Integrative Oncology in Young Women With Breast Cancer.

Small studies have demonstrated the benefit of integrative oncology (IO) therapies in patients with breast cancer; however, referral patterns and timing of therapies are unknown. This study describes the referral pattern and utilization of IO services by young women with breast cancer. A retrospective review identified female patients, 40 years or younger, with a breast cancer diagnosis between 2014 and 2019, and a documented IO consultation. Patient demographics, cancer characteristics, treatments, reasons for seeking and timing of IO consultation, and IO treatment modalities were analyzed. The IO program treated 64 young women with a median age of 38.6 years. Clinical staging was primarily IA (27%), IIA (34%), or IIB (27%), and 64% of patients were clinically node negative with no evidence of metastasis. Women utilized the IO program for recurrence risk reduction and for treatment-related adverse effects (TRAEs), most commonly vasomotor complaints (44%). Therapies utilized were acupuncture (36%), healing touch (28%), oncology massage (30%), and other (75%; music therapy, therapeutic art, spiritual care, meditation, t'ai chi, yoga, and nutrition), which were commonly initiated during treatment (69%). Our data suggest that young women utilize IO services to reduce their future cancer risk and TRAEs, but they are often referred after standard cancer care treatments have begun. Future studies could examine the optimal timing for IO intervention.

DNA mutagenic activity and capacity for HIV-1 restriction of the cytidine deaminase APOBEC3G depend on whether DNA or RNA binds to tyrosine 315.

APOBEC3G (A3G) belongs to the AID/APOBEC protein family of cytidine deaminases (CDA) that bind to nucleic acids. A3G mutates the HIV genome by deamination of dC to dU, leading to accumulation of virus-inactivating mutations. Binding to cellular RNAs inhibits A3G binding to substrate single-stranded (ss) DNA and CDA activity. Bulk RNA and substrate ssDNA bind to the same three A3G tryptic peptides (amino acids 181-194, 314-320, and 345-374) that form parts of a continuously exposed protein surface extending from the catalytic domain in the C terminus of A3G to its N terminus. We show here that the A3G tyrosines 181 and 315 directly cross-linked ssDNA. Binding experiments showed that a Y315A mutation alone significantly reduced A3G binding to both ssDNA and RNA, whereas Y181A and Y182A mutations only moderately affected A3G nucleic acid binding. Consistent with these findings, the Y315A mutant exhibited little to no deaminase activity in an Escherichia coli DNA mutator reporter, whereas Y181A and Y182A mutants retained ∼50% of wild-type A3G activity. The Y315A mutant also showed a markedly reduced ability to assemble into viral particles and had reduced antiviral activity. In uninfected cells, the impaired RNA-binding capacity of Y315A was evident by a shift of A3G from high-molecular-mass ribonucleoprotein complexes to low-molecular-mass complexes. We conclude that Tyr-315 is essential for coordinating ssDNA interaction with or entry to the deaminase domain and hypothesize that RNA bound to Tyr-315 may be sufficient to competitively inhibit ssDNA deaminase-dependent antiviral activity.

Pain Improvement After Healing Touch and Massage in Breast Cancer: an Observational Retrospective Study.

BACKGROUND: Healing Touch (HT) and Oncology Massage (OM) are nonpharmacologic pain interventions, yet a comparative effectiveness study has not been conducted for pain in breast cancer. PURPOSE: This breast cancer subgroup analysis compared the effectiveness of HT vs. OM on pain. SETTING: The research occurred at an outpatient setting at an academic hybrid, multi-site, community-based cancer institute and Department of Supportive Oncology across four regional locations. PARTICIPANTS: Breast cancer outpatients along the cancer continuum who experienced routine clinical, nonexperimentally manipulated HT or OM. RESEARCH DESIGN: The study was an observational, retrospective, comparative effectiveness post hoc subanalysis of a larger dataset. Patients reporting pain < 2 were excluded. Pre- and posttherapy pain scores and differences were calculated. Logistic regression modeled posttherapy pain by modality, adjusting for pretherapy pain. The proportions experiencing ≥ 2-point (clinically significant) pain reduction were compared with chi-square tests. INTERVENTION: The study focused on the first session of either HT or OM. MAIN OUTCOME MEASURES: Pre- and posttherapy pain (range: 0 = no pain to 10 = worst possible pain). RESULTS: A total of 407 patients reported pre- and posttherapy pain scores, comprised of 233 (57.3%) who received HT and 174 (42.8%) who received OM. Pretherapy mean pain was higher in HT (M=5.1, ± 2.3) than OM (M=4.3, ± 2.1) (p < .001); posttherapy mean pain remained higher in HT (M=2.7, ± 2.2) than OM (M=1.9, ± 1.7) (p < .001). Mean difference in pain reduction was 2.4 for both HT and OM. Both HT (p < .001) and OM (p < .001) were associated with reduced pain. Proportions of clinically significant pain reduction were similar (65.7% HT and 69.0% OM, p = .483). Modality was not associated with pain improvement (p = .072). CONCLUSIONS: Both HT and OM were associated with clinically significant pain improvement. Future research should explore attitudes toward the modalities and potential influence of cancer stage and treatment status on modality self-selection.

Pilot study of multi-gene pharmacogenetic testing for pain management in oncology palliative medicine.

Aim: We evaluated the application and clinical impact of multi-gene pharmacogenetic testing in oncology palliative medicine. Patients & methods: In a single-arm pilot trial, cancer patients with uncontrolled pain were assessed in a palliative medicine clinic at baseline and received pharmacogenetic testing. Results were used as applicable up to the final visit (day 30). Pain scores, opioid prescribing, and use of pharmacogenetic test results were collected. Results: In 75 patients, the median baseline pain score was 7/10. Of 54 evaluable at the final visit, 28 required opioid modifications and 19 had actionable genotypes, mostly CYP2D6. Pain improvement (≥2-point reduction) was higher than historical data (56 vs 30%; p < 0.001). There were no differences in pain improvement between those with and without actionable genotypes (61 vs 53%). Conclusion: Multi-gene testing identified actionable genotypes and may improve cancer pain.

Opioid Risk Screening in an Oncology Palliative Medicine Clinic.

PURPOSE: Little information exists on factors that predict opioid misuse in oncology. We adopted the Screener and Opioid Assessment for Patients With Pain-Short Form (SOAPP-SF) and toxicology testing to assess for opioid misuse risk. The primary objective was to (1) identify characteristics associated with a high-risk SOAPP-SF score and noncompliant toxicology test, and (2) determine SOAPP-SF utility to predict noncompliant toxicology tests. METHODS: From July 1, 2017, to December 31, 2017, new patients completed the Edmonton Symptom Assessment Scale (ESAS), SOAPP-SF, and narcotic use agreement. Toxicology test results were collected at subsequent visits. RESULTS: Of 223 distinct patients, 96% completed SOAPP-SF. Mean age was 61 ± 12.7 years, 58% were female, 68% were White, and 28% were Black. Eighty-three eligible patients (38%) completed toxicology testing. Younger age, male sex, and increased ESAS depression scores were associated with high-risk SOAPP-SF scores. Smoking habit was associated with an aberrant test. An SOAPP-SF score ≥ 3 predicted a noncompliant toxicology test. CONCLUSION: Male sex, young age, and higher ESAS depression score were associated with a high SOAPP-SF score. Smoking habit was associated with an aberrant test. An SOAPP-SF of ≥ 3 (sensitivity, 0.74; specificity, 0.64), not ≥ 4, was predictive of an aberrant test; however, performance characteristics were decreased from those published by Inflexxion, for ≥ 4 (sensitivity, 0.86; specificity, 0.67). The specificity warrants caution in falsely labeling patients. The SOAPP-SF may aid in meeting National Comprehensive Cancer Network recommendations to screen oncology patients for opioid misuse.

Pain Management Using Clinical Pharmacy Assessments With and Without Pharmacogenomics in an Oncology Palliative Medicine Clinic.

PURPOSE: Approximately 30% of patients with cancer who have pain have symptomatic improvement within 1 month using conventional pain management strategies. Engaging clinical pharmacists in palliative medicine (PM) and use of pharmacogenomic testing may improve cancer pain management. METHODS: Adult patients with cancer with uncontrolled pain had baseline assessments performed by PM providers using the Edmonton Symptom Assessment Scale. Pharmacotherapy was initiated or modified accordingly. A subset of patients consented to pharmacogenomic testing. The first pharmacy assessment occurred within 1 week of baseline and a second assessment was done within another week if intervention was required. Each patient's final visit was at 1 month. Pain improvement rate (a reduction of two or more points on a 0-to-10 pain scale) from baseline to final visit was compared applying the Fisher exact test to published historical control data, and between patients with and without pharmacogenomic testing. Multivariate logistic regression identified pain improvement covariates. RESULTS: Of 142 patients undergoing pharmacy assessments, 53% had pain improvement compared with 30% in historical control subjects (P < .001). Pain improvement was not different between those who received (n = 43) and did not receive (n = 99) pharmacogenomics testing (56% v 52%; P = .716). However, of 15 patients with an actionable genotype, 73% had pain improvement. Higher baseline pain (odds ratio [OR], 1.79; 95% CI, 1.43 to 2.24; P < .001), black or other race (OR, 0.42; 95% CI, 0.18 to 0.95; P = .04), and performance status 3 or 4 (OR, 0.18; 95% CI, 0.04 to 0.83; P = .03) were associated with odds of pain improvement, but pharmacogenomic testing was not (P = .64). CONCLUSION: Including pharmacists in PM improves pain management effectiveness. Although pharmacogenomics did not statistically improve pain, a subset of patients with actionable genotypes may have benefited, warranting larger and randomized studies.

Cognitive deficits in docosahexaenoic acid-deficient rats.

This study investigated the influence of brain docosahexaenoic acid (DHA) deficiency on simple and complex olfactory-based learning and memory in 2nd generation (F2) adult male rats. Rats raised and maintained on either an n-3-adequate or an n-3-deficient diet were tested for acquisition of an olfactory learning set and an olfactory memory task, and for motivation to obtain a water reward. Despite a 76% decrease in brain DHA, n-3-deficient rats were able to acquire most simple 2-odor discrimination tasks but were deficient in the acquisition of a 20-problem olfactory learning set. This deficit could not be attributed to changes in sensory capacity but, instead, appeared to represent a deficit in higher order learning.

Impact of dietary n-3 FA deficiency on rat bone tissue FA composition.

The effect of dietary n-3 FA deficiency on bone tissue FA composition was evaluated in growing rats. Two mixtures combining hydrogenated coconut oil with safflower oil served as the n-3-deficient dietary treatments and provided two levels of linoleic acid (LA). The n-3 treatments were formulated with added alpha-linolenic acid (LNA) from flaxseed oil (diet LNA) or LNA plus DHA, and both were balanced for LA. This study showed that bone is sensitive to changes in dietary n-3 FA and that DHA is more effective than LNA in maintaining DHA levels in these tissues.

Docosapentaenoic acid does not completely replace DHA in n-3 FA-deficient rats during early development.

The reciprocal replacement of DHA by docosapentaenoic acid (DPAn-6) was studied in rats that consumed an n-3 FA-deficient or n-3 FA-adequate diet. Dams were fed the two experimental diets from weaning and throughout pregnancy and lactation. Their pups were then fed the respective diets after weaning. Cortex FA analysis was performed at various times (0, 5, 10, 20, 50, and 91 d) after birth to determine whether DPAn-6 completely replaced DHA in the n-3-deficient group. Cortical DHA levels were significantly lower (average 86%) in the n-3-deficient rats. DPAn-6 increased significantly in the n-3-deficient rats starting with a 6.5-fold increase at day 0 up to a 54-fold increase at day 91 compared with the n-3-adequate group. However, this significant increase did not completely replace the loss of DHA at postnatal days 5, 10, and 20 in which there was still an 11.5, 10.3, and 8.0% deficit in the sum of DHA and DPAn-6, respectively, in the n-3-deficient group. Once docosatetraenoic (DTA) and arachidonic acids (AA) were included in the sum (DHA + DPAn-6 + DTA + AA), the levels between the two groups were similar. These results suggest that not only DPAn-6 but also other n-6 FA, including DTA and AA, replace DHA in n-3-deficient rats. The lack of total 22-carbon (22C) FA in the brain during the rapid membrane biogenesis that occurs during early development could be a factor in the nervous system functional deficits associated with n-3 FA deficiency.

Long-term n-3 FA deficiency modifies peroxisome proliferator-activated receptor beta mRNA abundance in rat ocular tissues.

Peroxisomal proliferator-activated receptors (PPAR) are a FA-response system involved in diverse cellular responses. FA regulate PPAR activity and modulate PPAR mRNA abundance. Increasing evidence indicates that PUFA are required for optimal neuronal development and function. To gain insight into the mechanism for nutrition-induced impairment of neuronal development and function we investigated the effect of chronic n-3 FA deficiency on PPAR mRNA levels in rat brain and ocular tissues. Rats were fed for three generations a diet designed to reduce DHA levels in tissues, and the abundance of PPARalpha and PPARbeta transcripts was measured by hybridization with specific probes. Chronic consumption of the a-linolenic acid (LNA)-insufficient diet caused a remarkable modification in DHA content in membrane phospholipids. The results reported here indicate that PPARa mRNA levels did not exhibit significant variation in ocular, hepatic, or nervous tissues from rats fed the experimental diet. In contrast, PPARalpha mRNA normalized to beta-actin mRNA was 21% higher in ocular tissue from F3 generation rats consuming the LNA-deficient diet but was independent of diet in hepatic and nervous tissues. The absolute abundance of PPARbeta transcripts showed a 17% increase in ocular tissue from rats consuming the LNA-deficient diet (F3 generation). The biological significance of the reported changes in PPARbeta mRNA in ocular tissue remains to be determined.

A decrease in cell size accompanies a loss of docosahexaenoate in the rat hippocampus.

Rats raised on n-3 essential fatty acid deficient diets demonstrate spatial memory deficits. To investigate neuroanatomical correlates of these deficits, morphological analysis of the hippocampus were carried out. Adult, female rats were raised for three generations on n-3 deficient or n-3 supplemented diets. Two n-3 deficient diets contained adequate linoleic acid (LA), or high linoleic acid (high LA), and two supplemented diets contained LA supplemented with alpha-linolenic acid (+LNA), or linoleic supplementation with alpha-linolenic and docosahexaenoic acids (+LNA/DHA). The total fatty acid composition of the hippocampus revealed a profound loss (90%) in docosahexaenoic acid (DHA) in the hippocampi of LA and high LA animals compared to those on +LNA and +LNA/DHA diets with a reciprocal increase in docosapentaenoic acid (DPAn-6) in all phospholipid species. The volume, density, total number, and cell body size of neurons in CA1-3, granular and hilar layers of the hippocampus were measured at septal and temporal locations using unbiased stereology. No differences were detected in any of these measures except for in cell body size; CA1 pyramidal neurons in the LA group were significantly (p < 0.04) smaller than neurons in the +LNA/DHA group at the septal location.

Gray and white matter brain volume in aged rats raised on n-3 fatty acid deficient diets.

Omega-3 or n-3 fatty acids, especially docosahexaenoic acid, are important structural lipids in the brain. Their deficiency leads to a number of sensory, cognitive and behavioral effects. In previous studies, we showed that n-3 deficiency led to a decrease in the neuronal size of a number of brain regions in young rats. In particular, the neuronal size in the hippocampus CA1-CA3 layers decreased with a slight increase in the volumes of these layers. Therefore, we asked whether fatty acid deficiency could affect rat brain morphology in older animals. To address this question, we carried out gross morphological analysis using Magnetic Resonance Imaging on the gray and white matter volumes of brains in older rats (> 15 months) that were raised on n-3 deficient diets for three generations. We did not detect any differences in the total or regional gray and white matter volumes of brains of old rats maintained on a n-3 deficient or supplemented diet.

Differential effects of n-3 fatty acid deficiency on phospholipid molecular species composition in the rat hippocampus.

In this study, we have examined the effects of n-3 fatty acid deficient diets on the phospholipids (PL) molecular species composition in the hippocampus. Female rats were raised for two generations on diets containing linoleic acid (18:2n-6), with or without supplementation of alpha-linolenic acid (18:3n-3) or 18:3n-3 plus docosahexaenoic acid (22:6n-3). At 84 days of age, the hippocampal phospholipids were analyzed by reversed phase HPLC-electrospray ionization mass spectrometry. Depleting n-3 fatty acids from the diet led to a reduction of 22:6n-3 molecular species in phosphatidylcholine (PC), phosphatidylethanolamine (PE), PE-plasmalogens (PLE), and phosphatidylserine (PS) by 70-80%. In general, 22:6n-3 was replaced with 22:5n-6 but the replacement at the molecular species level did not always occur in a reciprocal manner, especially in PC and PLE. In PC, the 16:0,22:6n-3 species was replaced by 16:0,22:5n-6 and 18:0,22:5n-6. In PLE, substantial increases of both 22:5n-6 and 22:4n-6 species compensated for the decreases in 22:6n-3 species in n-3 fatty acid deficient groups. While the total PL content was not affected by n-3 deficiency, the relative distribution of PS decreased by 28% with a concomitant increase in PC. The observed decrease of 22:6n-3 species along with PS reduction may represent key biochemical changes underlying losses in brain-hippocampal function associated with n-3 deficiency.

Effects of an n-3-deficient diet on brain, retina, and liver fatty acyl composition in artificially reared rats.

Rat pups born to dams fed a diet with 3.1% of total fatty acids as alpha-linolenic acid (LNA) were fed, using an artificial rearing system, either an n-3-deficient (n-3-Def) or an n-3-adequate (n-3-Adq) diet. Both diets contained 17.1% linoleic acid, but the n-3-Adq diet also contained 3.1% LNA. The percentage of brain docosahexaenoic acid (DHA) continuously decreased (71%) with time over the 29 days of the experiment, with concomitant increases in docosapentaenoic acid (DPAn-6). In the retina, the percentage of DHA rose in the n-3-Adq group, with an apparent increased rate around the time of eye opening. However, there was a flat curve for the percentage of DHA in the n-3-Def group and a rising DPAn-6 with time. Liver DHA was highest at the time of birth in the n-3-Adq group but fell off somewhat over the course of 29 days. This decrease was more pronounced in the n-3-Def group, and the DPAn-6 rose considerably during the second half of the experiment. This method presents a first-generation model for n-3 deficiency that is more similar to the case of human nutrition than is the commonly employed two-generation model.