Adherence to National Comprehensive Cancer Network ALK Testing Guidelines for Patients with Advanced Non-Small Cell Lung Cancer in U.S. Community Medical Centers.

BACKGROUND: National Comprehensive Cancer Network (NCCN) guidelines recommend biomarker testing as the first step in the management of patients with advanced non-small cell lung cancer (aNSCLC). We assessed anaplastic lymphoma kinase (ALK) testing rates and factors related to underuse in community medical systems between 2012 and 2019 to understand guideline adoption. METHODS: A retrospective observational study using a nationwide electronic health record (EHR)-derived deidentified database was conducted. Patients with aNSCLC diagnosed in community medical centers from January 2012 to May 2019 were included to describe the ALK testing trend. This cohort was further restricted to patients diagnosed after 2015 to understand factors associated with testing underuse using mixed-effects multivariable logistic regression models. RESULTS: Trends for increased ALK testing rates by year were observed in both NCCN guideline-eligible patients (59.5% in 2012 to 84.1% in 2019) and -ineligible patients (15.6% to 50.8%) in a cohort of 41,728 patients. Histology type and smoking status had the greatest impact on test use. Compared with patients with nonsquamous histology and no smoking history, patients with squamous histology and no smoking history (adjusted odds ratio [aOR], 7.6; 95% confidence interval [CI], 5.6-10.4), NSCLC histology not otherwise specified (NOS) with smoking history (aOR, 3.4; 95% CI, 2.8-4.2); NSCLC NOS/nonsmoker (aOR, 1.8; 95% CI, 1.1-3.2), and nonsquamous/smoker (aOR, 1.5; 95% CI, 1.3-1.7) were less likely to be tested. Factors related to underuse also included Eastern Cooperative Oncology Group performance status, stage at initial diagnosis, and demographics. CONCLUSION: This analysis of real-world data shows increasing test use by year; however, one fifth of patients eligible for ALK testing still remain untested and potentially missing therapeutic options. IMPLICATIONS FOR PRACTICE: Advancement in treatment of lung cancer is accompanied by an increasing number of tests that should be run to determine potential therapy options for each patient. This study assessed adoption of testing recommendations for anaplastic lymphoma kinase rearrangements in a national database. Although test use increased over the time period studied (2012-2019), there is still room for improvement. Efforts are needed to increase test use in undertested groups, thus enabling eligible patients to benefit from novel lung cancer therapies.

Tracing the Evolutionary History of the CAP Superfamily of Proteins Using Amino Acid Sequence Homology and Conservation of Splice Sites.

Proteins of the CAP superfamily play numerous roles in reproduction, innate immune responses, cancer biology, and venom toxicology. Here we document the breadth of the CAP (Cysteine-RIch Secretory Protein (CRISP), Antigen 5, and Pathogenesis-Related) protein superfamily and trace the major events in its evolution using amino acid sequence homology and the positions of exon/intron borders within their genes. Seldom acknowledged in the literature, we find that many of the CAP subfamilies present in mammals, where they were originally characterized, have distinct homologues in the invertebrate phyla. Early eukaryotic CAP genes contained only one exon inherited from prokaryotic predecessors and as evolution progressed an increasing number of introns were inserted, reaching 2-5 in the invertebrate world and 5-15 in the vertebrate world. Focusing on the CRISP subfamily, we propose that these proteins evolved in three major steps: (1) origination of the CAP/PR/SCP domain in bacteria, (2) addition of a small Hinge domain to produce the two-domain SCP-like proteins found in roundworms and anthropoids, and (3) addition of an Ion Channel Regulatory domain, borrowed from invertebrate peptide toxins, to produce full length, three-domain CRISP proteins, first seen in insects and later to diversify into multiple subtypes in the vertebrate world.

Engineered nanoparticles induced brush border disruption in a human model of the intestinal epithelium.

Nanoparticles hold great promise in cell biology and medicine due to the inherent physico-chemical properties when these materials are synthesized on the nanoscale. Moreover, their small size, and the ability to functionalize the outer nanoparticle surface makes them an ideal vector suited to traverse a number of physical barriers in the human body. While nanoparticles hold great promise for applications in cell biology and medicine, their downfall is the toxicity that accompanies exposure to biological systems. This chapter focuses on exposure via the oral route since nanomaterials are being engineered to act as carriers for drugs, contrast agents for specialized imaging techniques, as well as ingested pigments approved by regulatory agencies for human food products. After these nanomaterials are ingested they have the potential to interact with a number of biologically significant tissues, one of which is the epithelium of the small intestine. Within the small intestine exists enterocytes whose principal function is nutrient absorption. The absorptive process is aided by microvilli that act to increase the surface area of the epithelium. Dense arrays of microvilli, referred to as the brush border, have recently been shown to undergo disruption as a consequence of exposure to nanomaterials. This chapter aims to set the stage for detailed mechanistic studies at the cell biology level concerning this newly emerging nanotoxicity research paradigm, as the underlying structural characterization responsible for the existence of microvilli have been elucidated.

Adherence to guidelines-recommended diagnostic testing was associated with overall survival in patients with diffuse large B-cell lymphoma after rituximab-based treatment: an observational cohort study.

PURPOSE: This study assessed the impact of adherence to guidelines-recommended diagnostic testing on treatment selection and overall survival (OS) in patients with diffuse large B-cell lymphoma (DLBCL) initiated on rituximab-based first line of treatment (1-LOT). METHODS: This retrospective cohort study used a nationwide electronic health record-derived de-identified database, including diagnostic testing information on immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and karyotype analysis that were abstracted from pathology reports or clinical visit notes, where available. The study included patients above 18 years old who were diagnosed with DLBCL between January 2011 and December 2019 and initiated on rituximab-based 1-LOT. Patients were classified into 'non-adherence,' 'partial-adherence' and 'complete-adherence' groups according to the evidence/documentation of a confirmed known result for IHC and molecular profiling tests (FISH and karyotyping) on a selection of the markers prior to the initiation of 1-LOT. Logistic regression was used to evaluate associations of adherence to diagnostic testing with 1-LOT between R-CHOP and other rituximab-based regimens. Median OS after the start of rituximab-based 1-LOT was calculated using the Kaplan-Meier method. Multivariable-adjusted Cox proportional hazards regression was used to assess the risk of all-cause death after initiation of 1-LOT by the degrees of adherence to guidelines-recommended diagnostic testing. RESULTS: In total, 3730 patients with DLBCL who initiated on rituximab-based 1-LOT were included. No association was found between adherence to guidelines-recommended diagnostic testing and treatment selection of 1-LOT for R-CHOP versus other rituximab-based regimens. Patients with a higher degree of adherence to guidelines-recommended diagnostic testing survived longer (median OS at 5.1, 6.9 and 7.1 years for 'non-adherence,' 'partial-adherence' and 'complete-adherence' groups, respectively [log-rank p < 0.001]) and had a decreased mortality risk (multivariable-adjusted hazard ratio with 95% confidence intervals at 0.83 [0.70-0.99] for 'partial-adherence' and 0.77 [0.64-0.91] for 'complete-adherence' groups, respectively). CONCLUSION: Patients' adherence to guidelines-recommended diagnostic testing were associated with better survival benefit, reinforcing the need for adoption of diagnostic testing guidelines in routine clinical care.

Understanding Factors Associated With Anaplastic Lymphoma Kinase Testing Delays in Patients With Non-Small Cell Lung Cancer in a Large Real-World Oncology Database.

CONTEXT.­: With multiple therapeutic options available for patients with advanced non-small cell lung cancer, the timely ordering and return of results to determine therapy are of critical importance. OBJECTIVE.­: To assess factors impacting anaplastic lymphoma kinase (ALK) test ordering and time to result delivery. DESIGN.­: A retrospective study using a de-identified electronic health record database was performed. Postdiagnosis ALK tests (n = 14 657) were analyzed from 14 197 patients with advanced non-small cell lung cancer diagnosed between January 2015 and May 2019. Time from non-small cell lung cancer diagnosis to ALK sample receipt in the laboratory was a surrogate for test order time. Test ordering was considered delayed if order time was more than 20 days. Turnaround time from sample received to test result was calculated and considered delayed if more than 10 days. Multivariable logistic regression was used to assess factors associated with order time and turnaround time delays. RESULTS.­: Median ALK test order time was 15 days, and 36.4% (5342) of all 14 657 orders were delayed. Factors associated with delays were non-fluorescence in situ hybridization testing, send-out laboratories, testing prior to 2018, nonadenocarcinoma histology, and smoking history. Median turnaround time was 9 days, and 40.3% (5906) of all 14 657 test results were delayed. Non-fluorescence in situ hybridization testing, tissue sample, and orders combining ALK with other biomarkers were associated with delayed ALK result reporting. CONCLUSIONS.­: This study provides a snapshot of real-world ALK test ordering and reporting time in US community practices. Multiple factors impacted both test ordering time and return of results, revealing opportunities for improvement. It is imperative that patients eligible for targeted therapy be identified in a timely fashion.

Comorbidity Trajectories Associated With Alzheimer's Disease: A Matched Case-Control Study in a United States Claims Database.

Background: Trajectories of comorbidities among individuals at risk of Alzheimer's disease (AD) may differ from those aging without AD clinical syndrome. Therefore, characterizing the comorbidity burden and pattern associated with AD risk may facilitate earlier detection, enable timely intervention, and help slow the rate of cognitive and functional decline in AD. This case-control study was performed to compare the prevalence of comorbidities between AD cases and controls during the 5 years prior to diagnosis (or index date for controls); and to identify comorbidities with a differential time-dependent prevalence trajectory during the 5 years prior to AD diagnosis. Methods: Incident AD cases and individually matched controls were identified in a United States claims database between January 1, 2000 and December 31, 2016. AD status and comorbidities were defined based on the presence of diagnosis codes in administrative claims records. Generalized estimating equations were used to assess evidence of changes over time and between AD and controls. A principal component analysis and hierarchical clustering was performed to identify groups of AD-related comorbidities with respect to prevalence changes over time (or trajectory), and differences between AD and controls. Results: Data from 186,064 individuals in the IBM MarketScan Commercial Claims and Medicare Supplementary databases were analyzed (93,032 AD cases and 93,032 non-AD controls). In total, there were 177 comorbidities with a ≥ 5% prevalence. Five main clusters of comorbidities were identified. Clusters differed between AD cases and controls in the overall magnitude of association with AD, in their diverging time trajectories, and in comorbidity prevalence. Three clusters contained comorbidities that notably increased in frequency over time in AD cases but not in controls during the 5-year period before AD diagnosis. Comorbidities in these clusters were related to the early signs and/or symptoms of AD, psychiatric and mood disorders, cerebrovascular disease, history of hazard and injuries, and metabolic, cardiovascular, and respiratory complaints. Conclusion: We demonstrated a greater comorbidity burden among those who later developed AD vs. controls, and identified comorbidity clusters that could distinguish these two groups. Further investigation of comorbidity burden is warranted to facilitate early detection of individuals at risk of developing AD.

Anaplastic lymphoma kinase rearrangement prevalence in patients with advanced non-small cell lung cancer in the United States: retrospective real world data.

OBJECTIVE: This study assessed the prevalence of anaplastic lymphoma kinase (ALK) rearrangements in US oncology practices. MATERIALS AND METHODS: Using a nationwide real-world database, we included adults with advanced non-small cell lung cancer (aNSCLC, stage IIIB- IV) diagnosed January 2015 - May 2019, with documented ALK testing results and smoking status. Rearrangement prevalence was assessed overall and then stratified by patient characteristics. RESULTS: The cohort included 19,895 eligible patients with a mean age 68.5 years, majority ever-smokers (85.5%) and from community centers (92.2%). The overall ALK rearrangement prevalence was 2.6%. Positivity rate varied by histology and smoking status; it was the highest among non-smoking patients with non-squamous histology (9.3%). Differences in ALK status also varied by age and race, with young patients (18-39 years) having a higher prevalence (21.6%) vs. older patients (age ≥55 = 2.2%); Asian patients had a prevalence of 6.3%. Patients that were positive for other mutations or rearrangements had a lower ALK positivity rate (0.5%) and patients positive for PD-L1 had a rate of 3.0%. CONCLUSIONS: The likelihood of finding an ALK translocation was highest in younger patients and nonsmokers; however, age and smoking history were not discriminative enough to exclude testing based on clinical variables.