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Dynamin-1 (DNM1) is crucial for synaptic activity, neurotransmission, and associative memory, positioning it as a potential biomarker of cancer-related cognitive impairment (CRCI), a neurological consequence of cancer treatment characterized by memory loss, poor concentration, and impaired executive function. Through a stepwise approach, this study investigated the role of DNM1 in CRCI pathogenesis, incorporating both human data and animal models. The human study recruited newly diagnosed, chemotherapy-naïve adolescent and young adult cancer and non-cancer controls to complete a cognitive instrument (FACT-Cog) and blood draws for up to three time points. Following that, a syngeneic young-adult WT (C57BL/6) female mouse model of breast cancer chemobrain was developed to study DNM1 expression in the hippocampus. Samples from eighty-six participants with 30 adolescent and young adult (AYA) cancer and 56 non-cancer participants were analyzed. DNM1 levels were 32 ​% lower (P ​= ​0.041) among cancer participants compared to non-cancer prior to treatment. After receiving cytotoxic treatment, cognitively impaired cancer patients were found to have 46 ​% lower DNM1 levels than those without impairment (P ​= ​0.049). In murine breast cancer-bearing mice receiving chemotherapy, we found a greater than 40 ​% decline (P ​

Introduction: Coronavirus 2019 (COVID-19) has had a devastating impact on mental health and access to addiction treatment in the United States, including in California, which resulted in the highest rates of emergency department visits (ED) for opioid poisoning in 2020. As California slowly returns to pre-pandemic normalcy, it remains uncertain whether the rates of opioid-related events have slowed down over time. We hypothesized that the number of opioid-related ED visits were exacerbated after the period of the COVID-19 pandemic and continue at a high rate in the present.Methods: In this analysis we searched the University of California (UC) Health Data Warehouse—a database of electronic health records from six UC health centers—for opioid-related ED visits, identifiying using the following International Classification of Diseases, 10th Ed, Clinical Modification codes: F11 codes, and T40.0*, T40.1*, T40.2*, T40.3*, T40.4*, T40.6*. Opioid overdose-associated visits were classified by types of opioids involved: heroin (T40.1*); prescription opioids (T40.2* or T40.3*); and synthetic opioids (T40.4*). We performed interrupted time analysis to estimate the immediate (level) change and change-in-time trend (trend change), from before (January 2018–October 2019) and during the pandemic (April 2020–December 2022). Monthly visit rates were evaluated with negative binomial regression adjusted for first-order autoregression and using all-cause ED counts as the offset. We present effect sizes as rate ratios (RR) and 95% confidence intervals (CI), tested at α = .05.Results: Before COVID-19, a steadily increasing trend in ED visit rates was observed for all outcomes (P < 0.05) except synthetic opioids. Total opioid-related ED visit rates increased by 15% (RR 1.15, 95%CI 1.02–1.29, P = 0.20) immediately after March 2020 before decreasing by 0.5% every month, albeit without statistical significance (RR .995, 95% CI .991–1.00, P = 0.06). Similar trends were observed with prescription opioid overdoses, with a step increase of 44% (RR 1.44, 95% CI 1.10–1.89, P = .008) before plateauing after March 2020 (RR 1.01, 95% CI .998–1.02, P = 0.12). After March 2020, ED visit rates for synthetic opioid overdoses were increasing steadily by 4% every month (RR 1.04, 95% CI 1.02–1.06, P = .001), unlike with heroin, which was observed with an 8% monthly reduction (RR .92, 95% CI .90–.93, P < .001). No immediate increase in visit rates was observed for either opioid.Conclusion: While opioid-related ED admissions among the UC health centers showed an overall decrease, prescription and synthetic opioid overdoses remained significantly higher than pre-pandemic trends as of December 2022. A multilevel approach to improve awareness of new opioid health policies could ameliorate these alarming rises in the post-pandemic era.

IntroductionIdentifying reliable biomarkers that reflect cancer survivorship symptoms remains a challenge for researchers. DNA methylation (DNAm) measurements reflecting epigenetic changes caused by anti-cancer therapy may provide needed insights. Given lack of consensus describing utilization of DNAm data to predict survivorship issues, a review evaluating the current landscape is warranted.ObjectiveProvide an overview of current studies examining associations of DNAm with survivorship burdens in cancer survivors.MethodsA literature review was conducted including studies if they focused on cohorts of cancer survivors, utilized peripheral blood cell DNAm data, and evaluated the associations of DNAm and survivorship issues.ResultsA total of 22 studies were identified, with majority focused on breast (n = 7) or childhood cancer (n = 9) survivors, and half studies included less than 100 patients (n = 11). Survivorship issues evaluated included those related to neurocognition (n = 5), psychiatric health (n = 3), general wellness (n = 9), chronic conditions (n = 5), and treatment specific toxicities (n = 4). Studies evaluated epigenetic age metrics (n = 10) and DNAm levels at individual CpG sites or regions (n = 12) for their associations with survivorship issues in cancer survivors along with relevant confounding factors. Significant associations of measured DNAm in the peripheral blood samples of cancer survivors and survivorship issues were identified.Discussion/conclusionStudies utilizing epigenetic age metrics and differential methylation analysis demonstrated significant associations of DNAm measurements with survivorship burdens. Associations were observed encompassing diverse survivorship outcomes and timeframes relative to anti-cancer therapy initiation. These findings underscore the potential of these measurements as useful biomarkers in survivorship care and research.

Cranial radiation therapy (RT) for brain cancers is often associated with the development of radiation-induced cognitive dysfunction (RICD). RICD significantly impacts the quality of life for cancer survivors, highlighting an unmet medical need. Previous human studies revealed a marked reduction in plasma brain-derived neurotrophic factor (BDNF) post-chronic chemotherapy, linking this decline to a substantial cognitive dysfunction among cancer survivors. Moreover, riluzole (RZ)-mediated increased BDNF in vivo in the chemotherapy-exposed mice reversed cognitive decline. RZ is an FDA-approved medication for ALS known to increase BDNF in vivo. In an effort to mitigate the detrimental effects of RT-induced BDNF decline in RICD, we tested the efficacy of RZ in a cranially irradiated (9 Gy) adult mouse model. Notably, RT-exposed mice exhibited significantly reduced hippocampal BDNF, accompanied by increased neuroinflammation, loss of neuronal plasticity-related immediate early gene product, cFos, and synaptic density. Spatial transcriptomic profiling comparing the RT + Vehicle with the RT + RZ group showed gene expression signatures of neuroprotection of hippocampal excitatory neurons post-RZ. RT-exposed mice performed poorly on learning and memory, and memory consolidation tasks. However, irradiated mice receiving RZ (13 mg/kg, drinking water) for 6-7 weeks showed a significant improvement in cognitive function compared to RT-exposed mice receiving vehicle. Dual-immunofluorescence staining, spatial transcriptomics, and biochemical assessment of RZ-treated irradiated brains demonstrated preservation of synaptic integrity and mature neuronal plasticity but not neurogenesis and reduced neuroinflammation concurrent with elevated BDNF levels and transcripts compared to vehicle-treated irradiated brains. In summary, oral administration of RZ represents a viable and translationally feasible neuroprotective approach against RICD.

BackgroundThis study evaluated the real-world impact of acupuncture on analgesics and healthcare resource utilization among breast cancer survivors.MethodsFrom a United States (US) commercial claims database (25% random sample of IQVIA PharMetrics® Plus for Academics), we selected 18-63 years old malignant breast cancer survivors experiencing pain and ≥ 1 year removed from cancer diagnosis. Using the difference-in-difference technique, annualized changes in analgesics [prevalence, rates of short-term (

BackgroundAbout 4.5% of new cancer cases affect adolescent and young adult aged between 15 and 39 years in the United States (US). However, the effect of neuropsychiatric conditions on long-term adolescent and young adult cancer (AYAC) survivors has not been formally investigated. Thus, the impact and management of late neuropsychiatric complications in AYAC survivors compared to non-cancer-matched controls (NCMC) in the US were evaluated using the All of Us (AoU) Research Program.MethodsParticipants in the AoU Controlled Tier Dataset (v6) diagnosed with cancer between ages 15 and 39 were identified from electronic health records and surveys. AYAC survivors were matched with NCMC using the optimal pair-matching algorithm at a 1:4 ratio. Data on past diagnoses, current follow-up care, and treatment patterns of neuropsychiatric complications were collected.ResultsAnalysis was performed on 788 AYAC survivors and 3152 NCMC. AYAC survivors, with an average of 8.8 years since their first cancer diagnosis, were more likely than NCMC to receive a diagnosis of neuropathy, memory loss and epilepsy (p

Brain-derived neurotrophic factor (BDNF) improves cognitive function by stimulating neurogenesis and neuroplasticity. We hypothesize that higher plasma BDNF levels are protective against cognitive toxicity among adolescent and young adult cancer patients (15-39 years old). In a prospective, longitudinal study, we recruited 74 newly diagnosed cancer and 118 age-matched non-cancer controls who completed the Cambridge Neuropsychological Test Automated Battery (CANTAB), Functional Assessment of Cancer Therapy-Cognitive Function questionnaire (FACT-Cog) and blood draws. Plasma BDNF was quantified using an enzyme-linked immunosorbent assay. Genomic DNA from buffy coat was genotyped for BDNF Val66Met. Most cancer participants were diagnosed with breast (24%) and head/neck (22%) cancers. After adjusting for sociodemographic variables (age, gender, race, marital status, education years), cancer participants had lower BDNF levels (ng/mL) at baseline (median: 10.7 vs 21.6, p

IntroductionAdverse drug events (ADEs) are associated with poor outcomes and increased costs but may be prevented with prediction tools. With the National Institute of Health All of Us (AoU) database, we employed machine learning (ML) to predict selective serotonin reuptake inhibitor (SSRI)-associated bleeding.MethodsThe AoU program, beginning in 05/2018, continues to recruit ≥ 18 years old individuals across the United States. Participants completed surveys and consented to contribute electronic health record (EHR) for research. Using the EHR, we determined participants who were exposed to SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, vortioxetine). Features (n = 88) were selected with clinicians' input and comprised sociodemographic, lifestyle, comorbidities, and medication use information. We identified bleeding events with validated EHR algorithms and applied logistic regression, decision tree, random forest, and extreme gradient boost to predict bleeding during SSRI exposure. We assessed model performance with area under the receiver operating characteristic curve statistic (AUC) and defined clinically significant features as resulting in > 0.01 decline in AUC after removal from the model, in three of four ML models.ResultsThere were 10,362 participants exposed to SSRIs, with 9.6% experiencing a bleeding event during SSRI exposure. For each SSRI, performance across all four ML models was relatively consistent. AUCs from the best models ranged 0.632-0.698. Clinically significant features included health literacy for escitalopram, and bleeding history and socioeconomic status for all SSRIs.ConclusionsWe demonstrated feasibility of predicting ADEs using ML. Incorporating genomic features and drug interactions with deep learning models may improve ADE prediction.

The following correction should be noted to the caption for Fig. 5 in the article as original published: "..the percentage of BrdU+ cells (red) differentiating into the mature neurons (green, NeuN; C, c1, E)." should have read "..the percentage of BrdU+ cells (green) differentiating into the mature neurons (red, NeuN; C, c1, E)." The original article has been corrected.

Cancer-related cognitive impairment (CRCI) considerably affects the quality of life of millions of cancer survivors. Brain-derived neurotrophic factor (BDNF) has been shown to promote survival, differentiation, and maintenance of in vivo dentate neurogenesis, and chemotherapy induces a plethora of physiological and cellular alterations, including a decline in neurogenesis and increased neuroinflammation linked with cognitive impairments. In our clinical studies, breast cancer patients treated with doxorubicin (Adriamycin®, ADR) experienced a significant reduction in the blood levels of BDNF that was associated with a higher risk of CRCI. Our past rodent studies in CRCI have also shown a significant reduction in dentate neurogenesis accompanied by cognitive impairment. In this study, using a female mouse model of ADR-induced cognitive decline, we tested the impact of riluzole (RZ), an orally active BDNF-enhancing medication that is FDA-approved for amyotrophic lateral sclerosis. ADR-treated mice receiving RZ in the drinking water for 1 month showed significant improvements in hippocampal-dependent learning and memory function (spatial recognition), fear extinction memory consolidation, and reduced anxiety-like behavior. RZ prevented chemotherapy-induced reductions of BDNF levels in the hippocampus. Importantly, RZ mitigated chemotherapy-induced loss of newly born, immature neurons, dentate neurogenesis, and neuroinflammation. In conclusion, this data provides pre-clinical evidence for a translationally feasible approach to enhance the neuroprotective effects of RZ treatment to prevent CRCI.

PurposeYoung adult childhood cancer survivors (YACCSs) are often impacted by cancer-related cognitive impairment (CRCI) and psychological distress. Using the Project Forward Cohort, we evaluated the relationship between CRCI and substance use behaviors.MethodsYACCSs were surveyed between 2015 and 2018 (N = 1,106, female = 50.8%, Hispanic = 51.5%, median age = 25.5 years). Associations between CRCI and substance use (tobacco, binge drinking, marijuana, prescription drug misuse, and e-cigarette/vaporizer) were examined in multivariate logistic or log-binomial regressions, adjusting for child at diagnosis (0-14 years), years since diagnosis, sex, race/ethnicity, cancer type, and treatment intensity. Mediation analysis was performed to determine opportunities for interventions.ResultsCRCI was reported by 144 (13.0%) survivors. The highest prevalence was observed in CNS cancers (25.4%) and leukemia (13.3%) survivors. After covariate adjustment, CRCI was associated with 2.26 times the odds of prior 30-day vaping (95% CI, 1.24 to 4.11; P = .007). Mediators with significant indirect effects in the CRCI-vaping relationship include depressive symptoms (Center for Epidemiological Studies Depression Scale) and having two or more cancer-related late effects (P < .05).ConclusionCRCI among YACCSs was associated with reports of vaping. Oncologists should screen for vaping behavior if CRCI is apparent. Increasing access to long-term follow-up clinics, addressing physical and mental health issues, and monitoring and educating on vaping and other substance use behaviors is recommended to improve the long-term health of YACCSs.

BackgroundThere is little information about cancer-related cognitive impairment (CRCI) in adolescent and young adults (AYA, 15-39 years old) due to its rare incidence. Here, we present the pre-treatment (before chemotherapy or radiotherapy) evaluation of cognitive function and ability of AYA with cancer (AYAC) in a multicentered cohort study.MethodsNewly diagnosed AYAC and age-matched healthy controls (HC) were recruited between 2018 and 2021. The primary outcome was the comparison of pre-treatment cognitive impairment defined as 2 standard deviations (SDs) below the HC on ≥1 cognitive test, or >1.5 SDs below on ≥2 tests using CANTAB® between AYAC and HC. Secondary outcomes included self-perceived cognitive ability assessed by FACT-Cog v3 and biomarkers (inflammatory cytokines and brain-derived neurotrophic factor [BDNF]).ResultsWe recruited 74 AYAC (median age = 34) and 118 HC (median age = 32). On objective cognitive testing, we observed three times more AYAC patients performed poorly on at least 2 cognitive tests compared to HC (40.5% vs. 13.6%, p

BackgroundWe examined the research attitudes and willingness to participate in clinical research among cancer survivors with varying degrees of cognitive function.MethodsThis is a secondary analysis of data collected through the University of California Irvine Consent-to-Contact registry. Cancer survivors completed the Cognitive Function Instrument (CFI), the Research Attitudes Questionnaire (RAQ), and willingness to participate (WTP) in certain research procedures. Perceived cognitive impairment (CI) was defined as the worst 20% CFI scores.ResultsHere, 265 CI and 909 cognitively non-impaired (CNI) participants' data were analyzed. Mean age and sex distribution were similar, with fewer non-Hispanic Whites and education years among CI participants. More CI participants self-reported past diagnoses of Alzheimer's disease, mild cognitive impairment, stroke, depression, post-traumatic stress disorder, and alcohol abuse (all p < 0.05). CI participants were significantly more interested in studies investigating approved medications (92% vs. 87%, p = 0.030), lumbar puncture (47% vs. 38%, p = 0.027), and autopsy (78% vs. 69%, p = 0.022). After removing survivors with co-existing neuropsychiatric conditions, interest in autopsy studies remained statistically higher among CI (79% vs. 69%, p = 0.022).ConclusionsParticipants with cancer and CI are open to research procedures and interventions that are traditionally less utilized, which may facilitate the discovery of the pathogenesis and interventions for cancer-related cognitive impairment (CRCI).

BackgroundNeuropsychiatric symptoms, comprising cognitive impairment, fatigue, insomnia, depression, and anxiety, are prevalent and may co-occur during and after chemotherapy treatment for cancer. Electroacupuncture (EA), which involves mild electrical stimulation with acupuncture, holds great potential in addressing the management of individual symptoms. However, there is a lack of studies evaluating if EA can manage concurrent neuropsychiatric symptoms in cancer (i.e., symptom cluster). Hence, we designed a trial to evaluate the efficacy, safety, and feasibility of administering EA as an intervention to mitigate neuropsychiatric symptom clusters amongst cancer patients and survivors.MethodsThe EAST study is a randomized, sham-controlled, patient- and assessor-blinded clinical trial. Sixty-four cancer patients and survivors with complaints of one or more neuropsychiatric symptom(s) in the seven days prior to enrollment are recruited from the University of California Irvine (UCI) and Children's Hospital of Orange County (CHOC). Individuals with needle phobia, metastases, bleeding disorders, electronic implants, epilepsy, exposure to acupuncture in the three months prior to enrollment, and who are breastfeeding, pregnant, or planning to get pregnant during the duration of the study will be excluded. Screening for metal fragments and claustrophobia are performed prior to the optional neuroimaging procedures. Recruited patients will be randomized (1:1) in random blocks of four or six to receive either ten weekly verum EA (treatment arm, vEA) or weekly sham EA (control arm, sEA) treatment visits with a follow-up appointment four to twelve weeks after their last treatment visit. The treatment arm will receive EA at 13 acupuncture points (acupoints) chosen for their therapeutic effects, while the control arm receives minimal EA at 7 non-disease-related acupoints. Questionnaires and cognitive assessments are administered, and blood drawn to assess changes in symptom clusters and biomarkers, respectively.ConclusionThe EAST study can provide insight into the efficacy of EA, an integrative medicine modality, in the management of cancer symptom clusters in routine clinical practice.Trial registrationThis trial is registered with clinicaltrials.gov NCT05283577.

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect that is highly prevalent among cancer patients undergoing chemotherapy. There is a growing use of cryotherapy (CryTx) and compression therapy (ComTx) to prevent CIPN at cancer centers worldwide. In this study, we examined the awareness and recommendation of these modalities and evaluated factors associated with awareness. In addition, we investigated the type of technology utilized, barriers to implementation, and perceived adverse events of CryTx and ComTx.MethodsActive members of the Multinational Association of Supportive Care of Cancer (MASCC) were invited to complete an electronic survey that was sent via SurveyMonkey between September and October 2021. The survey assessed participants' awareness, recommendation, usage, barriers to utilization, and perceived adverse events of CryTx and ComTx. Descriptive statistics and multiple logistic regression were utilized to analyze findings.ResultsOut of 184 participants, 70.1% were physicians, 73.4% had over 10 years of practice, and 49.5% were practicing in an outpatient setting. While more than half (63.3%) of participants indicated awareness of CryTx for taxane-induced peripheral neuropathy, less than a quarter (22.8%) indicated recommendation in their practice setting. Factors associated with higher awareness of CryTx for patients receiving taxanes include living in Europe (OR = 2.69, 95% CI [1.28-5.64], p = 0.009), not practicing in an inpatient setting (OR = 3.15, 95% CI [1.45-6.85], p = 0.004), and self-identifying as non-physician (OR = 2.40, 95% CI [1.03-4.37], p = 0.041). Commercial cooling (31.5%) and compression (16.8%) gloves and socks were the most used modalities for CryTx and ComTx, respectively. The most identified barriers to CryTx and ComTx utilization include insufficient evidence (53.5%), logistics (34.8%), and patient discomfort (23.4%). Redness/irritation of skin (27.7%) and numbness/tingling (24.5%) accounted for about half of the perceived adverse events associated with use of CryTx and ComTx.ConclusionResults of our global survey illustrated that there are varying modes in the delivery of CryTx and ComTx among cancer centers around the world. Education of the utilization of CryTx and ComTx, in addition to efficacy and implementation studies, is needed to close the gap between awareness and implementation in clinical practice.

Brain-derived neurotrophic factor (BDNF) plays an essential role in neurogenesis and neuroplasticity and may be a key protein in cancer-related cognitive impairment (CRCI). This systematic review assessed the relationship between BDNF biomarkers and neurocognitive outcomes in cancer patients and survivors. A search in PubMed, Scopus, and PsycINFO yielded 638 articles, of which 26 were eligible. Fourteen (54 %) studied BDNF protein levels while 15 (58 %) analyzed BDNF rs6265 polymorphism. Of the nine observational studies reporting BDNF plasma/serum levels, five (56 %) exhibited a positive association between BDNF and cognitive function. One study reported intra-tumoral BDNF levels that were negatively associated with memory. For rs6265, three (20 %) of 15 studies reported an association with cognitive function with inconsistent directions. Among seven neuroimaging studies, three (43 %) demonstrated an effect of BDNF on brain function and structure. These results suggest that BDNF is a potential monitoring biomarker and druggable target for CRCI.

Cognitive impairment due to cancer and its therapy is a major concern among cancer patients and survivors. Extracellular vesicle (EVs) composition altered by cancer and chemotherapy may affect neurological processes such as neuroplasticity, potentially impacting the cognitive abilities of cancer patients and survivors. We investigated the EV proteome of breast cancer patients with and without cognitive impairment following anthracycline-based chemotherapy from longitudinally collected plasma. EVs were cup-shaped and positive for Flotillin-1 and TSG-101. We identified 517 differentially expressed EV proteins between the cognitive impaired and non-impaired groups during and post-chemotherapy. The observed decreased expression of p2X purinoceptor, cofilin-1, ADAM 10, and dynamin-1 in the plasma EVs of the cognitive impaired group may suggest alterations in the mechanisms underlying synaptic plasticity. The reduced expression of tight junction proteins among cognitive-impaired patients may imply weakening of the blood-brain barrier. These EV protein signatures may serve as a fingerprint that underscores the mechanisms underlying cognitive impairment in cancer patients and survivors.

Cognitive impairment due to cancer and its therapy is a major concern among cancer patients and survivors. Extracellular vesicle (EVs) composition altered by cancer and chemotherapy may affect neurological processes such as neuroplasticity, potentially impacting the cognitive abilities of cancer patients and survivors. We investigated the EV proteome of breast cancer patients with and without cognitive impairment following anthracycline-based chemotherapy from longitudinally collected plasma. EVs were cup-shaped and positive for Flotillin-1 and TSG-101. We identified 517 differentially expressed EV proteins between the cognitive impaired and non-impaired groups during and post-chemotherapy. The observed decreased expression of p2X purinoceptor, cofilin-1, ADAM 10, and dynamin-1 in the plasma EVs of the cognitive impaired group may suggest alterations in the mechanisms underlying synaptic plasticity. The reduced expression of tight junction proteins among cognitive-impaired patients may imply weakening of the blood-brain barrier. These EV protein signatures may serve as a fingerprint that underscores the mechanisms underlying cognitive impairment in cancer patients and survivors.

Introduction: We conducted a randomized controlled trial evaluating the efficacy and tolerability of cryotherapy in preventing chemotherapy-induced peripheral neuropathy (CIPN) in patients with early breast cancer receiving neo/adjuvant weekly paclitaxel. Methods: Patients were recruited from the National Cancer Centre Singapore and randomized (1:1) to receive either cryotherapy or usual care. Cryotherapy was applied as frozen gloves and socks on all extremities from 15 min before paclitaxel until 15 min post-infusion every cycle. Efficacy was measured by patient-reported outcomes (Patient Neurotoxicity Questionnaire [PNQ] and EORTC QLQ-CIPN20) and electrophysiological assessments. The primary endpoint was PNQ severity at 2 weeks after 12 cycles of weekly paclitaxel. Results: A total of 46 patients were recruited, of which 8 dropped out before paclitaxel treatment, leaving 38 evaluable. There was no significant difference in PNQ severity between cryotherapy and usual care at 2 weeks after paclitaxel treatment (sensory: p = 0.721; motor: p = 1.000). A benefit was observed at 3 months post-paclitaxel based on PNQ (sensory: 14.3 vs. 41.2%, p = 0.078; motor: 0 vs. 29.4%, p = 0.012) and CIPN20 (sensory: β = -3.6, 95%CI = -10.5-3.4, p = 0.308; motor: β = -7.3, 95%CI = -14.6-0, p = 0.051). Additionally, cryotherapy subjects have lower CIPN20 autonomic score (β = -5.84, 95%CI = -11.15 to -0.524, p = 0.031) and higher sympathetic skin response hand amplitudes (β = 0.544, 95%CI = 0.108-0.98, p = 0.014), suggesting possible autonomic benefits from cryotherapy. Temporary interruption with cryotherapy occurred in 80.9% of the subjects due to cold intolerance. Conclusions: There is insufficient evidence that cryotherapy prevents sensory neuropathy which may be due to the high rates of cryotherapy interruption in this study. The autonomic benefits of cryotherapy should be further investigated with appropriate outcome measures. Clinical Trial Registration: ClinicalTrials.gov: NCT03429972.

Introduction: We conducted a randomized controlled trial evaluating the efficacy and tolerability of cryotherapy in preventing chemotherapy-induced peripheral neuropathy (CIPN) in patients with early breast cancer receiving neo/adjuvant weekly paclitaxel. Methods: Patients were recruited from the National Cancer Centre Singapore and randomized (1:1) to receive either cryotherapy or usual care. Cryotherapy was applied as frozen gloves and socks on all extremities from 15 min before paclitaxel until 15 min post-infusion every cycle. Efficacy was measured by patient-reported outcomes (Patient Neurotoxicity Questionnaire [PNQ] and EORTC QLQ-CIPN20) and electrophysiological assessments. The primary endpoint was PNQ severity at 2 weeks after 12 cycles of weekly paclitaxel. Results: A total of 46 patients were recruited, of which 8 dropped out before paclitaxel treatment, leaving 38 evaluable. There was no significant difference in PNQ severity between cryotherapy and usual care at 2 weeks after paclitaxel treatment (sensory: p = 0.721; motor: p = 1.000). A benefit was observed at 3 months post-paclitaxel based on PNQ (sensory: 14.3 vs. 41.2%, p = 0.078; motor: 0 vs. 29.4%, p = 0.012) and CIPN20 (sensory: β = -3.6, 95%CI = -10.5-3.4, p = 0.308; motor: β = -7.3, 95%CI = -14.6-0, p = 0.051). Additionally, cryotherapy subjects have lower CIPN20 autonomic score (β = -5.84, 95%CI = -11.15 to -0.524, p = 0.031) and higher sympathetic skin response hand amplitudes (β = 0.544, 95%CI = 0.108-0.98, p = 0.014), suggesting possible autonomic benefits from cryotherapy. Temporary interruption with cryotherapy occurred in 80.9% of the subjects due to cold intolerance. Conclusions: There is insufficient evidence that cryotherapy prevents sensory neuropathy which may be due to the high rates of cryotherapy interruption in this study. The autonomic benefits of cryotherapy should be further investigated with appropriate outcome measures. Clinical Trial Registration: ClinicalTrials.gov: NCT03429972.