Risk profiling of patients with relapsed/refractory diffuse large B-cell lymphoma by measuring circulating tumor DNA.

Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have heterogeneous outcomes; durable remissions are infrequently observed with standard approaches. Circulating tumor DNA (ctDNA) assessment is a sensitive, potentially prognostic tool in this setting. We assessed baseline ctDNA to identify patients with R/R DLBCL at high risk of relapse after receiving polatuzumab vedotin and bendamustine plus rituximab (BR) or BR alone. Patients were transplant ineligible and had received ≥1 prior line of therapy. The ctDNA assay, based on a customized panel of recurrently mutated genes in DLBCL, measured mutant molecules per mL (MMPM) at baseline and end of treatment (EOT). Endpoints included progression-free survival (PFS) and overall survival (OS) in subgroups stratified by baseline ctDNA and log-fold change in ctDNA at EOT vs baseline. In biomarker-evaluable patients (n = 33), baseline ctDNA level correlated with serum lactate dehydrogenase (LDH) concentration, number of prior therapies, stage, and International Prognostic Index (IPI). After adjusting for number of prior therapies ≥2, IPI score ≥3, and LDH above the upper limit of normal, high (greater than median) baseline ctDNA MMPM was independently prognostic for shorter PFS (adjusted hazard ratio [HR], 0.18 [95% CI, 0.05-0.65]) and OS (adjusted HR, 0.20 [95% CI, 0.06-0.68]). In 23 patients with baseline and EOT samples, a significantly greater decrease in ctDNA MMPM was observed in patients with complete response (CR) (n = 13) than those without CR (n = 10); P = .0025. Baseline ctDNA assessment may identify patients at high risk of progression and should be further evaluated as a monitoring tool in R/R DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT02257567.

Haloperidol undermining gastroparesis symptoms (HUGS) in the emergency department.

BACKGROUND: Gastroparesis associated nausea, vomiting & abdominal pain (GP N/V/AP) are common presentations to the emergency department (ED). Treatment is often limited to antiemetic, prokinetic, opioid, & nonopioid agents. Haloperidol (HP) has been shown to have analgesic & antiemetic properties. We sought to evaluate HP in the ED as an alternative treatment of GP N/V/AP. METHODS: Using an electronic medical record, 52 patients who presented to the ED w/GP N/V/AP secondary to diabetes mellitus and were treated w/HP were identified. Patients who received HP were compared to themselves w/the most recent previous encounter in which HP was not administered. ED length of stay (LOS), additional antiemetics/prokinetics administered, hospital LOS, and morphine equivalent doses of analgesia (ME) from each visit were recorded. Descriptive statistics, categorical (Chi Square Test or Z-Test for proportion) and continuous (Wilcoxon Signed Rank Test) comparisons were calculated. Statistical significance was considered for two tail p-values less than 0.05. RESULTS: A statistically significant reduction in ME (Median 6.75 [IQR 7.93] v 10.75 [IQR12]: p=0.001) and reduced admissions for GP (5/52 v 14/52: p=0.02) when HP was administered was observed. There were no statistically significant differences in ED or hospital LOS, and additional antiemetics administered between encounters in which HP was administered and not administered. No complications were identified in patients who received HP. CONCLUSIONS: The rate of admission and ME was found to be significantly reduced in patients with GP secondary to diabetes mellitus who received HP. HP may represent an appropriate, effective, and safe alternative to traditional analgesia and antiemetic therapy in the ED management of GP associated N/V/AP.

Ubiquitin-Proteasome System in Neurodegenerative Disorders.

Cellular proteostasis is a highly dynamic process and is primarily carried out by the degradation tools of ubiquitin-proteasome system (UPS). Abnormalities in UPS function result in the accumulation of damaged or misfolded proteins which can form intra- and extracellular aggregated proteinaceous deposits leading to cellular dysfunction and/or death. Deposition of abnormal protein aggregates and the cellular inability to clear them have been implicated in the pathogenesis of a number of neurodegenerative disorders such as Alzheimer's and Parkinson's. Contrary to the upregulation of proteasome function in oncogenesis and the use of proteasome inhibition as a therapeutic strategy, activation of proteasome function would serve therapeutic objectives of treatment of neurodegenerative diseases. This review describes the current understanding of the role of the proteasome in neurodegenerative disorders and potential utility of proteasomal modulation therein.

Liposomes modified with superhydrophilic polymer linked to a nonphospholipid anchor exhibit reduced complement activation and enhanced circulation.

We report the synthesis of an acyl-anchored superhydrophilic polymer (SHP) for external surface modification of liposome surface. N¹-(2-aminoethyl)-N4-hexadecyl-2-tetradecylsuccinamide conjugated with SHP (HDAS-SHP) was synthesized and used for modifying the liposome surface. Unlike polyethylene glycol (PEG)-phospholipids, which are commonly used for manufacturing stealth liposomes, HDAS-SHP is devoid of both PEG and phosphoryl groups and possesses a zwitterionic polymeric chain. Circulation persistence of the 99(m)Tc-labeled HDAS-SHP liposomes was documented by gamma camera imaging. After 24 h postinjection, approximately 30% of injected HDAS-SHP liposomes were present in blood as compared with only 4.5% of the plain liposomes. HDAS-SHP liposomes inhibited complement activation. They were found to be amenable to pH-gradient-based active loading of Adriamycin in a stable manner. At 37°C, HDAS-SHP liposomes provided better encapsulation efficiencies than the liposomes modified with DSPE-PEG2000. These results provide a strong basis for HDAS-SHP as a viable alternative to PEG-phospholipids for imparting stealth characteristics to drug delivery vehicles such as liposomes. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:114-123, 2015.

Clinical outcome of isolated locoregional recurrence in patients with breast cancer according to their primary local treatment.

INTRODUCTION: This study assessed the clinical outcome and prognostic factors in patients with breast cancer who presented with isolated locoregional recurrence (ILRR) as a first event. MATERIALS AND METHODS: Between 1970 and 2008, 2960 patients with pT1-2, N0-3, M0 primary invasive breast cancer had either breast-conserving therapy (BCT) using lumpectomy and radiation therapy (RT) (group A = 1849 patients) or mastectomy without RT (group B = 1111 patients). Out of groups A and B, 117 and 103 patients, respectively, developed ILRR as a first event. Those 220 patients served as the basis for this study. A multivariate analysis was performed to estimate the clinical outcome of both groups, taking into account clinically relevant variables for the primary tumor and ILRR. RESULTS: The median follow-up after ILRR was 83 months. The median disease-free interval (DFI) was 79 and 38 months for groups A and B, respectively. The overall survival (OS) for group A was 81% and 69% at 5 and 8 years, respectively. For group B, it was 61% and 46%, respectively. The distant metastasis-free survival (DMFS) for group A was 84% at 5 years and remained 84% at 8 years. The DMFS for group B was 60% at 5 years and 52% at 8 years. In multivariate analysis, initial local treatment (BCT vs. mastectomy without RT), pathologic T stage, locoregional recurrence site (local vs. regional), and DFI (≤ 4 years vs. > 4 years) were significant prognostic variables for both OS and DMFS. CONCLUSION: Patients with breast cancer who developed ILRR after BCT as their initial local treatment have better clinical outcome compared with those who had mastectomy without RT.