Impact of Pain on Symptom Burden in Chemotherapy-Induced Peripheral Neurotoxicity.

BACKGROUND: Chemotherapy-induced peripheral neurotoxicity (CIPN) affects the quality of life of cancer survivors. However, the impact of pain on symptom burden remains undefined. This study aimed to define differences in the clinical symptom profile of patients with painful and nonpainful CIPN. PATIENTS AND METHODS: A total of 579 participants (median age, 59 years [IQR, 19 years]; F=66%) were assessed cross-sectionally 6 months posttreatment. CIPN severity was graded using multiple methods, including patient-reported outcome measures, a clinically graded scale (NCI-CTCAE), and a neurologic examination score. Participants were classified into subgroups based on patient symptom report, with painful CIPN characterized by the presence of shooting/burning pain, and nonpainful CIPN characterized by the presence of numbness or tingling without shooting/burning pain. Behavioral changes were assessed via structured patient interview regarding symptom impact on sleep, exercise, and treatment-seeking. RESULTS: Among 579 participants, 24% (n=140) reported painful CIPN, 48% (n=280) reported nonpainful CIPN, and 28% (n=159) had no CIPN. Participants with painful CIPN demonstrated higher CIPN severity than those with nonpainful CIPN across multiple measures, including NCI-CTCAE, neurologic grading, and patient report (all P<.05). Participants with painful CIPN were more likely to report that their symptoms affected their ability to exercise (P=.007), produced sleep impairment, and increased treatment-seeking behavior due to their symptoms (both P<.001) compared with participants with nonpainful CIPN. CONCLUSIONS: Overall, participants with painful CIPN reported higher scores across all CIPN severity measures, including behavioral changes. This study underlines the need for accurate identification of different CIPN subgroups in hopes of informing better treatment and rehabilitation options for cancer survivors with painful CIPN.

Characterising vincristine-induced peripheral neuropathy in adults: symptom development and long-term persistent outcomes.

BACKGROUND: Decades following the introduction of vincristine as treatment for haematological malignancies, vincristine-induced peripheral neuropathy (VIPN) remains a pervasive, untreatable side-effect. However there remains a gap in understanding the characteristics of VIPN in adults. This study presents a comprehensive phenotyping of VIPN. METHODS: Adult patients (n = 57; age = 59.8 ± 14.6) were assessed cross-sectionally following completion of vincristine (months post treatment = 16.3 ± 15.6, cumulative dose = 7.6 ± 4.4), with a subset of 20 patients assessed prospectively during treatment. Patient reported measures (EORTC-QLQ-CIPN20, R-ODS) were used to profile symptoms and disability. Neurological assessment was undertaken using the Total Neuropathy Score and nerve conduction studies. Sensory threshold and fine motor tasks were also undertaken. Comparisons of data between timepoints were calculated using paired-sample t tests or Wilcoxon matched-pairs signed-rank test. Comparisons between outcome measures were calculated with independent sample t tests or Mann-Whitney U tests for non-parametric data. RESULTS: The majority of patients developed VIPN by mid-treatment (77.8%, 7.0 ± 3.3 weeks post baseline) with the prevalence remaining stable by end-of-treatment (75%, 8.1 ± 1.7 weeks post mid-treatment). By 3 months post-completion, 50% of patients still reported VIPN although there were significant improvements on neurological grading and functional assessment (P < 0.05). VIPN presented with sensorimotor involvement in upper and lower limbs and was associated with decreased sensory and motor nerve amplitudes, reduced fine-motor function and increased disability. CONCLUSION: VIPN in adults presents as a sensorimotor, upper- and lower-limb neuropathy that significantly impacts disability and function. Neuropathy recovery occurs in a proportion of patients; however, VIPN symptoms may persist and continue to affect long-term quality of life.

Considerations for establishing and maintaining international research collaboration: the example of chemotherapy-induced peripheral neurotoxicity (CIPN)-a white paper.

PURPOSE: This white paper provides guidance regarding the process for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research. METHODS: An international multidisciplinary group of CIPN scientists, clinicians, research administrators, and legal experts have pooled their collective knowledge regarding recommendations for establishing and maintaining international collaboration to foster advancement of CIPN science. RESULTS: Experts provide recommendations in 10 categories: (1) preclinical and (2) clinical research collaboration; (3) collaborators and consortiums; (4) communication; (5) funding; (6) international regulatory standards; (7) staff training; (8) data management, quality control, and data sharing; (9) dissemination across disciplines and countries; and (10) additional recommendations about feasibility, policy, and mentorship. CONCLUSION: Recommendations to establish and maintain international CIPN research collaboration will promote the inclusion of more diverse research participants, increasing consideration of cultural and genetic factors that are essential to inform innovative precision medicine interventions and propel scientific discovery to benefit cancer survivors worldwide. RELEVANCE TO INFORM RESEARCH POLICY: Our suggested guidelines for establishing and maintaining international collaborations to conduct oncology/neurology-focused chemotherapy-induced peripheral neurotoxicity (CIPN) research set forth a challenge to multinational science, clinical, and policy leaders to (1) develop simple, streamlined research designs; (2) address logistical barriers; (3) simplify and standardize regulatory requirements across countries; (4) increase funding to support international collaboration; and (5) foster faculty mentorship.

Interventions for managing oral submucous fibrosis.

BACKGROUND: Oral submucous fibrosis (OSF) is a chronic disease of the oral cavity that causes progressive constriction of the cheeks and mouth accompanied by severe pain and reduced mouth opening. OSF has a significant impact on eating and swallowing, affecting quality of life. There is an increased risk of oral malignancy in people with OSF. The main risk factor for OSF is areca nut chewing, and the mainstay of treatment has been behavioural interventions to support habit cessation. This review is an update of a version last published in 2008. OBJECTIVES: To evaluate the benefits and harms of interventions for the management of oral submucous fibrosis. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 5 September 2022. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) of adults with a biopsy-confirmed diagnosis of OSF treated with systemic, locally delivered or topical drugs at any dosage, duration or delivery method compared against placebo or each other. We considered surgical procedures compared against other treatments or no active intervention. We also considered other interventions such as physiotherapy, ultrasound or alternative therapies. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. participant-reported resumption of normal eating, chewing and speech; 2. change or improvement in maximal mouth opening (interincisal distance); 3. improvement in range of jaw movement; 4. change in severity of oral/mucosal burning pain/sensation; 5. ADVERSE EFFECTS: Our secondary outcomes were 6. quality of life; 7. postoperative discomfort or pain as a result of the intervention; 8. participant satisfaction; 9. hospital admission; 10. direct costs of medication, hospital bed days and any associated inpatient costs for the surgical interventions. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We included 30 RCTs (2176 participants) in this updated review. We assessed one study at low risk of bias, five studies at unclear risk of bias and 24 studies at high risk of bias. We found diverse interventions, which we categorised according to putative mechanism of action. We present below our main findings for the comparison 'any intervention compared with placebo or no active treatment' (though most trials included habit cessation for all participants). Results for head-to-head comparisons of active interventions are presented in full in the main review. Any intervention versus placebo or no active treatment Participant-reported resumption of normal eating, chewing and speech No studies reported this outcome. Interincisal distance Antioxidants may increase mouth opening (indicated by interincisal distance (mm)) when measured at less than three months (mean difference (MD) 3.11 mm, 95% confidence interval (CI) 0.46 to 5.77; 2 studies, 520 participants; low-certainty evidence), and probably increase mouth opening slightly at three to six months (MD 8.83 mm, 95% CI 8.22 to 9.45; 3 studies, 620 participants; moderate-certainty evidence). Antioxidants may make no difference to interincisal distance at six-month follow-up or greater (MD -1.41 mm, 95% CI -5.74 to 2.92; 1 study, 90 participants; low-certainty evidence). Pentoxifylline may increase mouth opening slightly (MD 1.80 mm, 95% CI 1.02 to 2.58; 1 study, 106 participants; low-certainty evidence). However, it should be noted that these results are all less than 10 mm, which could be considered the minimal change that is meaningful to someone with oral submucous fibrosis. The evidence was very uncertain for all other interventions compared to placebo or no active treatment (intralesional dexamethasone injections, pentoxifylline, hydrocortisone plus hyaluronidase, physiotherapy). Burning sensation Antioxidants probably reduce burning sensation visual analogue scale (VAS) scores at less than three months (MD -30.92 mm, 95% CI -31.57 to -30.27; 1 study, 400 participants; moderate-certainty evidence), at three to six months (MD -70.82 mm, 95% CI -94.39 to -47.25; 2 studies, 500 participants; moderate-certainty evidence) and at more than six months (MD -27.60 mm, 95% CI -36.21 to -18.99; 1 study, 90 participants; moderate-certainty evidence). The evidence was very uncertain for the other interventions that were compared to placebo and measured burning sensation (intralesional dexamethasone, vasodilators). Adverse effects Fifteen studies reported adverse effects as an outcome. Six of these studies found no adverse effects. One study evaluating abdominal dermal fat graft reported serious adverse effects resulting in prolonged hospital stay for 3/30 participants. There were mild and transient general adverse effects to systemic drugs, such as dyspepsia, abdominal pain and bloating, gastritis and nausea, in studies evaluating vasodilators and antioxidants in particular. AUTHORS' CONCLUSIONS: We found moderate-certainty evidence that antioxidants administered systemically probably improve mouth opening slightly at three to six months and improve burning sensation VAS scores up to and beyond six months. We found only low/very low-certainty evidence for all other comparisons and outcomes. There was insufficient evidence to make an informed judgement about potential adverse effects associated with any of these treatments. There was insufficient evidence to support or refute the effectiveness of the other interventions tested. High-quality, adequately powered intervention trials with a low risk of bias that compare biologically plausible treatments for OSF are needed. It is important that relevant participant-reported outcomes are evaluated.

Patient-Reported Outcome Measures in Chemotherapy-Induced Peripheral Neurotoxicity: Defining Minimal and Clinically Important Changes.

BACKGROUND: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common complication of cancer treatment that produces functional disability. Increasingly, patient-reported outcome measures (PROMs) are used to assess CIPN, providing a broader symptom perspective than clinician-graded scales. Understanding when a reported change in CIPN symptoms meets the threshold for clinical significance is challenging. This study aimed to provide interpretation guidelines for validated CIPN PROMs, and thereby enable estimation of thresholds to identify clinically relevant symptoms. METHODS: Patients commencing neurotoxic cancer treatments were assessed at 3 timepoints: baseline, midtreatment, and end-of-treatment. Trajectory of CIPN development was assessed by means of CIPN PROMs, EORTC Quality of Life - Chemotherapy-Induced Peripheral Neuropathy questionnaire (QLQ-CIPN20), and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity questionnaire (FACT/GOG-NTX). Thresholds were estimated for CIPN PROMs using the NCI CTCAE sensory neuropathy scale as the clinical anchor by midtreatment and end-of-treatment. Patients were assigned to a clinical change group according to CIPN development: either no development; grade 1 neuropathy (minimally important difference [MID]); or grade 2 neuropathy (clinically important difference). Distribution-based estimates (SD, 0.5) were also evaluated as supportive evidence. RESULTS: In total, 406 patients were recruited to the study, of whom 62% (n=199/320) developed CIPN by midtreatment and 80% (n=274/343) by end-of-treatment. Anchor-based MID estimates by midtreatment were 5.06 (95% CI, 4.26-5.86) for the QLQ-CIPN20 and 3.54 (95% CI, 2.87-4.20) for the FACT/GOG-NTX. End-of-treatment MIDs were estimated to be 7.32 (95% CI, 6.23-8.40) for the QLQ-CIPN20 and 4.84 (95% CI, 3.98-5.70) for the FACT/GOG-NTX. Distribution-based MID estimations yielded lower values than anchor-based methods, at 3.73 for the QLQ-CIPN20 and 2.64 for the FACT/GOG-NTX at midtreatment and 5.52 for the QLQ-CIPN20 and 3.64 for the FACT/GOG-NTX at end-of-treatment. CONCLUSIONS: Findings from the present series aid meaningful interpretation for commonly used validated CIPN PROMs and provide thresholds that serve as guidance on how to interpret score changes, which will be useful for design and evaluation of clinical trials and clinical practice.

Sleep dysfunction associated with worse chemotherapy-induced peripheral neurotoxicity functional outcomes.

PURPOSE: Sleep problems are commonly reported by cancer survivors; however, knowledge of the impact of chemotherapy-induced peripheral neurotoxicity (CIPN) on sleep quality remains limited. In this study, we explored the impact of CIPN on sleep quality, as well as identified clinical characteristics associated with poor sleep quality. METHODS: Participants were assessed cross-sectionally post-neurotoxic chemotherapy. CIPN severity was graded using a range of questionnaires that assessed CIPN severity and quality of life, as well as neurological grading scales. Sleep quality was assessed using a self-rated questionnaire (Pittsburgh Sleep Quality Index, PSQI). Participants with poor sleep quality were further grouped according to whether sleep impairment was due to CIPN or other factors. RESULTS: Among 77 participants who reported CIPN, 75% (n = 58) reported poor sleep quality. Of those, 41% (n = 24) reported CIPN as contributing to sleep impairment, while 59% (n = 34) reported other causes. Participants with CIPN-induced sleep impairments had higher CIPN severity across all outcome measures, as well as greater neuropathic pain (all p < 0.05). Furthermore, participants with CIPN-induced sleep impairments reported worse impact of neuropathy on physical and social functioning, as well as emotional well-being (all p < 0.05). CONCLUSIONS: Participants with CIPN-induced poor sleep quality reported worse scores across all CIPN severity measures. This emphasises the negative impacts of CIPN symptoms on quality of life of chemotherapy-treated patients and highlights the importance of sleep quality assessment in cancer survivors.

First Report of Bacterial Leaf Streak of Barley (Hordeum vulgare) Caused by Xanthomonas translucens pv. translucens in British Columbia, Canada.

Bacterial leaf streak (BLS) of barley is caused by the Gram-negative bacterial pathogen Xanthomonas translucens (Sapkota et al. 2020). In 2021, we observed multiple hill plots with BLS symptomatic plants in a barley stripe rust nursery in Vancouver, BC, Canada. We collected 29 leaf samples showing typical BLS symptoms (e.g. necrotic lesions; Fig. S1) and stored at 4 oC until bacterial isolation. Samples were surface-sterilized in 10% NaOCl for 20 sec and rinsed twice. About 1 cm2 of leaf tissue containing BLS characteristic lesions was macerated in 200 µL sterile H2O on a petri dish, incubated for 15 min, and 10 µl of the homogenates was streaked onto Wilbrink's - Boric Acid - Cephalexin (WBC) agar medium. Plates were incubated at 28-30 oC for 48 hrs. Four single colonies were obtained: BC10-1-2a (USask BC10-2a), BC10-1-2b (USask BC10-2b), UBC026 and UBC028. Colonies were grown in WBC broth and gDNA was extracted using E.Z.N.A. Bacterial DNA Kit (Omega Bio-Tek) or DNeasy Plant Pro Kit® (Qiagen) following manufacturer protocols. Genus-level identification was achieved using 16S rRNA sequencing with 27F/1492R primers (Lane 1991) of UBC026 (1,399 bp; NCBI # OP327375) and UBC028 (1,415 bp; NCBI #OP327376). Complete 16S rRNA sequences (1,533bp) of BC10-2a and BC10-2b (1,533 bp) were extracted from the draft whole-genome sequences (WGS) generated in this study. The 16S rRNA sequence homology values of 99.0-100% were recorded between the 4 strains. BLAST analyses of the 16S rRNA sequences to GenBank entries exhibited 99.5-100% similarity values (100% coverage) with the pathotype strains of Xtt DSM 18974T (LT604072) and X. translucens pv. undulosa (Xtu) CFBP 2055 (CP074361). Whole genomes of BC10-2a (JANUQY01) and BC10-2b (JANUQZ01) were sequenced (150-bp; reads 33.1 million; mean coverage 2125x) using NovaSeq Illumina, assembled (Unicycler v0.4.8; Wick et al. 2017) and analyzed to identify the strains to the species-level (Tambong et al. 2021). WGS of strains USask BC10-2a and USask BC10-2b exhibited genome-based DNA-DNA hybridization (dDDH; Meier-Kolthoff et al. 2013) and BLAST-based average nucleotide identity (ANIb; Richter et al. 2015) of 100%. The two strains also showed dDDH and ANIb of 90.4% (species-leel cut-off of 70%) and 98.780% and 98.80% (cut-off of 96%), respectively, with Xtt DSM 18974T (LT604072). In contrast, the WGS of BC10-2a and BC10-2b exhibited only 78.2% dDDH homology values with Xtu CFBP 2055T, suggesting that the strains are genetically more similar to Xtt. The assignment of these strains to Xtt is corroborated by phylogenomic analysis (Fig. S2; Meier-Kolthoff and Göker 2019) that showed the two strains clustering together (100% bootstrap) with the type strain DSM 18974T. These data suggest that these strains are taxonomically members of Xtt. Identification was also confirmed to the genus-level by LAMP assay using published X. translucens primers (Langlois et al. 2017). Pathovar-level identification was confirmed using a cbsA and S8.pep multiplex PCR diagnostic assay (Roman-Reyna et al. 2022). Koch's postulates were verified by greenhouse inoculation via leaf infiltration of UBC026 and UBC028 on 21-day old barley plants (line HB522) using an inoculum of 108 CFU ml-1 followed by re-isolation of the bacteria on WBC. The inoculated plants showed typical BLS symptoms similar to those observed in the field (Fig. S1). Water-inoculated plants had no symptoms. To our knowledge, this is the first published report of BLS of barley in British Columbia.

Polygenic risk of paclitaxel-induced peripheral neuropathy: a genome-wide association study.

BACKGROUND: Genetic risk factors for chemotherapy-induced peripheral neuropathy (CIPN), a major dose-limiting side-effect of paclitaxel, are not well understood. METHODS: We performed a genome-wide association study (GWAS) in 183 paclitaxel-treated patients to identify genetic loci associated with CIPN assessed via comprehensive neuropathy phenotyping tools (patient-reported, clinical and neurological grading scales). Bioinformatic analyses including pathway enrichment and polygenic risk score analysis were used to identify mechanistic pathways of interest. RESULTS: In total, 77% of the cohort were classified with CIPN (n = 139), with moderate/severe neuropathy in 36%. GWAS was undertaken separately for the three measures of CIPN. GWAS of patient-reported CIPN identified 4 chromosomal regions that exceeded genome-wide significance (rs9846958, chromosome 3; rs117158921, chromosome 18; rs4560447, chromosome 4; rs200091415, chromosome 10). rs4560447 is located within a protein-coding gene, LIMCH1, associated with actin and neural development and expressed in the dorsal root ganglia (DRG). There were additional risk loci that exceeded the statistical threshold for suggestive genome-wide association (P < 1 × 10-5) for all measures. A polygenic risk score calculated from the top 46 ranked SNPs was highly correlated with patient-reported CIPN (r2 = 0.53; P = 1.54 × 10-35). Overlap analysis was performed to identify 3338 genes which were in common between the patient-reported CIPN, neurological grading scale and clinical grading scale GWAS. The common gene set was subsequently analysed for enrichment of gene ontology (GO) and Reactome pathways, identifying a number of pathways, including the axon development pathway (GO:0061564; P = 1.78 × 10-6) and neuronal system (R-HSA-112316; adjusted P = 3.33 × 10-7). CONCLUSIONS: Our findings highlight the potential role of axon development and regeneration pathways in paclitaxel-induced CIPN.

Prevalence of chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy in two regions of Australia.

INTRODUCTION/AIMS: Immune-mediated neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) produce significant disability and often require maintenance treatment. There is a paucity of epidemiological data on these conditions in Australia. METHODS: We undertook a prevalence study of CIDP and MMN in North Queensland and Tasmania, coinciding with a national census. Diagnoses were classified against the diagnostic criteria of the European Federation of Neurological Societies/Peripheral Nerve Society. Case ascertainment was undertaken via multiple methods, including survey of local neurologists across public and private clinics, search of neurophysiology, neurology and hospital databases, search of admitted hospital database collections using ICD codes and through immunoglobulin therapy prescription lists. RESULTS: The crude prevalence of CIDP was 5.00 per 100,000 (95% confidence interval [CI] 3.79-6.62) and the crude prevalence of MMN was 1.33 per 100,000 (95% CI 0.78-2.27). Prevalence was also investigated using National Blood Authority numbers of cases prescribed immunoglobulin therapy, indicating a CIDP prevalence of 5.72 per 100,000 (95% CI 4.41-7.43) and MMN prevalence of 1.94 per 100,000 (95% CI 1.24-3.03). There was no significant difference between these numbers and those calculated through access of patient records locally. There was no significant difference in prevalence between Tasmania and North Queensland for any category. DISCUSSION: This study updates the prevalence of CIDP and MMN in Australia. Understanding the distribution of CIDP and MMN patients and their need for treatment is essential for future resource planning and to enable monitoring and coordination of therapies such as immunoglobulin.

Assessing chemotherapy-induced peripheral neuropathy with patient reported outcome measures: a systematic review of measurement properties and considerations for future use.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity of cancer treatment, with potential to significantly impact cancer survivors' long-term quality of life. Patient reported outcome measures (PROMs) are increasingly utilised to evaluate CIPN. However, guidance remains lacking on how to identify fit for purpose PROMs with considerations necessarily differing when used in various research and in-clinic contexts. This study aimed to evaluate evidence about CIPN PROMs measurement properties and propose considerations to optimize CIPN PROM selection for each purpose. METHODS: A systematic review was conducted to identify literature assessing measurement properties of CIPN PROMs. These were evaluated against Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) criteria and International Society for Quality of Life minimum standards. Risk of Bias (RoB) was assessed using the COSMIN RoB checklist. RESULTS: Thirty-nine papers evaluating measurement properties of 13 PROMs were included. The European Organization for Research and Treatment of Cancer Quality of Life Chemotherapy-Induced Peripheral Neuropathy Questionnaire (QLQ-CIPN20) and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) were the most commonly investigated PROMs and had the most measurement properties meeting established criteria. CONCLUSION: The use of the QLQ-CIPN20 and FACT/GOG-Ntx to assess CIPN in research settings has the most supporting evidence. However other considerations including study aims, endpoints and target population also factor into PROM selection and need to be considered more often when determining the most suitable outcome measure. Evidence of CIPN PROMs use in clinical practice is limited and their adoption to individual-patient level management requires more evaluation.

Association of electrochemical skin conductance with neuropathy in chemotherapy-treated patients.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse event of cancer treatment that can affect sensory, motor, or autonomic nerves. Assessment of autonomic neuropathy is challenging, with limited available tools. Accordingly, it is not routinely assessed in chemotherapy-treated patients. In this study, we aimed to examine whether electrochemical skin conductance (ESC) via Sudoscan, a potential measure of autonomic function, associates with subjective and objective measures of CIPN severity and autonomic neuropathy. METHODS: A cross-sectional assessment of patients who completed neurotoxic chemotherapy 3-24 months prior was undertaken using CIPN patient-reported outcomes (EORTC-QLQ-CIPN20), clinically graded scale (NCI-CTCAE), neurological examination score (TNSc), autonomic outcome measure (SAS), and Sudoscan. Differences in CIPN severity between participants with or without ESC dysfunction were investigated. Linear regression analyses were used to identify whether ESC values could predict CIPN severity. RESULTS: A total of 130 participants were assessed, with 93 participants classified with CIPN according to the clinically graded scale (NCI-CTCAE/grade ≥ 1), while 49% demonstrated hands or feet ESC dysfunction (n = 46). Participants with ESC dysfunction did not significantly differ from those with no dysfunction on multiple CIPN severity measures (clinical-grade, patient-report, neurological examination), and no differences on the autonomic outcome measure (SAS) (all p > 0.0063). Linear regression analyses showed that CIPN could not be predicted by ESC values. CONCLUSIONS: The inability of ESC values via Sudoscan to predict clinically-graded and patient-reported CIPN or autonomic dysfunction questions its clinical utility for chemotherapy-treated patients. The understanding of autonomic neuropathy with chemotherapy treatment remains limited and must be addressed to improve quality of life in cancer survivors.

Psychologist homicide victims: The National Violent Death Reporting System and other sources.

OBJECTIVE: Homicide of healthcare workers has been reported but little is known about psychologists as victims of homicide. This study aimed to investigate what is known about homicide of psychologists. METHODS: The Centers for Disease Control and Prevention's National Center for Injury Prevention and Control's National Violent Death Reporting System (NVDRS) provides insights into violent deaths, including homicide. This study interrogated the NVDRS and conducted Internet searches about psychologist decedents of homicide. RESULTS: Between 2003 and 2018 the NVDRS identified 12 psychologist homicides. Internet searches revealed 15 psychologist homicides. Only three (11.1%) were known to have been killed by current or former patients. Another was by a colleague's patient. Another assailant was suspected to be a patient. We summarize patterns and circumstances of deaths, address issues related to violence in healthcare, and review selected resources addressing violence prevention. CONCLUSION: Psychologists, like other health professionals, may be victims of homicide. Such deaths have diverse contributing factors and are rarely perpetrated by patients. As concern about health professional safety mounts and the NVDRS becomes better established, it will hopefully become a more sensitive, precise, comprehensive and useful mechanism for tracking trends in violent deaths of psychologists and other health professionals and ultimately inform preventative strategies.

Weekly Paclitaxel-Induced Neurotoxicity in Breast Cancer: Outcomes and Dose Response.

BACKGROUND: Paclitaxel treatment produces significant peripheral neuropathy, but the time course of neuropathy development and outcomes are unclear. Dose reduction is the only strategy to prevent neurotoxicity, however, the impact of dose-reduction on neuropathy outcomes remains unknown. This study aimed to prospectively evaluated neuropathy development from weekly paclitaxel treatment and evaluate the impact of dose-reduction on post-treatment neuropathy outcomes. PATIENTS AND METHODS: Breast cancer patients receiving paclitaxel (80mg/m2 ) weekly for 12-weeks were prospectively assessed using patient reported (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity; FACTGOG-Ntx), clinical (Total Neuropathy Score clinical version; TNSc) and neurophysiological measures up to 12-months post completion. The impact of dose-reduction on post-treatment (3.6 ± 0.1 months) clinical and patient reported outcomes was evaluated in 105 weekly paclitaxel-treated patients. RESULTS: Significant neuropathy was present by 6-weeks across patient-reported, clinical, and objective neurophysiological assessments, increasing in prevalence and severity over the treatment course. Limited recovery occurred, with significant neuropathy being maintained up to 12 months (p < .05). Patients who received dose reduction had worse patient reported (FACT-GOG-Ntx: 40.2 ± .1.4) and clinical neuropathy outcomes (TNSc: 4.3 ± 0.4) compared to those who received the full dose (FACT-GOG-Ntx: 45.9 ± 0.9; TNSc: 3.3 ± 0.3, p < .05). Patients who ceased treatment early demonstrated the worse deficits (TNSc: 5.0 ± 0.6; FACT-GOG-Ntx: 37.3 ± 2.7) compared to those who received the complete dose (TNSc: 3.5 ± 0.3; FACT-GOG-Ntx: 45.3 ± 0.9, p < .05). CONCLUSION: Weekly paclitaxel produces symptomatic and objective neuropathy early in the treatment course which can persist. Dose reduction does not necessarily lead to more favorable neuropathy outcomes, with individual risk factors likely important in addition to cumulative dose. IMPLICATIONS FOR PRACTICE: Weekly paclitaxel schedules are extensively used in breast cancer. Patients may develop symptomatic and objective neuropathy early in the treatment course, with these individuals requiring closer monitoring. Furthermore, neuropathy is a long-term sequela that may impact quality of life and require appropriate supportive services. Results suggest that dose reduction does not necessarily lead to better neuropathy outcomes. Understanding schedule-specific toxicity and risk factors for neuropathy will be critical to determining individualized treatment strategies and improving quality of life in breast cancer survivors.

Chemotherapy and peripheral neuropathy.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a major dose-limiting side effect of many anti-cancer agents, including taxanes, platinums, vinca alkaloids, proteasome inhibitors, immunomodulatory drugs, and antibody-drug conjugates. The resultant symptoms often persist post treatment completion and continue to impact on long-term function and quality of life for cancer survivors. At present, dose reduction remains the only strategy to prevent severe neuropathy, often leading clinicians to the difficult decision of balancing maximal treatment exposure and minimal long-lasting side effects. This review examines the clinical presentations of CIPN with each class of neurotoxic treatment, describing signs, symptoms, and long-term outcomes. We provide an update on the proposed mechanisms of nerve damage and review current data on clinical and genetic risk factors contributing to CIPN development. We also examine recent areas of research in the treatment and prevention of CIPN, with specific focus on current clinical trials and consensus recommendations for CIPN management.

Characteristics and risk factors of bortezomib induced peripheral neuropathy: A systematic review of phase III trials.

Bortezomib-induced peripheral neuropathy (BIPN) is a common toxicity associated with the treatment of multiple myeloma (MM), typically requiring dose reduction, delay, or cessation of treatment protocol. This systematic review aimed to investigate risk factors, trends, and variability associated with the development of BIPN. Searches were undertaken using Medline, PubMed, Cochrane Central Register of Controlled Trials, Embase, Scopus, and Web of Science. Additional studies were identified by investigating authors' bibliographic references cited by original and review articles. Articles that reported on neuropathy in phase III randomised control trials involving bortezomib in any treatment arm for the treatment of MM were included in this review. A total of 43 full text articles met criteria, which examined 23 phase III trials (N = 8218). Overall incidence of neuropathy ranged from 8.4% to 80.5% (median = 37.8%) and severe neuropathy (grade 3-4) ranged from 1% to 33.2% (median = 8%). Similar reports of neuropathy of any grade and severe neuropathy were observed between the newly diagnosed and relapsed cohort. Bortezomib regimens with reduced dose intensity were associated with reduced neuropathy incidence. Increased cumulative dosing levels, intravenous compared with subcutaneous administration and combination therapy with thalidomide were associated with higher rates of BIPN. This analysis revealed that BIPN is a significant toxicity. More sensitive measures are required to capture the incidence and severity of BIPN. Better understanding of risk factors and reversibility profiles will minimise the number of cancer survivors living with residual treatment side effects.

Taxane-induced peripheral neuropathy: differences in patient report and objective assessment.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side-effect of neurotoxic cancer treatment impacting on long-term quality of life. Symptoms include numbness, tingling, and pain, affecting the distal extremities. However, patients often report symptoms discrepant from the expected symmetrical distribution and the degree of concurrence with objective assessment remains ill-defined. This study aimed to investigate severity and symmetry of neuropathy symptoms to enable comparison of objective measures and patient report. METHODS: Forty-five taxane-treated patients (F = 43, 66 ± 1.5 years, 19 months post-treatment) completed bilateral neuropathy assessments via clinical examination, sensory nerve conduction studies (NCS), and patient questionnaires. The laterality index (LI) was calculated as a ratio of smaller to larger side-to-side differences. RESULTS: Neuropathy was reported by 89% of the cohort. On clinical examination, 83% had ≥ 2 abnormalities, with 38-35% having upper or lower limb sensory amplitudes below normative range. Thirty-five percent indicated side-to-side symptom asymmetry; however, there was no significant asymmetry evident on clinical examination (LI Asym = .60 ± .10, Sym = .76 ± .05, NS) and no difference in side-to-side NCS (median LI:Asym = .69 ± .06, Sym = .81 ± .04, NS; Sural LI:Asym = .80 ± .04, Sym = .81 ± .04, NS). Accordingly, there was no statistical association between patient-reported and objective assessment of side-to-side asymmetry, suggesting discordance between patient experience and objective assessment. Similarly, discrepancies in symptom severity between hands and feet were reported by 32% of the cohort. However, patients reporting differences in symptom severity between the hands and feet were just as likely to present with comparable assessments as to demonstrate objective discrepancies. CONCLUSIONS: Discrepancies may exist between the patient experience of CIPN and objective assessments. Understanding these discrepancies may help to elucidate underlying mechanisms and better inform treatment strategies.

Balance Deficits and Functional Disability in Cancer Survivors Exposed to Neurotoxic Cancer Treatments.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) persists after treatment in up to 40% of cancer survivors and has been linked with increased balance deficits, disabilities, and fall occurrences. This study aimed to comprehensively assess the links between CIPN, balance deficits, and functional disability and to inform the development of clinical screening tools for patients at risk of these events. PATIENTS AND METHODS: A total of 190 cancer survivors exposed to neurotoxic chemotherapies (age, 57 ± 13 years; average time from completion of neurotoxic therapy, 12 ± 11 months) attended a neurology research clinic for a single cross-sectional assessment of patient-reported and objective CIPN, standing balance in 4 conditions of increasing difficulty, and functional disability. RESULTS: Most patients (68%) reported CIPN symptoms at assessment. Symptomatic patients displayed increased functional disability (F=39.4; P<.001) and balance deficits (F=34.5; P<.001), with degree of balance impairments consistent with a healthy elderly population (age ≥65 years) reporting multiple falls over the subsequent year. Increasing CIPN severity correlated with increasing functional disability (clinically assessed R2=0.46; patient-reported R2=0.49; P<.001) and balance deficits (clinically assessed R2=0.41; patient-reported R2=0.30; P<.001). A 5-factor model of key independent correlates-patient-reported numbness/tingling, weakness, and balance deficit; age; and vibration perception-was strongly linked to balance deficits (R2=0.46; P<.001) and functional disability (R2=0.56; P<.001). CONCLUSIONS: This study confirms links between increasing CIPN severity and increasing balance deficits and functional disability using comprehensive CIPN assessment methodology. The extent of balance deficits in patients with CIPN underscores the functional consequences of neurotoxicity. A 5-factor model provides a foundation for clinical screening tools to assess balance deficits and functional disability in patients exposed to neurotoxic chemotherapies.

Exercise-based rehabilitation for cancer survivors with chemotherapy-induced peripheral neuropathy.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) affects up to 40% of cancer survivors and is associated with functional deficits and an increased falls incidence. There are presently no strongly recommended treatment strategies for CIPN. The aim of this study was to evaluate the impact of a multimodal exercise intervention on CIPN symptoms and related functional deficits, as well as neurophysiologic parameters. METHODS: All outcomes were assessed before and after an 8-week exercise intervention (3-weekly sessions) and preceding 8-week control period at baseline, pre-exercise and post-exercise. Outcome measures were objective and patient-reported CIPN, standing and dynamic balance, mobility, quality of life, and sensory and motor nerve excitability and conduction studies. RESULTS: Twenty-nine cancer survivors (8 male, 21 female; mean age 61.6 ± 11.8 years) with CIPN symptoms affecting function completed all assessments. Objective and patient-reported CIPN, dynamic balance, standing balance in eyes open conditions, mobility and quality of life were improved from pre- to post-exercise (4.0 < F < 10.2; p < .05), with no changes over the control period (p > .21). No changes were observed in sensory or motor neurophysiologic parameters (p > .23). CONCLUSIONS: This study provides encouraging evidence of the rehabilitative potential of multimodal exercise for persisting CIPN in a post-treatment cohort. Large randomised controlled trials are justified to confirm observed benefits and determine the mechanisms and clinical significance.

Comparison of cross-sectional areas and distal-proximal nerve ratios in amyotrophic lateral sclerosis.

INTRODUCTION: This study explored potential diagnostic markers of nerve ultrasound in differentiating amyotrophic lateral sclerosis (ALS) from mimic disorders. METHODS: Ultrasound of the median, ulnar, and tibial nerves was conducted in 53 patients with ALS, 32 patients with ALS-mimic disorders, and 30 controls. Nerve cross-sectional area (CSA) and distal-proximal ratios were calculated. RESULTS: The median nerve CSA in the upper arm was decreased (7.9 ± 1.3 mm2 vs. 9.0 ± 1.4 mm2 , P < 0.05), and the median nerve wrist-upper arm ratio was increased in ALS patients compared with controls (1.3 ± 0.4 vs. 1.1 ± 0.2; P < 0.01). In differentiating ALS from mimic presentations, assessment of median nerve CSA in the upper arm and comparison of a median and ulnar nerve CSA distal-proximal ratio provide diagnostic potential. DISCUSSION: Assessment of nerve CSA combined with calculation of nerve CSA distal-proximal ratio provides a useful marker to aid in the diagnosis of ALS. Muscle Nerve 58:777-783, 2018.