An optimized five-gene multi-platform predictor of hormone receptor negative and triple negative breast cancer metastatic risk

Abstract Introduction Outcome predictors in use today are prognostic only for hormone receptor-positive (HRpos) breast cancer. Although microarray-derived multigene predictors of hormone receptor-negative (HRneg) and/or triple negative (Tneg) breast cancer recurrence risk are emerging, to date none have been transferred to clinically suitable assay platforms (for example, RT-PCR) or validated against formalin-fixed paraffin-embedded (FFPE) HRneg/Tneg samples. Methods Multiplexed RT-PCR was used to assay two microarray-derived HRneg/Tneg prognostic signatures IR-7 and Buck-4) in a pooled FFPE collection of 139 chemotherapy-naïve HRneg breast cancers. The prognostic value of the RT-PCR measured gene signatures were evaluated as continuous and dichotomous variables, and in conditional risk models incorporating clinical parameters. An optimized five-gene index was derived by evaluating gene combinations from both signatures. Results RT-PCR measured IR-7 and Buck-4 signatures proved prognostic as continuous variables; and conditional risk modeling chose nodal status, the IR-7 signature, and tumor grade as significant predictors of distant recurrence (DR). From the Buck-4 and IR-7 signatures, an optimized five-gene (TNFRSF17, CLIC5, HLA-F, CXCL13, XCL2) predictor was generated, referred to as the Integrated Cytokine Score (ICS) based on its functional pathway linkage through interferon-γ and IL-10. Across all FFPE cases, the ICS was prognostic as either a continuous or dichotomous variable, and conditional risk modeling selected nodal status and ICS as DR predictors. Further dichotomization of node-negative/ICS-low FFPE cases identified a subset of low-grade HRneg tumors with <10% 5-year DR risk. The prognostic value of ICS was reaffirmed in two previously studied microarray assayed cohorts containing 274 node-negative and chemotherapy naive HRneg breast cancers, including 95 Tneg cases where it proved prognostically independent of Tneg molecular subtyping. In additional HRneg/Tneg microarray assayed cohorts, the five-gene ICS also proved prognostic irrespective of primary tumor nodal status and adjuvant chemotherapy intervention. Conclusion We advanced the measurement of two previously reported microarray-derived HRneg/Tneg breast cancer prognostic signatures for use in FFPE samples, and derived an optimized five-gene Integrated Cytokine Score (ICS) with multi-platform capability of predicting metastatic outcome from primary HRneg/Tneg tumors independent of nodal status, adjuvant chemotherapy use, and Tneg molecular subtype

Plausibility criteria for putative pathophysiological mechanisms in functional gastrointestinal disorders: a consensus of experts

The functional gastrointestinal disorders (FGIDs), are extremely common conditions associated with a considerable personal, social and health economic burden. Managing FGIDs in clinical practice is challenging because of the uncertainty of symptom-based diagnosis, the high frequency of overlap between these conditions and the limited efficacy of available therapies. It has often been argued that successful drug development and management of FGIDs requires knowledge of the underlying pathophysiology. Numerous and highly variable candidate pathophysiological mechanisms have been implicated in the generation of FGID symptoms, but there is no current consensus on how to best define the relevance of these disturbances. Methods: A group of international experts on FGIDs developed plausibility criteria that should be fulfilled by relevant pathophysiological mechanisms in FGIDs. Results: Five criteria are proposed: 1) presence of the abnormality in a subset of patients; 2) temporal association between proposed mechanism and symptom(s); 3) correlation between the level of impairment of the mechanism and symptom(s); 4) induction of the symptom(s) by provoking the pathophysiological abnormality in healthy subjects and 5) treatment response by a therapy specifically correcting the underlying disorder, or congruent natural history of symptoms and dysfunction in the absence of specific therapy. Based on strength of evidence for these 5 criteria, a plausibility score is proposed. Conclusion: Evaluation of the strength of evidence for candidate pathophysiological abnormalities fulfilling these 5 plausibility criteria will help to identify the most relevant mechanisms to target for novel diagnostic approaches and for the development of new therapies

Reg4 and its downstream transcriptional activator CD44ICD in stage II and III colorectal cancer

Reg4 is highly expressed in gastrointestinal malignancies and acts as a mitogenic and pro-invasive factor. Our recent works suggest that Reg4 binds with CD44 and induces its proteolytic cleavage to release intra-cytoplasmic domain of CD44 (CD44ICD). The goal of this study is to demonstrate clinical significance of the Reg4-CD44/CD44ICD pathway in stage II/III colon cancer and its association with clinical parameters of aggression. We constructed a tissue microarray (TMA) of 93 stage II/III matched colon adenocarcinoma patients, 23 with recurrent disease. The TMA was immunohistochemically stained for Reg4, CD44, and CD44ICD proteins and analyzed to identify associations with tumor characteristics, recurrence and overall survival. The TMA data analysis showed a significant correlation between Reg4 and CD44 (

Diverticulosis Is Associated With Internal Hemorrhoids on Colonoscopy: Possible Clues to Etiology

Hemorrhoids are a common but poorly understood gastrointestinal condition. Bowel habits and fiber consumption are frequently cited as risk factors for hemorrhoids, but research has been inconclusive. Recent genome-wide association studies (GWAS) have suggested an association between diverticular disease and hemorrhoids. We sought to investigate the association between colonic diverticulosis and internal hemorrhoids to validate the prediction from the GWAS

Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and inter-leukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn’s Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P = 0.005 and P = 0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohn’s disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355.

An IL28B Genotype-Based Clinical Prediction Model for Treatment of Chronic Hepatitis C

BackgroundGenetic variation in IL28B and other factors are associated with sustained virological response (SVR) after pegylated-interferon/ribavirin treatment for chronic hepatitis C (CHC). Using data from the HALT-C Trial, we developed a model to predict a patient's probability of SVR based on IL28B genotype and clinical variables.MethodsHALT-C enrolled patients with advanced CHC who had failed previous interferon-based treatment. Subjects were re-treated with pegylated-interferon/ribavirin during trial lead-in. We used step-wise logistic regression to calculate adjusted odds ratios (aOR) and create the predictive model. Leave-one-out cross-validation was used to predict a priori probabilities of SVR and determine area under the receiver operator characteristics curve (AUC).ResultsAmong 646 HCV genotype 1-infected European American patients, 14.2% achieved SVR. IL28B rs12979860-CC genotype was the strongest predictor of SVR (aOR, 7.56; p&lt;.0001); the model also included HCV RNA (log10 IU/ml), AST∶ALT ratio, Ishak fibrosis score and prior ribavirin treatment. For this model AUC was 78.5%, compared to 73.0% for a model restricted to the four clinical predictors and 60.0% for a model restricted to IL28B genotype (p&lt;0.001). Subjects with a predicted probability of SVR &lt;10% had an observed SVR rate of 3.8%; subjects with a predicted probability &gt;10% (43.3% of subjects) had an SVR rate of 27.9% and accounted for 84.8% of subjects actually achieving SVR. To verify that consideration of both IL28B genotype and clinical variables is required for treatment decisions, we calculated AUC values from published data for the IDEAL Study.ConclusionA clinical prediction model based on IL28B genotype and clinical variables can yield useful individualized predictions of the probability of treatment success that could increase SVR rates and decrease the frequency of futile treatment among patients with CHC

Family Stool Donation Predicts Failure of Fecal Microbiota Transplant for Clostridioides difficile Infection

Background and Aims: Fecal microbiota transplant (FMT) via colonoscopy is highly effective treatment for Clostridioides difficile infection (CDI). We aimed to determine baseline patient characteristics that predict failure to respond to colonoscopy-based FMT. Methods: We evaluated adult patients who received FMT for CDI not responding to standard therapies at a single tertiary center between 2014 and 2018 in this retrospective cohort study. We defined clinical success as formed stool or C difficile-negative diarrhea at 2 months after FMT. If patients required a second FMT, follow-up was extended 2 months after repeat infusion. We performed multivariate logistic regression and a random forest model to identify variables predictive of response to FMT. Results: Clinical success was attained in 87.3% of 103 patients who underwent FMT for CDI. In the multivariate model, the odds of FMT failure for family donation compared with stool bank were odds ratio 4.13 (1.00-7.01 P = .049). Diarrhea while taking anti-CDI antibiotics was common (37.8% of patients) and did not predict failure (odds ratio 0.64, 0.19-2.11 P = .46) in the univariate model. A machine learning model to predict response using clinical factors only achieved a sensitivity of 70%, specificity of 77%, and negative predictive value of 96%. Conclusion: Colonoscopy-based FMT was highly effective for CDI, even in a population where immunosuppression and proton pump inhibitor use were common. Family stool donation was associated with FMT failure, compared with the use of a stool bank. The study suggests that the use of a stool bank may not only improve access to FMT but also its efficacy