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Older adults with plasma cell disorders (PCDs) experience cognitive dysfunction that may be attributable to the disease and associated therapies. Yet, this has seldom been reported in the literature. Our objectives were to describe cognitive function (objective and patient-reported) in adults with PCDs and to explore clinical correlates of cognitive impairment.Participants completed a geriatric assessment between March 2018 and February 2020. Cognitive function was evaluated using two objective measures - Montreal Cognitive Assessment (MoCA, cutpoint26) and Blessed Orientation Memory Concentration Test (BOMC, cutpoint4) - and two patient-reported outcome (PRO) measures - Patient-Reported Outcomes Measurement Information System Cognitive Function (PROMIS-CF, cutpoint45) and European Organization for Research and Treatment of Cancer Cognitive Functioning subscale (EORTC-CF, cutpoint75). Spearman correlations examined relationships among these measures and log binomial regression was used to examine characteristics associated with cognitive impairment, as defined by the MoCA and PROMIS-CF measures.Among 86 participants with a mean age of 69 (range: 46-91), the prevalence of cognitive dysfunction was between 20% (BOMC) and 63% (MoCA). There was moderate correlation among objective measures (r = 0.51, p 0.0001), moderate to high correlation among PRO measures (r = 0.69, p 0.0001), but no correlation between objective and PRO measures. Factors associated with objective impairment included ≤ high school education (RR 1.46, p = 0.009), living alone (RR 1.42, p = 0.02), relapsed/refractory disease (RR 1.39, p = 0.04), empirically de-intensified induction therapy (RR 1.62, p = 0.008), frailty (RR 1.49, p = 0.04), and peripheral vascular disease (RR 1.54, p = 0.002). Factors associated with PRO impairment included social isolation (RR 3.43, p = 0.003), depression (RR 3.30, p = 0.004) and anxiety (RR 4.43, p = 0.0002), frailty (RR 3.60, p = 0.02), falls in the previous 6 months (RR 2.53, p = 0.02), and deficits in physical function (RR 4.44, p = 0.01). Older age was not associated with either objective or PRO impairment.Cognitive impairment, using objective and PRO screening measures, was relatively common in adults with PCDs. Cancer-related factors and medical comorbidities were associated with objective cognitive impairment whereas psychosocial and functional factors were associated with PRO impairment.

OBJECTIVES: Findings from a brief geriatric assessment (GA) in a cohort of adults with multiple myeloma (MM) are presented, with particular attention to the utility of the GA in identifying important deficits in adults judged to have a normal Karnofsky Performance Status (KPS ≥ 80). MATERIALS AND METHODS: Adults age 18 and older with MM were recruited into an observational study from 2018 to 2020. A modified Cancer and Aging Research Group (CARG) GA was administered at enrollment. Enrollees also completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life of Cancer Patients Core 30 questionnaire (QLQ-C30), with subscales of physical, social, role, and cognitive functioning (range 0-100; higher values indicate better function). Data were analyzed using descriptive statistics for the full cohort and stratified by concurrent KPS (score < 80 vs ≥ 80). RESULTS: Among 89 adults, the mean age was 69.1 years, 68% were aged ≥ 65 years, and 70% were white. In this cohort, 78% had KPS ≥ 80. Among those with KPS ≥ 80, functional impairments (Timed Up and Go ≥ 14 seconds and dependence in ≥ 1 instrumental activity of daily living) were seen in 30% and 21%, respectively, with 11% reporting ≥ 1 fall in the prior 6 months. At least two GA-identified deficits were detected in 50% of the overall cohort and in 41% of those with KPS ≥ 80. Among those with KPS ≥ 80, self-reported physical impairment on EORTC QLQ-C30 was noted by 34%. CONCLUSION: Using a modified CARG GA and EORTC questionnaire, functional impairments were identified among adults considered to have a good performance status based on a KPS (≥ 80). Future studies should focus on using GA measures for therapy assignment and identifying opportunities for intervening upon GA-identified deficits.

PurposeTo describe breast cancer treatment patterns among premenopausal women by age and time since last pregnancy. MethodsData were analyzed from 1,179 women diagnosed with premenopausal breast cancer in the Carolina Breast Cancer Study. Of these, 160 had a recent pregnancy (within 5 years of cancer diagnosis). Relative frequency differences (RFDs) and 95% confidence intervals (CIs) were used to compare cancer stage, treatment modality received, treatment initiation delay (>30 days), and prolonged treatment duration (>2 to >8 months depending on the treatment received) by age and recency of pregnancy. ResultsRecently postpartum women were significantly more likely to have stage III disease [RFD (95% CI): 12.2% (3.6%, 20.8%)] and to receive more aggressive treatment compared to nulliparous women. After adjustment for age, race and standard clinical tumor characteristics, recently postpartum women were significantly less likely to have delayed treatment initiation [RFD (95% CI): -11.2% (-21.4%, -1.0%)] and prolonged treatment duration [RFD (95% CI): -17.5% (-28.0%, -7.1%)], and were more likely to have mastectomy [RFD (95% CI): 14.9% (4.8%, 25.0%)] compared to nulliparous. Similarly, younger women (

BACKGROUND AND OBJECTIVES: Novel, non-cytotoxic agents are driving a paradigm shift for treatment of older adults with acute myeloid leukemia (AML). Older patients who initially receive intensive cytotoxic induction may choose to not proceed with cytotoxic consolidation therapy. Lenalidomide is an orally-administered immunomodulatory small molecule with activity in AML and a favorable safety profile in older adults with active leukemia. We conducted a phase Ib study of lenalidomide as post-remission therapy in older adults and assessed its impact on geriatric functional domains. MATERIALS AND METHODS: Participants were patients with AML over age 60 years who had undergone induction therapy and were poor candidates for cytotoxic consolidation. Lenalidomide was administered for 28 days in three dose cohorts. A Bayesian dose-escalation method determined cohort assignment and maximum tolerated dose (MTD). Geriatric assessment (GA) was performed before and after the cycle of lenalidomide. RESULTS: Nineteen patients with median age 68 were treated with at least one 28-day course of lenalidomide. Dose-limiting toxicities were observed in three participants at 25 mg, zero participants at 35 mg, and one participant at 50 mg. MTD was 35 mg. Median relapse-free survival was 4.3 months. GA was completed before and after treatment in fifteen patients, demonstrating improved cognitive function and no changes in physical, psychological, or social function after lenalidomide. CONCLUSION: Lenalidomide can be safely administered to older adults with AML with preservation of functional domains important to older patients. Serial GA can be performed in a novel drug study as a tool to characterize treatment tolerability.

BackgroundThe plasma cell disorders (PCDs), multiple myeloma (MM), and light-chain amyloidosis (AL) are disproportionately diseases of older adults, whose care may be complicated by frailty associated with advancing age. We sought to evaluate the prevalence of functional deficits and symptoms in a cohort of persons with PCDs and associations of demographic, disease-related, functional, and psychosocial measures with quality of life (QoL).Patients and MethodsAdults with PCDs were recruited into an observational registry in 2018-2020. Patients completed a functional assessment and European Organization for Research and Treatment of Cancer QoL questionnaire (QLQ-C30). Associations of covariates of interest with QoL were evaluated via univariate linear regression.ResultsAmong 121 adults, the mean age was 68.6. Diagnoses were 74% MM, 14% AL, 7% both MM and AL, and 5% other PCDs. The median time from diagnosis was 34.9 months. Median lines of therapy were 2, with 11% having received ≥4th-line therapy.Patients with functional deficits had lower mean QoL scores: dependence in IADLs (66.3 vs. 79.9, P = .001) and recent falls (56.7 vs. 76.8, P = .001). Patients ≤6 months from diagnosis had lower QoL (66.7) than those ≥2 years from diagnosis (77.3, P = .03). However, patients on later lines of therapy (≥4th-line) had lower QoL (62.2) than those on 1st-line treatment (76.0, P = .04).ConclusionsPatients with physical impairments and more advanced PCDs had lower QoL than those without deficits or earlier in their disease course. Early identification of physical impairments may facilitate interventions that mitigate these deficits and thereby improve QoL for patients with PCDs.

Background: Breast cancers in recently postpartum women may have worse outcomes, but studies examining tumor molecular features by pregnancy recency have shown conflicting results. Methods: This analysis used Carolina Breast Cancer Study data to examine clinical and molecular tumor features among women less than 50 years of age who were recently (≤10 years prior) or remotely (>10 years prior) postpartum, or nulliparous. Prevalence odds ratios (POR) and 95% confidence intervals (CI) were estimated using multivariable models. Results: Recently postpartum women (N = 618) were more frequently lymph node–positive [POR (95% CI): 1.66 (1.26–2.19)], estrogen receptor (ER)-negative [1.37 (1.02–1.83)], and IHC-based triple negative [1.57 (1.00–2.47)] compared with nulliparous (N = 360) women. Some differences were identified between recent versus remotely postpartum; smaller tumor size [0.67 (0.52–0.86)], p53 wildtype [0.53 (0.36–0.77)], and non–basal-like phenotype [0.53 (0.33–0.84)] were more common among recently postpartum. Recently postpartum (vs. nulliparous) had significant enrichment for adaptive immunity, T cells, B cells, CD8 T cells, activated CD8 T cells/natural killer (NK) cells, and T follicular helper (Tfh) cells and higher overall immune cell scores. These differences were attenuated in remotely (compared with recently) postpartum women. Conclusions: These results suggest a dominant effect of parity (vs. nulliparity) and a lesser effect of pregnancy recency on tumor molecular features, although tumor immune microenvironments were altered in association with pregnancy recency. Impact: Our study is unique in examining tumor immune microenvironment and RNA-based markers according to time since last childbirth. Future studies should examine the interplay between tumor features, postdiagnostic treatment, and outcomes among recently postpartum women. See related commentary by McDonald et al., p. 518

Caco-2 cells are a commonly used model for estimating the intestinal bioavailability of single chemical entity pharmaceuticals. Caco-2 cells, when induced with calcitriol, also express other biological functions such as phase I (CYP) and phase II (glucuronosyltransferases) drug metabolizing enzymes which are relevant to drug-supplement interactions. Intestinal bioavailability is an important factor in the overall safety assessment of products consumed orally. Foods, including herbal dietary supplements, are complex substances with multiple chemical components. Because of potential interactions between components of complex mixtures, more reliable safety assessments can be obtained by studying the commercial products “as consumed” rather than by testing individual chemical components one at a time. The present study evaluated the apparent intestinal permeability (Papp) of a model herbal extract, Rauwolfia serpentina, using both whole plant extracts and the individual purified Rauwolfia alkaloids. All test compounds, endpoint substrates, and their metabolites were quantified using liquid chromatography and high-resolution mass spectrometry. The Papp values for individual Rauwolfia alkaloids were comparable whether measured individually or as components of the complete extract. Both Rauwolfia extract and all individual Rauwolfia alkaloids except yohimbine inhibited CYP3A4 activity (midazolam 1′-hydroxylation). Both Rauwolfia extract and all individual Rauwolfia alkaloids except corynanthine and reserpic acid significantly increased glucuronosyltransferase activity (glucuronidation of 4-methylumbelliferone). The positive control, ketoconazole, significantly inhibited both CYP3A4 and glucuronosyltransferase activities. These findings suggest that the Caco-2 assay is capable of simultaneously identifying both bioavailability and potentially hazardous intestinal drug-supplement interactions in complex mixtures.

e20004 Background: Multiple myeloma (MM) and immunoglobulin light chain (AL) amyloidosis are clonal plasma cell disorders (PCDs) of aging, with median ages at diagnosis of 69 and 76 years, respectively. The care of adults with these disorders is often challenging due to the higher prevalence of vulnerabilities with advancing age. We examined the prevalence of physical or cognitive impairments and associations with quality-of-life (QoL) ratings in a longitudinal cohort of adults with PCDs. Methods: Adults undergoing treatment for PCDs were recruited to a longitudinal observational study (NCT03717844) from 2018 to 2020. A modified Cancer and Aging Research Group (CARG) geriatric assessment (GA) was administered at enrollment. Patients also completed the European Organization for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ-C30), which provided subscales of physical function, cognitive function, and global QoL (range 0-100; higher values indicate better function or QoL). Univariate linear regression was used to evaluate associations at the time of enrollment. Results: Among 121 consecutive adults, the mean age was 69 years, 65.8% were aged ≥ 65 years, and 71.9% were white. Diagnoses included MM in 73.6%, AL amyloidosis in 14.0%, and both disorders in 7.4%. The remaining 5.0% had another PCD warranting chemotherapy. Time from diagnosis at enrollment was ≤ 6 months for 25.6%, 6 to 24 months for 18.1%, and ≥ 24 months for 56.3%. In this cohort, 80.2% had a clinician-assessed Karnofsky Performance Status (KPS) score ≥ 80. GA-identified impairments (Timed Up and Go ≥ 14 seconds and dependence in ≥ 1 instrumental activity of daily living [IADL]) were seen in 29.8% and 35.6%, respectively, with 13.5% reporting ≥ 1 fall in the prior 6 months. Polypharmacy (≥ 5 medications) was identified in 80.0%. Self-reported physical and cognitive impairments on QLQ-C30 were described by 48.7% and 20.2%, respectively. Patients with functional deficits had worse EORTC QoL scores compared to those without deficits: dependence in ≥ 1 IADL (mean QoL score 66.3 vs. 79.9, p = 0.0009), ≥ 1 fall (56.7 vs. 76.8, p = 0.0009), self-reported physical impairment on QLQ-C30 (64.0 vs. 84.5, p < 0.0001), and self-reported cognitive impairment on QLQ-C30 (61.2 vs. 77.7, p = 0.0012). Conclusions: Using a modified CARG GA and the EORTC QLQ-C30, we identified physical and cognitive impairments among adults undergoing treatment for PCDs. GA-identified impairments in physical function were more prevalent than clinician-assessed KPS would suggest. Patients with physical and cognitive impairments had worse QoL scores than those without deficits. Future research involving this cohort will investigate the longitudinal trajectory of physical and cognitive functioning, evaluate trends in QoL measurements, and test the feasibility of implementing GA-guided interventions for this population.

Synthesis and regulation of catecholamine neurotransmitters in the central nervous system are implicated in the pathogenesis of a number of neuropsychiatric disorders. To identify factors that regulate the presynaptic synthesis of catecholamines, we tested the hypothesis that the rate-limiting enzyme of the catecholamine biosynthetic pathway, tyrosine hydroxylase (TH), is locally synthesized in axons and presynaptic nerve terminals of noradrenergic neurons. To isolate pure axonal mRNA and protein, rat superior cervical ganglion sympathetic neurons were cultured in compartmentalized Campenot chambers. qRT-PCR and RNA in situ hybridization analyses showed that TH mRNA is present in distal axons. Colocalization experiments with nerve terminal marker proteins suggested that both TH mRNA and protein localize in regions of the axon that resemble nerve terminals (i.e., synaptic boutons). Analysis of polysome-bound RNA showed that TH mRNA is present in polysomes isolated from distal axons. Metabolic labeling of axonally synthesized proteins labeled with the methionine analog, L-azidohomoalanine, showed that TH is locally synthesized in axons. Moreover, the local transfection and translation of exogenous TH mRNA into distal axons facilitated axonal dopamine synthesis. Finally, using chimeric td-Tomato-tagged constructs, we identified a sequence element within the TH 3′UTR that is required for the axonal localization of the reporter mRNA. Taken together, our results provide the first direct evidence that TH mRNA is trafficked to the axon and that the mRNA is locally translated. These findings raise the interesting possibility that the biosynthesis of the catecholamine neurotransmitters is locally regulated in the axon and/or presynaptic nerve terminal.

Background: Renal and hepatotoxicity of diglycolic acid (DGA) has been described with in vitro cellular models as well as in vivo animal and human systems. The possibility of DGA being toxic

Of the 1.8 million global incident lung cancer cases estimated in 2012, approximately 58% occurred in less developed regions (LDRs). Studies conducted in more developed regions suggest potential gender differences in lung cancer risk, whereby women may be more susceptible to the carcinogenic effects of tobacco. However, studies of reproductive and hormonal factors and lung cancer among women have been inconsistent and to date, no prior study has assessed these relationships among Nepali women. Using data from a hospital-based case-control study conducted in B. P. Koirala Memorial Cancer Hospital (Nepal, 2009-2012), relationships between reproductive and hormonal factors and lung cancer were examined among women aged 23-85 years. Lung cancer cases (n = 268) were frequency-matched to controls (n = 226), on the basis of age (±5 years), ethnicity and residential area. Controls were selected from visitors of non-lung cancer patients within the same hospital. Participants completed an interviewer-administered questionnaire and provided detailed information on demographics, medical history, smoking history, and reproductive and hormonal factors. The main exposures in this analysis included menopausal status, age at menarche, age at menopause, menstrual duration, gravidity, and age at first live-birth. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. Final models include adjustment for key confounders including age and smoking status. Among postmenopausal women, those with a younger age at menopause ( Citation Format: Sanah N. Vohra, Amir Sapkota, Mei-Ling T. Lee, Mia Hashibe, Bhola Siwakoti, Chin B. Pun, Cher M. Dallal. Reproductive and hormonal factors in relation to lung cancer among Nepali women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1737.