Comparing Spinal Chloroprocaine to Hyperbaric and Isobaric Bupivacaine for Total Hip and Knee Arthroplasties: A Retrospective Study.

INTRODUCTION: Spinal anesthesia is commonly used for total knee and hip arthroplasties (TKA/THA). The rising popularity of ambulatory TKA and THAs require anesthetic techniques that provide rapid recovery of motor and sensory function while minimizing side effects like postoperative urinary retention. This single-center retrospective observational study compares the recovery profile of patients undergoing TKA and THA under chloroprocaine spinals compared to hyperbaric and isobaric bupivacaine spinals. METHODS: One hundred and twelve patients undergoing primary TKA and THA under spinal anesthesia at University of Florida Health were identified between September 1, 2019 and February 21, 2020. Their electronic medical records were reviewed. Patients were categorized based on the local anesthetic used in the spinal. Various demographic, intraoperative, and postoperative data were compiled and compared, including duration of surgery, time to physical therapy, time to post-anesthesia care unit (PACU) discharge, and time to spontaneous micturition. RESULTS: Time to spontaneous micturition and PACU discharge were significantly lower in the chloroprocaine spinal group compared to the hyperbaric bupivacaine group by 193 minutes and 42 minutes, respectively. Fewer patients receiving chloroprocaine spinals had their first physical therapy session limited by residual motor weakness compared to those in both bupivacaine groups. Additionally, mean duration of surgery was shorter in the chloroprocaine group compared to both bupivacaine groups (89 minutes compared to 111 minutes). Time to physical therapy completion was not different. All groups had <10% conversion to general anesthesia. CONCLUSION: Chloroprocaine spinals can be feasible options for TKAs and THAs with improved postoperative recovery profiles compared to bupivacaine spinals.

Health-Oriented Marketing on Alcoholic Drinks: An Online Audit and Comparison of Nutrition Content of Australian Products.

OBJECTIVE: Marketing, label design, and product innovation strategies are being used by the alcohol industry to position some products as "healthier choices." The aim of this study was to systematically document the content and prevalence of health-oriented marketing on alcohol products on the Australian market and to compare the online availability of nutrition information and the alcohol and nutrient content between products with and without such features. METHOD: Health-oriented marketing features on all beer, cider, and ready-to-drink (RTD) premixed drinks, and selected wines on the website of the largest liquor retailer in Australia were audited using a systematic coding protocol. Nutrition information was sought from manufacturer/brand websites. RESULTS: A total of 54% of beers, ciders, and RTDs featured health-oriented marketing, the most common forms being natural imagery or descriptors, or references to fruit ingredients. Twenty-one percent of audited wines featured health-oriented marketing. The prevalence of specific features varied by product category. Online availability of nutrition information for alcohol products was poor (12% of beer, cider, and RTDs). Products with health-oriented marketing were lower in energy and alcohol content than those without but were still classed as full-strength alcohol on average. CONCLUSIONS: Health-oriented marketing is prevalent on alcohol products sold in Australia. In the absence of universal and standardized health warning and energy content information on labels, permitted health-oriented marketing has the potential to mislead consumers about product healthiness or to detract from the perceived harm associated with alcohol consumption. Research to test this proposition is now needed to guide labeling policy reform.

Longitudinal therapy monitoring of ALK-positive lung cancer by combined copy number and targeted mutation profiling of cell-free DNA.

BACKGROUND: Targeted therapies (TKI) have improved the prognosis of ALK-rearranged lung cancer (ALK+ NSCLC), but clinical courses vary widely. Early identification and molecular characterisation of treatment failure have key importance for subsequent therapies. We performed copy number variation (CNV) profiling and targeted panel sequencing from cell-free DNA (cfDNA) to monitor ALK+ NSCLC. METHODS: 271 longitudinal plasma DNA samples from 73 patients with TKI-treated metastatic ALK+ NSCLC were analysed by capture-based targeted (average coverage 4,100x), and shallow whole genome sequencing (sWGS, 0.5x). Mutations were called using standard algorithms. CNVs were quantified using the trimmed median absolute deviation from copy number neutrality (t-MAD). FINDINGS: cfDNA mutations were identified in 58% of patients. They included several potentially actionable alterations, e.g. in the genes BRAF, ERBB2, and KIT. sWGS detected CNVs in 18% of samples, compared to 6% using targeted sequencing. Several of the CNVs included potentially druggable targets, such as regions harboring EGFR, ERBB2, and MET. Circulating tumour DNA (ctDNA) mutations and t-MAD scores increased during treatment, correlated with markers of higher molecular risk, such as the EML4-ALK variant 3 and/or TP53 mutations, and were associated with shorter patient survival. Importantly, t-MAD scores reflected the tumour remission status in serial samples similar to mutant ctDNA allele frequencies, and increased with disease progression in 79% (34/43) of cases, including those without detectable single nucleotide variant (SNV). INTERPRETATION: Combined copy number and targeted mutation profiling could improve monitoring of ALK+ NSCLC. Potential advantages include the identification of treatment failure, in particular for patients without detectable mutations, and broader detection of genomic changes acquired during therapy, especially in later treatment lines and in high-risk patients. FUNDING: This work was supported by the German Center for Lung Research (DZL), by the German Cancer Consortium (DKTK), by the Heidelberg Center for Personalized Oncology at the German Cancer Research Center (DKFZ-HIPO), and by Roche Sequencing Solutions (Pleasanton, CA, USA).

Serial liquid biopsies for detection of treatment failure and profiling of resistance mechanisms in KLC1-ALK-rearranged lung cancer.

Genetic rearrangements involving the anaplastic lymphoma kinase (ALK) gene confer sensitivity to ALK tyrosine kinase inhibitors (TKIs) and superior outcome in non-small-cell lung cancer (NSCLC). However, clinical courses vary widely, and recent studies suggest that molecular profiling of ALK+ NSCLC can provide additional predictors of therapy response that could assist further individualization of patient management. As repeated tissue biopsies often pose technical difficulties and significant procedural risk, analysis of tumor constituents circulating in the blood, including ctDNA and various proteins, is increasingly recognized as an alternative method of tumor sampling ("liquid biopsy"). Here, we report the case of a KLC1-ALK-rearranged NSCLC patient responding to crizotinib treatment and demonstrate how analysis of plasma and serum biomarkers can be used to identify the ALK fusion partner and monitor therapy over time. Results of ctDNA sequencing and copy-number alteration profiling as well as serum protein concentrations at various time points during therapy reflected the current remission status and could predict the subsequent clinical course. At the time of disease progression, we identified four distinct secondary mutations in the ALK gene in ctDNA potentially causing treatment failure, accompanied by rising levels of CEA and CYFRA 21-1. Moreover, several copy-number variations were detected at the end of the treatment, including an amplification of a region on Chromosome 12 encompassing the TP53 regulator MDM2 In summary, our findings illustrate the utility of noninvasive longitudinal molecular profiling for assessing remission status, exploring mechanisms of treatment failure, predicting subsequent clinical course, and dissecting dynamics of drug-resistant clones in ALK+ lung cancer.

Peripheral blood blast clearance is an independent prognostic factor for survival and response to acute myeloid leukemia induction chemotherapy.

In patients with acute myeloid leukemia (AML), rapid reduction of circulating blasts with induction chemotherapy may serve as an in vivo marker of chemosensitivity. We performed a retrospective analysis of 363 patients with untreated AML who received induction chemotherapy in order to determine the relationship between day of blast disappearance (DOBD) and complete remission (CR) rates, event-free survival (EFS), and overall survival (OS). DOBD ≤ 5 vs. >5 was identified as the most discriminating cutoff for OS. DOBD > 5 was observed in 35 patients (9.6%). The CR rate for patients with DOBD ≤ 5 vs. >5 was 74.0 and 28.6%, median EFS was 9.4 and 1.8 months, and median OS was 17.1 and 5.8 months, respectively (P < 0.001 for all). DOBD > 5 was independently associated with a lower CR rate and shorter EFS and OS (P < 0.001 for all). DOBD > 5 retained prognostic significance for EFS and OS when patients were stratified by cytogenetic risk group, de novo vs. secondary or therapy-related AML, European LeukemiaNet-based risk groups, and whether CR was achieved. We propose DOBD > 5 as a simple and early marker of disease resistance that identifies patients with poor prognosis who otherwise may not be identified with existing risk stratification systems. Am. J. Hematol. 91:1221-1226, 2016. © 2016 Wiley Periodicals, Inc.

In vitro assembly properties of mutant and chimeric intermediate filament proteins: insight into the function of sequences in the rod and end domains of IF.

The factors and mechanisms regulating assembly of intermediate filament (IF) proteins to produce filaments with their characteristic 10 nm diameter are not fully understood. All IF proteins contain a central rod domain flanked by variable head and tail domains. To elucidate the role that different domains of IF proteins play in filament assembly, we used negative staining and electron microscopy (EM) to study the in vitro assembly properties of purified bacterially expressed IF proteins, in which specific domains of the proteins were either mutated or swapped between a cytoplasmic (mouse neurofilament-light (NF-L) subunit) and nuclear intermediate filament protein (human lamin A). Our results indicate that filament formation is profoundly influenced by the composition of the assembly buffer. Wild type (wt) mouse NF-L formed 10 nm filaments in assembly buffer containing 175 mM NaCl, whereas a mutant deleted of 18 NH2-terminal amino acids failed to assemble under similar conditions. Instead, the mutant assembled efficiently in buffers containing CaCl2 > or = 6 mM forming filaments that were 10 times longer than those formed by wt NF-L, although their diameter was significantly smaller (6-7 nm). These results suggest that the 18 NH2-terminal sequence of NF-L might serve two functions, to inhibit filament elongation and to promote lateral association of NF-L subunits. We also demonstrate that lengthening of the NF-L rod domain, by inserting a 42 aa sequence unique to nuclear IF proteins, does not compromise filament assembly in any noticeable way. Our results suggests that the known inability of nuclear lamin proteins to assemble into 10 nm filaments in vitro cannot derive solely from their longer rod domain. Finally, we demonstrate that the head domain of lamin A can substitute for that of NF-L in filament assembly, whereas substitution of both the head and tail domains of lamins for those of NF-L compromises assembly. Therefore, the effect of lamin A "tail" domain alone, or the synergistic effect of lamin "head" and the "tail" domains together, interferes with assembly into 10-nm filaments.