Citations

Patient experience is emerging as a key differentiating factor in patients’ choice of healthcare system. Many healthcare organizations are attempting to improve their patient experience by data-driven, patient-centered initiatives. This involves engaging all staff along all the contact points of a patient’s journey in healthcare. Perhaps, the physicians or care providers are most important link in this chain but also the most challenging to engage in improvement efforts. Most healthcare organizations have some training or workshops to educate providers on communication skills and other tools to enhance patient experience. However, there seems to a paucity of a standardized approach or a roadmap to put together a robust physician or care provider coaching or improvement partnership program with patient experience (PX) staff. There seems to be several gaps in this process. The current article attempts to develop broad guidelines and suggest a roadmap to address these gaps. The article also suggests general templates for PX staff to use in conducting these improvement work with providers and suggestions for developing a standard physician observation or shadowing template for consistency. The article has woven several commonly used tools like motivational interviewing, change management (ADKAR model), and several communication tools to suggest a detailed blue print for provider patient experience improvement partnership.

Background:Injectable azacitidine (AZA) has been evaluated in a variety of malignancies, including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and solid tumors. CC‐486, the oral formulation of AZA, allows extended dosing schedules (>7 days per 28‐day treatment cycle) to increase AZA exposure to malignant cells over the course of the cycle. CC‐486 is under investigation in phase 3 clinical trials as maintenance therapy for patients with AML in first complete remission after induction chemotherapy (NCT01757535) and in lower‐risk MDS with concurrent thrombocytopenia and RBC transfusion dependence (NCT01566695). In these studies, patients receive CC‐486 300 mg QD administered in two 150 mg tablets. A single 300 mg CC‐486 tablet is in development for market approval.Aims:Evaluate the bioequivalence (BE) of a single 300 mg CC‐486 tablet relative to two 150 mg CC‐486 tablets, and the food effect (FE) on the bioavailability of the CC‐486 300 mg tablet.Methods:This was a phase 1, randomized, crossover study (NCT01519011). Adult patients had hematologic malignancies or solid tumors relapsed/refractory to prior therapy for which no standard treatments were available, and ECOG PS scores 0‐2. The BE phase assessed pharmacokinetic (PK) parameters of CC‐486 administered as two 150 mg tablets (formulation A) and as one 300 mg tablet (formulation B). Patients were randomized 1:1 to receive each formulation at least 48 hours apart. In the FE phase, patients were randomized to receive formulation B on each of 2 PK study days under fed (high fat, ∼800‐1000 calories) and fasted conditions. PK parameters, including area under the plasma concentration‐time curve from time 0 extrapolated to infinity (AUC∞), maximum plasma concentration (Cmax), time to Cmax (Tmax), terminal half‐life (t1/2), apparent total clearance (CL/F) and volume of distribution (Vz/F) were analyzed. BE of formulations A and B, and absence of FE on formulation B, were indicated when the 90% CI of the ratios of geometric means (RGM) based on log‐transformed data for AUC∞ and Cmax between formulations A and B, and between fed and fasted conditions, were within 80%>125%.Results:30 patients were enrolled in the BE phase (median age 68.5 yrs, range 46‐86); 3 patients (10%) had hematologic malignancies and 27 (90%) had solid tumors. Formulations A and B were bioequivalent: the Cmax RGM was 101.5% (90% CI 89.9, 114.7) and AUC∞ RGM was 105.7% (95.0, 117.6). Median Tmax was 1.0 hour for both formulations.57 patients enrolled in the FE phase (median age 62 yrs, 31‐88); all had solid tumors. Despite a lower Cmax under fed condition (RGM 78.9% [90%CI 68.6, 90.7]), overall drug exposure was similar (AUC∞ RGM 108.9% [90%CI 98.5, 120.5]) (Figure A). Consistent with an effect of gastric emptying, median Tmax was reached at 2 hrs and 1 hr post‐dose in fed and fasted states, respectively (Figure B) and mean t1/2 was 0.78 and 0.58 hr postdose. CL/F and Vz/F were comparable in fed and fasted states. Moderate to high intersubject variability was observed for all CC‐486 PK parameters (Figure A).Summary/Conclusion:A single oral CC‐486 300 mg tablet is bioequivalent to two 150 mg tablets. The PK profile for the CC‐486 300 mg tablet under fed and fasted conditions was comparable although Cmax occurred later and was decreased in fed vs. fasted condition. Systemic drug exposure (AUC∞) in fed and fasted states was similar and within the bioequivalence limits. Limited differences in other CC‐486 PK parameters between fed and fasted states are not expected to have a clinical impact.image

SUMMARY Image interpretation of Barrett's esophagus (BE) with volumetric laser endomicroscopy (VLE) can be enhanced by image processing software that highlights established features using a color-graded scale (intelligent real-time image segmentation, IRIS). This study aims to provide a description of IRIS features of various gastroesophageal tissue types using histologic correlation. A database of 80 VLE laser-marked targets with histologic correlation was reviewed for various tissue types. IRIS was applied off-line to the VLE scans, laser-marked targets were identified, and feature review was performed. Squamous epithelium targets (N = 7) showed IRIS layered architecture with lack of surface hyper-reflectivity and epithelial glands. Gastric cardia targets (N = 10) showed absent layering (100%) and surface hyper-reflectivity with epithelial glands (40%). Nondysplastic BE targets (N = 39) showed surface hyper-reflectivity (64%), epithelial glands (51%), and lack of layering (74%). Targets of BE with early neoplasia (N = 24), showed surface hyper-reflectivity (96%), epithelial glands (67%), and lack of layering (96%). IRIS features that characterize each tissue type appear to mirror the nonenhanced VLE counterparts that define them.

We set out to determine whether machine learning–based algorithms that included functionally validated pharmacogenomic biomarkers joined with clinical measures could predict selective serotonin reuptake inhibitor (SSRI) remission/response in patients with major depressive disorder (MDD). We studied 1,030 white outpatients with MDD treated with citalopram/escitalopram in the Mayo Clinic Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN‐AMPS; n = 398), Sequenced Treatment Alternatives to Relieve Depression (STAR*D; n = 467), and International SSRI Pharmacogenomics Consortium (ISPC; n = 165) trials. A genomewide association study for PGRN‐AMPS plasma metabolites associated with SSRI response (serotonin) and baseline MDD severity (kynurenine) identified single nucleotide polymorphisms (SNPs) in DEFB1, ERICH3, AHR, and TSPAN5 that we tested as predictors. Supervised machine‐learning methods trained using SNPs and total baseline depression scores predicted remission and response at 8 weeks with area under the receiver operating curve (AUC) > 0.7 (P < 0.04) in PGRN‐AMPS patients, with comparable prediction accuracies > 69% (P ≤ 0.07) in STAR*D and ISPC. These results demonstrate that machine learning can achieve accurate and, importantly, replicable prediction of SSRI therapy response using total baseline depression severity combined with pharmacogenomic biomarkers.

The NCCN Guidelines for Hepatobiliary Cancers provide treatment recommendations for cancers of the liver, gallbladder, and bile ducts. The NCCN Hepatobiliary Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s discussion and updated recommendations regarding systemic therapy for first-line and subsequent-line treatment of patients with hepatocellular carcinoma.

Rationale: Acute kidney injury (AKI) has a high prevalence and mortality in critically ill patients. It is also a powerful risk factor for heart failure incidence driven by hemodynamic changes and neurohormonal activation. However, no drugs have been approved by the Food and Drug Administration. Endogenous pGC-A (particulate guanylyl cyclase A receptor) activators were reported to preserve renal function and improve mortality in AKI patients, although hypotension accompanied by pGC-A activators have limited their therapeutic potential. Objective: We investigated the therapeutic potential of a nonhypotensive pGC-A activator/designer natriuretic peptide, CRRL269, in a short-term, large animal model of ischemia-induced AKI and also investigated the potential of uCNP (urinary C-type natriuretic peptide) as a biomarker for AKI. Methods and Results: We first showed that CRRL269 stimulated cGMP generation, suppressed plasma angiotensin II, and reduced cardiac filling pressures without lowering blood pressure in the AKI canine model. We also demonstrated that CRRL269 preserved glomerular filtration rate, increased renal blood flow, and promoted diuresis and natriuresis. Further, CRRL269 reduced kidney injury and apoptosis as evidenced by ex vivo histology and tissue apoptosis analysis. We also showed, compared with native pGC-A activators, that CRRL269 is a more potent inhibitor of apoptosis in renal cells and induced less decreases in intracellular Ca 2+ concentration in vascular smooth muscle cells. The renal antiapoptotic effects were at least mediated by cGMP/PKG pathway. Further, CRRL269 inhibited proapoptotic genes expression using a polymerase chain reaction gene array. Additionally, we demonstrated that AKI increased uCNP levels. Conclusions: Our study supports developing CRRL269 as a novel renocardiac protective agent for AKI treatment.

Abstract Background and study aims Precise staging in T1 esophageal adenocarcinoma (EAC) is critical in determining candidacy for curative endoscopic resection. High-frequency endoscopic ultrasound (EUS) has demonstrated suboptimal accuracy in T1 EAC staging due to insufficient spatial resolution. Volumetric laser endomicroscopy (VLE) allows for high-resolution wide-field visualization of the esophageal microstructure. We aimed to investigate the role of VLE in staging T1 EAC. Patients and methods Patients undergoing endoscopic mucosal resection (EMR) were prospectively enrolled and only T1 EAC cases were included. EMR specimens were imaged using second-generation VLE immediately after resection. VLE images were analyzed for signal intensity by depth and signal attenuation (dB/mm) in both cross-sectional and en-face orientation. A decision tree model was constructed to combine measured VLE parameters and delineate diagnostic thresholds. Results Thirty EMR scans were obtained – 15 T1a specimens from 9 patients and 15 T1b specimens from 11 patients. T1b specimen VLE scans exhibited higher signal intensity (P < 0.0001) and higher signal attenuation compared to T1a specimens (P = 0.03). A combination of signal attenuation and signal intensity at 150 µm depth yielded optimal diagnostic thresholds and an area under the curve (AUC) of 0.77. VLE signal attenuation was significantly associated with grade of differentiation, irrespective of EAC stage. Conclusions VLE signal intensity and signal attenuation are quantitatively distinct in T1a and T1b EAC and associated with grade of differentiation. This is the first study examining the role of VLE for staging of T1 EAC and demonstrates promising diagnostic performance. With further in vivo validation, VLE may serve a role in staging superficial EAC.

Despite optimal current therapies, cardiovascular disease remains the leading cause for death worldwide. Importantly, advances in peptide engineering have accelerated the development of innovative therapeutics for diverse human disease states. Additionally, the advancement of bispecific therapeutics targeting >1 signaling pathway represents a highly innovative strategy for the treatment of cardiovascular disease. We, therefore, engineered a novel, designer peptide, which simultaneously targets the pGC-A (particulate guanylyl cyclase A) receptor and the MasR (Mas receptor), potentially representing an attractive cardiorenoprotective therapeutic for cardiovascular disease. We engineered a novel, bispecific receptor activator, NPA7, that represents the fusion of a 22-amino acid sequence of BNP (B-type natriuretic peptide; an endogenous ligand of pGC-A) with Ang 1–7 (angiotensin 1–7)—the 7-amino acid endogenous activator of MasR. We assessed NPA7’s dual receptor activating actions in vitro (second messenger production and receptor interaction). Further, we performed an intravenous peptide infusion comparison study in normal canines to study its biological actions in vivo, including in the presence of an MasR antagonist. Our in vivo and in vitro studies demonstrate the successful synthesis of NPA7 as a bispecific receptor activator targeting pGC-A and MasR. In normal canines, NPA7 possesses enhanced natriuretic, diuretic, systemic, and renal vasorelaxing and cardiac unloading properties. Importantly, NPA7’s actions are superior to that of the individual native pGC-A or MasR ligands. These studies advance NPA7 as a novel, bispecific designer peptide with potential cardiorenal therapeutic benefit for the treatment of cardiovascular disease, such as hypertension and heart failure.

Objective Surveillance interval protocols after complete remission of intestinal metaplasia (CRIM) post radiofrequency ablation (RFA) in Barrett’s oesophagus (BE) are currently empiric and not based on substantial evidence. We aimed to assess the timeline, location and patterns of recurrence following CRIM to inform these guidelines. Design Data on patients undergoing RFA for BE were obtained from prospectively maintained databases of five (three USA and two UK) tertiary referral centres. RFA was performed until CRIM was confirmed on two consecutive endoscopies. Results 594 patients achieved CRIM as of 1 May 2017. 151 subjects developed recurrent BE over a median (IQR) follow-up of 2.8 (1.4–4.4) years. There was 19% cumulative recurrence risk of any BE within 2 years and an additional 49% risk over the next 8.6 years. There was no evidence of a clinically meaningful change in the recurrence hazard rate of any BE, dysplastic BE or high-grade dysplasia/cancer over the duration of follow-up, with an estimated 2% (95% CI −7% to 12%) change in recurrence rate of any BE in a doubling of follow-up time. 74% of BE recurrences developed at the gastro-oesophageal junction (GOJ) (24.1% were dysplastic) and 26% in the tubular oesophagus. The yield of random biopsies from the tubular oesophagus, in the absence of visible lesions, was 1% (BE) and 0.2% (dysplasia). Conclusions BE recurrence risk following CRIM remained constant over time, suggesting that lengthening of follow-up intervals, at least in the first 5 years after CRIM, may not be advisable. Sampling the GOJ is critical to detecting recurrence. The requirement for random biopsies of the neosquamous epithelium in the absence of visible lesions may need to be re-evaluated.