Biological predictors of chemotherapy-induced peripheral neuropathy (CIPN): MASCC neurological complications working group overview.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a number of chemotherapeutic agents. Drugs commonly implicated in the development of CIPN include platinum agents, taxanes, vinca alkaloids, bortezomib, and thalidomide analogues. As a drug response can vary between individuals, it is hypothesized that an individual's specific genetic variants could impact the regulation of genes involved in drug pharmacokinetics, ion channel functioning, neurotoxicity, and DNA repair, which in turn affect CIPN development and severity. Variations of other molecular markers may also affect the incidence and severity of CIPN. Hence, the objective of this review was to summarize the known biological (molecular and genomic) predictors of CIPN and discuss the means to facilitate progress in this field

The neurotoxin DSP-4 dysregulates the locus coeruleus-norepinephrine system and recapitulates molecular and behavioral aspects of prodromal neurodegenerative disease

The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-synuclein pathology in Alzheimer\u27s disease (AD) and Parkinson\u27s disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms. Because current therapeutic efforts are targeting early disease, interest in the LC has grown, and it is critical to identify the links between pathology and dysfunction. We employed the LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which preferentially damages LC axons, to model early changes in the LC-NE system pertinent to AD and PD in male and female mice. DSP-4 (two doses of 50 mg/kg, one week apart) induced LC axon degeneration, triggered neuroinflammation and oxidative stress, and reduced tissue NE levels. There was no LC cell death or changes to LC firing, but transcriptomics revealed reduced expression of genes that define noradrenergic identity and other changes relevant to neurodegenerative disease. Despite the dramatic loss of LC fibers, NE turnover and signaling were elevated in terminal regions and were associated with anxiogenic phenotypes in multiple behavioral tests. These results represent a comprehensive analysis of how the LC-NE system responds to axon/terminal damage reminiscent of early AD and PD at the molecular, cellular, systems, and behavioral levels, and provides potential mechanisms underlying prodromal neuropsychiatric symptoms

Dexamethasone to prevent everolimus-induced stomatitis (Alliance MIST trial: A221701)

mTOR inhibitors such as everolimus may cause oral stomatitis, often a dose-limiting toxicity. Prior clinical research has suggested that a dexamethasone mouth rinse might help prevent and/or treat this. Alliance A221701 was a randomized phase III trial of patients initiating 10 mg daily oral everolimus that compared dexamethasone mouthwash taken preventively (initial dexamethasone group) versus therapeutically (initial placebo group) to assess two coprimary endpoints: the incidence of mTOR inhibitor-associated stomatitis (mIAS), and the area under the curve (AUC) of mIAS-associated pain over an 8-week treatment period. A Fisher\u27s exact test was used to compare the incidences while a Wilcoxon rank-sum test was used to compare the AUCs. In addition, we performed an exploratory analysis of the association of everolimus trough concentrations and toxicity using a Mann-Whitney U test. Due to slow accrual, this study closed after 39 patients were randomized (19 to upfront placebo and 20 to upfront dexamethasone). There were no significant differences between groups seen in either of the coprimary endpoints; furthermore, we found no association between whole blood everolimus trough concentrations and toxicity. Although limited by poor enrollment, the results of this study do not suggest that prophylactic dexamethasone mouthwash is superior to therapeutic dexamethasone mouthwash (initiated at the first sign of mouth pain) for reducing the incidence or severity of mIAS from everolimus

The impact of responding to patient messages with large language model assistance

Documentation burden is a major contributor to clinician burnout, which is rising nationally and is an urgent threat to our ability to care for patients. Artificial intelligence (AI) chatbots, such as ChatGPT, could reduce clinician burden by assisting with documentation. Although many hospitals are actively integrating such systems into electronic medical record systems, AI chatbots utility and impact on clinical decision-making have not been studied for this intended use. We are the first to examine the utility of large language models in assisting clinicians draft responses to patient questions. In our two-stage cross-sectional study, 6 oncologists responded to 100 realistic synthetic cancer patient scenarios and portal messages developed to reflect common medical situations, first manually, then with AI assistance. We find AI-assisted responses were longer, less readable, but provided acceptable drafts without edits 58% of time. AI assistance improved efficiency 77% of time, with low harm risk (82% safe). However, 7.7% unedited AI responses could severely harm. In 31% cases, physicians thought AI drafts were human-written. AI assistance led to more patient education recommendations, fewer clinical actions than manual responses. Results show promise for AI to improve clinician efficiency and patient care through assisting documentation, if used judiciously. Monitoring model outputs and human-AI interaction remains crucial for safe implementation.Comment: 4 figures and tables in main, submitted for revie

Survivorship care for people affected by advanced or metastatic cancer: MASCC-ASCO standards and practice recommendations

PURPOSE: People with advanced or metastatic cancer and their caregivers may have different care goals and face unique challenges compared to those with early-stage disease or those nearing the end-of-life. These MASCC-ASCO standards and practice recommendations seek to establish consistent provision of quality survivorship care for people affected by advanced or metastatic cancer. METHODS: An expert panel comprising MASCC and ASCO members was formed. Standards and recommendations relevant to the provision of quality survivorship care for people affected by advanced or metastatic cancer were developed through conducting: (1) a systematic review of unmet supportive care needs; (2) a scoping review of cancer survivorship, supportive care, and palliative care frameworks and guidelines; and (3) an international modified Delphi consensus process. RESULTS: A systematic review involving 81 studies and a scoping review of 17 guidelines and frameworks informed the initial standards and recommendations. Subsequently, 77 experts (including 8 people with lived experience) across 33 countries (33% were low-to-middle resource countries) participated in the Delphi study and achieved ≥ 94.8% agreement for seven standards (1. Person-Centred Care; 2. Coordinated and Integrated Care; 3. Evidence-Based and Comprehensive Care; 4. Evaluated and Communicated Care; 5. Accessible and Equitable Care; 6. Sustainable and Resourced Care; 7. Research and Data-Driven Care) and ≥ 84.2% agreement across 45 practice recommendations. CONCLUSION: Standards of survivorship care for people affected by advanced or metastatic cancer are provided. These MASCC-ASCO standards will support optimization of health outcomes and care experiences by providing guidance to stakeholders in cancer care (healthcare professionals, leaders, and administrators; governments and health ministries; policymakers; advocacy agencies; cancer survivors and caregivers. Practice recommendations may be used to facilitate future research, practice, policy, and advocacy efforts

The relationship of primary health care use with persistence of insomnia: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Prevalence of insomnia symptoms in the general population is high. Insomnia is linked with high health care use and within primary care there are a number of treatment options available. The objective of this study was to determine the association of persistence and remission of insomnia with primary health care using a longitudinal study.</p> <p>Methods</p> <p>A postal survey of registered adult (over 18 years) populations of five UK general practices, repeated after 1 year, linked to primary care records. Baseline survey responders were assessed for persistence of insomnia symptoms at 12 months. The association of primary care consultation or prescription for any mood disorder (defined as anxiety, depression, stress, neurosis, or insomnia) in the 12 months between baseline and follow-up surveys with persistence of insomnia was determined.</p> <p>Results</p> <p>474 participants reporting insomnia symptoms at baseline were followed up at 12 months. 131(28%) consulted for mood problem(s) or received a relevant prescription. Of these 100 (76%) still had insomnia symptoms at one year, compared with 227 (66%) of those with no contact with primary care for this condition (OR 1.37; 95% CI 0.83, 2.27). Prescription of hypnotics showed some evidence of association with persistence of insomnia at follow-up (OR 3.18; 95% CI 0.93, 10.92).</p> <p>Conclusion</p> <p>Insomniacs continue to have problems regardless of whether or not they have consulted their primary care clinician or received a prescription for medication over the year. Hypnotics may be associated with persistence of insomnia. Further research is needed to determine more effective methods of identifying and managing insomnia in primary care. There may however be a group who have unmet need such as depression who would benefit from seeking primary health care.</p

Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update

PURPOSE To update the ASCO guideline on the recommended prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathy (CIPN) in adult cancer survivors. METHODS An Expert Panel conducted targeted systematic literature reviews to identify new studies. RESULTS The search strategy identified 257 new references, which led to a full-text review of 87 manuscripts. A total of 3 systematic reviews, 2 with meta-analyses, and 28 primary trials for prevention of CIPN in addition to 14 primary trials related to treatment of established CIPN, are included in this update. RECOMMENDATIONS The identified data reconfirmed that no agents are recommended for the prevention of CIPN. The use of acetyl-l-carnitine for the prevention of CIPN in patients with cancer should be discouraged. Furthermore, clinicians should assess the appropriateness of dose delaying, dose reduction, substitutions, or stopping chemotherapy in patients who develop intolerable neuropathy and/or functional impairment. Duloxetine is the only agent that has appropriate evidence to support its use for patients with established painful CIPN. Nonetheless, the amount of benefit from duloxetine is limited

Development and evaluation of an online three-level proton vs photon decision support prototype for head and neck cancer - Comparison of dose, toxicity and cost-effectiveness

AbstractTo quantitatively assess the effectiveness of proton therapy for individual patients, we developed a prototype for an online platform for proton decision support (PRODECIS) comparing photon and proton treatments on dose metric, toxicity and cost-effectiveness levels. An evaluation was performed with 23 head and neck cancer datasets

Acute Lead Exposure Increases Arterial Pressure: Role of the Renin-Angiotensin System

Background: Chronic lead exposure causes hypertension and cardiovascular disease. Our purpose was to evaluate the effects of acute exposure to lead on arterial pressure and elucidate the early mechanisms involved in the development of lead-induced hypertension. Methodology/Principal Findings: Wistar rats were treated with lead acetate (i.v. bolus dose of 320 μg/Kg), and systolic arterial pressure, diastolic arterial pressure and heart rate were measured during 120 min. An increase in arterial pressure was found, and potential roles of the renin-angiotensin system, Na+,K+-ATPase and the autonomic reflexes in this change in the increase of arterial pressure found were evaluated. In anesthetized rats, lead exposure: 1) produced blood lead levels of 37±1.7 μg/dL, which is below the reference blood concentration (60 μg/dL); 2) increased systolic arterial pressure (Ct: 109±3 mmHg vs Pb: 120±4 mmHg); 3) increased ACE activity (27% compared to Ct) and Na+,K+-ATPase activity (125% compared to Ct); and 4) did not change the protein expression of the α1-subunit of Na+,K+-ATPase, AT1 and AT2. Pre-treatment with an AT1 receptor blocker (losartan, 10 mg/Kg) or an ACE inhibitor (enalapril, 5 mg/Kg) blocked the lead-induced increase of arterial pressure. However, a ganglionic blockade (hexamethonium, 20 mg/Kg) did not prevent lead's hypertensive effect. Conclusion: Acute exposure to lead below the reference blood concentration increases systolic arterial pressure by increasing angiotensin II levels due to ACE activation. These findings offer further evidence that acute exposure to lead can trigger early mechanisms of hypertension development and might be an environmental risk factor for cardiovascular diseaseThis study was supported by grants from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico)/FAPES (Fundação de Amparo à Pesquisa do Espírito Santo)/FUNCITEC (Fundação de Ciência e Tecnologia)(39767531/07), Brazil and from MCINN (Ministerio de Ciencia e Innovación) (SAF 2009- 07201) and ISCIII (Instituto de Salud Carlos III) (Red RECAVA- Red Temática de Investigación en Enfermedades Cardiovasculares del Instituto de Salud Carlos III, RD06/0014/0011), Spai