Policy implications of heterogeneous demand reactions to changes in cost-sharing: Patient-level evidence from Austria.

Cost-sharing is a prominent tool in many healthcare systems, both for raising revenue and steering patient behaviour. Although the effect of cost-sharing on demand for healthcare services has been heavily studied in the literature, researchers often apply a macro-perspective to these issues, opening the door for policy makers to the fallacy of assuming uniform demand reactions across a spectrum of different forms of treatments and diagnostic procedures. We use a simple classification system to categorize 11 such healthcare services along the dimensions of urgency and price to estimate patients' (anticipatory) demand reactions to a reduction in the co-insurance rate by a sickness fund in the Austrian social health insurance system. We use a two-stage study design combining matching and two-way fixed effects difference-in-differences estimation. Our results highlight how an overall joint estimate of an average increase in healthcare service utilization (0.8%) across all healthcare services can be driven by healthcare services that are deferrable (+1%), comparatively costly (+1.4%) or both (+1.6%) and for which patients also postponed their consumption until after the cost-sharing reduction. In contrast, we do not find a clear demand reaction for inexpensive or urgent services. The detailed analysis of the demand reaction for each individual healthcare service further illustrates their heterogeneity. We show that even comparatively minor changes to the costs borne by patients may already evoke tangible (anticipatory) demand reactions. Our findings help policy makers better understand the implications of heterogeneous demand reactions across healthcare services for using cost-sharing as a policy tool.

Equal in ashes? Exploring socioeconomic inequalities in lifespan based on obituary data in Austria.

Understanding the emergence of and changes in socioeconomic inequalities in lifespan requires reliable, longitudinal data. In the absence of administrative data, published obituaries may be one such alternative source. With the validity of drawing relevant data from obituaries not yet established in population health research, this study addresses this gap by estimating socioeconomic inequalities in lifespan in Vorarlberg, Austria. Data for all individuals (n = 1490) with obituaries published (July to December 2022) in a regional newspaper (market share: 56%) were extracted, including different markers of the deceased's socioeconomic status. Linear regression analyses showed that, on average, individuals with medium-sized obituaries lived 6.02 years (95% CI: 4.19, 7.85) and individuals with the largest obituaries 12.04 years (95% CI: 7.04, 17.04) longer than individuals with small obituaries while blue-collar workers lived 10.50 years (95% CI: -14.51, -6.49) shorter than individuals with no occupation (reported). This socioeconomic gradient is in line with findings based on national data sources, and comparisons with official regional data are promising regarding data representativeness and completeness. With obituary size reflecting different costs (€210-€1626) and thus being a novel marker for financial ability, obituaries could also be a useful, innovative data source internationally for historical analyses or "nowcasting" health inequalities.

Exploring the effectiveness of demand-side retail pharmaceutical expenditure reforms : Cross-country evidence from weighted-average least squares estimation.

Increasing expenditures on retail pharmaceuticals bring a critical challenge to the financial stability of healthcare systems worldwide. Policy makers have reacted by introducing a range of measures to control the growth of public pharmaceutical expenditure (PPE). Using panel data on European and non-European OECD member countries from 1990 to 2015, we evaluate the effectiveness of six types of demand-side expenditure control measures including physician-level behaviour measures, system-level price-control measures and substitution measures, alongside a proxy for cost-sharing and add a new dimension to the existing empirical evidence hitherto based on national-level and meta-studies. We use the weighted-average least squares regression framework adapted for estimation with panel-corrected standard errors. Our empirical analysis suggests that direct patient cost-sharing and some-but not all-demand-side measures successfully dampened PPE growth in the past. Cost-sharing schemes stand out as a powerful mechanism to curb PPE growth, but bear a high risk of adverse effects. Other demand-side measures are more limited in effect, though may be more equitable. Due to limitations inherent in the study approach and the data, the results are only explorative.

A novel set of Austrian reference unit costs for comprehensive societal perspectives consistent with latest European costing methods for economic evaluations.

Decision making in public health often happens against the background of scarce resources. The systematic use of economic evaluations can be a main enabler in the alignment of public health goals with budgetary constraints. However, the lack of standardized methodology in terms of costing method and perspective are a critical barrier to the implementation of economic evaluations and the international comparability of results. We present a novel set of 22 reference unit costs (RUCs) optimized for cross-sectoral economic evaluations in Austria suitable for international comparability calculated using the standardized PECUNIA RUC Template. The common framework for costing and reporting, as well as the easy availability of the RUCs will reduce the burden on researchers and policy makers in future economic evaluations. The higher quality, accuracy, transparency and availability of economic evidence for policy design will help to improve the efficiency of public health-relevant healthcare decisions and make it easier for policy makers to bring funding arrangements and decision making across multiple sectors in line with Health-in-All-Policies goals.

In Search for Comparability: The PECUNIA Reference Unit Costs for Health and Social Care Services in Europe.

Improving the efficiency of mental healthcare service delivery by learning from international best-practice examples requires valid data, including robust unit costs, which currently often lack cross-country comparability. The European ProgrammE in Costing, resource use measurement and outcome valuation for Use in multi-sectoral National and International health economic evaluAtions (PECUNIA) aimed to harmonize the international unit cost development. This article presents the methodology and set of 36 externally validated, standardized reference unit costs (RUCs) for five health and social care services (general practitioner, dentist, help-line, day-care center, nursing home) in Austria, England, Germany, Hungary, The Netherlands, and Spain based on unambiguous service definitions using the extended DESDE PECUNIA coding framework. The resulting PECUNIA RUCs are largely comparable across countries, with any causes for deviations (e.g., country-specific scope of services) transparently documented. Even under standardized methods, notable limitations due to data-driven divergences in key costing parameters remain. Increased cross-country comparability by adopting a uniform methodology and definitions can advance the quality of evidence-based policy guidance derived from health economic evaluations. The PECUNIA RUCs are available free of charge and aim to significantly improve the quality and feasibility of future economic evaluations and their transferability across mental health systems.

Hydrophilic implants generated using a low-cost dielectric barrier discharge plasma device at the time of placement exhibit increased osseointegration in an animal pre-clinical study: An effect that is sex-dependent.

OBJECTIVES: Increased wettability of titanium and titanium alloy surfaces due to processing and storage methods increases osteoprogenitor cell differentiation and osseointegration compared to microroughness alone. Implants that are exposed to air have a hydrophobic surface due to adsorption of atmospheric hydrocarbons, which can limit overall implant success. Dielectric barrier discharge plasma (DBD) is one method to increase surface hydrophilicity. Although current DBD methods yield a hydrophilic surface, adsorbed hydrocarbons rapidly restore hydrophobicity. We demonstrated that application of DBD to implants previously packaged in a vacuum, generates a hydrophilic surface that supports osteoblastic differentiation in vitro and this can be done immediately prior to use. In the present study, we tested the hypothesis that DBD treatment to alter surface wettability at the time of implant placement will improve osseointegration in vivo. MATERIALS AND METHODS: Twenty male and sixteen female rabbits were used in a preclinical trans-axial femur model of osseointegration. Control and DBD treatment implants were inserted randomized per hind limb in each rabbit (1 implant/hind-limb). At 6 weeks post-surgery, bone-to-implant contact, adjacent bone volume, and torque to failure were assessed by micro-CT, calcified histology, and mechanical testing. RESULTS: DBD plasma treatment of vacuum-sealed implants increased surface wettability and did not change surface chemistry or roughness. Peak torque and torsional energy, and bone-to-implant contact increased with DBD treatment in males. In contrast, female rabbits showed increased osseointegration equal to DBD treated male implants regardless of DBD plasma treatment. CONCLUSION: DBD treatment is an effective method to enhance osseointegration by increasing surface wettability; however, this response is sex dependent. In healthy female patients, DBD treatment may not be necessary but in older patients or patients with compromised bone, this treatment could be an effective measure to ensure implant success.

The costs of bipolar disorder in the United Kingdom.

OBJECTIVES: To estimate the individual cost and population-level economic burden of Bipolar Disorder (BD), and explore the impact of clinical and sociodemographic factors on costs in the United Kingdom. METHODS: Annual UK health care, social care and societal cost data were collected from a prospective cohort of 91 BD patients using digital monitoring of symptoms. Costs (in £) were calculated for the year of resource use collection (2010-2011) and main results inflated to year 2018-2019. A Generalized Estimating Equation framework was used to investigate individual factors influencing costs. An economic burden estimate was derived by multiplying the mean annual cost per patient with literature-based population prevalence. RESULTS: The average annual cost of BD per patient was £12,617 (SE = ±£1085) or £14,938 (SE = ±£1281) at 2018-2019 prices with 68% of the total costs attributed to lost productivity and informal care, 31% to health care costs, 1% to private out-of-pocket expenses, and 0.5% to social care costs. A unit increase in average levels of depressive or manic symptoms were associated with 7% and 11% higher societal costs, respectively. The estimated annual prevalence of BD in the United Kingdom was 0.8% resulting in a population-level economic burden estimate of £5.1 billion for 2010-2011 or £6.43 billion for 2018-2019. CONCLUSIONS: BD is a disease of substantial costs in the United Kingdom with the majority of the economic burden falling outside the health care system in the form of productivity losses and informal care. These costs highly correlate with patient outcomes highlighting further needs for improved treatment efforts into functionality.

Regional medical practice variation in high-cost healthcare services : Evidence from diagnostic imaging in Austria.

Magnetic resonance imaging (MRI) is a popular yet cost-intensive diagnostic measure whose strengths compared to other medical imaging technologies have led to increased application. But the benefits of aggressive testing are doubtful. The comparatively high MRI usage in Austria in combination with substantial regional variation has hence become a concern for its policy makers. We use a set of routine healthcare data on outpatient MRI service consumption of Austrian patients between Q3-2015 and Q2-2016 on the district level to investigate the extent of medical practice variation in a two-step statistical analysis combining multivariate regression models and Blinder-Oaxaca decomposition. District-level MRI exam rates per 1.000 inhabitants range from 52.38 to 128.69. Controlling for a set of regional characteristics in a multivariate regression model, we identify payer autonomy in regulating access to MRI scans as the biggest contributor to regional variation. Nevertheless, the statistical decomposition highlights that more than 70% of the regional variation remains unexplained by differences between the observable district characteristics. In the absence of epidemiological explanations, the substantial regional medical practice variation calls the efficiency of resource deployment into question.

Insurance Status as a Predictor of Treatment in Human Papillomavirus Positive Oropharyngeal Cancer.

OBJECTIVES: The link between human papillomavirus (HPV) and oropharyngeal cancer (OPC) is well known. Locally advanced, HPV-positive OPC (HPV OPC) can be treated with either chemoradiation or primary surgery with or without adjuvant therapy. Head and neck cancer patients with government insurance or uninsured have been shown to have worse prognosis than similar patients with private insurance. In this study, we aimed to determine if insurance status would predict treatment modality in patients with HPV OPC. STUDY DESIGN: A retrospective analysis using the National Cancer Database (NCDB). METHODS: The National Cancer Database was used to identify patients with HPV OPC who underwent primary surgery or primary chemoradiation from 2010-2015. Insurance status was categorized as government, private, or no insurance. The relationship between insurance status and treatment was investigated using Chi square and multivariate regression models. Kaplan-Meier analyses were performed comparing overall survival (OS) by insurance status. RESULTS: There were 10,606 patients were included. There was a statistically significant correlation between insurance status and primary treatment modality for HPV OPC (P < .001). Patients with government insurance were 19.3% less likely to undergo surgery and uninsured patients were 36.9% less likely to undergo primary surgery when compared to those with private insurance (P < .001), even after correcting for TNM stage in multivariate analysis. There was an improved 5-year OS for patients with private insurance (86.6%) versus both government insurance (68.4%) and no insurance (69.9%) (P < .001). CONCLUSIONS: Patients with private insurance are more likely to undergo primary surgery in HPV OPC and have improved overall survival. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:776-781, 2021.

A National Evaluation of Food Insecurity in a Head and Neck Cancer Population.

OBJECTIVES/HYPOTHESIS: To determine the food security status of patients with a history of head and neck cancer and compare to other types of cancer. STUDY DEIGN: A retrospective analysis using the National Health Interview Series. METHODS: The National Health Interview Series (NHIS) for the calendar years 2014 to 18 was used to elicit food security status (secure, marginally secure/not secure) among adult patients with a history of throat/pharynx head and neck cancer (pHNC), thyroid cancer, and colon cancer. The relationship between food security and the primary site was compared and subanalyses were performed according to sex, race, and ethnicity. RESULTS: The study population included 199.0 thousand patients with pHNC, with 17.7% (95% confidence interval, 10.5%-28.1%) of pHNC patients reporting their food security status as marginally secure or not secure. Food insecurity was significantly higher among pHNC patients when compared to thyroid cancer (insecurity 10.7%, [7.7%-14.7%]) and colon cancer patients (10.1%, [7.8%-13.2%]). Among pHNC patients, there was no significant difference in rates of food insecurity when stratified by gender, race, or ethnicity. However, black individuals were more likely to have food insecurity with a history of thyroid or colon cancer (P < .042) and Hispanics were more likely to have food insecurity with a history of thyroid cancer (P = .005). CONCLUSIONS: Food insecurity disproportionally affects patients with a history of pHNC, though there is less demographic variability when compared to other cancer primary sites. Food security assessments should be part of the tailored approach to survivorship management in head and neck cancer. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1539-E1542, 2021.

Access to Allied Health Care Services in Canadian Interdisciplinary Complex Nerve Injury Programs.

Nerve transfer surgery for patients with nerve and spinal cord injuries can result in dramatic functional improvements. As a result, interdisciplinary complex nerve injury programs (CNIPs) have been established in many Canadian centers, providing electrodiagnostic and surgical consultations in a single encounter. We sought to determine which allied health care services are included in Canadian CNIPs, at the 3rd Annual Canadian Peripheral Nerve Symposium. Twenty CNIPs responded to a brief survey and reported access as follows: occupational therapy = 60%, physiotherapy = 40%, social work = 20%, and mental health = 10%. Access to allied health services is variable in CNIPs across Canada, possibly resulting in heterogeneity in patient care.

Determinants of soft budget constraints: How public debt affects hospital performance in Austria.

Soft budget constraints (SBCs) undermine reforms to increase hospital service efficiency when hospital management can count on being bailed out by (subnational) governments in case of deficits. Using cost accounting data on publicly financed, non-profit hospitals in Austria from 2002 to 2015, we analyse the association between SBCs and hospital efficiency change in a setting with negligible risk of hospital closure in a two-stage study design based on bias-corrected non-radial input-oriented data envelopment analysis and ordinary least squares regression. We find that the European debt crisis altered the pattern of hospital efficiency development: after the economic crisis, hospitals in low-debt states had a 1.1 percentage point lower annual efficiency change compared to hospitals in high-debt states. No such systematic difference is found before the economic crisis. The results suggest that sudden exogenous shocks to public finances can increase the budgetary pressure on publicly financed institutions, thereby counteracting a pre-existing SBC.

Prognostic Value of TERT Alterations, Mutational and Copy Number Alterations Burden in Urothelial Carcinoma.

Point mutations in the TERT gene promoter occur at high frequency in multiple cancers, including urothelial carcinoma (UC). However, the relationship between TERT promoter mutations and UC patient outcomes is unclear due to conflicting reports in the literature. In this study, we examined the association of TERT alterations, tumor mutational burden per megabase (Mb), and copy number alteration (CNA) burden with clinical parameters and their prognostic value in a cohort of 398 urothelial tumors. The majority of TERT mutations were located at two promoter region hotspots (chromosome 5, 1 295 228 C>T and 1 295 250 C>T). TERT alterations were more frequently present in bladder tumors than in upper tract tumors (73% vs 53%; p=0.001). ARID1A, PIK3CA, RB1, ERCC2, ERBB2, TSC1, CDKN1A, CDKN2A, CDKN2B, and PTPRD alterations showed significant co-occurrence with TERT alterations (all p<0.0025). TERT alterations and the mutational burden/Mb were independently associated with overall survival (hazard ratio[HR] 2.31, 95% confidence interval [CI] 1.46-3.65; p<0.001; and HR 0.96, 95% CI 0.93-0.99; p=0.002), disease-specific survival (HR 2.23, 95% CI 1.41-3.53; p<0.001; and HR 0.96, 95% CI 0.93-0.99; p=0.002), and metastasis-free survival (HR 1.63, 95% CI 1.05-2.53; p=0.029; and HR 0.98, 95% CI 0.96-1.00; p=0.063) in multivariate models. PATIENT SUMMARY: The majority of TERT gene mutations that we detected in urothelial carcinoma are located at two promoter hotspots. Urothelial tumors with TERT alterations had worse prognosis compared to tumors without TERT alterations, whereas tumors with a higher mutational burden had more favorable outcome compared to tumors with low mutational burden.

Updated report on incidence of infusion-site reactions associated with peripheral intravenous administration of fosaprepitant.

PURPOSE: Fosaprepitant (Emend®) is an antiemetic frequently used for the prevention of chemotherapy-induced nausea and vomiting. We previously documented an overall 28.7% incidence of infusion-site reactions in patients receiving fosaprepitant via peripheral venous access. These data resulted in a practice change within our institution; fosaprepitant is administered in more dilute concentrations over 30 min to prevent these adverse events. This retrospective study explored the impact of this practice change on the incidence of infusion-site reactions. METHODS: Medical records of patients with cancer receiving intravenous fosaprepitant through a peripheral intravenous line were reviewed. The primary objective of this study was to compare the incidence of infusion-site reactions before the practice change to the incidence after the practice change. Data collection included demographics, fosaprepitant infusion information, and grading of reactions. RESULTS: Between September 2013 and December of 2013, charts of 122 patients receiving intravenous fosaprepitant through a peripheral line at the The Arthur G. James Cancer Hospital at The Ohio State University were reviewed. We found a 5.74% incidence of infusion-site reactions which is significantly lower than the prechange incidence of 28.7% (p < 0.001). CONCLUSIONS: Infusion-site reactions were significantly reduced when fosaprepitant was diluted to 150 mg/250 ml and infused over 30 min. We recommend oncology pharmacists consider using the more dilute fosaprepitant preparation and 30 min infusion duration when administering via a peripheral intravenous line to improve patient tolerance.

Next-Generation Sequencing-Based Assessment of JAK2, PD-L1, and PD-L2 Copy Number Alterations at 9p24.1 in Breast Cancer: Potential Implications for Clinical Management.

Genomic amplification at 9p24.1, including the loci for JAK2, PD-L1, and PD-L2, has recently been described as a mechanism of resistance in postchemotherapy, triple-negative breast cancer. This genomic signature holds significant promise as a prognostic biomarker and has implications for targeted therapy with JAK2 inhibitors, as well as with immunotherapy. To guide future screening strategies, the frequency of these alterations was determined. A total of 5399 cases were included in the study. This encompassed 2890 institutional cases tested by the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets assay and 2509 cases from The Cancer Genome Atlas (TCGA). The combined incidence of 9p24.1 amplifications in both the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and TCGA cohorts was 1.0% (56/5399 cases) and showed a >10-fold higher incidence in triple-negative breast cancer (triple-negative: 5.1%; non-triple-negative: 0.5%). Tumor mutation burden and stromal tumor infiltrating lymphocytes, parameters used to assess response to immunotherapy, were not significantly higher for these cases. The significance of genomic losses at 9p24.1 is unclear, and further studies are needed. Herein, we studied the spectrum of copy number alterations in breast cancer cases within our institutional clinical sequencing cohort and those profiled by TCGA to determine the frequency of genomic alterations that may predict response or resistance to JAK2 inhibitors and/or immunotherapy.

Assessment of human papillomavirus awareness in association with head and neck cancer at a screening event.

OBJECTIVES/HYPOTHESIS: To assess the baseline awareness of human papillomavirus (HPV) infection as a cause of head and neck cancer (HNC) to design improved targeted screening and education efforts. STUDY DESIGN: Retrospective review of collected survey at a cancer screening event. METHODS: This was a screening event at three hospitals and one community center in Miami, Florida. Participants were recruited throughout the Greater Miami area. Descriptive statistics were used to summarize the demographic characteristics of those who were aware of HPV and those who were not. Adjusted odds ratios, odds ratios, and χ2 tests were used in statistical analysis. RESULTS: A total of 196 women and 112 men were screened across four sites, with 187 participants at hospital-based events and 124 participants at the community-based event. Forty percent of respondents had heard of HPV, and 28.0% identified HPV as a risk factor for HNC. Non-Hispanic and Hispanic respondents were 3.309 and 2.445 times, respectively, more likely than Haitian respondents to have heard of HPV. Women were 2.488 times more likely than men to be aware of HPV. College graduates were 2.268 times more likely than those with less than a college degree to be aware of HPV. Younger respondents were more likely to be aware of HPV. Of those who identified HPV as a risk factor for HNC, 95.4% also correctly identified smoking and 75.9% also correctly identified alcohol as risk factors. CONCLUSIONS: Disparities in HPV and HNC awareness were noted between gender, age, education level, and ethnicity. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:386-392, 2018.

Multi-Domain Assessment of Autonomic Function in Spinal Cord Injury Using a Modified Autonomic Reflex Screen.

The aim of this study was to characterize autonomic lesions in participants with spinal cord injury (SCI; n = 10) using an autonomic reflex screen, incorporating sudomotor, cardiovagal, and sympathetic adrenergic tests, as well as hemodynamic responses to head-up tilt (HUT). Hemodynamic responses were compared to healthy controls (n = 20) and previously published normative cutoffs in order better identify autonomic impairments. Sympathetic skin responses (SSRs), heart rate response to deep breathing (HRDB), and heart rate and beat-to-beat blood pressure responses to Valsalva maneuver (VM) and HUT were measured. SCI participants demonstrated impairment in at least one domain, with 7 of 10 demonstrating autonomic impairment across all domains. No single test was concordant with orthostatic hypotension on HUT, in all participants. Measures of cardiovagal function, including HRDB (SCI = 7.7 ± 3.8 beats/min vs. controls = 17.6 ± 8.1 beats/min) and Valsalva ratio (SCI = 1.53 ± 0.29 vs. controls = 1.85 ± 0.37), were significantly reduced in SCI participants, compared to controls (p < 0.05). These findings suggest that an autonomic reflex screen, which includes standardized testing protocol and normative data for comparison, is useful for determining the autonomic domains affected by the neurological injury in SCI. We also demonstrated significant cardiovagal impairment in SCI participants compared to controls, which warrants further investigation to determine whether cardiovagal dysfunction is associated with the negative cardiovascular outcomes, which are known to occur in SCI.

Preclinical Assessment of CD171-Directed CAR T-cell Adoptive Therapy for Childhood Neuroblastoma: CE7 Epitope Target Safety and Product Manufacturing Feasibility.

PURPOSE: The identification and vetting of cell surface tumor-restricted epitopes for chimeric antigen receptor (CAR)-redirected T-cell immunotherapy is the subject of intensive investigation. We have focused on CD171 (L1-CAM), an abundant cell surface molecule on neuroblastomas and, specifically, on the glycosylation-dependent tumor-specific epitope recognized by the CE7 monoclonal antibody. EXPERIMENTAL DESIGN: CD171 expression was assessed by IHC using CE7 mAb in tumor microarrays of primary, metastatic, and recurrent neuroblastoma, as well as human and rhesus macaque tissue arrays. The safety of targeting the CE7 epitope of CD171 with CE7-CAR T cells was evaluated in a preclinical rhesus macaque trial on the basis of CD171 homology and CE7 cross reactivity. The feasibility of generating bioactive CAR T cells from heavily pretreated pediatric patients with recurrent/refractory disease was assessed. RESULTS: CD171 is uniformly and abundantly expressed by neuroblastoma tumor specimens obtained at diagnoses and relapse independent of patient clinical risk group. CD171 expression in normal tissues is similar in humans and rhesus macaques. Infusion of up to 1 × 108/kg CE7-CAR+ CTLs in rhesus macaques revealed no signs of specific on-target off-tumor toxicity. Manufacturing of lentivirally transduced CD4+ and CD8+ CE7-CAR T-cell products under GMP was successful in 4 out of 5 consecutively enrolled neuroblastoma patients in a phase I study. All four CE7-CAR T-cell products demonstrated in vitro and in vivo antitumor activity. CONCLUSIONS: Our preclinical assessment of the CE7 epitope on CD171 supports its utility and safety as a CAR T-cell target for neuroblastoma immunotherapy. Clin Cancer Res; 23(2); 466-77. ©2016 AACR.

Reliable Pan-Cancer Microsatellite Instability Assessment by Using Targeted Next-Generation Sequencing Data.

PURPOSE: Microsatellite instability (MSI)/mismatch repair (MMR) status is increasingly important in the management of patients with cancer to predict response to immune checkpoint inhibitors. We determined MSI status from large-panel clinical targeted next-generation sequencing (NGS) data across various solid cancer types. METHODS: The MSI statuses of 12,288 advanced solid cancers consecutively sequenced with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets clinical NGS assay were inferred by using MSIsensor, a program that reports the percentage of unstable microsatellites as a score. Cutoff score determination and sensitivity/specificity were based on MSI polymerase chain reaction (PCR) and MMR immunohistochemistry. RESULTS: By using an MSIsensor score ≥ 10 to define MSI high (MSI-H), 83 (8%) of 996 colorectal cancers (CRCs) and 42 (16%) of 260 uterine endometrioid cancers (UECs) were MSI-H. Validation against MSI PCR and/or MMR immunohistochemistry performed for 138 (24 MSI-H, 114 microsatellite stable [MSS]) CRCs, and 40 (15 MSI-H, 25 MSS) UECs showed a concordance of 99.4%. MSIsensor also identified 68 MSI-H/MMR-deficient (MMR-D) non-CRC/UECs. Of 9,591 non-CRC/UEC tumors with MSS MSIsensor status, 456 (4.8%) had slightly elevated scores(≥3 and <10) of which 96.6% with available material were confirmed to be MSS by MSI PCR. MSI-H was also detected and confirmed in three non-CRC/UECs with low exonic mutation burden (< 20). MSIsensor correctly scored all 15 polymerase ε ultra-mutated cancers as negative for MSI. CONCLUSION: MSI status can be reliably inferred by MSIsensor from large-panel targeted NGS data. Concurrent MSI testing by NGS is resource efficient, is potentially more sensitive for MMR-D than MSI PCR, and allows identification of MSI-H across various cancers not typically screened, as highlighted by the finding that 35% (68 of 193) of all MSI-H tumors were non-CRC/ UEC.

Next-Generation Assessment of Human Epidermal Growth Factor Receptor 2 (ERBB2) Amplification Status: Clinical Validation in the Context of a Hybrid Capture-Based, Comprehensive Solid Tumor Genomic Profiling Assay.

Establishing ERBB2 [human epidermal growth factor receptor 2 (HER2)] amplification status in breast and gastric carcinomas is essential to treatment selection. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) constitute the current standard for assessment. With further advancements in genomic medicine, new clinically relevant biomarkers are rapidly emerging and options for targeted therapy are increasing in patients with advanced disease, driving the need for comprehensive molecular profiling. Next-generation sequencing (NGS) is an attractive approach for up-front comprehensive assessment, including ERBB2 status, but the concordance with traditional methods of HER2 assessment is not well established. The Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay, a hybrid capture-based NGS assay interrogating the coding regions of 410 cancer-related genes, was performed on manually macrodissected unstained sections from formalin-fixed, paraffin-embedded breast (n = 213) and gastroesophageal (n = 39) tumors submitted for clinical mutation profiling. ERBB2 status was assessed using a custom bioinformatics pipeline, and NGS results were compared to IHC and FISH. NGS ERBB2 amplification calls had an overall concordance of 98.4% (248/252) with the combined IHC/FISH results in this validation set. Discrepancies occurred in the context of low tumor content and HER2 heterogeneity. ERBB2 amplification status can be reliably determined by hybridization capture-based NGS methods, allowing efficient concurrent testing for other potentially actionable genomic alterations, particularly in limited material.