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Background: Depression is a pervasive symptom in patients with gynecological cancer undergoing chemotherapy., Objectives: Purposes were to identify subgroups of patients with distinct depression profiles and evaluate for differences in demographic and clinical characteristics, severity of common symptoms, and quality of life (QOL) outcomes among these subgroups., Methods: Patients with gynecological cancer (n = 231) completed the Center for Epidemiologic Studies-Depression Scale 6 times over 2 cycles of chemotherapy. All of the other measures were completed prior to the second or third cycle of chemotherapy. Latent profile analysis was done to identify the distinct depression profiles. Differences were evaluated using parametric and nonparametric tests., Results: Three distinct profiles were identified: low (60.1%), high (35.1%), and very high (4.8%). Compared with low class, the other 2 classes had lower functional status and were more likely to self-report a diagnosis of depression. Patients in the 2 worse profiles reported a higher comorbidity burden, higher levels of trait and state anxiety, sleep disturbance, and fatigue, as well as lower levels of cognitive function and poorer QOL. State and trait anxiety, evening fatigue, and sleep disturbance scores exhibit a "dose-response effect" (ie, as the depression profile worsened, the severity of these symptoms increased)., Conclusions: Almost 40% of our sample experienced high or very high levels of depression across 2 cycles of chemotherapy., Implications for Practice: Clinicians can use the identified risk factors to identify high patients risk and provide tailored psychological interventions aimed to decrease symptom burden and prevent decrements in QOL., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Desiccation is a fundamental challenge confronted by all terrestrial organisms, particularly insects. With a relatively small body size and large surface-to-volume ratio insects are susceptible to rapid evaporative water loss and dehydration. To counter these physical constraints, insects have acquired specialized adaptations, including a hydrophobic cuticle that acts as a physical barrier to transpiration. We previously reported that genetic ablation of the oenocytes - specialized cells required to produce cuticular hydrocarbons (HCs) - significantly reduced survivorship under desiccative conditions in the fruit fly, Drosophila melanogaster. Although increased transpiration - resulting from the loss of the oenocytes and HCs - was hypothesized to be responsible for the decrease in desiccation survival, this possibility was not directly tested. Here we investigate the underlying physiological mechanisms contributing to the reduced survival of oenocyte-less (oe-) flies. Using flow-through respirometry we show that oe- flies, regardless of sex, exhibited an increased rate of transpiration relative to wild-type controls, and that coating oe- flies with fly-derived HC extract restored the rate to near wild-type levels. Importantly, total body water stores, including metabolic water reserves, as well as dehydration tolerance, measured as the percent of total body water lost at time of death, were largely unchanged in oe- flies. Together, our results directly demonstrate the critically important role played by the oenocytes and cuticular HCs to promote desiccation resistance., (© 2024. Published by The Company of Biologists Ltd.)

Objectives: To identify subgroups of patients with distinct psychological profiles at the beginning of the COVID-19 pandemic and evaluate for differences., Sample & Setting: Online survey of patients with cancer during the COVID-19 pandemic., Methods & Variables: Patients completed measures of demographic and clinical characteristics, as well as cancer- and COVID-19-related stress, global stress, social isolation, loneliness, financial toxicity, and common symptoms. Latent profile analysis was used to identify distinct psychological profiles., Results: Among 1,145 patients, three subgroups were identified (i.e., no anxiety or depression and normative level of resilience; high depression, high anxiety, and low resilience; and very high depression, very high anxiety, and very low resilience). Patients with the two worst psychological profiles were younger, more likely to be female, more recently diagnosed with cancer, and more likely to have breast cancer., Implications for Nursing: Findings may assist clinicians to identify patients at increased risk for significant psychological morbidity and provide more timely, targeted, and cost-effective interventions.

We recently demonstrated that transient attenuation of Toll-like receptor 4 (TLR4) in dorsal root ganglion (DRG) neurons, can both prevent and reverse pain associated with chemotherapy-induced peripheral neuropathy (CIPN), a severe side effect of cancer chemotherapy, for which treatment options are limited. Given the reduced efficacy of opioid analgesics to treat neuropathic, compared with inflammatory pain, the cross talk between nociceptor TLR4 and mu-opioid receptors (MORs), and that MOR and TLR4 agonists induce hyperalgesic priming (priming), which also occurs in CIPN, we determined, using male rats, whether (1) antisense knockdown of nociceptor MOR attenuates CIPN, (2) and attenuates the priming associated with CIPN, and (3) CIPN also produces opioid-induced hyperalgesia (OIH). We found that intrathecal MOR antisense prevents and reverses hyperalgesia induced by oxaliplatin and paclitaxel, two common clinical chemotherapy agents. Oxaliplatin-induced priming was also markedly attenuated by MOR antisense. Additionally, intradermal morphine, at a dose that does not affect nociceptive threshold in controls, exacerbates mechanical hyperalgesia (OIH) in rats with CIPN, suggesting the presence of OIH. This OIH associated with CIPN is inhibited by interventions that reverse Type II priming [the combination of an inhibitor of Src and mitogen-activated protein kinase (MAPK)], an MOR antagonist, as well as a TLR4 antagonist. Our findings support a role of nociceptor MOR in oxaliplatin-induced pain and priming. We propose that priming and OIH are central to the symptom burden in CIPN, contributing to its chronicity and the limited efficacy of opioid analgesics to treat neuropathic pain., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Background: Interindividual variability in oncology patients' symptom experiences poses significant challenges in prioritizing symptoms for targeted intervention(s). In this study, computational approaches were used to unbiasedly characterize the heterogeneity of the symptom experience of oncology patients to elucidate symptom patterns and drivers of symptom burden., Methods: Severity ratings for 32 symptoms on the Memorial Symptom Assessment Scale from 3088 oncology patients were analyzed. Gaussian Graphical Model symptom networks were constructed for the entire cohort and patient subgroups identified through unsupervised clustering of symptom co-severity patterns. Network characteristics were analyzed and compared using permutation-based statistical tests. Differences in demographic and clinical characteristics between subgroups were assessed using multinomial logistic regression., Results: Network analysis of the entire cohort revealed three symptom clusters: constitutional, gastrointestinal-epithelial, and psychological. Lack of energy was identified as central to the network which suggests that it plays a pivotal role in patients' overall symptom experience. Unsupervised clustering of patients based on shared symptom co-severity patterns identified six patient subgroups with distinct symptom patterns and demographic and clinical characteristics. The centrality of individual symptoms across the subgroup networks differed which suggests that different symptoms need to be prioritized for treatment within each subgroup. Age, treatment status, and performance status were the strongest determinants of subgroup membership., Conclusions: Computational approaches that combine unbiased stratification of patients and in-depth modeling of symptom relationships can capture the heterogeneity in patients' symptom experiences. When validated, the core symptoms for each of the subgroups and the associated clinical determinants may inform precision-based symptom management., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

The primary cilium, a single microtubule-based organelle protruding from the cell surface and critical for neural development, also functions in adult neurons. While some dorsal root ganglion neurons elaborate a primary cilium, whether it is expressed by and functional in nociceptors is unknown. Recent studies have shown a role of Hedgehog, whose canonical signaling is primary cilium dependent, in nociceptor sensitization. We establish the presence of primary cilia in soma of rat nociceptors, where they contribute to mechanical threshold, prostaglandin E 2 (PGE 2 )-induced hyperalgesia, and chemotherapy-induced neuropathic pain (CIPN). Intrathecal administration of siRNA targeting Ift88 , a primary cilium-specific intra-flagellar transport (IFT) protein required for ciliary integrity, resulted in attenuation of Ift88 mRNA and nociceptor primary cilia. Attenuation of primary cilia was associated with an increase in mechanical nociceptive threshold in vivo, and decrease in nociceptor excitability in vitro , abrogation of hyperalgesia, and nociceptor sensitization induced by both a prototypical pronociceptive inflammatory mediator PGE 2 and paclitaxel CIPN, in a sex-specific fashion. siRNA targeting Ift52, another IFT protein, and knockdown of NompB, the Drosophila Ift88 ortholog, also abrogated CIPN and reduced baseline mechanosensitivity, respectively, providing independent confirmation for primary cilia control of nociceptor function. Hedgehog-induced hyperalgesia is attenuated by Ift88 siRNA, supporting a role for primary cilia in Hedgehog-induced hyperalgesia. Attenuation of CIPN by cyclopamine (intradermal and intra-ganglion), which inhibits Hedgehog signaling, supports a role of Hedgehog in CIPN. Our findings support a role of the nociceptor primary cilium in control of mechanical nociceptive threshold and inflammatory and neuropathic pain, the latter Hedgehog-dependent. Significance statement Many neurons have a tiny antenna-like structure, the primary cilium, protruding from their cell body, which processes information about the extracellular environment as well as regulates intracellular signaling. We report experiments aimed at understanding the role of the primary cilium in pain sensory neurons (nociceptors), including in the setting of inflammatory and neuropathic pain. We establish that nociceptors bear a primary cilium and show that this organelle regulates detection of noxious stimuli and contributes to nociceptor sensitization, using both the rat and the fruit fly as model organisms to manipulate primary cilia in pain states. We also identify primary cilium dependence of the contribution of Hedgehog to pain states., (Copyright © 2024 Fitzsimons et al.)

Background: Cancer-related cognitive impairment (CRCI) is reported by 45% of patients with cancer. Significant gaps in knowledge remain regarding the mechanisms that underlie CRCI., Objectives: Using a data-driven approach, the study purpose was to evaluate for perturbed pathways associated with membership in the High versus the Low CRCI profiles., Methods: Patients completed the Attentional Function Index six times over two cycles of chemotherapy. Using findings from a previous latent profile analysis, subgroups of patients with high versus low levels of CRCI were evaluated (i.e., High versus Low CRCI profiles). Gene expression was quantified using either ribonucleic (RNA)-sequencing or microarray analyses and pathway impact analyses were performed. Signaling pathways were defined using the Kyoto Encyclopedia of Genes and Genomes database., Results: A total of 508 patients had data available for analysis. Of the 261 patients in the RNA-sequencing sample, 48.7% were in the High class and 51.3% were in the Low class. Of the 247 patients the microarray sample, 46.6% were in the High class and 53.4% were in the Low class. Pathway impact analyses identified seven perturbed pathways related to neurotransmission (i.e., glutamatergic synapse, GABAergic synapse, dopaminergic synapse, serotonergic synapse, long-term depression, cholinergic synapse, retrograde endocannabinoid signaling)., Conclusions: This study is the first to describe associations between self-reported CRCI in patients receiving chemotherapy for breast, gastrointestinal, gynecological, or lung cancer and seven neurotransmission pathways. These findings provide new insights into potential targets for mechanistically based interventions., (© 2024. The Author(s).)

Background: Cancer-related cognitive impairment (CRCI) and anxiety co-occur in patients with cancer. Little is known about mechanisms for the co-occurrence of these two symptoms. The purposes of this secondary analysis were to evaluate for perturbed pathways associated with the co-occurrence of self-reported CRCI and anxiety in patients with low versus high levels of these two symptoms and to identify potential mechanisms for the co-occurrence of CRCI and anxiety using biological processes common across any perturbed neurodegenerative disease pathways., Methods: Patients completed the Attentional Function Index and the Spielberger State-Trait Anxiety Inventory six times over two cycles of chemotherapy. Based on findings from a previous latent profile analysis, patients were grouped into none versus both high levels of these symptoms. Gene expression was quantified, and pathway impact analyses were performed. Signaling pathways for evaluation were defined with the Kyoto Encyclopedia of Genes and Genomes database., Results: A total of 451 patients had data available for analysis. Approximately 85.0% of patients were in the none class and 15.0% were in the both high class. Pathway impact analyses identified five perturbed pathways related to neurodegenerative diseases (i.e., amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, prion disease, and pathways of neurodegeneration-multiple diseases). Apoptosis, mitochondrial dysfunction, oxidative stress, and endoplasmic reticulum stress were common biological processes across these pathways., Conclusions: This study is the first to describe perturbations in neurodegenerative disease pathways associated with CRCI and anxiety in patients receiving chemotherapy. These findings provide new insights into potential targets for the development of mechanistically based interventions., (© 2024 American Cancer Society.)

Objectives: Shortness of breath is a common symptom in patients with cancer. However, the mechanisms that underlie this troublesome symptom are poorly understood. Therefore, this study aimed to determine the prevalence of and associated risk factors for shortness of breath in women prior to breast cancer surgery and identify associations between shortness of breath and polymorphisms for potassium channel genes., Methods: Patients were recruited prior to breast cancer surgery and completed a self-report questionnaire on the occurrence of shortness of breath. Genotyping of single nucleotides polymorphism (SNPs) in potassium channel genes was performed using a custom array. Multiple logistic regression analyses were done to identify associations between the occurrence of shortness of breath and SNPs in ten candidate genes., Results: Of the 398 patients, 11.1% reported shortness of breath. These patients had a lower annual household income, a higher comorbidity burden, and a lower functional status. After controlling for functional status, comorbidity burden, genomic estimates of ancestry and self-reported race and ethnicity, the genetic associations that remained significant in the multiple regression analyses were for potassium voltage-gated channel subfamily D ( KCND2) rs12673992, potassium voltage-gated channel modifier subfamily S ( KCNS1) rs4499491, and potassium two pore channel subfamily K ( KCNK2) rs4411107., Conclusions: While these findings warrant replication, they suggest that alterations in potassium channel function may contribute to the occurrence of shortness of breath in women prior to breast cancer surgery., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Individuals who undergo chemotherapy for cancer are at elevated risk of developing depressive symptoms, yet substantial interindividual variation exists in trajectories of these symptoms., Objective: To examine interindividual variations in trajectories of depressive symptoms during 2 cycles of chemotherapy and to evaluate associations between demographic and clinical characteristics, symptom severity scores, psychological adjustment characteristics (eg, stress and coping), and initial levels and trajectories of depressive symptoms., Methods: Patients (n = 1323) diagnosed with breast, gynecologic, lung, or gastrointestinal cancer completed the Center for Epidemiological Studies-Depression Scale 6 times, over 2 cycles of chemotherapy. At enrollment, patients provided demographic information and completed a broad range of symptom, stress, and coping measures. Hierarchical linear modeling was used to identify characteristics associated with initial levels and trajectories of depressive symptoms., Results: Interindividual differences in initial levels of depressive symptoms were associated with marital status, functional status, level of comorbidity, chemotherapy toxicity, sleep disturbance, morning fatigue, cognitive function, global and cancer-related stress, and coping characteristics (ie, sense of coherence, venting, behavioral disengagement, and self-blame). Interindividual differences in depression trajectories were associated with education, cancer type, chemotherapy toxicity, sleep disturbance, evening energy, evening fatigue, cognitive function, global and cancer-related stress, and self-blame., Conclusions: We present new findings concerning the trajectories and predictors of depressive symptoms during chemotherapy., Implications for Practice: Modifiable risk factors (eg, stress and coping) are important targets for intervening to address depressive symptoms in oncology patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Decrements in energy were found in 67% of women who underwent breast cancer surgery. However, no information is available on chronic decrements in energy and associations with inflammation. Purposes were to identify latent classes of patients with distinct average energy profiles from prior to through 12 months after breast cancer surgery; evaluate for differences in demographic and clinical characteristics between the two extreme average energy classes; and evaluate for polymorphisms for cytokine genes associated with membership in the Low energy class., Methods: Women (n = 397) completed assessments of energy prior to and for 12 months following breast cancer surgery. Growth mixture modeling was used to identify classes of patients with distinct average energy profiles. Eighty-two single nucleotide polymorphisms (SNPs) among 15 cytokine genes were evaluated., Results: Three distinct energy profiles were identified (ie, Low [27.0%], Moderate [54.4%], Changing [18.6%]). Data from patients in the Low and Moderate energy classes were used in the candidate gene analyses. Five SNPs and one haplotype in six different genes remained significant in logistic regression analyses (ie, interleukin [IL]-1β rs1143623, IL1 receptor 1 rs3917332 IL4 rs2243263, IL6 HapA1 [that consisted of rs1800795, rs2069830, rs2069840, rs1554606, rs2069845, rs2069849, and rs2069861], nuclear factor kappa beta subunit 1 rs170731, tumor necrosis factor rs1799964). For several SNPs for IL6, expression quantitative trait locis were identified in subcutaneous and visceral adipose tissue and thyroid tissue. In addition, skeletal muscle was identified as an expression quantitative trait loci for nuclear factor kappa beta subunit 1., Conclusions: Findings suggest that cytokine genes are involved in the mechanisms that underlie chronic decrements in energy in women following breast cancer surgery. Given the roles of subcutaneous and visceral adipose and thyroid tissues in metabolism and energy balance, the findings related to IL6 suggest that these polymorphisms may have a functional role in the development and maintenance of chronic decrements in energy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To identify subgroups of patients with distinct cough occurrence profiles and evaluate for differences among these subgroups., Sample & Setting: Outpatients receiving chemotherapy (N = 1,338) completed questionnaires six times over two chemotherapy cycles., Methods & Variables: Occurrence of cough was assessed using the Memorial Symptom Assessment Scale. Latent class analysis was used to identify subgroups with distinct cough occurrence profiles. Parametric and nonparametric tests were used to evaluate for differences., Results: Four distinct cough profiles were identified (None, Decreasing, Increasing, and High). Risk factors associated with membership in the High class included lower annual household income; history of smoking; self-reported diagnoses of lung disease, heart disease, and back pain; and having lung cancer., Implications for Nursing: Clinicians need to assess all patients with cancer for cough and provide targeted interventions.

Objectives: To identify subgroups of patients with distinct chemotherapy-induced vomiting (CIV) profiles; determine how these subgroups differ on several demographic, clinical, and symptom characteristics; and evaluate factors associated with chemotherapy-induced nausea and CIV profiles., Sample & Setting: Adult patients (N = 1,338) receiving cancer chemotherapy., Methods & Variables: Data were collected on demographic, clinical, and symptom characteristics. Differences among subgroups of patients with distinct CIV profiles were evaluated using parametric and nonparametric tests., Results: Three CIV profiles (None, Decreasing, and Increasing) were identified. Compared with the None class, Decreasing and Increasing classes were more likely to have lower household income and a higher comorbidity burden, as well as to report higher rates of dry mouth, nausea, diarrhea, depression, anxiety, sleep disturbance, morning fatigue, and pain interference., Implications for Nursing: Clinicians need to assess common and distinct risk factors for CIV and chemotherapy-induced nausea.

Objectives: To evaluate for associations between the occurrence of palpitations reported by women prior to breast cancer surgery and single nucleotide polymorphisms (SNPs) for neurotransmitter genes., Sample & Setting: A total of 398 women, who were scheduled for unilateral breast cancer surgery, provided detailed information on demographic and clinical characteristics and the occurrence of palpitations prior to breast cancer surgery., Methods & Variables: The occurrence of palpitations was assessed using a single item (i.e., "heart races/pounds" in the past week ["yes"/"no"]). Blood samples were collected for genomic analyses. Multiple logistic regression analyses were used to identify associations between the occurrence of palpitations and variations in neurotransmitter genes., Results: Nine SNPs and two haplotypes among 11 candidate genes were associated with the occurrence of palpitations. These genes encode for a number of neurotransmitters and/or their receptors, including serotonin, norepinephrine, dopamine, gamma-amino butyric acid, Substance P, and neurokinin., Implications for Nursing: These findings suggest that alterations in a variety of neurotransmitters contribute to the development of this symptom.

Context: Breast cancer-related lymphedema (BCRL) is chronic condition that occurs in 5% to 75% of women following treatment for breast cancer. However, little is known about the risk factors and mechanisms associated with a worse BCRL profile., Objectives: Identify distinct BCRL profiles in women with the condition (i.e., lower vs. higher risk phenotype) and evaluate for associations with pro- and anti-inflammatory genes., Methods: Latent class profile analysis (LCPA) was used to identify the BCRL profiles using phenotypic characteristics evaluated prior to surgery. Candidate gene analyses were done to identify cytokine genes associated with the two BCRL profiles., Results: Of the 155 patients evaluated, 35.5% (n = 55) were in the Lower and 64.5% (n = 100) were in the Higher Risk classes. Risk factors for membership in the Higher class included: lower functional status, having sentinel lymph node biopsy, axillary lymph node dissection, mastectomy, higher number of positive lymph nodes, and receipt of chemotherapy. Polymorphisms for interleukin (IL)1-beta and IL6 were associated with membership in the Higher Risk class., Conclusion: The readily available and clinically relevant phenotypic characteristics associated with a worse BCRL profile can be used by clinicians to identify higher risk patients. If confirmed, these characteristics can be tested in predictive risk models. In addition, the candidate gene findings may guide the development of mechanistically-based interventions to decrease the risk of BCRL., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Social networks are a mathematical representation of interactions among individuals which are prevalent across various animal species. Studies of human populations have shown the breadth of what can spread throughout a social network: obesity, smoking cessation, happiness, drug use and divorce. 'Betweenness centrality' is a key property of social networks that indicates an individual's importance in facilitating communication and cohesion within the network. Heritability of betweenness centrality has been suggested in several species, however the genetic regulation of this property remains enigmatic. Here, we demonstrate that the gene CG14109, referred to as degrees of kevin bacon (dokb), influences betweenness centrality in Drosophila melanogaster. We identify strain-specific alleles of dokb with distinct amino acid sequences and when the dokb allele is exchanged between strains, flies exhibit the betweenness centrality pattern dictated by the donor allele. By inserting a GAL4 reporter into the dokb locus, we confirm that dokb is expressed in the central nervous system. These findings define a novel genetic entry point to study social network structure and thereby establish gene-to-social structure relationships. While dokb sequence homology is exclusive to Diptera, we anticipate that dokb-associated molecular pathways could unveil convergent neural mechanisms of social behaviour that apply in diverse animal species., (© 2024. The Author(s).)

Objectives: To evaluate for differences in global, cancer-specific, and cumulative life stress, as well as resilience and use of various coping strategies among five groups (no depression or sleep disturbance, no depression and moderate sleep disturbance, subsyndromal depression and very high sleep disturbance, moderate depression and moderate sleep disturbance [Both Moderate]; and high depression and very high sleep disturbance [Both High])., Sample & Setting: Patients (N = 1,331) receiving chemotherapy were recruited from outpatient oncology clinics., Methods & Variables: Measures of global, cancer-specific, and cumulative life stress, resilience, and coping were obtained. Differences were evaluated using parametric and nonparametric tests., Results: Global and cancer-specific stress scores increased as joint profiles worsened. Both Moderate and Both High classes had cancer-specific stress scores suggestive of post-traumatic stress. Both Moderate and Both High classes reported higher occurrence rates for several stressful life events and higher use of disengagement coping. Both Moderate and Both High classes had resilience scores below the normative score for the United States., Implications for Nursing: Clinicians need to screen vulnerable patients for post-traumatic stress disorder and implement interventions to reduce stress.

Objectives: To evaluate for associations of polymorphisms for potassium channel genes in patients with breast cancer who were classified as having high or low-moderate levels of cancer-related cognitive impairment (CRCI)., Sample & Setting: 397 women who were scheduled to undergo surgery for breast cancer on one breast were recruited from breast care centers located in a comprehensive cancer center, two public hospitals, and four community practices., Methods & Variables: CRCI was assessed using the Attentional Function Index prior to and for six months after surgery. The attentional function classes were identified using growth mixture modeling., Results: Differences between patients in the high versus low-moderate attentional function classes were evaluated. Six single nucleotide polymorphisms for potassium channel genes were associated with low-moderate class membership., Implications for Nursing: The results contribute to knowledge of the mechanisms for CRCI. These findings may lead to the identification of high-risk patients and the development of novel therapeutics.

Purpose: One plausible mechanistic hypothesis is the potential contribution of inflammatory mechanisms to shortness of breath. This study was aimed to evaluate for associations between the occurrence of shortness of breath and perturbations in inflammatory pathways., Methods: Patients with cancer reported the occurrence of shortness of breath six times over two cycles of chemotherapy. Latent class analysis was used to identify subgroups of patients with distinct shortness of breath occurrence profiles (i.e., none (70.5%), decreasing (8.2%), increasing (7.8%), high (13.5%)). Using an extreme phenotype approach, whole transcriptome differential gene expression and pathway impact analyses were performed to evaluate for perturbed signaling pathways associated with shortness of breath between the none and high classes. Two independent samples (RNA-sequencing (n = 293) and microarray (n = 295) methodologies) were evaluated. Fisher's combined probability method was used to combine these results to obtain a global test of the null hypothesis. In addition, an unweighted knowledge network was created using the specific pathway maps to evaluate for interconnections among these pathways., Results: Twenty-nine Kyoto Encyclopedia of Genes and Genomes inflammatory signaling pathways were perturbed. The mitogen-activated protein kinase signaling pathway node had the highest closeness, betweenness, and degree scores. In addition, five common respiratory disease-related pathways, that may share mechanisms with cancer-related shortness of breath, were perturbed., Conclusions: Findings provide preliminary support for the hypothesis that inflammation contribute to the occurrence of shortness of breath in patients with cancer. In addition, the mechanisms that underlie shortness of breath in oncology patients may be similar to other respiratory diseases., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Progress in the development of effective chemotherapy is producing a growing population of patients with acute and chronic painful chemotherapy-induced peripheral neuropathy (CIPN), a serious treatment-limiting side effect for which there is currently no US Food and Drug Administration-approved treatment. CIPNs induced by diverse classes of chemotherapy drugs have remarkably similar clinical presentations, leading to the suggestion they share underlying mechanisms. Sensory neurons share with immune cells the ability to detect damage associated molecular patterns (DAMPs), molecules produced by diverse cell types in response to cellular stress and injury, including by chemotherapy drugs. DAMPs, in turn, are ligands for pattern recognition receptors (PRRs), several of which are found on sensory neurons, as well as satellite cells, and cells of the immune system. In the present experiments, we evaluated the role of two PRRs, TLR4 and RAGE, present in dorsal root ganglion (DRG), in CIPN. Antisense (AS)-oligodeoxynucleotides (ODN) against TLR4 and RAGE mRNA were administered intrathecally before ('prevention protocol') or 3 days after ('reversal protocol') the last administration of each of three chemotherapy drugs that treat cancer by different mechanisms (oxaliplatin, paclitaxel and bortezomib). TLR4 and RAGE AS-ODN prevented the development of CIPN induced by all three chemotherapy drugs. In the reversal protocol, however, while TLR4 AS-ODN completely reversed oxaliplatin- and paclitaxel-induced CIPN, in rats with bortezomib-induced CIPN it only produced a temporary attenuation. RAGE AS-ODN, in contrast, reversed CIPN induced by all three chemotherapy drugs. When a TLR4 antagonist was administered intradermally to the peripheral nociceptor terminal, it did not affect CIPN induced by any of the chemotherapy drugs. However, when administered intrathecally, to the central terminal, it attenuated hyperalgesia induced by all three chemotherapy drugs, compatible with a role of TLR4 in neurotransmission at the central terminal but not sensory transduction at the peripheral terminal. Finally, since it has been established that cultured DRG neurons can be used to study direct effects of chemotherapy on nociceptors, we also evaluated the role of TLR4 in CIPN at the cellular level, using patch-clamp electrophysiology in DRG neurons cultured from control and chemotherapy-treated rats. We found that increased excitability of small-diameter DRG neurons induced by in vivo and in vitro exposure to oxaliplatin is TLR4-dependent. Our findings suggest that in addition to the established contribution of PRR-dependent neuroimmune mechanisms, PRRs in DRG cells also have an important role in CIPN., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Unrelieved pain and sleep disturbance are common symptoms in oncology patients. Increased stress may be an underlying cause for both symptoms., Objectives: The purposes of this study were to identify subgroups of outpatients with distinct pain and sleep disturbance profiles and to evaluate differences among these subgroups in demographic and clinical characteristics. Differences in global stress, cancer-specific stress, and cumulative life stress, as well as resilience and coping, were evaluated., Methods: Patients (N = 1343) completed self-report questionnaires for demographic and clinical characteristics and stress, resilience, and coping. Latent profile analysis was used to identify subgroups of patients with distinct pain and sleep disturbance profiles. Differences among the subgroups were determined using parametric and nonparametric tests., Results: Three distinct profiles were identified (ie, No Pain + Moderate Sleep Disturbance (SD) (27.6%), Moderate Pain + Moderate SD (38.6%), Severe Pain + High SD (33.8%)). Compared with the other 2 classes, Severe Pain + High SD class was younger, had fewer years of education, was more likely to be female, more likely to live alone, less likely to be employed, and had a higher level of comorbidity. This class had the highest stress scores and was more likely to report higher rates of adverse childhood experiences., Conclusion: Over 70% of our sample reported clinically meaningful levels of both symptoms, and 33.8% reported relatively high rates of adverse childhood experiences., Implication for Practice: Clinicians need to perform routine assessments, particularly of adverse childhood experiences, and initiate appropriate referrals., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To evaluate differences among stress, resilience, and coping strategies related to morning and evening fatigue profiles (both low, low morning and moderate evening, both moderate, and both high)., Sample & Setting: Data were collected from 1,334 adult patients with cancer receiving chemotherapy., Methods & Variables: Morning and evening fatigue severity were rated over two cycles of chemotherapy using the Lee Fatigue Scale. Latent profile analysis was used to identify patient subgroups with distinct joint morning and evening profiles. Data were collected on global, cancer-specific, and cumulative life stress; resilience; and coping strategies. Differences among the latent classes were evaluated using parametric and nonparametric tests., Results: Compared to the other three classes, the both high class reported the highest stress scores, highest occurrence of and effects from a variety of stressful life events, lowest resilience scores, and higher use of disengagement coping strategies. The both high class met the criteria for subsyndromal post-traumatic stress disorder., Implications for Nursing: When patients report high levels of fatigue, detailed assessments of stress are warranted to provide tailored interventions.

Background: By 2035, the number of newly diagnosed cancer cases will double and over 50% will be in older adults. Given this rapidly growing demographic, a need exists to understand how age influences oncology patients' symptom burden. The study purposes were to evaluate for differences in the occurrence, severity, and distress of 38 symptoms in younger (< 60 years) versus older (≥ 60 years) oncology patients undergoing chemotherapy and to evaluate for differences in the stability and consistency of symptom clusters across the two age groups., Methods: A total of 1329 patients were dichotomized into the younger and older groups. Patients completed demographic and clinical questionnaires prior to the initiation of their second or third cycle of chemotherapy. A modified version of Memorial Symptom Assessment Scale was used to evaluate the occurrence, severity, and distress of 38 common symptoms associated with cancer and its treatment. Differences between the two age groups in demographic and clinical characteristics and ratings of occurrence, severity, and distress for the 38 symptoms were evaluated using parametric and nonparametric tests. Exploratory factor analyses were done within each age group to identify symptom clusters using symptom occurrence rates., Results: Compared to the younger group (14.8 (± 7.0)), older adults reported a lower mean number of symptoms (12.9 (± 7.2)). Older patients experienced lower occurrence rates for almost 50% of the symptoms. Regarding symptom clusters, an eight-factor solution was selected for both age groups. Across the two age groups, the eight symptom clusters (i.e., physical and cognitive fatigue, respiratory, psychological, hormonal, chemotherapy-related toxicity, weight gain, gastrointestinal, epithelial) were stable. However, symptoms within the physical and cognitive, chemotherapy-related toxicity, and gastrointestinal clusters were not consistent across the age groups., Conclusions: To be able to provide tailored and effective symptom management interventions to older oncology patients, routine assessments of the core symptoms unique to the symptom clusters identified for this group warrants consideration. The underlying mechanism(s) for these inconsistencies in symptom burden is an important focus for future studies., (© 2024. The Author(s).)

Objectives: Purposes were to identify subgroups of adult oncology patients (n = 1342) with distinct joint profiles of worst pain and cognitive function (CF) and evaluate for differences in demographic and clinical characteristics, as well as the severity of three distinct types of stress, resilience, and coping., Data Sources: Measures of pain and CF were evaluated six times over two cycles of chemotherapy. The other measures of demographic and clinical characteristics, stress, resilience, and coping were completed at enrollment (ie, prior to the second or third cycle of chemotherapy)., Results: Using latent profile analysis, four distinct profiles were identified (ie, no pain + moderate CF [27.6%], moderate pain + high CF [22.4%] moderate pain and moderate CF [32.4%, both moderate], severe pain and low CF [17.5%, both severe]). Both moderate and both severe classes reported higher global, cancer-specific, and cumulative life stress, lower levels of resilience, and greater use of disengagement coping strategies. The Both severe class had higher occurrence rates for a number of adverse childhood experiences (ie, family violence in childhood, physical abuse at <16 years, forced sex at <16 years). Risk factors associated with membership in the two worst profiles included: being female, having a lower annual income, having a higher comorbidity burden, and having a poorer functional status., Conclusion: Findings suggest that 72.4% of the patients reported pain scores in the moderate to severe range and 77.6% reported low to moderate levels of CF. Clinicians need to assess for both symptoms and various types of stress on a routine basis., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Various types of stress and the choice of coping strategies may be risk factors for higher levels of sleep disturbance in oncology patients. Purposes were to evaluate for differences in global, cancer-specific, and cumulative life stress, as well as resilience and the use of coping strategies among three subgroups of patients with distinct sleep disturbance profiles (i.e., Low, High, Very High). Oncology outpatients (n = 1331) completed measures of global (Perceived Stress Scale), cancer-specific (Impact of Event Scale-Revised), and cumulative life (Life Stressor Checklist-Revised) stress, resilience (Connor-Davidson Resilience Scale) and coping (Brief Cope) prior to their second or third cycle of chemotherapy. Sleep disturbance was assessed six times over two chemotherapy cycles. Differences were evaluated using parametric and non-parametric tests. All stress measures showed a dose response effect (i.e., as the sleep disturbance profile worsened, levels of all types of stress increased). Compared to Low class, the other two classes reported higher levels of global perceived stress and higher occurrence rates and effect from previous stressful life events. Impact of Event Scale-Revised scores for the Very High class indicated post-traumatic symptomatology. Patients in High and Very High classes had resilience scores below the normative score for the United States population and used a higher number of disengagement coping strategies. Our findings suggest that very high levels of sleep disturbance are associated with higher levels of various types of stress, lower levels of resilience, and higher use of disengagement coping strategies. Clinicians need to perform routine assessments and implement symptom management interventions to reduce stress and encourage the use of engagement coping strategies., (© 2023 John Wiley & Sons Ltd.)

Background: Shortness of breath occurs in 10%-70% of oncology patients. Very little is known about interindividual variability in its severity and distress and associated risk factors. Using latent profile analyses (LPAs), purpose was to identify subgroups of patients with distinct severity and distress profiles for shortness of breath as single symptom dimensions. In addition, a joint LPA was done using patients' severity AND distress ratings. For each of the three LPAs, differences among the shortness of breath classes in demographic, clinical, symptom, stress, and resilience characteristics were evaluated., Methods: Patients completed ratings of severity and distress from shortness of breath a total of six times over two cycles of chemotherapy. All of the other measures were completed at enrollment (i.e., prior to the second or third cycle of chemotherapy). Separate LPAs were done using ratings of severity and distress, as well as a joint analysis using severity AND distress ratings. Differences among the latent classes were evaluated using parametric and nonparametric tests., Results: For severity, two classes were identified (Slight to Moderate [91.6%] and Moderate to Severe [8.4%]). For distress, two classes were identified (A Little Bit to Somewhat [83.9%] and Somewhat to Quite a Bit [16.1%]). For the joint LPA, two classes were identified (Lower Severity and Distress [79.9%] and Higher Severity and Distress [20.1%]). While distinct risk factors were associated with each of the LPAs, across the three LPAs, the common risk factors associated with membership in the worse class included: a past or current history of smoking, poorer functional status, and higher comorbidity burden. In addition, these patients had a higher symptom burden and higher levels of cancer-specific stress., Conclusions: Clinicians can use the information provided in this study to identify high-risk patients and develop individualized interventions., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Anxiety and fatigue are common problems in patients receiving chemotherapy. Unrelieved stress is a potential cause for the co-occurrence of these symptoms., Objectives: The aims of this study were to identify subgroups of patients with distinct state anxiety and morning fatigue profiles and evaluate for differences among these subgroups in demographic and clinical characteristics, as well as measures of global, cancer-specific, and cumulative life stress and resilience and coping., Methods: Patients (n = 1335) completed measures of state anxiety and morning fatigue 6 times over 2 cycles of chemotherapy. All of the other measures were completed prior to the second or third cycle of chemotherapy. Latent profile analysis was used to identify the state anxiety and morning fatigue profiles., Results: Three distinct joint profiles were identified: Low Anxiety and Low Morning Fatigue (59%), Moderate Anxiety and Moderate Morning Fatigue (33.4%), and High Anxiety and High Morning Fatigue (7.6%). Patients in the 2 highest classes were younger, were less likely to be married/partnered, and had a higher comorbidity burden. All of the stress scores demonstrated a dose-response effect (ie, as anxiety and morning fatigue profiles worsened, stress increased). Patients in the 2 highest classes reported higher rates of emotional abuse, physical neglect, physical abuse, and sexual harassment., Conclusions: More than 40% of these patients experienced moderate to high levels of both anxiety and morning fatigue. Higher levels of all 3 types of stress were associated with the 2 highest profiles., Implications for Practice: Clinicians need to perform comprehensive evaluations of patients' levels of stress and recommend referrals to psychosocial services., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Pruritis, the sensation of itch, is produced by multiple substances, exogenous and endogenous, that sensitizes specialized sensory neurons (pruriceptors and pruri-nociceptors). Unfortunately, many patients with acute and chronic pruritis obtain only partial relief when treated with currently available treatment modalities. We recently demonstrated that the topical application of high molecular weight hyaluronan (HMWH), when combined with vehicles containing transdermal transport enhancers, produce potent long-lasting reversal of nociceptor sensitization associated with inflammatory and neuropathic pain. In the present experiments we tested the hypothesis that the topical formulation of HMWH with protamine, a transdermal transport enhancer, can also attenuate pruritis. We report that this topical formulation of HMWH markedly attenuates scratching behavior at the nape of the neck induced by serotonin (5-hydroxytryptamine, 5-HT), in male and female rats. Our results support the hypothesis that topical HMWH in a transdermal transport enhancer vehicle is a strong anti-pruritic., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

While opioids remain amongst the most effective treatments for moderate-to-severe pain, their substantial side effect profile remains a major limitation to broader clinical use. One such side effect is opioid-induced hyperalgesia (OIH), which includes a transition from opioid-induced analgesia to pain enhancement. Evidence in rodents supports the suggestion that OIH may be produced by the action of opioids at Toll-like Receptor 4 (TLR4) either on immune cells that, in turn, produce pronociceptive mediators to act on nociceptors, or by a direct action at nociceptor TLR4. And, sub-analgesic doses of several opioids have been shown to induce hyperalgesia in rodents by their action as TLR4 agonists. In the present in vitro patch-clamp electrophysiology experiments, we demonstrate that low dose morphine directly sensitizes human as well as rodent dorsal root ganglion (DRG) neurons, an effect of this opioid analgesic that is antagonized by LPS-RS Ultrapure, a selective TLR4 antagonist. We found that low concentration (100 nM) of morphine reduced rheobase in human (by 36%) and rat (by 26%) putative C-type nociceptors, an effect of morphine that was markedly attenuated by preincubation with LPS-RS Ultrapure. Our findings support the suggestion that in humans, as in rodents, OIH is mediated by the direct action of opioids at TLR4 on nociceptors., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Hyperalgesic priming is a preclinical model of the transition from acute to chronic pain characterized by a leftward shift in the dose-response curve for and marked prolongation of prostaglandin E 2 (PGE 2 )-induced mechanical hyperalgesia, in vivo. In vitro, priming in nociceptors is characterized by a leftward shift in the concentration dependence for PGE 2 -induced nociceptor sensitization. In the present in vitro study we tested the hypothesis that a mu-opioid receptor (MOR) agonist opioid analgesic, morphine, can produce priming by its direct action on nociceptors. We report that treatment of nociceptors with morphine, in vitro, produces a leftward shift in the concentration dependence for PGE 2 -induced nociceptor sensitization. Our findings support the suggestion that opioids act directly on nociceptors to induce priming., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Abstract: The persistence of inflammatory and neuropathic pain is poorly understood. We investigated a novel therapeutic paradigm by targeting gene networks that sustain or reverse persistent pain states. Our prior observations found that Sp1-like transcription factors drive the expression of TRPV1, a pain receptor, that is blocked in vitro by mithramycin A (MTM), an inhibitor of Sp1-like factors. Here, we investigate the ability of MTM to reverse in vivo models of inflammatory and chemotherapy-induced peripheral neuropathy (CIPN) pain and explore MTM's underlying mechanisms. Mithramycin reversed inflammatory heat hyperalgesia induced by complete Freund adjuvant and cisplatin-induced heat and mechanical hypersensitivity. In addition, MTM reversed both short-term and long-term (1 month) oxaliplatin-induced mechanical and cold hypersensitivity, without the rescue of intraepidermal nerve fiber loss. Mithramycin reversed oxaliplatin-induced cold hypersensitivity and oxaliplatin-induced TRPM8 overexpression in dorsal root ganglion (DRG). Evidence across multiple transcriptomic profiling approaches suggest that MTM reverses inflammatory and neuropathic pain through broad transcriptional and alternative splicing regulatory actions. Mithramycin-dependent changes in gene expression following oxaliplatin treatment were largely opposite to and rarely overlapped with changes in gene expression induced by oxaliplatin alone. Notably, RNAseq analysis revealed MTM rescue of oxaliplatin-induced dysregulation of mitochondrial electron transport chain genes that correlated with in vivo reversal of excess reactive oxygen species in DRG neurons. This finding suggests that the mechanism(s) driving persistent pain states such as CIPN are not fixed but are sustained by ongoing modifiable transcription-dependent processes., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Background: Patients with gastrointestinal cancers experience diurnal variations in fatigue severity during chemotherapy that decrease their functional status and quality of life., Objectives: Study purposes were to identify subgroups of patients with distinct co-occurring morning and evening fatigue profiles and evaluate for differences among these subgroups in demographic, clinical, stress, and symptom characteristics., Methods: Patients with gastrointestinal cancers (n = 405) completed questionnaires 6 times over 2 cycles of chemotherapy. The Lee Fatigue Scale was used to evaluate diurnal variations in fatigue severity. Latent profile analysis was used to identify subgroups of patients with distinct co-occurring morning AND evening fatigue profiles. Differences among the subgroups in demographic, clinical, stress, and symptom characteristics at enrollment were evaluated using parametric and nonparametric analyses., Results: Two classes were identified, namely: low morning and moderate evening fatigue (ie, Low-Moderate, 60.0%) and high morning and high evening fatigue (ie, Both High, 40.0%). Compared with the Low-Moderate class, the Both High class was significantly younger, female, unmarried, and unemployed and lacked regular exercise. In addition, they had childcare responsibilities, lower annual income, lower functional status, higher comorbidity burden, and self-reported anemia and depression. Patients in the Both High class reported higher levels of anxiety, depressive symptoms, sleep disturbance, pain, and stress, and lower levels of energy and cognitive function., Conclusions: Findings provide new insights into the risk factors for higher levels of co-occurring morning and evening fatigue in patients with gastrointestinal cancers., Implications for Practice: Clinicians can use this information to identify high-risk patients and develop personalized symptom management interventions., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Identify subgroups of patients with distinct joint anxiety AND depression profiles and evaluate for differences in demographic and clinical characteristics, as well as stress, resilience, and coping., Design: Longitudinal study., Participants: Patients ( n  = 1328) receiving chemotherapy., Methods: Measures of state anxiety and depression were done six times over two cycles of chemotherapy. All of the other measures were completed prior to second or third cycle of chemotherapy. Latent profile analysis was used to identify the distinct joint anxiety and depression profiles., Findings: Three classes were identified (i.e. Low Anxiety and Low Depression (57.5%); Moderate Anxiety and Moderate Depression (33.7%), High Anxiety and High Depression (8.8%)). For all of the stress measures, a dose response effect was seen among the profiles. Two worst profiles reported higher occurrence rates for a number of adverse childhood experiences., Implications for Providers: Patients need referrals for stress reduction techniques and mental health and social services.

Objectives: Physical and cognitive function are two of the most important patient-reported outcomes. In oncology patients receiving chemotherapy (N = 1331), purposes were to identify subgroups of patients with distinct joint physical and cognitive function profiles and evaluate for differences in demographic and clinical characteristics, severity of common symptoms, and quality of life outcomes., Data Sources: Measures of physical and cognitive functions were obtained six times over two cycles of chemotherapy. All of the other measures were done prior to the second or third cycle of chemotherapy. Latent profile analysis was done to identify the distinct joint physical and cognitive function profiles. Differences among the profiles were evaluated using parametric and nonparametric tests., Conclusion: Five distinct profiles were identified (ie, Very Low Physical and Low Cognitive Function [18.4%; Both Low], Low Physical and High Cognitive Function [19.8%], Moderate Physical and Low Cognitive Function [26.7%], Changing Physical and Cognitive Function [5.4%], and Normal Physical and Cognitive Function [29.7%]). Patients in the Both Low class had the highest symptom burden and the poorest quality of life. Over 70% of the sample had moderate to severe decrements in one or both of these extremely important patient outcomes., Implications for Nursing Practice: Clinicians need to assess for both physical and cognitive function using simple subjective and objective measures., Competing Interests: Declaration of Competing Interest The authors have no competing interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: We sought to identify subgroups of patients with distinct joint cancer-related cognitive impairment (CRCI) AND anxiety profiles and evaluate for differences in demographic and clinical characteristics, as well as levels of global stress, cancer-specific stress, cumulative life stress, and resilience., Data Sources: Patients (n = 1332) completed the Attentional Function Index and the Spielberger State Anxiety Inventory six times over two cycles of chemotherapy. Global, cancer-specific, and cumulative life stress and resilience were evaluated using Perceived Stress Scale, Impact of Event Scale-Revised, Life Stressor Checklist-Revised, and Connor-Davidson Resilience Scale, respectively. Latent profile analysis was used to identify subgroups of patients with distinct joint CRCI AND anxiety profiles. Differences were evaluated using parametric and nonparametric tests., Results: Three classes were identified (ie, No CRCI and Low Anxiety [57.3%], Moderate CRCI and Moderate Anxiety [34.5%], and High CRCI and High Anxiety [8.2%]). All of the stress measures showed a dose-response effect (ie, as the CRCI AND anxiety profile worsened, scores for all three types of stress increased). The two highest symptom classes reported higher occurrence rates for six specific stressors (eg, emotional abuse, physical abuse, sexual harassment)., Conclusions: Findings suggest that higher levels of co-occurring CRCI AND anxiety are associated with some common risk factors, as well as higher levels of stress and lower levels of resilience. Increased knowledge of modifiable risk factors and sources of stress associated with the co-occurrence of these two symptoms will assist clinicians to identify high-risk patients and implement individualized interventions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abstract: We have previously shown that intradermal injection of high-molecular-weight hyaluronan (500-1200 kDa) produces localized antihyperalgesia in preclinical models of inflammatory and neuropathic pain. In the present experiments, we studied the therapeutic effect of topical hyaluronan, when combined with each of 3 transdermal drug delivery enhancers (dimethyl sulfoxide [DMSO], protamine or terpene), in preclinical models of inflammatory and neuropathic pain. Topical application of 500 to 1200 kDa hyaluronan (the molecular weight range used in our previous studies employing intradermal administration), dissolved in 75% DMSO in saline, markedly reduced prostaglandin E 2 (PGE 2 ) hyperalgesia, in male and female rats. Although topical 500- to 1200-kDa hyaluronan in DMSO vehicle dose dependently, also markedly, attenuated oxaliplatin chemotherapy-and paclitaxel chemotherapy-induced painful peripheral neuropathy (CIPN) in male rats, it lacked efficacy in female rats. However, following ovariectomy or intrathecal administration of an oligodeoxynucleotide antisense to G-protein-coupled estrogen receptor (GPR30) mRNA, CIPN in female rats was now attenuated by topical hyaluronan. Although topical coadministration of 150 to 300, 300 to 500, or 1500 to 1750 kDa hyaluronan with DMSO also attenuated CIPN, a slightly lower-molecular-weight hyaluronan (70-120 kDa) did not. The topical administration of a combination of hyaluronan with 2 other transdermal drug delivery enhancers, protamine and terpene, also attenuated CIPN hyperalgesia, an effect that was more prolonged than with DMSO vehicle. Repeated administration of topical hyaluronan prolonged the duration of antihyperalgesia. Our results support the use of topical hyaluronan, combined with chemically diverse nontoxic skin penetration enhancers, to induce marked antihyperalgesia in preclinical models of inflammatory and neuropathic pain., (Copyright © 2023 International Association for the Study of Pain.)

Purpose: Evaluate for perturbed signaling pathways associated with subgroups of patients with low versus high levels of state anxiety. These pathways were compared to the pathways identified across eight network pharmacology studies of the anxiolytic effect(s) of a variety of compounds., Methods: Adult outpatients had a diagnosis of breast, gastrointestinal, gynecological, or lung cancer; had received chemotherapy within the preceding four weeks; and were scheduled to receive at least two additional cycles of chemotherapy. Latent profile analysis was used to identify subgroups of patients with distinct anxiety profiles based on Spielberger State Anxiety Inventory scores that were obtained six times over two cycles of chemotherapy. Blood samples were processed using RNA sequencing (i.e., RNA-seq sample, n = 244) and microarray (i.e., microarray sample; n = 256) technologies. Pathway perturbations were assessed using pathway impact analysis. Fisher's combined probability method was used to combine test results using a false discovery rate of 0.01., Results: In the RNA-seq sample, 62.3% and 37.7% of the patients were in the low- and high-anxiety classes, respectively. In the microarray sample, 61.3% and 38.7% were in the low and high-anxiety classes, respectively. Forty-one perturbed signaling pathways were identified. Eight of these pathways were common to those identified in the network pharmacology studies., Conclusions: Findings increase our knowledge of the molecular mechanisms that underlie anxiety in patients receiving chemotherapy. This study provides initial insights into how anxiety in patients with cancer may share common mechanisms with anxiety in patients with other clinical conditions., (© 2023. The Author(s).)

Background: Anxiety and sleep disturbance are frequent symptoms during chemotherapy., Objectives: Purposes were to identify subgroups of oncology outpatients with distinct joint anxiety and sleep disturbance profiles, as well as evaluate for differences in demographic and clinical characteristics, sleep disturbance characteristics, severity of common symptoms, and quality-of-life outcomes among these subgroups., Methods: Oncology outpatients (n = 1331) completed self-report measures of anxiety and sleep disturbance 6 times over 2 chemotherapy cycles. Latent profile analysis was done to identify subgroups of patients with distinct joint anxiety and sleep disturbance profiles., Results: Three profiles were identified (ie, no anxiety and low sleep disturbance (59.7%), moderate anxiety and high sleep disturbance (32.5%), high anxiety and very high sleep disturbance (7.8%)). Compared with the no anxiety and low sleep disturbance class, the other 2 classes were younger; less likely to be married; had a lower annual household income; and had childcare responsibilities. Patients in the 2 worse profiles had problems with both sleep initiation and maintenance. These patients reported higher levels of depressive symptoms, trait and state anxiety, and evening fatigue, as well as lower levels of morning and evening energy, cognitive function, and poorer quality of life., Conclusions: More than 40% of patients had moderate or high levels of anxiety and high or very high levels of sleep disturbance. Modifiable risk factors associated with these profiles may be used to develop targeted interventions for 1 or both symptoms., Implications for Practice: Clinicians need to assess for the co-occurrence of anxiety and sleep disturbance., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Among four classes of patients with distinct shortness of breath profiles, evaluate for differences in levels of global, cancer-specific, and cumulative life stress, as well as resilience; evaluate for differences in the occurrence rates for various stressful life events, and evaluate for differences in the severity of common co-occurring symptoms., Data Sources: Outpatients (N = 1338) completed questionnaires six times over two cycles of chemotherapy. The occurrence of shortness of breath was assessed using the Memorial Symptom Assessment Scale. Latent class analysis was used to identify subgroups of patients with distinct shortness of breath profiles. Differences among the classes were evaluated using parametric and nonparametric tests., Conclusion: Shortness of breath classes were labeled based on their distinct occurrence trajectories: None (70.5%), Decreasing (8.2%), Increasing (7.8%), and High (13.5%). Compared to None class, Decreasing and High classes had higher global and cancer-specific stress scores. The High class reported higher occurrence rates for several adverse childhood experiences. Compared to None class, Decreasing and High classes had higher depression, anxiety, and morning fatigue scores and lower morning energy and cognitive function scores., Implications for Nursing Practice: Given the additive or synergistic relationships between stress, co-occurring symptoms, and shortness of breath, multimodal interventions that include stress management, exercise training, and/or symptom management may decrease shortness of breath in oncology patients., Competing Interests: Declaration of Competing Interest Dr. Wong reported conflicts of interest outside of the submitted work: An immediate family member is an employee of Genentech with stock ownership and Dr. Wong receives royalties from UpToDate. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate for subgroups of patients with distinct symptom profiles and differences in demographic and clinical characteristics and stress and resilience among these subgroups., Sample & Setting: 1,145 patients with cancer aged 18 years or older completed a survey online. Data were collected between May 2020 and February 2021., Methods & Variables: Patients completed measures for depression, state anxiety, cognitive function, morning fatigue, evening fatigue, morning energy, evening energy, sleep disturbance, pain, stress, and resilience. Latent class profile analysis was used to identify subgroups of patients with distinct symptom profiles. Differences among the subgroups on study measures were evaluated using parametric and nonparametric tests., Results: Four distinct profiles were identified (none, low, high, and very high). Patients in the high and very high classes reported clinically meaningful levels of all nine symptoms. Differences among the four profiles for stress and resilience exhibited a dose-response effect., Implications for Nursing: Findings can serve as benchmark data of the symptom burden of patients with cancer following the COVID-19 pandemic.

Objectives: In a sample of patients with gynecologic cancers who are receiving chemotherapy, subgroups of patients with distinct state anxiety profiles were identified, and differences among the subgroups in demographic and clinical characteristics, stress, exposure to stressful life events, resilience, and coping behaviors were evaluated., Data Sources: Patients (n = 230) completed questionnaires six times over two chemotherapy cycles. State anxiety was measured using the Spielberger State Anxiety Inventory. Subgroups of patients with distinct state anxiety profiles were identified using latent profile analysis. Differences among the classes were assessed using parametric and nonparametric tests., Conclusion: Three distinct state anxiety profiles were identified: low (55.2%), moderate (38.3%), and very high (6.5%). Compared with the low class, persons in the other two classes had lower functional status, more comorbidities, higher perceived stress, and lower resilience and were more likely to report a history of depression and to use disengagement coping strategies. Compared with the low class, the very high class was more likely to report childcare responsibilities; have a history of lung disease, stomach disease, or low back pain; have experienced physical neglect, serious money problems, a serious disaster, or foster care; or were a caregiver for someone with a severe disability., Implications for Nursing Practice: Nearly 45% of patients reported clinically meaningful levels of state anxiety that persisted over two cycles of chemotherapy. Experiences with a variety of stressors may be risk factors for higher levels of anxiety during chemotherapy. Clinicians need to perform comprehensive social histories and assess for anxiety in patients receiving chemotherapy., Competing Interests: Declaration of Competing Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Anxiety, depression, sleep disturbance, fatigue, cognitive dysfunction, and pain are common symptoms reported by patients with breast cancer. Recent evidence suggests that palpitations, a feeling of the heart racing or pounding, may be equally common. Study purpose was to compare the severity and clinically meaningful occurrence rates of common symptoms and quality of life (QOL) outcomes between patients with breast cancer who did and did not report palpitations prior to surgery., Methods: Patients (n = 398) were classified as having or not having palpitations using a single item from the Menopausal Symptoms Scale. Valid and reliable measures were used to assess state and trait anxiety, depression, sleep disturbance, fatigue, energy, cognitive function, breast symptoms, and QOL. Between group differences were evaluated using parametric and non-parametric tests., Results: Patients with palpitations (15.1%) reported significantly higher severity scores for state and trait anxiety, depression, sleep disturbance, and fatigue as well as significant decrements in energy and cognitive function (all p < .05). A higher percentage of these patients had clinically meaningful levels of state anxiety, depression, sleep disturbance and decrements in cognitive function (all p < .05). Except for spiritual well-being, QOL scores were lower in the palpitations group (all p < .001)., Conclusion: Findings support the need for routine assessment of palpitations and management of multiple symptoms in women prior to breast cancer surgery., Competing Interests: Declaration of competing interest Dr. Carpenter reports consulting fees from the University of Wisconsin and scale licensing fees from Mapi. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Purpose was to evaluate for associations between the severity of three distinct symptom clusters (ie, sickness-behavior, mood-cognitive, treatment-related) and polymorphisms for 16 genes involved in catecholaminergic, GABAergic, and serotonergic neurotransmission., Data Sources: Patients with breast and prostate cancer (n = 157) completed study questionnaires at the completion of radiation therapy. Memorial Symptom Assessment Scale was used to assess the severity of 32 common symptoms. Three distinct symptom clusters were identified using exploratory factor analysis. Associations between the symptom cluster severity scores and neurotransmitter gene polymorphisms were evaluated using regression analyses., Conclusion: Severity scores for the sickness-behavior symptom cluster were associated with polymorphisms for solute carrier family 6 (SLC6A) member 2 (SLC6A2), SLC6A3, SLC6A1, and 5-hydroxytryptamine receptor (HTR) 2A (HTR2A) genes. For the mood-cognitive symptom cluster, severity scores were associated with polymorphisms for adrenoreceptor alpha 1D, SLC6A2, SLC6A3, SLC6A1, HTR2A, and HTR3A. Severity scores for the treatment-related symptom cluster were associated with polymorphisms for SLC6A2, SLC6A3, catechol-o-methyltransferase, SLC6A1, HTR2A, SLC6A4, and tryptophan hydroxylase 2., Implications for Nursing Practice: Findings suggest that polymorphisms for several neurotransmitter genes are involved in the severity of sickness-behavior, mood-cognitive, and treatment-related symptom clusters in oncology patients at the completion of radiation therapy. Four genes with various associated polymorphisms were common across the three distinct symptom clusters (ie, SLC6A2, SLC6A3, SLC6A1, HTR2A) which suggest that these clusters have common underlying mechanisms., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective/background: An emerging area of research is the relationship between sleep disturbance and decrements in energy. Given the paucity of research on the co-occurrence of these two symptoms, study purposes were to identify subgroups of oncology patients with distinct joint sleep disturbance AND morning energy profiles and evaluate for differences among the subgroups in demographic, clinical, and sleep disturbance characteristics, as well as the severity of other common symptoms and QOL outcomes., Patients/methods: Patients (n = 1336) completed measures of sleep disturbance and energy 6 times over two cycles of chemotherapy. All of the other measures were completed at enrollment. Latent profile analysis was used to identify the distinct joint sleep disturbance and morning energy profiles., Results: Three distinct profiles were identified (i.e., Low Sleep Disturbance and High Morning Energy (Normal, 20.6%), Moderate Sleep Disturbance and Low Morning Energy (Moderately Severe, 52.1%), Very High Sleep Disturbance and Very Low Morning Energy (Very Severe, 27.3%). Compared to Normal class, other two classes were more likely to be female, less likely to be employed, and had higher comorbidity burden and poorer functional status. Symptom scores and QOL outcomes exhibited a dose response effect (i.e., as the profile worsened, symptom scores increased and QOL scores decreased)., Conclusions: Given the associations between sleep disturbance and decrements in energy and a higher symptom burden, poorer QOL outcomes, and increased mortality, assessment of these two symptoms needs to be a high priority for clinicians and appropriate interventions initiated., Competing Interests: Declaration of competing interest The authors have no competing interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Pain, fatigue, sleep disturbance, and depression are four of the most common symptoms in patients with gynecologic cancer. The purposes were to identify subgroups of patients with distinct co-occurring pain, fatigue, sleep disturbance, and depression profiles (i.e., pre-specified symptom cluster) in a sample of patients with gynecologic cancer receiving chemotherapy and assess for differences in demographic and clinical characteristics, as well as the severity of other common symptoms and QOL outcomes among these subgroups., Methods: Patients completed symptom questionnaires prior to their second or third cycle of chemotherapy. Latent profile analysis was used to identify subgroups of patients using the pre-specified symptom cluster. Parametric and nonparametric tests were used to evaluate for differences between the subgroups., Results: In the sample of 233 patients, two distinct latent classes were identified (i.e., low (64.8%) and high (35.2%)) indicating lower and higher levels of symptom burden. Patients in high class were younger, had child care responsibilities, were unemployed, and had a lower annual income. In addition, these women had a higher body mass index, a higher comorbidity burden, and a lower functional status. Patients in the high class reported higher levels of anxiety, as well as lower levels of energy and cognitive function and poorer quality of life scores., Conclusions: This study identified a number of modifiable and non-modifiable risk factors associated with membership in the high class. Clinicians can use this information to refer patients to dieticians and physical therapists for tailored interventions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Up to 45% of patients report cancer-related cognitive impairment (CRCI). A variety of characteristics are associated with the occurrence and/or severity of CRCI. However, an important gap in knowledge of risk factors for CRCI is the relative contribution of each factor. The multifactorial model of cancer-related cognitive impairment (MMCRCI) is a conceptual model of CRCI that can be used to evaluate the strength of relationships between various factors and CRCI., Objectives: The purpose of this study was to use structural regression methods to evaluate the MMCRCI using data from a large sample of outpatients receiving chemotherapy ( n = 1,343). Specifically, the relationships between self-reported CRCI and four MMCRCI concepts (i.e., social determinants of health, patient-specific factors, treatment factors, and co-occurring symptoms) were examined. The goals were to determine how well the four concepts predicted CRCI and determine the relative contribution of each concept to deficits in perceived cognitive function., Methods: This study is part of a larger, longitudinal study that evaluated the symptom experience of oncology outpatients receiving chemotherapy. Adult patients were diagnosed with breast, gastrointestinal, gynecological, or lung cancer; had received chemotherapy within the preceding 4 weeks; were scheduled to receive at least two additional cycles of chemotherapy; were able to read, write, and understand English; and gave written informed consent. Self-reported CRCI was assessed using the attentional function index. Available study data were used to define the latent variables., Results: On average, patients were 57 years of age, college educated, and with a mean Karnofsky Performance Status score of 80. Of the four concepts evaluated, whereas co-occurring symptoms explained the largest amount of variance in CRCI, treatment factors explained the smallest amount of variance. A simultaneous structural regression model that estimated the joint effect of the four exogenous latent variables on the CRCI latent variable was not significant., Discussion: These findings suggest that testing individual components of the MMCRCI may provide useful information on the relationships among various risk factors, as well as refinements of the model. In terms of risk factors for CRCI, co-occurring symptoms may be more significant than treatment factors, patient-specific factors, and/or social determinants of health in patients receiving chemotherapy., Competing Interests: The authors have no conflicts of interest to report., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)