The Lymphoma Epidemiology of Outcomes cohort study: Design, baseline characteristics, and early outcomes.

To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18-99). Participants came from 49 US states and included 538 Black/African-Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 years, and 1513 rural residents. At study baseline, we abstracted clinical, pathology, and treatment data; banked serum/plasma (N = 5883, 76.0%) and germline DNA (N = 5465, 70.7%); constructed tissue microarrays for four major NHL subtypes (N = 1189); and collected quality of life (N = 5281, 68.3%) and epidemiologic risk factor (N = 4489, 58.0%) data. Through August 2022, there were 1492 deaths. Compared to population-based SEER data (2015-2019), LEO participants had a similar distribution of gender, AA race, Hispanic ethnicity, and NHL subtype, while LEO was underrepresented for patients who were Asian and aged 80 years and above. Observed overall survival rates for LEO at 1 and 2 years were similar to population-based SEER rates for indolent B-cell (follicular and marginal zone) and T-cell lymphomas, but were 10%-15% higher than SEER rates for aggressive B-cell subtypes (diffuse large B-cell and mantle cell). The LEO cohort is a robust and comprehensive national resource to address the role of clinical, tumor, host genetic, epidemiologic, and other biologic factors in NHL prognosis and survivorship.

Characterizing Outcomes in Visceral Cutaneous T-Cell Lymphoma: A Single Center Retrospective Study.

INTRODUCTION: Visceral involvement of cutaneous T-cell lymphoma (vCTCL) is a rare but poorly studied complication of CTCL. We aimed to assess clinical characteristics, treatment, and outcomes, associated with vCTCL at our institution. METHODS: We conducted a retrospective review of patients with vCTCL among patients with a confirmed histopathologic diagnosis of CTCL seen at the Winship Cancer Institute in Emory University. vCTCL was defined as a highest TNMB stage of 4B with extracutaneous metastatic disease (M1) pathologically confirmed or strongly clinically suspected based on imaging, symptoms, and the clinical judgment of the treating physician. Patients were selected from our CTCL database containing 656 patients from 1990 to 2022. Clinical characteristics were characterized. Clinical outcomes were measured as overall survival (OS) and progression-free survival (PFS) using Kaplan-Meier curve and univariable Cox regression analysis. RESULTS: Twenty-six of 656 patients with vCTCL were identified. 42.3% of patients were black. Twenty-two patients were diagnosed with MF/SS and 4 had other CTCL subtypes including pcALCL, Gamma-Delta, and Cytotoxic T-Cell Lymphoma. The median PFS and OS were 7.3 months (3.8, 11) and 12.1 months (9.9, 18.2), respectively. Median time to metastasis from initial diagnosis was 12.1 months. The most common M1 sites were liver (19.2%) and lung (42.3%). M1 sites outside of liver or lung were associated with inferior OS (HR 8.9, 95%CI: 2.7-29.5, P-value <.001) and PFS (HR 4.3, 95%CI: 1.44-12.7, P-value = .009). No treatments or baseline factors were associated with improved survival. CONCLUSION: Our retrospective study confirms therapy resistance and dismal outcomes among patients with vCTCL.

Clinical Presentation and Outcome Differences Between Black Patients and Patients of Other Races and Ethnicities With Mycosis Fungoides and Sézary Syndrome.

Importance: Mycosis fungoides and Sézary syndrome (MF/SS) has an increased incidence in Black patients, but clinical characteristics, treatments, and outcomes have been poorly characterized. Objective: To assess racial differences in presentation and outcome and identify drivers for racial disparities in MF/SS. Design, Setting, and Participants: A retrospective cohort analysis was conducted of 566 patients with MF/SS diagnosed from 1990 to 2020 and seen at the Winship Cancer Institute of Emory University and Grady Memorial Hospital, both in Atlanta, Georgia. Self-reported race and ethnicity were obtained from patient medical records and analyzed as 2 groups: non-Hispanic Black (Black) and all other races and ethnicities, including Asian, Hispanic, White, and unknown/undeclared (non-Black). Main Outcomes and Measures: Univariate and multivariable models and Kaplan-Meier assessments were analyzed for overall survival and time to next treatment. The primary outcome was to assess differences in overall survival by racial and ethnic group. The hypotheses were formulated prior to data collection. Results: Of the 566 patients with MF/SS identified (mean [SD] age 55 [16.4] years; 270 (47.7%) female), 257 were Black and 309 were non-Black. Black race was associated with increased rates of progression to a higher TNMB stage (39.8% in Black patients vs 29.1% in non-Black patients; P < .001) but not survival. Black patients were younger and had increased female predominance, higher TNMB stage, higher tumor stage, nodal involvement, and higher lactate dehydrogenase level compared with non-Black patients with MF/SS. Hypopigmented MF (HMF) was found in 62 patients, who were mostly Black (n = 59). Hypopigmented MF was significantly associated with survival on univariate and multivariable models, with 10-year survival of 100% in patients with HMF compared with 51.8% in patients without HMF. Black race was only associated with inferior outcomes after excluding patients with HMF who were younger than 60 years (hazard ratio [HR], 1.61; 95% CI, 1.02-2.55; P = .04), but not in patients older than 60 years (HR, 1.20; 95% CI, 0.80-1.81; P = .37). On multivariate analysis, among the cohort without HMF who were younger than 60 years, Black race remained statistically significant when controlling for cancer stage and large-cell transformation (HR, 1.27; 95% CI, 1.08-2.87; P = .43). Conclusions and Relevance: In this cohort study, Black patients with MF/SS showed distinct clinical presentations and patterns of progression with heterogeneous outcomes depending on age at presentation and presence of HMF.

Identification of potent inhibitors of SARS-CoV-2 infection by combined pharmacological evaluation and cellular network prioritization.

Pharmacologically active compounds with known biological targets were evaluated for inhibition of SARS-CoV-2 infection in cell and tissue models to help identify potent classes of active small molecules and to better understand host-virus interactions. We evaluated 6,710 clinical and preclinical compounds targeting 2,183 host proteins by immunocytofluorescence-based screening to identify SARS-CoV-2 infection inhibitors. Computationally integrating relationships between small molecule structure, dose-response antiviral activity, host target, and cell interactome produced cellular networks important for infection. This analysis revealed 389 small molecules with micromolar to low nanomolar activities, representing >12 scaffold classes and 813 host targets. Representatives were evaluated for mechanism of action in stable and primary human cell models with SARS-CoV-2 variants and MERS-CoV. One promising candidate, obatoclax, significantly reduced SARS-CoV-2 viral lung load in mice. Ultimately, this work establishes a rigorous approach for future pharmacological and computational identification of host factor dependencies and treatments for viral diseases.

Humoral Responses Against SARS-CoV-2 and Variants of Concern After mRNA Vaccines in Patients With Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia.

PURPOSE: Patients with non-Hodgkin lymphoma including chronic lymphocytic leukemia (NHL/CLL) are at higher risk of severe SARS-CoV-2 infection. We investigated vaccine-induced antibody responses in patients with NHL/CLL against the original SARS-CoV-2 strain and variants of concern including B.1.167.2 (Delta) and B.1.1.529 (Omicron). MATERIALS AND METHODS: Blood from 121 patients with NHL/CLL receiving two doses of vaccine were collected longitudinally. Antibody binding against the full-length spike protein, the receptor-binding, and N-terminal domains of the original strain and of variants was measured using a multiplex assay. Live-virus neutralization against Delta, Omicron, and the early WA1/2020 strains was measured using a focus reduction neutralization test. B cells were measured by flow cytometry. Correlation between vaccine response and clinical factors was determined. RESULTS: Mean anti-SARS-CoV-2 spike immunoglobulin G-binding titers were 85-fold lower in patients with NHL/CLL compared with healthy controls, with seroconversion occurring in only 67% of patients. Neutralization titers were also lower and correlated with binding titers (P < .0001). Treatment with anti-CD20-directed therapies within 1 year resulted in 136-fold lower binding titers. Peripheral blood B-cell count also correlated with vaccine response. At 3 months from last anti-CD20-directed therapy, B-cell count ≥ 4.31/µL blood around the time of vaccination predicted response (OR 7.46, P = .04). Antibody responses also correlated with age. Importantly, neutralization titers against Delta and Omicron were reduced six- and 42-fold, respectively, with 67% of patients seropositive for WA1/2020 exhibiting seronegativity for Omicron. CONCLUSION: Antibody binding and live-virus neutralization against SARS-CoV-2 and its variants of concern including Delta and Omicron were substantially lower in patients with NHL/CLL compared with healthy vaccinees. Anti-CD20-directed therapy < 1 year before vaccination and number of circulating B cells strongly predict vaccine response.

Identification of druggable host targets needed for SARS-CoV-2 infection by combined pharmacological evaluation and cellular network directed prioritization both in vitro and in vivo.

Identification of host factors contributing to replication of viruses and resulting disease progression remains a promising approach for development of new therapeutics. Here, we evaluated 6710 clinical and preclinical compounds targeting 2183 host proteins by immunocytofluorescence-based screening to identify SARS-CoV-2 infection inhibitors. Computationally integrating relationships between small molecule structure, dose-response antiviral activity, host target and cell interactome networking produced cellular networks important for infection. This analysis revealed 389 small molecules, >12 scaffold classes and 813 host targets with micromolar to low nanomolar activities. From these classes, representatives were extensively evaluated for mechanism of action in stable and primary human cell models, and additionally against Beta and Delta SARS-CoV-2 variants and MERS-CoV. One promising candidate, obatoclax, significantly reduced SARS-CoV-2 viral lung load in mice. Ultimately, this work establishes a rigorous approach for future pharmacological and computational identification of novel host factor dependencies and treatments for viral diseases.

Antibody binding and neutralization of live SARS-CoV-2 variants including BA.4/5 following booster vaccination of patients with B-cell malignancies.

Non-Hodgkin lymphoma and chronic lymphocytic leukemia (NHL/CLL) patients elicit inadequate antibody responses after initial SARS-CoV-2 vaccination and remain at high risk of severe COVID-19 disease. We investigated IgG, IgA, and IgM responses after booster vaccination against recent SARS-CoV-2 variants including Omicron BA.5 in 67 patients. Patients had lower fold increase and total anti-spike binding titers after booster than healthy individuals. Antibody responses negatively correlated with recent anti-CD20 therapy and low B cell numbers. Antibodies generated after booster demonstrated similar binding properties against SARS-CoV-2 variants compared to those generated by healthy controls with lower binding against Omicron variants. Importantly, 43% of patients showed anti-Omicron BA.1 neutralizing antibodies after booster and all these patients also had anti-Omicron BA.5 neutralizing antibodies. NHL/CLL patients demonstrated inferior antibody responses after booster vaccination, particularly against Omicron variants. Prioritization of prophylactic and treatment agents and vaccination of patients and close contacts with updated vaccine formulations are essential.

Global COVID-19 vaccine inequity: The scope, the impact, and the challenges.

Global vaccine inequity is prolonging the COVID-19 pandemic. Here, we outline the scope and impact of inequitable vaccine distribution and identify challenges in vaccine development, manufacturing, and distribution as well as potential solutions to address this crisis.

ORF10-Cullin-2-ZYG11B complex is not required for SARS-CoV-2 infection.

In order to understand the transmission and virulence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is necessary to understand the functions of each of the gene products encoded in the viral genome. One feature of the SARS-CoV-2 genome that is not present in related, common coronaviruses is ORF10, a putative 38-amino acid protein-coding gene. Proteomic studies found that ORF10 binds to an E3 ubiquitin ligase containing Cullin-2, Rbx1, Elongin B, Elongin C, and ZYG11B (CRL2ZYG11B). Since CRL2ZYG11B mediates protein degradation, one possible role for ORF10 is to "hijack" CRL2ZYG11B in order to target cellular, antiviral proteins for ubiquitylation and subsequent proteasomal degradation. Here, we investigated whether ORF10 hijacks CRL2ZYG11B or functions in other ways, for example, as an inhibitor or substrate of CRL2ZYG11B While we confirm the ORF10-ZYG11B interaction and show that the N terminus of ORF10 is critical for it, we find no evidence that ORF10 is functioning to inhibit or hijack CRL2ZYG11B Furthermore, ZYG11B and its paralog ZER1 are dispensable for SARS-CoV-2 infection in cultured cells. We conclude that the interaction between ORF10 and CRL2ZYG11B is not relevant for SARS-CoV-2 infection in vitro.

Emerging opportunities to harness real world data: An introduction to data sources, concepts, and applications.

While randomized controlled trials (RCTs) are the gold standard for comparative effectiveness research, they are unable to provide the answers to all pertinent clinical and research questions. Real world evidence (RWE), that is, clinical evidence obtained outside RCTs and often through routine clinical practice, offers the potential to conduct observational studies that accelerate advances in care, improve outcomes for patients, and provide important insights that can answer important questions. Once appropriate information technology is available, real world data can be cost-effective to generate. RWE serves a vital role in the evaluation of treatment strategies for which there are no RCTs and for describing patterns of care. RWE also serves as an important adjunct to RCTs and can be used to determine if benefits seen in RCTs extend to clinical practice, provide insight into the findings of RCTs, generate hypotheses for future RCTs, and inform the design of future RCTs. These potential benefits must be balanced against some of the important limitations of RWE, including variable data quality, lack of granularity for important clinical variables, and the potential for bias and confounding. By using appropriate analytic techniques and study design, these limitations can be minimized but not eliminated. Going forward, RWE studies may be enhanced by using rigorous data quality standards, incorporating randomization, developing more prospective registries, and better leveraging data from electronic health records.

Keeping care connected: e-Consultation program improves access to nephrology care.

INTRODUCTION: Health systems are seeking innovative solutions to improve specialty care access. Electronic consultations (eConsults) allow specialists to provide formal clinical recommendations to primary care providers (PCPs) based on patient chart review, without a face-to-face visit. METHODS: We implemented a nephrology eConsult pilot program within a large, academic primary care practice to facilitate timely communication between nephrologists and PCPs. We used primary care referral data to compare wait times and completion rates between traditional referrals and eConsults. We surveyed PCPs to assess satisfaction with the program. RESULTS: For traditional nephrology referrals placed during the study period (July 2016-March 2017), there was a 51-day median appointment wait time and a 40.9% referral completion rate. For eConsults, there was a median nephrologist response time of one day and a 100% completion rate; 67.5% of eConsults did not require a subsequent face-to-face specialty appointment. For eConsults that were converted to an in-person visit, the median wait time and completion rate were 40 days and 73.1%, respectively. Compared to traditional referrals placed during the study period, eConsults converted to in-person visits were more likely to be completed ( p = 0.001). Survey responses revealed that PCPs were highly satisfied with the program and consider the quick turnaround time as the greatest benefit. DISCUSSION: Our eConsult pilot program reduced nephrology wait times and significantly increased referral completion rates. In large integrated health systems, eConsults have considerable potential to improve access to specialty care, reduce unnecessary appointments, and optimize the patient population being seen by specialists.

NF-κB inhibition by dimethylaminoparthenolide radiosensitizes non-small-cell lung carcinoma by blocking DNA double-strand break repair.

Despite optimal chemotherapy, radiotherapy (RT), and/or surgery, non-small-cell lung carcinoma (NSCLC) remains the leading cause of cancer-related death in the US and worldwide. Thoracic RT, a mainstay in the treatment of locally advanced NSCLC, is often restricted in efficacy by a therapeutic index limited by sensitivity of tissues surrounding the malignancy. Therefore, radiosensitizers that can improve the therapeutic index are a vital unmet need. Inhibition of the NF-κB pathway is a proposed mechanism of radiosensitization. Here we demonstrate that inhibition of the canonical NF-κB pathway by dimethylaminoparthenolide (DMAPT) radiosensitizes NSCLC by blocking DNA double-strand break (DSB) repair. NF-κB inhibition results in significant impairment of both homologous recombination (HR) and non-homologous end joining (NHEJ), as well as reductions in ionizing radiation (IR)-induced DNA repair biomarkers. NF-κB inhibition by DMAPT shows preclinical potential for further investigation as a NSCLC radiosensitizer.

Closing the Referral Loop: an Analysis of Primary Care Referrals to Specialists in a Large Health System.

PURPOSE: Ideally, a referral from a primary care physician (PCP) to a specialist results in a completed specialty appointment with results available to the PCP. This is defined as "closing the referral loop." As health systems grow more complex, regulatory bodies increase vigilance, and reimbursement shifts towards value, closing the referral loop becomes a patient safety, regulatory, and financial imperative. OBJECTIVE/DESIGN: To assess the ability of a large health system to close the referral loop, we used electronic medical record (EMR)-generated data to analyze referrals from a large primary care network to 20 high-volume specialties between July 1, 2015 and June 30, 2016. MAIN MEASURES: The primary metric was documented specialist appointment completion rate. Explanatory analyses included documented appointment scheduling rate, individual clinic differences, appointment wait times, and geographic distance to appointments. KEY RESULTS: Of the 103,737 analyzed referral scheduling attempts, only 36,072 (34.8%) resulted in documented complete appointments. Low documented appointment scheduling rates (38.9% of scheduling attempts lacked appointment dates), individual clinic differences in closing the referral loop, and significant differences in wait times and distances to specialists between complete and incomplete appointments drove this gap. Other notable findings include high variation in wait times among specialties and correlation between high wait times and low documented appointment completion rates. CONCLUSIONS: The rate of closing the referral loop in this health system is low. Low appointment scheduling rates, individual clinic differences, and patient access issues of wait times and geographic proximity explain much of the gap. This problem is likely common among large health systems with complex provider networks and referral scheduling. Strategies that improve scheduling, decrease variation among clinics, and improve patient access will likely improve rates of closing the referral loop. More research is necessary to determine the impact of these changes and other potential driving factors.

FANCD2 Maintains Fork Stability in BRCA1/2-Deficient Tumors and Promotes Alternative End-Joining DNA Repair.

BRCA1/2 proteins function in homologous recombination (HR)-mediated DNA repair and cooperate with Fanconi anemia (FA) proteins to maintain genomic integrity through replication fork stabilization. Loss of BRCA1/2 proteins results in DNA repair deficiency and replicative stress, leading to genomic instability and enhanced sensitivity to DNA-damaging agents. Recent studies have shown that BRCA1/2-deficient tumors upregulate Polθ-mediated alternative end-joining (alt-EJ) repair as a survival mechanism. Whether other mechanisms maintain genomic integrity upon loss of BRCA1/2 proteins is currently unknown. Here we show that BRCA1/2-deficient tumors also upregulate FANCD2 activity. FANCD2 is required for fork protection and fork restart in BRCA1/2-deficient tumors. Moreover, FANCD2 promotes Polθ recruitment at sites of damage and alt-EJ repair. Finally, loss of FANCD2 in BRCA1/2-deficient tumors enhances cell death. These results reveal a synthetic lethal relationship between FANCD2 and BRCA1/2, and they identify FANCD2 as a central player orchestrating DNA repair pathway choice at the replication fork.

Circulating miR-29a and miR-150 correlate with delivered dose during thoracic radiation therapy for non-small cell lung cancer.

BACKGROUND: Risk of normal tissue toxicity limits the amount of thoracic radiation therapy (RT) that can be routinely prescribed to treat non-small cell lung cancer (NSCLC). An early biomarker of response to thoracic RT may provide a way to predict eventual toxicities-such as radiation pneumonitis-during treatment, thereby enabling dose adjustment before the symptomatic onset of late effects. MicroRNAs (miRNAs) were studied as potential serological biomarkers for thoracic RT. As a first step, we sought to identify miRNAs that correlate with delivered dose and standard dosimetric factors. METHODS: We performed miRNA profiling of plasma samples obtained from five patients with Stage IIIA NSCLC at five dose-points each during radical thoracic RT. Candidate miRNAs were then assessed in samples from a separate cohort of 21 NSCLC patients receiving radical thoracic RT. To identify a cellular source of circulating miRNAs, we quantified in vitro miRNA expression intracellularly and within secreted exosomes in five NSCLC and stromal cell lines. RESULTS: miRNA profiling of the discovery cohort identified ten circulating miRNAs that correlated with delivered RT dose as well as other dosimetric parameters such as lung V20. In the validation cohort, miR-29a-3p and miR-150-5p were reproducibly shown to decrease with increasing radiation dose. Expression of miR-29a-3p and miR-150-5p in secreted exosomes decreased with radiation. This was concomitant with an increase in intracellular levels, suggesting that exosomal export of these miRNAs may be downregulated in both NSCLC and stromal cells in response to radiation. CONCLUSIONS: miR-29a-3p and miR-150-5p were identified as circulating biomarkers that correlated with delivered RT dose. miR-150 has been reported to decrease in the circulation of mammals exposed to radiation while miR-29a has been associated with fibrosis in the human heart, lungs, and kidneys. One may therefore hypothesize that outlier levels of circulating miR-29a-3p and miR-150-5p may eventually help predict unexpected responses to radiation therapy, such as toxicity.

USP9X inhibition promotes radiation-induced apoptosis in non-small cell lung cancer cells expressing mid-to-high MCL1.

BACKGROUND AND PURPOSE: Radiotherapy (RT) is vital for the treatment of locally advanced non-small cell lung cancer (NSCLC), yet its delivery is limited by tolerances of adjacent organs. We sought therefore to identify and characterize gene targets whose inhibition may improve RT. MATERIALS AND METHODS: Whole genome pooled shRNA cytotoxicity screens were performed in A549 and NCI-H460 using a retroviral library of 74,705 sequences. Cells were propagated with or without daily radiation Monday-Friday. Radiosensitization by top differential dropout hits was assessed by clonogenic assays. Apoptosis was assessed using a caspase 3/7 cell-based activity assay and by annexin V-FITC and PI staining. MCL1 expression was assessed by qPCR and Western blotting. RESULTS: USP9X, a deubiquitinase, was a top hit among druggable gene products. WP1130, a small molecule USP9X inhibitor, showed synergistic cytotoxicity with IR. MCL1, an anti-apoptotic protein deubiquitinated by USP9X, decreased with USP9X inhibition and IR. This was accompanied by increases in caspase 3/7 activity and apoptosis. In a panel of NSCLC lines, MCL1 and USP9X protein and gene expression levels were highly correlated. Lines showing high levels of MCL1 expression were the most sensitive to USP9X inhibition. CONCLUSIONS: These data support the use of MCL1 expression as a predictive biomarker for USP9X inhibitors in NSCLC therapy.

A systematic review: the effects of podiatrical deviations on nonspecific chronic low back pain.

Lower back pain (LBP) is a widespread, expensive, and debilitating problem in Western industrialized countries. Though LBP can be caused by acute injuries, biomechanical discrepancies have also been indicated to cause chronic LBP. A possible link between podiatrical deviations and LBP has been established in the literature; yet, no comprehensive review investigating the effects of foot and ankle deviations on low back pain has been published. The aim of this study was to assess the relevant literature concerning the effects of foot and ankle deviations on LBP. After review, it was determined that there is limited research regarding ankle and foot deviations and their connection to LBP. Reviewed studies have linked flat feet, ankle instability, sagittal plane blockage and excessive pronation to LBP. Specifically, excessive pronation has been shown to cause leg length discrepancies leading to pelvic tilts and LBP. Based on these results, ankle and foot deviations can be considered a potential cause for LBP due to the disruption of the kinetic chain from the foot to the back. Clinicians should consider the foot and ankle when addressing LBP, especially if more conventional etiologies fail to describe the condition.