Outcomes of Antineoplastic Immunotherapy at a Large Healthcare Organization: Impact of Provider, Race and Socioeconomic Status.

Purpose: Disparities in cancer care delivery remain a pressing health-care crisis within the United States (US). The use of immune checkpoint inhibitors (ICIs) and their management may be a disparity generator that impacts survival. This retrospective study assessed disparities in a cohort of patients with a variety of solid tumors treated with ICIs within a single health-care organization focusing on the impact of race, socioeconomic status (SES) and site of care delivery on survival and the development of severe immune-related adverse events (irAEs). Patients and Methods: Manual chart review was performed on all patients with solid tumors treated with ICIs within a health-care organization from 2012 to 2018. Care delivery was dichotomized as DOP (disease-oriented provider at academic center) and COP (community oncology provider). Primary and secondary outcomes were overall survival (OS) and rates of grade 3-4 irAEs, respectively. Relationships with covariates of interest, including race, socioeconomic status and type of care delivery, were assessed among both outcomes. Results: A total of 1070 eligible patients were identified. Of those, 11.4% were of Black race, 59.7% had either non-small cell lung cancer (NSCLC) or melanoma and 82.8% had stage IV disease. Patients of Black race and lower SES were more likely to be treated by DOPs (p<0.0001). A superior OS was associated with care delivered by DOPs when compared to COPs (HR 0.68; 95% CI 0.56-0.84; p=0.0002), which was durable after accounting for race, SES, histopathologic diagnosis and disease stage. Melanoma patients experienced higher rates of severe irAEs (HR 2.37; 95% CI 1.42-3.97; p=0.001). Race, SES and site of care delivery were not related to rates of severe irAEs. Conclusion: In a large health-care organization, patients treated with checkpoint inhibitors by DOPs benefited from a significant OS advantage that was durable after controlling for racial and socioeconomic factors, providing evidence that disease-oriented care has the potential to mitigate racial and socioeconomic disparities.

Survival in elderly patients with breast cancer with and without autoimmune disease.

BACKGROUND: Patients with certain autoimmune conditions are at a reduced risk of developing breast cancer compared to the general population. Despite this, little is known about outcomes in patients with breast cancer who have a concurrent autoimmune diagnosis. METHODS: This study compared differences in outcomes between women with breast cancer who had or did not have an autoimmune diagnosis. The SEER-Medicare databases (2007-2014) were used to identify patients with breast cancer and diagnosis codes were used to identify those with an autoimmune disorder. RESULTS: The studied autoimmune diseases had a prevalence of 27% among the 137,324 patients with breast cancer. Autoimmune disease was associated with significantly longer overall survival (OS) and significantly lower cancer-specific mortality (CSM) among stage IV breast cancer patients (p < 0.0001). After controlling for the effects of age, race, chronic kideny disease, chemotherapy, and radiation therapy autoimmune disease was still predictive of improved OS (HR: 1.45, 95% CI: 1.35-1.55, p < 0.0001) and CSM (HR: 1.40, 95% CI: 1.29-1.5, p < 0.0001). By contrast, in patients with stage I-III breast cancer, the presence of an autoimmune diagnosis was associated with a lower OS (p < 0.0001, p < 0.0001, and p = 0.026, respectively), compared to patients without autoimmune disease. CONCLUSIONS: We found a higher prevalence of rheumatoid arthritis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus in patients with breast cancer compared to age matched cohorts in the general population. The presence of an autoimmune diagnosis was associated with a lower OS in stages I-III breast cancer and improved OS and CSM in patients with stage IV disease. These results suggest that anti-tumor immunity plays an important role in late stage breast cancer and could potentially be exploited to improve the effectiveness of immunotherapy.

Deep-learning-based hepatic fat assessment (DeHFt) on non-contrast chest CT and its association with disease severity in COVID-19 infections: A multi-site retrospective study.

BACKGROUND: Hepatic steatosis (HS) identified on CT may provide an integrated cardiometabolic and COVID-19 risk assessment. This study presents a deep-learning-based hepatic fat assessment (DeHFt) pipeline for (a) more standardised measurements and (b) investigating the association between HS (liver-to-spleen attenuation ratio <1 in CT) and COVID-19 infections severity, wherein severity is defined as requiring invasive mechanical ventilation, extracorporeal membrane oxygenation, death. METHODS: DeHFt comprises two steps. First, a deep-learning-based segmentation model (3D residual-UNet) is trained (N.ß=.ß80) to segment the liver and spleen. Second, CT attenuation is estimated using slice-based and volumetric-based methods. DeHFt-based mean liver and liver-to-spleen attenuation are compared with an expert's ROI-based measurements. We further obtained the liver-to-spleen attenuation ratio in a large multi-site cohort of patients with COVID-19 infections (D1, N.ß=.ß805; D2, N.ß=.ß1917; D3, N.ß=.ß169) using the DeHFt pipeline and investigated the association between HS and COVID-19 infections severity. FINDINGS: The DeHFt pipeline achieved a dice coefficient of 0.95, 95% CI [0.93...0.96] on the independent validation cohort (N.ß=.ß49). The automated slice-based and volumetric-based liver and liver-to-spleen attenuation estimations strongly correlated with expert's measurement. In the COVID-19 cohorts, severe infections had a higher proportion of patients with HS than non-severe infections (pooled OR.ß=.ß1.50, 95% CI [1.20...1.88], P.ß<.ß.001). INTERPRETATION: The DeHFt pipeline enabled accurate segmentation of liver and spleen on non-contrast CTs and automated estimation of liver and liver-to-spleen attenuation ratio. In three cohorts of patients with COVID-19 infections (N.ß=.ß2891), HS was associated with disease severity. Pending validation, DeHFt provides an automated CT-based metabolic risk assessment. FUNDING: For a full list of funding bodies, please see the Acknowledgements.

Machine learning derived ECG risk score improves cardiovascular risk assessment in conjunction with coronary artery calcium scoring.

Background: Precision estimation of cardiovascular risk remains the cornerstone of atherosclerotic cardiovascular disease (ASCVD) prevention. While coronary artery calcium (CAC) scoring is the best available non-invasive quantitative modality to evaluate risk of ASCVD, it excludes risk related to prior myocardial infarction, cardiomyopathy, and arrhythmia which are implicated in ASCVD. The high-dimensional and inter-correlated nature of ECG data makes it a good candidate for analysis using machine learning techniques and may provide additional prognostic information not captured by CAC. In this study, we aimed to develop a quantitative ECG risk score (eRiS) to predict major adverse cardiovascular events (MACE) alone, or when added to CAC. Further, we aimed to construct and validate a novel nomogram incorporating ECG, CAC and clinical factors for ASCVD. Methods: We analyzed 5,864 patients with at least 1 cardiovascular risk factor who underwent CAC scoring and a standard ECG as part of the CLARIFY study (ClinicalTrials.gov Identifier: NCT04075162). Events were defined as myocardial infarction, coronary revascularization, stroke or death. A total of 649 ECG features, consisting of measurements such as amplitude and interval measurements from all deflections in the ECG waveform (53 per lead and 13 overall) were automatically extracted using a clinical software (GE Muse™ Cardiology Information System, GE Healthcare). The data was split into 4 training (Str) and internal validation (Sv) sets [Str (1): Sv (1): 50:50; Str (2): Sv (2): 60:40; Str (3): Sv (3): 70:30; Str (4): Sv (4): 80:20], and the results were compared across all the subsets. We used the ECG features derived from Str to develop eRiS. A least absolute shrinkage and selection operator-Cox (LASSO-Cox) regularization model was used for data dimension reduction, feature selection, and eRiS construction. A Cox-proportional hazards model was used to assess the benefit of using an eRiS alone (Mecg), CAC alone (Mcac) and a combination of eRiS and CAC (Mecg+cac) for MACE prediction. A nomogram (Mnom) was further constructed by integrating eRiS with CAC and demographics (age and sex). The primary endpoint of the study was the assessment of the performance of Mecg, Mcac, Mecg+cac and Mnom in predicting CV disease-free survival in ASCVD. Findings: Over a median follow-up of 14 months, 494 patients had MACE. The feature selection strategy preserved only about 18% of the features that were consistent across the various strata (Str). The Mecg model, comprising of eRiS alone was found to be significantly associated with MACE and had good discrimination of MACE (C-Index: 0.7, p = <2e-16). eRiS could predict time-to MACE (C-Index: 0.6, p = <2e-16 across all Sv). The Mecg+cac model was associated with MACE (C-index: 0.71). Model comparison showed that Mecg+cac was superior to Mecg (p = 1.8e-10) or Mcac (p < 2.2e-16) alone. The Mnom, comprising of eRiS, CAC, age and sex was associated with MACE (C-index 0.71). eRiS had the most significant contribution, followed by CAC score and other clinical variables. Further, Mnom was able to identify unique patient risk-groups based on eRiS, CAC and clinical variables. Conclusion: The use of ECG features in conjunction with CAC may allow for improved prognostication and identification of populations at risk. Future directions will involve prospective validation of the risk score and the nomogram across diverse populations with a heterogeneity of treatment effects.

Socioeconomic Factors and Survival of Multiple Myeloma Patients.

BACKGROUND: Outcome of Multiple Myeloma (MM) patients has improved as the result of the introduction of novel medications and use of autologous hematopoietic cell transplantation. However, this improvement comes at the expense of increased financial burden. It is largely unknown if socioeconomic factors influence MM survival. METHODS: We used the National Cancer Database, a database that houses data on 70% of cancer patients in the US, to evaluate the effect of socioeconomic factors on the survival of 117,926 MM patients diagnosed between 2005 and 2014. RESULTS: Patients aged ≥65 years who were privately insured lived longer than patients with Medicare (42 months vs. 31 months, respectively, p < 0.0001). Treatment in academic institutions led to better survival (HR: 1.49, 95% CI: 1.39, 1.59). Younger age, fewer comorbidities, treatment in academic centers, and living in a higher median income area were significantly associated with improved survival. After adjusting for confounders, survival of Medicare patients was similar to those with private insurance. However, the hazard of death remained higher for patients with Medicaid (HR: 1.59, 95% CI: 1.36, 1.87) or without insurance (HR: 1.62, 95% CI: 1.32, 1.99), compared to privately insured patients. CONCLUSION: Economic factors and treatment facility type play an important role in the survival of MM patients.

Efficacy and cost-benefit of filgrastim administered after early assessment bone marrow biopsy during induction therapy for acute myeloid leukemia.

The role of filgrastim during acute myeloid leukemia (AML) induction therapy remains controversial. At our institution, newly diagnosed AML patients from 2003 through 2019 were retrospectively evaluated. Patients were stratified on whether they received filgrastim within 5 days after early assessment bone marrow (BMBx) and divided into early GCSF group (eGCSF) and no-eGCSF group. A total of 121 patients were included. We found significantly shorter hospital stay (median 24 vs 26 days, p < .01), absolute neutrophil count recovery days (median 23 vs 25 days, p = .03), and intravenous antibiotics days (mean 18.5 vs 21.4 days, p = .01) in patients with eGCSF comparing with no-eGCSF. There was no significant difference regarding complete response rates; however, for those failed to achieve remission, eGCSF was associated with higher blast count. There was no significant difference regarding overall survival or progression-free survival. The use of eGCSF was associated with cost savings of $5199 per patient over no-eGCSF.

Temporal Pattern of Co-Development of Internalizing and Externalizing Problem Behaviors: An Application of Bivariate Mixed-Effects Models.

BACKGROUND: Although previous research has shown that internalizing and externalizing behavior problems often co-occur, the relationship between the developmental trajectories of these two types of behavior problems is understudied. The co-occurring evolutions of developmental trajectories of two behaviors has two components: 1) the correlation between the slopes of two behavior profiles (termed the association of the evolutions); and 2) the marginal correlation of two development trajectory profiles, which is the development of correlation between internalizing and externalizing behavior over time (termed the evolution of the association). The association of the evolutions and the evolution of the association have not been fully explored in the context of the development of internalizing and externalizing behavior problems among kindergarteners in the United States. METHODS: The random-effects approach for joint modeling of multivariate longitudinal profiles was used to evaluate the co-development and its temporal pattern of internalizing and externalizing behavior problems on a nationally representative sample of 9791 kindergarteners from the Early Childhood Longitudinal Study-Kindergarten Class of 1998-99 (ECLS-K). RESULTS: There was a moderate positive association between the evolutions of the two behavior problems with correlation coefficient of 0.319. The evolution of association between the two behaviors was increasing over time with the correlation coefficient from 0.195 at the Fall of kindergarten to 0.291 by the time of fifth grade in general. Race and age groups act differently on the evolution of association. The associations were getting stronger for the Asian group and older groups than their peer groups. CONCLUSION: This investigation of the association of evolutions and the evolution of association between the internalizing and externalizing behaviors show that the two problem behaviors reciprocally reinforce each other and lead to increases in the other in a moderate strength and the strength is increasing over time.

Indices to measure risk of HIV acquisition in Rakai, Uganda.

INTRODUCTION: Targeting most-at-risk individuals with HIV preventive interventions is cost-effective. We developed gender-specific indices to measure risk of HIV among sexually active individuals in Rakai, Uganda. METHODS: We used multivariable Cox proportional hazards models to estimate time-to-HIV infection associated with candidate predictors. Reduced models were determined using backward selection procedures with Akaike's information criterion (AIC) as the stopping rule. Model discrimination was determined using Harrell's concordance index (c index). Model calibration was determined graphically. Nomograms were used to present the final prediction models. RESULTS: We used samples of 7,497 women and 5,783 men. 342 new infections occurred among females (incidence 1.11/100 person years,) and 225 among the males (incidence 1.00/100 person years). The final model for men included age, education, circumcision status, number of sexual partners, genital ulcer disease symptoms, alcohol use before sex, partner in high risk employment, community type, being unaware of a partner's HIV status and community HIV prevalence. The Model's optimism-corrected c index was 69.1 percent (95% CI = 0.66, 0.73). The final women's model included age, marital status, education, number of sex partners, new sex partner, alcohol consumption by self or partner before sex, concurrent sexual partners, being employed in a high-risk occupation, having genital ulcer disease symptoms, community HIV prevalence, and perceiving oneself or partner to be exposed to HIV. The models optimism-corrected c index was 0.67 (95% CI = 0.64, 0.70). Both models were well calibrated. CONCLUSION: These indices were discriminative and well calibrated. This provides proof-of-concept that population-based HIV risk indices can be developed. Further research to validate these indices for other populations is needed.

Multi-institutional phase I trials of anticancer agents.

PURPOSE: Physicians involved in the conduct of phase I studies of novel anticancer agents have raised concerns about the emergence of multi-institutional phase I trials and about using the optimal biologic dose (OBD) as an alternative to the maximum-tolerated dose (MTD) as the primary end point in early drug development. We sought to determine the factors associated with multi-institutional phase I studies and OBD determination. PATIENTS AND METHODS: We reviewed all published phase I trials between January 1998 and June 2006 from two major clinical cancer journals. The following components from each trial were determined: number of participating sites, sponsor, nation where study was conducted, MTD or OBD established, number of patients accrued, mechanism of action of the studied agent, accrual time, and tumor type. RESULTS: We identified 463 trials. Fifty-six percent were performed in single institutions. Only 30% reported accrual time. The number of patients enrolled on single institution studies was significantly lower than on multi-institutional studies (P < .05), but there was no difference in accrual time. There was no association between the number of institutions and the sponsor or the mechanism of drug action. National Institutes of Health-sponsored trials enrolled fewer patients per trial than pharmaceutical-sponsored trials (P < .05). Although 99% of trials with cytotoxic agents determined an MTD, only 64% of trials with targeted agents did. CONCLUSION: Multi-institutional phase I studies do not decrease the time to study completion and result in an increase in number of patients per trial. One third of trials with targeted agents failed to determine an MTD.

Capacity building for the clinical investigation of AIDS malignancy in East Africa.

PURPOSE: To build capacity in the resource-poor setting to support the clinical investigation and treatment of AIDS-related malignancies in a region of the world hardest hit by the AIDS pandemic. METHODS: An initial MEDLINE database search for international collaborative partnerships dedicated to AIDS malignancies in developing countries failed to identify any leads. This search prompted us to report progress on our collaboration in this aspect of the epidemic. Building on the formal Uganda-Case Western Reserve University (Case) Research Collaboration dating back to 1987, established NIH-supported centers of research excellence at Case, and expanding activities in Kenya, scientific and training initiatives, research capital amongst our institutions are emerging to sustain a international research enterprise focused on AIDS and other viral-related malignancies. RESULTS: A platform of clinical research trials with pragmatic design has been developed to further enhance clinical care and sustain training initiatives with partners in East Africa and the United States. An oral chemotherapy feasibility trial in AIDS lymphoma is near completion; a second lymphoma trial of byrostatin and vincristine is anticipated and a feasibility trial of indinavir for endemic Kaposi's sarcoma is planned. CONCLUSIONS: In the absence of published reports of evolving international partnerships dedicated to AIDS malignancy in resource constrained settings, we feel it important for such progress on similar or related international collaborative pursuits to be published. The success of this effort is realized by the long-term international commitment of the collaborating investigators and institutions to sustain this effort in keeping with ethical and NIH standards for the conduct of research; the provision of formal training of investigators and research personnel on clinical problems our East African partners are faced with in practice and the development of pragmatic clinical trials and therapeutic intervention to facilitate technology transfer and enhance clinical practice.