUSION: Our experience illustrates that QI methodology can be used successfully to improve and standardize the steroid weaning process, leading to shortened steroid duration and without increased flares and hospitalizations.

Comparison of budesonide vehicles in inducing histologic remission in pediatric eosinophilic esophagitis.

OBJECTIVES: Oral viscous budesonide (OVB) is a common medication used to treat eosinophilic esophagitis (EoE). It is typically mixed with Splenda to produce a slurry, but other delivery vehicles have been used in clinical practice. We aimed to evaluate outcomes of pediatric EoE patients treated with OVB using different drug delivery vehicles. METHODS: We performed a retrospective chart review of pediatric EoE patients treated with OVB. The primary aim was to evaluate rates of histologic remission (defined by <15 eosinophils per high power field in both mid and distal esophagus) after 6-12 weeks of OVB treatment for each delivery vehicle. Secondary aims were to evaluate histologic response and endoscopic response and remission of different delivery vehicles, and to compare the efficacy of different treatment regimens. RESULTS: A total of 111 patients were included in the study. Median treatment duration was 3.4 months. Overall rate of histologic remission with OVB was 52.6%. There was no difference in rates of histologic remission (p = 0.313) or response (p = 0.195 and p = 0.681 in mid and distal esophagus, respectively) among the different vehicle types or treatment regimens. Similarly, there was no difference in endoscopic remission and response among the different vehicle types (p = 0.853 and p = 0.727) or treatment regimens (p = 0.244 and p = 0.157). Patients who achieve histologic remission were more likely to be non-Hispanic Caucasian. CONCLUSION: Our findings suggest there is no difference in histologic and endoscopic outcomes with various delivery vehicles or combination therapy with OVB in the treatment of EoE. More palatable and cost-effective vehicles can be used to treat EoE.

Building resilience among families supporting relatives with ABI in rural NSW: testing the feasibility of telephone delivery of Strength2Strength program.

BACKGROUND: Strength2Strength (S2S) is a group psychoeducational program aiming to build resilience among families supporting relatives after traumatic injury. OBJECTIVE: To test the feasibility, acceptability and outcomes of teleconference delivery of a 5 hour S2S program in rural New South Wales. METHODS: A mixed methods design investigated the (i) convenience of telephone-based delivery; and (ii) acceptability of the program material (purpose-designed survey and the Narrative Evaluation of Intervention Interview). Program efficacy was measured with the Resilience Scale (RS) and Connor-Davidson Resilience Scale (CD-RISC); the Positive and Negative Affect Scale (PANAS); Depression, Anxiety and Stress Scale - 21 (DASS-21); Carer Assessment of Managing Index (CAMI); and Caregiver Burden Scale (CBS). Participant outcome data were collected at baseline, post program and 3 months follow-up. RESULTS: 11 participants supporting adult relatives with severe brain injury completed the program. All participants and facilitators commented positively about the cost, ease of use and quality of the teleconference facility. Statistically significant gains were found between pre-program and follow-up scores on the RS, CD-RISC, PANAS-Positive, and CAMI, with statistically significant reductions found on the DASS-21 Depression Scale and CBS scores. CONCLUSION: The study provides preliminary evidence for the efficacy of telephone-based delivery of S2S to family participants.

Neonatal Intensive Care Unit Mixed Lipid Emulsion Use Associated With Reduced Cholestasis at Discharge in Surgical Patients.

INTRODUCTION: Parenteral nutrition associated cholestasis (PNAC) is a common morbidity in neonates requiring total parenteral nutrition (TPN). Previous studies in infants with intestinal failure have shown a benefit of mixed lipid emulsion (MLE) in reducing PNAC. It is not known whether this benefit extends to a general neonatal intensive care unit (NICU) population, where MLE is used on a selective basis. The objective of this study is to examine associations between MLE use and PNAC rate in the general NICU setting. METHODS: This is a retrospective review of NICU patients who received TPN for 7 or more days. We compared patients born between 1/1/2014 and 12/31/2015 (pre-MLE) to patients born between 7/1/2017 and 12/31/2018 (post-MLE). Fisher's exact test and two-sample t-test were used to compare the two groups. RESULTS: There were 353 patients in 2014-2015 and 271 patients in 2017-2018. Demographics were similar between the two groups, but there were more patients with congenital heart disease in the MLE era (P < 0.001). Mortality was similar (6.2% pre-MLE versus 6.3% post-MLE). There was no significant difference in PNAC rate between the pre-MLE (11.5%) and post-MLE (14.1%) patient cohorts (P = 0.342). Among patients receiving MLE (n = 38), 58% developed PNAC, while only 6.4% of the post-MLE cohort not receiving MLE developed PNAC. Of the patients coded with a surgical diagnosis, there was no significant difference in PNAC rates between pre-MLE and post-MLE groups. Discharge rates of PNAC did differ between pre-MLE surgical patients (13.0%) and post-MLE surgical patients (8.2%). In the subgroup of post-MLE surgical patients, PNAC rate differed significantly between those receiving MLE (43.5%) and not receiving MLE (15.4%). However, this difference was resolved by discharge (8.7% versus 7.7%). CONCLUSIONS: There were no significant differences in PNAC rates between the pre-MLE and post-MLE cohorts. However, in surgical patients, MLE was associated with reduced PNAC at discharge, with levels equivalent to those seen in neonates receiving TPN for 7 or more days, despite having a higher starting rate of PNAC. Further studies are needed to determine whether the general NICU population may benefit from MLE or certain selective subpopulations like surgical patients.

Molecular Profiling of Exceptional Responders to Cancer Therapy.

BACKGROUND: The vast majority of metastatic cancers cannot be cured. Palliative treatment may relieve disease symptoms by stopping or slowing cancer growth and may prolong patients' lives, but almost all patients will inevitably develop disease progression after initial response. However, for reasons that are not fully understood, a very few patients will have extraordinary durable responses to standard anticancer treatments. MATERIALS AND METHODS: We analyzed exceptional responders treated at Fox Chase Cancer Center between September 2009 and November 2017. An exceptional response was defined as a complete response lasting more than 1 year or a partial response or stable disease for more than 2 years. Tumor samples were analyzed using an Ambry Genetics test kit with a 142-gene panel. Messenger RNA expression was evaluated using NanoString's nCounter PanCancer Pathways Panel and Immune Profiling Panel and compared with matched controls for gender, age, and cancer type. RESULTS: Twenty-six exceptional responders with metastatic bladder, kidney, breast, lung, ovarian, uterine, and colon cancers were enrolled. Mutations were identified in 45 genes. The most common mutation was an EPHA5 nonsynonymous mutation detected in 87.5% of patients. Mutations in DNA damage repair pathway genes were also frequent, suggesting increased genome instability. We also found varying expression of 73 genes in the Pathways panel and 85 genes in the Immune Profiling panel, many of them responsible for improvement in tumor recognition and antitumor immune response. CONCLUSIONS: The genomic instability detected in our exceptional responders, plus treatment with DNA damage compounds combined with favorable anticancer immunity, may have contributed to exceptional responses to standard anticancer therapies in the patients studied. IMPLICATIONS FOR PRACTICE: With recent advances in the treatment of cancer, there is increased emphasis on the importance of identifying molecular markers to predict treatment outcomes, thereby allowing precision oncology. In this study, it was hypothesized that there is a "specific biologic signature" in the biology of the cancer in long-term survivors that allows sensitivity to systemic therapy and durability of response. Results showed that DNA damage repair pathway alterations, combined with favorable anticancer immunity, may have contributed to exceptional responses. It is very likely that an in-depth examination of outlier responses will become a standard component of drug development in the future.

Prognostic Features of Biochemical Recurrence of Prostate Cancer Following Radical Prostatectomy Based on Multiparametric MRI and Immunohistochemistry Analysis of MRI-guided Biopsy Specimens.

Background Although prostate MRI is routinely used for the detection and staging of localized prostate cancer, imaging-based assessment and targeted molecular sampling for risk stratification are an active area of research. Purpose To evaluate features of preoperative MRI and MRI-guided biopsy immunohistochemistry (IHC) findings associated with biochemical recurrence (BCR) of prostate cancer after surgery. Materials and Methods In this retrospective case-control study, patients underwent multiparametric MRI before MRI-guided biopsy followed by radical prostatectomy between 2008 and 2016. Lesions were retrospectively scored with the Prostate Imaging Reporting and Data System (PI-RADS) (version 2) by radiologists who were blinded to the clinical-pathologic results. The IHC staining, including stains for the ETS-related gene, phosphatase and tensin homolog, androgen receptor, prostate specific antigen, and p53, was performed with targeted biopsy specimens of the index lesion (highest suspicion at MRI and pathologic grade) and scored by pathologists who were blinded to clinical-pathologic outcomes. Cox proportional hazards regression analysis was used to evaluate associations with recurrence-free survival (RFS). Results The median RFS was 31.7 months (range, 1-101 months) for 39 patients (median age, 62 years; age range, 47-76 years) without BCR and 14.6 months (range, 1-61 months) for 40 patients (median age, 59 years; age range, 47-73 years) with BCR. MRI features that showed a significant relationship with the RFS interval included an index lesion with a PI-RADS score of 5 (hazard ratio [HR], 2.10; 95% CI: 1.05, 4.21; P = .04); index lesion burden, defined as ratio of index lesion volume to prostate volume (HR, 1.55; 95% CI: 1.2, 2.1; P = .003); and suspicion of extraprostatic extension (EPE) (HR, 2.18; 95% CI: 1.1, 4.2; P = .02). Presurgical multivariable analysis indicated that suspicion of EPE at MRI (adjusted HR, 2.19; 95% CI: 1.1, 4.3; P = .02) and p53 stain intensity (adjusted HR, 2.22; 95% CI: 1.0, 4.7; P = .04) were significantly associated with RFS. Conclusion MRI features, including Prostate Imaging Reporting and Data System score, index lesion burden, extraprostatic extension, and preoperative guided biopsy p53 immunohistochemistry stain intensity are associated with biochemical relapse of prostate cancer after surgery. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Costa in this issue.

Investigating the Model of Community-Based Case Management in the New South Wales Brain Injury Rehabilitation Program: A Prospective Multicenter Study.

OBJECTIVE: To investigate a model of community-based case management (CM). SETTING: New South Wales (NSW) Brain Injury Rehabilitation Program (BIRP). PARTICIPANTS: All clinicians (N = 72) providing CM within 14 BIRP community rehabilitation teams. DESIGN: A prospective, multicenter study. MAIN MEASURES: A purpose-designed survey. METHODS: Participants from the 12 adult and 2 pediatric services (8 located in metropolitan areas, 6 in rural areas) completed a 3-part survey investigating their organizational context, clinical approach, and CM interventions. Between-groups analyses explored differences among individual services, as well as differences based on age (adult vs pediatric) and location (metropolitan vs rural). RESULTS: All services provided a direct service model of CM. The underlying principles were uniform across services (more direct than indirect service provision; with more client-related than administrative-related tasks; more holistic than service-led in defining client needs; with decision making equally directed by staff and clients; and undertaking a more comprehensive than minimalist range of tasks). CM interventions included the provision of individual support, family support, advocacy, and community development alongside assessment, monitoring, referral, and liaison tasks. There were little differences in practice based on age or location. CONCLUSION: The NSW BIRP has drawn upon the results to produce a model of service for CM.

TMPRSS2:ERG Gene Fusions in Prostate Cancer of West African Men and a Meta-Analysis of Racial Differences.

The prevalence of fusions of the transmembrane protease, serine 2, gene (TMPRSS2) with the erythroblast transformation-specific-related gene (ERG), or TMPRSS2:ERG, in prostate cancer varies by race. However, such somatic aberration and its association with prognostic factors have neither been studied in a West African population nor been systematically reviewed in the context of racial differences. We used immunohistochemistry to assess oncoprotein encoded by the ERG gene as the established surrogate of ERG fusion genes among 262 prostate cancer biopsies from the Ghana Prostate Study (2004-2006). Poisson regression with robust variance estimation provided prevalence ratios and 95% confidence intervals of ERG expression in relation to patient characteristics. We found that 47 of 262 (18%) prostate cancers were ERG-positive, and being negative for ERG staining was associated with higher Gleason score. We further conducted a systematic review and meta-analysis of TMPRSS2:ERG fusions in relation to race, Gleason score, and tumor stage, combining results from Ghana with 40 additional studies. Meta-analysis showed the prevalence of TMPRSS2:ERG fusions in prostate cancer to be highest in men of European descent (49%), followed by men of Asian (27%) and then African (25%) descent. The lower prevalence of TMPRSS2:ERG fusions in men of African descent implies that alternative genomic mechanisms might explain the disproportionately high prostate cancer burden in such populations.

Speech pathology and occupational therapy students participating in placements where their supervisor works in a dual role.

OBJECTIVE: To investigate the facilitating factors and barriers to students participating in placements where their supervisor works in a dual role. DESIGN: A combination of semi structured interviews and focus groups were used. Data was analysed using thematic analysis. SETTING: Regional brain injury rehabilitation programs and university programs. PARTICIPANTS: Eleven Speech Pathologists or Occupational Therapists who worked in regional brain injury rehabilitation programs as both a case manager and within their discipline. Five Speech Pathology or Occupational Therapy university academics who were employed in a role central to facilitating student clinical placements. RESULTS: 6 themes emerged. These included the supervisor's experience of a non-traditional model, communication, perceptions of a clinical placement, supervision, student cohort and assessment criteria. CONCLUSIONS: It appears that students are able to participate in placements where their supervisor works within a specific discipline, as well as a case manager. There are particular factors that are likely to make this experience successful. It is important for all stakeholders to communicate about the placement and their expectations, which may assist with managing perceptions of what an appropriate placement is. Utilising different supervisory models is also necessary. There are factors that do not appear to have a significant effect on the success of such a placement. There is no consensus about the particular level of experience that a student should have to manage this type of placement. The assessment criteria that supervisors are required to complete does not appear to be a barrier to students participating. While there are challenges, benefits for all stakeholders are identified.

Evaluation of ERG responsive proteome in prostate cancer.

BACKGROUND: Gene fusion between TMPRSS2 promoter and the ERG proto-oncogene is a major genomic alteration found in over half of prostate cancers (CaP), which leads to aberrant androgen dependent ERG expression. Despite extensive analysis for the biological functions of ERG in CaP, there is no systematic evaluation of the ERG responsive proteome (ERP). ERP has the potential to define new biomarkers and therapeutic targets for prostate tumors stratified by ERG expression. METHODS: Global proteome analysis was performed by using ERG (+) and ERG (-) CaP cells isolated by ERG immunohistochemistry defined laser capture microdissection and by using TMPRSS2-ERG positive VCaP cells treated with ERG and control siRNA. RESULTS: We identified 1,196 and 2,190 unique proteins stratified by ERG status from prostate tumors and VCaP cells, respectively. Comparative analysis of these two proteomes identified 330 concordantly regulated proteins characterizing enrichment of pathways modulating cytoskeletal and actin reorganization, cell migration, protein biosynthesis, and proteasome and ER-associated protein degradation. ERPs unique for ERG (+) tumors reveal enrichment for cell growth and survival pathways while proteasome and redox function pathways were enriched in ERPs unique for ERG (-) tumors. Meta-analysis of ERPs against CaP gene expression data revealed that Myosin VI and Monoamine oxidase A were positively and negatively correlated to ERG expression, respectively. CONCLUSIONS: This study delineates the global proteome for prostate tumors stratified by ERG expression status. The ERP data confirm the functions of ERG in inhibiting cell differentiation and activating cell growth, and identify potentially novel biomarkers and therapeutic targets.

A selective CutMix approach improves generalizability of deep learning-based grading and risk assessment of prostate cancer.

The Gleason score is an important predictor of prognosis in prostate cancer. However, its subjective nature can result in over- or under-grading. Our objective was to train an artificial intelligence (AI)-based algorithm to grade prostate cancer in specimens from patients who underwent radical prostatectomy (RP) and to assess the correlation of AI-estimated proportions of different Gleason patterns with biochemical recurrence-free survival (RFS), metastasis-free survival (MFS), and overall survival (OS). Training and validation of algorithms for cancer detection and grading were completed with three large datasets containing a total of 580 whole-mount prostate slides from 191 RP patients at two centers and 6218 annotated needle biopsy slides from the publicly available Prostate Cancer Grading Assessment dataset. A cancer detection model was trained using MobileNetV3 on 0.5 mm × 0.5 mm cancer areas (tiles) captured at 10× magnification. For cancer grading, a Gleason pattern detector was trained on tiles using a ResNet50 convolutional neural network and a selective CutMix training strategy involving a mixture of real and artificial examples. This strategy resulted in improved model generalizability in the test set compared with three different control experiments when evaluated on both needle biopsy slides and whole-mount prostate slides from different centers. In an additional test cohort of RP patients who were clinically followed over 30 years, quantitative Gleason pattern AI estimates achieved concordance indexes of 0.69, 0.72, and 0.64 for predicting RFS, MFS, and OS times, outperforming the control experiments and International Society of Urological Pathology system (ISUP) grading by pathologists. Finally, unsupervised clustering of test RP patient specimens into low-, medium-, and high-risk groups based on AI-estimated proportions of each Gleason pattern resulted in significantly improved RFS and MFS stratification compared with ISUP grading. In summary, deep learning-based quantitative Gleason scoring using a selective CutMix training strategy may improve prognostication after prostate cancer surgery.

Increased frequency of CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression without inducing homologous recombination deficiency.

We analyzed genomic data derived from the prostate cancer of African and European American men in order to identify differences that may contribute to racial disparity of outcome and that could also define novel therapeutic strategies. In addition to analyzing patient derived next generation sequencing data, we performed FISH based confirmatory studies of Chromodomain helicase DNA-binding protein 1 (CHD1) loss on prostate cancer tissue microarrays. We created CRISPR edited, CHD1 deficient prostate cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. We found that subclonal deletion of CHD1 is nearly three times as frequent in prostate tumors of African American men than in men of European ancestry and it associates with rapid disease progression. We further showed that CHD1 deletion is not associated with homologous recombination deficiency associated mutational signatures in prostate cancer. In prostate cancer cell line models CHD1 deletion did not induce HR deficiency as detected by RAD51 foci formation assay or mutational signatures, which was consistent with the moderate increase of olaparib sensitivity. CHD1 deficient prostate cancer cells, however, showed higher sensitivity to talazoparib. CHD1 loss may contribute to worse outcome of prostate cancer in African American men. A deeper understanding of the interaction between CHD1 loss and PARP inhibitor sensitivity will be needed to determine the optimal use of targeted agents such as talazoparib in the context of castration resistant prostate cancer.

Natural History of Pediatric Patients With Crohn's Disease Treated With Mesalamine Therapy.

Background: 5-aminosalicylates (5-ASA) are used to treat mild to moderate ulcerative colitis. Despite their lack of efficacy in Crohn disease (CD), they are still used in real-world practice. Additionally, when patients have progressive disease, they may escalate to biologic therapy, at which time 5-ASA may or may not be discontinued. Objectives: The aim of this study is to assess the clinical outcomes of patients started on 5-ASA for the treatment of pediatric CD. The secondary aims were to evaluate the outcomes of those who continue 5-ASA to those who discontinue 5-ASA upon biologic escalation. Methods: We performed a single-center retrospective chart review of pediatric CD patients from 2010 to 2019 who were initially treated with 5-ASA. Demographics, medication and laboratory data, and clinical disease activity were collected. Results: Sixty-one patients were included in the study; the majority had inflammatory CD with ileocolonic involvement. Twenty-four patients were on a concomitant immunomodulator. The majority of patients (85.2%) required escalation to biologics. Thirty-two patients (61.5%) who escalated to biologic therapy continued on 5-ASA. Eighty percent of patients achieved clinical remission at 1 year, and there was no difference between those who continued 5-ASA at time of biologic initiation compared to those who did not continue the medication. Patients who discontinued 5-ASA had an average annual cost savings of $6741. Conclusion: 5-ASA is not a durable monotherapy for the treatment of pediatric CD. Patients who require escalation from 5-ASA to biologic therapy do not benefit from concomitant 5-ASA therapy. Further prospective studies are needed to confirm these findings.

Immunologic Assessment of Tumors from a Race-matched Military Cohort Identifies Mast Cell Depletion as a Marker of Prostate Cancer Progression.

Elucidating the cellular immune components underlying aggressive prostate cancer, especially among African American (AA) men who are disproportionately affected by this disease compared with Caucasian American (CA) men, will support more inclusive precision medicine treatment strategies. We aimed to evaluate which immune-related genes and cell types are differentially expressed in AA tumors and how immunobiology impacts prostate cancer progression. We purified nucleic acid from tumor biopsies, obtained following radical prostatectomy, from 51 patients (AA = 26, CA = 25). Gene expression was measured using the NanoString platform from which we estimated immune cell abundances and assessed differences between groups based on clinicopathologic data. Product-limit estimates determined associations with biochemical recurrence (BCR)-free and metastasis-free survival. DVL2 and KLRC2 were significantly upregulated in CA tumors and were also associated with worse disease progression. No significant differences in immune cell abundances by race were observed. Highly significant reductions in abundances of mast cells versus tumor-infiltrating lymphocytes (TIL) were found in men with high-grade pathologies and in men who later developed metastases. Low ratios of mast cells versus TILs were associated with worse BCR-free survival and metastasis-free survival. Although estimated immune cell abundances were not different by race, we identified genes involved in metabolism and natural killer cell functions that were differentially expressed between AA and CA tumors. Among the entire cohort, depletion of mast cells within prostatectomy tumors was characteristic of advanced disease and susceptibility to disease progression. Significance: Our findings demonstrate that there are immune-related genes and pathways that differ by race. Impaired intratumoral cellular immune composition, especially for TIL-normalized mast cells, may be vital in predicting and contributing to prostate cancer disease progression.

Development and characterization of an ETV1 rabbit monoclonal antibody for the immunohistochemical detection of ETV1 expression in cancer tissue specimens.

BACKGROUND: Aberrant ETV1 overexpression arising from gene rearrangements or mutations occur frequently in prostate cancer, round cell sarcomas, gastrointestinal stromal tumors, gliomas, and other malignancies. The absence of specific monoclonal antibodies (mAb) has limited its detection and our understanding of its oncogenic function. METHODS: An ETV1 specific rabbit mAb (29E4) was raised using an immunogenic peptide. Key residues essential for its binding were probed by ELISA and its binding kinetics were measured by surface plasmon resonance imaging (SPRi). Its selective binding to ETV1 was assessed by immunoblots and immunofluorescence assays (IFA), and by both single and double-immuno-histochemistry (IHC) assays on prostate cancer tissue specimens. RESULTS: Immunoblot results showed that the mAb is highly specific and lacked cross-reactivity with other ETS factors. A minimal epitope with two phenylalanine residues at its core was found to be required for effective mAb binding. SPRi measurements revealed an equilibrium dissociation constant in the picomolar range, confirming its high affinity. ETV1 (+) tumors were detected in prostate cancer tissue microarray cases evaluated. IHC staining of whole-mounted sections revealed glands with a mosaic staining pattern of cells that are partly ETV1 (+) and interspersed with ETV1 (-) cells. Duplex IHC, using ETV1 and ERG mAbs, detected collision tumors containing glands with distinct ETV1 (+) and ERG (+) cells. CONCLUSIONS: The selective detection of ETV1 by the 29E4 mAb in immunoblots, IFA, and IHC assays using human prostate tissue specimens reveals a potential utility for the diagnosis, the prognosis of prostate adenocarcinoma and other cancers, and the stratification of patients for treatment by ETV1 inhibitors.

Soy-derived di- and tripeptides alleviate colon and ileum inflammation in pigs with dextran sodium sulfate-induced colitis.

We evaluated the antiinflammatory activity of soy-derived di- and tripeptides in a dextran sodium sulfate (DSS)-induced pig model of intestinal inflammation. In the DSS-positive control (POS) and DSS-positive with soy peptide treatment (SOY) groups (n = 6/group), DSS was administered to piglets via i.g. catheter for 5 d, followed by a 5-d administration of saline or soy-derived peptides, respectively. A negative control (NEG) group received saline in lieu of the DSS and soy peptides. The severity of inflammation was assessed by clinical signs, morphological and histological measurements, gut permeability, and neutrophil infiltration. Local production of TNF and IL6 were measured by ELISA, colonic and ileal inflammatory gene expression were assessed by real-time RT-PCR, and CD4+CD25+ lymphocyte populations were analyzed by flow cytometry. Crypt elongation and muscle thickness, d-mannitol gut permeation, colonic expression of the inflammatory mediators IFNG, IL1B, TNF, RORC, and IL17A as well as the FOXP3 T-regulatory transcription factor, and myeloperoxidase activity were lower (P < 0.05) in the SOY pigs than in POS pigs. Messenger RNA levels of ileal IFNG, TNF, IL12B, and IL17A were lower (P < 0.05) and FOXP3 expression was greater (P < 0.05) in SOY piglets than in the POS group. In the mesenteric lymph nodes, CD4+CD25+ T cells were higher (P < 0.05) in both the POS and SOY groups than in NEG controls. Soy-derived peptides exert antiinflammatory activity in vivo, suggesting their usefulness for the treatment of inflammatory disorders.

Focal p53 protein expression and lymphovascular invasion in primary prostate tumors predict metastatic progression.

TP53 is one of the most frequently altered genes in prostate cancer. The precise assessment of its focal alterations in primary tumors by immunohistochemistry (IHC) has significantly enhanced its prognosis. p53 protein expression and lymphovascular invasion (LVI) were evaluated for predicting metastatic progression by IHC staining of representative whole-mounted prostate sections from a cohort of 189 radical prostatectomy patients with up to 20 years of clinical follow-up. Kaplan-Meier survival curves were used to examine time to distant metastasis (DM) as a function of p53 expression and LVI status. TP53 targeted sequencing was performed in ten tumors with the highest expression of p53 staining. Nearly half (49.8%) of prostate tumors examined showed focal p53 expression while 26.6% showed evidence of LVI. p53(+) tumors had higher pathologic T stage, Grade Group, Nuclear Grade, and more frequent LVI. p53 expression of > 5% and LVI, individually and jointly, are associated with poorer DM-free survival. TP53 mutations were detected in seven of ten tumors sequenced. Four tumors with the highest p53 expression harbored likely pathogenic or pathogenic mutations. High levels of p53 expression suggest the likelihood of pathogenic TP53 alterations and, together with LVI status, could enhance early prognostication of prostate cancer progression.

Germline mutation landscape of DNA damage repair genes in African Americans with prostate cancer highlights potentially targetable RAD genes.

In prostate cancer, emerging data highlight the role of DNA damage repair genes (DDRGs) in aggressive forms of the disease. However, DDRG mutations in African American men are not yet fully defined. Here, we profile germline mutations in all known DDRGs (N = 276) using whole genome sequences from blood DNA of a matched cohort of patients with primary prostate cancer comprising of 300 African American and 300 European Ancestry prostate cancer patients, to determine whether the mutation status can enhance patient stratification for specific targeted therapies. Here, we show that only 13 of the 46 DDRGs identified with pathogenic/likely pathogenic mutations are present in both African American and European ancestry patients. Importantly, RAD family genes (RAD51, RAD54L, RAD54B), which are potentially targetable, as well as PMS2 and BRCA1, are among the most frequently mutated DDRGs in African American, but not in European Ancestry patients.

Association of Fecal Calprotectin With Endoscopic and Histologic Activity in Pediatric Inflammatory Bowel Disease.

Fecal calprotectin (FC) is a noninvasive marker of intestinal inflammation used for screening and ongoing monitoring of inflammatory bowel disease (IBD); it is unclear the association of specific FC values with disease activity. The aim of our study was to examine the association of FC values with endoscopic and histologic severity. Methods: We performed a retrospective chart review of patients who had FC done between 30 days and 1 day before colonoscopy at our institution. IBD patients were graded using the simple endoscopic score for Crohn's disease or Mayo endoscopic score for ulcerative colitis. Histologic slides were graded using the Geboes method. Results: Three-hundred thirty-one patients were included in the study and 107 had IBD. For endoscopy, median FC was lowest for all IBD patients with no disease (181 µg/g) and highest in severe disease (921 µg/g), with significant difference between no disease and moderate and severe disease (P = 0.019, 0.003), and between mild and severe disease (P = 0.012). For histology, median FC was lowest with no disease (328 µg/g) and highest in severe disease (895 µg/g), with significant difference between no disease and moderate and severe disease (P = 0.021, 0.018). The control population had a significantly lower median FC than the IBD population in endoscopic remission (35.5 versus 181 µg/g; P = 0.018). Conclusions: There was a linear increase in FC values associated with increasing disease severity in the undifferentiated IBD cohort. Values for IBD patients in endoscopic remission were significantly different from our control population. FC may be a useful noninvasive marker to assess disease severity.

Prognostic features of Annexin A2 expression in prostate cancer.

ANXA2 (Annexin A2 or Annexin II) is a calcium dependent phospholipid binding protein with diverse cellular functions. While ANXA2 is either absent or expressed focally in the prostate epithelium of well and moderately differentiated tumours, it is highly expressed in a subset of poorly differentiated tumours. Here we examined the association between ANXA2 expression and tumour progression, with consideration of ERG expression status and patient race (Caucasian American and African American). We evaluated ANXA2 and ERG expression in index tumours by immunohistochemistry of whole mounted prostate sections and tissue microarrays derived from radical prostatectomies of 176 patients, matched for long term post-radical prostatectomy follow-up of up to 22 years (median 12.6 years), race and pathological stage. Expression of ERG and ANXA2 was analysed for correlation with grade group (GG), and pathological T (pT) stage. Kaplan-Meier estimation curves were used to examine associations between ANXA2 or ERG expression and biochemical recurrence (BCR) free survival, and distant metastasis free survival. Significant associations were found between ANXA2(+) index tumours and poorest grade groups (GG 4-5, p=0.0037), and worse pathological stage (pT 3-4, p=0.0142). Patients with ANXA2(+) prostate tumours showed trends towards earlier BCR and metastatic progression. ANXA2(+)/ERG(-) tumours were found to be associated with GG 4-5; ANXA2(-)/ERG(+) tumours, with GG 1-2 (p=0.0036). ANXA2 expression was not associated with patient race. The association between high ANXA2 expression and prostate tumours of higher grade (GG 4-5) and stage (pT 3-4) suggests a potential use for ANXA2 as a prognostic biomarker of aggressive prostate cancer.