Phase Ib study of avadomide (CC-122) in combination with rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma and follicular lymphoma.

The multicenter, phase Ib CC-122-DLBCL-001 dose-expansion study (NCT02031419) explored the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC-122) plus rituximab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Patients received avadomide 3 mg/day 5 days on/2 days off plus rituximab 375 mg/m2 on day 8 of cycle 1, day 1 of cycles 2 through 6, and day 1 of every third subsequent cycle for 2 years. Primary endpoints were safety and tolerability; preliminary efficacy was a secondary endpoint. A total of 68 patients were enrolled (DLBCL [n = 27], FL [n = 41; 31 lenalidomide-naïve, 10 lenalidomide-treated]). Median age was 62 years (range, 33-84 years), and patients had received a median of 3 (range, 1-8) prior regimens. Among patients with DLBCL, 66.7% had primary refractory disease (partial response or less to initial therapy). Among patients with FL, 65.9% were rituximab-refractory at study entry and 10.0% were lenalidomide-refractory. The most common any-grade avadomide-related adverse events (AEs) were neutropenia (63.2%), infections/infestations (23.5%), fatigue (22.1%), and diarrhea (19.1%). The most common grade 3/4 avadomide-related AEs were neutropenia (55.9%) infections/infestations (8.8%), and febrile neutropenia (7.4%). In patients with DLBCL, overall response rate (ORR) was 40.7% and median duration of response (mDOR) was 8.0 months. In patients with FL, ORR was 80.5% and mDOR was 27.6 months; response rates were similar in lenalidomide-naïve and -treated patients. Avadomide plus rituximab was well tolerated, and preliminary antitumor activity was observed in patients with R/R DLBCL and FL, including subgroups with typically poor outcomes. These results support further investigation of novel CELMoD agents in combination with rituximab in R/R DLBCL and FL.

Phase Ib study of combinations of avadomide (CC-122), CC-223, CC-292, and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma.

There is a need for additional treatment options for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not benefit from available therapies. We examined combinations of the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC-122), the selective, ATP-competitive mammalian target of rapamycin kinase inhibitor CC-223, and the potent, selective, covalent Bruton tyrosine kinase inhibitor CC-292 in patients with relapsed/refractory (R/R) DLBCL. In the multicenter, phase Ib CC-122-DLBCL-001 study (NCT02031419), the dose-escalation portion explored combinations of CC-122, CC-223, and CC-292 administered as doublets or triplets with rituximab in patients with chemorefractory DLBCL. Primary endpoints were safety, tolerability, and dose-limiting toxicities; additional endpoints included pharmacokinetics, pharmacodynamics, biomarkers, and preliminary efficacy. As of December 1, 2017, 106 patients were enrolled across four cohorts. The median age was 65 years (range 24-84 years), and patients had a median of 3 (range 1-10) prior to regimens. A total of 101 patients (95.3%) discontinued, most commonly due to disease progression (49.1%). The most common any-grade adverse events (AEs) across treatment arms were gastrointestinal and hematologic; the most common grade 3/4 AEs were hematologic. CC-122 was well tolerated, with no unexpected safety concerns. Preliminary efficacy was observed in three of four treatment arms. CC-122 plus rituximab was considered suitable for dose expansion, whereas CC-223 and CC-292 combinations were associated with enhanced toxicity and/or insufficient improvement in responses. CC-122 plus rituximab was well tolerated, with preliminary antitumor activity in patients with R/R DLBCL. This innovative study demonstrates the feasibility of assessing the tolerability and preliminary efficacy of novel combinations utilizing a multi-arm dose-finding design.

Lumbar Spine Fusion Surgery in Solid Organ Transplant Recipients Is Associated With Increased Medical Complications and Mortality.

STUDY DESIGN: Retrospective database review. OBJECTIVE: To characterize the outcomes of solid organ transplant (SOT) patients after one- or two-level lumbar fusion surgery. SUMMARY OF BACKGROUND DATA: Over the past decade advances in SOT patients have improved graft survival. As such, this patient population is increasingly eligible for elective surgery such as lumbar fusion procedures to improve mobility and quality of life. However, the outcomes of spine surgery in this population are not well defined. METHODS: Data from the full 100% Medicare sample between 2005 and 2014 were used for the study. Patients were included if they had an elective one- or two-level lumbar spine fusion and previous history of renal, heart, liver, or lung SOT patients during this period. SOT patients were compared to non-SOT patients with respect to baseline characteristics, 90-day medical complications, 1-year rate of revision surgery, and 1-year mortality. RESULTS: There were 961 patients in the transplant cohort and 258,342 in the non-SOT cohort. Seventy-seven percent of the SOT patients had prior renal transplant. SOT patients had a longer length of stay (P < 0.001), and a higher 30-day readmission rate compared to non-SOT patients (P =  < 0.001). In addition, SOT patients experienced a 23.8% rate of 90-day postoperative major medical complications and 3.0%, 1-year mortality, significantly larger than respective rates in the control population (P < 0.001). One-year infection, revision surgery rates, and wound dehiscence were not significantly different between the two cohorts. CONCLUSION: Spine surgery is associated with significant medical complications and 1-year mortality in the SOT population. Although there may be a substantial benefit from lumbar fusion in the SOT population, judicious patient selection is of paramount importance. LEVEL OF EVIDENCE: 3.

Pigs, Unlike Mice, Have Two Distinct Colonic Stem Cell Populations Similar to Humans That Respond to High-Calorie Diet prior to Insulin Resistance.

Basal colonic crypt stem cells are long lived and play a role in colon homeostasis. Previous evidence has shown that high-calorie diet (HCD) enhances colonic stem cell numbers and expansion of the proliferative zone, an important biomarker for colon cancer. However, it is not clear how HCD drives dysregulation of colon stem cell/colonocyte proliferative kinetics. We used a human-relevant pig model and developed an immunofluorescence technique to detect and quantify colonic stem cells. Pigs (n = 8/group) were provided either standard diet (SD; 5% fat) or HCD (23% fat) for 13 weeks. HCD- and SD-consuming pigs had similar total calorie intake, serum iron, insulin, and glucose levels. However, HCD elevated both colonic proliferative zone (KI-67) and stem cell zone (ASCL-2 and BMI-1). Proliferative zone correlated with elevated innate colonic inflammatory markers TLR-4, NF-κB, IL6, and lipocalin-2 (r ≥ 0.62, P = 0.02). Elevated gut bacterial phyla proteobacteria and firmicutes in HCD-consuming pigs correlated with proliferative and stem cell zone. Colonic proteome data revealed the upregulation of proteins involved in cell migration and proliferation and correlated with proliferative and stem cell zone expansion. Our study suggests that pig colon, unlike mice, has two distinct stem cells (ASCL-2 and BMI-1) similar to humans, and HCD increases expansion of colonic proliferative and stem cell zone. Thus, pig model can aid in the development of preventive strategies against gut bacterial dysbiosis and inflammation-promoted diseases, such as colon cancer. Cancer Prev Res; 10(8); 442-50. ©2017 AACR.

The future of safety science is happening now: The modernization of the benefit-risk paradigm.

The future of safety science is happening now and has the potential to improve patient outcomes through an evolving approach to benefit-risk assessment. Three building blocks for the future of safety science, cognitive and behavioral systems, medical assessment, and data science, individually and collaboratively advance and modernize the benefit-risk paradigm. Incorporating the patient perspective and patient experiences will help identify tools that are useful in real-world practice. Medical assessment teams will bring together the study of toxicity and toxicogenomics, biomarkers, and special populations to personalize the benefit-risk profile. Personalized benefit-risk profiles for patients will help improve outcomes. Data science and related quantitative sciences such as safety statistics, database integration, technology, and epidemiology will provide new approaches and tools for analysis of safety data as well as more rapid access to insights that benefit patients.

The Association of Perioperative Glycemic Control with Deep Postoperative Infection After Anterior Cervical Discectomy and Fusion in Patients with Diabetes.

OBJECTIVE: To evaluate the association of perioperative hemoglobin A1c (HbA1c) level in patients with diabetes with the incidence of infection after anterior cervical discectomy and fusion requiring operative intervention, in addition to determining if a threshold level of HbA1c above which the risk of infection increases significantly exists. METHODS: A national administrative database was queried for patients who underwent primary anterior cervical discectomy and fusion with diabetes who had a perioperative HbA1c level recorded within 3 months of surgery. These patients were stratified based on their HbA1c level in 0.5-mg/dL increments from <5.49 mg/dL to >11.5 mg/dL. The incidence of infection requiring operative intervention within 1 year was then identified using Current Procedural Terminology and International Classification of Diseases, Ninth Revision codes. A receiver operating characteristic (ROC) analysis was performed to determine a threshold value of the HbA1c level. RESULTS: A total of 3341 patients with a perioperative HbA1c level were included. The rate of deep infection requiring irrigation and debridement postoperatively stratified by HbA1c level ranged from a low of 1.5% to a high of 6.4% and was significantly correlated with increasing HbA1c levels (P = 0.005). The results of ROC analysis determined that the inflection point of the ROC curve corresponded to an HbA1c level higher than 7.5 mg/dL (P = 0.022; area under the curve, 0.67; specificity, 68%; sensitivity, 46%). CONCLUSIONS: The risk of deep postoperative infection in patients with diabetes mellitus increases as the perioperative HbA1c level increases. ROC analysis determined that a perioperative HbA1c level higher than 7.5 mg/dL could serve as a threshold for a significantly increased risk of infection.

A food-based approach that targets interleukin-6, a key regulator of chronic intestinal inflammation and colon carcinogenesis.

Studies have shown a causal link between high-calorie diet (HCD) and colon cancer. However, molecular mechanisms are not fully elucidated. To understand etiology of HCD-induced colon carcinogenesis, we screened 10 pathways linked to elevated colonic cell proliferation and chronic inflammation in an HCD-consuming human-relevant pig model. We observed elevated colonic mucosal interleukin-6 (IL-6) expression in HCD-consuming pigs compared to standard diet controls (SD, P=.04), and IL-6 strongly correlated with Ki-67 proliferative index and zone, early biomarkers of colon cancer risk (r=0.604 and 0.743 and P=.017 and .002, respectively). Liquid chromatography-tandem mass spectrometry-based proteomic analysis and Ingenuity Pathway Analysis showed that HCD consumption altered IL-6 signaling pathway proteins (PI3KR4, IL-1α, Mapk10, Akt3, PIK3CG, PIK3R5, Map2k2). Furthermore, these proteins also correlated with Ki-67 proliferative index/zone. Anti-IL-6 therapeutics are available for treating colon cancer; however, they are expensive and induce negative side effects. Thus, whole foods could be a better way to combat low-grade chronic colonic inflammation and colon cancer. Whole plant foods have been shown to decrease chronic diseases due to the potential of anti-inflammatory dietary compounds acting synergistically. We observed that supplementation of HCD with anthocyanin-containing purple-fleshed potatoes (10% w/w), even after baking, suppressed HCD-induced IL-6 expression (P=.03) and the IL-6-related proteins IL-1α and Map2k1 (P≤.1). Our results highlight the importance of IL-6 signaling in diet-linked induction/prevention of colonic inflammation/cancer and demonstrate the potential of a food-based approach to target IL-6 signaling.

Does the Timing of Preoperative Epidural Steroid Injection Affect Infection Risk After ACDF or Posterior Cervical Fusion?

STUDY DESIGN: A retrospective database analysis. OBJECTIVE: The aim of this study was to determine whether any association exists between preoperative cervical epidural steroid injections (CESIs) at various time intervals before anterior cervical discectomy and fusion (ACDF) or posterior cervical fusion (PCF) and the incidence of postoperative infection. SUMMARY OF BACKGROUND DATA: Although infectious complications following CESI are uncommon, the association between preoperative CESI and postoperative infection following ACDF or PCF has yet to be evaluated in the current literature. METHODS: A national insurance database was utilized to compare postoperative infection rates within 90 days in patients who received a CESI before ACDF or PCF. Three cohorts were created for each procedure: PCF (n = 402) or ACDF (n = 4354) within 3 months, PCF (n = 586) or ACDF (n = 5183) between 3 and 6 months, and PCF (n = 629) or ACDF (3648) between 6 and 12 months following a CESI. These cohorts were compared with control cohorts who underwent PCF (n = 61,253) or ACDF (n = 241,678) without prior CESI. Postoperative infection rates within 90 days were assessed using International Classification of Disease, 9th Revision (ICD-9) and Current Procedural Terminology (CPT) codes. Odds ratios (ORs), 95% confidence intervals (95% CIs), and P values were then calculated using SPSS. A multivariate binomial logistic regression analysis was performed to determine the independent effect of preoperative injection on postoperative infection following ACDF or PCF controlling for known risk factors for infection, including age, gender, obesity, diabetes, and smoking. RESULTS: Patients who underwent CESI within 3 months (OR 2.21, P < 0.0001) and within 3 to 6 months (OR 1.95, P = 0.0002) before PCF had significantly increased odds of developing a postoperative infection. Patients who underwent CESI within 3 months (OR 1.83, P < 0.0001) before ACDF had significantly increased odds of developing a postoperative infection. CONCLUSION: The present study demonstrates that cervical ESI within 6 months of PCF, and within 3 months of ACDF, is independently associated with significantly increased rates of postoperative infection. LEVEL OF EVIDENCE: 3.

Regional efficacy assessment in multiregional clinical development.

It is common in multiregional clinical development that data from a global trial and a local trial (in a target country) together will be used to support local filing in the target country. This approach is considered efficient drug development both globally and in the target country. However, it remains a challenge how to combine global trial data and local trial data toward local filing. To address this challenge, we propose an "interpretation-centric" evaluation criterion based on a weighted estimator that weights data from the target country and outside of the target country. This approach provides an unbiased estimate of a global treatment effect with appropriate representation of the target country patient population, where the "appropriate representation" is the desired proportion of the target country participants in a global trial and is measured by the weight parameter. This natural interpretation can facilitate drug development discussion with local regulatory agencies. Sample size of the local trial can be determined using the proposed weighted estimator. Approaches for weight determination are also discussed.

Bioinformatic analysis of microRNA networks following the activation of the constitutive androstane receptor (CAR) in mouse liver.

The constitutive androstane receptor (CAR; NR1I3) is a member of the nuclear receptor superfamily that functions as a xenosensor, serving to regulate xenobiotic detoxification, lipid homeostasis and energy metabolism. CAR activation is also a key contributor to the development of chemical hepatocarcinogenesis in mice. The underlying pathways affected by CAR in these processes are complex and not fully elucidated. MicroRNAs (miRNAs) have emerged as critical modulators of gene expression and appear to impact many cellular pathways, including those involved in chemical detoxification and liver tumor development. In this study, we used deep sequencing approaches with an Illumina HiSeq platform to differentially profile microRNA expression patterns in livers from wild type C57BL/6J mice following CAR activation with the mouse CAR-specific ligand activator, 1,4-bis-[2-(3,5,-dichloropyridyloxy)] benzene (TCPOBOP). Bioinformatic analyses and pathway evaluations were performed leading to the identification of 51 miRNAs whose expression levels were significantly altered by TCPOBOP treatment, including mmu-miR-802-5p and miR-485-3p. Ingenuity Pathway Analysis of the differentially expressed microRNAs revealed altered effector pathways, including those involved in liver cell growth and proliferation. A functional network among CAR targeted genes and the affected microRNAs was constructed to illustrate how CAR modulation of microRNA expression may potentially mediate its biological role in mouse hepatocyte proliferation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

The Effect of Local Intraoperative Steroid Administration on the Rate of Postoperative Dysphagia Following ACDF: A Study of 245,754 Patients.

STUDY DESIGN: A retrospective database analysis. OBJECTIVE: The aim of this study is to compare rates of postoperative dysphagia, length of stay, infection, and wound complications following short and long anterior cervical discectomy and fusion (ACDF) in patients who received local intraoperative steroids and those who did not. SUMMARY OF BACKGROUND DATA: Only one prior small institutional study has investigated the application of local steroids at the time of ACDF to decrease postoperative dysphagia. METHODS: A large administrative database was utilized to compare rates of postoperative dysphagia, length of stay, and infectious complications within 90 days in patients who received local steroid following short (1-2 level) and long (3 or more level) ACDF and control groups who did not. Nonobtainable information within the database included type of steroid, application technique, outcome data, and incidence of miscoding and noncoding by physicians. Odds ratios (ORs), 95% confidence intervals (95% CIs) and P values were then calculated using SPSS. RESULTS: The incidence of dysphagia was significantly lower (9.0% vs. 14.6%, P = 0.005) in patients who received local steroid in the long ACDF group (n = 322) than a control group who did not (n = 45,432). This was not observed (P = 0.198) in the short ACDF group who received steroid (n = 1770) compared with a control group who did not (n = 198,230). The mean difference in length of stay was 1 day less for patients who received local steroid in both the short and long ACDF groups (P < 0.0001). The combined rate of postoperative infection and wound complications was not significantly different between steroid and control groups (P = 0.717). CONCLUSION: This analysis of a large administrative database suggests that local intraoperative steroid is associated with a significantly reduced rate of postoperative dysphagia after long ACDF and reduced average length of stay following both long and short ACDF without any increase in the rate of postoperative infection or wound complication. LEVEL OF EVIDENCE: 3.

Weighted Youden index and its two-independent-sample comparison based on weighted sensitivity and specificity.

BACKGROUND: Most indices for evaluating a diagnostic test can be expressed as functions of sensitivity (SEN) and specificity (SPE). Practically, all existing methods suffer from the inability to weight sensitivity and specificity relative to their importance. In this paper, we developed a novel index, the weighted Youden index, that allows Youden index to be a combination of sensitivity and specificity with user-defined weights. METHODS: The weighted Youden index Jw is defined as Jw = 2(w×SEN + (1-w)SPE)-1 (0 ≤ w ≤ 1). It has three properties: (1) the sum of the weights which are attached to sensitivity and specificity should be equal to 1; (2) the range of Jw should be within [-1, 1], which is the range of the Youden index J; (3) Jw should be equal to J when sensitivity and specificity have equal weights. According to the central limit theorem, we obtain the standard error of Jw, and propose a statistical inference method to compare two weighted Youden indices. The monotonicity of the test statistic was discussed. RESULTS: An example of comparing two diagnostic tests for pheochromocytoma was used to demonstrate the weighted Youden index method. Weighted Youden index, the confidence interval for each test and the hypothesis test of comparing two independent diagnostic tests were presented. Assigning the weights is essential to the weighted Youden index approach. CONCLUSION: The weighted Youden index can broaden its applications in diagnostic test development and motivate further research in weighting sensitivity and specificity explicitly.

Experience with an online prospective database on adolescent idiopathic scoliosis: development and implementation.

Considerable variability exists in the surgical treatment and outcomes of adolescent idiopathic scoliosis (AIS). This is due to the lack of evidence-based treatment guidelines and outcome measures. Although clinical trials have been extolled as the highest form of evidence for evaluating treatment efficacy, the disadvantage of cost, time, lack of feasibility, and ethical considerations indicate a need for a new paradigm for evidence based research in this spinal deformity. High quality clinical databases offer an alternative approach for evidence-based research in medicine. So, we developed and established Scolisoft, an international, multidimensional and relational database designed to be a repository of surgical cases for AIS, and an active vehicle for standardized surgical information in a format that would permit qualitative and quantitative research and analysis. Here, we describe and discuss the utility of Scolisoft as a new paradigm for evidence-based research on AIS. Scolisoft was developed using dot.net platform and SQL server from Microsoft. All data is deidentified to protect patient privacy. Scolisoft can be accessed at (www.scolisoft.org). Collection of high quality data on surgical cases of AIS is a priority and processes continue to improve the database quality. The database currently has 67 registered users from 21 countries. To date, Scolisoft has 200 detailed surgical cases with pre, post, and follow up data. Scolisoft provides a structured process and practical information for surgeons to benchmark their treatment methods against other like treatments. Scolisoft is multifaceted and its use extends to education of health care providers in training, patients, ability to mine important data to stimulate research and quality improvement initiatives of healthcare organizations.

Innovative approaches for designing and analyzing adaptive dose-ranging trials.

Inadequate selection of the dose to bring forward in confirmatory trials has been identified as one of the key drivers of the decreasing success rates observed in drug development programs across the pharmaceutical industry. In recognition of this problem, the Pharmaceutical Research and Manufacturers of America (PhRMA), formed a working group to evaluate and develop alternative approaches to dose finding, including adaptive dose-ranging designs. This paper summarizes the work of the group, including the results and conclusions of a comprehensive simulation study, and puts forward recommendations on how to improve dose ranging in clinical development, including, but not limited to, the use of adaptive dose-ranging methods.

Thigh pain after cementless total hip arthroplasty: evaluation and management.

Data from short- and long-term follow-up studies indicate that thigh pain is a significant complication after apparently successful cementless total hip arthroplasty. In most cases, reported symptoms are mild to moderate, resolve spontaneously or do not progress, and require little or no therapeutic intervention. However, persistent thigh pain may be a source of dissatisfaction or may present as severe, disabling pain. Possible causes include bone-prosthesis micromotion, excessive stress transfer to the femur, periosteal irritation, or a mismatch in Young's modulus of elasticity that increases the structural rigidity of the prosthetic stem relative to the femur. Thorough diagnostic evaluation of thigh pain is essential to rule out prosthetic infection or loosening, stress fracture, or spinal pathology as the primary source. Treatment options in the aseptic, well-fixed femoral component include medical management, revision of the femoral component, or cortical strut grafting at the tip of the implant.