Risk of Venous Thromboembolism in Patients with Lung Cancer Treated with Immune Checkpoint Inhibitors

Background: Thromboembolism (TE) in cancer significantly contributes to morbidity and mortality. Cancer immunotherapy is linked to several inflammatory immune mediated adverse events. Inflammation plays a key role in thrombosis but the association between immunotherapy and venous thromboembolism (VTE) has not been thoroughly investigated. Here, we report the incidence of thromboembolism in patients with lung cancer treated with immune checkpoint inhibitors (ICIs). Methods: A single institution retrospective cohort of 514 adult patients with lung cancer who received ICIs (pembrolizumab, nivolumab, atezolizumab, ipilumab, avelumab) between 2013 and 2017 was included. Diagnosis of VTE (deep vein thrombosis and/or pulmonary embolism, and visceral vein thrombosis "VVT") was confirmed by imaging. Overall survival (OS) was estimated by Kaplan-Meier and compared using log rank test. Cumulative incidence rate of VTE was estimated and compared using Gray's method. Results: Of 514 patients (pts), 58.75% were males, 83.27% were white with a median age of 67 (range 22-91). Nivolumab was most commonly used (52.14%), followed by Pembrolizumab (30.16%), Atezolizumab (10.89%), combination of ipilimumab plus nivolumab (6.61), ipilimumab (2.33%), Avelumab (1.17%). 88.52% had stage 4 disease at treatment initiation. VTE events occurred in 62 pts (12%) (3.5% DVT, 4.47% PE, 2.72% both, 0.97 VVT, 0.19 VVT + PE, 0.19% VVT+DVT+PE). The cumulative incidence rate of VTE of all pts at 6-month and 1-year post IO was 7.6% (95% CI:5.3-9.9%) and 11.6% (95% CI:8.7-14.6%) respectively. The rate of survival without VTE at 6 months after IO treatment was 91% (95% CI: 89-94%). None of the following factors (age, gender, race, cancer staging, IO type or line) were significantly associated with time-to-VTE (TTVTE) survival post treatment (P >0.05). Median OS of all pts was 12.6 months (95% CI: 11.0-16.7 months), with 2-year OS rate of 35% (95% CI: 31-41%). Conclusion: ICIs in lung cancer are associated with higher VTE risk within six months and a year of initiation of treatment. Further studies are needed to investigate the risk factors for ICIs-associated VTE. Disclosures Pennell: Astrazeneca: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; G1 therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Mirati Therapeutics, Inc.: Consultancy, Honoraria; Viosera Therapeutics: Consultancy, Honoraria; Eli Lilly: Consultancy, Honoraria; BMS: Consultancy, Honoraria. McCrae: Sanofi, Novartis, Alexion, and Johnson & Johnson: Consultancy, Honoraria; Dova, Novartis, Rigel, and Sanofi Genzyme: Consultancy. Khorana: Pfizer: Consultancy, Honoraria; Anthos: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Halozyme: Consultancy, Honoraria; Bayer: Consultancy, Honoraria.

The Correlation between temperature and COVID-19 Incidence: An ecologic study

Background It has been hypothesized that the COVID-19 is less prevalent in regions with warm climates. Here we investigated the correlation between temperature and the cumulative COVID-19 incidence rate. Method Daily data of the temperature and the cumulative COVID-19 incidence rate were obtained from meteorological stations’ reports and CORONALAB database, respectively, for every 36 counties of Fars province, southern Iran. Results A decreasing pattern in the cumulative incidence rate of COVID-19 was occurred at 20-25°C and 25-35°C for counties with the cold climate and counties with the warm climate, respectively; while it was increased at both upper and lower temperatures. Conclusion It appears that higher rates of disease transmission at temperatures below 20°C and above 35°C might be linked to people’s indoor gatherings, coupled with insufficient ventilation.

Incidence and Risk Factors of Epiretinal Membrane after Cataract Surgery

Purpose: To investigate the incidence and risk factors of epiretinal membrane (ERM) after cataract surgery.Methods: We reviewed the medical records of patients who underwent cataract surgery between January 2016 and December 2018. Eyes with ERM, as observed by optical coherence tomography performed 1-2 months after surgery, were excluded from the study. ERM was diagnosed by fundus photography. The incidence rate was determined 2-6, 6-12, and 12-24 months after surgery. The cumulative incidence rate of ERM was calculated by Kaplan-Meier analysis. Data were analyzed using logistic regression to determine the associations between ERM development and various factors.Results: The study included 218 eyes of 161 patients with a mean age of 66.6 ± 9.7 years at the time of surgery. ERM was observed in 3 of 218 eyes (1.4%) between 2 and 6 months, 15 of 176 eyes (8.3%) between 6 and 12 months, and 14 of 150 eyes (10.3%) between 12 and 24 months after surgery. The cumulative incidence rate of ERM was 11.7% over the 24-month period after surgery. In multivariate logistic regression analysis, older age (≥65 years; odds ratio [OR], 8.59, 95% confidence interval [CI], 1.43-51.49), fellow eye with ERM (OR, 3.63; 95% CI, 1.04-12.73), longer axial length (≥26 mm; OR, 8.02; 95% CI, 1.08-59.66), and complete posterior vitreous detachment development (OR, 7.48; 95% CI, 1.64-34.14) were significantly associated with ERM development.Conclusions: ERM is not rare after cataract surgery. Long-term retinal examination should be required after cataract surgery.

Stereotactic ablative radiotherapy in operable stage I NSCLC patients: Long-term results of the expanded STARS clinical trial.

8506 Background: We published a pooled analysis of 2 randomized trials (STARS/ROSEL) that compared lobectomy with mediastinal lymph node dissection (L-MLND) vs stereotactic ablative radiotherapy (SABR) in operable stage I NSCLC. There were no significant differences in disease progression but significantly higher 3-year overall survival (OS) in the SABR arm (95% vs 79%). Owing to concerns regarding the small sample size (n = 58), short follow-up (3 years), and non-uniform use of video-assisted thoracoscopic surgery (VATS), we expanded the STARS protocol to a single-arm SABR trial with a protocol-specified comparison to a published, longitudinally-followed institutional cohort of stage IA NSCLC status post VATS L-MLND (n = 229). Methods: Inclusion criteria were stage IA NSCLC (≤3 cm, N0M0 and staged by PET/CT with EBUS) with Zubrod performance status (PS) 0-2, baseline FEV1 > 40% and DLCO > 40% and deemed operable by a multidisciplinary team. SABR utilized 4-dimensional CT simulation and volumetric image guidance; 54 Gy in 3 fractions were delivered to planning target volumes (PTVs) located peripherally, or 50 Gy in 4 fractions to more central PTVs. All patients were followed by chest CT every three months for the first two years, every 6 months for another three years, and then annually. Non-inferiority of SABR could be claimed if the 3-year OS was not lower than the historical VATS L-MLND cohort by more than 12%. We conducted a risk-factor matched comparison study of the primary outcome between the SABR and the historical VATS L-MLND. Results: The median follow-up among the 80 SABR patients was 61 months (range, 34-79 months). The OS and progression-free survival (PFS) were 91% (95% CI: 85̃98%) and 80% (95% CI: 72̃89%) at 3 years, and 87% (95% CI: 79̃95%) and 77% (95% CI: 68̃87%) at 5 years, respectively. The 5-year cumulative incidence rate counting death as competing risk was 6.3% (95% CI: 2.3̃13.2%) local, 12.5% (95% CI: 6.4̃20.8%) regional, and 8.8% (95% CI: 3.8̃16.2%) distant (any recurrence 17.6% (95% CI: 10.1̃26.7%)). The 5 year cumulative incidence rate of second lung primary was 6.9% (95% CI: 2.5̃14.6%). There were 1.3% grade 3 and no grade 4-5 toxicities. The propensity score matched (age, gender, tumor size, histology, PS) comparison of SABR vs VATS L-MLND revealed no significant differences in PFS (p = 0.063), lung cancer-specific survival (p = 0.075), or cumulative incidence rates of local (p = 0.54), regional (p = 0.97), or distant failures (p = 0.33). The SABR arm was associated with significantly higher OS (91% vs 82% at 3 years and 87% vs 72% at 5 years; p = 0.012 from log-rank test). The hazard ratio was 0.411 (95% CI: 0.193̃0.875; p = 0.021). Conclusions: The long-term OS and PFS of SABR is not inferior to VATS L-MLND for operable stage IA NSCLC. SABR remains a promising approach for this population, but multidisciplinary management is strongly recommended. Clinical trial information: NCT02357992.

Depletion of circulating IgM memory B cells predicts unfavourable outcome in COVID-19

Impaired immune responses have been hypothesised to be a possible trigger of unfavourable outcomes in coronavirus disease 2019 (COVID-19). We aimed to characterise IgM memory B cells in patients with COVID-19 admitted to an internal medicine ward in Northern Italy. Overall, 66 COVID-19 patients (mean age 74 ± 16.6 years; 29 females) were enrolled. Three patients (4.5%; 1 female) had been splenectomised and were excluded from further analyses. Fifty-five patients (87.3%) had IgM memory B cell depletion, and 18 (28.6%) died during hospitalisation (cumulative incidence rate 9.26/100 person-week; 5.8–14.7 95% CI). All patients who died had IgM memory B cell depletion. A superimposed infection was found in 6 patients (9.5%), all of them having IgM memory B cell depletion (cumulative incidence rate 3.08/100 person-week; 1.3–6.8 95% CI). At bivariable analyses, older age, sex, number of comorbidities, and peripheral blood lymphocyte count < 1500/µl were not correlated with IgM memory B cell depletion. A discrete-to-marked reduction of the B-cell compartment was also noticed in autoptic spleen specimens of two COVID-19 patients. We conclude that IgM memory B cells are commonly depleted in COVID-19 patients and this correlates with increased mortality and superimposed infections.

Superiority of Thiotepa-Containing Conditioning Regimens in Patients with Primary Diffuse Large B-Cell Lymphoma (DLBCL) of the Central Nervous System (CNS) Undergoing Autologous Hematopoietic Cell Transplantation (autoHCT)

INTRODUCTION Primary DLBCL of the CNS (PCNSL) is a rare, extra-nodal non-Hodgkin lymphoma with high risk of relapse without consolidation therapies. AutoHCT has emerged as an accepted consolidation strategy, especially with increasing use of CNS penetrant chemotherapy agents in transplant conditioning. However, studies defining the optimal conditioning regimen for PCNSL have not been performed. The use of two common conditioning regimens in the U.S., thiotepa/busulfan/cyclophosphamide (TBC) and thiotepa/carmustine (TT-BCNU), is supported by phase II trials, but lack comparative data. Extrapolating experience from systemic lymphomas, BEAM (BCNU/etoposide/cytarabine/melphalan) is also prescribed for PCNSL in the U.S. Using the Center for International Blood & Marrow Transplant Research (CIBMTR) registry, we compared outcomes for PCNSL patients undergoing autoHCT using the three most commonly employed conditioning regimens: TBC vs. TT-BCNU vs. BEAM. METHODS Six hundred and eight adult PCNSL patients who underwent a first autoHCT between 2010-2018 were included. Conditioning regimens included TBC (n = 265), TT-BCNU (n = 278), and BEAM (n = 65). The primary endpoint was progression-free survival (PFS). Secondary endpoints included (a) time to hematopoietic recovery, (b) relapse/progression, (c) non-relapse mortality (NRM), and (d) overall survival (OS). Kaplan-Meier method was used to estimate probabilities of PFS and OS. Cox proportional hazard analysis was used to identify prognostic factors for relapse, NRM, PFS, and OS. Variables considered in regression model include patient age, sex, race, performance status, HCT-comorbidity index (HCT-CI), rituximab use during conditioning, interval between diagnosis and HCT, and remission status. Covariates with a p&lt;0.05 were considered significant. RESULTS Baseline characteristics are presented in Table 1. The groups were comparable with regards to median patient age, gender, race, HCT-CI, and remission status. The cumulative incidences of neutrophil recovery at 1-month for the three conditioning regimens were: TBC 96% (95%CI 94-98%), TT-BCNU 100% (95%CI 98-100%), and BEAM 100% (95%CI 100%), (p &lt; 0.001). The cumulative incidence rate of relapse for TBC, TT-BCNU, and BEAM at 1-year were 6% (95%CI 3-9%), 10% (95%CI 7-14%), and 23% (95%CI 14-35%), respectively (p = 0.003). The corresponding cumulative incidence rate of relapse at 3-years were 11% (95%CI 7-16%), 15% (95%CI 10-20%) and 37% (95%CI 25-50%) (p &lt; 0.001) respectively. The adjusted NRM were higher for TBC: 100-day 7% (95%CI 4-10%) and 1-year 11% (95%CI 7-15%), compared to TT-BCNU: 100-day 2% (95%CI 0.2-3%) and 1-year 4% (95%CI 2-6%), and BEAM: 100-day 0% (95%CI 0%) and 1-year 4% (95%CI 0-9%) (1-year p=0.01). The 3-year adjusted PFS across the three conditioning regimens were: TBC 75% (95%CI 69-81%), TT-BCNU 76% (95%CI 70-82%), and BEAM 58% (95%CI 46-70%) (p = 0.03) [Figure 1a]. The adjusted OS at 3-years were: TBC 81% (95%CI 75-86%), TT-BCNU 78% (95%CI 72-85%) and BEAM 69% (95%CI 58-80%), (p = 0.17) [Figure 1b]. Relapse of primary disease was the most common cause of death in all three cohorts: TBC 38% (n=20), TT-BCNU 72% (n=33) and BEAM 76% (n=19). Other significant causes of death in the TBC group included infections 15% (n=8) and organ failure 21% (n=11). CONCLUSIONS In this CIBMTR analysis in patients with PCNSL, we found favorable outcomes with thiotepa-containing conditioning regimens. Adjusted 3-year PFS favored TBC and TT-BCNU over BEAM and suggest that use of BEAM should be discouraged in this specific setting. Whether TBC or TT-BCNU is the optimal conditioning regimen requires further inquiry in a prospective clinical trial. Disclosures Scordo: McKinsey & Company: Consultancy; Omeros Corporation: Consultancy; Kite - A Gilead Company: Other: Ad-hoc advisory board; Angiocrine Bioscience, Inc.: Consultancy, Research Funding. Kharfan-Dabaja:Pharmacyclics: Consultancy; Daiichi Sankyo: Consultancy. Herrera:Pharmacyclics: Research Funding; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Research Funding; Immune Design: Research Funding; Seattle Genetics: Consultancy, Research Funding. Hamadani:Janssen R&D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Sanofi Genzyme, AstraZeneca: Speakers Bureau; Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Sauter:Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharamaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy, Research Funding; Kite - a Gilead Company: Consultancy; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Juno Therapeutics: Consultancy, Research Funding.

Community-level socioeconomic inequality in the incidence of ischemic heart disease: a nationwide cohort study

Background The purpose of this study was to confirm that inequalities in community-level social economic status (SES) do actually impact the incidence of ischemic heart disease (IHD) using the Korean population-based cohort study of the National Health Insurance Service–National Sample Cohort (NHIS-NSC) database. Methods This study used the NHIS-NSC database, a population-based cohort database established by the NHIS in South Korea. Community-level SES was classified into three categories, i.e. low, moderate, and high, according to the rank. The outcome measure of interest was IHD, which was defined according to the International Classification of Disease, 10th Revision (ICD-10) codes. Results In the low community-level SES group, the incidence of IHD was 3.56 per 1,000 person years (cumulative incidence rate, 1.78%), and in the high community level SES group, it was 3.13 per 1,000 person years (cumulative incidence rate, 1.57%). Multivariate analysis showed that the incidence of IHD was higher in the low community-level SES group (p=0.029). The log-rank test showed that the cumulative incidence of IHD was higher in the low community level SES group than the high community-level SES group (adjusted hazard ratio, 1.16; 95% CI, 1.01-1.32) Conclusions People living in areas with low community-level SES show an increased incidence of IHD. Therefore, intervention in active, health-risk behavior corrections at the local level will be required to reduce the incidence of IHD.

Community-level socioeconomic inequality in the incidence of ischemic heart disease: a nationwide cohort study

Background The purpose of this study was to confirm that inequalities in community-level social economic status (SES) do actually impact the incidence of ischemic heart disease (IHD) using the Korean population-based cohort study of the National Health Insurance Service–National Sample Cohort (NHIS-NSC) database. Methods This study used the NHIS-NSC database, a population-based cohort database established by the NHIS in South Korea. Community-level SES was classified into three categories, i.e. low, moderate, and high, according to the rank. The outcome measure of interest was IHD, which was defined according to the International Classification of Disease, 10th Revision (ICD-10) codes. Results In the low community-level SES group, the incidence of IHD was 3.56 per 1,000 person years (cumulative incidence rate, 1.78%), and in the high community level SES group, it was 3.13 per 1,000 person years (cumulative incidence rate, 1.57%). Multivariate analysis showed that the incidence of IHD was higher in the low community-level SES group (p=0.029). The log-rank test showed that the cumulative incidence of IHD was higher in the low community level SES group than the high community-level SES group (adjusted hazard ratio, 1.16; 95% CI, 1.01-1.32) Conclusions People living in areas with low community-level SES show an increased incidence of IHD. Therefore, intervention in active, health-risk behavior corrections at the local level will be required to reduce the incidence of IHD.

Incidence of Cancer after a Second Unprovoked Venous Thromboembolic Event

Patients with two unprovoked venous thromboembolism (VTE) events could be at high risk for cancer diagnosis and may therefore benefit from extended cancer screening strategies. However, accurate data on the incidence of cancer in this population is lacking. In a prospective cohort study, we followed-up with all patients who experienced two unprovoked symptomatic VTE events that occurred in less than 2 years apart. We estimated the 1-year incidence rate of cancer following the second unprovoked VTE event using the Kaplan–Meier method. Potential predictors for cancer diagnosis were assessed using a Cox proportional hazard regression model. Between May 2000 and December 2013, we included 197 patients with two episodes of symptomatic unprovoked VTE that occurred in less than 2 years apart. Their mean age was 66.2 ± 16.3 years, and 122 (51.8%) were male. Seventeen patients were diagnosed with cancer during the year following the second episode of unprovoked VTE, corresponding to a cumulative incidence rate of 9.19% (95% confidence interval [CI]: 5.81–14.37). The 1-year cumulative incidence rate of cancer was 35.88% (95% CI: 19.75–59.25) in patients with VTE recurrence on anticoagulation, 5.51% (95% CI: 2.9–10.32) among patients with a second episode of unprovoked VTE occurring after stopping anticoagulation and 1.15% (95% CI: 0.16–7.88) when time elapsed between the first and recurrent VTE was > 1 year. Our study suggests that the incidence of cancer in patients with a second episode of unprovoked VTE that occurs off anticoagulation, or > 1 year after the first event, is similar to that of patients with a first unprovoked VTE event.