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Supplementary Data from Metabolomic Biomarkers in Blood Samples Identify Cancers in a Mixed Population of Patients with Nonspecific Symptoms

Purpose:Early diagnosis of cancer is critical for improving patient outcomes, but cancers may be hard to diagnose if patients present with nonspecific signs and symptoms. We have previously shown that nuclear magnetic resonance (NMR) metabolomics analysis can detect cancer in animal models and distinguish between differing metastatic disease burdens. Here, we hypothesized that biomarkers within the blood metabolome could identify cancers within a mixed population of patients referred from primary care with nonspecific symptoms, the so-called “low-risk, but not no-risk” patient group, as well as distinguishing between those with and without metastatic disease.Experimental Design:Patients (n = 304 comprising modeling, n = 192, and test, n = 92) were recruited from 2017 to 2018 from the Oxfordshire Suspected CANcer (SCAN) pathway, a multidisciplinary diagnostic center (MDC) referral pathway for patients with nonspecific signs and symptoms. Blood was collected and analyzed by NMR metabolomics. Orthogonal partial least squares discriminatory analysis (OPLS-DA) models separated patients, based upon diagnoses received from the MDC assessment, within 62 days of initial appointment.Results:Area under the ROC curve for identifying patients with solid tumors in the independent test set was 0.83 [95% confidence interval (CI): 0.72–0.95]. Maximum sensitivity and specificity were 94% (95% CI: 73–99) and 82% (95% CI: 75–87), respectively. We could also identify patients with metastatic disease in the cohort of patients with cancer with sensitivity and specificity of 94% (95% CI: 72–99) and 88% (95% CI: 53–98), respectively.Conclusions:For a mixed group of patients referred from primary care with nonspecific signs and symptoms, NMR-based metabolomics can assist their diagnosis, and may differentiate both those with malignancies and those with and without metastatic disease.See related commentary by Van Tine and Lyssiotis, p. 1477

BackgroundThe COVID-19 pandemic has profoundly affected UK primary care, and as a result the route to cancer diagnosis for many patients.AimTo explore how the pandemic affected primary care practice, in particular cancer suspicion, referral, and diagnosis, and how this experience evolved as the pandemic progressed.Design and settingSeventeen qualitative interviews were carried out remotely with primary care staff.MethodStaff from practices in England that expressed an interest in trialling an electronic safety-netting tool were invited to participate. Remote, semi-structured interviews were conducted from September 2020 to March 2021. Data analysis followed a thematic analysis and mind-mapping approach.ResultsThe first lockdown was described as providing time to make adjustments to allow remote and minimal-contact consultations but caused concerns over undetected cancers. These concerns were realised in summer and autumn 2020 as the participants began to see higher rates of late-stage cancer presentation. During the second and third lockdowns patients seemed more willing to consult. This combined with usual winter pressures, demands of the vaccine programme, and surging levels of COVID-19 meant that the third lockdown was the most difficult. New ways of working were seen as positive when they streamlined services but also unsafe if they prevented GPs from accessing all relevant information and resulted in delayed cancer diagnoses.ConclusionThe post-pandemic recovery of cancer care is dependent on the recovery of primary care. The COVID-19 pandemic has highlighted and exacerbated vulnerabilities in primary care but has also provided new ways of working that may help the recovery.

BackgroundGut feelings may be useful when dealing with uncertainty, which is ubiquitous in primary care. Both patients and GPs experience this uncertainty but patients’ views on gut feelings in the consultation have not been explored.AimTo explore patients’ perceptions of gut feelings in decision making, and to compare these perceptions with those of GPs.Design and settingQualitative interviews with 21 patients in Oxfordshire, UK.MethodPatients whose referral to a cancer pathway was based on their GP’s gut feeling were invited to participate. Semi-structured interviews were conducted from November 2019 to January 2020, face to face or over the telephone. Data were analysed with a thematic analysis and mind-mapping approach.ResultsSome patients described experiencing gut feelings about their own health but often their willingness to share this with their GP was dependent on an established doctor–patient relationship. Patients expressed similar perspectives on the use of gut feelings in consultations to those reported by GPs. Patients saw GPs’ gut feelings as grounded in their experience and generalist expertise, and part of a process of evidence gathering. Patients suggested that GPs were justified in using gut feelings because of their role in arranging access to investigations, the difficult ‘grey area’ of presentations, and the time- and resource-limited nature of primary care. When GPs communicated that they had a gut feeling, some saw this as an indication that they were being taken seriously.ConclusionPatients accepted that GPs use gut feelings to guide decision making. Future research on this topic should include more diverse samples and address the areas of concern shared by patients and GPs.

BackgroundGrowing evidence for the role of GPs’ gut feelings in cancer diagnosis raises questions about their origin and role in clinical practice.AimTo explore the origins of GPs’ gut feelings for cancer, their use, and their diagnostic utility.Design and settingSystematic review and meta-analysis of international research on GPs’ gut feelings in primary care.MethodSix databases were searched from inception to July 2019, and internet searches were conducted. A segregated method was used to analyse, then combine, quantitative and qualitative findings.ResultsTwelve articles and four online resources were included that described varied conceptualisations of gut feelings. Gut feelings were often initially associated with patients being unwell, rather than with a suspicion of cancer, and were commonly experienced in response to symptoms and non-verbal cues. The pooled odds of a cancer diagnosis were four times higher when gut feelings were recorded (OR 4.24, 95% confidence interval = 2.26 to 7.94); they became more predictive of cancer as clinical experience and familiarity with the patient increased. Despite being included in some clinical guidelines, GPs had varying experiences of acting on gut feelings as some specialists questioned their diagnostic value. Consequently, some GPs ignored or omitted gut feelings from referral letters, or chose investigations that did not require specialist approval.ConclusionGPs’ gut feelings for cancer were conceptualised as a rapid summing up of multiple verbal and non-verbal patient cues in the context of the GPs’ clinical knowledge and experience. Triggers of gut feelings not included in referral guidance deserve further investigation as predictors of cancer. Non-verbal cues that trigger gut feelings appear to be reliant on continuity of care and clinical experience; they tend to remain poorly recorded and are, therefore, inaccessible to researchers.

UNSTRUCTURED The management of diagnostic uncertainty is part of every primary care physician’s role. Electronic safety netting (e-safety-netting) tools help healthcare professionals to manage diagnostic uncertainty. Using software in addition to verbal and/or paper based safety-netting methods could make diagnostic delays and errors less likely. There are an increasing number of software products identifying as e-safety-netting tools, particularly since the COVID-19 pandemic. E-safety-netting tools can have a variety of functions including clinician alerts, administrative tasking, decision support and triggering reminder text messages to patients. However, these tools have not been evaluated using robust research designs for patient safety interventions. We present an emergent framework of criteria for effective e-safety netting tools, to support the development of software. The framework is based on validated frameworks from electronic health record development and patient safety. There are currently no tools available that meet all of the criteria in the framework. We hope the framework will stimulate clinical and public conversation about e-safety netting tools. In the future, a validated framework would drive audit and improvement. We outline key areas for future research, both in primary care and within integrated care systems.

Background One-stop clinics provide comprehensive diagnostic testing in one outpatient appointment. They could benefit patients with conditions, such as cancer, whose outcomes are improved by early diagnosis, and bring efficiency savings for health systems. Objective To assess the use and outcomes of one-stop clinics for symptoms where cancer is a possible diagnosis. Design and setting Systematic review of studies reporting use and outcomes of one-stop clinics in primary care patients. Method We searched MEDLINE, Embase, and Cochrane Library for studies assessing one-stop clinics for adults referred after presenting to primary care with any symptom that could be indicative of cancer. Study selection was carried out independently in duplicate with disagreements resolved through discussion. Results Twenty-nine studies were identified, most were conducted in the UK and observational in design. Few included a comparison arm. A pooled comparison of the cancer conversion rate of one-stop and multi-stop clinics was only possible for breast symptoms, and we found no significant difference. One-stop clinics were associated with significant reductions in the interval from referral to testing (15 versus 75 days) and more patients diagnosed on the same day (79% versus 25%) compared to multi-stop pathways. The majority of patients and GPs found one-stop clinics to be acceptable. Conclusion This review found one-stop clinics were associated with reduced time from referral to testing, increased same day diagnoses, and were acceptable to patients and GPs. Our conclusions are limited by high levels of heterogeneity, scarcity of comparator groups, and the overwhelmingly observational nature of included studies.

For the past decade, within family medicine there has been a focus on cultivating doctors gut feelings as 'a way of knowing' in cancer diagnostics. In this paper, building on interviews with family doctors in Oxford shire, UK we explore the embodied and temporal dimensions of clinical reasoning and how the cultivation of doctors' gut feelings is related to hierarchies of medical knowledge, professional training, and doctors' fears of litigation. Also, we suggest that the introduction of gut feeling in clinical practice is an attempt to develop a theory of clinical reasoning that fits the biopolitics of our contemporary. The turn towards predictive medicine and the values introduced by accelerated diagnostic regimes, we conclude, introduce a need for situated and embodied modes of reading bodies. We contribute theoretically by framing our analysis within a sensorial anthropology approach.

BackgroundThe use of gut feelings to guide clinical decision making in primary care has been frequently described but is not considered a legitimate reason for cancer referral.AimTo explore the role that gut feeling plays in clinical decision making in primary care.Design and settingQualitative interview study with 19 GPs in Oxfordshire, UK.MethodGPs who had referred patients to a cancer pathway based on a gut feeling as a referral criterion were invited to participate. Interviews were conducted between November 2019 and January 2020, and transcripts were analysed using the one sheet of paper method.ResultsGut feeling was seen as an essential part of decision making that facilitated appropriate and timely care. GPs distanced their gut feelings from descriptions that could be seen as unscientific, describing successful use as reliant on experience and clinical knowledge. This was especially true for patients who fell within a ‘grey area’ where clinical guidelines did not match the GP’s assessment of cancer risk, either because the guidance inadequately represented or did not include the patient’s presentation. GPs sought to legitimise their gut feelings by gathering objective clinical evidence, careful examination of referral procedures, and consultation with colleagues.ConclusionGPs described their gut feelings as important to decision making in primary care and a necessary addition to clinical guidance. The steps taken to legitimise their gut feelings matched that expected in good clinical practice.

Acetyl-dl-leucine is a derivative of the branched chain amino acid leucine. In observational clinical studies, acetyl-dl-leucine improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder, Niemann-Pick disease type C1. Here, we investigated acetyl-dl-leucine and its enantiomers acetyl-l-leucine and acetyl-d-leucine in symptomatic Npc1−/− mice and observed improvement in ataxia with both individual enantiomers and acetyl-dl-leucine. When acetyl-dl-leucine and acetyl-l-leucine were administered pre-symptomatically to Npc1−/− mice, both treatments delayed disease progression and extended life span, whereas acetyl-d-leucine did not. These data are consistent with acetyl-l-leucine being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were implicated as one of the potential mechanisms of action of the l-enantiomer in Npc1−/− mice. When the standard of care drug miglustat and acetyl-dl-leucine were used in combination significant synergy resulted. In agreement with these pre-clinical data, when Niemann-Pick disease type C1 patients were evaluated after 12 months of acetyl-dl-leucine treatment, rates of disease progression were slowed, with stabilization or improvement in multiple neurological domains. A beneficial effect of acetyl-dl-leucine on gait was also observed in this study in a mouse model of GM2 gangliosidosis (Sandhoff disease) and in Tay-Sachs and Sandhoff disease patients in individual-cases of off-label-use. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-l-leucine and underlying mechanisms of action in lysosomal storage diseases, supporting its further evaluation in clinical trials in lysosomal disorders., This study investigates the disease-modifying effect of acetyl-DL-leucine in two neurodegenerative lysosomal storage diseases with different aetiologies: Niemann-Pick type C and GM2 gangliosidosis in both murine models and clinical studies. Acetyl-DL-leucine and its L enantiomer provide neuroprotection likely by altering metabolism – a new therapeutic approach for these diseases., Graphical Abstract Graphical Abstract

BackgroundDirect access (DA) testing allows GPs to refer patients for investigation without consulting a specialist. The aim is to reduce waiting time for investigations and unnecessary appointments, enabling treatment to begin without delay.AimTo establish the proportion of patients diagnosed with cancer and other diseases through DA testing, time to diagnosis, and suitability of DA investigations.Design and settingSystematic review assessing the effectiveness of GP DA testing in adults.MethodMEDLINE, Embase, and the Cochrane Library were searched. Where possible, study data were pooled and analysed quantitatively. Where this was not possible, the data are presented narratively.ResultsThe authors identified 60 papers that met pre-specified inclusion criteria. Most studies were carried out in the UK and were judged to be of poor quality. The authors found no significant difference in the pooled cancer conversion rate between GP DA referrals and patients who first consulted a specialist for any test, except gastroscopy. There were also no significant differences in the proportions of patients receiving any non-cancer diagnosis. Referrals for testing were deemed appropriate in 66.4% of those coming from GPs, and in 80.9% of those from consultants; this difference was not significant. The time from referral to testing was significantly shorter for patients referred for DA tests. Patient and GP satisfaction with DA testing was consistently high.ConclusionGP DA testing performs as well as, and on some measures better than, consultant triaged testing on measures of disease detection, appropriateness of referrals, interval from referral to testing, and patient and GP satisfaction.

Sandhoff disease is a rare neurodegenerative lysosomal storage disease associated with the storage of GM2 ganglioside in late endosomes/lysosomes. Here, we explored the efficacy of acetyl-DL-leucine (ADLL), which has been shown to improve ataxia in observational studies in patients with Niemann–Pick Type C1 and other cerebellar ataxias. We treated a mouse model of Sandhoff disease (Hexb-/-) (0.1 g/kg/day) from 3 weeks of age with this orally available drug. ADLL produced a modest but significant increase in life span, accompanied by improved motor function and reduced glycosphingolipid (GSL) storage in the forebrain and cerebellum, in particular GA2. ADLL was also found to normalize altered glucose and glutamate metabolism, as well as increasing autophagy and the reactive oxygen species (ROS) scavenger, superoxide dismutase (SOD1). Our findings provide new insights into metabolic abnormalities in Sandhoff disease, which could be targeted with new therapeutic approaches, including ADLL.

Niemann-Pick C disease (NPC) is an autosomal recessive lysosomal storage disorder resulting from mutations in the NPC1 (95% of cases) or NPC2 genes. Disturbance of copper homeostasis has been reported in NPC1 disease.In this study we have used whole-body positron emission tomography (PET) and brain electronic autoradiography with copper-64 (64Cu), in the form of the copper(II) bis(thiosemicarbazonato) complex 64Cu-GTSM, to imageshort-term changes in copper trafficking after intravenous injection in a transgenic mouse model of NPC1 disease. 64Cu-GTSM is taken up in all tissues and dissociates rapidly inside cells, allowing monitoring of the subsequentefflux and redistribution of 64Cu from all tissues. Significantly enhanced retention of 64Cu radioactivity was observed in brain, lungs and blood at 15 h post-injection in symptomatic Npc1-/- transgenic mice compared towildtype controls. The enhanced retention of 64Cu in brain was confirmed by electronic autoradiography, particularly in the midbrain, thalamus, medulla and pons regions. PET imaging with 64Cu in selected chemical forms could be a useful diagnostic and research tool for the management and understanding of NPC1 disease.

It is estimated that 400 children suffer from an arterial ischaemic stroke (AIS) or haemorrhagic stroke (HS) in the UK each year with up to 40% dying from it, and approximately 60% of those surviving the initial attack going on to have recurrent strokes.1 Although in recent years the recognition of stroke as a disease that affects children has increased, many still experience delays in diagnosis or misdiagnosis.2 3 The view that stroke is an illness of the middle-to-late adult years may have also hindered research into stroke in childhood. The need for a clinical guideline was clear; it would provide a practical guide that should aid clinical decision-making and improve patient care,4 but when there are gaps in the literature, creating guidelines presents a challenge. A guideline development group (GDG) was established that consisted of clinical experts from specialties relevant to the topic of the guideline, parent representatives whose children had suffered a stroke and systematic reviewers from the Royal College of Paediatrics and Child Health, following accepted practice.5 The scope of the guideline was drafted, and after stakeholder consultation, specific clinical questions were formed. ### Systematic review Clinical questions were grouped into subtopics and review protocols were written. Searches were carried out in five databases, MEDLINE, Embase, PsycInfo, Cochrane Library and CINAHL, between 1995 and 2016, these were screened and data extracted from relevant studies. Our expectation was that the literature on rehabilitation following stroke in childhood would not be sufficient to answer all of our clinical questions and so our inclusion and exclusion criteria allowed for the inclusion of studies carried out in children with similar deficits, for example, as a result of acquired brain injury. Despite this, we still found that 36% of all our clinical questions had two or fewer studies on which to base recommendations. The …

Background. Placebos are widely used in clinical practice in spite of ethical restrictions. Whether such use is justified depends in part on the relative benefit of placebos compared to ‘active’ treatments. A direct test for differences between placebo and ‘active’ treatment effects has not been conducted. Objectives. We aimed to test for differences between treatment and placebo effects within similar trial populations. Data Sources. A Cochrane Review compared placebos with no treatment in three-armed trials (no treatment, placebo, and treatment). We added an analysis of treatment and placebo differences within the same trials. Synthesis Methods. For continuous outcomes we compared mean differences between placebo and no treatment with mean differences between treatment and placebo. For binary outcomes we compared the risk ratio for treatment benefit (versus placebo) with the risk ratio for placebo benefit (versus no treatment). We conducted several preplanned subgroup analyses: objective versus subjective outcomes, conditions tested in three or more trials, and trials with varying degrees of bias. Results. In trials with continuous outcomes (n = 115) we found no difference between treatment and placebo effects (MD = −0.29, 95% CI −0.62 to 0.05, P = 0.10). In trials with binary outcomes (n = 37) treatments were significantly more effective than placebos (RRR = 0.72, 95%CI = 0.61 to 0.86, P = 0.0003). Treatment and placebo effects were not different in 22 out of 28 predefined subgroup analyses. Of the six subgroups with differences treatments were more effective than placebos in five. However when all criteria for reducing bias were ruled out (continuous outcomes) placebos were more effective than treatments (MD = 1.59, 95% CI = 0.40 to 2.77, P = 0.009). Conclusions and Implications. Placebos and treatments often have similar effect sizes. Placebos with comparatively powerful effects can benefit patients either alone or as part of a therapeutic regime, and trials involving such placebos must be adequately blinded.

Background Worrying about wasting GP time is frequently cited as a barrier to help-seeking for cancer symptoms. Aim To explore the circumstances under which individuals feel that they are wasting GP time. Design and setting Community-based, qualitative interview studies that took place in London, the South East and the North West of England. Method Interviewees (n = 62) were recruited from a sample (n = 2042) of adults aged ≥50 years, who completed a ‘health survey’ that included a list of cancer ‘alarm’ symptoms. Individuals who reported symptoms at baseline that were still present at the 3-month follow-up (n = 271), and who had also consented to be contacted (n = 215), constituted the pool of people invited for interview. Analyses focused on accounts of worrying about wasting GP time. Results Participants were worried about wasting GP time when time constraints were visible, while dismissive interactions with their GP induced a worry of unnecessary help-seeking. Many felt that symptoms that were not persistent, worsening, or life-threatening did not warrant GP attention. Additionally, patients considered it time-wasting when they perceived attention from nurses or pharmacists to be sufficient, or when appointment structures (for example, ‘one issue per visit’) were not adhered to. Close relationships with GPs eased worries about time-wasting, while some patients saw GPs as fulfilling a service financed by taxpayers. Conclusion Worrying about wasting GP time is a complex barrier to help-seeking. GP time and resource scarcity, symptom gravity, appointment etiquette, and previous GP interactions contribute to increasing worries. Friendly GP relationships, economic reasoning, and a focus on the GP’s responsibilities as a medical professional reduce this worry.

BACKGROUND: Encouraging prompt help-seeking for cancer symptoms can help shorten the patient interval and improve timely diagnosis. We explored factors associated with help-seeking in a primary care sample reporting 'alarm' symptoms. METHODS: A questionnaire was mailed to 9771 adults (⩾50 years of age and no cancer diagnosis) and 3766 (39%) returned it. Our sample included 1732 adults reporting at least one cancer 'alarm' symptom; with a total of 2726 symptoms. Respondents completed questions relating to help-seeking, demographic and symptom characteristics (e.g., type, knowledge, concern, interference and attribution). RESULTS: Over a third of people who reported a cancer 'alarm' symptom in the past 3 months had not sought help from a doctor. An unexplained lump (odds ratio (OR) 2.46, 1.42-4.26) and persistent unexplained pain (OR 1.79, 1.19-2.69) were associated with increased likelihood of help-seeking. Symptom concern (OR 3.10, 2.19-4.39) and interference (OR 3.06, 2.15-4.36) were associated with an increased likelihood of seeking help independently of symptom type. People who were not working (OR 1.41, 1.09-1.83), were married/cohabiting rather than single (OR 1.38, 1.10-1.74) and were older (60-69 years) rather than younger (50-59 years; OR 1.33, 1.02-1.75) were more likely to have sought help. CONCLUSIONS: Our findings highlighted symptom type and symptom characteristics as key drivers of help-seeking. We also found that there may be specific demographic groups where encouraging help-seeking might be warranted.British Journal of Cancer (2015) advance online publication 21 January 2016; doi:10.1038/bjc.2015.445 www.bjcancer.com.

Among studies with continuous outcomes in our systematic review comparing placebo effect sizes with treatment effect sizes we calculated mean differences between to estimate placebo effects, treatment effects, and the difference between placebo and treatment effects. In fact the standardized mean difference should have been used. There was no error in the calculations among studies with binary outcomes. We have corrected this error and revised Figs ​Figs3,3, ​,44 and ​and55 from our review here. Correcting the error strengthened our conclusion that there is rarely a statistically significant difference (at P = 0.05 or lower) between the magnitude of placebo effects and the magnitude of treatment effects. In the original review placebo effect sizes and treatment effect sizes did not differ by a statistically significant amount in the three subgroup analyses: all studies with objective outcomes (treatment effects larger), studies of anxiety treatments (treatment effects larger), and studies where all criteria for ruling out bias were met (placebo effects larger). Fig 3 Placebo versus treatment effects (continuous outcomes) Fig 4 Conditions tested in three or more trials (continuous outcomes) Fig 5 Trials with varying degrees of bias (continuous outcomes) Our corrected analysis revealed no statistically significant difference between placebo effect sizes and treatment effect sizes in all but two subgroup analyses, and in both of them placebo effects were larger. These were: all studies that reported clear allocation concealment, and studies where all criteria for bias ruled out (placebo effects larger). Since placebo effects appear to be relatively greater when bias is ruled out, our corrected conclusions also reduce the possibility that placebo effects are attributable to bias. It is important to note that the placebo and treatment effects may not be independent. For example large placebo effects could be correlated with small treatment effects. Hence there is currently no perfect statistical solution to the problem of comparing effects of placebos and treatments within three-armed trials (no treatment, placebo, treatment). However using the within study difference in effects (placebo effect–treatment effect) and an estimate of the standard deviation of this comparison based on assuming (perhaps incorrectly) independence between effects, allows the use of the standardized mean difference to obtain a pooled estimate of the difference between these two effects. Professor Stephen Senn assisted with the analysis that allowed us to recalculate the differences between placebo and treatment effects in this Erratum.