Intrapatient variation in PD-L1 expression and tumor mutational burden and the impact on outcomes to immune checkpoint inhibitor therapy in patients with non-small-cell lung cancer.

BACKGROUND: Programmed death receptor ligand 1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden (TMB) are key predictive biomarkers for immune checkpoint inhibitor (ICI) efficacy in non-small-cell lung cancer (NSCLC). Data on their variation across multiple samples are limited. PATIENTS AND METHODS: Patients with NSCLC and multiple PD-L1 TPS and/or TMB assessments were included. Clinicopathologic and genomic data were analyzed according to PD-L1 and TMB variation. RESULTS: In total, 402 PD-L1 sample pairs and 413 TMB sample pairs were included. Concordance between pairs was moderate for PD-L1 (ρ = 0.53, P < 0.0001) and high for TMB (ρ = 0.80, P < 0.0001). Shorter time between biopsies correlated with higher concordance in PD-L1, but not in TMB. Major increases (ΔTPS ≥ +50%) and decreases (ΔTPS ≤ -50%) in PD-L1 were observed in 9.7% and 8.0% of cases, respectively. PD-L1, but not TMB, decreased with intervening ICI (P = 0.02). Acquired copy number loss of CD274, PDCD1LG2, and JAK2 were associated with major decrease in PD-L1 (q < 0.05). Among patients with multiple PD-L1 assessments before ICI, cases where all samples had a PD-L1 ≥1%, compared to cases with at least one sample with PD-L1 <1% and another with PD-L1 ≥1%, achieved improved objective response rate and progression-free survival (PFS). Among patients with at least one PD-L1 <1% and one ≥1% before ICI, cases where the most proximal sample was PD-L1 ≥1% had longer median PFS compared to cases where the most proximal PD-L1 was <1%. Among patients with multiple TMB assessments before ICI, patients with a TMB ≥10 mut/Mb based on the most recent assessment, as compared to those with a TMB <10 mut/Mb, achieved improved PFS and overall survival to ICI; instead, no differences were observed when patients were categorized using the oldest TMB assessment. CONCLUSIONS: Despite intrapatient concordance in PD-L1 and TMB, variation in these biomarkers can influence ICI outcomes, warranting consideration for reassessment before ICI initiation when feasible.

Impact of direct-acting antiviral treatment of hepatitis C on the quality of life of adults in Ukraine.

BACKGROUND: Direct-acting antivirals (DAAs) are highly effective in achieving sustained virologic response among those with chronic hepatitis C virus (HCV) infection. Quality of life (QOL) benefits for an HCV-infected population with high numbers of people who inject drugs and people living with HIV (PLHIV) in Eastern Europe have not been explored. We estimated such benefits for Ukraine. METHODS: Using data from a demonstration study of 12-week DAA conducted in Kyiv, we compared self-reported QOL as captured with the MOS-SF20 at study entry and 12 weeks after treatment completion (week 24). We calculated domain scores for health perception, physical, role and social functioning, mental health and pain to at entry and week 24, stratified by HIV status. RESULTS: Among the 857 patients included in the final analysis, health perception was the domain that showed the largest change, with an improvement of 85.7% between entry and week 24. The improvement was larger among those who were HIV negative (104.4%) than among those living with HIV (69.9%). Other domains that showed significant and meaningful improvements were physical functioning, which improved from 80.5 (95% CI 78.9-82.1) at study entry to 89.4 (88.1-90.7) at 24 weeks, role functioning (64.5 [62.3-66.8] to 86.5 [84.9-88.2]), social functioning (74.2 [72.1-76.2] to 84.8 [83.2-86.5]) and bodily pain (70.1 [68.2-72.0] to 89.8 [88.5-91.1]). Across all domains, QOL improvements among PLHIV were more modest than among HIV-negative participants. CONCLUSION: QOL improved substantially across all domains between study entry and week 24. Changes over the study period were smaller among PLHIV.

Ambulatory myocardial ischaemia in stable angina.

Episodes of ischaemic ST segment depression detected by continuous ambulatory electrocardiographic (Holter) monitoring have been extensively investigated for over two decades, but no consensus has emerged about their clinical significance. This review examines the prevalence and reported prognostic importance of ambulatory myocardial ischaemia in patients with stable angina, and discusses whether or not detection and treatment of ischaemic episodes in ambulant angina patients can be justified on the basis of the available evidence.

Incidence, clinical characteristics, and short-term prognosis of angina pectoris.

OBJECTIVES: To estimate the clinical incidence and short-term prognosis of patients presenting with typical angina pectoris in the general population. DESIGN: Prospective survey of all patients referred by 117 general practitioners from a random sample of 17 general practices serving a population of 191,677 with a median follow up of 16 months. SETTING: A special open access chest pain clinic, based in the non-invasive cardiology department of a teaching hospital, set up for this study. PATIENTS: 110 consecutive patients < or = 70 years age with no history of coronary heart disease presenting for the first time with typical angina. MAIN OUTCOME MEASURES: Age and sex specific incidences, persistence of chest pain, revascularisation procedures, myocardial infarction, and death. RESULTS: The crude annual incidence of angina pectoris (95% confidence interval) was 0.83 (0.66 to 1.0) per thousand population aged 31-70 years; the rates were 1.13 (0.85 to 1.40) for men and 0.53 (0.33 to 0.72) for women. On resting electrocardiography 5% of patients had > or = 1 mm horizontal or downsloping ST depression, 5% had Q/QS patterns, and in one (1%) there was complete left bundle branch block. Among the 103 patients who underwent a Bruce protocol exercise test, 29% had > or = 3 mm ST segment depression induced at a low workload. Of 107 patients at a median (range) follow up of 15.8 (7-30) months, angina remitted spontaneously in 12 patients (11%), 20 (19%) underwent revascularisation, eight (7%) sustained a non-fatal myocardial infarction, and four (4%) died. CONCLUSION: Incidence of new cases of angina pectoris in the United Kingdom is conservatively estimated from this study to be 22,600 patients per annum. Almost one third of these patients will have positive exercise tests at low workload, so the potential for coronary angiography and revascularisation is considerable. With one in 10 patients experiencing a non-fatal myocardial infarction or coronary death within a year of presentation the prognosis of angina is not benign. Further research is required to identify those patients in the general population who would benefit most from coronary revascularisation.

Management of angina pectoris in general practice: a questionnaire survey of general practitioners.

BACKGROUND: Little is known about the current management of angina pectoris in general practice. AIM: This survey set out to assess general practitioners' perceptions of current investigation and treatment for angina pectoris. METHOD: A postal questionnaire was sent to all 217 general practitioners listed with the Hampshire Family Health Services Authority who have access to a regional cardiac centre in Southampton. RESULTS: The response rate was 79% (171 of 217). The majority (80%) of general practitioners reported referring 10% or fewer of their patients with angina to a cardiologist at the regional centre, and 72% reported referring a quarter or fewer of their patients to a hospital physician. Most (77%) considered an exercise test useful for diagnosis of angina, but almost half (47%) were uncertain about its prognostic value. Most respondents (79%) were not confident of interpreting the results of an exercise test. The majority (79%) believed that there was scientific evidence to show that coronary angioplasty relieves symptoms and 21% were of the opinion that it prolongs survival. Ninety six per cent believed coronary artery bypass grafting relieves symptoms and 62% that it prolongs survival. CONCLUSION: General practitioners do not appear to refer the majority of patients with angina pectoris for hospital investigation, and express divergent and contradictory opinions about exercise testing and the scientific evidence for the benefits of coronary angioplasty and coronary artery bypass surgery. Easier access to cardiological investigation and population based data about the value of exercise testing and survival benefits from coronary intervention are required to optimize selection of patients in the community who are most likely to benefit from coronary revascularization.

Characteristics and clinical significance of ambulatory myocardial ischemia in men and women in the general population presenting with angina pectoris.

OBJECTIVES: The aim of this study was to determine the frequency and prognostic importance of ambulatory myocardial ischemia and its association with cardiovascular risk factors in men and women in the general population presenting for the first time with typical angina pectoris. BACKGROUND: Previous studies in selected "low" and "high" risk patients with stable coronary heart disease report a wide range in the frequency of ischemia (24% to 82%) and there is no agreement about whether ambulatory ischemia is of prognostic importance for the generality of patients with stable angina. METHODS: Consecutive patients < or = 70 years of age from a randomly selected population with no previous coronary heart disease were assessed prospectively, and 96 patients with typical angina and 95 age-, gender- and practice-matched asymptomatic control subjects underwent 24-h ambulatory ST segment monitoring before antianginal therapy. All recordings were analyzed in blinded fashion. Follow-up evaluation of patients with angina to assess for revascularization, myocardial infarction and death was undertaken at a mean of 15.8 months (range 7 to 30) after the initial evaluation. RESULTS: Transient episodes of ischemic ST segment depression were detected in 50 patients (52%) with angina and 9 control subjects (9%). In patients with angina, 159 episodes (71%) were silent, median duration of ischemia was 66 min (range 1 to 782) and mean +/- SD ST depression was 2.4 +/- 1.1 mm. In logistic regression analysis, serum cholesterol (p < 0.05) and ischemia on exercise (p < 0.01) were independently associated with the presence of ambulatory ischemia in men with angina, but only the latter was significant in women; this may reflect a different pathophysiologic basis for ambulatory ischemia in women. During follow-up, there were 29 events. Kaplan-Meier survival analysis revealed no significant difference in event-free survival between patients with angina who did and did not have ischemic episodes (66% vs. 72%, p = NS). CONCLUSIONS: This is the first study representative of new patients with angina pectoris in the general population and shows that ischemia during daily living activities is present in > 50% of these patients but appears to be of no prognostic value.