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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.

Diabetic peripheral neuropathy (DPN) is a debilitating complication of type 2 diabetes (T2D) and is often diagnosed only after irreparable nerve damage has occurred. Mechanical allodynia, previously nonpainful stimuli that becomes painful, presents early in the disease, and precedes irreparable nerve damage. Previous studies suggest the development of DPN is associated with increased inflammation, which can result from elevated pro-inflammatory and/or reduced anti-inflammatory cytokines. OBJECTIVE: To investigate the role of anti-inflammatory cytokines in the development of DPN. We hypothesized that reduced interleukin (IL)-4 and IL-10 levels would precede the development of mechanical allodynia in a diabetic rat model. METHODS: Bimonthly hemoglobin A1c (HbA1c) measures were obtained from male University of California Davis-T2D rats, ≥ 5.6% used as diagnostic criteria. Age-matched, healthy Sprague-Dawley rats were used as controls. Mechanical allodynia was assessed monthly using von Frey filaments (North Coast Medical, Morgan Hill, CA) and is presented as 50% paw withdrawal threshold. Tail vein blood draws were also performed monthly. Serum IL-4 and IL-10 concentrations were assessed using a rat multiplex kit (Millipore, RECYTMAG, Burlington, MA). Data are presented as mean ± SD and were analyzed using a two-way, repeated measures ANOVA with Holm-Sidak post hoc analyses. Von Frey data were converted to a logarithmic scale for parametric statistical analyses. RESULTS: 50% paw withdrawal threshold was significantly decreased at both 3 and 4 mo relative to onset in T2D rats (n=18; Onset: 1.48±0.2 log(g); 3 mo: 1.28±0.3 log(g), P=0.033; 4 mo: 1.31±0.3 log(g), P=0.023). The same comparisons in control rats demonstrated a significant increase (n=20; Onset: 1.67±0.2 log(g); 3 mo: 1.91±0.1 log(g), P This project was supported by NIH R01 HL144723. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

It is well established that prostaglandins, a product of cyclooxygenase (COX) enzymes contribute to evoking the exercise pressor reflex. Previous studies suggest that COX expression is upregulated in the peripheral nerves of those with type 2 diabetes (T2D), likely due to low grade inflammation associated with the disease. The purpose of this study was to determine if COX activity in the exercising skeletal muscle exaggerates the exercise pressor reflex in T2D. We hypothesized that inhibiting COX activity in the hindlimb would reduce the exaggerated pressor response to muscle contraction in T2D rats. To do this, we evoked the exercise pressor reflex by statically contracting the skeletal muscle for 30s in unanesthetized, decerebrate rats. Experiments were performed on male University of California Davis (UCD)-T2D (n=8; body weight: 526 ± 42g) and Sprague Dawley rats (n=3; body weight: 473 ± 10g). Changes (Δ) in peak mean arterial pressure (MAP) and heart rate (HR) responses to exercise were compared before and after locally injecting indomethacin (1 mg/kg in 0.2 mL of 100 mM sodium carbonate), a COX 1 and 2 inhibitor, or its vehicle (0.2 mL of 100 mM sodium carbonate) into the arterial supply of the ipsilateral (contracting) and contralateral (non-contracting) hindlimb. Data are presented as mean ± SD. We found that local injection of indomethacin into the contracting hindlimb reduced the exaggerated peak pressor (ΔMAP: 30 ± 14 mmHg to 18 ± 8 mmHg; P0.99; ΔHR: 10 ± 5 bpm to 13 ± 7 bpm; P=0.67). Conversely, local injection of indomethacin into the non-contracting hindlimb (n=4), as well as injection of the vehicle in the contracting hindlimb (n=4), did not affect the pressor response to muscle contraction in T2D rats. Developed tensions during muscle contraction were similar for all comparisons. In summary, our findings suggest that COX activity contributes to the exaggerated pressor response to muscle contraction in T2D rats. This project was supported by NIH R01 HL144723. This project was supported by NIH R01 HL144723. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background Assessing the pre- and post-test probability of disease in the context of routine health care is challenging. We wished to study how test performance parameters relating to clinical utility vary by clinical indication in a ‘real-world’ setting. Methods The diagnostic accuracy of serum total B12 and Active-B12® (holotranscobalamin) was evaluated in a primary care population, using serum methylmalonic acid as the reference standard. We used electronic requesting to establish the clinical indication for each request. Routine requests from primary care for serum total B12 were included if creatinine was also measured and estimated glomerular filtration rate was at least 60 mL/min/1.73 m2. Results Clinical indications included peripheral neuropathy ( n = 168), anaemia ( n = 168), cognitive decline ( n = 125), suspected dietary deficiency ( n = 76), other ( n = 362). For peripheral neuropathy, the area under the receiver operator curve ± 95% confidence interval (AUC ± CI) was 0.63 (0.54–0.71) ( P = 0.002) for total B12 and 0.68 (0.60–0.77) ( P 12®. For anaemia, AUC ± CI was 0.56 (0.47–0.66) ( P = 0.10) for total B12 and 0.69 (0.59–0.78) ( P 12®. For cognitive decline, AUC ± CI was 0.54 (0.43–0.65) ( P = 0.26) for total B12 and 0.69 (0.58–0.80) ( P = 0.0002) for Active-B12®. The pre–post-test change in probability of disease varied by clinical indication. Conclusion Combining diagnostic accuracy studies and electronic testing in a ‘real-world’ setting allows clinical utility to be assessed by clinical indication. Wider application of this would permit more personalised laboratory medicine. In this study, diagnostic performance of total B12 and Active-B12® varied across all indications. Active-B12® provided better discrimination, but this may have reflected the cut-offs used.

We present a novel index that represents, in one combined metric, the integrity of terrestrial ecosystems globally at 1km2 resolution: the Ecosystem Integrity Index (EII). The index provides a simple, yet scientifically robust, way of measuring, monitoring and reporting on ecosystem integrity at any geographical scale. It is formed of three components, structure, composition, and function, and measured against a natural (current potential) baseline on a scale of 0 to 1. The index has been developed to help national governments measure and report on various of the goals and targets being developed within the draft post-2020 global biodiversity framework being negotiated under the Convention on Biological Diversity, and for non-state actor contributions to also be recognized. In doing so, it will enable these actors to make informed decisions on the conservation, restoration and sustainable use of ecosystems for which they are wholly or partly responsible. We find that ecosystem integrity is rapidly declining in terrestrial areas globally, with countries, on average, retaining less than half of their natural ecosystem integrity with a mean EII across all countries of 0.45 (SD: 0.20). This poses a challenge for nations and businesses seeking to halt and reverse decades of loss of nature around the world, but one that is not insurmountable. With sufficient effort, values of EII can increase at national and other scales, representing progress towards the vision of living in harmony with nature.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of neurotoxic cancer treatment, often impacting treatment tolerability and patient functioning. Factors predicting an individual’s vulnerability for developing CIPN remain ill-defined. However, patient characteristics may contribute to CIPN risk, with obesity being a prevalent patient comorbidity. This study was aimed at evaluate if being overweight (BMI ≥ 25 kg/m2) was associated with worse symptomatic, clinical, and functional CIPN following neurotoxic cancer treatment. Three hundred seventy-nine cancer survivors were assessed 5 (IQR 3–5) months post oxaliplatin or paclitaxel treatment via comprehensive patient-reported, clinical, and functional CIPN measures. Patients classified as overweight (BMI ≥ 25 kg/m2) were compared to those within the normal BMI range (< 25 kg/m2). Multilinear regression was conducted to evaluate the association between patient clinical factors and CIPN severity. Most patients reported CIPN symptoms (78%), with deficits evident on clinical examination. Overweight patients (n = 242, 63.8%) had significantly worse CIPN across symptomatic, objective clinical, and functional outcomes compared to those with a normal BMI (p < .05). In multivariate linear regression, older age (B = .088, 95%CI = .053–.122, p < .001), larger waist circumference (B = .030, 95%CI = .001–.059, p < .05), and larger BSA (B = 2.41, 95%CI = .34–04.48, p < .05) were associated with CIPN. Diabetes and BMI were significant on univariate analysis but not in the final models. Overweight patients represent a large proportion of cancer survivors who may be particularly impacted by CIPN, requiring closer monitoring and referral to supportive services. Accessible data such as a patient’s general and abdominal obesity status may aid in formulating personalized treatment. Identifying routinely measured patient characteristics which may contribute to an individual’s CIPN risk profile could assist with informing treatment decisions.

BACKGROUND: Little has been published regarding how doctors think and talk about prognosis and the potential benefits of adjuvant therapy. OBJECTIVE: We sought predictions of survival rates and survival times, for patients with and without adjuvant therapy, from the clinicians of patients participating in a randomised trial of adjuvant sorafenib after nephrectomy for renal cell carcinoma. METHODS: A subset of medical oncologists and urologists in the SORCE trial completed questionnaires eliciting their predictions of survival rates and survival times, with and without adjuvant sorafenib, for each of their participating patients. To compare predictions elicited as survival times versus survival rates, we transformed survival times to survival rates. To compare predicted benefits elicited as absolute improvements in rates and times, we transformed them into hazard ratios (HR), a measure of relative benefit.We postulated that a plausible benefit in overall survival (OS) should be smaller than that hypothesized for disease–free survival (DFS) in the trials original sample size justification (i.e. HR for OS should be ≥ 0.75). RESULTS: Sixty–one medical oncologists and 17 urologists completed questionnaires on 216 patients between 2007 and 2013. Predictions of survival without adjuvant sorafenib were similar whether elicited as survival rates or survival times (median 5–year survival rate of 61% vs 60%, p = 0.6). Predicted benefits of sorafenib were larger when elicited as improvements in survival rates than survival times (median HR 0.76 vs 0.83, p < 0.0001). The proportion of HR for predicted OS with sorafenib that reflected a plausible benefit (smaller effect of sorafenib on OS than hypothesized on DFS, i.e. HR ≥ 0.75) was 51% for survival rates, and 65% for survival times. CONCLUSIONS: The predicted benefits of adjuvant sorafenib were larger when elicited as improvements in survival rates than as survival times, and were often larger than the sample size justification for the trial. These potential biases should be considered when thinking and talking about individual patients in clinical practice, and when designing clinical trials.

Purpose Camrelizumab inhibits PD-1 in non-clinical models and showed typical non-clinical pharmacokinetic (PK) and safety profiles for an IgG4 monoclonal antibody. We report results from the First-in-Human Phase 1 trial of camrelizumab in Australian population.

International audience; Simple Summary There have been huge improvements in both vaccination and the management of COVID-19 in patients with cancer. In addition, different variants may be associated with different presentations. Therefore, we examined whether indicators of the severity of COVID-19 in patients with cancer who present to hospital varied during different waves of the pandemic and we showed that these indicators remained predictive. We validated that the COVID-19 Risk in Oncology Evaluation Tool (CORONET), which predicts the severity of COVID-19 in cancer patients presenting to hospital, performed well in all waves. In addition, we examined patient outcomes and the factors that influence them and found that there was increased vaccination uptake and steroid use for patients requiring oxygen in later waves, which may be associated with improvements in outcome. Patients with cancer have been shown to have increased risk of COVID-19 severity. We previously built and validated the COVID-19 Risk in Oncology Evaluation Tool (CORONET) to predict the likely severity of COVID-19 in patients with active cancer who present to hospital. We assessed the differences in presentation and outcomes of patients with cancer and COVID-19, depending on the wave of the pandemic. We examined differences in features at presentation and outcomes in patients worldwide, depending on the waves of the pandemic: wave 1 D614G (n = 1430), wave 2 Alpha (n = 475), and wave 4 Omicron variant (n = 63, UK and Spain only). The performance of CORONET was evaluated on 258, 48, and 54 patients for each wave, respectively. We found that mortality rates were reduced in subsequent waves. The majority of patients were vaccinated in wave 4, and 94% were treated with steroids if they required oxygen. The stages of cancer and the median ages of patients significantly differed, but features associated with worse COVID-19 outcomes remained predictive and did not differ between waves. The CORONET tool performed well in all waves, with scores in an area under the curve (AUC) of >0.72. We concluded that patients with cancer who present to hospital with COVID-19 have similar features of severity, which remain discriminatory despite differences in variants and vaccination status. Survival improved following the first wave of the pandemic, which may be associated with vaccination and the increased steroid use in those patients requiring oxygen. The CORONET model demonstrated good performance, independent of the SARS-CoV-2 variants.

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.

An innovative program, 'Paramedics Providing Palliative Care at Home,' was implemented in Nova Scotia, Canada in 2015. Roles like this are part of an evolving professional identity; role discordance or lack of clarity not only hinders professionalization but may impair the wellbeing, and career longevity of paramedics. This study explored the alignment of providing palliative support at home with paramedic professional identity.Qualitative description was employed, with thematic analysis of focus groups with paramedics and palliative health care providers. Recruitment posters were sent through the professional college (paramedics) and program managers (health care providers). Focus groups followed a semi-structured guide, discussing understanding of and experiences with the role and its alignment with professional identity. Challenges to paramedic palliative support and fit with professional identify were explored. Thematic content analysis was ongoing while focus groups were being conducted, until no new codes were found. Codes were combined, sorted into categories, and ultimately, agreed-upon themes. Saturation of themes was reached.Eleven paramedics and twenty palliative health care providers participated. Four themes reflected paramedic's expanded role: (1) patient centeredness and job satisfaction with provision of palliative support, (2) a bridging role, (3) paramedic as advocate and educator, (4) provision of psychosocial support. Four themes reflected paramedic's professional identity: (1) evolution of paramedicine as a skilled clinical profession, (2) helping people and communities, (3) paramedic skill set aligns with work in palliative care, and (4) changing paramedic mindset.Paramedics and palliative health care providers highlighted the provision of palliative care as part of a positive growth of paramedicine as a health profession, and a good fit with professional identity. Novel roles like this are important in the evolution of our health care system faced with increasing pressures to get the right care with the right provider at the right time.RéSUMé: CONTEXTE: Un programme innovant, " Programme de soins palliatifs paramédicaux à domicile ", a été mis en œuvre en Nouvelle-Écosse, au Canada, en 2015. Les rôles de ce type font partie d'une identité professionnelle en évolution ; la discordance ou le manque de clarté des rôles non seulement entrave la professionnalisation, mais peut aussi nuire au bien-être et à la longévité de la carrière des ambulanciers paramédicaux. Cette étude a exploré l'alignement de la prestation de soutien palliatifs à domicile avec l’identité professionnelle des ambulanciers paramédicaux. MéTHODES: Une description qualitative a été employée, avec une analyse thématique de groupes de discussion avec des ambulanciers paramédicaux et des prestataires de soins palliatifs. Des affiches de recrutement ont été envoyées par le biais du collège professionnel (paramédicaux) et des gestionnaires de programmes (prestataires de soins de santé). Les groupes de discussion ont suivi un guide semi-structuré, discutant de la compréhension et des expériences du rôle et de son alignement avec l'identité professionnelle. Les défis du soutien palliatif paramédical et son adéquation avec l'identité professionnelle ont été explorés. L'analyse du contenu thématique s'est poursuivie pendant la tenue des groupes de discussion, jusqu'à ce qu'aucun nouveau code ne soit trouvé. Les codes ont été combinés, triés en catégories et, finalement, en thèmes convenus. La saturation des thèmes a été atteinte. RéSULTATS: Onze ambulanciers paramédicaux et vingt prestataires de soins palliatifs ont participé. Quatre thèmes reflétaient le rôle élargi des ambulanciers paramédicaux : 1) l’orientation vers le patient et la satisfaction professionnelle à l’égard de la prestation de soutien palliatifs, 2) un rôle de transition, 3) les ambulanciers paramédicaux à titre de défenseurs et d’éducateurs, 4) un soutien psychosocial. Quatre thèmes reflétaient l’identité professionnelle des ambulanciers paramédicaux : 1) l’évolution de la profession paramédicale en tant que profession clinique qualifiée, 2) l’aide aux personnes et aux collectivités, 3) l’ensemble des compétences des ambulanciers paramédicaux s’harmonise avec le travail en soins palliatifs, et 4) l’évolution de l’état d’esprit des ambulanciers paramédicaux. CONCLUSION: Les ambulanciers paramédicaux et les prestataires de soins palliatifs ont souligné que la prestation de soins palliatifs faisait partie d’une croissance positive de la profession paramédicale en tant que profession de la santé et correspondait bien à l’identité professionnelle. Des rôles novateurs comme celui-ci sont importants dans l'évolution de notre système de soins de santé, confronté à des pressions croissantes pour obtenir les bons soins auprès du bon prestataire au bon moment.

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;PP2=0.46; patient-reported R2=0.49;P2=0.41; patient-reported R2=0.30;P2=0.46;P2=0.56;PConclusions: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.

Background Non–clear-cell renal cell carcinoma (nccRCC) and renal cell carcinoma with sarcomatoid features (scRCC) are rare, and represent subtypes with less defined treatment strategies. The aim of this study is to describe the patterns of care and outcomes of these patients in 2 tertiary referral centers in South Western Sydney Local Health District over a 10-year period. Patients and Methods Patients with RCC seen at South Western Sydney Local Health District from January 1, 2005 to December 31, 2015 were identified from electronic medical records. For each patient, we extracted details regarding demographics, tumor characteristics, treatment, recurrences, and survival, which was analyzed using the Kaplan-Meier method. Results Of 178 patients with RCC identified between 2005 and 2015, 23% (n = 41) had nccRCC and 8% (n = 15) had scRCC. Twenty-five patients in total had de novo metastatic disease or disease recurrence. The median follow-up was 46 and 16 months for nccRCC and scRCC, respectively. The median overall survival for nccRCC with metastatic disease was 34 months (range, 14 months to not reached). Seventy percent of these patients received systemic therapy. By contrast, the median overall survival for scRCC with metastatic disease was 10 months (range, 1.6-89 months). Less than one-half of the patients with scRCC received systemic therapy in our cohort, with only 34% receiving no more than 1 line of treatment. Conclusions Our data confirm the rapid and aggressive course of scRCC, highlighting the need for more effective therapeutic strategies in this rare patient population.

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 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.

Background Cancer patients are at increased risk of death from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer and its treatment affect many haematological and biochemical parameters, therefore we analysed these prior to and during coronavirus disease 2019 (COVID-19) and correlated them with outcome. Patients and methods Consecutive patients with cancer testing positive for SARS-CoV-2 in centres throughout the United Kingdom were identified and entered into a database following local governance approval. Clinical and longitudinal laboratory data were extracted from patient records. Data were analysed using Mann–Whitney U test, Fisher's exact test, Wilcoxon signed rank test, logistic regression, or linear regression for outcomes. Hierarchical clustering of heatmaps was performed using Ward's method. Results In total, 302 patients were included in three cohorts: Manchester (n = 67), Liverpool (n = 62), and UK (n = 173). In the entire cohort (N = 302), median age was 69 (range 19-93 years), including 163 males and 139 females; of these, 216 were diagnosed with a solid tumour and 86 with a haematological cancer. Preinfection lymphopaenia, neutropaenia and lactate dehydrogenase (LDH) were not associated with oxygen requirement (O2) or death. Lymphocyte count (P < 0.001), platelet count (P = 0.03), LDH (P < 0.0001) and albumin (P < 0.0001) significantly changed from preinfection to during infection. High rather than low neutrophils at day 0 (P = 0.007), higher maximal neutrophils during COVID-19 (P = 0.026) and higher neutrophil-to-lymphocyte ratio (NLR; P = 0.01) were associated with death. In multivariable analysis, age (P = 0.002), haematological cancer (P = 0.034), C-reactive protein (P = 0.004), NLR (P = 0.036) and albumin (P = 0.02) at day 0 were significant predictors of death. In the Manchester/Liverpool cohort 30 patients have restarted therapy following COVID-19, with no additional complications requiring readmission. Conclusion Preinfection biochemical/haematological parameters were not associated with worse outcome in cancer patients. Restarting treatment following COVID-19 was not associated with additional complications. Neutropaenia due to cancer/treatment is not associated with COVID-19 mortality. Cancer therapy, particularly in patients with solid tumours, need not be delayed or omitted due to concerns that treatment itself increases COVID-19 severity., Highlights • Pre-infection haematological/biochemical characteristics are not associated with COVID-19 severity. • Significant haematological/biochemical changes occur upon infection with heterogeneity in response observed. • High not low neutrophils were associated with oxygen requirement and COVID-19 mortality – GCSF should be used with caution. Age, haematological cancer, high neutrophil:lymphocyte ratio, CRP and low albumin were significant predictors of death in multivariable analysis. No significant complications requiring readmission were seen upon restart of cancer therapy following diagnosis of COVID-19.

Background: Patients with cancer are at increased risk of severe COVID-19, but have heterogeneous presentations and outcomes. Decision-making tools for hospital admission, severity prediction and increased monitoring for early intervention are critical. We sought to identify features of COVID-19 in cancer patients predicting severe disease and build a decision-support online tool; COVID-19 Risk in Oncology Evaluation Tool (CORONET). Methods: Patients with active cancer (stage I-IV) and laboratory confirmed COVID-19 presenting to hospitals worldwide were included. Discharge (within 24hrs), admission (≥24hrs inpatient), oxygen requirement (O2) and death were combined in a 0-3 point severity scale. Association of features with outcome were investigated using Lasso regression and Random Forest (RF) combined with SHapley Additive exPlanations (SHAP). RF was further validated in 4 cohorts, split by geography. The CORONET model was then examined in the entire cohort to build an online CORONET decision-support tool. Admission and severe disease thresholds were established through pragmatically defined cost functions. Findings: The dataset comprised 920 patients; median age 70 (range 5-99), 56% males, 44% females, 81% solid vs. 19% haematological cancers. In derivation, RF demonstrated superior performance over Lasso with lower mean squared error (0.801 vs. 0.807) and was selected for development. During validation, RF achieved mean AUROC 0.77, 0.80 and 0.75 for prediction of admission, O 2 and death, respectively. Using the entire cohort, CORONET cut-offs for admission and mortality of 1.0 and 2.3 were established. The CORONET decision support tool recommended admission for 95% of patients eventually requiring oxygen and 97% of those who died. SHAP explanations revealed National-Early-Warning-Score-2, C-reactive protein and albumin were the most important features contributing to COVID-19 severity prediction in patients with cancer at time of hospital presentation. Interpretation: CORONET, a decision-support tool validated in healthcare systems worldwide can aid admission decisions and predict COVID-19 severity in patients with cancer. Funding Information: R. Lee and T. Robinson and J. Weaver are supported by the National Institute for Health Research as Clinical Lecturers. T. Bhogal is supported by the National Institute for Health Research as an academic clinical fellow. U. Khan is an MRC Clinical Training Fellow based at the University of Liverpool supported by the North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the Medical Research Council (Award Ref. MR/N025989/1). The Liverpool Experimental Cancer Medicine Centre for providing infrastructure support (Grant Reference: C18616/A25153) and The Clatterbridge Cancer charity (North West Cancer Research). C. Dive is funded by CRUK Core funding to Manchester Institute (C5757/A27412) and is supported by the CRUK Manchester Centre Award (C5759/A25254), and by the NIHR Manchester Biomedical Research Centre. C. Zhou is funded by the CRUK Manchester Centre Award (C5759/A25254), J. Stevenson and P. Fitzpatrick are funded by the CRUK Accelerator Award (29374). This research was funded in part, by the Wellcome Trust [205228/Z/16/Z]. LT is also supported by the National Institute for Health Research Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections (NIHR200907) at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. LT is based at University of Liverpool. MS is supported by a grant from the Ministry of Science and Higher Education of the Russian Federation for the state support for the creation and development of World Class Research Centers "Digital biodesign and personalized healthcare” N.075-15-2020-926. Declaration of Interests: R Lee research funding (institution) BMS and speaker fees Astrazeneca. A. Croitoru Consulting or Advisory Role: Lilly, Merck, Roche, Bayer, Novartis, Ipsen, Research Funding me and my hospital: Gilead Sciences, Pfizer, Canfite, NanoCarrier, Bristol-Myers Squibb, Merck, Amgen, Servier, Five Prime Therapeutics, Travel Accommodations: Pfizer, Genekor, and oz, Merck, Pfizer, Servier, Roche. O. Michielin reports personal fees from Bristol-Myers Squibb, personal fees from MSD, personal fees from Novartis, personal fees from Roche, personal fees from Amgen, personal fees from NeraCare GmbH, outside the submitted work. E. Romano institutional research grants from Amgen, Astra Zeneca, Bristol-Myers Squibb. G. Pentheroudakis advisory board for Amgen, Astra Zeneca, Bristol-Myers Squibb, Lilly, Merck, MSD, Roche, Abbvie, institutional research grants from Amgen, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Debbio, Enorasis, Genekor, Ipsen, Janssen, Lilly, Merck, MSD, Pfizer, Roche, Sanofi, Servier. Solange Peters reports consultation/advisory role: AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Bio Invent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Elsevier, F. Hoffmann-La Roche/Genentech, Foundation Medicine, Illumina, Incyte, IQVIA, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Pharma Mar, Phosplatin Therapeutics, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Vaccibody, talk in a company’s organized public event: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, e-cancer, Eli Lilly, F. Hoffmann-La Roche/Genentech, Illumina, Medscape, Merck Sharp and Dohme, Novartis, PER, Pfizer, Prime, RTP, Sanofi, Takeda, receipt of grants/research supports: (Sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche/Genentech, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics. M Rowe honoraria from Astellas Pharma, speaker fees MSD and Servier. C. Wilson consultancy and speaker fees Pfizer, Amgen, Novartis, A Armstrong conference fee Merck, spouse shares in Astrazeneca. T Robinson financial support to attend educational workshops from Amgen and Daiichi-Sankyo. C Dive, outside of this scope of work, has received research funding from AstraZeneca, Astex Pharmaceuticals, Bioven, Amgen, Carrick Therapeutics, Merck AG, Taiho Oncology, Clearbridge Biomedics, Angle PLC, Menarini Diagnostics, GSK, Bayer, Boehringer Ingelheim, Roche, BMS, Novartis, Celgene, Thermofisher. C Dive is on advisory boards for, and has received consultancy fees/honoraria from, AstraZeneca, Biocartis and Merck KGaA. No other authors have nothing to declare. Ethics Approval Statement: Approval (reference 20/WA/0269) was granted from the UK Research Ethics Committee for the study. Information regarding governance/regulatory approvals for each international cohort are available in the Supp. Methods.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of neurotoxic cancer treatment, often impacting treatment tolerability and patient functioning. Factors predicting an individual's vulnerability for developing CIPN remain ill-defined. However, patient characteristics may contribute to CIPN risk, with obesity being a prevalent patient comorbidity. This study was aimed at evaluate if being overweight (BMI ≥ 25 kg/mThree hundred seventy-nine cancer survivors were assessed 5 (IQR 3-5) months post oxaliplatin or paclitaxel treatment via comprehensive patient-reported, clinical, and functional CIPN measures. Patients classified as overweight (BMI ≥ 25 kg/mMost patients reported CIPN symptoms (78%), with deficits evident on clinical examination. Overweight patients (n = 242, 63.8%) had significantly worse CIPN across symptomatic, objective clinical, and functional outcomes compared to those with a normal BMI (p.05). In multivariate linear regression, older age (B = .088, 95%CI = .053-.122, p.001), larger waist circumference (B = .030, 95%CI = .001-.059, p.05), and larger BSA (B = 2.41, 95%CI = .34-04.48, p.05) were associated with CIPN. Diabetes and BMI were significant on univariate analysis but not in the final models.Overweight patients represent a large proportion of cancer survivors who may be particularly impacted by CIPN, requiring closer monitoring and referral to supportive services. Accessible data such as a patient's general and abdominal obesity status may aid in formulating personalized treatment.Identifying routinely measured patient characteristics which may contribute to an individual's CIPN risk profile could assist with informing treatment decisions.

BackgroundCancer patients are at increased risk of severe COVID-19. As COVID-19 presentation and outcomes are heterogeneous in cancer patients, decision-making tools for hospital admission, severity prediction and increased monitoring for early intervention are critical.ObjectiveTo identify features of COVID-19 in cancer patients predicting severe disease and build a decision-support online tool; COVID-19 Risk in Oncology Evaluation Tool (CORONET)MethodData was obtained for consecutive patients with active cancer with laboratory confirmed COVID-19 presenting in 12 hospitals throughout the United Kingdom (UK). Univariable logistic regression was performed on pre-specified features to assess their association with admission (≥24 hours inpatient), oxygen requirement and death. Multivariable logistic regression and random forest models (RFM) were compared with patients randomly split into training and validation sets. Cost function determined cut-offs were defined for admission/death using RFM. Performance was assessed by sensitivity, specificity and Brier scores (BS). The CORONET model was then assessed in the entire cohort to build the online CORONET tool.ResultsTraining and validation sets comprised 234 and 66 patients respectively with median age 69 (range 19-93), 54% males, 46% females, 71% vs 29% had solid and haematological cancers. The RFM, selected for further development, demonstrated superior performance over logistic regression with AUROC predicting admission (0.85 vs. 0.78) and death (0.76 vs. 0.72). C-reactive protein was the most important feature predicting COVID-19 severity. CORONET cut-offs for admission and mortality of 1.05 and 1.8 were established. In the training set, admission prediction sensitivity and specificity were 94.5% and 44.3% with BS 0.118; mortality sensitivity and specificity were 78.5% and 57.2% with BS 0.364. In the validation set, admission sensitivity and specificity were 90.7% and 42.9% with BS 0.148; mortality sensitivity and specificity were 92.3% and 45.8% with BS 0.442. In the entire cohort, the CORONET decision support tool recommended admission of 99% of patients requiring oxygen and of 99% of patients who died.Conclusions and RelevanceCORONET, a decision support tool validated in hospitals throughout the UK showed promise in aiding decisions regarding admission and predicting COVID-19 severity in patients with cancer presenting to hospital. Future work will validate and refine the tool in further datasets.

Background The primary aim of this study was to evaluate the activity of intraperitoneal bevacizumab (IP-bev) in delaying re-accumulation of malignant ascites in women with chemotherapy-resistant epithelial ovarian cancer (CR-EOC) who have ceased chemotherapy. Secondary outcomes were safety and quality of life. Methods Women with CR-EOC and malignant ascites that reaccumulated within 28 days of their last paracentesis (P-1) were administered IP-bev 5 mg/kg following their first therapeutic paracentesis on study (P0). Additional doses of IP-bev were allowed at each subsequent paracentesis (P1, P2, etc) provided the interval from the last dose was 42 days or greater (median time from first to second therapeutic ascitic drainage). Results 24 participants (median age 67 years [range 38–86]; median 4.5 lines prior systemic treatment [range 1–12]; ECOG performance status of 0 in 1, 1 in 8, and 2–3 in 15) were recruited. The doses of IP-bev administered were 1 in 13 participants, 2 in 5, 3 in 2, 4 in 1, and 5 in 1. The proportion with a TTP of >42 days using competing risk analysis was 77% (95% CI 58–92). Median time from P0 to P1 or death was 48 days (range 8–248). Median paracentesis-free interval (P0–P1 or death) was 4.29-fold (95% CI 2.4–5.8) higher following a first dose of IP-bev compared with the time between paracenteses prior to study entry (P-1–P0). Conclusion IP-bev was safe, active, and warrants further study as a palliative intervention for recurrent ascites in CR-EOC patients receiving best supportive care.

Instructional designers are in a unique position to provide leadership and support for advancement of new technologies and practices. There is a paucity of research on current and potential roles of Instructional designers in incorporating and advocating for open educational practices at their higher education institutions. Against the background of emerging open educational practices, a survey and interviews were conducted with instructional design professionals to establish, from their experience and practice, their roles and potential for advocacy for open educational practices (OEP) including open educational resources (OER). Among the results of the analysis, it was found that while instructional designers have a strong awareness of and desire to advocate for OEP in their institutions, their ability to move forward was limited by perceived barriers such as lack of relevant mandates and professional workload recognition, policy development and funding, awareness and leadership support. In addition, there were gaps identified between what they most valued about OEP, such as implementing innovative pedagogies, and what they could actually initiate and advocate for in practice (adopt and support OER). They pointed to a lack of formal learning opportunities around OEP and expressed that their main sources of learning and support were of an informal nature, acquired through their networks and collaborations with peers.

Aboriginal and Torres Strait Islander (Indigenous) health professionals working in the alcohol and other drugs field perform a complex role in tackling substance misuse and related harms. Professional training and development opportunities for these “frontline” Indigenous alcohol and other drugs staff is key to prevent burnout and to allow them to work to their full potential. However, there are many barriers for those seeking to improve their skills. A number of teaching approaches have been described as important, but we were unable to identify peer-reviewed publications that detail the optimal approach to tailor university learning to meet the needs of Indigenous alcohol and other drugs health professionals. This article reflects on the experience of providing one such programme: a graduate diploma in Indigenous health and substance use, designed and delivered specifically for Aboriginal and Torres Strait Islander mature-aged students.

PURPOSE Rare cancers are challenging for researchers, as clinicians and scientists have difficulty recruiting sufficient patient cases to power studies appropriately. Likewise, patients often are frustrated by a lack of specific information or evidence base for their cancer and, although eager to participate in research, have limited opportunities. We established CART-WHEEL.org, an online patient-entered database, to directly engage patients in the research process, collect rare cancer data, and facilitate their entry into additional research. PATIENTS AND METHODS Patients access CART-WHEEL.org directly online. Clinical information is collected from users via a streamlined questionnaire developed collaboratively with consumer groups to ensure accessibility and relevance. Data collected include the following: patient demographics, comorbidities, and risk factors and tumor diagnostic, biomarker, and treatment history. Patients can download a medical summary for personal use; consent for research use of data; and indicate willingness to be contacted about other research or clinical trials. We describe data collected to date and its validation, and we provide examples of how CART-WHEEL.org can facilitate rare cancer research. RESULTS From January 2010 to March 2018, 558 patients provided consent and entered their rare cancer data. One hundred distinct rare tumor types and patients from 22 countries were included. Validation of data entered by 21 patients with sarcoma against a hospital database demonstrated accuracy sufficient to facilitate future research in key fields, such as tumor site (95%) and histopathologic diagnosis (90%). Examples of CART-WHEEL–based disease-specific projects, subsequent recruitment to other rare cancer projects, and rare cancer patient cases of interest are described. CONCLUSIONS Online platforms like CART-WHEEL.org can engage consumers directly, facilitating collection of patient-entered rare cancer data for hypothesis generation, and connect patients with researchers to enable specific rare cancer research and clinical trials.

Purpose Camrelizumab inhibits PD-1 in non-clinical models and showed typical non-clinical pharmacokinetic (PK) and safety profiles for an IgG4 monoclonal antibody. We report results from the First-in-Human Phase 1 trial of camrelizumab in Australian population. Methods Camrelizumab was administered to patients with advanced solid tumors who had failed standard therapies. In the dose-escalation phase (n=23), camrelizumab was administered intravenously at 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg every 2 weeks. In dose expansion (n=26), camrelizumab was given at 200 mg or 600 mg every 4 weeks. Results Two dose-limiting toxicities were observed during dose escalation: transaminase elevation and diarrhea (both grade 3). Overall, treatment-related adverse events were consistent with the expected toxicity profile of immune checkpoint inhibition, with the striking exception of the dose-related development of angiomatous skin lesions characterized as reactive cutaneous capillary endothelial proliferation. The PK profile showed a dose-progressive increase in half-life from 3 days at 1 mg/kg to 7 days at 10 mg/kg. Moreover, receptor occupancy assays showed a PD-1 occupancy of >50% in most patients out to 28 days post-dose. The objective response rate was 15.2% (95% CI 6.3–28.9). Conclusion Camrelizumab has manageable toxicity and encouraging preliminary antitumor activity in advanced solid tumors in Australia. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT02492789.

Aim To evaluate the suitability of a deep-learning (DL) algorithm for identifying normality as a rule-out test for fully automated diagnosis in frontal adult chest radiographs (CXR) in an active clinical pathway. Materials and methods This multicentre study included 3,887 CXRs from four distinct NHS institutions. A convolutional neural network (CNN) was developed and trained prior to this study and was used to classify a subset of examinations with the lowest abnormality scores as high confidence normal (HCN). For each radiograph, the ground truth (GT) was established using two independent reviewers and an arbitrator in case of discrepancy. Results The DL algorithm was able to classify 15% of all examinations as HCN, with a corresponding precision of 97.7%. There were 0.33% of examinations classified incorrectly as HCN, with 84.6% of these examinations identified as borderline cases by the radiologist GT process. Conclusion A DL algorithm can achieve a high level of precision as a fully automated diagnostic tool for reporting a subset of CXRs as normal. The removal of 15% of all CXRs has the potential to significantly reduce workload and focus radiology resources on more complex examinations. To optimise performance, site-specific deployment of algorithms should occur with robust feedback mechanisms for incorrect classifications.

4565 Background: Immunotherapy targeting PD1 is active across many cancers, but many people are failed by PD1 inhibition alone. UNISON (ANZUP 1602/NCT03177239) has previously reported the activity and outcomes of nivolumab monotherapy in people with nccRCC (OTRR 17%, PFS6 45%; part 1), and here we report the outcomes of combining ipilimumab (I) and nivolumab (N), in people whose cancers are refractory to N alone (part 2). Methods: Participants (pts) with advanced nccRCC with good performance status (ECOG 0/1), were initially enrolled and took N alone. 41 pts refractory to N were offered the combination I (1mg/kg) + N (3mg/kg) every 3 weeks for up to 4 doses. Pts with disease control after N, or N + I could continue N for up to 1 year. UNISON was powered to distinguish a clinically relevant improvement in objective tumour response rate (OTRR) from 15% to 30% in people taking I+N in part 2. Results: 85 pts were enrolled and received N. 41 pts were refractory to N, were well enough to take I+N, and had a representative spectrum of nccRCC histologies (n=41; papillary 44%, chromophobe 20%, Xp11 translocation 12%, RCC unclassified 7%, other 17%). The median time on treatment was 2.1 months, the median number of doses was 3; median follow up at the time of reporting was 20.3 months. The OTRR of I+N in pts refractory to N was 10% with 1 complete and 3 partial responses. Stable disease was experienced by 36% of pts and disease progression by 52%. The disease control rate at 6 months was 45% (95% CI: 34%, 56%). The median PFS was 2.6 months (95% CI: 2.2, 3.8). The 6 month progression-free survival (PFS) was 25% (95% CI: 13-39). Only 14% of patients were free of progression at 12 months. The safety of I+N appeared similar to previous reports. 68% of pts experienced serious adverse events, 34% treatment related SAE. One pt died from refractory pneumonitis. 11 pts (27%) experienced treatment delays or permanent treatment discontinuation. Conclusions: The primary endpoint of the study was not met. A minority of pts with nccRCC refractory to nivolumab derive benefit from combination I+N but many pts remain refractory to immunotherapy. No new safety issues were identified. More effective therapeutic options are needed for people with rare variant renal cell carcinoma. Clinical trial information: NCT03177239.