Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1).

Programmed death-ligand 1 (PD-L1) expression on tumor cells (TCs) by immunohistochemistry is rapidly gaining importance as a diagnostic for the selection or stratification of patients with non-small cell lung cancer (NSCLC) most likely to respond to single-agent checkpoint inhibitors. However, at least two distinct patterns of PD-L1 expression have been observed with potential biological and clinical relevance in NSCLC: expression on TC or on tumor-infiltrating immune cells (ICs). We investigated the molecular and cellular characteristics associated with PD-L1 expression in these distinct cell compartments in 4,549 cases of NSCLC. PD-L1 expression on IC was more prevalent and likely reflected IFN-γ-induced adaptive regulation accompanied by increased tumor-infiltrating lymphocytes and effector T cells. High PD-L1 expression on TC, however, reflected an epigenetic dysregulation of the PD-L1 gene and was associated with a distinct histology described by poor immune infiltration, sclerotic/desmoplastic stroma, and mesenchymal molecular features. Importantly, durable clinical responses to atezolizumab (anti-PD-L1) were observed in patients with tumors expressing high PD-L1 levels on either TC alone [40% objective response rate (ORR)] or IC alone (22% ORR). Thus, PD-L1 expression on TC or IC can independently attenuate anticancer immunity and emphasizes the functional importance of IC in regulating the antitumor T cell response.

Discovery of a putative blood-based protein signature associated with response to ALK tyrosine kinase inhibition.

BACKGROUND: ALK tyrosine kinase inhibition has become a mainstay in the clinical management of ALK fusion positive NSCLC patients. Although ALK mutations can reliably predict the likelihood of response to ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, they cannot reliably predict response duration or intrinsic/extrinsic therapeutic resistance. To further refine the application of personalized medicine in this indication, this study aimed to identify prognostic proteomic biomarkers in ALK fusion positive NSCLC patients to crizotinib. METHODS: Twenty-four patients with advanced NSCLC harboring ALK fusion were administered crizotinib in a phase IV trial which included blood sampling prior to treatment. Targeted proteomics of 327 proteins using MRM-MS was used to measure plasma levels at baseline (including pre-treatment and early treatment blood samples) and assess potential clinical association. RESULTS: Patients were categorized by duration of response: long-term responders [PFS ≥ 24 months (n = 7)], normal responders [3 < PFS < 24 months (n = 10)] and poor responders [PFS ≤ 3 months (n = 5)]. Several proteins were identified as differentially expressed between long-term responders and poor responders, including DPP4, KIT and LUM. Next, using machine learning algorithms, we evaluated the classification potential of 40 proteins. Finally, by integrating the different analytic methods, we selected 22 proteins as potential candidates for a blood-based prognostic signature of response to crizotinib in NSCLC patients harboring ALK fusion. CONCLUSION: In conjunction with ALK mutation, the expression of this proteomic signature may represent a liquid biopsy-based marker of long-term response to crizotinib in NSCLC. Expanding the utility of prognostic biomarkers of response duration could influence choice of therapy, therapeutic sequencing, and potentially the need for alternative or combination therapy.Trial registration ClinicalTrials.gov, NCT02041468. Registered 22 January 2014, https://clinicaltrials.gov/ct2/show/NCT02041468?term=NCT02041468&rank=1.

Comparison of Intravenous Ketorolac at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial.

STUDY OBJECTIVE: Nonsteroidal anti-inflammatory drugs are used extensively for the management of acute and chronic pain, with ketorolac tromethamine being one of the most frequently used parenteral analgesics in the emergency department (ED). The drugs may commonly be used at doses above their analgesic ceiling, offering no incremental analgesic advantage while potentially adding risk of harm. We evaluate the analgesic efficacy of 3 doses of intravenous ketorolac in ED patients with acute pain. METHODS: We conducted a randomized, double-blind trial to assess the analgesic efficacy of 3 doses of intravenous ketorolac (10, 15, and 30 mg) in patients aged 18 to 65 years and presenting to the ED with moderate to severe acute pain, defined by a numeric rating scale score greater than or equal to 5. We excluded patients with peptic ulcer disease, gastrointestinal hemorrhage, renal or hepatic insufficiency, allergies to nonsteroidal anti-inflammatory drugs, pregnancy or breastfeeding, systolic blood pressure less than 90 or greater than 180 mm Hg, and pulse rate less than 50 or greater than 150 beats/min. Primary outcome was pain reduction at 30 minutes. We recorded pain scores at baseline and up to 120 minutes. Intravenous morphine 0.1 mg/kg was administered as a rescue analgesic if subjects still desired additional pain medication at 30 minutes after the study drug was administered. Data analyses included mixed-model regression and ANOVA. RESULTS: We enrolled 240 subjects (80 in each dose group). At 30 minutes, substantial pain reduction was demonstrated without any differences between the groups (95% confidence intervals 4.5 to 5.7 for the 10-mg group, 4.5 to 5.6 for the 15-mg group, and 4.2 to 5.4 for the 30-mg group). The mean numeric rating scale pain scores at baseline were 7.7, 7.5, and 7.8 and improved to 5.1, 5.0, and 4.8, respectively, at 30 minutes. Rates of rescue analgesia were similar, and there were no serious adverse events. Secondary outcomes showed similar rates of adverse effects per group, of which the most common were dizziness, nausea, and headache. CONCLUSION: Ketorolac has similar analgesic efficacy at intravenous doses of 10, 15, and 30 mg, showing that intravenous ketorolac administered at the analgesic ceiling dose (10 mg) provided effective pain relief to ED patients with moderate to severe pain without increased adverse effects.

Appropriate vitamin D loading regimen for patients with advanced lung cancer.

BACKGROUND: Most patients attending cancer clinics have hypovitaminosis D. Correcting or preventing this abnormal condition could mitigate the emotional and physical complications of their disease, but clinical trials of vitamin D therapy in this setting are hindered by the unavailability of safe, effective and practical loading dose regimens. METHODS: In this single arm open-label pharmacokinetic trial, outpatients with advanced lung cancer consumed 20,000 IU vitamin D daily with the largest meal of the day for 14 days followed by 10,000 IU per day for a further 7 days. Plasma concentrations of 25-hydroxyvitamin D [25(OH)D], parathyroid hormone, calcium, vitamin C and C-reactive protein were measured on protocol days 0, 14 and 21, and serum vitamin D binding protein (VDBP) concentrations on days 0 and 21. As a secondary objective, preliminary information was obtained regarding clinical effects of rapid vitamin D loading on mood and symptoms by administering appropriate questionnaires two times at baseline and after 14 and 21 days of vitamin D therapy. RESULTS: Of the 91 patients enrolled in the study, 85 % had hypovitaminosis D and 41 % had hypovitaminosis C. Plasma VDBP concentrations were in the normal range. The vitamin D load increased the average plasma 25(OH)D concentration to 116 ± 34 nmol/L (mean ± SD); the median concentration was 122 nmol/L (interquartile range 103-134); VDBP concentrations did not change. Final plasma 25(OH)D concentrations were subnormal (<75 nmol/L) for 13 % of the patients and sub-target (<120 nmol/L) for 44 % of them. In most cases, subnormal and sub-target 25(OH)D concentrations were attributable to obesity and/or a low baseline 25(OH)D concentration. Mood and symptom scores did not change significantly throughout the 3-week protocol. CONCLUSION: Hypovitaminosis D and C are very common in outpatients with advanced lung cancer. A vitamin D load of 20,000 IU per day for 14 days failed to achieve the target concentration in 44 % of the participants in this trial. These results suggest that a loading dose of 30,000 IU per day for 14 days would be safe and effective for patients who are obese or at risk of severe hypovitaminosis D. The preliminary nature of the study design, and the failure to achieve target 25(OH)D concentrations for a large proportion of the patients, do not allow any firm conclusion about the clinical effects of correcting hypovitaminosis D in this patient population. Nevertheless, no evidence was obtained that partial correction of hypovitaminosis D greatly improved mood, reduced distress or relieved cancer-related symptoms. This trial was registered at clinicaltrials.gov as NCT01631526.

Longitudinal Changes in Multiple Biomarkers Are Associated with Cardiotoxicity in Breast Cancer Patients Treated with Doxorubicin, Taxanes, and Trastuzumab.

BACKGROUND: Biomarkers may play an important role in identifying patients at risk for cancer therapy cardiotoxicity. Our objectives were to define the patterns of change in biomarkers with cancer therapy and their associations with cardiotoxicity. METHODS: In a multicenter cohort of 78 breast cancer patients undergoing doxorubicin and trastuzumab therapy, 8 biomarkers were evaluated at baseline and every 3 months over a maximum follow-up of 15 months. These biomarkers, hypothesized to be mechanistically relevant to cardiotoxicity, included high-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity C-reactive protein (hsCRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and galectin 3 (gal-3). We determined if biomarker increases were associated with cardiotoxicity at the same visit and the subsequent visit over the entire course of therapy. Cardiotoxicity was defined by the Cardiac Review and Evaluation Criteria; alternative definitions were also considered. RESULTS: Across the entire cohort, all biomarkers except NT-proBNP and gal-3 demonstrated increases by 3 months; these increases persisted for GDF-15, PlGF, and hs-cTnI at 15 months. Increases in MPO, PlGF, and GDF-15 were associated with cardiotoxicity at the same visit [MPO hazard ratio 1.38 (95% CI 1.10-1.71), P = 0.02; PlGF 3.78 (1.30-11.0), P = 0.047; GDF-15 1.71 (1.15-2.55), P = 0.01] and the subsequent visit. MPO was robust to alternative outcome definitions. CONCLUSIONS: Increases in MPO are associated with cardiotoxicity over the entire course of doxorubicin and trastuzumab therapy. Assessment with PlGF and GDF-15 may also be of value. These findings motivate validation studies in additional cohorts.

Intravenous Subdissociative-Dose Ketamine Versus Morphine for Analgesia in the Emergency Department: A Randomized Controlled Trial.

STUDY OBJECTIVE: We assess and compare the analgesic efficacy and safety of subdissociative intravenous-dose ketamine with morphine in emergency department (ED) patients. METHODS: This was a prospective, randomized, double-blind trial evaluating ED patients aged 18 to 55 years and experiencing moderate to severe acute abdominal, flank, or musculoskeletal pain, defined as a numeric rating scale score greater than or equal to 5. Patients were randomized to receive ketamine at 0.3 mg/kg or morphine at 0.1 mg/kg by intravenous push during 3 to 5 minutes. Evaluations occurred at 15, 30, 60, 90, and 120 minutes. Primary outcome was reduction in pain at 30 minutes. Secondary outcome was the incidence of rescue analgesia at 30 and 60 minutes. RESULTS: Forty-five patients per group were enrolled in the study. The primary change in mean pain scores was not significantly different in the ketamine and morphine groups: 8.6 versus 8.5 at baseline (mean difference 0.1; 95% confidence interval -0.46 to 0.77) and 4.1 versus 3.9 at 30 minutes (mean difference 0.2; 95% confidence interval -1.19 to 1.46; P=.97). There was no difference in the incidence of rescue fentanyl analgesia at 30 or 60 minutes. No statistically significant or clinically concerning changes in vital signs were observed. No serious adverse events occurred in either group. Patients in the ketamine group reported increased minor adverse effects at 15 minutes post-drug administration. CONCLUSION: Subdissociative intravenous ketamine administered at 0.3 mg/kg provides analgesic effectiveness and apparent safety comparable to that of intravenous morphine for short-term treatment of acute pain in the ED.

Diltiazem vs. Metoprolol in the Management of Atrial Fibrillation or Flutter with Rapid Ventricular Rate in the Emergency Department.

BACKGROUND: Diltiazem (calcium channel blocker) and metoprolol (beta-blocker) are both commonly used to treat atrial fibrillation/flutter (AFF) in the emergency department (ED). However, there is considerable regional variability in emergency physician practice patterns and debate among physicians as to which agent is more effective. To date, only one small prospective, randomized trial has compared the effectiveness of diltiazem and metoprolol for rate control of AFF in the ED and concluded no difference in effectiveness between the two agents. OBJECTIVE: Our aim was to compare the effectiveness of diltiazem with metoprolol for rate control of AFF in the ED. METHODS: A convenience sample of adult patients presenting with rapid atrial fibrillation or flutter was randomly assigned to receive either diltiazem or metoprolol. The study team monitored each subject's systolic and diastolic blood pressures and heart rates for 30 min. RESULTS: In the first 5 min, 50.0% of the diltiazem group and 10.7% of the metoprolol group reached the target heart rate (HR) of <100 beats per minute (bpm) (p < 0.005). By 30 min, 95.8% of the diltiazem group and 46.4% of the metoprolol group reached the target HR < 100 bpm (p < 0.0001). Mean decrease in HR for the diltiazem group was more rapid and substantial than that of the metoprolol group. From a safety perspective, there was no difference between the groups with respect to hypotension (systolic blood pressure < 90 mm Hg) and bradycardia (HR < 60 bpm). CONCLUSIONS: Diltiazem was more effective in achieving rate control in ED patients with AFF and did so with no increased incidence of adverse effects.

Characteristics That Define a Successful Pharmacy Resident as Perceived by Residency Programs.

PURPOSE: To identify the subjective and objective characteristics that pharmacy residency programs use to define a successful resident and to determine what percentage of their 2009-2010 residency class they felt were successful. METHODS: An electronic survey was sent via e-mail to all residency program directors (RPDs) of postgraduate year 1 (PGY1) and postgraduate year 2 (PGY2) pharmacy residency programs in the United States. A 3-part survey instrument was developed following validation of questions for clarity and reliability using a pilot survey. Respondents were asked to rank the importance of 20 subjective characteristics for a resident to possess in order to be considered successful and the importance of different objective measurements of accomplishment in the definition of a "successful" resident using a Likert scale where 1 = not at all important, 2 = some importance, 3 = very important, and 4 = critical. RESULTS: Of the 1,081 surveys sent to RPDs, 473 respondents answered at least one question, yielding a response rate of 43.8%. The most critically important subjective characteristics in defining a successful resident as ranked among PGY1 residency programs are dependability, professionalism, self-motivation/initiative, and work ethic. PGY2 programs ranked clinical knowledge and skills, critical thinking, and dependability as the most important. The most critically important objective characteristic in defining a successful resident as ranked among both PGY1 and PGY2 programs is obtaining a clinical position. The majority of PGY1 and PGY2 respondents felt that 76% to 100% of their 2009-2010 residency class was successful based on the characteristics they rated most important. CONCLUSION: Identification of the characteristics that pharmacy residency programs use to define success will allow them to identify predictors of success and optimal methods of selecting residents who possess these characteristics.

Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial.

BACKGROUND: Dacomitinib is an irreversible pan-HER tyrosine-kinase inhibitor with preclinical and clinical evidence of activity in non-small-cell lung cancer. We designed BR.26 to assess whether dacomitinib improved overall survival in heavily pretreated patients with this disease. METHODS: In this double-blind, randomised, placebo-controlled, phase 3 trial, we enrolled adults (aged ≥18 years) with advanced or metastatic non-small-cell lung cancer from 75 centres in 12 countries. Eligible patients had received up to three previous lines of chemotherapy and either gefitinib or erlotinib, and had assessable disease (RECIST 1.1) and tumour tissue samples for translational studies. Patients were stratified according to centre, performance status, tobacco use, best response to previous EGFR tyrosine-kinase inhibitor, weight loss within the previous 3 months, and ethnicity, and were then randomly allocated 2:1 to oral dacomitinib 45 mg once-daily or matched placebo centrally via a web-based system. Treatment continued until disease progression or unacceptable toxicity. The primary outcome was overall survival in the intention-to-treat population; secondary outcomes included overall survival in predefined molecular subgroups, progression-free survival, the proportion of patients who achieved an objective response, safety, and quality of life. This study is completed, although follow-up is ongoing for patients on treatment. This study is registered with ClinicalTrials.gov, number NCT01000025. FINDINGS: Between Dec 23, 2009, and June 11, 2013, we randomly assigned 480 patients to dacomitinib and 240 patients to placebo. At the final analysis (January, 2014), median follow-up was 23·4 months (IQR 15·6-29·6) for patients in the dacomitinib group and 24·4 months (11·5-38·9) for those in the placebo group. Dacomitinib did not improve overall survival compared with placebo (median 6·83 months [95% CI 6·08-7·49] for dacomitinib vs 6·31 months [5·32-7·52] for placebo; hazard ratio [HR] 1·00 [95% CI 0·83-1·21]; p=0·506). However, patients in the dacomitinib group had longer progression-free survival than those in the placebo group (median 2·66 months [1·91-3·32] vs 1·38 months [0·99-1·74], respectively; HR 0·66 [95% CI 0·55-0·79]; p<0·0001), and a significantly greater proportion of patients in the dacomitinb group achieved an objective response than in the placebo group (34 [7%] of 480 patients vs three [1%] of 240 patients, respectively; p=0·001). Compared with placebo, the effect of dacomitinib on overall survival seemed similar in patients with EGFR-mutation-positive tumours (HR 0·98, 95% CI 0·67-1·44) and EGFR wild-type tumours (0·93, 0·71-1·21; pinteraction=0·69). However, we noted qualitative differences in the effect of dacomitinib on overall survival for patients with KRAS-mutation-positive tumours (2·10, 1·05-4·22) and patients with KRAS wild-type tumours (0·79, 0·61-1·03; pinteraction=0·08). Compared with placebo, patients allocated dacomitinib had significantly longer time to deterioration of cough (p<0·0001), dyspnoea (p=0·049), and pain (p=0·041). 185 (39%) of 477 patients who received dacomitinib and 86 (36%) of 239 patients who received placebo had serious adverse events. The most common grade 3-4 adverse events were diarrhoea (59 [12%] patients on dacomitinib vs no controls), acneiform rash (48 [10%] vs one [<1%]), oral mucositis (16 [3%] vs none), and fatigue (13 [3%] vs four [2%]). INTERPRETATION: Dacomitinib did not increase overall survival and cannot be recommended for treatment of patients with advanced non-small-cell lung cancer previously treated with chemotherapy and an EGFR tyrosine-kinase inhibitor. FUNDING: Canadian Cancer Society Research Institute and Pfizer.

Real-World Evidence of the Impact of the COVID-19 Pandemic on Lung Cancer Survival: Canadian Perspective.

Background: The effect of COVID-19 on treatment outcomes in the literature remains limited and is mostly reported either as predictive survival using prioritization and modeling techniques. We aimed to quantify the effect of COVID-19 on lung cancer survival using real-world data collected at the Jewish General Hospital, Montreal. Methods: This is a retrospective chart review study of patients diagnosed between March 2019 and March 2022. We compared three cohorts: pre-COVID-19, and 1st and 2nd year of the pandemic. Results: 417 patients were diagnosed and treated with lung cancer at our centre: 130 in 2019, 103 in 2020 and 184 in 2021. Although the proportion of advanced/metastatic-stage lung cancer remained the same, there was a significant increase in the late-stage presentation during the pandemic. The proportion of M1c (multiple extrathoracic sites) cases in 2020 and 2021 was 57% and 51%, respectively, compared to 31% in 2019 (p < 0.05). Median survival for early stages of lung cancer was similar in the three cohorts. However, patients diagnosed in the M1c stage had a significantly increased risk of death. The 6-month mortality rate was 53% in 2021 compared to 47% in 2020 and 29% in 2019 (p = 0.004). The median survival in this subgroup of patients decreased significantly from 13 months in 2019 to 6 months in 2020 and 5 months in 2021 (p < 0.001). Conclusions: This study is, to our knowledge, the largest single-institution study in Canada looking at lung cancer survival during the COVID-19 pandemic. Our study looks at overall survival in the advanced/metastatic setting of NSCLC during the COVID-19 pandemic. We have previously reported on treatment pattern changes and increased wait times for NSCLC patients during the pandemic. In this study, we report that the advanced/metastatic subgroup had both an increase in the 6-month mortality rate and worsening overall survival during this same time period. Although there was no statistical difference in the proportion of patients with advanced disease, there was a concerning trend of increased M1c disease in cohorts 2 and 3. The higher M1c disease during the COVID-19 pandemic (cohorts 2 and 3) likely played a crucial role in increasing the 6-month mortality rate and leading to a reduced overall survival of lung cancer patients during the pandemic. These findings are more likely to be better identified with longer follow-up.

Using a Built-in Clinical Decision Support to Improve Phosphate Repletion Practice: A Quasi-Experimental Study.

BACKGROUND: Inpatient serum phosphate replacement is common, but there is great variability in replacement practice, which leads to overuse. Electronic health record (EHR) interventions with clinical decision support (CDS) can be effective tools to guide clinicians toward best clinical practices. The authors' objective was to use CDS tools to reduce overuse of hypophosphatemia corrections at a large safety-net health care system. METHODS: The first intervention involved enhancing an existing order set for phosphate repletion by incorporating CDS to guide appropriate repletion orders based on deficit severity and simplifying ordering. The second intervention was a Best Practice Advisory (BPA) that triggered when an intravenous (IV) phosphate repletion was ordered for a patient with mild to moderate phosphate deficiency without an existing nil per os (NPO) order. The primary outcome measure was the number of patients with mild and moderate hypophosphatemia receiving IV replacement without NPO orders per 1,000 patient-days. RESULTS: Across all hospitals, rate of IV replacement in patients with mild to moderate hypophosphatemia (1.0 to 1.9 mg/dL) without NPO orders decreased from 7.22 to 3.40 per 1,000 patient-days (53.0% reduction, p < 0.001), while the oral replacements in this population increased from 6.39 to 8.87 (38.8% increase, p < 0.001). For patients with phosphate levels ≥ 2.0, IV replacements decreased from 10.66 to 5.36 (49.8% reduction, p < 0.001), and oral replacements from decreased 19.78 to 16.69 (15.6% reduction, p < 0.01). CONCLUSION: This intervention successfully reduced inpatient IV phosphate replacements by 53.0% in patients with mild to moderate hypophosphatemia using a two-pronged EHR intervention across a large safety-net setting.

Choosing Wisely and Promoting High-Value Care and Staff Safety During the COVID-19 Pandemic in a Large Safety Net System.

BACKGROUND AND OBJECTIVES: As the COVID-19 pandemic brought surges of hospitalized patients, it was important to focus on reducing overuse of tests and procedures to not only reduce potential harm to patients but also reduce unnecessary exposure to staff. The objective of this study was to create a Choosing Wisely in COVID-19 list to guide clinicians in practicing high-value care at our health system. METHODS: A Choosing Wisely in COVID-19 list was developed in October 2020 by an interdisciplinary High Value Care Council at New York City Health + Hospitals, the largest public health system in the United States. The first phase involved gathering areas of overuse from interdisciplinary staff across the system. The second phase used a modified Delphi scoring process asking participants to rate recommendations on a 5-point Likert scale based on criteria of degree of evidence, potential to prevent patient harm, and potential to prevent staff harm. RESULTS: The top 5 recommendations included avoiding tracheal intubation without trial of noninvasive ventilation (4.4); not placing routine central venous catheters (4.33); avoiding routine daily laboratory tests and batching laboratory draws (4.19); not ordering daily chest radiographs (4.17); and not using bronchodilators in the absence of reactive airway disease (4.13). CONCLUSION: We successfully developed Choosing Wisely in COVID-19 recommendations that focus on evidence and preventing patient and staff harm in a large safety net system to reduce overuse.

Osimertinib is associated with improved outcomes in pre-treated non-small cell lung cancer leptomeningeal metastases: A systematic review and meta-analysiss.

Purpose: Leptomeningeal metastasis (LM) is a severe complication of non-small cell lung cancer (NSCLC). In patients with NSCLC LM harboring epidermal growth factor receptor (EGFR) mutations, osimertinib is favored over alternative EGFR tyrosine kinase inhibitors (TKIs). However, the efficacy of osimertinib relative to other EGFR-TKIs is not well established for patients with LM. We aimed to compare the efficacy of EGFR-TKIs in EGFR-mutated NSCLC LM. Methods: This systematic review and meta-analysis performed according to PRISMA guidelines included studies of adult patients with EGFR-mutated NSCLC and a diagnosis of LM who received an EGFR-TKI for the treatment of LM. We searched Medline ALL, Embase, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science Core Collection. The evaluation of biases was done by using the Ottawa-Newscastle scale. The hazard ratio was used as the parameter of interest for overall survival (OS) and central nervous system-specific progression-free survival (PFS). Results: 128 publications were included with 243 patients and 282 lines of EGFR-TKI for NSCLC LM that met inclusion criteria. The median PFS in patients receiving any EGFR-TKI was 9.1 months, and the median OS was 14.5 months. In univariate analyses of the entire cohort, osimertinib treatment demonstrated significantly prolonged PFS, but not OS, compared to other EGFR-TKIs. Osimertinib demonstrated significantly prolonged PFS and OS in the subset of patients who were previously treated with EGFR-TKIs, but not in EGFR-TKI naïve patients. Conclusion: Osimertinib is associated with improved outcomes compared to other EGFR-TKIs, particularly in patients previously treated with EGFR-TKIs. An important limitation is that most patients were derived from retrospective reports. These results highlight the need for prospective studies for this difficult-to-treat patient population.

Feasibility of a pharmacy-based influenza immunization program in an academic emergency department.

BACKGROUND: From September 2002 to August 2010, 13 patients who were discharged from the emergency department (ED) were immunized against influenza. This correlates with a time when pharmacists were not permitted to vaccinate patients in New York. OBJECTIVE: The objectives of this study were to determine the feasibility of a pharmacist-based influenza vaccination program in the ED, assess patients' willingness to be vaccinated by a pharmacist, and identify reasons for declination. METHODS: This was a cross-sectional study involving English-speaking patients older than 18 years. The pharmacist vaccinated patients, if they consented. Patients who refused to be vaccinated were asked why they did not want to receive the vaccine and their perception of pharmacists vaccinating patients in the ED. The percentage of patients vaccinated; time elements associated with the process of screening, counseling, and vaccinating; and the type and frequency of adverse events were recorded. RESULTS: Of 149 patients, 62 patients (41%) agreed to receive the vaccine, a 4-fold increase from the previous 8 years. The median screening and vaccination time was 8 minutes. Of those not receiving a vaccine in the ED, 74% were willing to receive the influenza vaccine from a pharmacist, and 78% were willing to receive the vaccine in the ED. The most common reason for refusal was perception of low self-risk (43.9%). No adverse events were reported. CONCLUSIONS: A pharmacist-based influenza immunization program is feasible in the ED and has the potential to successfully and safely increase the percentage of adult patients receiving the vaccine.

Cell-Free Tumor DNA (ctDNA) Utility in Detection of Original Sensitizing and Resistant EGFR Mutations in Non-Small Cell Lung Cancer (NSCLC).

BACKGROUND: Recent studies have demonstrated the utility of cell-free tumor DNA (ctDNA) from plasma as an alternative source of genomic material for detection of sensitizing and resistance mutations in NSCLC. We hypothesized that the plasma level of ctDNA is an effective biomarker to provide a non-invasive and thus a less risky method to determine new resistance mutations and to monitor response to treatment and tumor progression in lung cancer patients. METHODS: This prospective cohort study was approved and conducted at the Peter Brojde Lung Cancer Centre, Montreal. Blood was collected in STRECK tubes at four time points. DNA was extracted from plasma, and ctDNA was analyzed for the presence of mutations in the EGFR gene using the COBAS® EGFR v2 qPCR (Roche) test. RESULTS: Overall, 75 pts were enrolled in the study. In total, 23 pts were TKI-naïve, and 52 were already receiving first-line TKI treatment. ctDNA detected the original mutations (OM) in 35/75 (48%) patients. Significantly higher detection rates were observed in TKI-naïve patients compared to the TKI-treated group, 70% versus 37%, respectively (p = 0.012). The detection of the original mutation at the study baseline was a negative predictor of progression-free survival (PFS) and overall survival (OS). The resistance mutation (T790M) was detected in 32/74 (43%) patients. In 27/32 (84%), the T790M was detected during treatment with TKI: in 25/27 patients, T790M was detected at the time of radiologic progression, in one patient, T790M was detected before radiologic progression, and in one patient, T790M was detected four weeks after starting systemic chemotherapy post progression on TKI. At the time of progression, the detection of T790M significantly correlates with the re-appearance of OM (p = 0.001). CONCLUSION: Plasma ctDNA is a noninvasive patient-friendly test that can be used to monitor response to treatment, early progression, and detection of acquired resistant mutations. Monitoring of clearance and re-emergence of driver mutations during TKI treatment effectively identifies progression of the disease. As larger NGS panels are available for ctDNA testing, these findings may also have implications for other biomarkers. The results from ongoing and prospective studies will further determine the utility of plasma testing to diagnose, monitor for disease progression, and guide treatment decisions in NSCLC.

The Impact of COVID-19 on the Diagnosis and Treatment of Lung Cancer over a 2-Year Period at a Canadian Academic Center.

BACKGROUND: We have recently reported a 35% drop in new lung cancer diagnoses and a 64% drop in lung cancer surgeries during the first year of the pandemic. METHODS: The target population was divided into three cohorts: pre-COVID-19 (2019), first year of COVID-19 (2020), and second year of COVID-19 (2021). RESULTS: The number of new lung cancer diagnoses during the second year of the pandemic increased by 75%, with more than 50% being in the advanced/metastatic stage. There was a significant increase in cases with multiple extrathoracic sites of metastases during the pandemic. During the first year of the pandemic, significantly more patients were treated with radiosurgery compared to the pre-COVID-19 year. During the second year, the number of radiosurgery and surgical cases returned to pre-COVID-19 levels. No significant changes were observed in systemic chemotherapy and targeted therapy. No statistical difference was identified in the mean wait time for diagnosis and treatment during the three years of observation. However, the wait time for surgery was prolonged compared to the pre-COVID-19 cohort. CONCLUSIONS: The significant drop in new diagnoses of lung cancer during the first year of the pandemic was followed by an almost two-fold increase in the second year, with the increased rate of metastatic disease with multiple extra-thoracic site metastases. Limited access to surgery resulted in the more frequent use of radiosurgery.

The economic value of liquid biopsy for genomic profiling in advanced non-small cell lung cancer.

Background: Liquid biopsy (LB) can detect actionable genomic alterations in plasma circulating tumor circulating tumor DNA beyond tissue testing (TT) alone in advanced non-small cell lung cancer (NSCLC) patients. We estimated the cost-effectiveness of adding LB to TT in the Canadian healthcare system. Methods: A cost-effectiveness analysis was conducted using a decision analytic Markov model from the Canadian public payer (Ontario) perspective and a 2-year time horizon in patients with treatment-naïve stage IV non-squamous NSCLC and ⩽10 pack-year smoking history. LB was performed using the comprehensive genomic profiling Guardant360™ assay. Standard of care TT for each participating institution was performed. Costs and outcomes of molecular testing by LB + TT were compared to TT alone. Transition probabilities were calculated from the VALUE trial (NCT03576937). Sensitivity analyses were undertaken to assess uncertainty in the model. Results: Use of LB + TT identified actionable alterations in more patients, 68.5 versus 52.7% with TT alone. Use of the LB + TT strategy resulted in an incremental cost savings of $3065 CAD per patient (95% CI, 2195-3945) and a gain in quality-adjusted life-years of 0.02 (95% CI, 0.01-0.02) versus TT alone. More patients received chemo-immunotherapy based on TT with higher overall costs, whereas more patients received targeted therapy based on LB + TT with net cost savings. Major drivers of cost-effectiveness were drug acquisition costs and prevalence of actionable alterations. Conclusion: The addition of LB to TT as initial molecular testing of clinically selected patients with advanced NSCLC did not increase system costs and led to more patients receiving appropriate targeted therapy.

Cardiac arrest with residual blindness after overdose of Tessalon® (benzonatate) perles.

BACKGROUND: The extent to which benzonatate (Tessalon®), a structurally similar agent to other local anesthetics including tetracaine and procaine, poses a risk to the public is not fully appreciated as it is still one of the most widely prescribed antitussives available. OBJECTIVES: To report a case of cardiac arrest with residual blindness after Tessalon® overdose, review its clinical manifestations, toxicology and management considerations, and describe the need for rational prescribing. CASE REPORT: A 17-year-old woman with no previous medical history presented to the Emergency Department (ED) status post cardiac arrest. One to two hours prior, the patient had ingested at least 10 200-mg Tessalon® capsules as part of a suicide attempt. The patient was sedated, intubated, and given magnesium as prophylaxis against recurrent dysrhythmias. Emergent gastric lavage was performed and well tolerated. A 24-h hypothermia protocol with 6-h cooling period was initiated. Toxicological studies, chest radiograph, and a computed tomography scan of the head were all unremarkable. The patient was admitted to the Pediatric Intensive Care Unit for further work-up and supportive care. The patient was extubated and able to follow some commands 1 week post-admission. The patient developed blindness and experienced generalized confabulations, which did not resolve. CONCLUSION: Ingestion of Tessalon®, a seemingly innocuous and widely prescribed antitussive, may pose a risk to patients due to its potential for the rapid development of life-threatening adverse events and limited treatment options in the overdose setting. Rational prescribing and patient education is needed.

Tarka® (trandolapril/verapamil hydrochloride extended-release) overdose.

BACKGROUND: Patients with fixed-dose combination product overdoses involving verapamil and trandolapril may present differently than sole calcium channel blocker (CCB) or angiotensin-converting enzyme inhibitor (ACE-I) overdose alone, and may have implications for the toxicological management. The ACE-I component may confound the traditional response to antidotal and supportive therapy recommended for CCB overdoses. In such cases, it may be prudent to manage the trandolapril component concurrently while administering traditional CCB antidotes. OBJECTIVES: To report a probable case and review the toxicological management of a fixed-dose antihypertensive combination product toxicity involving verapamil and trandolapril (Tarka®). CASE REPORT: A 60-year-old man experienced dizziness and fell after ingesting five tablets of Tarka®. Eight hours later, he was found to be hypotensive and bradycardic. Therapy for CCB toxicity was initiated, including fluids, modified hyperglycemia-euglycemia insulin therapy, calcium chloride, activated charcoal, and glucagon. The patient's blood pressure and heart rate stabilized only after the administration and titration of dopamine and episodes of profuse vomiting in response to glucagon. The patient was transferred to the Cardiac Intensive Care Unit for further monitoring. He was considered stable to the point of all therapies being discontinued only 12 h post-ingestion. The patient was discharged 40 h after ingestion with no further sequelae. CONCLUSIONS: Lack of familiarity with the components of fixed-dose combination products poses a problem during overdose situations and may confound the presentation and delay resuscitation and acute stabilization.