Citations

TPS8584 Background: The first-line standard of care for the majority of patients (pts) with extensive-stage small-cell lung cancer (ES-SCLC) is platinum-based chemotherapy with etoposide, but survival outcomes remain poor (median OS, < 1 year) despite initial response rates ranging from 50-70%. Atezolizumab (atezo), an anti–PD-L1 mAb, prevents the binding of PD-L1 with its receptors PD-1 and B7.1 and restores anticancer T-cell activity. Tolerable safety with promising durability of response has been shown with atezo in pts with ES-SCLC: confirmed ORR was 6% (n = 1/17 [partial response]; DOR of 7 mo) by RECIST v1.1 and 24% by immune-related response criteria (irRC; n = 4/17, with 2 pts on atezo for ≥ 12 mo). Preliminary data also indicate the potential synergy between atezo and platinum-based chemotherapy in NSCLC, whereby durable responses may translate into improved survival over atezo alone. IMpower133 (NCT02763579), a global, Phase I/III, randomized, multicenter, double-blinded, placebo-controlled trial will evaluate the efficacy and safety of 1L atezo + carboplatin + etoposide compared with placebo + carboplatin + etoposide in treatment-naive pts with ES-SCLC. Methods: Pts with measurable (RECIST v1.1) ES-SCLC, who have ECOG PS 0-1 and no prior systemic anticancer treatment, are eligible for the study. Exclusion criteria include untreated CNS metastases and history of autoimmune disease. The study requires submission of tumor tissue, but pts will be enrolled regardless of biomarker status. Pts will be stratified by sex, ECOG PS and presence of treated brain metastases. Eligible pts will be randomized 1:1 to receive four 21-day cycles of atezo (1200 mg IV) or placebo in combination with carboplatin (AUC 5 mg/mL/min IV, d 1) and etoposide (100 mg/m2 IV, d 1-3), followed by maintenance therapy with atezo or placebo until PD per RECIST v1.1. Pts can continue with treatment until persistent radiographic PD, symptomatic deterioration or unacceptable toxicity. Co-primary endpoints are investigator-assessed PFS per RECIST v1.1 and OS. Secondary efficacy endpoints include investigator-assessed ORR and DOR. Safety and tolerability will also be assessed. Approximately 400 pts will be enrolled. Clinical trial information: NCT02763579.

ObjectiveTo confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder.MethodData were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth‐cohort, family history, polarity of first episode and country physician density.ResultsThere was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth‐cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth‐cohort (all estimated coefficientsP< 0.001).ConclusionA large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LEDlighting, mobile devices backlit withLEDs) may influence adaptability to a springtime circadian challenge.

ObjectiveTo study the relationship between serum hydroxychloroquine (HCQ) concentrations and flares of systemic lupus erythematosus (SLE) in a longitudinal cohort of patients.MethodsPatients who fulfilled ≥4 American College of Rheumatology classification criteria for SLE and had been treated with HCQ for >6 months were studied. Blood was assayed for HCQ levels by tandem mass spectrometry. Patients were serially assessed for disease activity, using the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and flares (SELENA flares instrument). Comparison of the mean summated SLEDAI scores over time and rates of flares in groups with different HCQ levels was performed by the Kruskal‐Wallis test.ResultsA total of 276 SLE patients were studied (93% women, mean ± SD age 41.0 ± 13.8 years). The proportion of patients with HCQ levels <10 (total noncompliance), 10–500 (subtherapeutic), and >500 ng/ml (therapeutic) was 11%, 77%, and 12%, respectively. HCQ levels correlated significantly with the prescribed dose but not with body weight or renal function. The prescribed HCQ dose also correlated significantly with baseline SLEDAI scores, indicating that higher doses were used for more active manifestations. After a mean ± SD observation period of 32.5 ± 5.5 months, the mean summated SLEDAI score and the incidence of SLE flares was not statistically different among patients with different baseline HCQ levels. In a subgroup of 73 patients with serologic and clinical remission and having therapeutic HCQ levels, a trend of lower disease activity and fewer incidences of flares was observed.ConclusionNoncompliance and subtherapeutic serum HCQ levels were seen frequently in these SLE patients, which was partly due to the low prescribed dose. In patients in remission, higher HCQ concentrations were associated with a trend showing fewer flares over time.

Background— The appropriate indication for coronary computed tomographic angiography (CTA) as a part of preoperative evaluation has not been defined yet. We investigated the value of coronary CTA in patients undergoing noncardiac surgery. Methods and Results— We included 844 patients (median age, 67 years; male sex, 62%) who underwent coronary CTA for screening of coronary artery disease before noncardiac surgery. Clinically determined revised cardiac risk index were compared with the extent and severity of coronary artery disease assessed by coronary CTA. Perioperative major cardiac event (PMCE), defined as cardiac death, myocardial infarction, or pulmonary edema within postoperative 30 days, developed in 25 patients (3.0%). Significant coronary CTA finding was defined as >3 any lesions with ≥1 (diameter stenosis ≥70%) stenosis based on the relationship between the severity of coronary artery disease and PMCE risk. The risk of PMCE was 14.0% in patients with significant CTA findings, whereas 2.2% of patients without significant CTA findings regardless of revised cardiac risk index score. The predictive performance of revised cardiac risk index could be improved significantly after addition of significant coronary CTA findings (c-statistics=0.631 versus 0.757; net reclassification improvement=0.923; integrated discrimination improvement=0.051). On the basis of revised cardiac risk index and coronary CTA, the risk of PMCE could be estimated with sensitivity, specificity, positive predictive value, and negative predictive value of 76%, 73%, 8%, and 99%, respectively. Conclusions— Addition of coronary CTA to clinical risk improved perioperative risk stratification. Absence of significant coronary CTA findings conferred low PMCE risk with high specificity and negative predictive value regardless of clinical risk. Coronary CTA may improve perioperative risk stratification in patients undergoing noncardiac surgery.