Evaluation of Culture Conducive to Academic Success by Gender at a Comprehensive Cancer Center.

INTRODUCTION: The primary objective of this study was to determine whether workplace culture in academic oncology differed by gender, during the COVID-19 pandemic. MATERIALS AND METHODS: We used the Culture Conducive to Women's Academic Success (CCWAS), a validated survey tool, to investigate the academic climate at an NCI-designated Cancer Center. We adapted the CCWAS to be applicable to people of all genders. The full membership of the Cancer Center was surveyed (total faculty = 429). The questions in each of 4 CCWAS domains (equal access to opportunities, work-life balance, freedom from gender bias, and leadership support) were scored using a 5-point Likert scale. Median score and interquartile ranges for each domain were calculated. RESULTS: A total of 168 respondents (men = 58, women = 106, n = 4 not disclosed) submitted survey responses. The response rate was 39% overall and 70% among women faculty. We found significant differences in perceptions of workplace culture by gender, both in responses to individual questions and in the overall score in the following domains: equal access to opportunities, work-life balance, and leader support, and in the total score for the CCWAS. CONCLUSIONS: Our survey is the first of its kind completed during the COVID-19 pandemic at an NCI-designated Cancer Center, in which myriad factors contributed to burnout and workplace challenges. These results point to specific issues that detract from the success of women pursuing careers in academic oncology. Identifying these issues can be used to design and implement solutions to improve workforce culture, mitigate gender bias, and retain faculty.

Where the Sidewalk Ends: Parenting as a Trainee during COVID-19.

Physicians who are also parents have faced significant difficulties during the COVID-19 pandemic. However, most studies of the physician-parent workforce have focused on the experiences of attending physicians. In this commentary, we highlight the ways that trainee parents have uniquely experienced three major stressors during the pandemic: (1) childcare challenges, (2) scheduling difficulties, and (3) career uncertainties. We discuss potential solutions to mitigate these challenges for the future hematology/oncology workforce. As the pandemic continues, we hope that these steps can improve the ability of trainee parents to care both for their patients and their families.

Professional Challenges for United States Hematology/Oncology Trainees during COVID-19.

COVID-19 has been devastating for patients with cancer. In this commentary, we chronicle the pandemic's downstream impacts on United States hematology/oncology trainees in terms of professional development and career advancement. These include loss of access to clinical electives and protocol workshops, delays in research approval and execution, mentor shortages due to academic burnout, and obstacles with career transitions (most notably the post-fellowship job search). While certain silver linings from the pandemic have undoubtedly emerged, continued progress against COVID-19 will be essential to fully overcome the professional challenges it has created for the future hematology/oncology workforce.

Older patients with primary central nervous system lymphoma: Survival and prognostication across 20 U.S. cancer centers.

There is a paucity of large-scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We retrospectively analyzed 539 newly-diagnosed PCNSL patients ages ≥60 years across 20 U.S. academic centers. The median age was 70 years (range 60-88); at least one geriatric syndrome was present in 46%; the median Cumulative Index Ratings Scale-Geriatrics (CIRS-G) score was 6 (range, 0-27); and 36% had impairment in activities of daily living (ADL). The most common induction regimens were high-dose methotrexate (HD-MTX) ± rituximab; methotrexate, temozolomide, rituximab (MTR); and rituximab, methotrexate, procarbazine, vincristine (R-MPV). Overall, 70% of patients achieved remission, with 14% undergoing consolidative autologous stem cell transplant (ASCT) and 24% receiving maintenance. With 58-month median follow-up, median progression-free survival (PFS) and overall survival (OS) were 17 months (95% CI 13-22 months) and 43 months (95% CI 31-56 months), respectively. Three-year PFS and OS were highest with MTR (55% and 74%, respectively). With single-agent methotrexate ± rituximab, 3-year PFS and OS were 30% (p = .0002) and 47% (p = .0072). On multivariate analysis, increasing age at diagnosis and Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS; age, hypoalbuminemia, higher CIRS-G score, and ECOG PS adversely affected OS. Among patients receiving maintenance, 3-year PFS was 65% versus 45% without maintenance (p = 0.02), with 3-year OS of 84% versus 61%, respectively (p = .0003). Altogether, outcomes in older PCNSL patients appeared optimized with HD-MTX combination induction regimens and maintenance therapy. Furthermore, several prognostic factors, including geriatric measures, were associated with inferior outcomes.

On point in primary CNS lymphoma.

Primary CNS lymphoma (PCNSL) is an aggressive brain tumor that represents a significant challenge both to elucidate its biological pathogenesis as well as to develop definitive precision medicines with minimal collateral toxicity. We highlight the key issues in diagnosis and treatment and focus on emerging technologies, current options among consolidation strategies, and biological agents. We anticipate that further development of molecular diagnostics and molecular imaging approaches that elucidate minimal residual disease in brain parenchyma, leptomeninges, intraocular compartments and even bone marrow will greatly impact the delivery and timing of cytotoxic and biological therapies. Implementation of these approaches is likely essential to clarify ongoing discrepancies in the interpretation of clinical trial results that currently are based on relatively unrefined definitions of response. While the results of early phase investigations involving ibrutinib and the IMiD agents, lenalidomide, pomalidomide, as well as avadomide, strongly support the hypothesis that the B-cell receptor (BCR) pathway, involving MYD88 and CD79B and NF-kB activation, is critical to the pathogenesis of PCNSL, much work is needed to elucidate mechanisms of resistance. Similarly, development of strategies to overcome immunosuppressive mechanisms that are upregulated in the tumor microenvironment is a high priority. Finally, ongoing evidence supports the hypothesis that the blood-brain barrier represents a significant impediment to efficient brain tumor penetration of novel therapeutic agents and innovative strategies of drug delivery remain essential to further improve outcomes.

Should IGHV status and FISH testing be performed in all CLL patients at diagnosis? A systematic review and meta-analysis.

Since the first description of the natural history of chronic lymphocytic leukemia (CLL) by David Galton in 1966, the considerable heterogeneity in the disease course has been well recognized. The Rai and Binet staging systems described ∼40 years ago have proven to be robust prognostic tools. Over the past 2 decades, several novel biological, genetic, and molecular markers have been shown to be useful adjuncts to the Rai and Binet staging systems. In this systematic review, we examined the role of immunoglobulin heavy-chain variable region gene (IGHV) mutation status and genetic abnormalities determined by interphase fluorescence in situ hybridization (FISH) in patients with newly diagnosed CLL. The cumulative evidence presented in this systematic review is sufficient to recommend that FISH and IGHV be performed as standard clinical tests for all patients with newly diagnosed CLL in those countries with the resources to do so. In addition to clinical stage, these parameters could represent the minimal standard initial prognostic evaluation for patients with CLL. This approach will allow the application of powerful, recently developed prognostic indices (all of which are dependent on IGHV and FISH results) to all patients with newly diagnosed CLL.

Iron oxide nanoparticles as a clinically acceptable delivery platform for a recombinant blood-stage human malaria vaccine.

This study explored the novel use of iron oxide (IO) nanoparticles (<20 nm) as a vaccine delivery platform without additional adjuvants. A recombinant malaria vaccine antigen, the merozoite surface protein 1 (rMSP1), was conjugated to IO nanoparticles (rMSP1-IO). Immunizations in outbred mice with rMSP1-IO achieved 100% responsiveness with antibody titers comparable to those obtained with rMSP1 formulated with a clinically acceptable adjuvant, Montanide ISA51 (2.7×10 vs. 1.6×10; respectively). Only rMSP1-1O could induce significant levels (80%) of parasite inhibitory antibodies. The rMSP1-IO was highly stable at 4°C and was amenable to lyophilization, maintaining its antigenicity, immunogenicity, and ability to induce inhibitory antibodies. Further testing in nonhuman primates, Aotus monkeys, also elicited 100% immune responsiveness and high levels of parasite inhibitory antibodies (55-100% inhibition). No apparent local or systemic toxicity was associated with IO immunizations. Murine macrophages and dendritic cells efficiently (>90%) internalized IO nanoparticles, but only the latter were significantly activated, with elevated expression/secretion of CD86, cytokines (IL-6, TNF-α, IL1-b, IFN-γ, and IL-12), and chemokines (CXCL1, CXCL2, CCL2, CCL3, CCL4, and CXCL10). Thus, the IO nanoparticles is a novel, safe, and effective vaccine platform, with built-in adjuvancy, that is highly stable and field deployable for cost-effective vaccine delivery.

Palliative and End-of-Life Care in Hematologic Malignancies: Progress and Opportunities.

@JCOOP_ASCO editorial on unique needs of end-of-life care for different blood cancers discusses: #pallheme improves QOL but less utilized in cancers. Contextualize Weisse et al study. More #pallheme research needed for lymphoma and myeloma in era of cell therapy.

Transformative Peer Connections: Early Experiences From the ASCO Palliative Care Community of Practice.

The integration of palliative care into routine oncology practice is the standard of care by most leading cancer organizations. Palliative medicine helps to deliver higher quality of care at a lower cost. However, there are barriers to implementing palliative oncology at many institutions for myriad reasons. In this article, we discuss an innovative strategy that ASCO implemented called the Communities of Practice (CoP). We share our experiences as the Palliative Care CoP and how our group seeks to develop processes and structures to collectively promote systemic change and enhance palliative care delivery for people with cancer. Our Palliative Care CoP engages with senior leaders, administrators, and those in power to achieve a shared vision of delivering holistic health care for people with serious illness. We continue to evolve to meet our members' growing needs by addressing eight main domains: (1) increasing palliative care education and resources; (2) creating opportunities for global palliative care research; (3) providing peer mentorship and community building; (4) engaging with patient advocates; (5) supporting and developing interdisciplinary teams; (6) assisting with professional development and identity formation, especially for trainees and early career faculty; (7) extending our outreach through social media; and (8) enhancing the clinical practice of palliative oncology. The ASCO CoP has been a vital forum to realize ASCO's mission of conquering cancer and advancing the Art and Science of Cancer Care: From Comfort to Cure.

Measurable Residual Disease and Clinical Outcomes in Chronic Lymphocytic Leukemia: A Systematic Review and Meta-Analysis.

Importance: Measurable residual disease (MRD) refers to the presence of disease at low levels not detected by conventional pathologic analysis. The association of MRD status as a surrogate end point of clinical outcome in chronic lymphocytic leukemia (CLL) has not been established in the era of targeted agents. Assessing the association of MRD with progression-free survival (PFS) may improve its role as a surrogate marker and allow its use to accelerate drug development. Objective: To assess the association between MRD and PFS in CLL using data from prospective clinical trials that studied targeted agents or obinutuzumab-based treatment. Data Sources: Clinical studies on CLL were identified via searches of PubMed, Embase, Scopus, and Web of Science from inception through July 31, 2023. Study Selection: Prospective, single-arm, and randomized clinical trials that assessed targeted agents or obinutuzumab-based treatment and reported PFS by MRD status were included. Studies with insufficient description of MRD information were excluded. Data Extraction and Synthesis: Study sample size, median patient age, median follow-up time, line of treatment, MRD detection method and time points, and survival outcomes were extracted. Main Outcomes and Measures: Analyses of survival probabilities and hazard ratios (HRs) were conducted for PFS according to MRD status. Meta-analyses were performed using a random-effects model. Results: A total of 11 prospective clinical trials (9 randomized and 2 nonrandomized) including 2765 patients were analyzed. Achieving undetectable MRD (uMRD) at 0.01% was associated with an HR of 0.28 (95% CI, 0.20-0.39; P < .001) for PFS. Median PFS was not reached in both groups (uMRD vs MRD), but the estimated 24-month PFS was better in the uMRD group (91.9% [95% CI, 88.8%-95.2%] vs 75.3% [95% CI, 64.7%-87.6%]; P < .001). The association of uMRD with PFS was observed in subgroup analyses in the first-line treatment setting (HR, 0.24; 95% CI, 0.18-0.33), relapsed or refractory disease setting (HR, 0.34; 95% CI, 0.16-0.71), and trials using time-limited therapy (HR, 0.28; 95% CI, 0.19-0.40). Conclusions and Relevance: The findings of this systematic review and meta-analysis suggest that assessing MRD status as an end point in clinical trials and as a surrogate of PFS may improve trial efficiency and potentially allow for accelerated drug registration.

Hypertension treatment for patients receiving ibrutinib: a multicenter retrospective study.

ABSTRACT: Although Bruton tyrosine kinase inhibitors (BTKis) are generally well tolerated and less toxic than chemotherapy alternatives used to treat lymphoid malignancies, BTKis like ibrutinib have the potential to cause new or worsening hypertension (HTN). Little is known about the optimal treatment of BTKi-associated HTN. Randomly selected patients with lymphoid malignancies on a BTKi and antihypertensive drug(s) and with at least 3 months of follow-up data were sorted into 2 groups: those diagnosed with HTN before BTKi initiation (prior-HTN), and those diagnosed with HTN after BTKi initiation (de novo HTN). Generalized estimating equations assessed associations between time varying mean arterial pressures (MAPs) and individual anti-HTN drug categories. Of 196 patients included in the study, 118 had prior-HTN, and 78 developed de novo HTN. Statistically significant mean MAP reductions were observed in patients with prior-HTN who took ß blockers (BBs) with hydrochlorothiazide (HCTZ), (-5.05 mmHg; 95% confidence interval [CI], 10.0 to -0.0596; P = .047), and patients diagnosed with de novo HTN who took either an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) with HCTZ (-5.47 mmHg; 95% CI, 10.9 to -0.001; P = .05). These regimens also correlated with the greatest percentages of normotensive MAPs. Treatment of HTN in patients taking a BTKi is challenging and may require multiple antihypertensives. Patients with prior-HTN appear to benefit from combination regimens with BBs and HCTZ, whereas patients with de novo HTN appear to benefit from ACEi/ARBs with HCTZ. These results should be confirmed in prospective studies.

EBV-positive PCNSL in older patients: incidence, characteristics, tumor pathology, and outcomes across a large multicenter cohort.

The objective of this multicenter retrospective study was to examine the incidence, patient characteristics, pathology, and outcomes associated with Epstein-Barr virus (EBV)-related CNS lymphoma (CNSL) in older patients. Among 309 CNSL patients aged ≥60, 11.7% had EBV + tumors of which 72.2% were solid organ transplant (SOT)-related post-transplant lymphoproliferative disorders (PTLD). Younger age, SOT or autoimmune disease, and immunosuppressive treatment correlated highly with EBV-positivity. EBV + tumors were associated with absent C-MYC and BCL6 expression. EBV + PTLD was more likely to be associated with the absence of CD5 expression. EBV + non-PTLD had better median OS (not reached) compared to EBV + PTLD (10.8 months) and EBV-negative patients (43 months). Multivariable Cox regression analysis showed that age, performance status, and PTLD were negative predictors of OS. EBV status and immunosuppressive treatment were not correlated with OS. Our findings merit further investigation of EBV + PCNSL tumors and EBV-directed therapies.

Decision-making about clinical trial options among older patients with metastatic cancer who have exhausted standard therapies.

OBJECTIVES: Older adults under-enroll in early phase cancer clinical trials. There are limited data on their trial experiences, which hampers our ability to understand potential reasons and responses to under-enrollment. We aimed to explore older adults' experiences and deliberations with phase 1 trials. MATERIALS AND METHODS: We analyzed 101 in-depth interviews with 39 adults (average 2.6 interviews per participant) about their experiences with phase 1 trials. All respondents were ≥ 65 years and had advanced cancer. Interviews lasted 60-90 min and were audio-recorded, transcribed, and analyzed to identify respondents' understanding of clinical research, perceptions of early phase trials, and experiences with enrollment. RESULTS: Clinical trial participation was an interactive process that unfolded over time. Older adults relied on ongoing guidance and discussion with their oncologist to navigate the process. Respondents were generally interested in life-prolonging therapies, including enrollment in early phase clinical trials, but did not necessarily state this explicitly to their oncologist. While respondents did not mention age as a limitation to trials participation, participants age > 70 were less enthusiastic about participation and more often discussed their quality of life and weighed benefits of trial participation in the context of their remaining months of life. CONCLUSION: Early phase clinical trial enrollment is complex, and older adults rely on their oncologist to navigate this process. Acknowledging this complexity through shared decision-making may ensure that older adults have appropriate opportunities to enroll in early phase clinical trials and guard against inappropriate under-enrollment.

The epidemiology of preexisting geriatric and palliative conditions in older adults with poor prognosis cancers.

BACKGROUND: Older patients with poor prognosis cancers have complex needs that can benefit from geriatrics and palliative care principles. Because they are not routinely assessed, the prevalence of preexisting geriatric and palliative conditions in this population is unknown. METHODS: We used the nationally representative Health and Retirement Study (HRS) linked with Medicare claims (1998-2016) to identify adults aged ≥65 years diagnosed with poor prognosis cancers (cancers with a median survival ≤1 year). Using the HRS interview before the first Medicare cancer claim, we used survey-weighted descriptive statistics and modified Poisson regression analysis to examine the prevalence of the following clinically significant conditions: functional impairment, difficulty with mobility, falls and injurious falls, social support, cognition, advance care planning, use of pain or sleep medications, and presence of pain or breathlessness. RESULTS: Of 2105 participants (mean age 76, 53% women, 34% lung cancer, 21% gastrointestinal cancer), the median survival was 9.6 months. Approximately 65% had difficulty climbing stairs (95% CI 63%-67%), 49% had no advance directive (95% CI 45%-54%), 35% lived alone (95% CI 33%-37%), 36% fell in the last 2 years (95% CI 34%-38%), and 32% rated their memory as poor (95% CI 29%-34%). After adjusting for gender, cancer type, and HRS survey time before the first Medicare claim for a poor prognosis cancer, functional impairment and falls were highest among adults aged 85+. Adults aged 65-74 years were less likely to have an advance directive. After adjusting for age, cancer type, and HRS survey time, women had a higher rate of pain and physical impairment. In exploratory analyses, race and socioeconomic status predicted difficulty with mobility and instrumental activities of daily living, living alone, and advance directive completion. CONCLUSIONS: Due to a high prevalence across multiple domains, all older adults with poor prognosis cancers should be assessed for geriatric and palliative care conditions.

Geriatric assessment in older adults with non-Hodgkin lymphoma: A Young International Society of Geriatric Oncology (YSIOG) review paper.

Non-Hodgkin lymphoma (NHL) is a disease of older adults, with a median age at diagnosis of 67 years. Treatment in older adults with NHL is challenging. The aging process is associated with a decline in functional reserve that varies among individuals, and results in an increasing risk of treatment-related toxicity and mortality. Chronological age and performance status fail to capture the multidimensional and heterogeneous nature of the aging process. A geriatric assessment (GA) screens multiple geriatric domains and provides a more accurate assessment of functional reserve. Several abbreviated GA tools have been developed for use in oncology clinics and help identify patients at high risk for chemotherapy-related toxicity and mortality. In this review, we explore GA tools validated for use in patients with NHL. We discuss the evidence behind GA-guided treatment in NHL and present a suggested approach to assessing frailty in this patient population.

Key recommendations from the 2021 "inclusion of older adults in clinical research" workshop.

Older adults are often underrepresented in clinical research, even though older adults are major consumers of novel therapies. We present major themes and recommendations from the 2021 "Inclusion of Older Adults in Clinical Research" Workshop, convened by the Clinical and Translational Science Award (CTSA) Inclusion of Older Adults as a Model for Special Populations Workgroup and the Research Centers Collaborative Network (RCCN). The goal of this workshop was to develop strategies to assist the research community in increasing the inclusion of older adults in clinical research. Major identified barriers include historical lack of federal guidelines, ageist biases and stereotypes, and lack of recruitment and retention techniques or infrastructure focused on older adults. Three key recommendations emerged: 1) engaging with the policymaking process to further promote inclusion; 2) using the CTSA Workgroup Presentation Materials Library and other resources to overcome ageism, and 3) building institutional capacity to support age inclusion.

Older patients' experiences following initial diagnosis of acute myeloid leukemia: A qualitative study.

INTRODUCTION: The onset of symptoms and the diagnosis of acute myeloid leukemia (AML) often occur suddenly and may lead to a range of emotional responses. Understanding patients' experiences and emotional states allows clinicians to tailor care to patients' needs. Previous studies have largely focused on patients' experiences at diagnosis and after remission has been achieved among those who received intensive chemotherapy. In this study, we evaluated experiences of older patients with AML who had received or were receiving treatments of varying intensity, in both outpatient and inpatient settings, and who were at different stages in their treatment course at the time of our interviews. MATERIALS AND METHODS: We conducted a single center qualitative study which aimed to understand factors influencing older patients' treatment decision-making and the findings were previously reported. This analysis specifically explored older patients' experiences at various stages after AML diagnosis. We purposively sampled patients based on treatment intensity and stage of treatment (undergoing induction treatment, post-remission treatment, or post-allogeneic hematopoietic stem cell transplant). We recruited fifteen patients aged ≥60 years with AML. The sample size was determined based on reaching data saturation for the primary study aim. For this analysis, data saturation was reached by the fourteenth manuscript. In-depth semi-structured interviews that had been recorded and transcribed were re-analyzed using inductive thematic analysis to explore patients' experiences. Coding was performed using Atlas.ti. We identified themes with the aim of capturing the most commonly shared experiences. RESULTS: Mean age of the fifteen patients was 72.1 years; all had received one or more treatments including intensive induction therapy (10/15), lower-intensity treatment (7/15), and/or hematopoietic stem cell transplant (3/15). Patients experienced strong negative emotional responses, including shock, that were barriers to processing information and meaningful communication. Patients also shared their perspectives on communication with healthcare professionals (including thoughts on adequacy of information provided) and coping strategies. DISCUSSION: Understanding older patients' experiences, including emotional responses and barriers to communication and decision making, at AML diagnosis and throughout the illness trajectory allows clinicians to address patients' supportive care needs during this difficult period.

Primary central nervous system lymphoma in older adults and the rationale for maintenance strategies: a narrative review.

OBJECTIVE: To provide a summary and analysis of the evidence for various agents applied as maintenance therapy and highlight ongoing trials or trials in development that evaluate the efficacy of maintenance therapy strategies in older patients with primary central nervous system lymphoma (PCNSL). BACKGROUND: PCNSL are rare neoplasms that can have an aggressive course with short-lived remissions when compared to systemic diffuse large B-cell lymphoma (DLBCL). There is currently a paucity of evidence on treatment in older adults with PCNSL, who may be unfit to tolerate effective therapies for PCNSL. Those who can tolerate these therapies and survive PCNSL are at increased risk from developing treatment-related toxicity, functional decline, and debilitating neurotoxicity. While there is no clearly defined role for maintenance therapy after treatment of systemic DLBCL, it should be considered in PCNSL because central nervous system (CNS) recurrence often has a devastating and irreversible impact on neurologic function. Therefore, at least theoretically, use of effective maintenance therapy in older adults with PCNSL, either in lieu of consolidation or after consolidation therapy, may be better tolerated and help delay tumor progression, resulting in an improved overall global neurologic function and quality of life. METHODS: We systematically searched MEDLINE (via PubMed) for all studies of drug treatments for maintenance therapy in PCNSL and also relied on expert opinion. We provide a summary and analysis of the evidence for various maintenance therapy agents, including methotrexate, rituximab, lenalidomide, temozolomide, ibrutinib, and procarbazine. We also highlight ongoing trials or trials in development that evaluate the efficacy of maintenance therapy in PCNSL. CONCLUSIONS: Prospective clinical studies focusing on PCNSL patients who are not candidates for intensive post-induction therapy are scarce. To date, there are no studies that clarify whether maintenance therapy can be used in lieu of consolidation therapy with autologous stem cell transplant or radiation. Prospective studies may provide critical data regarding the identification of optimal agents, whether consolidation therapy could be replaced by maintenance therapy, and the overall role of maintenance therapy as a means to potentially improve survival and preserve quality of life and function in a vulnerable, older patient population.

Tumor metabolism and neurocognition in CNS lymphoma.

BACKGROUND: The mechanistic basis for neurocognitive deficits in central nervous system (CNS) lymphoma and other brain tumors is incompletely understood. We tested the hypothesis that tumor metabolism impairs neurotransmitter pathways and neurocognitive function. METHODS: We performed serial cerebrospinal fluid (CSF) metabolomic analyses using liquid chromatography-electrospray tandem mass spectrometry to evaluate changes in the tumor microenvironment in 14 patients with recurrent CNS lymphoma, focusing on 18 metabolites involved in neurotransmission and bioenergetics. These were paired with serial mini-mental state examination (MMSE) and MRI studies for tumor volumetric analyses. Patients were analyzed in the setting of the phase I trial of lenalidomide/rituximab. Associations were assessed by Pearson and Spearman correlation coefficient. Generalized estimating equation (GEE) models were also established, adjusting for within-subject repeated measures. RESULTS: Of 18 metabolites, elevated CSF lactate correlated most strongly with lower MMSE score (P < 8E-8, ρ = -0.67). High lactate was associated with lower gamma-aminobutyric acid (GABA), higher glutamate/GABA ratio, and dopamine. Conversely, high succinate correlated with higher MMSE scores. Serial analysis demonstrated a reproducible, time-dependent, reciprocal correlation between changes in lactate and GABA concentrations. While high lactate and low GABA correlated with tumor contrast-enhancing volume, they correlated more significantly with lower MMSE scores than tumor volumes. CONCLUSIONS: We provide evidence that lactate production and Warburg metabolism may impact neurotransmitter dysregulation and neurocognition in CNS lymphomas. We identify novel metabolomic biomarkers that may be applied in future studies of neurocognition in CNS lymphomas. Elucidation of mechanistic interactions between lymphoma metabolism, neurotransmitter imbalance, and neurocognition may promote interventions that preserve cognitive function.