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Introduction: The full impact of COVID-19 infections on patients with cancer who are actively being treated with chemotherapy or immune checkpoint inhibitors (ICIs) has not been fully defined. Our goal was to track clinical outcomes in this specific patient population. Methods: We performed a retrospective chart review of 121 patients (age > 18 years) at the University of Alabama at Birmingham from January 2020 to December 2021 with an advanced solid malignancy that were eligible to be treated with ICIs or on current therapy within 12 months of their COVID-19 diagnosis. Results: A total of 121 patients were examined in this study, and 61 (50.4%) received immunotherapy treatment within 12 months. One quarter of the patients on ICIs passed away, compared to 13% of the post-chemotherapy cohort. Patients who were vaccinated for COVID-19 had lower mortality compared to unvaccinated patients (X2 = 15.19, p < 0.001), and patients with lower ECOG (0.98) were associated with lower mortality compared to patients with worse functional status (0.98 vs. 1.52; t = 3.20; p < 0.01). Conclusions: COVID-19-related ICI mortality was higher compared to patients receiving chemotherapy. However, ICI cessation or delay is unwarranted as long there has been a risk–benefit assessment undertaken with the patient.

Multiple myeloma (MM) is an incurable plasma cell neoplasm. In this study, we aimed to analyze the impact of time to initiation of systemic therapy for MM on overall survival (OS).We identified cases diagnosed with MM from the National Cancer Database from 2004 to 2013.A total of 38,178 MM patients were included in the analysis. The median time to systemic therapy in our cohort was 17 days (range 0-120). The median OS for patients who initiated therapy 30-days after diagnosis was longer than those who received it ≤ 7 days (46 vs. 27-month, p 0.001). On multivariable analysis, patients who received treatment ≤ 7 days from diagnosis had worse mortality compared with those receiving treatment 30 days (HR 1.5; 95% CI 1.4-1.6).In our study, time to initiation of systemic therapy was an independent prognostic factor in MM. Similar to other lymphoid malignancies, this metric may be a surrogate for high-risk disease in MM, and future trials may need to investigate time-to-treatment as a factor to allow enrollment of potentially sick patients.

The ideal non-operative treatment for patients with large, node-negative non-small cell lung cancer (NSCLC) is poorly defined. To inform optimal treatment paradigms for this cohort, we examined patterns of failure and the impact of radiation therapy (RT) and chemotherapy receipt.Node-negative NSCLC patients with 5+ cm primary tumors receiving definitive RT at our institution were identified. Sites of initial progression were analyzed. Local progression, regional/distant progression, progression-free survival, and overall survival were analyzed via cumulative incidence function and Kaplan-Meier. Associations between local vs. regional/distant progression with treatment and clinicopathologic variables were assessed via univariable and multivariable competing risks regression.We identified 88 patients for analysis. Among patients with recurrent disease (N = 36), initial patterns of failure analysis showed that isolated distant (27.8%) and isolated regional progression (22.2%) were most common. Distant or regional failure as a component of initial failure was seen in 88.9% of patients who progressed, while isolated local failure was uncommon (11.1%). Univariable and multivariable competing risks regression showed that receipt of SBRT was associated with reduced risk of local progression (HR 0.23, P = .012), and receipt of chemotherapy was associated with reduced risk of regional/distant progression (HR 0.12, P = .040). In conclusion, patients with large, node-negative NSCLC treated with definitive RT are at high risk of regional and distant progression. SBRT correlates with a reduced risk of local failure while chemotherapy is associated with reduced regional/distant progression in this patient population. Ideal treatment may include SBRT when feasible with appropriate systemic therapy.

e19545 Background: High-dose methotrexate (HD-MTX) at a dose between 2.5 to 5 gm/m2 is commonly administered in conjunction with standard induction chemotherapy to patients with Diffuse Large B Cell Lymphoma (DLBCL) at high risk of central nervous system (CNS) relapse, as defined by the Lymphoma International Prognostic Index (CNS-IPI). Optimal timing of HD-MTX in relation to induction chemotherapy is unknown. A recent study suggested that HD-MTX intercalated with R-CHOP cycles was associated with increased toxicity and treatment delays without improvement in survival or CNS relapse compared with end of treatment MTX (Wilson et al 2020). This retrospective study evaluates the toxicities and treatment delays associated with HD-MTX administered on day 1 of cycles of chemo-immunotherapy. Methods: This single center retrospective cohort study included 45 patients (pts) with DLBCL with concurrent CNS disease or at high risk of CNS relapse who received HD MTX on day 1 of chemo-immunotherapy at our center. Data was abstracted from chart review and included variables describing clinical and treatment characteristics, time to MTX clearance, toxicities experienced and treatment delays. Results: 31 pts received HD-MTX on the day of R-CHOP chemotherapy, 6 pts received HD-MTX on the day of R-EPOCH (Rituximab, Etoposide, Doxorubicin, Vincristine, Cyclophosphamide, and Prednisone), and 8 pts received HD-MTX with R-MiniCHOP (dose reduced R-CHOP). Same day HD MTX with chemo-immunotherapy was associated with acute kidney injury (AKI; 17-25%), treatment delays >7 days (13-17%), and grade 2 mucositis (11-50%). The burden of toxicities was numerically higher in patients treated with R-EPOCH vs. R-CHOP (Table). Clinical outcomes are summarized in table below. Conclusions: In our heterogeneous population of pts, we describe that the incidence of toxicities and treatment delays experienced with same day HD-MTX are higher with R-EPOCH than with R-CHOP. Comparative studies with intercalated or end of treatment MTX will determine if the incidence of treatment delays, toxicities and de-escalations are higher with same day HD-MTX administration. [Table: see text]

Immune checkpoint inhibitors (ICIs) are immunomodulatory antibodies that intensify the host immune response, thereby leading to cytotoxicity. The primary targets for checkpoint inhibition have included cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death receptor-1 (PD-1) or programmed cell death ligand-1 (PD-L1). ICIs have resulted in a change in treatment landscape of various neoplasms. Among hematologic malignancies, ICIs have been most successful in certain subtypes of lymphomas such as classic Hodgkin lymphoma (cHL) and primary mediastinal B-cell lymphoma (PMBCL). However, there have been several challenges in harnessing the host immune system through ICI use in other lymphomas. The underlying reasons for the low efficacy of ICI monotherapy in most lymphomas may include defects in antigen presentation, non-inflamed tumor microenvironment (TME), immunosuppressive metabolites, genetic factors, and an overall lack of predictive biomarkers of response. In this review, we outline the existing and ongoing studies utilizing ICI therapy in various lymphomas. We also describe the challenges leading to the lack of efficacy with ICI use and discuss potential strategies to overcome those challenges including: chimeric antigen receptor T-cell therapy (CAR-T therapy), bispecific T-cell therapy (BiTE), lymphocyte activation gene-3 (LAG-3) inhibitors, T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) inhibitors, vaccines, promotion of inflammatory macrophages, indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors, DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi). Tumor mutational burden and interferon-gamma release assays are potential biomarkers of ICI treatment response beyond PD-L1 expression. Further collaborations between clinicians and scientists are vital to understand the immunopathology in ICI therapy in order to improve clinical outcomes.

7515 Background: Primary refractory disease (PRD) and early relapse (ER) are predictors of poor prognosis in classic Hodgkin lymphoma (cHL). In this multicenter retrospective study, we describe outcomes of PRD and ER in pts with relapsed/refractory (R/R) cHL treated with salvage therapy (ST) and autologous stem cell transplant (ASCT). Methods: Of 14 sites, adult patients with R/R cHL who received ST and underwent ASCT were enrolled. PRD was defined as progression on frontline chemoimmunotherapy or within 6 months of diagnosis. ER was defined as relapse from 6 months-1 yr of diagnosis. Pts who relapsed >1 yr of diagnosis were called late relapses (LR). Study objectives were Overall response rates (ORR), CR rates, PFS, and OS. Results: Of 986 total pts, 160 had PRD, 365 had ER and 461 had LR. Significantly higher number of pts with PRD, but not ER, had bulky disease (41% vs 27%, p1 line of ST (44% vs 30% vs 23%, p

e18699 Background: Cancer patients infected with COVID-19 are very vulnerable to increased complications and mortality while actively being treated with chemotherapy or immune checkpoint inhibitors (ICIs). The full impact of COVID-19 infections on this subset of patients has not been fully defined. Our goal was to track clinical outcomes in patients with an underlying malignancy and COVID-19 infection who received chemotherapy or ICIs. Methods: We performed a retrospective chart review of 121 patients (age > 18 years) at the University of Alabama-Birmingham from January 2020 till November 2021 with an advanced solid malignancy that were treated with chemotherapy or ICIs within 12 months of their COVID-19 diagnosis. The aim of this study was to track clinical outcomes including: hospitalization rates, ICU admissions, treatments, and deaths of any cause. Results: A total of 121 patients were examined in this study and 61 received immunotherapy treatment within 12 months. The median age at diagnosis for the ICI group was 62.3 years and 54% were male while for the patients that receive chemotherapy the median age at diagnosis was 65.1 years and 53% were male (Table1). The 3 most common cancers represented in the ICI cohort were lung (30%, NSCLC), liver (13%, HCC) and renal (11%, RCC). While in the chemotherapy group, the 3 most cancers were NSCLC (40%), HCC (12%,), and head & neck (10%, H&N). 25% of patients on ICIs died while only 13% of patients died post chemotherapy. Of the ICI patients that died, 33% were admitted to the intensive care unit (ICU) and 53% received oxygen, steroids and antiviral therapy. For the chemotherapy patients that died, 25% were admitted to the ICU and 50% received oxygen, steroids and antiviral therapy. Patients with lower ECOG (0.98) had lower mortality compared to patients with worse functional status (0.98 vs 1.52; t = 3.20; p < 0.01). Factors associated with increased admission were higher ECOG (1.07 vs 1.67; f = 3.05; p = 0.05), higher AST (21.2 vs 40.9, f = 10.2; p < 0.001), lower absolute lymphocyte count (1122.8 vs 408.9, f = 5.99; p < 0.01) and higher oxygen needs (0.02 vs 1.11, f = 29.5; p < 0.001). Conclusions: ICI mortality was higher compared to patients receiving chemotherapy, especially for those with reduced functional status. Factors for hospitalization included: higher ECOG, higher AST, lower lymphocyte count and increased oxygen needs. However, further investigation still needs to be undertaken to understand if the PD-1-PD-L1 pathway with the subsequent inflammatory cascade post COVID-19 can impact overall survival.[Table: see text]

e16109 Background: Gallbladder cancer is one of the highest fatal malignancy. We conducted a retrospective analysis to study the outcomes of gallbladder malignancy in an academic care setting. Methods: Data was collected retrospectively on patients treated at University of Alabama at Birmingham between January 2005 and June 2015 from the electronic medical record using a standardized data collection tool (Redcap). We evaluated for predictors of overall survival (OS) and progression-free survival (PFS). Results: Of the 93 patients in this study, 66% were female. Adjuvant chemotherapy (CT) was given to 11% and adjuvant chemoradiation (CRT) to 14%. On multivariate analysis, albumin > 3.5, uninvolved margins, absence of lymphovascular/peri-neural invasion were independent predictors of OS and PFS (Table). The overall median survival was 24.3 months with a 5-year median OS at 23.7%. Surgery with CRT for the full cohort had a median OS of 54.4 vs 15.6 (p = 0.0048) months compared to surgery CT alone. The OS in stage 3-4 patients with surgery alone vs surgery & CT was 5.5 versus 28.7 months respectively (p = 0.0052). The PFS for the same group was 17.5 vs 4.6 months (p = 0.0052). Conclusions: The dismal survival rates of gallbladder cancer made. adjuvant therapy (CT or CRT) critically important. Concurrent chemoradiation needs to be evaluated in randomized clinical trials for potential improvement in clinical outcomes compared to currently approved standard of care, adjuvant CT alone. [Table: see text]

Background: The role of adjuvant chemotherapy (CT) or combination chemoradiation (CRT) remains uncertain for ampullary carcinoma (AC). In this analysis, we reviewed our institution’s experience with early-stage AC. Methods: AC patients who had definitive surgical intervention at the University of Alabama, Birmingham, between 2005 and 2015, were identified. Clinicopathologic factors and disease statuses were obtained from chart review. The univariate Cox proportional hazard model was conducted for evaluating the parameters associated with overall survival (OS). Kaplan-Meier method and log-rank method were used to compare the time-to-events. We estimated the survival for the patients who had definitive surgery (pancreaticoduodenectomy (PD) or ampullectomy), and followed them up with assessing the influence of adjuvant treatment (chemoradiotherapy or CT) alone on the survival in the early-stage (stage I/II) AC. Results: A total of 63 patients had definitive surgery. The median OS and progression-free survival (PFS) for all the patients who had definitive surgery were 40.5 months and 28 months, respectively. Adjuvant treatment was administered in 60% of patients with early-stage (stage I/II) AC (CT 36% and CRT 24%), while 22% were on surveillance post surgery. The pathological stage ? 2, Lymph node (LN) metastasis, peri-nodal extension (PNE) and peri-pancreatic extension (PPE) were found to be the determinants for poor OS and PFS by univariate analysis. Multiple Cox regression of these variables showed a significant influence of PPE and pathological staging on the OS and PFS, respectively. In the early-stage AC with no high-risk features, adjuvant therapy did not improve the survival over surgery alone (40.5 vs. 51.7 months, P = 0.93). The addition of radiation to CT did not yield improved outcome in early-stage cancers. For CRT and CT, OS was 22.8 versus 65.7 months (P = 0.3975), and PFS was 25.3 versus 65.7 months (P = 0.4699). Conclusions: In the early-stage AC, adjuvant therapy may not improve the outcome in the short term but may benefit over a long period. It should be considered, especially in patients with adverse risk factors. Radiation therapy may not be useful in managing AC in the adjuvant setting. J Clin Med Res. 2020;12(9):560-567 doi: https://doi.org/10.14740/jocmr4267

BACKGROUND The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) was created to establish a standard terminology regarding thyroid nodules that can be shared between endocrinologists, pathologists, radiologists, and surgeons. Since its inception and use in 2009, multiple large hospitals and academic institutions have performed retrospective studies to compare their classification rates, specifically those of atypia of undetermined significance (AUS) and follicular lesion of undetermined significance (FLUS), with the recommended rates created by the National Cancer Institute. The current study compared AUS/FLUS rates at a private suburban endocrine practice with those of previous publications from large institutions and the rates established by the National Cancer Institute. METHODS Charts from 893 patients with fine-needle aspiration (FNA) performed in 2015 were reviewed. Data specific to thyroid aspirates classified as AUS/FLUS were organized into whether patients underwent surgery, underwent subsequent repeat FNA, or required continued observation. These results then were calculated to reveal the rate of malignancy in the AUS/FLUS category with surgical pathology in the study institution. RESULTS A total of 893 patients underwent FNA, with 43 patients (4.82%) shown to have AUS/FLUS. A total of 21 patients proceeded to undergo thyroidectomy or lobectomy, with 7 patients (33.3%) found to have papillary or follicular thyroid carcinoma. CONCLUSIONS The rate of use of the AUS/FLUS category for thyroid nodules examined at the study institution was found to be within the recommended range set forth by TBSRTC. However, the malignancy rates on histopathology in the study institution were found to be higher than the new proposed malignancy rates from TBSRTC published in 2017. This finding is comparable to those of multiple other community and academic institutions performed prior to and after institution of the new guidelines.

Traumatic Brain injury affects at least 1.7 million people in the United States alone each year. The majority of injuries are categorized as mild but these still produce lasting symptoms that plague the patient and the medical field. Currently treatments are aimed at reducing a patient’s symptoms, but there is no effective method to combat the source of the problem, neuronal loss. We tested a mild, closed head traumatic brain injury model for the effects of modulation of the antioxidant transcription factor Nrf2 by the chemical activator, tert-butylhydroquinone (tBHQ). We found that post-injury visual memory was improved by a 7 day course of treatment and that the level of activated caspase-3 in the hippocampus was reduced. The injury-induced memory loss was also reversed by a single injection at 30 min after injury. Since the protective stress response molecule, HSP70, can be upregulated by Nrf2, we examined protein levels in the hippocampus, and found that HSP70 was elevated by the injury and then further increased by the treatment. To test the possible role of HSP70, model neurons in culture exposed to a mild injury and treated with the Nrf2 activator displayed improved survival that was blocked by the HSP70 inhibitor, VER155008. Following mild traumatic brain injury, there may be a partial protective response and patients could benefit from directed enhancement of regulatory pathways such as Nrf2 for neuroprotection. Published by Elsevier Ltd. on behalf of IBRO.

Repetitive mild traumatic brain injury (mTBI) represents a major public health problem. Many individuals who suffer repetitive mTBIs suffer from Post-Concussion Syndrome, a constellation of neuropsychiatric symptoms that includes depression, anxiety, and problems with memory and other cognitive processes. Significantly, Post-Concussion Syndrome is resistant to existing therapeutic strategies. To provide better treatment options for this patient population, the underlying pathophysiology of repetitive mTBI must be understood. A first step in this process is the establishment of an in vitro model system that recapitulates the biological changes that occur in the brains of repetitively injured humans. The availability of a model with immortalized cell lines would remove the considerable barriers of time, expense, and difficulties with genetic manipulation that exist with the use of primary neuronal cultures. Here we report the development and functional characterization of an in vitro laboratory model of repetitive TBI using immortalized neuronal cell lines. These results indicate that the moderate, repetitive injury reduces viability, numbers and lengths of neurites, and that the neuronal loss mechanism includes caspase activation.

Traumatic brain injury (TBI) afflicts approximately 1.4 million people in the United States and TBIs have been labeled a major cause of death and disability on a global scale. Regulatory responses in a variety of neuronal loss conditions have supported the protective involvement of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor. Nrf2 regulates antioxidant enzyme genes, and an increase in Nrf2 expression may counteract oxidative damage that results from TBI. Elevated Nrf2 may ultimately act through the upregulation of downstream target genes such as thioredoxin (Trx) and heat-shock protein-70 (HSP70) and this may reduce neuronal loss. We performed multiple mild biaxial stretch injuries to neuroblastoma cells in culture, and examined the effects of the Nrf2 activator, tert-butylhydroquinone (tBHQ). We also compared the stretch injury to oxidative insult. We confirmed that Trx and HSP70 were upregulated by treatment with tBHQ. We observed that tBHQ protected neurons from either insult, and that this was evident by different measures of cell viability and a decrease in annexin V binding. Neuronal health after insult was improved approximately 50% by tBHQ, indicating that neurons exposed to TBI in vitro can be protected.