Citations

TPS3113 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation upon interaction with its ligands PD-L1 or PD-L2. Increased PD-L1 expression has been reported with various hematologic malignancies and may prevent the host immune response from exerting an antitumor effect on the malignant cells. Nivolumab, a fully human IgG4 monoclonal PD-1 receptor blocking antibody, has demonstrated antitumor activity in pts with solid tumors including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. We hypothesized that nivolumab could also mediate antitumor activity in pts with hematologic malignancies, a significant area of unmet medical need. We describe a phase I study to evaluate the effects of nivolumab in pts with select hematologic malignancies. Methods: This open-label, two-part study will enroll approximately 100 pts. During dose escalation, successive cohorts of pts with relapsed or refractory hematologic malignancies will be treated using a 6+3 escalation design. Pts will receive 1 or 3 mg/kg nivolumab IV every 2 weeks (wks) (the first dose will be followed by a 3-wk evaluation period), for 2 years, with the potential for an additional year of therapy for pts who progress during the follow-up period. Subsequently, 5 tumor-specific cohorts of 16 pts will be enrolled at the maximum tolerated dose (MTD) for multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma/primary mediastinal B-cell lymphoma, and chronic myelogenous leukemia. Response will be assessed at wks 4, 8, 16, 24, and every 16 wks thereafter. The primary study objective is to establish dose limiting toxicities, the MTD, and the recommended phase II nivolumab dose. Secondary objectives are to characterize nivolumab pharmacokinetics, immunogenicity, preliminary antitumor activity, and the potential association between PD-L1 expression on tumor cells and clinical efficacy. Exploratory objectives include investigation of the immunoregulatory effects of nivolumab in peripheral blood, bone marrow, and/or tumor. Pts are currently being enrolled at 3 mg/kg. Clinical trial information: NCT01592370.

8093 Background: Activation of the hepatocyte growth factor (HGF)/MET receptor pathway promotes tumor growth, invasion and dissemination. LY is a humanized IgG4 monoclonal bivalent antibody against MET which inhibits ligand dependent- and ligand independent activation of MET. Based on preclinical results, we examined LY alone in patients with advanced solid tumors and LY+E in advanced NSCLC patients. Methods: LY monotherapy was administered 20-2,000 mg Q2W IV to 23 patients with advanced solid tumors. Combination therapy with 700-2,000 mg Q2W IV of LY and E (150 mg QD) was completed in 14 patients with advanced NSCLC. The primary objective was to determine a recommended phase II dose (RPTD) for LY and LY+E. Secondary objectives included assessment of toxicity, PK, PD (including MET extracelluar domain and HGF), and antitumor activity. Results: LY and LY+E were well tolerated. No dose-limiting toxicities, serious adverse events, or ≥ Grade 3 adverse events (AEs) possibly related to LY have been observed. The most frequent (≥5% of patients) AEs possibly related to LY2875358 monotherapy were nausea (8.7 %), vomiting (8.7%), and diarrhea (8.7%). The most frequent (≥10% of patient) grade 1 or 2 adverse event possibly related to LY2875358 in patients treated with LY+E were fatigue (21.4%) and anorexia (14.3%). Durable PR according to RECIST were observed for LY (n=1) and LY+E (n=2 out of 13 evaluable patients; both PR patients positive for MET protein expression). Conclusions: LY appears to be safe when administered as single agent and in combination with E up to 2,000 mg Q2W IV. The RPTD of LY is 750 mg Q2W IV for monotherapy and in combination with E based on PK/PD data. Clinical trial information: NTC 01287546.

Abstract Background The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation is routinely used to assess renal function but exhibits varying accuracy depending on patient characteristics and clinical presentation. The overall aim of the present study was to assess if and to what extent glomerular filtration rate (GFR) estimation based on creatinine can be improved. Methods In a cross-sectional analysis covering the years 2003–17, CKD-EPI was validated against measured GFR (mGFR; using various tracer methods) in patients with high likelihood of chronic kidney disease (CKD; five CKD cohorts, n = 8365) and in patients with low likelihood of CKD (six community cohorts, n = 6759). Comparisons were made with the Lund–Malmö revised equation (LMR) and the Full Age Spectrum equation. Results 7In patients aged 18–39 years old, CKD-EPI overestimated GFR with 5.0–16 mL/min/1.73 m2 in median in both cohort types at mGFR levels <120 mL/min/1.73 m2. LMR had greater accuracy than CKD-EPI in the CKD cohorts (P30, the percentage of estimated GFR within 30% of mGFR, 83.5% versus 76.6%). CKD-EPI was generally the most accurate equation in the community cohorts, but all three equations reached P30 above the Kidney Disease Outcomes Quality Initiative benchmark of 90%. Conclusions None of the evaluated equations made optimal use of available data. Prospects for improved GFR estimation procedures based on creatinine exist, particularly in young adults and in settings where patients with suspected or manifest CKD are investigated.

AbstractThe dense formation of abnormal scar tissue after total knee arthroplasty results in arthrofibrosis, an unfortunate sequela of inflammation. The purpose of this study was to use a validated rabbit model to assess the effects on surgically‐induced knee joint contractures of two combined pharmacological interventions: celecoxib (CXB) loaded on an implanted collagen membrane, and subcutaneously (SQ) injected ketotifen. Thirty rabbits were randomly divided into five groups. The first group received no intervention after the index surgery. The remaining four groups underwent intra‐articular implantation of collagen membranes loaded with or without CXB at the time of the index surgery; two of which were also treated with SQ ketotifen. Biomechanical joint contracture data were collected at 8, 10, 16, and 24 weeks. At the time of necropsy (24 weeks), posterior capsule tissue was collected for messenger RNA and histopathologic analyses. At 24 weeks, there was a statistically significant increase in passive extension among rabbits in all groups treated with CXB and/or ketotifen compared to those in the contracture control group. There was a statistically significant decrease in COL3A1, COL6A1, and ACTA2 gene expression in the treatment groups compared to the contracture control group (P < .001). Histopathologic data also demonstrated a trend towards decreased fibrous tissue density in the CXB membrane group compared to the vehicle membrane group. The present data suggest that intra‐articular placement of a treated collagen membrane blunts the severity of contracture development in a rabbit model of arthrofibrosis, and that ketotifen and CXB may independently contribute to the prevention of arthrofibrosis. Statement of clinical significance: Current literature has demonstrated that arthrofibrosis may affect up to 5% of primary total knee arthroplasty patients. For that reason, novel pharmacologic prophylaxis and treatment modalities are critical to mitigating reoperations and revisions while improving the quality of life for patients with this debilitating condition.

AbstractDeletion of TGFβ inducible early gene‐1 (TIEG) in mice results in an osteopenic phenotype that exists only in female animals. Molecular analyses on female TIEG knockout (KO) mouse bones identified increased expression of sclerostin, an effect that was confirmed at the protein level in serum. Sclerostin antibody (Scl‐Ab) therapy has been shown to elicit bone beneficial effects in multiple animal model systems and human clinical trials. For these reasons, we hypothesized that Scl‐Ab therapy would reverse the low bone mass phenotype of female TIEG KO mice. In this study, wildtype (WT) and TIEG KO female mice were randomized to either vehicle control (Veh, n = 12/group) or Scl‐Ab therapy (10 mg/kg, 1×/wk, s.c.; n = 12/group) and treated for 6 weeks. Following treatment, bone imaging analyses revealed that Scl‐Ab therapy significantly increased cancellous and cortical bone in the femur of both WT and TIEG KO mice. Similar effects also occurred in the vertebra of both WT and TIEG KO animals. Additionally, histomorphometric analyses revealed that Scl‐Ab therapy resulted in increased osteoblast perimeter/bone perimeter in both WT and TIEG KO animals, with a concomitant increase in P1NP, a serum marker of bone formation. In contrast, osteoclast perimeter/bone perimeter and CTX‐1 serum levels were unaffected by Scl‐Ab therapy, irrespective of mouse genotype. Overall, our findings demonstrate that Scl‐Ab therapy elicits potent bone‐forming effects in both WT and TIEG KO mice and effectively increases bone mass in female TIEG KO mice.

Abstract Background: The value of the ratio of plasma aldosterone concentration (aldosterone) to plasma renin activity (renin) to identify patients at risk for primary aldosteronism is controversial. We determined the sensitivity, specificity, and predictive value of the ratio to identify combinations of renin and aldosterone compatible with primary aldosteronism. Methods: The ratio was calculated in 505 adults with essential hypertension (143 black women, 82 black men, 122 white women, and 158 white men). We used a conventional cutpoint for an increased ratio (i.e., 20 mL/dL · h). The primary combination of renin and aldosterone considered compatible with primary aldosteronism was increased aldosterone for the concomitant renin, defined as aldosterone in the highest quartile predicted by linear regression on renin. Renin was considered low if it was in the lowest quartile of the sample distribution. Results: The sensitivity of the ratio to identify individuals with increased aldosterone for the concomitant renin was 66% (80% in blacks and 56% in whites; P = 0.009), and the specificity of the ratio was 67% (46% in blacks and 84% in whites; P &lt;0.0001). In 36% of instances of an increased ratio, it was a measure of low renin alone without increased aldosterone for renin (32% in blacks and 45% in whites; P = 0.072). The positive predictive value of the ratio to identify individuals with increased aldosterone for the concomitant renin was 34% (49% in whites and 27% in blacks; P &lt;0.002). Conclusion: The aldosterone/renin ratio lacks sensitivity and specificity and has only a modest predictive value for combinations of renin and aldosterone that are compatible with primary aldosteronism.

Abstract Background Electrophoretic methods to detect, characterize and quantify M-proteins play an important role in the management of patients with monoclonal gammopathies (MGs). Significant uncertainty in the quantification and limit of detection (LOD) is documented when M-proteins are <10 g/L. Using spiked sera, we aimed to assess the variability in intact M-protein quantification and LOD across 16 laboratories. Methods Sera with normal, hypo- or hyper-gammaglobulinemia were spiked with daratumumab or elotuzumab, with concentrations from 0.125 to 10 g/L (n = 62) along with a beta-migrating sample (n = 9). Laboratories blindly analyzed samples according to their serum protein electrophoresis (SPEP)/isotyping standard operating procedures. LOD and intra-laboratory percent coefficient of variation (%CV) were calculated and further specified with regard to the method (gel/capillary electrophoresis [CZE]), gating strategy (perpendicular drop [PD]/tangent skimming [TS]), isotyping (immunofixation/immunosubtraction [ISUB]) and manufacturer (Helena/Sebia). Results All M-proteins ≥1 g/L were detected by SPEP. With isotyping the LOD was moderately more sensitive than with SPEP. The intensity of polyclonal background had the biggest negative impact on LOD. Independent of the method used, the intra-laboratory imprecision of M-protein quantification was small (mean CV = 5.0%). Low M-protein concentration and high polyclonal background had the strongest negative impact on intra-laboratory precision. All laboratories were able to follow trend of M-protein concentrations down to 1 g/L. Conclusions In this study, we describe a large variation in the reported LOD for both SPEP and isotyping; overall LOD is most affected by the polyclonal immunoglobulin background. Satisfactory intra-laboratory precision was demonstrated. This indicates that the quantification of small M-proteins to monitor patients over time is appropriate, when subsequent testing is performed within the same laboratory.

Abstract Background Serum protein electrophoresis (SPEP) is used to quantify the serum monoclonal component or M-protein, for diagnosis and monitoring of monoclonal gammopathies. Significant imprecision and inaccuracy pose challenges in reporting small M-proteins. Using therapeutic monoclonal antibody-spiked sera and a pooled beta-migrating M-protein, we aimed to assess SPEP limitations and variability across 16 laboratories in three continents. Methods Sera with normal, hypo- or hypergammaglobulinemia were spiked with daratumumab, Dara (cathodal migrating), or elotuzumab, Elo (central-gamma migrating), with concentrations from 0.125 to 10 g/L (n = 62) along with a beta-migrating sample (n = 9). Provided with total protein (reverse biuret, Siemens), laboratories blindly analyzed samples according to their SPEP and immunofixation (IFE) or immunosubtraction (ISUB) standard operating procedures. Sixteen laboratories reported the perpendicular drop (PD) method of gating the M-protein, while 10 used tangent skimming (TS). A mean percent recovery range of 80%–120% was set as acceptable. The inter-laboratory %CV was calculated. Results Gamma globulin background, migration pattern and concentration all affect the precision and accuracy of quantifying M-proteins by SPEP. As the background increases, imprecision increases and accuracy decreases leading to overestimation of M-protein quantitation especially evident in hypergamma samples, and more prominent with PD. Cathodal migrating M-proteins were associated with less imprecision and higher accuracy compared to central-gamma migrating M-proteins, which is attributed to the increased gamma background contribution in M-proteins migrating in the middle of the gamma fraction. There is greater imprecision and loss of accuracy at lower M-protein concentrations. Conclusions This study suggests that quantifying exceedingly low concentrations of M-proteins, although possible, may not yield adequate accuracy and precision between laboratories.

Objectives This proposed systematic review will identify the existing evidence on medication‐overuse headache in children and adolescents. Background A number of medications have been shown to be effective for acute treatment of migraine in children and adolescents. However, patients may find they need to use their acute medications more frequently when migraine frequency is high. This has led to concern about their potential to develop medication‐overuse headache. Methods We will search PubMed, Embase, Web of Science, PsycINFO, and Cochrane databases from their inception to present time. We will also search conference proceedings of the last 4 scientific meetings of relevant societies and scan the reference lists of studies identified through the search. Study designs will include case series, cross‐sectional, cohort, case‐control, and interventional studies. Participants will include children and adolescents under 18 years of age with primary headache disorders. We aim to determine whether frequency of acute medication use is associated with headache frequency in children and adolescents. Outcomes of interest include: (1) headache frequency; (2) change in headache frequency, with time and in relationship to use of acute medications; and (3) headache‐related disability. We will also review data addressing treatment/management of medication overuse or medication‐overuse headache in children and adolescents. Relevant comparators will be withdrawal vs reduction of acute medication, initiation of preventive therapy vs no initiation with or without withdrawal of acute medication, and initiation of preventive therapy early vs late. Outcomes of interest include (1) days of acute medication use; (2) headache frequency; (3) change in headache frequency; and (4) headache‐related disability. After screening for inclusion, 2 team members will independently review and extract relevant data, and any discrepancies will be resolved through discussion and arbitration. We will assess risk of bias using appropriate tools (Cochrane Risk of Bias for randomized controlled trials (RCT) and Newcastle‐Ottawa Score for observational studies). Data will be summarized descriptively in text and tables. Results This systematic review will provide an overview of the available evidence on medication‐overuse headache in children and adolescents. Conclusions Findings from this review will aid clinicians by clarifying for them the current state of the evidence base, and will inform design of future research on this topic.