Citations

We believe this is the first documented case of a critically ill patient managed by telepharmacy in a remote, rural critical access hospital. We outline the case and the benefits of telepharmacy in under-resourced, rural critical access emergency departments.

LBA8501 Background: Plasma cfDNA genomic analysis is used widely for the care of advanced lung cancer, but its suitability for early stage lung cancer detection is not well established. CCGA (NCT02889978) is a prospective, multi-center, observational study launched for the development of a noninvasive assay for cancer detection. Methods: Blood was prospectively collected (N = 1627) from 749 controls (no cancer diagnosis) and 878 participants (pts) with newly-diagnosed untreated cancer in this preplanned substudy, including 127 pts with lung cancer. Three prototype sequencing assays were performed: paired cfDNA and white blood cell (WBC) targeted sequencing (507 genes, 60,000X) for single nucleotide variants/indels; paired cfDNA and WBC whole genome sequencing (WGS) for copy number variation (30X); and cfDNA whole genome bisulfite sequencing (WGBS) for methylation (30X). For each assay, a classification model using 10-fold cross-validation was developed for all pts with cancer, then evaluated in the pts with lung cancer; sensitivity was estimated at 95% specificity. Results: We evaluated pts with lung cancer (127) and a subset of controls (580) with similar ages (mean±SD yrs: 67±9, 60±13), 85% and 43% were ever-smokers, and 46% and 22% were men, respectively. Of 3055 nonsynonymous mutations detected across 122 evaluable pts with lung cancer, > 50% were detected in WBC consistent with clonal hematopoiesis (CH). Accounting for CH, sensitivity in 63 stage I-IIIA pts evaluable across all 3 assays was 48% (35-61, targeted), 54% (41-67, WGS), and 56% (43-68, WGBS); in 54 stage IIIB-IV pts it was 85% (73-93, targeted), 91% (80-97, WGS), and 93% (82-98, WGBS) . Similar sensitivities were observed across histological subtypes (adenocarcinoma, squamous cell, small cell). Comparison to tumor WGS and multi-assay classification will be reported. Conclusions: Early stage lung cancers are detectable in cfDNA using a genome-wide sequencing approach. For lung cancer detection using targeted assays, CH must be accounted for to minimize false positives. Assay optimization is ongoing to allow further clinical development in the intended use population. Clinical trial information: NCT02889978.

Oncogenic K-RAS mutations are found in virtually all pancreatic cancers, making K-RAS one of the most targeted oncoproteins for drug development in cancer therapies. Despite intense research efforts over the past three decades, oncogenic K-RAS has remained largely “undruggable”. Rather than targeting an upstream component of the RAS signaling pathway (i.e., EGFR/HER2) and/or the midstream effector kinases (i.e., RAF/MEK/ERK/PI3K/mTOR), we propose an alternative strategy to control oncogenic K-RAS signal by targeting its most downstream signaling module, Seven-In-Absentia Homolog (SIAH). SIAH E3 ligase controls the signal output of oncogenic K-RAS hyperactivation that drives unchecked cell proliferation, uncontrolled tumor growth, and rapid cancer cell dissemination in human pancreatic cancer. Therefore, SIAH is an ideal therapeutic target as it is an extraordinarily conserved downstream signaling gatekeeper indispensable for proper RAS signaling. Guided by molecular insights and core principles obtained from developmental and evolutionary biology, we propose an anti-SIAH-centered anti-K-RAS strategy as a logical and alternative anticancer strategy to dampen uncontrolled K-RAS hyperactivation and halt tumor growth and metastasis in pancreatic cancer. The clinical utility of developing SIAH as both a tumor-specific and therapy-responsive biomarker, as well as a viable anti-K-RAS drug target, is logically simple and conceptually innovative. SIAH clearly constitutes a major tumor vulnerability and K-RAS signaling bottleneck in pancreatic ductal adenocarcinoma (PDAC). Given the high degree of evolutionary conservation in the K-RAS/SIAH signaling pathway, an anti-SIAH-based anti-PDAC therapy will synergize with covalent K-RAS inhibitors and direct K-RAS targeted initiatives to control and eradicate pancreatic cancer in the future.

ABSTRACT Background: MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear. Objective: To study the role of MAPT variants in rapid eye movement sleep behavior disorder. Methods: Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and controls (n = 981); (B) dementia with Lewy bodies patients with rapid eye movement sleep behavior disorder (n = 271) and controls (n = 950). MAPT ‐associated variants and the entire coding sequence of MAPT were analyzed. Age‐, sex‐, and ethnicity‐adjusted analyses were performed to examine the association between MAPT , PD, and rapid eye movement sleep behavior disorder. Results: MAPT‐ H2 variants were associated with PD (odds ratios: 0.62‐0.65; P = 0.010‐0.019), but not with rapid eye movement sleep behavior disorder. In PD, the H1 haplotype odds ratio was 1.60 (95% confidence interval: 1.12‐2.28; P = 0.009), and the H2 odds ratio was 0.68 (95% confidence interval: 0.48‐0.96; P = 0.03). The H2/H1 haplotypes were not associated with rapid eye movement sleep behavior disorder. Conclusions: Our results confirm the protective effect of the MAPT ‐H2 haplotype in PD, and define its components. Furthermore, our results suggest that MAPT does not play a major role in rapid eye movement sleep behavior disorder, emphasizing different genetic background than in PD in this locus. © 2018 International Parkinson and Movement Disorder Society

Purpose: Anterior cervical discectomy and fusion has a low but well-established profile of adverse events. The goal of this study was to gauge surgeon opinion regarding the frequency and acceptability of these events. Methods: A 2-page survey was distributed to attendees at the 2015 Cervical Spine Research Society (CSRS) meeting. Respondents were asked to categorize 18 anterior cervical discectomy and fusion–related adverse events as either: “common and acceptable,” “uncommon and acceptable,” “uncommon and sometimes acceptable,” or “uncommon and unacceptable.” Results were compiled to generate the relative frequency of these responses for each complication. Responses for each complication event were also compared between respondents based on practice location (US vs. non-US), primary specialty (orthopedics vs. neurosurgery) and years in practice. Results: Of 150 surveys distributed, 115 responses were received (76.7% response rate), with the majority of respondents found to be US-based (71.3%) orthopedic surgeons (82.6%). Wrong level surgery, esophageal injury, retained drain, and spinal cord injury were considered by most to be unacceptable and uncommon complications. Dysphagia and adjacent segment disease occurred most often, but were deemed acceptable complications. Although surgeon experience and primary specialty had little impact on responses, practice location was found to significantly influence responses for 12 of 18 complications, with non-US surgeons found to categorize events more toward the uncommon and unacceptable end of the spectrum as compared with US surgeons. Conclusions: These results serve to aid communication and transparency within the field of spine surgery, and will help to inform future quality improvement and best practice initiatives.

Key Points There was no difference in overall survival after allogeneic transplant between patients aged 55-64 years and patients ≥65 years. Age alone should not be a determinant for allogeneic transplant eligibility among older non-Hodgkin lymphoma patients.

Although immune checkpoint inhibitors have resulted in durable clinical benefits in a subset of patients with advanced cancer, some patients who did not respond to initial anti–PD-1 therapy have been found to benefit from the addition of salvage chemotherapy. However, the mechanism responsible for the successful chemoimmunotherapy is not completely understood. Here we show that a subset of circulating CD8 + T cells expressing the chemokine receptor CX3CR1 are able to withstand the toxicity of chemotherapy and are increased in patients with metastatic melanoma who responded to chemoimmunotherapy (paclitaxel and carboplatin plus PD-1 blockade). These CX3CR1 + CD8 + T cells have effector memory phenotypes and the ability to efflux chemotherapy drugs via the ABCB1 transporter. In line with clinical observation, our preclinical models identified an optimal sequencing of chemoimmunotherapy that resulted in an increase of CX3CR1 + CD8 + T cells. Taken together, we found a subset of PD-1 therapy–responsive CD8 + T cells that were capable of withstanding chemotherapy and executing tumor rejection with their unique abilities of drug efflux (ABCB1), cytolytic activity (granzyme B and perforin), and migration to and retention (CX3CR1 and CD11a) at tumor sites. Future strategies to monitor and increase the frequency of CX3CR1 + CD8 + T cells may help to design effective chemoimmunotherapy to overcome cancer resistance to immune checkpoint blockade therapy.