• Carcinoma of Unknown Primary (CUP) in a patient presenting with lower back pain: An Important Clinical Lesson

      Hind, Jamie; Sidhu, Gur Aziz; Powell, Chris; Lacon, Andrew; Ashwood, Neil (2020-09)
      Carcinoma of unknown primary (CUP) is associated with high rates of morbidity and mortality. We report a case of a 33-year-old female, diagnosed with CUP, after presenting with gradual onset worsening lower back pain. Immunohistochemistry, blood tests, further investigations, and Multidisciplinary team meetings failed to identify the primary malignancy. This is not an uncommon pathway for patients with CUP. This report highlights how CUP can affect the quality of life of patients and how management for CUP should be focused on enhancing Quality of Life (QOL). It also addresses the difficulty of identifying which group of patients may benefit from further investigations to identify the primary and thus receive target treatment therapy.
    • Cellulitis in chronic oedema of the lower leg: an international cross-sectional study

      Keeley, Vaughan (2021-01)
      Background: Cellulitis and chronic oedema are common conditions with considerable morbidity. The number of studies designed to assess the epidemiology of cellulitis in chronic oedema are scarce. Objectives: To investigate the prevalence and risk factors of cellulitis in chronic leg oedema, including lymphoedema. Methods: A cross-sectional study, including 40 sites in nine countries, 2014-2017. Adults with clinically proven unilateral or bilateral chronic oedema (oedema >3 months) of the lower leg were included. The main outcome measures were frequency and risk factors for cellulitis within the last 12 months. Results: Out of 7477 patients, 15⋅78% had cellulitis within the last 12 months, with a life-time prevalence of 37⋅47%. The following risk factors for cellulitis were identified by multivariable analysis: wounds [odds ratio (OR) 2⋅37, 95% confidence interval (CI) 2⋅03-2⋅78], morbid obesity (OR 1⋅51, CI 95% 1⋅27-1⋅80), obesity (OR 1⋅21, CI 95% 1⋅03-1⋅41), midline swelling (OR 1⋅32, CI 95% 1⋅04-1⋅66), male sex (OR 1⋅32, CI 95% 1⋅15-1⋅52) and diabetes (OR 1⋅27, CI 95% 1⋅08-1⋅49). Controlled swelling was associated with a reduced risk (OR 0⋅59, CI 95% 0⋅51-0⋅67). In a subgroup analysis, the risk increased with the stage of oedema [International Society of Lymphology (ISL), stage II OR 2⋅04, CI 95% 1⋅23-3⋅38, and stage III OR 4⋅88, CI 95% 2⋅77-8⋅56]. Conclusions: Cellulitis in chronic leg oedema is a global problem. Several risk factors for cellulitis were identified, of which some are potentially preventable. Our findings suggest that oedema control, is one of these. We also identified that advanced stages of oedema, with hard/fibrotic tissue, might be an important clinical indicator to identify patients at particular risk.
    • Chronic oedema: a prevalent health care problem for UK health services

      Keeley, Vaughan; Moffatt, Christine; Rich, Anna (2016-12)
      Chronic oedema (CO) is a major clinical problem worldwide, which has many important secondary consequences for health, activity and participation. Effective treatment planning and organisation of services is dependent on an understanding of the condition and its epidemiology. This cross-sectional study was designed to estimate the point prevalence of CO within the health services of one UK urban population and to determine the proportions that have concurrent leg ulceration. Patients with CO in all anatomic sites were ascertained by health care professionals in one acute and one community hospital, all relevant outpatient and community nursing services, general practices and all nursing/residential homes in one urban catchment area (Derby City). The presence and distribution of oedema was confirmed through a brief clinical examination. A battery of demographic and clinical details was recorded for each case. Within the study population of Derby City residents, 971 patients were identified with CO [estimated crude prevalence 3·93 per 1000, 95% confidence interval (CI) 3·69–4·19]. The prevalence was the highest among those aged 85 or above (28·75 per 1000) and was higher among women (5·37 per 1000) than men (2·48 per 1000). The prevalence among hospital inpatients was 28·5%. Only five (3%) patients in the community population had oedema related to cancer or cancer treatment. Of the 304 patients identified with oedema from the Derby hospitals or community health services, 121 (40%) had a concurrent leg ulcer. Prevalence statistics and current demographic trends indicate that CO is a major and growing health care problem.
    • Clinical Outcomes and Survival Following Treatment of Metastatic Castrate-Refractory Prostate Cancer With Docetaxel Alone or With Strontium-89, Zoledronic Acid, or Both: The TRAPEZE Randomized Clinical Trial.

      Chakraborti, Prabir (2016-04)
      IMPORTANCE: Bony metastatic castrate-refractory prostate cancer (CRPC) has a poor prognosis and high morbidity. Zoledronic acid (ZA) is commonly combined with docetaxel in practice but lacks evidence that combining is effective, and strontium-89 (Sr89) is generally used palliatively in patients unfit for chemotherapy. Phase 2 analysis of the TRAPEZE trial confirmed combining the agents was safe and feasible, and the objectives of phase 3 include assessment of the treatments on survival. OBJECTIVE: To determine clinical effectiveness and cost-effectiveness of combining docetaxel, ZA, and Sr89, all having palliative benefits and used in bony metastatic CRPC to control bone symptoms and, for docetaxel, to prolong survival. DESIGN, SETTING, AND PARTICIPANTS: The TRAPEZE trial is a 2 × 2 factorial trial comparing docetaxel alone or with ZA, Sr89, or both. A cohort of 757 participants were recruited between February 2005 and February 2012 from hospitals in the United Kingdom. Overall, 169 participants (45%) had received palliative radiotherapy, and the median (IQR) prostate-specific antigen level was 146 (51-354). Follow-ups were performed for at least 12 months. INTERVENTIONS: Up to 10 cycles of docetaxel alone; docetaxel with ZA; docetaxel with a single Sr89 dose after 6 cycles; or docetaxel with both ZA and Sr89. MAIN OUTCOMES AND MEASURES: Primary outcomes included clinical progression-free survival (CPFS) (pain progression, skeletal-related events [SREs], or death) and cost-effectiveness. Secondary outcomes included SRE-free interval, pain progression-free interval, total SREs, and overall survival (OS). RESULTS: Overall, of 757 participants, 349 (46%) completed docetaxel treatment. Median (IQR) age was 68 (63-73) years. Clinical progression-free survival did not reach statistical significance for either Sr89 or ZA. Cox regression analysis adjusted for all stratification variables showed benefit of Sr89 on CPFS (hazard ratio [HR], 0.85; 95% CI, 0.73-0.99; P = .03) and confirmed no effect of ZA (HR, 0.98; 95% CI, 0.85-1.14; P = .81); ZA had a significant effect on SRE-free interval (HR, 0.78; 95% CI, 0.65-0.95; P = .01). For OS, there was no effect of either Sr89 (HR, 0.92; 95% CI, 0.79-1.08; P = 0.34) or ZA (HR, 0.99; 95% CI, 0.84-1.16; P = 0.91). CONCLUSIONS AND RELEVANCE: Strontium-89 combined with docetaxel improved CPFS but did not improve OS, SRE-free interval, or total SREs; ZA did not improve CPFS or OS but did significantly improve median SRE-free interval and reduced total SREs by around one-third, suggesting a role as postchemotherapy maintenance therapy. TRIAL REGISTRATION: isrctn.com Identifier: ISRCTN12808747.
    • Continuous Hyperfractionated Accelerated Radiotherapy (CHART) for Non-small Cell Lung Cancer (NSCLC): 7 Years' Experience From Nine UK Centres.

      Walker, GA; Keni, Manjusha (2018-01)
      AIM: Continuous hyperfractionated accelerated radiotherapy (CHART) remains an option to treat non-small cell lung cancer (NSCLC; NICE, 2011). We have previously published treatment outcomes from 1998-2003 across five UK centres. Here we update the UK CHART experience, reporting outcomes and toxicities for patients treated between 2003 and 2009. MATERIALS AND METHODS: UK CHART centres were invited to participate in a retrospective data analysis of NSCLC patients treated with CHART from 2003 to 2009. Nine (of 14) centres were able to submit their data into a standard database. The Kaplan-Meier method estimated survival and the Log-rank test analysed the significance. RESULTS: In total, 849 patients had CHART treatment, with a median age of 71 years (range 31-91), 534 (63%) were men, 55% had undergone positron emission tomography-computed tomography (PET-CT) and 26% had prior chemotherapy; 839 (99%) patients received all the prescribed treatment. The median overall survival was 22 months with 2 and 3 year survival of 47% and 32%, respectively. Statistically significant differences in survival were noted for stage IA versus IB (33.2 months versus 25 months; P = 0.032) and IIIA versus IIIB (20 months versus 16 months; P = 0.018). Response at 3 months and outcomes were significantly linked; complete response showing survival of 34 months against 19 months, 15 months and 8 months for partial response, stable and progressive disease, respectively (P < 0.001). Age, gender, performance status, prior chemotherapy and PET-CT did not affect the survival outcomes. Treatment was well tolerated with <5% reporting ≥grade 3 toxicity. CONCLUSION: In routine practice, CHART results for NSCLC remain encouraging and we have been able to show an improvement in survival compared with the original trial cohort. We have confirmed that CHART remains deliverable with low toxicity rates and we are taking a dose-escalated CHART regimen forward in a randomised phase II study of sequential chemoradiotherapy against other accelerated dose-escalated schedules.
    • Cost-effectiveness of zoledronic acid and strontium-89 as bone protecting treatments in addition to chemotherapy in patients with metastatic castrate-refractory prostate cancer: results from the TRAPEZE trial (ISRCTN 12808747).

      Chakraborti, Prabir (2016-06)
      OBJECTIVES: To evaluate the cost-effectiveness of adding zoledronic acid (ZA) or strontium-89 (Sr89) to standard docetaxel chemotherapy for patients with castrate-refractory prostate cancer (CRPC). PATIENTS AND METHODS: Data on resource use and quality of life for 707 patients collected prospectively in the TRAPEZE 2x2 factorial randomised trial (ISRCTN 12808747) were used to assess the cost-effectiveness of i) zoledronic acid versus no zoledronic acid (ZA vs. no ZA), and ii) strontium-89 versus no strontium-89 (Sr89 vs. no Sr89). Costs were estimated from the perspective of the NHS and included expenditures for trial treatments, concomitant medications and use of related hospital and primary care services. QALYs were calculated according to patients' responses to the generic EuroQol EQ-5D-3L instrument. Results are expressed as incremental cost-effectiveness ratios (ICER) and cost-effectiveness acceptability curves. RESULTS: The per-patient cost for ZA was £12,667, £251 higher than the equivalent cost in the no ZA group. Patients in the ZA group experienced on average 0.03 QALYs more than their counterparts in no ZA. The incremental cost-effectiveness ratio (ICER) for this comparison was £8,005. Sr89 was associated with a cost of £13,230, £1,365 higher than no Sr89, and a gain of 0.08 QALYs compared to no Sr89. The ICER for Sr89 was £16,884. The probabilities of ZA and Sr89 being cost-effective were 0.64 and 0.60, respectively. CONCLUSIONS: The addition of bone-targeting treatments to standard chemotherapy led to a small improvement in QALYs for a modest increase in cost (or cost-savings). ZA and Sr89 resulted in ICERs below conventional willingness-to-pay per QALY thresholds, suggesting that their addition to chemotherapy may represent a cost-effective use of resources This article is protected by copyright. All rights reserved.
    • Demographics, management and survival of patients with malignant pleural mesothelioma in the National Lung Cancer Audit in England and Wales

      Beckett, Paul (2015-06)
      INTRODUCTION AND METHODS: Malignant pleural mesothelioma (MPM) is an uncommon cancer with poor survival. We have used data collected for the UK National Lung Cancer Audit to assess current practice and to highlight regional variation in the management of mesothelioma patients, as well as to describe survival patterns in subgroups. RESULTS: Our data on 8740 cases seen in hospitals in England and Wales is the largest cohort of MPM in the literature and represents approximately 80% of the total incident cases. 83% are male and median age is 73 years. Performance status is recorded in 81% and of these approximately 70% are PS 0-2. Stage is poorly recorded and unreliable in this dataset. The patient pathway is similar to lung cancer with approximately one-fifth having a non-elective referral to secondary care. A histo-cytological diagnosis is made in 87% and varies across organisations. Only 67% have anti-cancer treatment, and this also varies across organisations, but there has been an annual increase in the proportion receiving chemotherapy. Overall median survival was 9.5 months, with a 1YS of 41.4% and 3YS of 12.0%, but was strongly linked to performance status and histological subtype. Median survival also varied by cancer network from 209 days to 349 days, but appeared to increase from of 9.2 months in 2008 to 10.5 months in 2012. CONCLUSION: Our data provide a large scale, detailed assessment of MPM epidemiology, treatment choices and outcomes. Incidence is increasing in line bwith predictions and uptake of treatments has generally mirrored publication of key MPM treatment trials, in particular increasing use of chemotherapy but low uptake of radical surgery. However, there is significant variation in care patterns and outcomes that may reflect limited expertise in area with low incidence. Initiatives to improve outcomes should include improved recording of clinical stage.
    • Development of Prognosis in Palliative care Study (PiPS) predictor models to improve prognostication in advanced cancer: prospective cohort study

      Keeley, Vaughan (2015-12)
      OBJECTIVE: To develop a novel prognostic indicator for use in patients with advanced cancer that is significantly better than clinicians' estimates of survival. DESIGN: Prospective multicentre observational cohort study. SETTING: 18 palliative care services in the UK (including hospices, hospital support teams, and community teams). PARTICIPANTS: 1018 patients with locally advanced or metastatic cancer, no longer being treated for cancer, and recently referred to palliative care services. MAIN OUTCOME MEASURES: Performance of a composite model to predict whether patients were likely to survive for "days" (0-13 days), "weeks" (14-55 days), or "months+" (>55 days), compared with actual survival and clinicians' predictions. RESULTS: On multivariate analysis, 11 core variables (pulse rate, general health status, mental test score, performance status, presence of anorexia, presence of any site of metastatic disease, presence of liver metastases, C reactive protein, white blood count, platelet count, and urea) independently predicted both two week and two month survival. Four variables had prognostic significance only for two week survival (dyspnoea, dysphagia, bone metastases, and alanine transaminase), and eight variables had prognostic significance only for two month survival (primary breast cancer, male genital cancer, tiredness, loss of weight, lymphocyte count, neutrophil count, alkaline phosphatase, and albumin). Separate prognostic models were created for patients without (PiPS-A) or with (PiPS-B) blood results. The area under the curve for all models varied between 0.79 and 0.86. Absolute agreement between actual survival and PiPS predictions was 57.3% (after correction for over-optimism). The median survival across the PiPS-A categories was 5, 33, and 92 days and survival across PiPS-B categories was 7, 32, and 100.5 days. All models performed as well as, or better than, clinicians' estimates of survival. CONCLUSIONS: In patients with advanced cancer no longer being treated, a combination of clinical and laboratory variables can reliably predict two week and two month survival.
    • Effect of colon cancer and surgical resection on skeletal muscle mitochondrial enzyme activity in colon cancer patients: a pilot study.

      Lund, Jonathan (2013-03)
      BACKGROUND: Colon cancer (CC) patients commonly suffer declines in muscle mass and aerobic function. We hypothesised that CC would be associated with reduced muscle mass and mitochondrial enzyme activity and that curative resection would exacerbate these changes. METHODS: We followed age-matched healthy controls and CC patients without distant metastasis on radiological imaging before and 6 weeks after hemi-colectomy surgery. Body composition was analysed using dual energy X-ray absorptiometry. Mitochondrial enzyme activity and protein concentrations were analysed in vastus lateralis muscle biopsies. RESULTS: In pre-surgery, there were no differences in lean mass between CC patients and age-matched controls (46.1 + 32.5 vs. 46.1 + 37.3 kg). Post-resection lean mass was reduced in CC patients (43.8 + 30.3 kg, P < 0.01). When comparing markers of mitochondrial function, the following were observed: pyruvate dehydrogenase (PDH) activity was lower in CC patients pre-surgery (P < 0.001) but normalized post-resection and cytochrome c oxidase and pyruvate dehydrogenase E2 subunit protein expression were lower in CC patients pre-surgery and not restored to control values post-resection (P < 0.001). Nuclear factor kappa-B, an inflammatory marker, was higher in CC patients pre-surgery compared to controls (P < 0.01), returning to control levels post-resection. CONCLUSION: Muscle mass was affected by surgery rather than cancer per se. PDH activity was however lower in cancer patients, suggesting that muscle mass and mitochondrial enzyme activity are not inextricably linked. This reduction in mitochondrial enzyme activity may well contribute to the significant risks of major surgery to which CC patients are exposed.
    • Evaluation of a nudge intervention providing simple feedback to clinicians of the consequence of radiation exposure on demand for computed tomography: a controlled study.

      Young, B; Shaw, D; Langley, T; Norwood, Mark (2019-07)
      Computed tomography (CT) is readily available in developed countries. As one of the side effects includes an increased risk of cancer, interventions that may encourage more judicious use of CT are important. Behavioural economics theory includes the use of nudges that aim to help more informed decisions to be made, although these have been rarely used in hospitals to date. We aimed to evaluate the impact of a simple educational message appended to the CT report on subsequent numbers of CT completed using a controlled interrupted time series design based in two teaching hospitals in the UK. The intervention was the addition of a non-directional educational message on the risk of ionising radiation to all CT reports. There was a statistically significant reduction in the number of CT requested in the intervention hospital compared to the control hospital (-4.6%, 95% confidence intervals -7.4 to -1.7, p=0.002) in the 12 months after the intervention was implemented. We conclude that a simple, non-directional nudge intervention has the capacity to modify clinician use of CT. This approach is cheap, and has potential in helping support doctors make informed decisions.
    • Faecal occult blood testing (FOBT) and interval bowel cancers-results of a multicentre study

      George, Anil Thomas (2015-06)
      Introduction We aimed to assess the incidence and demographics of interval cancers (cancers diagnosed within 2 years of a negative FOBT screening) in the eligible population of the East Midlands region. Method The National Bowel Cancer Audit Programme data from three centres (Queens Medical Centre, Nottingham; Royal Derby Hospital and Sherwood Forest Hospitals) for all colorectal cancers in the screening age group (60-74 years)over a 2- year period (August 2011-August 2013) were linked for their FOBT screening status (BCSP database/Eastern Hub). Three cancer groups were identified: interval cancers, screen detected (positive FOBT) and those in the non-uptake group (eligible patients who declined screening). Tumours at and distal to the splenic flexure were classed as left sided tumours. Dukes C and D tumours were classed as advanced tumours. All three centres were in incident rounds of screening. Results Of the 521 colorectal cancers identified, 128 (25%) were interval cancers, 162(31%) were screen detected and 231 (44%) were from the non-uptake group. Gender, ethnicity and Deprivation index were comparable between the three groups. The mean age in the interval cancer group was greater (67 yrs) compared to the screen detected (66 yrs) (p = 0.005). The interval cancer group had a higher incidence of right sided cancers (38% vs. 25% and 29%; X2=6.59; p = 0.033) compared to the screen-detected and non-uptake groups. Cancers detected in the interval cancer group were of a more advanced stage (Dukes C/D) (70% vs. 34% and 54%; X2=37.2;p < 0.005) in comparison to screen-detected and non-uptake groups. The one year mortality in the interval cancer group (16%) was higher than the non-uptake group (12%) and the screen detected group (3%) (16%vs12% and 3%; X2=13.8;p < 0.005). Conclusion A quarter of colorectal cancers identified in our screening-eligible population were interval cancers. We highlight the probability that these cancers were 'missed' by the guaiacbased FOBT screening tests. The interval cancer group also had poorer outcomes when compared to the screen-detected group. We highlight the need for a test with a lower false negative rate for population based FOBT screening.
    • Future Research Priorities for Morbidity Control of Lymphedema.

      Keeley, Vaughan (2017-01)
      BACKGROUND: Innovation in the treatment of lower extremity lymphedema has received low priority from the governments and pharmaceutical industry. Advancing lymphedema is irreversible and initiates fibrosis in the dermis, reactive changes in the epidermis and subcutis. Most medical treatments offered for lymphedema are either too demanding with a less than satisfactory response or patients have low concordance due to complex schedules. A priority setting partnership (PSP) was established to decide on the future priorities in lymphedema research. METHODS: A table of abstracts following a literature search was published in workshop website. Stake holders were requested to upload their priorities. Their questions were listed, randomized, and sent to lymphologists for ranking. High ranked ten research priorities, obtained through median score, were presented in final prioritization work shop attended by invited stake holders. A free medical camp was organized during workshop to understand patients' priorities. RESULTS: One hundred research priorities were selected from priorities uploaded to website. Ten priorities were short listed through a peer review process involving 12 lymphologists, for final discussion. They were related to simplification of integrative treatment for lymphedema, cellular changes in lymphedema and mechanisms of its reversal, eliminating bacterial entry lesions to reduce cellulitis episodes, exploring evidence for therapies in traditional medicine, improving patient concordance to compression therapy, epidemiology of lymphatic filariasis (LF), and economic benefit of integrative treatments of lymphedema. CONCLUSION: A robust research priority setting process, organized as described in James Lind Alliance guidebook, identified seven priority areas to achieve effective morbidity control of lymphedema including LF. All stake holders including Department of Health Research, Government of India, participated in the PSP.
    • Gastrointestinal Stromal Tumors (GISTs) as Incidental Findings in Gynecological Surgery.

      Phillips, A
      Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract that may be diagnosed incidentally as a part of intra-abdominal surgery for other diseases. This is a single center review to document the incidental finding of GIST at surgery for gynecological malignancies during a 10-yr period. Sixteen cases of incidental GISTs were identified in women ranging in age from 39 to 82 yr. GISTs presented as incidental secondary lesions in women undergoing surgery for other indications, typically primary debulking surgery for tubo-ovarian high-grade serous carcinoma. The GIST was located in the stomach wall in 9 cases. Other sites were cecum, omentum, and mesentery. Diagnosis of GIST was supported by immunohistochemistry in all cases and by molecular studies in 3 cases. Seventy-five percent of cases were micro-GISTs, measuring <2 cm in diameter and, where Miettinen and Lasota criteria could be applied, fitted into "no risk," "very low risk" or "low risk" prognostic groups. Seventy-five percent of women for whom survival data was available, showed disease-free survival at follow-up. The 2 women who died had concurrent high stage or high-grade gynecological malignancy at initial diagnosis.
    • Impact of a CUP service at the Royal Derby Hospital - One year on

      Warren, Rebecca; Raworth, Alison; Shankland, Catherine (2016-11)
      Background: 9600 UK patients are diagnosed with Cancer of Unknown Primary (CUP) each year. CUP represents 3-5% of all malignancies. Studies showthe diagnostic pathway to be lengthy, fractured between specialities, and that patients find it a difficult diagnosis to accept. In 2010 National Institute of Health & Clinical Excellence (NICE) issued guidelines recommending a Multidisciplinary Team (MDT) approach to managing patients with CUP. In 2013 Royal Derby Hospital (RDH), serving 600,000 people, launched a CUP MDT led by a Consultant Oncologist and two Specialist Nurses. Method: Utilising an in-house database of patients referred to CUP MDT, data for May 2014-15 was extracted, analysed and compared with data audited from May 2013-14. Results: 119 patients were referred to CUP MDT in May 2014-15. 74% of patients were seen by a member of CUP MDT. 56 (47.1%) were eventually diagnosed with CUP, 50 (42%) had a primary cancer site identified and 13 (10.9%) did not have cancer. Mean age was 72.2 years with minimal gender variation. Mean survival was 62 days with patients who died before registration, and 71 days without that data set. There were substantial reductions in number of MDT discussions per patient. 13 (10.9%) patients had Positron Emission Tomography (PET) scans. 58 (48.7%) patients solely received best supportive care. Conclusion: Average age, gender, life expectancy, and cancer subtypes reflect national trends. Primary site identification, investigations and treatment show alignment with national guidelines. Reduction in number of MDT discussions is encouraging as it improves patient experience, as do Palliative Medicine and Specialist Nurse input. RDH CUP MDT has demonstrated improvements in speed and accuracy of diagnosis in a well co-ordinated approach to care. A recommendation would be to participate in future gene expression profiling trials, when available, to optimise diagnostic accuracy, treatment options and survival.
    • Impact of straight to test pathways on time to diagnosis in oesophageal and gastric cancer.

      Leeder, Paul (2018-07)
      Background: Cancer survival in the UK has doubled in the last 40 years; however, 1-year and 5-year survival rates are still lower than other countries. One cause may be a delay between referral into secondary care and subsequent investigation. We set out to evaluate the impact of a straight to test pathway (STTP) on time to diagnosis for upper gastrointestinal (UGI) cancer. Methods: Six hospital Trusts across the East Midlands Clinical Network introduced a STTP enabling general practitioners to refer patients with suspected UGI cancer (oesophageal/gastric) for immediate investigation, without the need to see a hospital specialist first. Data were collected for all patients referred between 2013 and 2015 with suspected UGI cancer and stratified by STTP or traditional referral pathway. Overall time from referral to diagnosis was compared. Data from two Trusts who did not implement STTP acted as control. Results: 340 patients followed the STTP pathway and 495 followed the traditional route. STTP saved a mean of 7 days from referral to treatment (with a 95% CI of 3 to 11 days, p<0.008) and a mean of 16 days from referral to diagnosis, when compared with a traditional referral pathway. The number of diagnostic tests performed using STTP or traditional referral pathways were similar. Conclusion: A STTP is associated with an overall reduction of 1 week from referral to treatment for UGI cancer. The approach is feasible and did not require more resource. Larger studies are required to assess whether this time saving translates into improved cancer outcomes.
    • Impact of the menstrual cycle on commercial prognostic gene signatures in oestrogen receptor-positive primary breast cancer

      Sibbering, Mark (2021)
      Purpose: Changes occur in the expression of oestrogen-regulated and proliferation-associated genes in oestrogen receptor (ER)-positive breast tumours during the menstrual cycle. We investigated if Oncotype® DX recurrence score (RS), Prosigna® (ROR) and EndoPredict® (EP/EPclin) prognostic tests, which include some of these genes, vary according to the time in the menstrual cycle when they are measured. Methods: Pairs of test scores were derived from 30 ER-positive/human epidermal growth factor receptor-2-negative tumours sampled at two different points of the menstrual cycle. Menstrual cycle windows were prospectively defined as either W1 (days 1-6 and 27-35; low oestrogen and low progesterone) or W2 (days 7-26; high oestrogen and high or low progesterone). Results: The invasion module score of RS was lower (- 10.9%; p = 0.098), whereas the ER (+ 16.6%; p = 0.046) and proliferation (+ 7.3%; p = 0.13) module scores were higher in W2. PGR expression was significantly increased in W2 (+ 81.4%; p = 0.0029). Despite this, mean scores were not significantly different between W1 and W2 for any of the tests and the two measurements showed high correlation (r = 0.72-0.93). However, variability between the two measurements led to tumours being assigned to different risk categories in the following proportion of cases: RS 22.7%, ROR 27.3%, EP 13.6% and EPclin 13.6%. Conclusion: There are significant changes during the menstrual cycle in the expression of some of the genes and gene module scores comprising the RS, ROR and EP/EPclin scores. These did not affect any of the prognostic scores in a systematic fashion, but there was substantial variability in paired measurements.
    • Improving primary care identification of familial breast cancer risk using proactive invitation and decision support.

      Chorley, W (2020-06)
      Family history of breast cancer is a key risk factor, accounting for up to 10% of cancers. We evaluated the proactive assessment of familial breast cancer (FBC) risk in primary care. Eligible women (30 to 60 years) were recruited from eight English general practices. Practices were trained on FBC risk assessment. In four randomly-assigned practices, women were invited to complete a validated, postal family history questionnaire, which practice staff inputted into decision support software to determine cancer risk. Those with increased risk were offered specialist referral. Usual care was observed in the other four practices. In intervention practices, 1127/7012 women (16.1%) returned family history questionnaires, comprising 1105 (98%) self-reported white ethnicity and 446 (39.6%) educated to University undergraduate or equivalent qualification, with 119 (10.6%) identified at increased breast cancer risk and offered referral. Sixty-seven (56%) women recommended referral were less than 50 years old. From 66 women attending specialists, 26 (39.4%) were confirmed to have high risk and recommended annual surveillance (40-60 years) and surgical prevention; while 30 (45.5%) were confirmed at moderate risk, with 19 offered annual surveillance (40-50 years). The remaining 10 (15.2%) managed in primary care. None were recommended chemoprevention. In usual care practices, only ten women consulted with concerns about breast cancer family history. This study demonstrated proactive risk assessment in primary care enables accurate identification of women, including many younger women, at increased risk of breast cancer. To improve generalisability across the population, more active methods of engagement need to be explored.Trial registration: CRUK Clinical Trials Database 11779.
    • Individualising breast cancer treatment to improve survival and minimise complications in older women: a research programme including the PLACE RCT.

      Riches, Katie (2019-08)
      BACKGROUND: Over 44,000 women are diagnosed with breast cancer annually in the UK. The research comprised three workstreams (WSs) focused on older women. MAXIMISING SURVIVAL: WS1 – to identify the role of older women’s and surgeons’ preferences in cancer treatment decisions and whether comorbidity or fitness for surgery has an impact on survival. MINIMISING COMPLICATIONS: WS2 – to assess multifrequency bioimpedance (BEA) compared with perometry in identifying women predisposed to develop lymphoedema after axillary node clearance (ANC) surgery. WS3 – to assess, in women at risk of lymphoedema, whether or not applying compression garments prevents the onset of lymphoedema. DESIGN: WS1 – a prospective, consecutive cohort of surgical consultations with women aged ≥ 70 years with operable breast cancer. Interviews and questionnaire surveys of surgeons’ and women’s perceptions of responsibility for treatment decisions (Controlled Preference Score), effects related to survival and secondary outcomes. WS2 – women undergoing ANC for cancer in 21 UK centres underwent baseline and subsequent BEA, and perometer arm measurements and quality-of-life (QoL) assessments. WS3 – a randomised controlled trial testing standard versus applying graduated compression garments to the affected arm, for 1 year, in WS2 patients developing arm swelling. SETTING: Breast outpatient clinics in hospitals with specialist lymphoedema clinics. PARTICIPANTS: WS1 – patients aged ≥ 70 years with newly diagnosed, operable, invasive breast cancer. WS2 – women with node-positive cancer scheduled to undergo ANC. WS3 – WS2 participants developing a 4–9% increase in arm volume. INTERVENTIONS: WS1 – observational study. WS2 – observational study. WS3 – application of graduated compression garments to affected arm, compared with standard management, for 1 year. OUTCOMES: WS1 – self-report and clinically assessed health, QoL, complications and survival. WS2 – perometer and bioimpedance spectroscopy (BIS) measurements, QoL and health utility; and sensitivity and specificity of BIS for detecting lymphoedema compared with perometer arm measurements; in addition, a health economics assessment was performed. WS3 – time to the development of lymphoedema [≥ 10% relative arm-volume increase (RAVI)] from randomisation. RESULTS: WS1 – overall, 910 women were recruited, but numbers in the substudies differ depending on consent/eligibility. In a study of patient/surgeon choice, 83.0% [95% confidence interval (CI) 80.4% to 85.6%] had surgery. Adjusting for health and choice, only women aged > 85 years had reduced odds of surgery [odds ratio (OR) 0.18, 95%CI 0.07 to 0.44]. Patient role in treatment decisions made no difference to receipt of surgery. A qualitative study of women who did not have surgery identified three groups: ‘patient declined’, ‘patient considered’ and ‘surgeon decided’. In a survival substudy, adjusting for tumour stage, comorbidity and functional status, women undergoing surgery had one-third the hazard of dying from cancer. Serious complications from surgery were low and not predicted by older age. In a substudy of the effect of surgical decision-making on HRQoL, 59 (26%) received preferred treatment decision-making style. In multivariate analyses, change in HRQoL was associated neither with congruence (p = 0.133) nor with receipt of surgery (p = 0.841). In a substudy of receipt of chemotherapy in women aged ≥ 65 years, adjusting for tumour characteristics, health measures and choice, women aged ≥ 75 years had reduced odds of chemotherapy (OR 0.06, 95%CI 0.02 to 0.16). WS2 – lymphoedema by 24 months was detected in 21.4% of women by perometry (24.4% sleeve application) and in 39.4% by BIS. Perometer and BIS measurements correlated at 6 months (r = 0.61). Specificity for sleeve application was greater for perometry (94% CI 93% to 96%) at 24 months, as was a positive predictive value of 59% (95% CI 48% to 68%). Lymphoedema diagnosis reduced QoL scores. Sleeve application in the absence of RAVI of > 9% did not improve QoL or symptoms. A composite definition of lymphoedema was developed, comprising a 9% cut-off point for perometer and self-reported considerable swelling. Diagnostic accuracy was ≥ 94% at 6, 12 and 24 months. WS3 – the PLACE (Prevention of Lymphoedema After Clearance of External compression) trial recruited 143 patients, but recruitment was slow and closed early on the advice of the Independent Data Monitoring Committee. A qualitative substudy identified a number of barriers to recruitment. CONCLUSIONS: Half of older patients felt that they influenced decisions about their treatment. No relationship between decision preference being fulfilled and HRQoL in elderly patients diagnosed with cancer occurred, and older age did not predict complications. Primary surgery reduced the hazard of dying of cancer by two-thirds, independent of age, health and tumour characteristics. Women aged ≥ 75 years have reduced odds of receiving chemotherapy. Lymphoedema (along with a BMI of > 30 kg/m2, cigarette smoking and chemotherapy) reduces QoL. Changes in arm volume of > 9% predicted lymphoedema requiring and benefiting from sleeve application. The PLACE trial qualitative work provides a number of insights into problems of recruitment that were specific to this trial (stigma of compression garments) but that are also generalisable to other RCTs. LIMITATIONS: Both WS1 and WS2 were large, multicentre, UK cohort, observational studies. The WS3 PLACE trial has not reported yet but closed with approximately half of the patients originally planned. FUTURE WORK: Research producing objective measures for sleeve prescription in the NHS is required. TRIAL REGISTRATION: Current Controlled Trials ISRCTN48880939. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 7, No. 5. See the NIHR
    • Indolent CD8-positive lymphoid proliferation of acral sites: three further cases of a rare entity and an update on a unique patient.

      Persic, Mojca (2016-02)
      BACKGROUND: Primary cutaneous indolent CD8-positive lymphoid proliferation is an emerging entity characterized by slowly enlarging papules and nodules that are pathologically comprised of clonal nonepidermotropic medium-sized atypical CD8(+) T-cells. Although the majority of lesions are solitary and located on the ears,v bilateral symmetrical presentations have been described and lesions may arise at other peripheral or 'acral' sites. Patients follow a benign clinical course and systemic involvement has not yet been observed. Despite this, some medical practitioners classify such lesions as peripheral T-cell lymphoma, NOS, a category implying aggressive disease. OBJECTIVES: We present three cases seen in our institutions and provide an update on a previously reported unique patient who continues to develop recurrent and multifocal skin lesions. RESULTS: Systemic disease progression has not been observed, even in the presence of recurrent and multifocal cutaneous disease. CONCLUSIONS: Indolent CD8-positive lymphoid proliferation of acral sites is a distinctive and readily identifiable entity and should be included in the next consensus revision of cutaneous lymphoma classification. Although cases described thus far have followed an indolent clinical course, dermatologists should remain guarded about the prognosis and full staging and longitudinal observation are recommended until this condition is better understood