Multidimensional biomarker predicts disease control in response to immunotherapy in recurrent or metastatic head and neck squamous-cell carcinoma.

PURPOSE: Anti-PD-1 therapy provides clinical benefit in 40-50% of patients with relapsed and/or metastatic head and neck squamous cell carcinoma (RM-HNSCC). Selection of anti- PD-1 therapy is typically based on patient PD-L1 immunohistochemistry (IHC) which has low specificity for predicting disease control. Therefore, there is a critical need for a clinical biomarker that will predict clinical benefit to anti-PD-1 treatment with high specificity. METHODS: Clinical treatment and outcomes data for 103 RM-HNSCC patients were paired with RNA-sequencing data from formalin-fixed patient samples. Using logistic regression methods, we developed a novel biomarker classifier based on expression patterns in the tumor immune microenvironment to predict disease control with monotherapy PD-1 inhibitors (pembrolizumab and nivolumab). The performance of the biomarker was internally validated using out-of-bag methods. RESULTS: The biomarker significantly predicted disease control (65% in predicted non-progressors vs. 17% in predicted progressors, p < 0.001) and was significantly correlated with overall survival (OS; p = 0.004). In addition, the biomarker outperformed PD-L1 IHC across numerous metrics including sensitivity (0.79 vs 0.64, respectively; p = 0.005) and specificity (0.70 vs 0.61, respectively; p = 0.009). CONCLUSION: This novel assay uses tumor immune microenvironment expression data to predict disease control and OS with high sensitivity and specificity in patients with RM-HNSCC treated with anti-PD-1 monotherapy.

Validation of Immunotherapy Response Score as Predictive of Pan-solid Tumor Anti-PD-1/PD-L1 Benefit.

Immunotherapy response score (IRS) integrates tumor mutation burden (TMB) and quantitative expression biomarkers to predict anti-PD-1/PD-L1 [PD-(L)1] monotherapy benefit. Here, we evaluated IRS in additional cohorts. Patients from an observational trial (NCT03061305) treated with anti-PD-(L)1 monotherapy were included and assigned to IRS-High (-H) versus -Low (-L) groups. Associations with real-world progression-free survival (rwPFS) and overall survival (OS) were determined by Cox proportional hazards (CPH) modeling. Those with available PD-L1 IHC treated with anti-PD-(L)1 with or without chemotherapy were separately assessed. Patients treated with PD-(L)1 and/or chemotherapy (five relevant tumor types) were assigned to three IRS groups [IRS-L divided into IRS-Ultra-Low (-UL) and Intermediate-Low (-IL), and similarly assessed]. In the 352 patient anti-PD-(L)1 monotherapy validation cohort (31 tumor types), IRS-H versus IRS-L patients had significantly longer rwPFS and OS. IRS significantly improved CPH associations with rwPFS and OS beyond microsatellite instability (MSI)/TMB alone. In a 189 patient (10 tumor types) PD-L1 IHC comparison cohort, IRS, but not PD-L1 IHC nor TMB, was significantly associated with anti-PD-L1 rwPFS. In a 1,103-patient cohort (from five relevant tumor types), rwPFS did not significantly differ in IRS-UL patients treated with chemotherapy versus chemotherapy plus anti-PD-(L)1, nor in IRS-H patients treated with anti-PD-(L)1 versus anti-PD-(L)1 + chemotherapy. IRS associations were consistent across subgroups, including both Europeans and non-Europeans. These results confirm the utility of IRS utility for predicting pan-solid tumor PD-(L)1 monotherapy benefit beyond available biomarkers and demonstrate utility for informing on anti-PD-(L)1 and/or chemotherapy treatment. Significance: This study confirms the utility of the integrative IRS biomarker for predicting anti-PD-L1/PD-1 benefit. IRS significantly improved upon currently available biomarkers, including PD-L1 IHC, TMB, and MSI status. Additional utility for informing on chemotherapy, anti-PD-L1/PD-1, and anti-PD-L1/PD-1 plus chemotherapy treatments decisions is shown.

Development and validation of an integrative pan-solid tumor predictor of PD-1/PD-L1 blockade benefit.

BACKGROUND: Anti-PD-1 and PD-L1 (collectively PD-[L]1) therapies are approved for many advanced solid tumors. Biomarkers beyond PD-L1 immunohistochemistry, microsatellite instability, and tumor mutation burden (TMB) may improve benefit prediction. METHODS: Using treatment data and genomic and transcriptomic tumor tissue profiling from an observational trial (NCT03061305), we developed Immunotherapy Response Score (IRS), a pan-tumor predictive model of PD-(L)1 benefit. IRS real-world progression free survival (rwPFS) and overall survival (OS) prediction was validated in an independent cohort of trial patients. RESULTS: Here, by Cox modeling, we develop IRS-which combines TMB with CD274, PDCD1, ADAM12 and TOP2A quantitative expression-to predict pembrolizumab rwPFS (648 patients; 26 tumor types; IRS-High or -Low groups). In the 248 patient validation cohort (248 patients; 24 tumor types; non-pembrolizumab PD-[L]1 monotherapy treatment), median rwPFS and OS are significantly longer in IRS-High vs. IRS-Low patients (rwPFS adjusted hazard ratio [aHR] 0.52, p = 0.003; OS aHR 0.49, p = 0.005); TMB alone does not significantly predict PD-(L)1 rwPFS nor OS. In 146 patients treated with systemic therapy prior to pembrolizumab monotherapy, pembrolizumab rwPFS is only significantly longer than immediately preceding therapy rwPFS in IRS-High patients (interaction test p = 0.001). In propensity matched lung cancer patients treated with first-line pembrolizumab monotherapy or pembrolizumab+chemotherapy, monotherapy rwPFS is significantly shorter in IRS-Low patients, but is not significantly different in IRS-High patients. Across 24,463 molecularly-evaluable trial patients, 7.6% of patients outside of monotherapy PD-(L)1 approved tumor types are IRS-High/TMB-Low. CONCLUSIONS: The validated, predictive, pan-tumor IRS model can expand PD-(L)1 monotherapy benefit outside currently approved indications.

Therapies activating the immune system (checkpoint inhibitors) have revolutionized the treatment of patients with advanced cancer, however new molecular tests may better identify patients who could benefit. Using treatment data and clinical molecular test results, we report the development and validation of Immunotherapy Response Score (IRS) to predict checkpoint inhibitor benefit. Across patients with more than 20 advanced cancer types, IRS better predicted checkpoint inhibitor benefit than currently available tests. Data from >20,000 patients showed that IRS identifies ~8% of patients with advanced cancer who may dramatically benefit from checkpoint inhibitors but would not receive them today based on currently available tests. Our approach may help clinicians to decide which patients should receive checkpoint inhibitors to treat their disease.

Real-World Performance of a Comprehensive Genomic Profiling Test Optimized for Small Tumor Samples.

PURPOSE: Tissue-based comprehensive genomic profiling (CGP) is increasingly used for treatment selection in patients with advanced cancer; however, tissue availability may limit widespread implementation. Here, we established real-world CGP tissue availability and assessed CGP performance on consecutively received samples. MATERIALS AND METHODS: We conducted a post hoc, nonprespecified analysis of 32,048 consecutive tumor tissue samples received for StrataNGS, a multiplex polymerase chain reaction (PCR)-based comprehensive genomic profiling (PCR-CGP) test, as part of an ongoing observational trial (NCT03061305). Sample characteristics and PCR-CGP performance were assessed across all tested samples, including exception samples not meeting minimum input quality control (QC) requirements (< 20% tumor content [TC], < 2 mm2 tumor surface area [TSA], DNA or RNA yield < 1 ng/µL, or specimen age > 5 years). Tests reporting ≥ 1 prioritized alteration or meeting TC and sequencing QC were considered successful. For prostate carcinoma and lung adenocarcinoma, tests reporting ≥ 1 actionable or informative alteration or meeting TC and sequencing QC were considered actionable. RESULTS: Among 31,165 (97.2%) samples where PCR-CGP was attempted, 10.7% had < 20% TC and 59.2% were small (< 25 mm2 tumor surface area). Of 31,101 samples evaluable for input requirements, 8,089 (26.0%) were exceptions not meeting requirements. However, 94.2% of the 31,101 tested samples were successfully reported, including 80.5% of exception samples. Positive predictive value of PCR-CGP for ERBB2 amplification in exceptions and/or sequencing QC-failure breast cancer samples was 96.7%. Importantly, 84.0% of tested prostate carcinomas and 87.9% of lung adenocarcinomas yielded results informing treatment selection. CONCLUSION: Most real-world tissue samples from patients with advanced cancer desiring CGP are limited, requiring optimized CGP approaches to produce meaningful results. An optimized PCR-CGP test, coupled with an inclusive exception testing policy, delivered reportable results for > 94% of samples, potentially expanding the proportion of CGP-testable patients and impact of biomarker-guided therapies.

Treatment in a preventive cardiology clinic utilizing advanced practice providers effectively closes atherosclerotic cardiovascular disease risk-management gaps among a primary-prevention population compared with a propensity-matched primary-care cohort: A team-based care model and its impact on lipid and blood pressure management.

BACKGROUND: Advanced practice providers (APPs) can fill care gaps created by physician shortages and improve adherence/compliance with preventive ASCVD interventions. HYPOTHESIS: APPs utilizing guideline-based algorithms will more frequently escalate ASCVD risk factor therapies. METHODS: We retrospectively reviewed data on 595 patients enrolled in a preventive cardiology clinic (PCC) utilizing APPs compared with a propensity-matched cohort (PMC) of 595 patients enrolled in primary-care clinics alone. PCC patients were risk-stratified using Framingham Risk Score (FRS) and coronary artery calcium scoring (CACS). RESULTS: Baseline demographics were balanced between the groups. CACS was more commonly obtained in PCC patients (P < 0.001), resulting in reclassification of 30.6% patients to a higher risk category, including statin therapy in 26.6% of low-FRS PCC patients with CACS ≥75th MESA percentile. Aspirin initiation was higher for high and intermediate FRS patients in the PCC (P < 0.001). Post-intervention mean LDL-C, non-HDL-C, and triglycerides (all P < 0.05) were lower in the PCC group. Compliance with appropriate lipid treatment was higher in intermediate to high FRS patients (P = 0.004) in the PCC group. Aggressive LDL-C and non-HDL-C treatment goals (<70 mg/dL, P = 0.005 and < 130 mg/dL, P < 0.001, respectively), were more commonly achieved in high-FRS PCC patients. Median post-intervention SBP was lower among intermediate and low FRS patients (P = 0.001 and P < 0.001, respectively). Cumulatively, this resulted in a reduction in median post-intervention PCC FRS across all initial FRS risk categories (P < 0.001 for all). CONCLUSIONS: APPs within a PCC effectively risk-stratify and aggressively manage ASCVD risk factors, resulting in a reduction in post-intervention FRS.

Chamber dimensions and functional assessment with coronary computed tomographic angiography as compared to echocardiography using American Society of Echocardiography guidelines.

BACKGROUND: The correlation between normal cardiac chamber linear dimensions measured during retrospective coronary computed tomographic angiography as compared to transthoracic echocardiography using the American Society of Echocardiography guidelines is not well established. METHODS: We performed a review from January 2005 to July 2011 to identify subjects with retrospective electrocardiogram-gated coronary computed tomographic angiography scans for chest pain and transthoracic echocardiography with normal cardiac structures performed within 90 days. Dimensions were manually calculated in both imaging modalities in accordance with the American Society of Echocardiography published guidelines. Left ventricular ejection fraction was calculated on echocardiography manually using the Simpson's formula and by coronary computed tomographic angiography using the end-systolic and end-diastolic volumes. RESULTS: We reviewed 532 studies, rejected 412 and had 120 cases for review with a median time between studies of 7 days (interquartile range (IQR25,75) = 0-22 days) with no correlation between the measurements made by coronary computed tomographic angiography and transthoracic echocardiography using Bland-Altman analysis. We generated coronary computed tomographic angiography cardiac dimension reference ranges for both genders for our population. CONCLUSION: Our findings represent a step towards generating cardiac chamber dimensions' reference ranges for coronary computed tomographic angiography as compared to transthoracic echocardiography in patients with normal cardiac morphology and function using the American Society of Echocardiography guideline measurements that are commonly used by cardiologists.

A rare case of effusive constrictive cholesterol pericarditis: a case report and review.

Effusive constrictive cholesterol pericarditis is exceedingly rare. Most cases have an unclear etiology but can be associated with rheumatoid arthritis, tuberculosis infection, and hypothyroidism. The hallmark of the effusion is the distinctively high levels of cholesterol. We present the case of a 68-year-old male with prolonged symptoms of dyspnea with associated moderate pericardial effusion that were later determined to be constrictive effusive etiology, and the patient was referred for stripping with pathologic cholesterol crystal formation on pathology review.

Fatal aortic dissection in a patient with giant cell arteritis: a case report and review of the literature.

Giant cell arteritis may lead to catastrophic, large-vessel complications from chronic vascular wall inflammation without prompt diagnosis and treatment. We describe a rare case of acute aortic dissection without preceding aneurysm secondary to histologically confirmed giant cell arteritis (GCA) in an 85-year-old female with a four-year history of polymyalgia rheumatica and temporal arteritis diagnosed per biopsy six months prior to presentation. The literature is reviewed and the clinical implications of this case are discussed.

A case of congenitally corrected transposition of the great arteries discovered on coronary computed tomography.

Congenitally corrected transposition of the great arteries is a rare condition accounting for less than 1% of all congenital cardiac diseases. The fundamental nature of this condition involves a blend of atrioventricular as well as ventriculoarterial discordance. Congenitally corrected transposition of the great arteries is classically associated with three additional abnormalities, including ventricular septal defect, right ventricular outflow tract obstruction, and tricuspid valve abnormalities. Patients with this anomaly have been shown to exhibit reduced exercise tolerance as well as reduced health-related quality of life when compared to patients with normal cardiovascular anatomy. We present the case of a 33-year-old active duty lieutenant in the United States Air Force referred to the cardiology clinic for evaluation of valvular heart disease with subsequent discovery of congenitally corrected transposition of the great arteries on cardiac gated computed tomography.

Computed tomography coronary angiography versus stress myocardial perfusion imaging for risk stratification in patients with high occupational risk.

PURPOSE: To compare the performance of myocardial perfusion imaging (MPI) versus cardiac computed tomographic angiography (CCTA) in patients with a low pretest likelihood of obstructive coronary artery disease and high-risk occupation. MATERIALS AND METHODS: We performed a retrospective chart review of all MPI and CCTA studies performed at our institution from January 2006 to May 2008. The primary outcome measure was the incidence of referral to invasive coronary angiography (ICA). RESULTS: There were 512 MPS and 170 CCTA studies performed during the study period that met the study criteria. The average age was 35±10 for the CCTA arm and 45±5 for the myocardial perfusion scans (MPS) arm, which was statistically significant (P<0.001), with similar sex distribution between the 2 arms (21% female patients in the MPI arm and 20% female patients in the CCTA arm). The incidence of referral to ICA was 15.8% (81/512) after MPS versus 2.4% (4/170) with CCTA (P<0.001). Among patients referred for ICA, the false-positive rate was 93% (75/81) and 50% (2/4) with MPI and CCTA, respectively (P=0.043). CONCLUSIONS: Compared with MPI, CCTA significantly reduced ICA referral and false-positive noninvasive imaging rates among symptomatic patients with a low probability of coronary artery disease but high occupational risk.

Rosiglitazone and fenofibrate additive effects on lipids.

Background. To evaluate the effect of rosiglitazone, fenofibrate, or their combined use on plasma lipids in normoglycemic healthy adults. Methods and Results. Subjects were randomized in a double-blind fashion to rosiglitazone + placebo, fenofibrate + placebo, rosiglitazone + fenofibrate, or matching double placebo. The between-group difference in the change in fasting TG, high-density lipoprotein cholesterol (HDL-C), LDL-C, and plasma apolipoproteins A-I, A-II, and C-III level were compared after 12 weeks of treatment. A total of 548 subjects were screened and 41 met the inclusion criteria. After 12 weeks of therapy, the median change in the triglyceride levels showed a significant reduction ranging from 47 to 55 mg per deciliter in the fenofibrate only and rosiglitazone/fenofibrate groups compared with placebo (P = 0.0496). However, the rosiglitazone only group did not show significant change in triglyceride level. The change in the Apo AII showed increase in all the treatment groups compared with placebo (P = 0.009). There was also significant change in the Apo CIII that showed reduction of its level in the fenofibrate only and rosiglitazone/fenofibrate groups (P = 0.0003). Conclusion. Rosiglitazone does not appear to modulate hypertriglyceridemia in patients with elevated triglycerides independent of glucose metabolism.

The effect of airway pressure release ventilation on pulmonary catheter readings: specifically pulmonary capillary wedge pressure in a Swine model.

Background. Airway pressure release ventilation (APRV) is a mode of mechanical ventilation that theoretically believed to improve cardiac output by lowering right atrial pressure. However, hemodynamic parameters have never been formally assessed. Methods. Seven healthy swine were intubated and sedated. A baseline assessment of conventional ventilation (assist control) and positive end-expiratory pressure (PEEP) of 5 cm H(2)O was initiated. Ventilator mode was changed to APRV with incremental elevations of CPAP-high from 10 to 35 cm H(2)O. After a 3-to-5-minute stabilization period, measurements of hemodynamic parameters (PCWP, LAP, and CVP) were recorded at each level of APRV pressure settings. Results. Increasing CPAP caused increased PCWP and LAP measurements above their baseline values. Mean PCWP and LAP were linearly related (LAP = 0.66(∗)PCWP + 4.5 cm H(2)O, R(2) = 0.674, and P < .001) over a wide range of high and low CPAP values during APRV. With return to conventional ventilation, PCWP and LAP returned to their baseline values. Conclusion. PCWP is an accurate measurement of LAP during APRV over variable levels of CPAP. However, PCWP and LAP may not be accurate measurements of volume when CPAP is utilized.

Platypnea-orthodeoxia: an unusual case of hypoxemia.

A 52 year old female presented for two weeks of acute onset dyspnea on exertion. She was found to be hypoxic with a room air saturation of 88%. Baseline echocardiogram was normal with the exception of aortic root dilation. Right and left heart catheterizations were performed. The coronary arteries were normal in original and without disease. The right heart catheterization demonstrated normal pulmonary pressures and "no evidence of intra-cardiac shunt". Repeat echocardiogram was performed with agitated saline contrast and revealed a small amount of right to left shunting across the intra-atrial septum with cough while supine and significant right to left shunting while upright; these findings were consistent with the presence of a patent foramen ovale (PFO) and platypnea-orthodeoxia syndrome. The patient underwent percutaneous closure of her PFO with an Amplatzer device, and exhibited rapid resolution of her symptoms and hypoxia. She is off oxygen and has returned to work as a nurse practitioner. The case highlights the importance of clinical vigilance and consideration of this syndrome in the differential diagnosis of unexplained hypoxia. Our patient had a dramatic and positive outcome: complete alleviation of dyspnea and oxygen dependence after PFO closure.

Marathon running as a cause of troponin elevation: a systematic review and meta-analysis.

BACKGROUND: Cardiac troponin (cTn) has high sensitivity and specificity for myocardial injury in acute coronary syndrome. Our objective was to review the published literature regarding the incidence of cTn elevations in marathon runners. METHODS: Systematic review and meta-analysis of observational studies published before September 2009. We included studies of patients who had completed a marathon and had serum cTn levels within 24 hours. The primary outcome was the odds ratio for conversion of a normal pre-marathon cTn to an elevated post-marathon cTn. Secondary outcomes included the pooled prevalence of cTn elevation and comparison of the odds ratio for post-marathon elevation of cTnI versus cTnT. RESULTS: Sixteen studies of 939 participants met criteria for inclusion. The mean age was 39 ± 4 years and patients were 74 ± 14% male. There were 6 pre-marathon cTn elevations and 579 post-race elevations. The pooled odds ratio for converting from a normal pre-race to an elevated post-race cTn was 51.84 (95% CI 16-168, I² = 66%, P < 0.001). The pooled incidence of a post-marathon cTn elevation was 51% (95% CI 33-69, I² = 98%, P < 0.001) of all runners. For the primary outcome there was no significant publication bias. Age and gender were not associated, but publication date and assay sensitivity was associated with cTn elevation. cTnI was less commonly elevated versus cTnT. CONCLUSIONS: The available data demonstrate that cTn levels are frequently elevated after a marathon with unclear cardiovascular significance. This elevation of cTn appears to be consistent among a diverse patient population.

Coronary thrombus detected by cardiac CT angiography before cardiac catheterization.

A patient presented with a complaint of pleuritic chest discomfort with elevated cardiac biomarkers. After a cardiac magnetic resonance imaging scan for the suspicion of myopericarditis showed a potential myocardial infarct, a coronary CT scan was performed. This revealed a thrombus of the left anterior descending artery. Cardiac catheterization confirmed the findings, and a small clot was removed. To our knowledge, this is the first reported case of coronary thrombus being detected by CT angiography with cardiac catheterization correlation. Coronary CT angiography has been increasingly used to evaluate acute chest pain with a negative predictive value close to 100%. In a young patient with suspicion of myopericarditis, CT angiography proved to be useful in diagnosing thrombus in the coronary tree.

The Effects of Extended Release Niacin in Combination with Omega 3 Fatty Acid Supplements in the Treatment of Elevated Lipoprotein (a).

Objective. To assess the effectiveness of niacin/fish oil combination therapy in reducing Lipoprotein (a) [Lp(a)] levels after twelve weeks of therapy. Background. Lipoprotein (a) accumulates in atherosclerotic lesions and promotes smooth muscle cell growth and is both atherogenic and thrombogenic. A clinical trials of combination therapy for the reduction of Lp(a) has not been previously reported. Methods. The study was an observational study following subjects with an elevated Lp(a) (>70 nmol/L) to assess impact of 12 weeks of combination Omega 3FA, niacin, and the Mediterranean diet on Lp(a). Results. Twenty three patients were enrolled with 7 patients lost to follow up and 2 patients stopped due to adverse events. The average Lp(a) reduction in the remaining 14 subjects after 12 weeks of combination therapy was 23% ± 17% [P = .003] with a significant association of the reduction of Lp(a) with increasing baseline levels of Lp(a) [R(2) = 0.633, P = .001]. Conclusions. There was a significant reduction in Lp(a) levels with combination therapy. A more pronounced effect was noted in patients with higher baseline levels of Lp(a).