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Background: The multidisciplinary diagnostic clinic (MDC) model for 'non-specific' symptoms has been piloted in the UK. We aimed to assess the degree to which the MDC pathway was influenced by socioeconomic factors., Methods: We collected data for all patients referred to the MDC from 01 January 2017 - 28 March 2019. Indices of multiple deprivation (IMD) scores were matched to patients' postcodes and referring general practitioner (GP) location. Socioeconomic data for MDC patients was compared with all other cancer patients diagnosed in the MDC's base hospital, Airedale General Hospital (AGH), in 2018. Statistical significance was tested using the Mann-Whitney U test and Spearman's rank correlation., Results: No significant difference was found between MDC pathway and the rest of AGH when comparing social deprivation of patients.There was a moderate negative correlation between the IMD associated with the location of GP premises and the number of referrals; practices in more deprived locations referred fewer patients (p≤0.025)., Conclusion: The MDC pathway referral rate seems to be affected by social deprivation in a similar manner to other cancer diagnosis pathways. Our work highlights the importance of engaging GP practices with socially deprived populations as the MDC programme is rolled out across the UK., (© Royal College of Physicians 2022. All rights reserved.)

During the first 3 months of 2020, as the COVID-19 pandemic developed, it was noticed that requests from primary care for investigations were decreasing, including those that form part of the diagnostic process for cancers. We therefore obtained data on the requests from primary care for chest X-rays (CXRs) and CA125 measurement our hospital received in the first half of 2020 and compared them with 2019. The number of CXRs declined by 93% in April 2020 compared with 2019, with the decline being greater for patient living in outlying areas. Requests from the emergency department also declined. Requests for CA125 measurement similarly fell by 77% from all areas. The requests increased in June, CA125 more than CXR. If this phenomenon is widespread it may have an impact on diagnosis of major conditions, particularly cancers and tuberculosis., (© Royal College of Physicians 2021. All rights reserved.)

A mechanistic model of the immune response was evaluated for its ability to predict anti-drug antibody (ADA) and their impact on pharmacokinetics (PK) and pharmacodynamics (PD) for a biotherapeutic in a phase 1 clinical trial. Observed ADA incidence ranged from 33 to 67% after single doses and 27-50% after multiple doses. The model captured the single dose incidence well; however, there was overprediction after multiple dosing. The model was updated to include a T-regulatory (Treg) cell mediated tolerance, which reduced the overprediction (relative decrease in predicted incidence rate of 21.5-59.3% across multidose panels) without compromising the single dose predictions (relative decrease in predicted incidence rate of 0.6-13%). The Treg-adjusted model predicted no ADA impact on PK or PD, consistent with the observed data. A prospective phase 2 trial was simulated, including co-medication effects in the form of corticosteroid-induced immunosuppression. Predicted ADA incidences were 0-10%, depending on co-medication dosage. This work demonstrates the utility in applying an integrated, iterative modeling approach to predict ADA during different stages of clinical development.

Background: Poor geographical access to health services and routes to a cancer diagnosis such as emergency presentations have previously been associated with worse cancer outcomes. However, the extent to which access to GPs determines the route that patients take to obtain a cancer diagnosis is unknown., Methods: We used a linked dataset of cancer registry and hospital records of patients with a cancer diagnosis between 2006 and 2010 across eight different cancer sites. Primary outcomes were defined as 'desirable routes to diagnosis' [screen-detected and 2-week wait (TWW) referrals] and 'less desirable routes' [emergency presentations and death certificate only (DCO)]. All other routes (GP referral, inpatient elective and other outpatient) were specified as the reference category. Geographical access was measured as travel time in minutes from patients to their GP, and multinomial logistic regression was used to estimate relative risk ratios (RRR)., Results: Longer travel was associated with increased risk of diagnosis via emergency and DCO, but decreased risk of diagnosis via screening and TWW. Patients travelling over 30 minutes had the highest risk of a DCO diagnosis, which was statistically significant for breast, colorectal, lung, prostate, stomach and ovarian cancers (compared with patients with travel times ≤10 minutes: RRR 5.89, 7.02, 2.30, 4.75, 10.41; P < 0.01 and 3.51, P < 0.05)., Discussion: Poor access to GPs may discourage early engagement with health services, decreasing the likelihood of screening uptake and increasing the likelihood of emergency presentations. Extra effort is needed to promote early diagnosis in more distant patients., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: This study investigated the awareness of non-oncology specialist medical staff about commonly used oral anticancer medicines (OAMs)., Methods: Interviews conducted with a range of non-oncology specialist doctors., Results: The recognition of OAMs was poor by all grades of doctors, with capecitabine being the only drug recognised by more than half the doctors (26 of 40; 65%). Consultant medical staff scored significantly better than most junior grades of staff., Conclusions: A barrier to safe patient care appears to be the initial identification of OAMs on acute admission. Once a drug had been identified as an OAM, doctors are aware that they should not prescribe it and should contact the acute oncology service for advice. A range of measures has been introduced to improve the identification of OAMs by doctors., Competing Interests: Competing interests: None declared.

Background: Ovarian cancer presents later in the UK compared to economically similar countries. National guidance suggests measuring CA125 in primary care as a means of bringing patients to specialist attention., Aim: To investigate the outcome of CA125 values measured in accordance with this policy., Setting and Design: Examination of the laboratory records of female patients from the usual catchment population of one general hospital in whom CA125 was measured from primary care in a calendar year., Methods: Those with values >35 u/ml were identified. Electronic records within the hospital were interrogated to identify what further evaluation had been undertaken whether ovarian or primary peritoneal cancer had been diagnosed or what other pathology was identified. We also reviewed the CA125 measurement history of patients diagnosed over 3 years by any route., Results: One hundred and sixty-four new cases of CA125 ≥35 u/ml were found. Further information was available for 152 of them. Sixteen had ovarian or primary peritoneal cancer and 16 had other cancers. In 50 no cause for the abnormality was found. The remainder had various non-malignant conditions. The specificity for carcinoma of ovary/primary peritoneal carcinoma was 95.4% [95% confidence interval: 94.8-96.0). In a 3-year period, 65 patients were diagnosed with ovarian or primary peritoneal cancer, 5 had values of CA125 between 20 and 35 u/ml shortly before diagnosis., Conclusions: The CA125 level is a useful diagnostic test for ovarian cancer which has been embraced by primary care but higher sensitivity for earlier disease will require strategies to improve the specificity.

We developed a homogeneous bridging anti-drug antibody (ADA) assay on an electro chemiluminescent immunoassay (ECLIA) platform to support the immunogenicity evaluation of a dimeric domain antibody (dAb) therapeutic in clinical studies. During method development we evaluated the impact of different types of acid at various pH levels on polyclonal and monoclonal ADA controls of differing affinities and on/off rates. The data shows for the first time that acids of different pH can have a differential effect on ADA of various affinities and this in turn impacts assay sensitivity and drug tolerance as defined by these surrogate controls. Acid treatment led to a reduction in signal of intermediate and low affinity ADA, but not high affinity or polyclonal ADA. We also found that acid pretreatment is a requisite for dissociation of drug bound high affinity ADA, but not for low affinity ADA-drug complexes. Although we were unable to identify an acid that would allow a 100% retrieval of ADA signal post-treatment, use of glycine pH3.0 enabled the detection of low, intermediate and high affinity antibodies (Abs) to various extents. Following optimization, the ADA assay method was validated for clinical sample analysis. Consistencies within various parameters of the clinical data such as dose dependent increases in ADA rates and titers were observed, indicating a reliable ADA method. Pre- and post-treatment ADA negative or positive clinical samples without detectable drug were reanalyzed in the absence of acid treatment or presence of added exogenous drug respectively to further assess the effectiveness of the final acid treatment procedure. The overall ADA results indicate that assay conditions developed and validated based on surrogate controls sufficed to provide a reliable clinical data set. The effect of low pH acid treatment on possible pre-existing ADA or soluble multimeric target in normal human serum was also evaluated, and preliminary data indicate that acid type and pH also affect drug-specific signal differentially in individual samples. The results presented here represent the most extensive analyses to date on acid treatment of a wide range of ADA affinities to explore sensitivity and drug tolerance issues. They have led to a refinement of our current best practices for ADA method development and provide a depth of data to interrogate low pH mediated immune complex dissociation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: A potential impact of the centralisation of cancer services in the UK is difficulty in gaining access for members of the population living far from them. This could lead to delayed presentation of cancer with more advanced disease and clinical deterioration at diagnosis. A patient may be recorded in the cancer registry as having cancer of unknown primary (CUP) if the clinical state at presentation precludes investigation. Other patients may be so recorded if investigation identifies sites of metastatic tumour but the primary is not found. We hypothesised that the first group would include more patients who experienced difficulties in gaining access to health services through residing in deprived areas or through poorer geographical access to healthcare facilities., Materials and Methods: We compared the diagnosis of CUP with a comparator tumour, carcinoma of the rectum, where diagnosis is facilitated by an alarm symptom and where variations in access are lower. Records from the Northern and Yorkshire Cancer Registry from 1994 to 2002 with ICD 10 C77-C80 (CUP, including categories where investigations may have been incomplete or no primary cancer was found) and C20 (malignant neoplasm of rectum) were combined with travel time to services (primary care, secondary and tertiary services) and the Index of Multiple Deprivation. Logistic regression modelled predictors of CUP were compared with C20 and, within CUP, the odds of a histological basis of diagnosis., Results: The registry classified 7428 patients as C80, 8849 as C77-C79, and 10 804 as C20. Compared with C20, the number of cases of C80 showed a statistically significant increasing trend with increasing travel time to primary care. Risk also increased strongly with age and deprivation. The results for C77-C79 were similar to those for C80, except that the travel time to primary care showed no effect. Considering all CUP alone, histological diagnosis significantly declined with travel time to the nearest hospital. There was no association with gender and the likelihood of histological diagnosis, but a marked decline with age, a downward trend with deprivation, and an increase when the nearest hospital was a cancer centre., Conclusions: These findings facilitate the understanding of factors associated with the group of patients that includes those with the least effective access to cancer services., (Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

This study seeks to examine the extent to which cancer services are geographically located according to cancer incidence, and assess the association with cancer survival. We identified hospital sites serving English PCTs (Primary Care Trusts) with the management and treatment of breast, lung and colorectal cancer. Geographical access was estimated as travel time in minutes from LSOAs (Lower Super Output Areas) to the nearest hospital site and aggregated to PCT level. Correlations between PCT level mean travel times and cancer cases were estimated using Spearman's rank correlation. Associations between PCT level mean travel times and cancer relative survival rates were estimated using linear regression with adjustment for area deprivation and for a PCT level measure of the reported ease of obtaining a doctor's appointment. We found that cancer services tended to be located farther from areas with more cancer cases, and longer average travel times are associated with worse survival after adjustment for age, sex, year and area deprivation. This suggests that geographical access to cancer services remains a concern in England., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background and Aims: Substance use and risk-taking are common during emerging adulthood, a transitional period when peer influences often increase and family influences decrease. Investigating relationships between social network features and substance use can inform community-based prevention programs. This study investigated whether substance use among emerging adults living in disadvantaged urban areas was influenced by peer and family social network messages that variously encouraged and discouraged substance use., Design: Cross-sectional, naturalistic field study., Setting and Participants: Lower-income neighborhoods in Birmingham, Alabama, USA with 344 participants (110 males, 234 females, ages 15-25 years; mean = 18.86 years), recruited via respondent-driven sampling., Measurements: During structured interviews conducted in community locations, the Alcohol, Smoking and Substance Involvement Screening Test assessed substance use and related problems. Predictor variables were network characteristics, including presence of substance-using peers, messages from friends and family members about substance use and network sources for health information., Findings: Higher substance involvement was associated with friend and family encouragement of use and having close peer network members who used substances (Ps < 0.001). Peer discouragement of substance use was associated with reduced risk (b = - 1.46, P < 0.05), whereas family discouragement had no protective association., Conclusions: Social networks appear to be important in both promoting and preventing substance use in disadvantaged young adults in the United States., (© 2015 Society for the Study of Addiction.)

The nature of cancer control is changing, with an increasing emphasis, fuelled by public and political demand, on prevention, early diagnosis, and patient experience during and after treatment. At the same time, primary care is increasingly promoted, by governments and health funders worldwide, as the preferred setting for most health care for reasons of increasing need, to stabilise health-care costs, and to accommodate patient preference for care close to home. It is timely, then, to consider how this expanding role for primary care can work for cancer control, which has long been dominated by highly technical interventions centred on treatment, and in which the contribution of primary care has been largely perceived as marginal. In this Commission, expert opinion from primary care and public health professionals with academic and clinical cancer expertise—from epidemiologists, psychologists, policy makers, and cancer specialists—has contributed to a detailed consideration of the evidence for cancer control provided in primary care and community care settings. Ranging from primary prevention to end-of-life care, the scope for new models of care is explored, and the actions needed to effect change are outlined. The strengths of primary care—its continuous, coordinated, and comprehensive care for individuals and families—are particularly evident in prevention and diagnosis, in shared follow-up and survivorship care, and in end-of-life care. A strong theme of integration of care runs throughout, and its elements (clinical, vertical, and functional) and the tools needed for integrated working are described in detail. All of this change, as it evolves, will need to be underpinned by new research and by continuing and shared multiprofessional development., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: New strategies are required to rapidly identify novel cytostatic agents before embarking on large randomized trials. This study investigates whether a change in rate of rise (slope) of serum CA125 from before to after starting a novel agent could be used to identify cytostatic agents. Tamoxifen was used to validate this hypothesis., Methods: Asymptomatic patients with relapsed ovarian cancer who had responded to chemotherapy were enrolled and had CA125 measurements taken every 4 weeks, then more frequently when rising. Once levels reached 4 times the upper limit of normal or nadir, they started continuous tamoxifen 20 mg daily, as well as fortnightly CA125 measurements until symptomatic progression. Because of the potentially nonlinear relationship of CA125 over time, it was felt that to enable normal approximations to be utilized a natural logarithmic standard transformation [ln(CA125)] was the most suitable to improve linearity above the common logarithmic transformation to base 10., Results: From 235 recruited patients, 81 started tamoxifen and had at least 4 CA125 measurements taken before and 4 CA125 measurements taken after starting tamoxifen, respectively. The mean regression slopes from using at least 4 1n(CA125) measurements immediately before and after starting tamoxifen were 0·0149 and 0·0093 [ln(CA125)/d], respectively. This difference is statistically significant, P = 0·001. Therefore, in a future trial with a novel agent, at least as effective as tamoxifen, using this effect size, the number of evaluable patients needed, at significance level of 5% and power of 80%, is 56., Conclusions: Further validation of this methodology is required, but there is potential to use comparison of mean regression slopes of ln(CA125) as an interim analysis measure of efficacy for novel cytostatic agents in relapsed ovarian cancer.

Over the past two decades, considerable attention has been given to the development of new ligands for the palladium-catalyzed arylation of amines and related NH-containing substrates (i.e., Buchwald-Hartwig amination). The generation of structurally diverse ligands, by research groups in both academia and industry, has facilitated the accommodation of sterically and electronically divergent substrates including ammonia, hydrazine, amines, amides, and NH heterocycles. Despite these achievements, problems with catalyst generality persist and access to multiple ligands is necessary to accommodate all of these NH-containing substrates. In our quest to address this significant limitation we identified the BippyPhos/[Pd(cinnamyl)Cl]2 catalyst system as being capable of catalyzing the amination of a variety of functionalized (hetero)aryl chlorides, as well as bromides and tosylates, at moderate to low catalyst loadings. The successful transformations described herein include primary and secondary amines, NH heterocycles, amides, ammonia and hydrazine, thus demonstrating the largest scope in the NH-containing coupling partner reported for a single Pd/ligand catalyst system. We also established BippyPhos/[Pd(cinnamyl)Cl]2 as exhibiting the broadest demonstrated substrate scope for metal-catalyzed cross-coupling of (hetero)aryl chlorides with NH indoles. Furthermore, the remarkable ability of BippyPhos/[Pd(cinnamyl)Cl]2 to catalyze both the selective monoarylation of ammonia and the N-arylation of indoles was exploited in the development of a new one-pot, two-step synthesis of N-aryl heterocycles from ammonia, ortho-alkynylhalo(hetero)arenes and (hetero) aryl halides through tandem N-arylation/hydroamination reactions. Although the scope in the NH-containing coupling partner is broad, BippyPhos/[Pd(cinnamyl)Cl]2 also displays a marked selectivity profile that was exploited in the chemoselective monoarylation of substrates featuring two chemically distinct NH-containing moieties., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An improved and scalable synthesis of the unsubstituted 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene framework facilitates access to the previously unreported parent dipyrrin HCl salt, as well as 4,4-dichloro-4-bora-3a,4a-diaza-s-indacene.

Background: The National Epirubicin Adjuvant Trial (NEAT) and BR9601 trials tested the benefit of epirubicin when added to cyclophosphamide, methotrexate and 5-fluorouracil (E-CMF) compared with standard CMF in adjuvant chemotherapy for women with early breast cancer. This report details longer follow-up with interesting additional time-dependent analyses., Methods: National Epirubicin Adjuvant Trial used epirubicin (E) 3-weekly for four cycles followed by classical (c) CMF for four cycles (E-CMF) compared with cCMF for six cycles. BR9601 used E 3-weekly for four cycles followed by CMF 3-weekly for four cycles, compared with CMF 3-weekly for eight cycles., Results: In all, 2391 eligible patients were randomised and with a median 7.4-year follow-up, E-CMF confirmed a significant benefit over CMF in both relapse-free survival (RFS) (78% vs 71% 5 years RFS, respectively, hazard ratio (HR)=0.75 (95% CI: 0.65-0.86), P<0.0001) and overall survival (OS) (84% vs 78% 5 years OS, respectively, HR=0.76 (95% CI: 0.65-0.89), P=0.0007). Interaction of treatment effect and prognostic factors was demonstrated for duplication of chromosome 17 centromeric enumeration (Ch17CEP) as previously reported. Poor prognostic factors at diagnosis (ER and PR negative and HER2 positive) showed time-dependent annual hazard rates for RFS and OS. In univariate analysis, these factors demonstrated more favourable HRs for RFS after 5 years. Treatment effects also suggested a differential benefit for E-CMF within the first 5 years for poor prognosis tumours., Conclusion: Longer follow-up has confirmed E-CMF as significantly superior to CMF for all patients. Ch17CEP duplication was the only biomarker that demonstrated significant treatment interaction. Standard poor prognostic factors at diagnosis were time-dependent, and after 5 years disease-free, poor prognosis patients demonstrated favourable HRs for survival.