Citations

PurposeTerumo BCT Spectra Optia (O) and Fenwal Amicus (A) can perform therapeutic plasma exchange (TPE). We compared these systems in a prospective, randomized, crossover study of 81 paired procedures. Primary objective was to determine if there was a difference in platelet loss between the instruments. Secondary objectives were to determine differences in procedure time (PT), plasma removal efficiency (PRE 1), plasma removal rate (PRR), and fluid balance (FB).MethodsFifty‐seven adults undergoing 162 procedures were included. Diagnoses included neurologic, nephrologic, and hematologic diseases. Replacement fluids included 5% normal serum albumin and/or fresh frozen plasma. The first instrument (randomized) established the inlet flow rate for the second with a maximum inlet rate of 120 ml/min. Spun HCT was used to program the procedure. One plasma volume was exchanged, for both instruments. Multivariable general estimating equations were used to assess the relationship between the outcome variables with machine after adjusting for covariates, with P values <.05 significant.ResultsMedian total blood volume (4,775 mL‐A, 4,775 mL‐O) and preprocedure spun HCT (33%‐A, 34%‐O) were not statistically different. The plasma removed (3196 mL‐A, 3120 mL‐O), PLT in waste plasma (0.62 × 1011‐A, 0.33 × 1011‐O), PLT decline (8.5%‐A, 6.5%‐O), and PRR (48.1 mL/min‐A, 49.2 mL/min‐O) were not statistically different. There were statistically significant, but clinically irrelevant, differences in PLT CE1 (6.2%‐A, 3.6%‐O), PRE 1 (85.3%‐A, 83.9%‐O), FB (+2 mL‐A,+15 mL‐O), and PT (71 min‐A, 71 min‐O).ConclusionsStatistical differences were seen but none were of a magnitude to be clinically relevant, indicating comparable TPE performance.

Isothermal titration calorimetry (ITC) and circular dichroism (CD) were used to study the thermodynamics of RPC·G‐quadruplex DNA (G4) complex formation. The ruthenium polypyridyl complexes (RPCs) were [Ru(phen)3]2+ (12+), [Ru(phen)2(dppz)]2+ (22+), [Ru(phen)2(tatpp)]2+ (32+), and [Ru(phen)2(tatpp)(phen)2Ru]4+ (44+), and target DNAs were c‐MYC NHE‐III1 promoter sequence mutants forming 1‐2‐1 and 1‐6‐1 G‐quadruplexes. Formation of the 2:1 RPC·G4 complexes is characterized by entropy driven RPC binding to the top and bottom of G‐tetrad faces. 12+ appears to bind very weakly or not at all to G4 DNA. 22+ having a dipyridophenazine group to stack on the top and bottom of the G4 core, exhibits an average Ka = 6.7 × 104 m–1. 32+, with a larger G4 interactive tetraazatetrapyridopentacene group, binds with significantly higher affinity, Ka = 1.1 × 106 m–1. 22+ and 32+ appear to bind independently of G4 folding topology and RPC conformation. The thermograms for the titration of G4 DNA with rac‐44+ are characterized by two binding modes exhibiting higher and lower affinity (Ka,1 = 3.6 × 107 m–1 and Ka,2 = 3.2 × 105 m–1). The two binding modes are attributed to preferential binding of one of the 44+ enantiomers (e.g. ΛΛ) over the other isomers (e.g. ΔΔ or ΔΛ). Tighter binding of the preferred 44+ enantiomer, in comparison to 32+, is due to additional favorable entropy for locating a second [(phen)2Ru–]2+ moiety in a G4 groove. Weaker binding of the disfavored 44+ isomers must be due to a poorer fit of these isomers with the G4 faces.

Abstract Background: Endemic nasopharyngeal carcinoma (NPC) refers to non-keratinizing (NK) subtypes harboring Epstein Barr virus (EBV) that frequently express programmed death-ligand 1 (PD-L1). We recently reported ≥30% of NPC harbor MHC class 1 gene alterations in a whole genome study. Method: We investigated the activity of nivolumab (NIVO) & relationship with PD-L1 & HLA expression (exp) in tumor cells (TC) & tumor infiltrating cells (TIL). Eligible patient (pt)s had to fail ≥ 1 prior line of platinum-based chemo. NIVO (3mg/kg IV, q2 weeks) was given until disease progression (PD). Archived tumors were analyzed for PD-L1 (DAKO) & HLA mutations (indicated by loss of HLA-A &/or B exp). Result: A total of 45 pts were enrolled across 11 sites from Oct 2015 to June 2016. Overall, 43 and 44 pts were evaluable respectively for response rate (RR, RECIST) & adverse events (AE). The median age was 57 years, 77% pts were males & 84% were Asians. The median number of prior chemo was 3 (range 1-9 lines). Of the 43 evaluable pts, there were 8 confirmed (19%, 95% CI: 8-33%) & 1 unconfirmed partial response (PR), 17 PD (40%), 14 stable disease (SD, 33%) & 3 pts were not assessed. One pt (MD015-027) had an unconfirmed clinical CR in an occipital metastasis (met). Pts received a median of 3 cycles of NIVO (range 1 - 14). Median overall survival has not been reached yet. Of the 44 pts evaluable for AE, 8 (18.2%) had grade 3 or higher treatment-related AEs & 1 pt died of sepsis. The most common grade 3 or higher AEs were increase in alanine/aspartate aminotransferase (n=3), & 1 pt respectively for hyponatremia, neutropenia, fatigue & diarrhea. Of the 21 tumor samples analyzed, 11/21 (52%) had &gt;1% PD-L1 expressed mainly in TC. Table 1 outlines relationship between RR & PD-L1 exp. All pts with PR had &gt;5% PD-L1 exp & one pt (34003-022) with CR (nasopharynx) & PR (lung mets) had the highest exp (80%). Majority of pts with PD had &lt;1% PD-L1 exp tumors. One primary progressor (34003-032) had a PD-L1 +ve tumor harboring a complete loss of HLA-B signal (TC), but intact signal in TILs & stromal cells. Conclusion: NIVO is active in this heavily pre-treated group of pts with NK-NPC and longer follow-up is needed for survival endpoints. Preliminary result suggests PD-L1 exp may predict benefit from NIVO. The analytical result of all 45 tumors will be presented. Table 1.PD-L1 exp and RECIST response in 21 ptsPD-L1%espRR%PRSDPD0-11&lt;1%-265%24-10%--120%-1-30%11-80%1--Total498 Citation Format: Brigette B. Ma, Boon Cher Goh, Wan T. Lim, Kwok W. Lo, Edwin P. Hui, Jonathan W. Riess, Mark Agulnik, Alex Y. Chang, Julie A. Kish, Dean W. Lim, Douglas R. Adkins, Kevin J. Cullen, Barbara J. Gitlitz, Nathan R. Foster, Adam M. Pettinger, Sanna Mckinzie, Ka F. To, Brian Costello, Howard Streicher, Anthony T. Chan. Multicenter phase II study of nivolumab in previously treated patients with recurrent and metastatic non-keratinizing nasopharyngeal carcinoma - Mayo clinic Phase 2 Consortium P2C-MN026, NCI9742, NCT02339558 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT076. doi:10.1158/1538-7445.AM2017-CT076

AbstractInvited for the cover of this issue is the group of Edwin Lewis, Mississippi State University, in collaboration with Frederick MacDonnell, University of Texas at Arlington, USA. The cover image shows Ru(phen)2(tatpp)]2+ binding to DNA.

Purpose To evaluate the minimum 2‐year postoperative clinical outcomes and the rate of return to sports in athletes who underwent capsular plication for the treatment of ligamentous laxity and/or borderline dysplasia during hip arthroscopy for the treatment of femoroacetabular impingement and labral pathology. Methods Since 2008, data were prospectively collected on patients who underwent hip arthroscopy for the treatment of femoroacetabular impingement and/or labral tears. Inclusion criteria were as follows: athlete at the high school, collegiate, or professional levels preoperatively, underwent capsular plication, and preoperatively recorded patient‐reported outcome scores including modified Harris hip score (mHHS), nonarthritic athletic hip score (NAHS), hip outcome score—sports‐specific subscale (HOS‐SSS), and visual analog scale (VAS). Exclusion criteria were as follows: <16 years old, preoperative Tönnis grade >1, and previous hip conditions. Sports activity and competitive levels were collected at a minimum of 2 years postoperatively. Results Fifty‐one hips (49 patients) met the inclusion criteria, and 41 hips (39 patients) had minimum 2‐year follow‐up (80.4% follow‐up). Mean mHHS increased from 67.1 preoperatively to 83.5 ( P < .0001). Mean NAHS increased from 66.8 to 88.8 ( P < .0001). Mean HOS‐SSS improved from 46.8 to 80.1 ( P < .0001). Mean VAS decreased from 5.1 to 1.7 ( P < .0001). Thirty‐five (85.4%) hip arthroscopies allowed the patients to return to sports at follow‐up. Thirty‐four (82.9%) hip arthroscopies allowed the patients to maintain their competitive physical abilities at follow‐up. Conclusions Patient‐reported outcomes and VAS in athletes significantly improved at a minimum of 2 years after capsular plication as a part of hip arthroscopy addressing varying pathologies. In addition, most patients returned to sports at similar or higher competitive levels. These results suggest that capsular plication is a favorable treatment option in athletes with ligamentous laxity and/or borderline dysplasia. Level of Evidence Level IV, therapeutic case series.

The ruthenium(II) polypyridyl complexes (RPCs), [(phen)2Ru(tatpp)]Cl2 (3Cl2) and [(phen)2Ru (tatpp)Ru(phen)2]Cl4 (4Cl4), containing the large planar and redox‐active tetraazatetrapyrido‐pentacene (tatpp) ligand, cleave DNA in the presence of reducing agents in cell‐free assays and show significant tumor regression in mouse tumor models with human non‐small cell lung carcinoma xenografts. ITC, CD, and ESI‐MS techniques were used to study the thermodynamics of RPC·DNA complex formation and the complex structure for binding three different RPCs to duplex DNA. The specific RPCs were [Ru(phen)3]2+ (12+), [Ru(phen)2(dppz)]2+ (22+), and [Ru(phen)2(tatpp)]2+ (32+). We examined the enatiomerically pure Δ‐RPC and Λ‐RPC isomers as well as the racemic mixture in terms of their binding to B‐DNA. B‐DNA binding of the three RPCs is characterized by a combination of groove binding (including electrostatic effects) and intercalation, with the thermodynamics being very similar for binding both the enantiomerically pure compounds and the racemic mixture. 12+ is the weakest DNA binder, exhibiting a Ka = 1.3 × 104 m–1 while 22+ binds with significantly higher affinity, Ka,1 = 1.4 × 106 m–1, and 32+ exhibits the tightest binding, Ka = 4.7 × 106 m–1. The trend is to increase the affinity as longer bridging ligands engage in additional π‐bonding with the DNA base pairs via an intercalative binding mode. A second binding mode, two orders of magnitude weaker was also seen for 22+. The ITC values for binding the racemic mixtures exhibit ΔGs ranging from –5.6 to –9.1 kcal mol–1 (12+·DNA and 32+·DNA respectively), while the ITC values for ΔH range from +4.9 to –5.0 kcal mol–1 (32+·DNA and mode 2 binding for 22+·DNA respectively). All of the primary complexes exhibit very negative values for –TΔS ranging from –7.3 to –14.0 kcal mol–1 (mode 1 binding for 22+·DNA and 32+·DNA respectively). To further understand the intercalation vs. groove binding contributions to the overall binding energy we compared the thermodynamics for formation of the 12+·DNA, 22+·DNA, and 32+·DNA complexes to the thermodynamics for formation of the 44+·DNA complex. The RPC binding affinities to duplex DNA follow the trend: 12+ < 44+ < 22+ < 32+. Differences in the affinity for binding 12+ vs. 22+ or 32+ are almost entirely due to the size of the intercalating moiety, e.g. phen which can only be partially intercalated in comparison to dppz and tatpp which can be completely intercalated. The lower affinity for the dinuclear ruthenium 44+ is due to the solvation penalty for the second Ru core complex that extends out from the major groove. Comparing these results, we have begun to develop the structure function relationships for the interaction of RPCs with B‐DNA.

3 Background: There is a clear need to develop a clinically relevant molecular subtyping approach for prostate cancer. We hypothesized that prostate cancer can be subtyped based on luminal versus basal lineage. Methods: We applied the PAM50 classifier, which is used clinically to identify luminal and basal cancers in breast cancer, to subtype a total of 3,782 prostate cancer samples using a high-density microarray platform run in a CLIA-certified laboratory. We examined the associations of these subtypes and clinical outcomes. Results: We demonstrate that PAM50 segregates prostate cancer into three reproducible subtypes in both retrospective cohorts and on prospective validation: luminal A (33.3%-34.3%), luminal B (28.5%-32.6%), and basal (34.1%-37.1%). Luminal B prostate cancers exhibited the worst clinical prognoses, followed by basal and luminal A subtypes (10-year biochemical recurrence-free survival: 29/39/41%; distant metastasis-free survival: 53/73/73%; prostate cancer-specific survival: 78/86/89%; overall survival: 69/80/82% respectively) on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors. Known luminal lineage markers, such as NKX3.1 and KRT18, and the basal lineage CD49f signature, were enriched in luminal- and basal-like cancers respectively, demonstrating the connection between these subtypes and established prostate cancer biology. While both luminal-like subtypes were associated with increased AR expression and signaling, only luminal B prostate cancers were significantly associated with post-operative response to androgen deprivation therapy (ADT) in a subset analysis matching patients based on clinicopathologic variables (interaction p = 0.006, luminal B 10-year metastasis: 33% (treated) vs. 55% (untreated), non-luminal B: 37% (treated) vs. 21% (untreated)). Conclusions: These findings contribute novel insight into the biology of prostate cancer, and provide translatable clinical tools for personalizing post-operative ADT for patients with prostate cancer. Similar to breast cancer, these findings suggest that luminal/basal subtyping may be useful in treatment selection in prostate cancer.