The value of comprehensive genomic sequencing to maximize the identification of clinically actionable alterations in advanced cancer patients: a case series.

PURPOSE: We present seven cases of advanced cancer patients who initially underwent tumor testing utilizing smaller, panel-based tests, followed by a variety of therapeutic treatments which ultimately resulted in progression of their disease. These cases demonstrate the value of utilizing WES/RNA seq and characterization following disease progression in these patients and the determination of clinically targetable alterations as well as acquired resistance mutations. MATERIALS AND METHODS: All patients are part of an IRB approved observational study. WES and RNA sequencing were performed, using GEM ExTra® on tumor and blood samples obtained during routine clinical care. To accurately determine somatic versus germline alterations the test was performed with paired normal testing from peripheral blood. RESULTS: The presented cases demonstrate the clinical impact of actionable findings uncovered using GEM ExTra® in patients with advanced disease who failed many rounds of treatment. Unique alterations were identified resulting in newly identified potential targeted therapies, mechanisms of resistance, and variation in the genomic characterization of the primary versus the metastatic tumor. CONCLUSIONS: Taken together our results demonstrate that GEM ExTra® maximizes detection of actionable mutations, thus allowing for appropriate treatment selection for patients harboring both common and rare genomic alterations.

Analytic validation and clinical utilization of the comprehensive genomic profiling test, GEM ExTra®.

We developed and analytically validated a comprehensive genomic profiling (CGP) assay, GEM ExTra, for patients with advanced solid tumors that uses Next Generation Sequencing (NGS) to characterize whole exomes employing a paired tumor-normal subtraction methodology. The assay detects single nucleotide variants (SNV), indels, focal copy number alterations (CNA), TERT promoter region, as well as tumor mutation burden (TMB) and microsatellite instability (MSI) status. Additionally, the assay incorporates whole transcriptome sequencing of the tumor sample that allows for the detection of gene fusions and select special transcripts, including AR-V7, EGFR vIII, EGFRvIV, and MET exon 14 skipping events. The assay has a mean target coverage of 180X for the normal (germline) and 400X for tumor DNA including enhanced probe design to facilitate the sequencing of difficult regions. Proprietary bioinformatics, paired with comprehensive clinical curation results in reporting that defines clinically actionable, FDA-approved, and clinical trial drug options for the management of the patient's cancer. GEM ExTra demonstrated analytic specificity (PPV) of > 99.9% and analytic sensitivity of 98.8%. Application of GEM ExTra to 1,435 patient samples revealed clinically actionable alterations in 83.9% of reports, including 31 (2.5%) where therapeutic recommendations were based on RNA fusion findings only.

Intermittent pneumatic compression is a cost-effective method of orthopedic postsurgical venous thromboembolism prophylaxis.

BACKGROUND: Venous thromboembolism (VTE) is a major complication after lower-limb arthroplasty that increases costs and reduces patient's quality of life. Using anticoagulants for 10-35 days following arthroplasty is the standard prophylaxis, but its cost-effectiveness after accounting for bleeding complications remains unproven. METHODS: A comprehensive, clinical model of VTE was created using the incidences, clinical effects (including bleeding), and costs of VTE and prophylaxis from randomized controlled trials, meta-analyses, and large observational studies. Over 50 years, the total health care costs and clinical impact of three prophylaxis strategies, that are as follows, were compared: low-molecular-weight heparin (LMWH) alone, intermittent pneumatic compression (IPC), and IPC with LMWH (IPC+LMWH). The cost per VTE event that was avoided and cost per quality-adjusted life year (QALY) gained in both the US and Australian health care settings were calculated. RESULTS: For every 2,000 patients, the expected number of VTE and major bleeding events with LMWH were 151 and 6 in the USA and 160 and 46 in Australia, resulting in a mean of 11.3 and 9.1 QALYs per patient, respectively. IPC reduced the expected VTE events by 11 and 8 in the USA and Australia, respectively, compared to using LMWH alone. IPC reduced major bleeding events compared to LMWH, preventing 1 event in the US and 7 in Australia. IPC+LMWH only reduced VTE events. Neither intervention substantially impacted QALYs but both increased QALYs versus LMWH. IPC was cost-effective followed by IPC+LMWH. CONCLUSION: IPC and IPC+LMWH are cost-effective versus LMWH after lower-limb arthroplasty in the USA and Australia. The choice between IPC and IPC+LMWH depends on expected bleeding risks.

Hospital Inpatient Admissions With Dehydration and/or Malnutrition in Medicare Beneficiaries Receiving Enteral Nutrition: A Cohort Study.

BACKGROUND: Enteral nutrition (EN) supports many older and disabled Americans. This study describes the frequency and cost of acute care hospitalization with dehydration and/or malnutrition of Medicare beneficiaries receiving EN, focusing on those receiving home EN. METHODS: Medicare 5% Standard Analytic Files were used to determine Medicare spending for EN supplies and the proportion and cost of beneficiaries receiving EN, specifically home EN, admitted to the hospital with dehydration and/or malnutrition. RESULTS: In 2013, Medicare paid $370,549,760 to provide EN supplies for 125,440 beneficiaries, 55% of whom were also eligible for Medicaid. Acute care hospitalization with dehydration and/or malnutrition occurred in 43,180 beneficiaries receiving EN. The most common principal diagnoses were septicemia (21%), aspiration pneumonitis (9%), and pneumonia (5%). In beneficiaries receiving EN at home, >one-third (37%) were admitted with dehydration and/or malnutrition during a mean observation interval of 231 ± 187 days. Admitted patients were usually hospitalized more than once with dehydration and/or malnutrition (1.73 ± 1.30 admissions) costing $23,579 ± 24,966 per admitted patient, totaling >$129,685,622 during a mean observation interval of 276 ± 187 days. Mortality in the year following enterostomy tube placement was significantly higher for admitted compared with nonadmitted patients (40% vs 33%; P = .05). CONCLUSION: Acute care hospitalizations with dehydration and/or malnutrition in Medicare beneficiaries receiving EN were common and expensive. Additional strategies to reduce these, with particular focus on vulnerable populations such as Medicaid-eligible patients, are needed.