Measuring quality of life in people living with and beyond cancer in the UK.

PURPOSE: The aim of this study was to identify the most appropriate measure of quality of life (QoL) for patients living with and beyond cancer. METHODS: One hundred eighty-two people attending cancer clinics in Central London at various stages post-treatment, completed a series of QoL measures: FACT-G, EORTC QLQ-C30 , IOCv2 (positive and negative subscales) and WEMWBS, a wellbeing measure. These measures were chosen as the commonest measures used in previous research. Correlation tests were used to assess the association between scales. Participants were also asked about pertinence and ease of completion. RESULTS: There was a significant positive correlation between the four domain scores of the two health-related QoL measures (.32 ≤ r ≤ .72, P < .001), and a significant large negative correlation between these and the negative IOCv2 subscale scores (- .39 ≤ r ≤ - .63, P < .001). There was a significant moderate positive correlation between positive IOCv2 subscale and WEMWBS scores (r = .35, P < .001). However, neither the FACT-G nor the EORTC showed any significant correlation with the positive IOCv2 subscale. Participants rated all measures similarly with regards to pertinence and ease of use. CONCLUSION: There was little to choose between FACT-G, EORTC, and the negative IOC scales, any of which may be used to measure QoL. However, the two IOCv2 subscales capture unique aspects of QoL compared to the other measures. The IOCv2 can be used to identify those cancer survivors who would benefit from interventions to improve their QoL and to target specific needs thereby providing more holistic and personalised care beyond cancer treatment.

Dose-dense chemotherapy for untreated poor-prognosis and relapsed germ-cell tumours: an 18-year experience with GAMEC chemotherapy.

OBJECTIVE: To report a single-centre experience of the regimen GAMEC (granulocyte colony-stimulating factor, actinomycin-D, methotrexate with folinic acid rescue, etoposide and cisplatin) over 18 years in both untreated disease and relapse settings. METHODS: This retrospective cohort study was based on 162 patients who received GAMEC dose-dense chemotherapy incorporating actinomycin and high dose methotrexate. Survival outcomes were compared. Risk categorization based on (1) the International Prognostic Factor Study Group (IPFSG) criteria and (2) two factors, lactate dehydrogenase (LDH) levels greater than the upper limit of normal and age ≥35 years, were also compared in terms of survival outcomes using Cox proportional hazard regression modelling. RESULTS: Seventy-five patients with poor-prognosis disease, according to International Germ Cell Cancer Collaborative Group classification, received GAMEC as initial therapy. With a median follow-up of 63 months, the median progression-free survival (PFS) was >14 months. The 2-year PFS rate was 61.5% (95% confidence interval [CI] 49.1-71.6), and the 3-year overall survival (OS) rate was 71.9%. Seventy-six patients received GAMEC as second-line therapy (following failure of bleomycin, etoposide and cisplatin or etoposide cisplatin). The median PFS was 7.5 months (95% CI 5.2-not evaluable), the 2-year PFS rate was 43.5% (95% CI 32.1-54.4) and the 3-year OS rate was 53.7% (95% CI 41.6-64.3). In the third-line setting (n = 11), the 2-year PFS was 18.2% (95% CI 2.8-44.2). Overall, the treatment-related death rate declined from 10.5% in the first 15 years to 2.6% in the last 5 years. CONCLUSION: GAMEC was an effective regimen in untreated poor-prognosis disease and on relapse following conventional cisplatin and etoposide-based chemotherapy. Risk categorization based on LDH/age is more sensitive than that based on the updated IPFSG criteria. It is possible to identify patients who are particularly likely to benefit from this treatment, which has the important advantages of short duration and absence of bleomycin, particularly in patients with central nervous system and mediastinal disease. Low-dose induction treatment is associated with safer delivery of treatment without compromising survival.

Durable graft-versus-leukaemia effects without donor lymphocyte infusions - results of a phase II study of sequential T-replete allogeneic transplantation for high-risk acute myeloid leukaemia and myelodysplasia.

Allogeneic haematopoietic stem-cell transplantation remains the only curative treatment for relapsed/refractory acute myeloid leukaemia (AML) and high-risk myelodysplasia but has previously been limited to patients who achieve remission before transplant. New sequential approaches employing T-cell depleted transplantation directly after chemotherapy show promise but are burdened by viral infection and require donor lymphocyte infusions (DLI) to augment donor chimerism and graft-versus-leukaemia effects. T-replete transplantation in sequential approaches could reduce both viral infection and DLI usage. We therefore performed a single-arm prospective Phase II clinical trial of sequential chemotherapy and T-replete transplantation using reduced-intensity conditioning without planned DLI. The primary endpoint was overall survival. Forty-seven patients with relapsed/refractory AML or high-risk myelodysplasia were enrolled; 43 proceeded to transplantation. High levels of donor chimerism were achieved spontaneously with no DLI. Overall survival of transplanted patients was 45% and 33% at 1 and 3 years. Only one patient developed cytomegalovirus disease. Cumulative incidences of treatment-related mortality and relapse were 35% and 20% at 1 year. Patients with relapsed AML and myelodysplasia had the most favourable outcomes. Late-onset graft-versus-host disease protected against relapse. In conclusion, a T-replete sequential transplantation using reduced-intensity conditioning is feasible for relapsed/refractory AML and myelodysplasia and can deliver graft-versus-leukaemia effects without DLI.

Loss of MMP-8 in ductal carcinoma in situ (DCIS)-associated myoepithelial cells contributes to tumour promotion through altered adhesive and proteolytic function.

BACKGROUND: Normal myoepithelial cells (MECs) play an important tumour-suppressor role in the breast but display an altered phenotype in ductal carcinoma in situ (DCIS), gaining tumour-promoter functions. Matrix metalloproteinase-8 (MMP-8) is expressed by normal MECs but is lost in DCIS. This study investigated the function of MMP-8 in MECs and the impact of its loss in DCIS. METHODS: Primary normal and DCIS-associated MECs, and normal (N-1089) and DCIS-modified myoepithelial (ß6-1089) cell lines, were used to assess MMP-8 expression and function. ß6-1089 lacking MMP-8 were transfected with MMP-8 WT and catalytically inactive MMP-8 EA, and MMP-8 in N-1089 MEC was knocked down with siRNA. The effect on adhesion and migration to extracellular matrix (ECM), localisation of α6ß4 integrin to hemidesmosomes (HD), TGF-ß signalling and gelatinase activity was measured. The effect of altering MEC MMP-8 expression on tumour cell invasion was investigated in 2D and 3D organotypic models. RESULTS: Assessment of primary cells and MEC lines confirmed expression of MMP-8 in normal MEC and its loss in DCIS-MEC. Over-expression of MMP-8 WT but not MMP-8 EA in ß6-1089 cells increased adhesion to ECM proteins and reduced migration. Conversely, knock-down of MMP-8 in N-1089 reduced adhesion and increased migration. Expression of MMP-8 WT in ß6-1089 led to greater localisation of α6ß4 to HD and reduced retraction fibre formation, this being reversed by MMP-8 knock-down in N-1089. Over-expression of MMP-8 WT reduced TGF-ß signalling and gelatinolytic activity. MMP-8 knock-down enhanced TGF-ß signalling and gelatinolytic activity, which was reversed by blocking MMP-9 by knock-down or an inhibitor. MMP-8 WT but not MMP-8 EA over-expression in ß6-1089 reduced breast cancer cell invasion in 2D and 3D invasion assays, while MMP-8 knock-down in N-1089 enhanced cancer cell invasion. Staining of breast cancer cases for MMP-8 revealed a statistically significant loss of MMP-8 expression in DCIS with invasion versus pure DCIS (p = 0.001). CONCLUSIONS: These data indicate MMP-8 is a vital component of the myoepithelial tumour-suppressor function. It restores MEC interaction with the matrix, opposes TGF-ß signalling and MMP-9 proteolysis, which contributes to inhibition of tumour cell invasion. Assessment of MMP-8 expression may help to determine risk of DCIS progression.

Comparison of the impact of cancer between British and US long-term non-Hodgkin lymphoma survivors.

PURPOSE: The aims of this study were to examine quality of life, using the Impact of Cancer version 2 (IOCv2), in British non-Hodgkin lymphoma (NHL) survivors and investigate differences between survivors in the UK and the USA. METHODS: NHL survivors (326 UK and 667 US) completed the 37-item IOCv2 and psychological distress, fatigue and social support questionnaires. RESULTS: The IOCv2 showed good reliability in the British sample with higher internal consistency (Cronbach alpha 0.7-0.9) and no floor and ceiling effects. UK survivors showed significantly higher negative (p < 0.001) and higher positive (p = 0.003) IOC compared to US survivors. Younger survivors (p = 0.003), those with shorter time since diagnosis (p < 0.001) and with lower levels of social support (p = 0.001), showed more negative IOC in both groups. Higher negative IOC was also significantly associated with fatigue (p < 0.001) and depressive symptoms (p < 0.001) in both countries. Higher positive IOC was associated with female gender (p < 0.001), longer time since diagnosis (p = 0.02), those diagnosed at later stage (p < 0.05) and with greater social support (p = 0.004). Whereas significantly lower positive IOC was associated with white ethnicity (p < 0.001), higher education levels (p < 0.05) and fatigue (p = 0.001). CONCLUSIONS: The IOCv2 is reliable and applicable in UK and US populations. Both negative and positive IOC scores were higher in British compared to US survivors. However, in both countries, psychosocial factors consistently showed the greatest impact on QOL irrespective of clinical characteristics. Recognition and treatment of individuals with these risk factors is a high priority for improving QOL in long-term cancer survivors, as is the development of modular interventions aimed at increasing positive IOC as well as decreasing negative impact. The IOCv2 shows great potential both as a screening and assessment measure for examining cancer-related outcomes among survivors.

Heterogeneous response and progression patterns reveal phenotypic heterogeneity of tyrosine kinase inhibitor response in metastatic renal cell carcinoma.

BACKGROUND: Molecular intratumour heterogeneity (ITH) is common in clear cell renal carcinomas (ccRCCs). However, it remains unknown whether this is mirrored by heterogeneity of drug responses between metastases in the same patient. METHODS: We performed a retrospective central radiological analysis of patients with treatment-naïve metastatic ccRCC receiving anti-angiogenic tyrosine kinase inhibitors (TKIs) (sunitinib or pazopanib) within three similar phase II trials. Treatment was briefly interrupted for cytoreductive nephrectomy. All patients had multiple metastases that were measured by regular computed tomography scans from baseline until Response Evaluation Criteria In Solid Tumours (RECIST)-defined progression. Each metastasis was categorised as responding, stable or progressing. Patients were classed as having a homogeneous response if all lesions were of the same response category and a heterogeneous response if they differed. RESULTS: A total of 115 metastases were assessed longitudinally in 27 patients. Of these patients, 56% had a heterogeneous response. Progression occurred through the appearance of new metastases in 67%, through progression of existing lesions in 11% and by both in 22% of patients. Despite RECIST-defined progression, 57% of existing metastases remained controlled. The sum of controlled lesions was greater than that of uncontrolled lesions in 47% of patients who progressed only with measurable new lesions. CONCLUSIONS: We identified frequent ITH of anti-angiogenic TKI responses, with subsets of metastases responding and progressing within individual patients. This mirrors molecular ITH and may indicate that anti-angiogenic drug resistance is confined to subclones and not encoded on the trunk of the tumours' phylogenetic trees. This is clinically important, as patients with small-volume progression may benefit from drug continuation. Predominant progression with new rather than in existing metastases supports a change in disease biology through anti-angiogenics. The results highlight limitations of RECIST in heterogeneous cancers, which may influence clinical trial data validity. This analysis requires prospective confirmation. TRIAL REGISTRATION: European Clinical Trials Database(EudraCT): 2009-016675-29 , registered 17 March 2010; EudraCT: 2006-004511-21 , registered 09 March 2007; EudraCT: 2006-006491-38 , registered 22 December 2006.

Simulation-based sample-sizing and power calculations in logistic regression with partial prior information.

There have been many approximations developed for sample sizing of a logistic regression model with a single normally-distributed stimulus. Despite this, it has been recognised that there is no consensus as to the best method. In pharmaceutical drug development, simulation provides a powerful tool to characterise the operating characteristics of complex adaptive designs and is an ideal method for determining the sample size for such a problem. In this paper, we address some issues associated with applying simulation to determine the sample size for a given power in the context of logistic regression. These include efficient methods for evaluating the convolution of a logistic function and a normal density and an efficient heuristic approach to searching for the appropriate sample size. We illustrate our approach with three case studies. Copyright © 2016 John Wiley & Sons, Ltd.

Aspergillus-Specific Lateral-Flow Device and Real-Time PCR Testing of Bronchoalveolar Lavage Fluid: a Combination Biomarker Approach for Clinical Diagnosis of Invasive Pulmonary Aspergillosis.

Clinical experience with the impact of serum biomarkers for invasive fungal disease (IFD) varies markedly in hemato-oncology. Invasive pulmonary aspergillosis (IPA) is the most common manifestation, so we evaluated biomarkers in bronchoalveolar lavage (BAL) fluid. An Aspergillus-specific lateral-flow device (LFD), quantitative real-time PCR (qPCR), and the galactomannan (GM) test were used with 32 BAL fluid samples from 32 patients at risk of IPA. Eight patients had proven IPA, 3 had probable IPA, 6 had possible IPA, and 15 patients had no IPA by European Organization for Research and Treatment of Cancer Invasive Fungal Infections Cooperative Group/Mycoses Study Group of the National Institute of Allergy and Infectious Diseases (EORTC/MSG) criteria. The diagnostic accuracies of the tests were evaluated, and pairwise agreement between biomarkers was calculated. The diagnostic performance of the EORTC/MSG criteria was evaluated against the test(s) identified to be the most useful for IPA diagnosis. Using the EORTC/MSG criteria, the sensitivities of qPCR and LFD were 100% and the sensitivity of the GM test was 87.5% (GM test index cutoff, >0.8), with the tests having specificities of between 66.7 and 86.7%. The agreement between the results of qPCR and LFD was almost perfect (Cohen's kappa coefficient = 0.93, 95% confidence interval, 0.81 to 1.00). LFD and qPCR combined had a sensitivity of 100% and a specificity of 85.7%. Calcofluor staining and culture of all BAL fluid samples were negative for fungal infection. The median time from the start of mold-active antifungal therapy to the time of collection of BAL fluid was 6 days. Reversing roles and using dual testing by LFD and qPCR to classify cases, the EORTC/MSG criteria had a sensitivity of 83.3%. All three tests are useful for the diagnosis of IPA in BAL fluid samples. Despite the significant delays between the start of antifungal therapy and bronchoscopy, unlike microscopy and culture, the biomarkers remained informative. In particular, the combination of LFD and qPCR allows the sensitive and specific detection of IPA.

Psychosocial factors associated with impact of cancer in longterm haematological cancer survivors.

To assess the impact of cancer (IOC) on subsequent quality of life (QOL), 718 long-term haematological cancer survivors completed validated psychosocial, functional and QOL scales, including IOC. Fifteen percent reported significant psychological distress, 18% high levels of fatigue and 10% moderate to severe functional impairment. These groups of participants also showed poorer QOL. There were no significant differences in psychological distress (P = 0·76), fatigue (P = 0·23) or functional impairment (P = 0·74) across different cancer subtypes. Two separate hierarchical regression analyses examined the combined association of disease-type, psychosocial and other factors on negative and positive IOC scores respectively. Higher negative IOC scores were significantly associated (P ≤ 0·001) with medical comorbidity, psychological distress, lower social support, high fatigue levels and functional impairment. Paediatric patients (diagnosed at <17 years) had significantly higher negative IOC scores than adult patients (P = 0·001); greater years since diagnosis was significantly (P < 0·001) associated with less negative IOC. Higher positive IOC was associated with acute leukaemia (P = 0·01); lower positive IOC with paediatric patients (P < 0·001), white ethnicity (P < 0·001), higher education (P = 0·003), no partner (P = 0·01) and lower social support (P = 0·01). Screening for medical comorbidity, psychological distress and fatigue identifies those needing most support and should allow earlier interventions to address negative and positive IOC to improve the well-being of cancer survivors.

Fertility and sexual function in long-term survivors of haematological malignancy: using patient-reported outcome measures to assess a neglected area of need in the late effects clinic.

Problems of sexual function and fertility in long-term survivors (≥5 years) of haematological malignancy are often neglected in clinic. Our centre carried out a questionnaire study in this population addressing patient-perceived fertility and sexual function. 718 patients responded (56% of those invited; 39% Hodgkin, 45% non-Hodgkin lymphoma, 16% acute leukaemia). Respondent women were more likely to remain childless than a normal control population. Self-reported infertility was more likely in men than women [odds ratio (OR) 1·77, P = 0·001]. Myeloablative therapy increased the likelihood of childlessness (OR 2·48, P = 0·004). Few attended fertility support services (12%). 24% of men banked sperm and 29% of these used the sample, of which 46% resulted in successful pregnancy. Fertility clinic attendance and sperm storage was more likely post-1990 (OR 4·05, P < 0·001; OR 5·05, P < 0·001 respectively). Reporting a negative impact of cancer on sexual function was more common in women than men (OR 2·20, P < 0·001), and increased with current age and age at diagnosis (by 3-4% per year, P ≤ 0·001) but decreased with longer follow-up (by 2%/year, P = 0·005). Patients on anti-depressants and those reporting cancer-related body change/appearance concerns more frequently reported a negative impact (P < 0·04 and P < 0·03 respectively). These self-reported outcomes confirm literature findings, suggest improvement over time, but highlight a need for involvement of support services.

Objective assessment of skills acquisition during laparoscopic surgery courses.

BACKGROUND: The aim of this prospective study is to objectively assess the acquisition of skills of trainees attending laparoscopic surgery courses. METHODS: Thirty-four junior surgical trainees had their laparoscopic skills assessed before and after attending 1 of 3 separate runs of 3-day core skills in laparoscopic surgery course. Nine control trainees were also included who did not attend the course. Three virtual tasks (camera navigation, hand-eye coordination, and 2-handed maneuver) were used from a virtual reality simulator (Simbionix) for assessment. Camera navigation was assessed by completion time and maintenance of horizontal view, whereas the other 2 tasks were assessed by completion time, path length (both hands), and the number of movements (both hands). A composite score of overall performance was calculated by combining all the 12 parameters. RESULTS: The course significantly (P < 0.001) improved 91% of the junior trainees' precourse laparoscopic skills. Around 70% to 85% of the participants had improvement in skills in all the parameters following the course. The significant improvements were seen in 10 out of 12 task-specific parameters (P ≤ .004) except path length of the left hand. No significant improvement in skills was seen in any 1 of the 12 parameters for the control participants except for a slight reduction in performance matrics. Foundation and core trainees had acquired significantly (P = .02) more skills (23% improvement) than the specialist trainees (8% improvement). Overall acquired skills did not differ significantly in terms of age, sex, or dominant hand of trainees. CONCLUSION: Objective validated methods can be used to demonstrate course efficacy in addition to providing participants with an insight into their skills. Junior trainees with little or no previous experience benefit the most from such courses irrespective of their age, sex, and dominant hand.

Significant decline in Galactomannan Signal during storage of clinical serum samples.

Galactomannan (GM) is widely used for detection of invasive aspergillosis in high-risk haemato-oncology patients. Recent publications have reported a lack of repeatability of GM detection. The objective of this retrospective study was to assess the repeatability of GM levels during storage of clinical samples. In a GM screening strategy, positive sera were repeat tested as per manufacturer's recommendations. Short-term (ST) storage of samples was at +4 °C while long-term (LT) storage was at -80 °C. Bronchoalveolar (BAL) fluid was also repeating tested after ST storage and LT storage. Wilcoxon Signed Ranks Test was employed to assess the repeatability of GM levels. In a subset of 14 GM positive sera, repeat testing was performed on both the original serum and ethylenediaminetetraacetic acid (EDTA) pre-treated sample. There was a significant reduction in GM signals on repeat testing following ST storage (median GM index: 0.65 vs. 0.19; p < 0.001) and LT storage (median GM index: 0.56 vs. 0.10; p < 0.001) of serum samples. Of samples that were initially GM positive, an average GM index reduction of 50% was seen, with approximately two-thirds becoming GM negative on repeat testing of the same sample. In contrast, GM signal loss was not seen on repeat testing of BAL fluid following ST or LT storage. When GM positive serum samples were repeat tested using EDTA pre-treated serum from the first step of the testing protocol, all samples remained GM positive. In contrast, when the same samples were repeat tested from the original collected serum, 9 samples (64%) became GM negative. The significant reduction in GM signals during ST and LT storage of serum samples has implications for clinical management. Although the reasons for GM decline are unknown, they occur prior to the EDTA pre-treatment stage, indicating that the time from phlebotomy to testing should be minimized. BAL fluid GM index values remain stable.

Comparison of 2 extended activities of daily living scales with the Barthel Index and predictors of their outcomes: cohort study within the South London Stroke Register (SLSR).

BACKGROUND AND PURPOSE: Basic activities of daily living measures are often supplemented by extended activities of daily living. We compared the Frenchay Activities Index (FAI) and Nottingham Extended Activities of Daily Living (NEADL) with the Barthel Index (BI) in terms of distribution of scores, concurrent validity, reliability, and their agreement and investigated the predictors of scales outcomes. METHODS: Two hundred thirty-eight patients from the population-based South London Stroke Register were assessed with the BI, FAI, and NEADL 3 months after a first-ever stroke. The pairwise relationship was studied using correlations, fractional polynomial regression, and Bland and Altman plot; the baseline predictors, for example, sociodemography, case severity: National Institutes of Health Stroke Scale, and 7-day Abbreviated Memory Test, comorbidities, and acute treatments by negative binomial regression. RESULTS: The BI was highly affected by a ceiling effect (33% had the highest score), FAI was only affected by floor effect (19%), but NEADL was symmetrical with only 4% highest and lowest score. Despite high concurrent validity of the scales (r ≥0.80, P<0.001), they agreed poorly only for the highest and the lowest level of activities. The association and agreement of NEADL with BI was higher than that of FAI with BI. Severe stroke patients (National Institutes of Health Stroke Scale >13) had 28% lower BI (79% lower FAI and 62% lower NEADL) score than nonsevere patients (P≤0.001). Cognitively intact patients (Abbreviated Memory Test: 8-10) had 2.3 times greater FAI values (65% higher NEADL) compared with impaired patients (P<0.001). CONCLUSIONS: The NEADL scale was symmetrical, concurrently valid with no floor and ceiling effects. It corresponded better with BI than FAI did confirming its basic activities of daily living properties, yet it is a more sensitive tool for extended activities of daily living without the floor and ceiling effects. Future functional status could be predicted by the acute stage National Institutes of Health Stroke Scale score, whereas only extended activities of daily living status could be predicted by the Abbreviated Memory Test score. Predicting future functional status at the acute stage may decrease unnecessary length of stay in acute care settings.

Surgical management and outcomes for stage 1 malignant ovarian germ cell tumours: A UK multicentre retrospective cohort study.

OBJECTIVE: To describe the current surgical management of stage 1 malignant ovarian germ cell tumours and correlated oncological outcomes. STUDY DESIGN: We undertook a retrospective study of all stage 1 primary ovarian germ cell tumours treated in four major UK gynaecology oncology centres over 12 years. We assessed route of surgery, fertility-sparing approaches, ovarian cystectomy alone, and surgical staging and correlated these with clinical outcomes. RESULTS: Eighty-six patients were followed-up for a median of 4.4 years (IQR 4.3). The median age was 26 (range 11-47). There were 24 (27.9%) dysgerminomas, 13 (15.1%) yolk sac tumours, 10 (11.3%) mixed germ cell tumours, and 39 (45.3%) immature teratomas. Overall survival was 96.6% (OS, 95% CI 91.9-100%), with event free survival of 81.8% (EFS, 95% CI 72.5-92.3) at 5 years. The majority had fertility-sparing surgery (93%, n = 80). In a subset of patients with immature teratoma, there was no significant difference in recurrence or survival if patients underwent unilateral cystectomy only or salpingo-oophorectomy. Laparotomy was the most common approach (n = 66, 76.7%), used more frequently for larger tumours > 10 cm. Surgical staging procedures were undertaken in 42 (48.6%) patients with no significant difference in rates of staging across histological subtypes. Peritoneal biopsies were taken in 11 (12.7%), omental assessment in 40 (46.5%) and lymphadenectomy in 10 (11.6%). There was no significant difference in EFS between patients who underwent staging procedures (83%, CI 71-98%) versus those that did not (84%, CI 72-98%). There was no significant difference in the rate of staging procedures in paediatric (42.1% 8/19) and adult (57.9% 34/67) populations. CONCLUSIONS: Across all histologies and ages, the absence of surgical staging did not impact upon disease free or overall survival in this cohort. This study also raises the possibility of a role for ovarian cystectomy in immature teratoma. These findings warrant investigation in larger prospective studies.

Individual care plans can reduce hospital admission rate for patients who frequently attend the emergency department.

AIM: To investigate the impact, in terms of hospital admission and investigations, of individual care plans for patients who frequently attend the emergency department (ED). METHOD: 32 patients who regularly attended the ED at St Thomas' Hospital were included in the study. After review of ED and hospital case records, an individual care plan was prepared for future attendances. The numbers of ED attendances, hospital admissions and investigations were collated from the electronic patient record system and compared for the 12 months prior to and 12 months after introduction of the care plan. Primary outcome measure was reduction in the number of hospital admissions (as a percentage of ED attendance). Secondary outcome measures were a reduction in the number of investigations and ED attendances. RESULTS: In the 12 months prior to introduction of the individual care plans, the 32 patients accounted for 858 ED attendances and 209 admissions to hospital. In 12 months after introduction of the care plans, the number of ED attendances fell to 517, with only 77 hospital admissions. Median number of hospital admissions (as a percentage of ED attendances) fell from 18.8% to 7.1% (p=0.014) after introduction of the care plan. There were also reductions in median number of ED attendances (19 vs. 5, p=0.001), median number of radiology tests (4 vs 1, p=0.001) and median number of blood tests (55 vs. 12, p<0.001). CONCLUSIONS: Individual care plans for a carefully selected group of patients who frequently attend the emergency department can result in a decrease in the number of hospital admissions and number of investigations.

Uncovering trends in training progression for a national cohort of psychiatry trainees: discrete-time survival analysis.

BACKGROUND: The global rise in mental health issues calls for a strong psychiatry workforce. Yet, psychiatry training worldwide is facing recruitment challenges, causing unfilled consultant posts and possibly threatening the quality of patient care. An in-depth understanding of trainees' progression through training is warranted to explore what happens to recruited trainees during training. AIMS: To uncover current trends in psychiatry trainees' progression through training in the UK. METHOD: This national retrospective cohort study with data from the UK Medical Education Database used discrete-time survival analysis to analyse training progression for those trainees who started their core psychiatry post in 2012-2017 (2820 trainees; 59.6% female, 67.6% UK graduates (UKGs)). The impact of sociodemographic characteristics on training progression were also investigated. RESULTS: The overall probability of completing training in 6 years (minimum years required to complete psychiatry training in the UK) was 17.2% (ranging from 4.8% for non-UKG females to 29% for UKG males). The probability to not progress was highest (57.1%) from core to specialty training. For UKGs, trainees from ethnicities other than White, trainees with a disability, and trainees who had experienced childhood social deprivation (measured as entitlement to free school meals) had a significantly (P ≤ 0.02) lower probability of completing training in 6 years. CONCLUSIONS: Less than one in five psychiatry trainees are likely to complete training in 6 years and this probability varies across groups of doctors. Completing psychiatry training in 6 years is, therefore, the exception rather than the norm and this has important implications for trainees, those planning psychiatry workforces or responsible for psychiatry training.

What Is the Best Option for Treating Venous Leg Ulcer Infection? Is It Systemic or Local Antimicrobials or a Combination of Both? A Retrospective Cohort Study.

Study aimed to find out best option (systemic or local antimicrobial or combination of both) for treating venous leg ulcer infection. Patients' files were reviewed retrospectively. Participants were divided into three groups. First group was treated by systemic antibiotics only (SABG). Second group received local antibiotics only (LABG). Third group was treated by combination of both (SLABG). Treatment strategies were compared based on multiple parameters using Pearson chi-squared test & relative risk (RR). 456 participants identified: 153 in SABG, 152 in LABG and 151 in SLABG. It was found that SLABG group was statistically significantly better than other single treatment strategies regarding all parameters (except bacterial resistance): (i) ulcer healing within usual duration (10-14 days) was 2.4 time higher (RR 2.4, 95% CI: 1.84, 3.12), (ii) probability of not recurring ulcer was 2.6 time higher (iii) probability of not getting increased wound size, abscess,cellulites was 5 times higher (iv) probability of not developing septicemia was 40% higher (v) probability of not requiring surgical intervention was 30% higher (vi) fewer patients needed prolonged hospitalization & lower cost was 8 times more likely (vii) patients were 3 times more satisfied during treatment .Probability of bacterial resistance was six times higher with SLABG and 5 times higher with SABG compared to LABG. For RR & CI values for all above parameters, see results below Ultimately, combination of both systemic and local antimicrobials may be best option to treat venous leg ulcer infection with out- weight with emergence of antibiotic-resistance microorganism.

Cross-sectional exploration of the impact of the Dr Bawa-Garba case on doctors' professional behaviours and attitudes towards the regulator.

OBJECTIVE: This paper examines the impact on doctors' attitudes towards the General Medical Council (GMC) and on professional behaviours (reflective practice and raising concerns) following the Dr Bawa-Garba case. DESIGN: A cross-sectional survey designed using the theoretical lens of the theory of planned behaviour (TPB) was administered from September 2017 to February 2019. By chance, this coincided with critical events in the Dr Bawa-Garba case. SETTING: Primary and secondary care settings across a broad geographical spread in England. PARTICIPANTS: 474 doctors. OUTCOME MEASURES: Attitudes towards the GMC and two professional behaviours in TPB dimensions. RESULTS: Attitudes towards the GMC became more negative during the period that the Medical Practitioners Tribunal Service and GMC suspended and subsequently erased Dr Bawa-Garba from the medical register. Specifically, confidence that doctors are well regulated by the GMC and that the GMC's disciplinary procedures produce fair outcomes was rated more negatively. After this period, overall attitudes start to recover and soon returned close to baseline; however, confidence in how the GMC regulates doctors and their disciplinary procedures improved but still remained below baseline. There was no change in doctors' attitudes or intention to reflect or raise concerns. CONCLUSIONS: The lack of change in doctors' attitudes towards the GMC's guidance, the approachability of the regulator, defensive practice and professional behaviours as a response to the Dr Bawa-Garba case demonstrates the resilient and indelible nature of medical professionalism. At the time, professional bodies reported that repairing doctors' trust and confidence would take time and a significant effort to restore. However, this study suggests that attitudes are more fluid. Despite the high-profile nature of this case and concerns articulated by medical bodies regarding its impact on trust, the actual decline in doctors' overall attitudes towards the GMC was relatively short lived and had no measurable impact on professionalism.

Obesity and diabetes are major risk factors for epicardial adipose tissue inflammation.

BACKGROUNDEpicardial adipose tissue (EAT) directly overlies the myocardium, with changes in its morphology and volume associated with myriad cardiovascular and metabolic diseases. However, EAT's immune structure and cellular characterization remain incompletely described. We aimed to define the immune phenotype of EAT in humans and compare such profiles across lean, obese, and diabetic patients.METHODSWe recruited 152 patients undergoing open-chest coronary artery bypass grafting (CABG), valve repair/replacement (VR) surgery, or combined CABG/VR. Patients' clinical and biochemical data and EAT, subcutaneous adipose tissue (SAT), and preoperative blood samples were collected. Immune cell profiling was evaluated by flow cytometry and complemented by gene expression studies of immune mediators. Bulk RNA-Seq was performed in EAT across metabolic profiles to assess whole-transcriptome changes observed in lean, obese, and diabetic groups.RESULTSFlow cytometry analysis demonstrated EAT was highly enriched in adaptive immune (T and B) cells. Although overweight/obese and diabetic patients had similar EAT cellular profiles to lean control patients, the EAT exhibited significantly (P ≤ 0.01) raised expression of immune mediators, including IL-1, IL-6, TNF-α, and IFN-γ. These changes were not observed in SAT or blood. Neither underlying coronary artery disease nor the presence of hypertension significantly altered the immune profiles observed. Bulk RNA-Seq demonstrated significant alterations in metabolic and inflammatory pathways in the EAT of overweight/obese patients compared with lean controls.CONCLUSIONAdaptive immune cells are the predominant immune cell constituent in human EAT and SAT. The presence of underlying cardiometabolic conditions, specifically obesity and diabetes, rather than cardiac disease phenotype appears to alter the inflammatory profile of EAT. Obese states markedly alter EAT metabolic and inflammatory signaling genes, underlining the impact of obesity on the EAT transcriptome profile.FUNDINGBarts Charity MGU0413, Abbott, Medical Research Council MR/T008059/1, and British Heart Foundation FS/13/49/30421 and PG/16/79/32419.

Capivasertib Plus Paclitaxel Versus Placebo Plus Paclitaxel As First-Line Therapy for Metastatic Triple-Negative Breast Cancer: The PAKT Trial.

PURPOSE: The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is frequently activated in triple-negative breast cancer (TNBC). The AKT inhibitor capivasertib has shown preclinical activity in TNBC models, and drug sensitivity has been associated with activation of PI3K or AKT and/or deletions of PTEN. The PAKT trial was designed to evaluate the safety and efficacy of adding capivasertib to paclitaxel as first-line therapy for TNBC. PATIENTS AND METHODS: This double-blind, placebo-controlled, randomized phase II trial recruited women with untreated metastatic TNBC. A total of 140 patients were randomly assigned (1:1) to paclitaxel 90 mg/m2 (days 1, 8, 15) with either capivasertib (400 mg twice daily) or placebo (days 2-5, 9-12, 16-19) every 28 days until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), PFS and OS in the subgroup with PIK3CA/AKT1/PTEN alterations, tumor response, and safety. RESULTS: Median PFS was 5.9 months with capivasertib plus paclitaxel and 4.2 months with placebo plus paclitaxel (hazard ratio [HR], 0.74; 95% CI, 0.50 to 1.08; 1-sided P = .06 [predefined significance level, 1-sided P = .10]). Median OS was 19.1 months with capivasertib plus paclitaxel and 12.6 months with placebo plus paclitaxel (HR, 0.61; 95% CI, 0.37 to 0.99; 2-sided P = .04). In patients with PIK3CA/AKT1/PTEN-altered tumors (n = 28), median PFS was 9.3 months with capivasertib plus paclitaxel and 3.7 months with placebo plus paclitaxel (HR, 0.30; 95% CI, 0.11 to 0.79; 2-sided P = .01). The most common grade ≥ 3 adverse events in those treated with capivasertib plus paclitaxel versus placebo plus paclitaxel, respectively, were diarrhea (13% v 1%), infection (4% v 1%), neutropenia (3% v 3%), rash (4% v 0%), and fatigue (4% v 0%). CONCLUSION: Addition of the AKT inhibitor capivasertib to first-line paclitaxel therapy for TNBC resulted in significantly longer PFS and OS. Benefits were more pronounced in patients with PIK3CA/AKT1/PTEN-altered tumors. Capivasertib warrants further investigation for treatment of TNBC.