Compromised Outcomes in Stage IV Non-Small-Cell Lung Cancer With Actionable Mutations Initially Treated Without Tyrosine Kinase Inhibitors: A Retrospective Analysis of Real-World Data.

PURPOSE: Identification and targeting of actionable oncogenic drivers (AODs) in advanced non-small-cell lung cancer (NSCLC) has dramatically improved outcomes. However, genomic testing uptake is variable and hampered by factors including slow turnaround time, frequently resulting in initial non-tyrosine kinase inhibitor (TKI) treatment. We investigate how this behavior affects outcomes. METHODS: This retrospective analysis of real-world, deidentified data from the Integra Connect Database included adults with stage IV NSCLC newly diagnosed from January 1, 2018, to December 31, 2020, with mutations of EGFR, ALK, ROS1, BRAF, MET, RET, ERBB2, or NTRK. Outcomes were reported as time to next treatment or death (TTNT) and overall survival (OS). RESULTS: Five hundred ten patients harboring AODs were identified and grouped as follows: group A (n = 379) were treated after the AOD was reported and served as the comparator. One hundred thirty-one patients treated before their AOD report were divided into group B (n = 47) who were initially started on chemotherapy and/or checkpoint inhibitor but switched to appropriate TKI within 35 days and group C (n = 84) who were also started empirically on non-TKI and did not switch within 35 days. Survival (OS) was significantly superior in group A compared with group C; TTNT was significantly superior in group A compared with groups B and C. CONCLUSION: For patients harboring AODs in advanced NSCLC, initial treatment before receipt of genomic test results yields significantly inferior outcomes and should be avoided. Molecular profiling panels with rapid turnaround times are essential to optimize patient outcomes and should be standard of care.

Real-world relationship of early end points to survival end points in patients with resectable non-small-cell lung cancer.

Aim: Pathologic response has been shown to be a promising surrogate for survival in non-small-cell lung cancer. We examined the real-world relationship between these end  points in patients with resectable stage IB-IIIA non-small-cell lung cancer receiving neoadjuvant chemotherapy/chemoradiotherapy (CT/CRT). Methods: Electronic health records/medical charts were analyzed. Overall and event-free survival (OS/EFS) were assessed by Kaplan-Meier stratified by pathologic response. Associations between the end  points were assessed by Cox analyses. Results: A total of 425 patients were selected for the study; 147 and 278 received CT and CRT, respectively. Pathologic complete response (pCR) was associated with longer OS (adjusted HR = 0.50; 95% CI: 0.29-0.85) and EFS (adjusted HR = 0.44; 95% CI: 0.28-0.68) versus no pCR, and EFS was associated with OS (HR = 0.51, 95% CI: 0.38, 0.69). Conclusion: In patients receiving neoadjuvant CT/CRT, pCR and EFS were associated with improved survival in this real-world dataset.

Real-world patterns of biomarker testing and targeted therapy in de novo metastatic non-small cell lung cancer patients in the US oncology network.

BACKGROUND: This study investigated biomarker testing and biomarker-guided treatment among patients with metastatic NSCLC in a real-world setting. METHODS: This retrospective study examined adult patients diagnosed with de novo mNSCLC between 01-Jan-2016 and 30-Sep-2019, with follow-up through 31-Dec-2019 using The US Oncology Network structured electronic health records data, with chart review for a subset. RESULTS: Of 2257 patients, 76.3% had results for ≥1 driver mutation (DM) or programmed death ligand-1 (PD-L1) during the study observation period. The proportion with results for all 4 DM before 1L initiation increased from 2017 to 2019. Over 40% had results for anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), and c-ros oncogene 1 (ROS1) and 22% for B-Raf proto-oncogene (BRAF) before 1L initiation by structured data. In the chart review subset (n = 197), >70% had results for ALK, EGFR, or ROS1 with 44% for BRAF. Of the 42 ALK+ patients, 5 had results before 1L treatment and 3 received 1L ALK inhibitors. Similar, for the other biomarkers, not all who tested positive for a DM received 1L targeted therapy. The proportion of biomarker-positive patients receiving 1L targeted therapy was higher in chart review versus structured data. However, in both analyses, a substantial proportion did not have results for all 4 DM plus PD-L1 tests for appropriate biomarker-directed 1L treatment selection. CONCLUSIONS: Despite increasing biomarker testing rates, reduced turnaround times, and availability of promising biomarker-based therapies, inadequate testing in the community oncology setting means that not all eligible patients are receiving the most effective therapies up front.

Hybrid intervention approach to coronary artery and valvular heart disease.

Coronary angiography is used to assess the burden of coronary artery disease prior to surgical valve repair/replacement and often leads to concomitant bypass and valve surgery. We sought to evaluate outcomes of an alternative, hybrid approach involving percutaneous coronary intervention (PCI) and valve surgery, assessing the rate of stent thrombosis as a primary outcome. We reviewed charts of consecutive patients who underwent planned PCI prior to surgical valve repair/replacement by a single surgeon from January 2008 to December 2016. We calculated rates of surgical complication, duration of dual antiplatelet therapy (DAPT) prior to surgery, and rates of stent thrombosis and in-stent restenosis. Twenty-four patients were included in this study. Surgery was performed a median of 52.5 days following PCI. DAPT was withheld an average of 8 days before and resumed an average of 4 days after surgery. Ninety-two percent of surgeries were minimally invasive. There were no bleeding complications, stent thromboses, or restenosis events. All patients survived the 1-year follow-up. For patients with mixed coronary and valvular heart disease, a heart team approach involving preoperative PCI followed by staged minimally invasive valvular surgery appears to be safe and warrants further exploration.

Comparison of Frequency of Vascular Complications With Ultrasound-Guided Versus Fluroscopic Roadmap-Guided Femoral Arterial Access in Patients Who Underwent Transcatheter Aortic Valve Implantation.

To compare outcomes of ultrasound guidance (USG) versus fluoroscopy roadmap guidance (FG) angiography for femoral artery access in patients who underwent transfemoral (TF) transcatheter aortic valve implantation (TAVI) to determine whether routine USG use was associated with fewer vascular complications. Vascular complications are the most frequent procedural adverse events associated with TAVI. USG may provide a decreased rate of access site complications during vascular access compared with FG. Patients who underwent TF TAVI between July 2012 and July 2017 were reviewed and outcomes were compared. Vascular complications were categorized by Valve Academic Research Consortium-2 criteria and analyzed by a multivariable logistic regression adjusting for potential confounding risk factors including age, gender, body mass index, peripheral vascular disease, Society of Thoracic Surgeons score and sheath to femoral artery ratio. Of the 612 TAVI patients treated, 380 (63.1%) were performed using USG for access. Routine use of USG began in March 2015 and increased over time. Vascular complications occurred in 63 (10.3%) patients and decreased from 20% to 3.9% during the study period. There were fewer vascular complications with USG versus FG (7.9% vs 14.2%, p = 0.014). After adjusting for potential confounding risk factors that included newer valve systems, smaller sheath sizes and lower risk patients, there was still a 49% reduction in vascular complications with USG (odds ratio 0.51, 95% confidence interval 0.29 to 0.88, p = 0.02). In conclusion, USG for TF TAVI was associated with reduced vascular access site complications compared with FG access even after accounting for potential confounding risk factors and should be considered for routine use for TF TAVI.

Validating a prediction tool to determine the risk of nosocomial multidrug-resistant Gram-negative bacilli infection in critically ill patients: A retrospective case-control study.

BACKGROUND: The Singapore GSDCS score was developed to enable clinicians predict the risk of nosocomial multidrug-resistant Gram-negative bacilli (RGNB) infection in critically ill patients. We aimed to validate this score in a UK setting. METHOD: A retrospective case-control study was conducted including patients who stayed for more than 24h in intensive care units (ICUs) across two tertiary National Health Service hospitals in London, UK (April 2011-April 2016). Cases with RGNB and controls with sensitive Gram-negative bacilli (SGNB) infection were identified. RESULTS: The derived GSDCS score was calculated from when there was a step change in antimicrobial therapy in response to clinical suspicion of infection as follows: prior Gram-negative organism, Surgery, Dialysis with end-stage renal disease, prior Carbapenem use and intensive care Stay of more than 5 days. A total of 110 patients with RGNB infection (cases) were matched 1:1 to 110 geotemporally chosen patients with SGNB infection (controls). The discriminatory ability of the prediction tool by receiver operating characteristic curve analysis in our validation cohort was 0.75 (95% confidence interval 0.65-0.81), which is comparable with the area under the curve of the derivation cohort (0.77). The GSDCS score differentiated between low- (0-1.3), medium- (1.4-2.3) and high-risk (2.4-4.3) patients for RGNB infection (P<0.001) in a UK setting. CONCLUSION: A simple bedside clinical prediction tool may be used to identify and differentiate patients at low, medium and high risk of RGNB infection prior to initiation of prompt empirical antimicrobial therapy in the intensive care setting.

Association between irritable bowel syndrome and asthma: a meta-analysis and systematic review.

BACKGROUND: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder often seen in outpatient clinics. Diagnosing IBS is often challenging, as it frequently presents with other complicated rheumatological and psychiatric conditions. Asthma has often been associated with gastrointestinal conditions such as gastroesophageal reflux disease and eosinophilic esophagitis. This review and meta-analysis aimed at a better understanding of the association between the conditions. METHODS: A comprehensive literature review was completed using MEDLINE and EMBASE databases through January 2019. Case-control, cross-sectional and cohort studies that evaluated the association between asthma and IBS were divided into 2 groups: the first included studies that identified patients with asthma first and then looked for the presence of IBS. The second group included studies that identified IBS patients first and then looked for the presence of asthma. Random effects meta-analysis was conducted using STATA 15. RESULTS: The search strategy generated a total of 634 studies and 10 eligible studies (8 case-control and 2 cross-sectional) were selected for meta-analysis. Analysis showed that asthmatics have twice the risk of having IBS (pooled odds ratio [OR] 2.0, 95% confidence interval [CI] 1.5-2.8), and patients with IBS have twice the risk of having asthma (pooled OR 2.2, 95%CI 1.3-3.9). CONCLUSIONS: This study highlights that the risk of asthma is considerably higher in IBS patients and vice versa. Physicians should look out for pulmonary symptoms in IBS patients and consider evaluation with spirometry when necessary. Likewise, asthmatics presenting with gastrointestinal symptoms may need consultation and evaluation for IBS.

Outcomes of Isolated Tricuspid Valve Surgery Have Improved in the Modern Era.

BACKGROUND: Surgery for isolated tricuspid valve (TV) disease remains relatively infrequent because of significant patient comorbidities and poor surgical outcomes. This study reviewed the experience with isolated TV surgery in the current era to determine whether outcomes have improved. METHODS: From 2007 through 2017, 685 TV operations were performed in a single institution, of which 95 (13.9%) operations were isolated TV surgery. Patients were analyzed for disease origin, risk factors, operative mortality and morbidity, and long-term survival. RESULTS: A total of 95 patients underwent isolated TV surgery, an average of 9 patients per year increasing from an average of 5 per year to 15 per year during the study period. Surgery was reoperative in 41% (38 of 95) of patients, including 11.6% (11 of 95) with prior coronary artery bypass grafting and 29.4% (28 of 95) with prior valve surgery (9 TV, 11 mitral, 2 aortic, 5 mitral and aortic, and 1 mitral and TV). Repair was performed in 71.6% (68 of 95) of patients, and replacement was performed in 28.4% (27 of 95). Operative mortality was 3.2% (3 of 95), with no mortality in the most recent 73 patients over the last 6 years. Stroke occurred in 2.1% (2 of 95) of patients, acute kidney injury requiring dialysis in 5.3% (5 of 95), and the need for new permanent pacemaker in 16.8% (16 of 95). CONCLUSIONS: In the current era with careful patient selection and periprocedural management, isolated TV surgery can be performed with lower morbidity and mortality than has traditionally been reported with good long-term survival. These outcomes can also serve as a benchmark for catheter-based TV intervention outcomes.

Frequency of abnormal fractional flow reserve measurements among major coronary arteries.

BACKGROUND: Fractional flow reserve(FFR) is a validated tool for evaluating functional severity and guiding the revascularization of angiographically moderate coronary artery lesions. OBJECTIVE: To study if there is a higher frequency of positive FFR measurements in the left anterior descending(LAD) versus other major coronary arteries and also evaluate the differences in the total length of the stent placed. METHODS: A retrospective cohort study including all subjects (January 2011 to December 2015) who had fractional flow reserve (FFR) measured during coronary catheterization was conducted. Coronary catheterizations with FFR at a single tertiary care center were reviewed and FFR ≤ 0.80 post adenosine was deemed positive. The differences in the baseline characteristics and the degree of stenosis were compared between the different vessel groups. RESULTS: Of the 758 vessels included in the analysis, the majority were LAD(51.3%) followed by right coronary artery(RCA)(22.8%), Circumflex(22.2%), Left main(2.2%), and Ramus intermedius(1.5%). 25.1% of 758 vessels were FFR positive. The proportion of positive FFR were higher among LAD versus other vessels(33.2%vs.16.5%,p < 0.001), while no differences were noted between RCA and circumflex(p = 0.87) or other vessels excluding LAD(p = 0.69). Of 175 patients who received stents, no statistical difference was noted in the median[range] total length of the stent between LAD(22[9-64]) and the other coronary arteries (18[8-42])(p = 0.19). In patients with an FFR <0.75, we found that the stent length(median [range]) was significantly longer in LAD(28[9-42]) than the other coronary arteries(18[8-42])(p = 0.03). CONCLUSION: In our study, FFR was almost twice as likely to be positive in the LAD when compared to other major coronary arteries. Furthermore, there was a trend towards FFR positive LAD lesions needing longer stents than other coronary arteries. This data should encourage operators to evaluate moderate, long lesions in the LAD with FFR, as they have a higher probability of functional significance.

Frequency of atrial arrhythmias after atrial flutter ablation and the effect of presenting rhythm on the day of ablation.

Radiofrequency catheter ablation of the cavotricuspid isthmus is a proven therapy for typical atrial flutter (AFl); however, in some patients, new atrial arrhythmias (AA) may occur after AFl ablation. This study explored the difference in the occurrence of spontaneous AA after AFl ablation as a function of the patient's presenting rhythm on the day of the AFl ablation. A retrospective study of consecutive patients who underwent AFl ablation at Baylor University Medical Center at Dallas was performed. A total of 188 subjects were included; 50% (94) presented in AFl (Group AFl) on the day of the ablation procedure and 94 presented in sinus rhythm (SR; Group SR). Group AFl patients were older (P < 0.001), more likely to have diabetes (P = 0.03), and more likely to have undergone previous heart surgery (P = 0.03). The median size of the left atrium was 4 cm (range 2.8-6.8) in Group AFl compared with 3.8 cm (range 2.6-5.6) in Group SR (P = 0.009). Atrial fibrillation was induced during the ablation procedure in 7.5% and 21.3% of patients in Groups AFl and SR, respectively (P = 0.007). Overall, 29 of 188 (15.4%) patients developed new AA within 1 year of the procedure, 13.8% in Group AFl vs 17.0% in Group SR (P = 0.57). In conclusion, patients presenting for AFl ablation in SR were younger and healthier but had more atrial fibrillation induced during their ablation procedure, with a trend toward more postablation AA due to additional arrhythmia substrate.

Spinal Implants Can Be Inserted in Patients With Deep Spine Infection: Results From a Large Cohort Study.

STUDY DESIGN: A retrospective, cohort study of 84 patients with deep spine infection managed at a major tertiary hospital over 14 years with a minimum follow up of 2 years. OBJECTIVE: To determine the role of instrumentation in spines with deep infection. SUMMARY OF BACKGROUND DATA: It is often believed that implants should not be inserted in patients with deep spine infection because of the risk of persistent or recurrent infection. However, there are often concerns about spinal stability and a paucity of evidence to guide clinical practice in this field. METHODS: We compared the mortality, reoperation, and reinfection rates in patients with spine infection treated with antibiotics alone, antibiotics with debridement, and antibiotics with debridement and instrumentation. Significant outcome predictors were determined using multivariable logistic regression model. RESULTS: Forty-nine males and 35 females with a mean age was 62.0 years had spine infection affecting the lumbar spine predominantly. The most common form of infection was osteomyelitis and spondylodiscitis (69.4%). Staphylococcus aureus was the most common causative organism (61.2%).There was no difference in terms of reoperation or relapse for patients treated with antibiotics alone, antibiotics with debridement, or antibiotics with debridement and instrumentation. However, compared with antibiotics alone, the crude inhospital mortality was lower for patients treated with instrumentation (odds ratio, OR, 0.82; P = 0.01), and antibiotics with debridement (OR 0.80; P = 0.02). CONCLUSION: Spinal instrumentation in an infected spine is safe and not associated with higher reoperation or relapse rates. Mortality is lower for patients treated with instrumentation. LEVEL OF EVIDENCE: 3.

Residual thromboxane activity and oxidative stress: influence on mortality in patients with stable coronary artery disease.

BACKGROUND: Aspirin use is effective in the prevention of cardiovascular disease; however, not all patients are equally responsive to aspirin. Oxidative stress reflected by F2-isoprostane [8-iso-prostaglandin-F2α (8-IsoPGF2α)] is a potential mechanism of failure of aspirin to adequately inhibit cyclooxygenase-1. The objective was to examine the relation between all-cause mortality and the concentrations of urinary 11-dehydro thromboxane B2 (11dhTxB2) and 8-IsoPGF2α in patients with stable coronary artery disease (CAD). METHODS: The data for this analysis are from a prospective study in which patients were categorized into four groups based on the median values of 11dhTxB2 and 8-IsoPGF2α. RESULTS: There were 447 patients included in this analysis with a median (range) age of 66 (37-91) years. The median (range) values of 11dhTxB2 and 8-IsoPGF2α were 1404.1 (344.2-68296.1) and 1477.9 (356.7-19256.3), respectively. A total of 67 (14.9%) patients died over a median follow-up of 1149 days. The reference group for the Cox proportional hazards survival analysis was patients with values of 11dhTxB2 and 8-IsoPGF2α below their corresponding medians. Adjusting for the age and sex, patients with values of 11dhTxB2 greater than the median had a significantly higher risk of mortality when compared with the reference group (high 11dhTxB2 and low 8-IsoPGF2αadj: hazard ratio: 3.2, 95% confidence interval: 1.6-6.6, P=0.002; high 11dhTxB2 and 8-IsoPGF2αadj: hazard ratio: 3.6, 95% confidence interval: 1.8-7.3, P<0.001). The findings were similar when we adjusted for the comorbidities of cancer, kidney function, and ejection fraction. CONCLUSION: We found that 11dhTxB2 appears to be a better prognostic marker for mortality as compared with 8-IsoPGF2α, suggesting aspirin resistance itself is a stronger independent determinant of death in CAD patients treated with aspirin.

A prediction tool for nosocomial multi-drug Resistant Gram-Negative Bacilli infections in critically ill patients - prospective observational study.

BACKGROUND: The widespread use of empiric broad spectrum antibiotics has contributed to the global increase of Resistant Gram-Negative Bacilli (RGNB) infections in intensive care units (ICU). The aim of this study was to develop a tool to predict nosocomial RGNB infections among ICU patients for targeted therapy. METHODS: We conducted a prospective observational study from August'07 to December'11. All adult patients who were admitted and stayed for more than 24 hours at the medical and surgical ICU's were included. All patients who developed nosocomial RGNB infections 48 hours after ICU admission were identified. A prediction score was formulated by using independent risk factors obtained from logistic regression analysis. This was prospectively validated with a subsequent cohort of patients admitted to the ICUs during the following time period of January-September 2012. RESULTS: Seventy-six patients with nosocomial RGNB Infection (31bacteremia) were compared with 1398 patients with Systemic Inflammatory Response Syndrome (SIRS) without any gram negative bacterial infection/colonization admitted to the ICUs during the study period. The following independent risk factors were obtained by a multivariable logistic regression analysis - prior isolation of Gram negative organism (coeff: 1.1, 95% CI 0.5-1.7); Surgery during current admission (coeff: 0.69, 95% CI 0.2-1.2); prior Dialysis with end stage renal disease (coeff: 0.7, 95% CI 0.1-1.1); prior use of Carbapenems (coeff: 1.3, 95% CI 0.3-2.3) and Stay in the ICU for more than 5 days (coeff: 2.4, 95% CI 1.6-3.2). It was validated prospectively in a subsequent cohort (n = 408) and the area-under-the-curve (AUC) of the GSDCS score for predicting nosocomial ICU acquired RGNB infection and bacteremia was 0.77 (95% CI 0.68-0.89 and 0.78 (95% CI 0.69-0.89) respectively. The GSDCS (0-4.3) score clearly differentiated the low (0-1.3), medium (1.4-2.3) and high (2.4-4.3) risk patients, both for RGNB infection (p:0.003) and bacteremia (p:0.009). CONCLUSION: GSDCS is a simple bedside clinical score which predicts RGNB infection and bacteremia with high predictive value and differentiates low versus high risk patients. This score will help clinicians to choose appropriate, timely targeted antibiotic therapy and avoid exposure to unnecessary treatment for patients at low risk of nosocomial RGNB infection. This will reduce the selection pressure and help to contain antibiotic resistance in ICUs.

Single-nucleotide polymorphism-array improves detection rate of genomic alterations in core-binding factor leukemia.

Acute myeloid leukemia (AML) is a group of clonal diseases, resulting from two classes of mutation. Investigation for additional abnormalities associated with a well-recognized subtype, core-binding factor AML (CBF-AML) can provide further understanding and discrimination to this special group of leukemia. In order to better define genetic alterations in CBF-AML and identify possible cooperating lesions, a single-nucleotide polymorphism-array (SNP-array) analysis was performed, combined to KIT mutation screening, in a set of cases. Validation of SNP-array results was done by array comparative genomic hybridization and FISH. Fifteen cases were analyzed. Three cases had microscopic lesions better delineated by arrays. One case had +22 not identified by arrays. Submicroscopic abnormalities were mostly non-recurrent between samples. Of relevance, four regions were more frequently affected: 4q28, 9p11, 16q22.1, and 16q23. One case had an uncovered unbalanced inv(16) due to submicroscopic deletion of 5´MYH11 and 3´CBFB. Telomeric and large copy number neutral loss of heterozygosity (CNN-LOH) regions (>25 Mb), likely representing uniparental disomy, were detected in four out of fifteen cases. Only three cases had mutation on KIT gene, enhancing the role of abnormalities by SNP-array as presumptive cooperating alterations. Molecular karyotyping can add valuable information to metaphase karyotype analysis, emerging as an important tool to uncover and characterize microscopic, submicroscopic genomic alterations, and CNN-LOH events in the search for cooperating lesions.

Risk factors for infection/colonization caused by resistant Gram negative bacilli in critically ill patients (an observational study of 1633 critically ill patients).

OBJECTIVE: The objective of this study is to identify risk factors associated with multi-resistant Gram negative (RGNB) infection and colonization among critically ill patients. METHODS: A prospective cohort study of all patients aged 21-90 admitted for more than 24 hours in Medical and Surgical intensive care units (ICU) at a large teaching hospital in Singapore for the period of Aug '07-Dec '09 was conducted. Patient demographics, comorbidities, antibiotics, invasive devices, and culture results were collected. Forward stepwise logistic regression analyses were done to identify risk factors associated with RGNB infection and colonization. RESULTS: Of the 1373 patients included in the analysis, 13.5% developed RGNB infection. A logistic regression analysis including variables with a p value of <0.2 in the univariate analysis showed that recent surgery (OR 2.1, 95% CI 1.2-3.6), renal impairment (OR 2.9, 95% CI 1.5-5.4), liver disease (OR: 3.8, 95% CI 1.7-8.8), central line (OR 1.8, 95% CI 1.01-3.4) were independently associated with RGNB infection in the ICU. Surgery (OR 3.9, 95% CI 2.7-5.7), third-line antibiotics (carbapenem, vancomycin, linezolid) (OR 1.8, 95% CI 1.2-2.9) were independently associated with RGNB infection during their hospitalization. CONCLUSION: The major risk factors identified for RGNB infection and colonization in the ICU were mainly patient dependent. However, broad spectrum initial antibiotic treatment remains an important independent modifiable risk factor. Interventions aimed at reducing initial broad spectrum antibiotics are clearly needed to help control the spread of these difficult to treat infections.