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Background There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy. Trial design A Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority trial assessing treatment breaks in patients with renal cell carcinoma. Methods Participants Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals. Interventions At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death. Objective To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years. Co-primary outcomes For non-inferiority to be concluded, a margin of ≤ 7.5% in overall survival and ≤ 10% in quality-adjusted life-years was required in both intention-to-treat and per-protocol analyses. This equated to the 95% confidence interval of the estimates being above 0.812 and −0.156, respectively. Quality-adjusted life-years were calculated using the utility index of the EuroQol-5 Dimensions questionnaire. Results Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat −0.05 (−0.15 to 0.05); per-protocol 0.04 (−0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ −0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years. Limitations The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison. Future work Future studies should investigate treatment breaks with more contemporary treatments for renal cell carcinoma. Conclusions Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians’ perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible. Trial registration This trial is registered as ISRCTN06473203. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information. Plain language summary Treatment breaks in cancer are of significant interest to patients and health professionals. Renal cell carcinoma is the most common type of kidney cancer. Sunitinib and pazopanib are both targeted treatments. They were commonly used to treat advanced kidney cancer but often cause side effects, sometimes requiring use of a reduced dose or even stopping treatment. The STAR trial was designed to see whether planned treatment breaks made patients with advanced kidney cancer being treated with sunitinib and pazopanib feel better, without substantially affecting how well the treatment worked. After 24 weeks of treatment, patients took sunitinib and pazopanib either as they normally would or in the alternative way with planned treatment breaks. Treating patients in this way was continued until drug-related side effects stopped treatment, patients’ disease worsened while taking treatment or the patient died. The trial compared how well the different treatment strategies worked in terms of how long patients lived and their quality of life over that time. This trial is the largest United Kingdom trial in advanced renal cell carcinoma. Patients took part from 60 United Kingdom centres between 2012 and 2017. It was funded by the National Institute for Health and Care Research Health Technology Assessment Programme and run by the Leeds Clinical Trials Research Unit. In total, 920 patients took part. Four hundred and sixty-one patients were allocated to continue treatment and 459 were allocated to start at least one treatment break. Treatment breaks lasted on average 87 days. The length of time patients lived in both arms of the trial appeared similar, but this cannot be concluded due to insufficient information. Being allocated to have treatment breaks rather than continuing treatment did not negatively impact a patient’s quality of life. Additionally, allocating patients to have treatment breaks was shown to have significant cost savings compared to just continuing treatment. Importantly planned treatment breaks were shown to be feasible. Scientific summary Background There is increasing interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy. STAR was designed to determine if a tyrosine kinase inhibitor (TKI) drug-free interval strategy (DFIS) was non-inferior to a conventional continuation strategy (CCS) in the first-line treatment of advanced renal cell carcinoma (RCC). Objectives The overall primary objective was to determine whether a sunitinib or pazopanib DFIS is non-inferior in terms of overall survival (OS) and quality-adjusted life-year (QALY) compared to a sunitinib or pazopanib CCS in patients with locally advanced and/or metastatic clear cell RCC. Secondary objectives included comparing a DFIS to a CCS in terms of summative progression-free interval, time to strategy failure, time to treatment failure, toxicity (common terminology criteria for adverse events v.4.0), quality of life (QoL) [Functional Assessment of Cancer Therapy – Kidney Symptom Index (FKSI-15), Functional Assessment of Cancer Therapy-G (FACT-G), EuroQol-5 Dimensions (EQ-5DTM) and EQ-Visual Analogue Scale (VASTM)], cost effectiveness, progression-free survival (PFS). Three ancillary studies were also included in the trial. The Patient Preference and Understanding Study was designed to understand the participants’ experiences of taking part in the trial. The dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) substudy was designed to investigate whether early DCE-MRI could predict progressive disease (PD) at 24 weeks. The computerised tomography (CT) substudy was designed to determine CT as a potential biomarker and predictor of PD at 24 weeks. Methods STAR was a UK Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority (NI) trial. The trial recruited adults, with histologically confirmed locally advanced or metastatic clear cell, uni-dimensionally measurable, RCC who required but had not received prior systemic therapy. Participants were required to have an Eastern Cooperative Oncology Group performance status of 0–1, meet pre-specified blood parameters prior to randomisation, provide written informed consent, be able and willing to comply with the terms of the protocol and follow approved pregnancy prevention guidelines. Exclusion criteria included pulmonary or mediastinal disease, life expectancy < 6 months, previous treatment with or known contraindications or hypersensitivity to TKIs, untreated brain metastases, concurrent or previous invasive cancers which could confuse diagnosis or end points, use of contraindicated concomitant medication or substances and poorly controlled hypertension. At trial entry, participants were randomised (1 : 1) centrally by Leeds CTRU to a CCS or a DFIS. Randomisation was stratified by Motzer prognostic group (favourable, intermediate, poor), trial site, gender, age (< 60, ≥ 60 years), disease status (metastatic, locally advanced), previous nephrectomy (yes, no), TKI (sunitinib, pazopanib). Both strategies received an initial 4 cycles of trial treatment [sunitinib: 1 cycle of treatment refers to 50 mg (starting dose) on days 1–28, repeated every 42 days; pazopanib: 1 cycle of treatment refers to 800 mg (starting dose) on days 1–42, repeated every 42 days] following which participants in the DFIS arm took up their first treatment break. Following disease progression on a treatment break, DFIS participants restarted their treatment. Additional breaks were permitted following a further 4 cycles of treatment at the treating clinician’s discretion. The trial strategy continued until death, progression while receiving treatment, unacceptable toxicity (clinical withdrawal) or participant withdrawal. Following cessation of the trial strategy, participants were followed up after 6 months and then annually thereafter until death, patient withdrawal or the end of the trial. All trial data were collected on trial-specific case report forms (CRFs). All CRFs, apart from the questionnaires for the patient-reported outcome measures (FSKI-15, FACT-G, EQ-5D and EQ-VAS) were completed by research staff at the site. Overall survival was defined as time from randomisation to death from any cause. For NI to be concluded, a margin of ≤ 7.5% in OS was pre-specified. The survival at 2 years in the CCS arm was assumed to be 48.5%. A 7.5% NI margin led to the survival at 2 years in the DFIS arm assumed to be at least 41%, leading to a hazard ratio (HR) of 0.812. This along with a one-sided 2.5% significance level, 5% dropout rate and 80% power required 920 participants. Where 80% power would be attained when 720 events were observed. Quality-adjusted life-years were defined as the time spent in each health state over trial and follow-up, calculated as the utility index of the EQ-5D questionnaire, which was collected frequently (6-weekly for 24 weeks, 2-weekly for 24 weeks, 6-weekly while on study, 6 months post end of trial strategy and annually thereafter). For NI to be concluded a margin of ≤ 10% in mean QALYs was pre-specified. The power for the QALY comparison was derived using simulations. Under the assumptions of a 0.9 HR in favour of CCS, a sample size of 920, 5.83 years of recruitment and 3.25 years of follow-up a CCS QALY estimate of 1.56 was derived along with a power of 69.94%. The CCS QALY estimate of 1.56 in conjunction with the 10% margin equates to a NI boundary of −0.156 for the difference in mean QALYs. It was pre-specified that NI was required in both intention-to-treat (ITT) and per-protocol (PP) analyses, in both end points, to be concluded overall. An in-depth qualitative inductive study of 11 patients on the DFIS arm was conducted to better understand their acceptability of extended treatment breaks. A thematic analysis using a comparative and contrastive approach was employed. An economic evaluation was also conducted which estimated the cost effectiveness of DFIS versus CCS at 2 years (within-trial analysis) and over the patients’ lifetime (decision modelling analysis). Results Participant flow Two thousand one hundred and ninety-seven patients were screened; of these, 920 were randomised (CCS: 461, DFIS: 459). In total, 878 (95.4%) participants ceased trial treatment prior to the end of follow-up. Radiological disease progression was the most frequent reason for treatment discontinuation at 43.7% (CCS: 48.4%, DFIS: 39.0%). Overall, 13,147 (78.6%, n = 16,726) (CCS: 5764/7401, 77.9%; DFIS: 7383/9327, 79.2%) of QoL questionnaire booklets were returned on the trial. The proportions of reasons for missing booklets were similar between the two arms, where the highest reason was ‘missed by site in error’ (overall: 27%, CCS: 28.4%, DFIS: 25.8%). However, the majority of reasons for missing were missing (overall: 52.1%, CCS: 50.6%, DFIS: 53.4%). Overall, 63 participants (6.8%, n = 920) withdrew from some aspect of the trial. This resulted in 21 (2.82%, n = 920) participants being formally lost to follow-up (CCS: 11, 2.4%; DFIS: 10, 2.2%). An additional DFIS participant was lost to follow-up due to the participant moving away. However, all participants were included in the analysis. Numbers analysed Nine hundred and nineteen participants (CCS: 461, DFIS: 458) were included in the ITT population as one DFIS participant did not have RCC. Similarly, 871 participants (CCS: 453, DFIS: 418) were included in the PP population, 916 participants (CCS: 485, DFIS: 431) were included in the safety population, 869 participants (CCS: 438, DFIS: 431) were included in the EuroQol-5 Dimensions, three-level version (EQ-5D-3L) population, 856 participants (CCS: 425, DFIS: 431) were included in the FACT-G population and 882 participants (CCS: 436, DFIS: 446) were included in the FKSI population. Baseline characteristics and treatment (on trial and in follow-up) Key demographic and disease-related characteristics were similar across both randomisation allocation and randomised under TKI for all analysis populations. STAR participants were predominantly white (ITT – 96.3%), male (ITT – 72.7%) and aged ≥ 60 at randomisation (ITT – 73.4%). On average, participants in both arms received a similar number of treatment cycles [ITT median (interquartile range, IQR): 5 (2, 10) vs. 4 (2, 9)]. Overall, 248 participants (56.3%, n = 459) in the DFIS arm continued on the trial after week 24. The majority of these (127, 51.2%) only started one treatment break. Thirty-eight (15.3%) of these had 2 treatment breaks and 68 (27.4%) took 3 or more treatment breaks. The maximum number of treatment breaks taken by 1 participant was 9, and 15 participants (6%) did not take up a treatment break despite continuing on study after week 24. Overall, 61.6% of participants received further systemic anticancer therapy treatment during follow-up, with a higher proportion in the CCS arm (68.5%, n = 461) compared to the DFIS arm (54.6%, n = 458). Co-primary end points Median (IQR) follow-up for OS in the PP population was 58 months (46, 72). In total 648 (74.4%, n = 871) of PP participants died prior to the end of follow-up (31 December 2020) [CCS: 330 (72.8%, n = 453), DFIS: 318 (76.1%, n = 418)]. Renal cancer was related to the cause of 607 (93.7%, n = 648) deaths [CCS: 314 (95.2%, n = 330), DFIS: 293 (92.1%, n = 318)]. Median OS [95% confidence interval (CI)] in the CCS arm was 28 months (24, 32) and 27 months (23, 31) in the DFIS arm. At 2 years post randomisation (95% CI), 54.2% (50.8%, 57.5%) of PP participants were alive. This was similar between the two arms [CCS: 55.2% (50.5%, 59.7%), DFIS: 53.1% (48.2%, 57.8%)]. On application of a Cox proportional hazards (PH) model adjusted for the stratification factors of the trial, the HR for randomisation allocation, CCS versus DFIS (95% CI) was 0.94 (0.80 to 1.09). Comparing the lower bound of the CI to the NI boundary of 0.812. At the 2.5% significance level, we do not reject the null hypothesis that DFIS is not non-inferior to CCS in terms of OS. There is insufficient evidence to conclude NI. However, the analyses conducted in the ITT population along with the sensitivity analysis conducted in the PP population using a piecewise hazards model and a Cox regression model where Motzer Score at randomisation was considered as two categories did conclude NI between the two arms. The mean QALY (95% CI) for PP participants in the CCS arm was 1.73 (1.60 to 1.86) and 1.80 (1.65 to 1.95) in the DFIS arm derived by combining the results across 52 imputed data sets. The marginal effect (95% CI) of randomisation allocation, DFIS versus CCS was 0.04 (−0.14 to 0.21). Comparing the lower bound of the CI to the NI boundary of 0.156. As the lower bound of the CI is above −0.156, we conclude that the DFIS arm is non-inferior to the CCS arm in terms of QALYs in the PP population. This conclusion remained consistent across all the sensitivity analyses; ITT population, derived from week 24, measured up to 12, 24 and 36 months post randomisation, complete case analysis, analysis conducted using a multivariate linear regression analysis and analysis conducted under missing not at random scenario 1 (worst-case scenario). Secondary end points All secondary time to event end-point analysis was conducted in the ITT population. With the exception of PFS, all analyses showed a significant difference in favour of the DFIS compared to the CCS when applied in a Cox PH model adjusted for the stratification factors of the trial. As PFS measures to the first progression and does therefore not account for successful rechallenge of TKI in the DFIS arm post progression this was expected. There was little difference in the summary statistics of the various QoL questionnaire scores and subscales (FKSI-15, FACT-G, EQ-5D-3L and EQ5D-VAS) when considered by randomisation allocation in each of their populations. A difference only appeared around week 294 when few participants remained on the CCS arm. The multilevel modelling conducted on the FKSI-15 and the FACT-G questionnaires concluded some significant differences between the DFIS and the CCS in favour of the DFIS. However, these differences were small and not consistently observed in the sensitivity analysis, which modelled the questionnaires up to regular intervals post randomisation. The within-trial economic evaluation at 2 years indicated that DFIS was highly likely to be cost-effective. DFIS was found to provide a small QALY benefit (0.049) and substantial cost savings (£3235) over CCS. The value-for-money metric was principally driven by savings in medicine costs. There were relatively minor differences in resource use between arms. The lifetime cost-effectiveness modelling led to the same conclusion yielding QALY gains of 0.08 and cost savings of £2420 (both probabilistic values) in favour of DFIS. The probabilistic sensitivity analyses indicated that DFIS had a 96% chance of being cost saving and a 68% chance of yielding QALY gains versus CCS. The conclusions of both the trial- and model-based analyses were relatively robust to a series of supplementary and sensitivity analyses. Safety All participants bar three in the safety population (CCS: 1, DFIS: 2) experienced an adverse event (AE) during the course of the trial. Overall, a higher proportion of participants in the DFIS arm experienced an AE grade 3 or above (CCS: 70.7%, n = 485, DFIS: 76.1%, n = 431). This difference between arms continues when considering serious adverse events (SAEs) by arm overall and pre and post week 24 (overall – CCS: 45.8%, n = 485, DFIS: 54.1%, n = 431, pre CCS: 32.8%, n = 485, DFIS: 35.5%, n = 431, post CCS: 32.8%, n = 265, DFIS: 48.4%, n = 223). However, this may be explained through the reporting requirements. Participants on DFIS will have reported AEs and SAEs for longer due to their increased time on trial strategy. On consideration of serious AEs deemed to be related to the participants TKI [serious adverse reactions (SARs)], which were collected for the duration of the trial, the difference, in favour of CCS, is more evident prior to week 24 when both strategies are the same (overall – CCS: 18.8%, n = 485, DFIS: 23.4%, n = 431, pre CCS: 13.2%, n = 485, DFIS: 19.3%, n = 431, post CCS: 11.7%, n = 265, DFIS: 9.4%, n = 223). The majority of SAEs and SARs resulted in recovery or recovery with sequelae (SAEs: 80.1%, n = 744, SARs: 87.6%, n = 226). There were 13 suspected unexpected serious adverse reactions (CCS: 5, DFIS: 8) on the trial. Substudies The qualitative substudy concluded that if a DFIS approach was implemented in practice some thought should be given to how patients should be supported during the extended break to cope with and alleviate worries related to ongoing monitoring and tumour growth. The magnetic resonance imaging (MRI) feasibility study demonstrated that DCE-MRI-derived biomarkers of tumour perfusion (perfused tumour volume, Ktrans and extracellular volume) as potential surrogate biomarkers to predict disease progression following TKI therapy in metastatic RCC and the technique of DCE-MRI assessment is reproducible. The CT substudy demonstrated that assessment of enhancement as well as size change alters the categorisation of response. Use of modified Choi (mChoi) criteria may allow for earlier detection of disease progression, and more representative separation of participants with partial response versus stable disease. While published literature has suggested an association of mChoi criteria with time to progression, in terms of prediction of early progression within 6 months of treatment initiation, no association was shown in this cohort. Conclusions Implications for health care The STAR trial is an exemplar trial, being one of the first to be powered on a QALY end point. It demonstrated no substantial detriment in terms of OS and QALY from a DFIS compared to a CCS. However, NI between the two arms cannot be concluded due to a lack of statistical power for the analysis of OS, as a result of fewer than expected OS events due to the changing landscape of effective treatments for relapsed advanced RCC during the trial. These results provide evidence-based reassurance for people who received National Institute for Health and Care Excellence (NICE)-approved treatment breaks in this setting during the COVID-19 pandemic. Through compliance with the protocol, treatment breaks within the trial were shown to be acceptable to patients and health professionals. Future research implications Further discussion is required with patient and public involvement (PPI) and NICE regarding the implications of these results after the NHS interim treatment options following the COVID-19 pandemic end. The STAR trial has provided significant learning regarding the development, design and delivery of intermittent therapy trials. Trial registration This trial is registered as ISRCTN06473203. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information.

Abstract Introduction Pancreatic ductal adenocarcinoma (PDAC) is an aggressive neoplasm, with surgical resection and adjuvant chemotherapy the only curative treatment. Treatment-related toxicities place a considerable burden on patients although exercise training has shown promise is helping to manage such adversities and facilitate rehabilitation. The feasibility and safety of exercise training as a supportive therapy during adjuvant chemotherapy remains unknown. Methods Patients with PDAC were screened post-surgical resection and enrolled in a 16-week, progressive, concurrent exercise programme alongside their chemotherapy regimen. Feasibility was the primary objective detailing recruitment, retention and adherence rates throughout as well as the safety and fidelity of the intervention. Secondarily, the impact on functional fitness and patient-reported outcomes was captured at baseline, post-intervention and 3-month follow up. Results Eight patients consented to participate in this trial, with five proceeding to enrol in exercise training. Concurrent exercise training is feasible and safe during adjuvant chemotherapy and prevented an expected decline in functional fitness and patient-reported outcomes during this time. Discussion This case series provides preliminary evidence that concurrent exercise training during adjuvant therapy is safe, feasible and well tolerated, preventing an expected decline in functional fitness, muscular strength and health-related quality of life (HRQoL). Given the adverse effects of treatment, these findings are promising and provide further evidence for the inclusion of exercise training as a standard of care for surgical rehabilitation and managing treatment-related toxicities. Future research should explore the impact of exercise training during neoadjuvant chemotherapy, with prehabilitation now standard practice for borderline resectable disease. Trial registration ClinicalTrials.gov Identifier: NCT04305067, prospectively registered 12/03/2020, https://classic.clinicaltrials.gov/ct2/show/NCT04305067 .

PurposeTo evaluate the efficacy and safety of pegvorhyaluronidase alfa (PEGPH20) plus nab-paclitaxel/gemcitabine (AG) in patients with hyaluronan-high metastatic pancreatic ductal adenocarcinoma (PDA).Patients and methodsHALO 109-301 was a phase III, randomized, double-blind, placebo-controlled study. Patients ≥ 18 years of age with untreated, metastatic, hyaluronan-high PDA were randomly assigned 2:1 to PEGPH20 plus AG or placebo plus AG. Treatment was administered intravenously in 4-week cycles (3 weeks on, 1 week off) until progression or intolerable adverse events: PEGPH20 3.0 µg/kg twice per week for cycle 1 and once per week thereafter; nab-paclitaxel 125 mg/m2 once per week; and gemcitabine 1,000 mg/m2 once per week. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Response was independently assessed per RECIST v1.1.ResultsAt data cutoff, 494 patients were randomly assigned, with 492 (327 for PEGPH20 and 165 for placebo) included in intention-to-treat analyses. Baseline characteristics were balanced for PEGPH20 plus AG versus placebo plus AG. There were 330 deaths, with a median OS of 11.2 months for PEGPH20 plus AG versus 11.5 months for placebo plus AG (hazard ratio [HR], 1.00; 95% CI, 0.80 to 1.27; P = .97); median PFS was 7.1 months versus 7.1 months (HR, 0.97 [95% CI, 0.75 to 1.26]); ORR was 47% versus 36% (ORR ratio, 1.29 [95% CI, 1.03 to 1.63]). Grade ≥ 3 adverse events with a ≥ 2% higher rate with PEGPH20 plus AG than with placebo plus AG included fatigue (16.0% v 9.6%), muscle spasms (6.5% v 0.6%), and hyponatremia (8.0% v 3.8%).ConclusionThe addition of PEGPH20 to AG increased the ORR but did not improve OS or PFS. The safety profile of PEGPH20 plus AG was consistent with that found in previous studies. These results do not support additional development of PEGPH20 in metastatic PDA.

Simple Summary: The coagulation protein tissue factor (TF) is upregulated in a number of cancer types and can activate signalling pathways, which promote cancer progression. One of the mechanisms by which TF induces signalling in cancer cells is by interacting with the cell adhesion molecule β1-integrin. However, the domains within the proteins responsible for complex formation are not known. Examination of the nature of the interaction between TF and β1-integrin suggested that the upper fibronectin-like domain of TF interacted with the EGF4 domain of β1-integrin and induced signalling that resulted in cell proliferation. In addition, the lower fibronectin-like domain of TF robustly interacted with the βTD domain of β1-integrin reinforcing complex formation. These findings suggest a mechanism by which TF aids cancer cells in sustaining adhesion-free survival and may provide an explanation of why tumours that express high levels of TF exhibit aggressive and malignant phenotypes. Background: Interactions between tissue factor (TF) and β1-integrin induce cell signals, but the molecular mechanisms are not completely understood. The extracellular domain of TF and EGF4-βTD domains of β1-integrin were hypothesised to be the most likely domains involved in the interaction. Additionally, the interaction may induce a conformational change in β1-integrin, which results in changes in signalling. Methods: Peptide constructs corresponding to the upper (residues 1–110; UED), lower (residues 106–219; LED) or combined extracellular domain (residues 1–219; TED) of TF were produced, as well as peptides corresponding to EGF4-βTD or EGF4 domains of β1-integrin. These constructs were expressed in TF-rich MDA-MB-231 cells and TF-deficient primary endothelial cells. The association of the peptides with endogenous-TF or β1-integrin was assessed by a proximity ligation assay and co-immunoprecipitation. Additionally, the influence of the constructs on β1-integrin conformation and the outcome on ERK1/2 activation, cyclin D expression and cell proliferation was analysed. Results: In MDA-MB-231 cells, all TF-constructs were associated with β1-integrin whilst LED was co-immunopurified with β1-integrin. EGF4-βTD was associated with and co-immunopurified with endogenous TF. Additionally, the expression of UED or EGF4-βTD reduced ERK phosphorylation and cyclin D expression and suppressed proliferation. In endothelial cells, the expression of UED, and to a lesser extent, LED, reduced the proportion of β1-integrin in the active conformation and induced ERK1/2 phosphorylation but did not induce cyclin D expression or proliferation. Conclusions: Collectively, these data indicate the extracellular domains of TF function together, with the lower domain forming a robust interaction with the βTD of β1-integrin and the upper domain inducing cell signalling by regulating β1-integrin conformation. [ABSTRACT FROM AUTHOR]

Background Clinical prediction rules (CPRs) developed to predict adverse outcomes of suspected pulmonary embolism (PE) and facilitate outpatient management have limitations in discriminating outcomes for ambulatory cancer patients with unsuspected PE (UPE). The HULL Score CPR uses a 5‑point scoring system incorporating performance status and self-reported new or recently evolving symptoms at UPE diagnosis. It stratifies patients into low, intermediate and high risk for proximate mortality. This study aimed to validate the HULL Score CPR in ambulatory cancer patients with UPE. Patients and methods 282 consecutive patients managed under the UPE-acute oncology service in Hull University Teaching Hospitals NHS Trust were included from January 2015 to March 2020. The primary end-point was all-cause mortality, and outcome measures were proximate mortality for the three risk categories of the HULL Score CPR. Results 30-day, 90-day and 180-day mortality rates for the whole cohort were 3.4% (n=7), 21.1% (n=43) and 39.2% (n=80), respectively. The HULL Score CPR stratified patients into low-risk (n=100, 35.5%), intermediate-risk (n=95, 33.7%) and high-risk (n=81, 28.7%) categories. Correlation of the risk categories with 30-day mortality (area under the curve (AUC) 0.717, 95% CI 0.522–0.912), 90-day mortality (AUC 0.772, 95% CI 0.707–0.838), 180-day mortality (AUC 0.751, 95% CI 0.692–0.809) and overall survival (AUC 0.749, 95% CI 0.686–0.811) was consistent with the derivation cohort. Conclusion This study validates the capacity of the HULL Score CPR to stratify proximate mortality risk in ambulatory cancer patients with UPE. The score uses immediately available clinical parameters and is easy to integrate into an acute outpatient oncology setting.

Introduction: The restriction of prolyl-protein cis/trans isomerase 1 (Pin1) activity has been shown to prevent the release of tissue factor (TF) leading to the accumulation of the latter protein within the cell. This study tested the ability of novel small molecules to inhibit Pin1, suppress TF activity and release, and induce cellular apoptosis. Methods: Four compounds were designed and synthesised based on modification of 5-(p-methoxyphenyl)-2-methylfuran-3-carbonyl amide and the outcome on MDA-MB-231 and primary cells examined. These compounds contained 3-(2-naphthyl)-D-alanine (4a), D-tryptophan (4b), D-phenylalanine (4c), and D-tyrosine (4d) at the amino-termini. Results: Treatment of cells with compound 4b and 4d reduced the cell-surface TF activity after 60 min on MDA-MB-231 cells. Incubation with compound 4d also reduced TF antigen on the cell surface and its incorporation into microvesicles, while compounds 4a and 4b significantly increased TF release. None of the four compounds significantly altered the total amount of TF antigen or TF mRNA expression. Compound 4b and 4d also suppressed the binding of Pin1 to TF-cytoplasmic domain peptide. However, compound 4d reduced while compound 4b increased the Pin1 isomerase activity. Finally, treatment with compound 4b and 4d reduced the cell numbers, increased nuclear localisation of p53, Bax protein and bax mRNA expression and induced cellular apoptosis in MDA-MB-231 but not primary endothelial cells. Conclusions: In conclusion, we have identified small molecules to regulate the function of TF within cells. Two of these compounds may prove to be beneficial in moderating TF function specifically and restrain TF-mediated tumour growth without detrimental outcomes on normal vascular cells.

Abstract Background Several independent risk factors have been reported to influence viral shedding following COVID-19 infection, but the influence of host-related molecular factors has not yet been described. We report a case of a cancer patient with Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) who manifested SARS-CoV-2 PCR (polymerase chain reaction) positivity for at least 54 days after contracting mild COVID-19 illness. We propose that deficient mismatch repair (MMR) may play a role in the prolonged SARS-CoV-2 RNA shedding. Case presentation A patient with Lynch syndrome was under surveillance for metastatic adenocarcinoma after completing palliative chemotherapy in October 2019. Between the period of April 2020 to June 2020, he was admitted multiple times to address several clinical needs mainly related to his underlying malignancy. These included progressive disease observed in the aortocaval lymph nodes leading to recurrent episodes of upper gastrointestinal bleeding, dehydration resulting in acute kidney injury and a short-lived episode of pyrexia. A SARS-CoV-2 PCR of the nasopharyngeal swab (NPS) was positive at his initial admission with mild COVID-19 symptoms. He remained positive on subsequent admissions when tested routinely for SARS-CoV-2 without demonstrating any apparent clinical features of COVID-19 infection. The MMR pathway, a component of DNA damage response (DDR), is impaired in Lynch syndrome due to an inherited genetic mutation. This pathway is also required for viral clearance from the host cells following certain RNA viral infections like influenza virus and other coronaviridae. Here we provide a current understanding of the importance of DDR deficiencies in the clearance of RNA virus and suggest how this may play a similar role in the clearance of COVID-19, as evident in our case that demonstrated persistent positivity. Conclusion The importance of understanding the scientific basis of extended viral shedding during the COVID-19 pandemic is now centre-stage in the establishment of robust track and trace services to allow the recovery and function of societies and economies. This patient with Lynch syndrome recovered from infection but had prolonged viral positivity, which might merit further investigation to better understand the effect of this condition on infection duration and outcome.

Abstract Background Advanced pancreatic ductal adenocarcinoma (aPDAC) patients have a lifetime all type thromboembolic event (ATTE) rate of 25–35%. Efficacy and safety of increased dose primary thromboprophylaxis (IDPTP) with low molecular heparin (LMWH) given for 3 months has been shown in two prospective randomized trials. Objectives To report on efficacy -reduction of all type thromboembolic events (ATTE)-, safety -incidence of Major Bleeding (MB)- and compliance in a single-centre cohort of aPDAC patients receiving first line chemotherapy and LMWH-IDPTP. Methods From May 2009 to October 2016, 82 patients received IDPTP –LMWH with dalteparin. Schedule: 55 kg and below: 7500 IU, between 55 and 80 kg: 10,000 IU, above 80 kg: 12,500 IU. MB is reported using the International Society of Thrombosis and Haemostasis (ISTH) criteria. ATTE was defined as any arterial or venous event, incidental or clinically symptomatic, including visceral VTE. Results Mean and median time on dalteparin was 10.2 (95%CI 8.1, 12.4) and 8.0 (95%CI 6.2, 9.7) months respectively. ATTE was observed in 7 (8.5%) of patients, with a median time on IDPTP of 6.2 months (95% CI 10.0, 13.2). MB was seen in 10 (12.2%) patients with a median time on IDPTP of 4.5 months (95% CI 1.6, 7.4). Six major bleeds (60%) were the direct or indirect result of aPDAC. Eighty-one patients had died at the time of data collection with a median overall survival time of 8.7 months (95%CI 6.4, 11.0). Thromboembolism and bleeding were late events. No impact of thromboembolism or bleeding on overall survival was observed. Conclusions IDPTP-dalteparin was associated with lower ATTE occurrence rates than expected and comparable major bleeding rates. ATTE and MB were late events, the majority of MB was from direct or indirect result of locally progressing aPDAC. Since these conditions can frequently arise in aPDAC, IDPTP should be regularly reviewed beyond 3 months.

BackgroundThe diagnosis of symptomatic cancer-associated thrombosis often causes distress and alarm for patients, especially for those unaware of the risk, or the signs and symptoms to look out for. There are few data about cancer patients' experiences of incidentally diagnosed pulmonary embolism (IPE), where lack of warning (recognised signs, symptoms) may cause delayed diagnosis and aggravate distress.ObjectivesTo explore cancer patients' experience of the diagnosis of and living with incidental pulmonary embolism treated with anticoagulation.MethodsA qualitative study using modified grounded theory approach. Semi-structured interviews were conducted as part of a mixed- methods prospective observational survey study of consenting patients with IPE. Data were subjected to thematic analysis. The qualitative findings are presented.FindingsEleven participants were interviewed (mean age 68.3 years, range 38-82 years; various forms of cancer and stages). Three major themes and one cross-cutting theme were generated. Theme (1): IPE is experienced in the context of cancer and concomitant comorbidities. Issues are understood in the shadow of-and often overshadowed by-current serious illness. Theme (2): Being diagnosed with IPE. Misattribution to cancer or other comorbidities caused delay in help-seeking and diagnosis. Theme (3): Coping with anticoagulation. Participants' incorporated anticoagulation treatment and its effects into their daily routine with acceptance and stoicism. Finally, the cross-cutting theme relates to a lack of information and uncertainty, contributing to distress throughout the experience.ConclusionThe diagnosis of IPE was upsetting and unexpected. Expert and timely information was valued by those with IPE. Education called for about the increased risk of cancer-associated thrombosis and the signs and symptoms to be aware of.

This document is a guideline from the British Society for Haematology on the treatment of cancer-associated venous thrombosis (CAT) in adults. It emphasizes the importance of considering factors such as bleeding risk, tumor site, oral medication suitability, drug interactions, and patient preferences when deciding on the most appropriate treatment. The guideline also provides recommendations for thromboprophylaxis in hospitalized patients, surgical patients, and ambulatory cancer outpatients. It highlights the high risk of VTE in patients with pancreatic cancer and multiple myeloma and discusses specific thromboprophylaxis strategies for these populations. The document also discusses the management of catheter-related thrombosis and the use of inferior vena cava filters. Thrombocytopenia, a condition characterized by low platelet count, is discussed, and it is suggested that anticoagulation should be continued in thrombocytopenic patients during the first 4-6 weeks after thrombosis. The document also discusses the treatment of recurrent VTE (venous thromboembolism) in cancer patients and suggests that supratherapeutic doses of LMWH (low molecular weight heparin) may be effective in reducing the risk of further recurrence. [Extracted from the article]

Abstract Background Around 20% of venous thromboembolism (VTE) cases occur in patients with cancer. Current guidelines recommend low molecular weight heparin (LMWH) as the preferred anticoagulant for VTE treatment. However, some guidelines state that vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) are acceptable alternatives for long-term therapy in some patients if LMWHs are not available. LMWHs and VKAs have a number of drawbacks that can increase the burden on patients. DOACs, such as rivaroxaban, can ameliorate some burdens and may offer an opportunity to increase patient satisfaction and health-related quality of life (HRQoL). The Cancer-associated thrOmboSIs – patient-reported outcoMes with rivarOxaban (COSIMO) study is designed to provide real-world information on treatment satisfaction in patients with active cancer who switch from LMWH or VKA to rivaroxaban for the treatment of acute VTE or to prevent recurrent VTE. Methods COSIMO is a prospective, non-interventional, single-arm cohort study that aims to recruit 500 patients in Europe, Canada and Australia. Adults with active cancer who are switching to rivaroxaban having received LMWH/VKA for the treatment and secondary prevention of recurrent VTE for at least the previous 4 weeks are eligible. Patients will be followed for 6 months. The primary outcome is treatment satisfaction assessed as change in the Anti-Clot Treatment Scale (ACTS) Burdens score at week 4 after enrolment compared with baseline. Secondary outcomes include treatment preferences, measured using a discrete choice experiment, change in ACTS Burdens score at months 3 and 6, and change in HRQoL (assessed using the Functional Assessment of Chronic Illness Therapy – Fatigue questionnaire). COSIMO will collect data on patients’ medical history, patterns of anticoagulant use and incidence of bleeding and thromboembolic events. Study recruitment started in autumn 2016. Conclusions COSIMO will provide information on outcomes associated with switching from LMWH or VKA therapy to rivaroxaban for the treatment or secondary prevention of cancer-associated thrombosis in a real-life setting. The key goal is to assess whether there is a change in patient-reported treatment satisfaction. In addition, COSIMO will facilitate the evaluation of the safety and effectiveness of rivaroxaban in preventing recurrent VTE in this patient population. Trial registration NCT02742623. Registered 19 April 2016.

Abstract Background An incidental/unsuspected diagnosis of pulmonary embolism (IPE) in cancer patients is a frequent occurrence. This single-institution analysis of uniformly managed patients investigates short and long-term outcomes and proposes a prognostic risk score, aiming to assist clinical decision-making. Methods Data from a prospectively recorded cohort of 234 consecutive cancer patients with IPE were analysed. Multivariate logistic regression and the Cox regression survival methods were used to identify factors with independent association with early (30-day, 3-month, 6-month) mortality and survival. Receiver operator characteristic analysis (ROC) was used to assess appropriate cut-offs for continuous variables and the fitness of prognostic scoring. Results 30-day, 3-month and 6-month mortality was 3.4% (n = 8), 15% (n = 35) and 31% (n = 72) respectively. Recurrence during anticoagulation occurred in 2.6% (n = 6) and major haemorrhage in 2.1% (n = 5) of the patients. A prognostic score incorporating performance status (0 vs 1–2 vs 3–4) and the presence of new or worsening symptoms, with and without the consideration of the presence of incurable malignancy, correlated with overall survival (p

Abstract Background Deep vein thrombosis (DVT) is a common complication of peripherally inserted central catheters (PICCs). PICCs are increasingly utilised in the management of cancer patients, a group which carries both additional risks for vascular thromboembolism as well as for complex morbidity. We analysed a cohort of cancer patients subjected to PICC insertion in a single cancer centre for the incidence of all-type vascular thromboembolism (VTE) and investigated relative risk factors. Methods In this clinical audit, the records of patients referred for PICC insertion in our centre in the period between 1/1/2011 and 1/4/2014 were retrospectively reviewed. The primary outcomes investigated were a) PICC-related deep vein thrombosis (PRDVT) and b) distant VTE (lower limb DVT and pulmonary embolism). 4Fr single lumen PICCs were placed in all patients. The Kaplan Meier method was used to study time from PICC insertion to PRDVT/VTE. Survival curves were compared using the log rank method. Logistic and Cox regression analyses were used to assess local, distant and combined endpoints. Results Four hundred ninety patients were included in the analysis of which 27 (5.5%) developed a PRDVT. Statistically significant risk factors for developing PRDVT in multivariate analysis included more than one attempt for insertion (OR 2.61, 95%CI: 1.12–6.05) and the use of fluoropyrimidine containing chemotherapy (OR 4.27, 95%CI 1.3–14.07). Twenty-six patients developed a distant VTE. Male gender was the only significant risk factor for distant VTE. When all-type VTE were considered together fluoropyrimidine containing chemotherapy (OR 4.54, 95% CI 1.63–12.61), male gender (OR 2.03, 95% CI 1.04–3.93) and white cell count (OR 1.12, 95% CI 1.00–1.26) were statistically significant as risk factors in this analysis. Conclusions This is a large study of VTE following PICC insertion in cancer patients which also looks at the rate of distant VTE. The observed PRDVT incidence is comparable with available literature. Fluoropyrimidine containing chemotherapy and more than one attempt for PICC insertion were independent predictors of PICC-associated VTE whilst the former remained an independent predictor of all-type VTE. Anticoagulation did not prevent thrombotic events in this cohort.