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Abstract Background Adalimumab (ADA) is efficacious and well tolerated in adult patients with ulcerative colitis (UC).1,2 SERENE-UC (NCT02065622) is a study evaluating higher ADA dosing regimens from which induction study results have previously been reported3; here, we report data from the maintenance study. Methods This Phase 3, double-blind, randomised, multicentre study evaluated higher vs. standard ADA dosing regimens for induction and maintenance therapy in adult patients with moderately to severely active UC. Following completion of the induction study at Week 8, all patients were re-randomised 2:2:1 to ADA 40 mg every week (40 EW), ADA 40 mg every other week (40 EOW), or exploratory ADA 40 mg with therapeutic drug monitoring (TDM) regimens, stratified by induction treatment regimen, clinical response status at Week 8, and clinical remission (CRem) status at Week 8 among Week 8 responders. Efficacy endpoints were evaluated in Week 8 responders (ITT-RP) unless indicated differently. The primary efficacy endpoint was proportion of patients achieving CRem (full Mayo Score ≤2 with no subscore >1) at Week 52. The endoscopic component of the Mayo Score was scored via central reading. Non-responder imputation was used for missing values. Comparisons between 40 EW and 40 EOW dosing regimens used the Cochran–Mantel–Haenszel test adjusted for stratification. Safety assessment included a collection of adverse events (AEs), vital signs, and laboratory data. Results Of 852 patients in the Global (ex-Japan) induction study, 757 were re-randomised at Week 8 and 371 were included in the ITT-RP. In the ITT-RP, induction baseline demographics and disease characteristics were generally balanced across the 3 treatment arms; range across arms for mean UC disease duration was 6.2–7.8 years, 6.8–11.7% had prior infliximab use, and 62.5–63.5% were receiving corticosteroids. The overall mean ADA exposure was 252.2 days. The table displays results for efficacy endpoints. The observed safety profile was similar between maintenance treatment arms, including AEs of special interest (generally <1% across arms). Conclusion In the Global (ex-Japan) study of SERENE-UC, CRem at Week 52 was numerically higher among Week 8 responders in patients receiving ADA 40 EW compared with 40 EOW maintenance regimens (∆ = 10.5%), but not statistically significant. Higher maintenance treatment with 40 EW was generally safe and well tolerated with a similar safety profile to 40 EOW. No new long-term safety concerns were observed. References

Abstract Background Anaemia is a frequent complication in patients with Crohn’s disease and ulcerative colitis (UC), and patients who respond to treatment generally show improvement in anaemia. Decrease in haemoglobin (Hgb) levels and anaemia may be associated with Janus kinase (JAK) inhibitors. Upadacitinib (UPA), an oral JAK1 selective inhibitor, has demonstrated favourable dose-dependent efficacy in patients with moderately to severely active UC.1 This analysis of data from the U-ACHIEVE study addressed effects of UPA treatment on Hgb levels in patients with UC. Methods U-ACHIEVE (NCT02819635) was a randomised, double-blind, placebo (PBO)-controlled phase 2b clinical trial. Adults with moderately to severely active UC were randomised to receive 7.5, 15, 30, or 45 mg UPA or PBO once daily (QD) for 8 weeks. Hgb levels were measured for all groups at baseline (BL) and weeks 2, 4, 6, and 8. Mean change from BL was calculated for each group. p-values for comparison between UPA and PBO groups were calculated using one-way ANOVA; no multiplicity adjustment was applied. Percentage of patients with Hgb values grade 2 (15–20 g/l Hgb decrease from BL), grade 3 (<80 g/l Hgb level or 21–29 g/l Hgb decrease from BL), and grade 4 (<70 g/l Hgb level or >29 g/l Hgb decrease BL) anaemia were determined for all treatment groups using the Common Terminology Criteria for Adverse Events version 5. Adverse events (AE) were reported by investigators. Results Included in the analysis were 250 patients (mean age ± SD, 42.3 ± 14.2 years; disease duration, 8.2 ± 2.5 years). At BL, most treatment groups had similar mean Hgb levels, except for the 15 mg UPA group, which had significantly lower Hgb levels vs. PBO group (Table). Increased or stable mean levels of Hgb at week 8 vs. BL were observed in most UPA treatment groups. The PBO group had the greatest decrease in Hgb vs. BL at week 8 compared with UPA treatment groups (Figure). Grade ≥2 anaemia was reported in 17.4% of patients receiving PBO and 14.4% of all patients receiving UPA (14.9%, 12.2%, 12.0%, and 17.9% of patients receiving 7.5, 15, 30, and 45 mg UPA, respectively). Grade ≥3 anaemia was reported in 8.7% of patients receiving PBO and 5% of all patients receiving UPA (6.4%, 6.1%, 6.0%, and 1.8% of patients receiving 7.5, 15, 30, and 45 mg UPA, respectively). One subject receiving 7.5 mg QD UPA had grade 4 anaemia. AE of anaemia was reported in 6.5% of patients receiving PBO and in 2.1%, 8.2%, and 3.8% of patients receiving 7.5, 15, and 30 mg UPA, respectively, but not in the 45 mg UPA group. Conclusion Decreased Hgb levels over time were observed more frequently in the PBO group. The maintenance of Hgb levels in patients receiving UPA was likely because of improvement of underlying UC. Reference

Context.— Pulmonary carcinoids are classified as typical or atypical by assessing necrosis and mitoses, which usually cannot be adequately assessed on small biopsies. Ki-67 is not currently used to grade pulmonary carcinoids, but it may be helpful to determine preliminary grade in biopsies. However, the rate at which Ki-67 could underestimate or overestimate grade on small biopsies has not been well studied. Objective.— To compare Ki-67 labeling obtained on small biopsies to subsequent resection. Design.— Ki-67 was performed on paired biopsy and resection specimens from 55 patients. Slides were scanned using Aperio ScanScope. Labeling index was determined using automated hot spot and tumor tracing methods. Results.— The study included 41 typical and 14 atypical carcinoids. Atypical carcinoids were larger and had more distant metastases. Death from disease occurred in 3 patients (all had atypical carcinoids). Median hot spot Ki-67 labeling index was greater in resection compared with biopsy by 0.7% (P = .02). Median tumor tracing Ki-67 was lower in resection compared with biopsy by 0.5% (P < .001). Receiver-operating characteristic analysis showed similar hot spot Ki-67 cutoffs to predict atypical histology (3.5% for biopsy, 3.6% for resection; area under the curve [AUC], 0.75 and 0.74, respectively). Different optimal cutoffs were needed for tracing method based on biopsy (2.1%; AUC, 0.75) compared with resection (1.0%; AUC, 0.67). Conclusions.— Hot spot Ki-67 tends to underestimate grade on small biopsies, whereas grade is overestimated by tumor tracing. Hot spot Ki-67 cutoff of 3.5% predicted atypical histology for both biopsy and resection. Different biopsy and resection cutoffs were necessary for tumor tracing, which would make clinical implementation more difficult.

AbstractNuclear actin plays a critical role in mediating mesenchymal stem cell (MSC) fate commitment. In marrow-derived MSCs, the principal diaphanous-related formin Diaph3 (mDia2) is present in the nucleus and regulates intranuclear actin polymerization, whereas Diaph1 (mDia1) is localized to the cytoplasm and controls cytoplasmic actin polymerization. We here show that mDia2 can be used as a tool to query actin-lamin nucleoskeletal structure. Silencing mDia2 affected the nucleoskeletal lamin scaffold, altering nuclear morphology without affecting cytoplasmic actin cytoskeleton, and promoted MSC differentiation. Attempting to target intranuclear actin polymerization by silencing mDia2 led to a profound loss in lamin B1 nuclear envelope structure and integrity, increased nuclear height, and reduced nuclear stiffness without compensatory changes in other actin nucleation factors. Loss of mDia2 with the associated loss in lamin B1 promoted Runx2 transcription and robust osteogenic differentiation and suppressed adipogenic differentiation. Hence, mDia2 is a potent tool to query intranuclear actin-lamin nucleoskeletal structure, and its presence serves to retain multipotent stromal cells in an undifferentiated state.

Abstract The objective of the study was to assess racial disparities in the treatment and outcomes among white, African American, and Hispanic patients with multiple myeloma (MM). Patients with an MM diagnosis from the Surveillance Epidemiology and End Results (SEER)–Medicare (2007-2013) database were included. Continuous Medicare enrollment for 6 months before (baseline) and after MM diagnosis was required unless death occurred. Time from MM diagnosis to novel therapy initiation and autologous stem cell transplant (ASCT), overall survival (OS), and MM-specific survival (MSS) was evaluated. Unadjusted and multivariable regressions compared African Americans and Hispanics vs whites. Trends of novel therapy and ASCT use across MM diagnosis years were assessed using linear regression models. The study included 3504 whites, 858 African Americans, and 468 Hispanics. African Americans and Hispanics had a longer time from MM diagnosis to novel therapy initiation vs whites (median: 5.2 and 4.6 vs 2.7 months, respectively). All cohorts had an increasing trend of novel therapy initiation within 6 months of MM diagnosis, particularly whites (all P < .05). Median MSS was significantly longer for African Americans (5.4 years) than whites (4.5 years; P < .05), and was comparable for Hispanics and whites. Median OS was similar overall (2.6-2.8 years). ASCT rate within 1 year of MM diagnosis rose among whites and African Americans (P < .05), but not Hispanics, who were less likely to receive ASCT vs whites. Significant variations in novel therapy and ASCT use were observed among different racial/ethnic groups with MM. Although OS was similar, both African Americans and Hispanics may not be fully benefitting from the introduction of novel therapies, as they receive them later than whites.

Abstract Introduction: In multiple myeloma, randomized trials of maintenance therapy using thalidomide or lenalidomide following autologous transplant (ASCT) demonstrated prolonged progression-free survival (PFS), but overall survival benefit was inconsistent. The MY.10 trial (n=332) demonstrated improved PFS with thalidomide-prednisone maintenance therapy, but quality of life was inferior and overall survival was not improved. As a randomized trial with a no-treatment control arm and biospecimen collection, MY.10 provides a unique opportunity to identify predictors of benefit from therapy that could be used to personalize treatment. Immunomodulatory drug action is mediated in part through binding to cereblon (CRBN) and downregulation of IRF4. Candidate single nucleotide polymorphisms (SNPs) were selected from the CRBN/IRF4 pathway and other genes previously associated with myeloma prognosis, drug response and toxicity from literature review. The aim of this study was to investigate associations between candidate SNPs and benefit from immunomodulatory compound-based maintenance therapy, as well as prognostic impact. Methods: Genomic DNA was extracted from samples preserved in Trizol¨. SNPs were genotyped using TaqMan¨ genotyping assays on the ViiA7 qPCR platform. Analysis was performed on 187 patients with available samples and clinical data (86 in treatment arm; 101 in observation arm). Cox regression models were performed using SAS clinical 2.0 for prognostic impact of a single SNP on PFS, assessed with and without adjusted covariates (age, stage, performance status and response to ASCT). In treatment benefit analysis, PFS was modeled with genotype, treatment assignment and their interaction term. Results: SNPs with significant prognostic impact for PFS in all 187 patients were found in CRBN (rs1672753) (HR 0.59, 95%CI 0.4-0.86; p=0.006) and the following SNPs which had been found to be prognostic in prior studies were validated: CYP1A1 (rs1048943) (HR 1.98, 95%CI 1.19-3.27; p=0.008), CYP1B1 (rs1056836) (HR 0.72, 95%CI 0.52-0.99; p=0.043), and trend toward significance for SNP in CYP1A2 (rs2069514) (HR 2.02, 95%CI 0.98-4.15; p=0.057). Of these, only the CYP1A1 SNP was found to be possibly predictive of greater benefit from maintenance therapy. A SNP in ABCA1 (rs363717), previously associated with thalidomide-induced neuropathy,‎ was prognostic in this study (HR 1.44, 95%CI 1.03-2.02; p=0.033) but not predictive of treatment benefit. Table 1 lists SNPs associated with a differential level of benefit from maintenance therapy, including SNPs in FAM179a and ICAM1 that were possibly associated with harm from maintenance therapy. Table 1. SNPs and treatment interaction with significant impact on PFS. HR represent hazard ratio of treatment versus observation for a given genotype group. Asterisk Indicates trend toward significance. Wildtype Heterozygote & mutant p-value interaction Gene dbSNP ID SNP HR 95% CI HR 95% CI FAM179A rs1053667 T>C 0.46 0.33, 0.66 2.28 0.78, 6.65 0.003 ICAM1 rs1799969 G>A 0.51 0.36, 0.73 1.75 0.83, 3.70 0.007 CASP3 rs1049216 A>G 0.82 0.54, 1.25 0.41 0.25, 0.69 0.029 IRF4 rs12203592 C>T 0.69 0.47, 1.02 0.38 0.21, 0.69 0.062* CYP1A1 rs1048943 A>G 0.62 0.44, 0.87 0.11 0.02, 0.52 0.079* Conclusion: Previously identified SNPs in drug metabolism and drug efflux genes were validated to be prognostic in this cohort. The prognostic but not predictive significance of a SNP in CRBN suggests a possible role for CRBN in multiple myeloma disease biology independent of immunomodulatory therapy. SNPs predictive of differing degrees of benefit from immunomodulatory maintenance were found in genes involved in immunomodulatory activation, drug action and cell adhesion mediated drug resistance; SNPs in FAM179A and ICAM1 were possibly associated with harm from thalidomide maintenance and could potentially be used to identify patients unsuitable for immunomodulatory maintenance therapy. These results may be applicable to lenalidomide and pomalidomide, since immunomodulatory compounds exhibit similar chemical structures and mechanisms of action. Validation of these SNPs in prospective clinical trials involving other immunomodulatory can test this hypothesis. Further studies are needed to confirm our findings. Disclosures Off Label Use: thalidomide and prednisone maintenance for multiple myeloma. Bahlis:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy; Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Johnson & Johnson: Research Funding. Song:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Celgene Canada: Honoraria, Research Funding. Chen:Celgene: Consultancy, Honoraria, Research Funding. Seftel:Celgene: Honoraria, Research Funding. Howsen-Jan:Celgene: Honoraria, Research Funding. Reece:Amgen: Honoraria; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Novartis: Honoraria, Research Funding; Onyx: Consultancy; Millennium Takeda: Research Funding; Lundbeck: Honoraria; Otsuka: Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Shepherd:Celgene: Honoraria, Research Funding. Chen:Celgene: Honoraria, Research Funding. Djurfeldt:Celgene: Research Funding. Reiman:Soricimed Biopharma Inc: Consultancy, Other: Scientific Advisory Board for Soricimed.

INTRODUCTION: An unmet need exists to find effective therapy in more severe ulcerative colitis (UC) patients, especially those who have failed multiple therapies. The efficacy and safety of upadacitinib, a selective Janus Kinase 1 inhibitor, has been assessed in an 8-week double-blind, placebo-controlled, dose-ranging, phase 2b induction study in adult patients with moderately-to-severely active UC (U-ACHIEVE). 1,2 METHODS: In U-ACHIEVE, adult patients with moderately-to-severely active UC as determined by the Adapted Mayo Score (5-9 points and centrally-read endoscopy subscore 2-3) were randomized to receive extended-release upadacitinib 7.5, 15, 30, 45 mg once daily (QD) or placebo for 8 weeks. In the current sub-analysis, the efficacy of upadacitinib in more severe and/or more refractory patient populations was assessed. Patients who at baseline had failed ≥2 prior biologic agents, had pancolitis, and/or an Adapted Mayo score >7, were included. Pairwise comparisons between upadacitinib doses and placebo for the primary endpoint, clinical remission per Adapted Mayo Score at Week 8 (defined as stool frequency subscore ≤1, rectal bleeding subscore = 0, and endoscopic subscore ≤1) and secondary endpoints were conducted using the Fisher's Exact test and no multiplicity adjustments were applied. Non-responder imputation was utilized for missing values. RESULTS: At baseline, 142 (56.8% of the total study population) patients had failed ≥2 prior biologics, 135 (54.0%) patients had pancolitis, and 90 (36.0%) patients had an Adapted Mayo score >7. The proportions of patients achieving endoscopic improvement, clinical response per Adapted Mayo score, and clinical response per Partial Mayo score were significantly higher (nominal P -value < 0.05) with upadacitinib doses ≥30 mg QD versus the placebo group in patients who failed ≥2 biologics or had pancolitis at baseline (Table 1). Trends of higher proportions of patients achieving clinical remission per Adapted Mayo score, endoscopic improvement, clinical response per Adapted Mayo score, and clinical response per Partial Mayo score were observed with all upadacitinib groups versus placebo in all the sub-analyses. CONCLUSION: In this dose-ranging induction study, upadacitinib demonstrated greater efficacy compared to placebo with dose response in the more severe and refractory population; significantly greater efficacy was demonstrated with upadacitinib at doses ≥30 mg QD for most of the endpoints evaluated.

Background Male breast cancer (MBC) is a rare disease for which there is limited understanding of treatment patterns and prognostic factors. Methods Men with TNM stage I to stage III breast cancer diagnosed between 2004 and 2014 in the National Cancer Data Base were included. Trends in treatment modalities were described using the average annual percentage change (AAPC) and estimated using Joinpoint software for the analysis of trends. Kaplan‐Meier curves and the multivariate Cox proportional hazards regression model were used to compare survival between subgroups and to identify prognostic factors. Results A total of 10,873 MBC cases were included, with a median age at diagnosis of 64 years. Breast‐conserving surgery was performed in 24% of patients, and 70% of patients undergoing breast conservation received radiotherapy. Approximately 44% of patients received chemotherapy, and 62% of patients with estrogen receptor–positive disease received endocrine therapy. Oncotype DX was ordered in 35% of patients with lymph node–negative, estrogen receptor–positive/human epidermal growth factor receptor 2 (HER2)‐negative tumors. During the study period, there was a significant increase in the rates of total mastectomy, contralateral prophylactic mastectomy, radiotherapy after breast conservation, ordering of Oncotype DX, and the use of endocrine therapy ( P < .05). On multivariate analysis, factors found to be associated with worse overall survival were older age, black race, higher Charlson Comorbidity Index, high tumor grade and stage of disease, and undergoing total mastectomy. Residing in a higher income area; having progesterone receptor–positive tumors; and receipt of chemotherapy, radiotherapy, and endocrine therapy were associated with better overall survival. Conclusions Despite the lack of prospective randomized trials in patients with MBC, the results of the current study demonstrated that the treatment of this disease has evolved over the years. These findings further the understanding of the modern treatment and prognosis of MBC, and identify several areas for further research.

Hereditary renal cystic diseases are characterized by defects in primary cilia of renal tubular epithelial cells and abnormality of tubular epithelium, which ultimately result in the development of renal cysts. However, the mechanism leading from abnormality of the tubular epithelium to cystogenesis is not well understood. In this report, we demonstrate a critical role for Robo2 in regulating epithelial development, including ciliogenesis, polarization, and differentiation. We found that Robo2 deficiency results in cystic kidneys, and the cyst cells showed defective cilia and polarity defects in tubular epithelium. The cyst cells, less than terminally differentiated, continue to proliferate. We further established that Robo2 works with p53 as well as polarity and ciliary proteins (Par3, PKCς, ZO-2, and Claudin-2) to regulate these processes. Robo2 binds to Baiap2 (also known as IRSp53) through the IRSp53/MIM homology domain in renal epithelial cells. This binding allows Robo2 to phosphorylate MDM2 at Ser166 via Baiap2 and maintain p53 homeostasis. Disruption of the Robo2-Baiap2 complex causes MDM2 to be subjected to dephosphorylation, leading to a high level of active p53, and initiated p53-mediated cellular senescence via p21 and decreased the expression of ZO-1, ZO-2, PKCς, Par3, and Claudin-2 proteins, resulting in defects in epithelial development, including ciliogenesis, polarization, and differentiation. Importantly, double knockout of Robo2 and p53 rescued all the epithelial defects in kidneys compared with those in Robo2 -knockout kidneys. Taken together, the present results demonstrate that Robo2 deficiency causes renal cystic disease, which is largely dependent on defective Robo2-Baiap2 integrated signaling in kidneys.