Publications by authors named "Shah-Jalal Sarker"

33 Publications

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

JCI Insight 2021 Jul 20. Epub 2021 Jul 20.

William Harvey Research Institute, Queen Mary University of London, London, United Kingdom.

Background: Epicardial 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. This study aimed to define the immune phenotype of EAT in humans, and compare such profiles across lean, obese and diabetic patients.

Methods: A total of 152 adult patients undergoing open chest coronary artery bypass grafting (CABG), valve repair/replacement (VR) surgery or combined CABG/valve surgery were recruited to the study. Patients' clinical and biochemical data alongside epicardial adipose tissue (EAT), subcutaneous adipose tissue (SAT) and pre-operative 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 different metabolic profiles to assess whole transcriptome changes observed in these groups.

Results: Flow cytometry analysis demonstrated that EAT is highly enriched in adaptive immune (T and B) cells. Whilst overweight/obese and diabetic patients had similar EAT cellular profiles to lean control patients, the EAT exhibited significantly (P≤.01) raised expression of immune mediators including: interleukin1 (IL1), IL6, tumour necrosis factorα (TNFα) and interferonγ (IFNγ). These changes were not observed in either 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.

Conclusions: Adaptive 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 signalling genes, underlining the impact of obesity on the EAT transcriptome profile.
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http://dx.doi.org/10.1172/jci.insight.145495DOI Listing
July 2021

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

BJPsych Open 2021 Jun 28;7(4):e120. Epub 2021 Jun 28.

Research Department of Medical Education, UCL Medical School, University College London, UK.

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.
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http://dx.doi.org/10.1192/bjo.2021.958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269924PMC
June 2021

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

Support Care Cancer 2021 Mar 30. Epub 2021 Mar 30.

Centre for Psychiatry, Wolfson Institute of Preventive Medicine, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, 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.
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http://dx.doi.org/10.1007/s00520-021-06105-zDOI Listing
March 2021

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.

Int J Low Extrem Wounds 2021 Jan 22:1534734620980850. Epub 2021 Jan 22.

UCL Medical School, London, UK.

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.
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http://dx.doi.org/10.1177/1534734620980850DOI Listing
January 2021

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

J Clin Oncol 2020 02 16;38(5):423-433. Epub 2019 Dec 16.

Institute of Cancer Research, London, United Kingdom.

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/m (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 // 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 = .06 [predefined significance level, 1-sided = .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 = .04). In patients with //-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 = .01). The most common grade ≥ 3 adverse events in those treated with capivasertib plus paclitaxel versus placebo plus paclitaxel, respectively, were diarrhea (13% 1%), infection (4% 1%), neutropenia (3% 3%), rash (4% 0%), and fatigue (4% 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 //-altered tumors. Capivasertib warrants further investigation for treatment of TNBC.
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http://dx.doi.org/10.1200/JCO.19.00368DOI Listing
February 2020

Can Waterlow score predict 30-day mortality and length of stay in acutely admitted medical patients (aged ≥65 years)? Evidence from a single centre prospective cohort study.

BMJ Open 2019 11 14;9(11):e032347. Epub 2019 Nov 14.

Cardiology, Lister Hospital, Stevenage, UK.

Objective: This study aimed to explore the potential for the Waterlow score (WS) to be used as a predictor of 30-day mortality and length of hospital stay (LHS) in acutely admitted medical patients aged 65 years and older.

Design: Prospective observational cohort study.

Setting: UK District General Hospital.

Subjects: 834 consecutive patients aged 65 years and older admitted acutely to medical specialties between 30 May and 22 July 2014.

Methods: Admission WS (range 4-64) assessment paired with the patient's status at 30 days in terms of mortality and their LHS.

Primary Outcomes: 30-day mortality and length of inpatient stay.

Results: 834 consecutive acute medical admissions had their WS recorded. 30-day mortality was 13.1% (109 deaths). A significant difference in the distribution of WS (p<0.001) was seen between those who survived (median 12) and those who died (median 16) within 30 days, particularly within respiratory (p<0.001), stroke (p<0.001), cardiology (p<0.016), non-respiratory infections (p<0.018) and trauma (p<0.044) subgroups. Odds of dying within 30 days increased threefold for every 10-unit increase in the WS (p<0.001, 95% CI 2.1 to 4.3). LHS was also positively linearly associated with the WS in those who survived 30 days (median=5, IQR=10; r=0.32, p<0.01). A five-unit increase in WS was associated with approximately 5 days increase in LHS. On the other hand, quadratic regression showed this relationship was curvilinear and negative (concave) for those who died within 30 days where a five-unit increase in WS was associated with an approximately 10 days decrease in LHS.

Conclusion: This study demonstrates an association between a high WS and both 30-day mortality and LHS. This is particularly significant for mortality in patients in the respiratory, stroke and cardiac subcategories. The WS, a nursing-led screening tool that is carried out on virtually all admissions to UK hospitals, could have additional use at the time of patient admission as a risk assessment tool for 30-day mortality as well as a predictor of LHS.
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http://dx.doi.org/10.1136/bmjopen-2019-032347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886901PMC
November 2019

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

BJU Int 2020 06 4;125(6):843-852. Epub 2020 May 4.

Department of Medical Oncology, St Bartholomew's Hospital, London, UK.

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.
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http://dx.doi.org/10.1111/bju.14947DOI Listing
June 2020

Fulvestrant Plus Vistusertib vs Fulvestrant Plus Everolimus vs Fulvestrant Alone for Women With Hormone Receptor-Positive Metastatic Breast Cancer: The MANTA Phase 2 Randomized Clinical Trial.

JAMA Oncol 2019 Nov;5(11):1556-1564

Barts Cancer Institute, Centre for Experimental Cancer Medicine, Queen Mary University of London, London, United Kingdom.

Importance: Randomized clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Everolimus inhibits the mammalian target of rapamycin complex 1 (mTORC1) complex but not mTORC2, which can set off an activating feedback loop via mTORC2. Vistusertib, a dual inhibitor of mTORC1 and mTORC2, has demonstrated broad activity in preclinical breast cancer models, showing superior activity to everolimus.

Objective: To evaluate the safety and efficacy of vistusertib in combination with fulvestrant compared with fulvestrant alone or fulvestrant plus everolimus in postmenopausal women with estrogen receptor-positive advanced or metastatic breast cancer.

Design, Setting, And Participants: The MANTA trial is an open-label, phase 2 randomized clinical trial in which 333 patients with estrogen receptor-positive breast cancer progressing after prior aromatase inhibitor treatment underwent randomization (2:3:3:2) between April 1, 2014, and October 24, 2016, at 88 sites in 9 countries: 67 patients were assigned to receive fulvestrant, 103 fulvestrant plus vistusertib daily, 98 fulvestrant plus vistusertib intermittently, and 65 fulvestrant plus everolimus. Treatment was continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. Analysis was performed on an intention-to-treat basis.

Interventions: Fulvestrant alone or in combination with vistusertib (continuous or intermittent dosing schedules) or everolimus.

Main Outcomes And Measures: The primary end point was progression-free survival (PFS).

Results: Among the 333 women in the study (median age, 63 years [range, 56-70 years]), median PFS was 5.4 months (95% CI, 3.5-9.2 months) with fulvestrant, 7.6 months (95% CI, 5.9-9.4 months) with fulvestrant plus daily vistusertib, 8.0 months (95% CI, 5.6-9.9 months) with fulvestrant plus intermittent vistusertib, and 12.3 months (95% CI, 7.7-15.7 months) with fulvestrant plus everolimus. There was no significant difference in PFS between those receiving fulvestrant plus daily or intermittent vistusertib and fulvestrant alone (hazard ratio, 0.88 [95% CI, 0.63-1.24]; P = .46; and hazard ratio, 0.79 [95% CI, 0.55-1.12]; P = .16).

Conclusions And Relevance: The combination of fulvestrant plus everolimus demonstrated significantly longer PFS compared with fulvestrant plus vistusertib or fulvestrant alone. The trial failed to demonstrate a benefit of adding the dual mTORC1 and mTORC2 inhibitor vistusertib to fulvestrant.

Trial Registration: ClinicalTrials.gov identifier: NCT02216786 and EudraCT number: 2013-002403-34.
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http://dx.doi.org/10.1001/jamaoncol.2019.2526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865233PMC
November 2019

A phase II study of carboplatin AUC-10 guided by positron emission tomography-defined metabolic response in metastatic seminoma.

Eur J Cancer 2019 07 25;115:128-135. Epub 2019 May 25.

Department of Oncology, Hillingdon Hospitals NHS Foundation Trust, London, United Kingdom.

Introduction: Carboplatin monotherapy for metastatic seminoma at a dose of AUC-10 has shown promising activity. Three or four cycles have been given with most haematological side-effects seen with the 4th cycle. An early response might allow de-escalation of therapy.

Methods: Forty-eight patients with metastatic seminoma (International Germ Cell Cancer Collaborative Group good prognosis) were recruited. Positron emission tomography (PET) scanning was performed before and after one cycle of carboplatin. Those with a Deauville score of 3 or less were given a total of three cycles of carboplatin, the rest received four.

Results: PET scanning allowed 44% to receive three cycles of carboplatin. With a median follow-up of 31.2 months, 95.6% (95% confidence interval: 83.5%-98.9%) were progression free. The overall survival at 2-years was 100%. Lower stage (2A and 2B) disease was significantly (P = 0.001) associated with the better metabolic response, but the association was not strong (correlation coefficient = -0.48). Over a third of the blood products given were used to support the 4th cycle. The regimen was well tolerated with a low incidence of grade III neutropenic sepsis or nausea and vomiting (<3% cycles).

Conclusion: Carboplatin AUC-10 monotherapy is effective with low toxicity. Early changes during PET scanning may allow de-escalation of therapy in high volume disease-comparison against combination therapy is warranted. CLINICALTRIALS.

Gov Identifier: NCT02272816.

Eudract Number: 2009-009882-33.
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http://dx.doi.org/10.1016/j.ejca.2019.04.013DOI Listing
July 2019

Is abdominal drainage after open emergency appendectomy for complicated appendicitis beneficial or waste of money? A single centre retrospective cohort study.

Ann Med Surg (Lond) 2018 Dec 9;36:168-172. Epub 2018 Nov 9.

UCL Medical School, UCL, Research Department of Medical Education, Room GF/664, Royal Free Campus, Hampstead, London, NW3 2PR, UK.

Background: Appendicitis is a medical condition that causes painful inflammation of the appendix. For acute appendicitis, appendectomy is immediately required as any delay may lead to serious complications such as gangrenous or perforated appendicitis with or without localized abscess formation. Patients who had appendectomy for complicated appendicitis are more prone to develop post-operative complications such as peritoneal abscess or wound infection. Sometimes, abdominal drainage is used to reduce these complications. However, the advantage of the abdominal drainage to minimize post-operative complications is not clear. Therefore, the aim of this study was to investigate whether the use of abdominal drainage after open emergency appendectomy for complicated appendicitis (perforated appendicitis with localized abscess formation only) can prevent or significantly reduce post-operative complications such as intra-peritoneal abscess formation or wound infection.

Methods: In this retrospective cohort study, files and notes were reviewed retrospectively for patients who had open emergency appendectomy for complicated appendicitis (perforated appendicitis with localized abscess formation only) and who had already been admitted and discharged from the surgical wards of Kerbala medical university/Imam Hussein medical city hospital/Kerbala/Iraq. Patients were selected according to specific inclusion and exclusion criteria. Patients were divided into two groups; drainage and non-drainage groups. The drainage group had intra-abdominal drain inserted after the surgery, while the non-drainage group had no drain placed post-operatively. A comparison between both groups was done in terms of these parameters; (i) the development of post operative intra-peritoneal abscess and or wound infection. (ii) The length and cost of hospital stay. (iii) The mortality outcomes. Statistical analysis was done using Pearson Chi-square test, Independent sample -test and Mann-Whitney Test.

Results: Of 227 patients with open emergency appendectomy for complicated appendicitis, 114 had received abdominal drain after the surgery. Fifty out of 114 patients (43.9%) with abdominal drainage developed post-operative intra-peritoneal abscess (abdominal or pelvic) while 53 out of 113 patients (46.9%) without drainage developed the same complication ( = 0.65). It was also revealed that for patients with drainage, 42 patients (36.8%) had post-operative wound infection, whereas this number was 38 (33.6%) for patients without drainage ( = 0.61). On the other hand, the patients with drain had significantly longer length of hospital stay (mean length of stay: 4.99 days versus 2.12 days,  < 0.001) and significantly higher cost (median cost per patient: $120 versus $60,  < 0.001).

Conclusion: Installation of abdominal drainage after open emergency appendectomy for complicated appendicitis did not bring any considerable advantage in terms of prevention or significant reduction of post-operative intra-peritoneal abscess and wound infection. Rather, it lengthened the hospital stay and doubled the cost of operation.
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http://dx.doi.org/10.1016/j.amsu.2018.10.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247409PMC
December 2018

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.

Br J Haematol 2018 02 26;180(3):346-355. Epub 2017 Oct 26.

Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.

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.
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http://dx.doi.org/10.1111/bjh.14980DOI Listing
February 2018

Patient-specific prediction of functional recovery after stroke.

Int J Stroke 2017 07 25;12(5):539-548. Epub 2017 Apr 25.

1 Division of Health and Social Care, King's College London, London, UK.

Background and aims Clinical predictive models for stroke recovery could offer the opportunity of targeted early intervention and more specific information for patients and carers. In this study, we developed and validated a patient-specific prognostic model for monitoring recovery after stroke and assessed its clinical utility. Methods Four hundred and ninety-five patients from the population-based South London Stroke Register were included in a substudy between 2002 and 2004. Activities of daily living were assessed using Barthel Index) at one, two, three, four, six, eight, 12, 26, and 52 weeks after stroke. Penalized linear mixed models were developed to predict patients' functional recovery trajectories. An external validation cohort included 1049 newly registered stroke patients between 2005 and 2011. Prediction errors on discrimination and calibration were assessed. The potential clinical utility was evaluated using prognostic accuracy measurements and decision curve analysis. Results Predictive recovery curves showed good accuracy, with root mean squared deviation of 3 Barthel Index points and a R of 83% up to one year after stroke in the external cohort. The negative predictive values of the risk of poor recovery (Barthel Index <8) at three and 12 months were also excellent, 96% (95% CI [93.6-97.4]) and 93% [90.8-95.3], respectively, with a potential clinical utility measured by likelihood ratios (LR+:17 [10.8-26.8] at three months and LR+:11 [6.5-17.2] at 12 months). Decision curve analysis showed an increased clinical benefit, particularly at threshold probabilities of above 5% for predictive risk of poor outcomes. Conclusions A recovery curves tool seems to accurately predict progression of functional recovery in poststroke patients.
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http://dx.doi.org/10.1177/1747493017706241DOI Listing
July 2017

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

Breast Cancer Res 2017 03 23;19(1):33. Epub 2017 Mar 23.

Centre for Tumour Biology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.

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 (β6-1089) cell lines, were used to assess MMP-8 expression and function. β6-1089 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 α6β4 integrin to hemidesmosomes (HD), TGF-β 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 β6-1089 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 β6-1089 led to greater localisation of α6β4 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-β signalling and gelatinolytic activity. MMP-8 knock-down enhanced TGF-β 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 β6-1089 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-β 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.
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http://dx.doi.org/10.1186/s13058-017-0822-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363009PMC
March 2017

Phase III, Double-Blind, Randomized Trial That Compared Maintenance Lapatinib Versus Placebo After First-Line Chemotherapy in Patients With Human Epidermal Growth Factor Receptor 1/2-Positive Metastatic Bladder Cancer.

J Clin Oncol 2017 Jan 28;35(1):48-55. Epub 2016 Oct 28.

Thomas Powles, Shah-Jalal Sarker, Charlotte Ackerman, and Daniel Berney, Queen Mary University of London; Simon Hughes and Simon Chowdhury, Guy's and St Thomas' National Health Service (NHS) Foundation Trust, London; Robert A. Huddart, Institute of Cancer Research, Sutton; Tony Elliott, Christie Hospital NHS Foundation Trust, Manchester; Robert Jones, University of Glasgow, Glasgow; Syed Hussain, University of Liverpool, Liverpool; Simon Crabb, University of Southampton, Southampton; Satinder Jagdev, St James's University Hospital, Leeds; John Chester, Cardiff University, Cardiff; Serena Hilman, Bristol Haematology and Oncology Centre, Bristol; Mark Beresford, Royal United Hospitals Bath, Bath; Graham Macdonald, Aberdeen Royal Infirmary, Aberdeen; Sundar Santhanam, Nottingham University Hospitals NHS Trust, Nottingham; John A. Frew, Northern Centre for Cancer Care, Newcastle upon Tyne; and Andrew Stockdale, University Hospital, Coventry, United Kingdom.

Purpose To establish whether maintenance lapatinib after first-line chemotherapy is beneficial in human epidermal growth factor receptor (HER) 1/HER2-positive metastatic urothelial bladder cancer (UBC). Methods Patients with metastatic UBC were screened centrally for HER1/HER2 overexpression. Patients who screened positive for HER1/2 and who did not have progressive disease during chemotherapy (four to eight cycles) were randomly assigned one to one to lapatinib or placebo after completion of first-line/initial chemotherapy for metastatic disease. The primary end point was progression-free survival (PFS). Results Between 2007 and 2013, 446 patients with UBC were screened, and 232 with HER1- or HER2-positive disease were randomly assigned. The median PFS for lapatinib and placebo was 4.5 (95% CI, 2.8 to 5.4) and 5.1 (95% CI, 3.0 to 5.8) months, respectively (hazard ratio, 1.07; 95% CI, 0.81 to 1.43; P = .63). The overall survival for lapatinib and placebo was 12.6 (95% CI, 9.0 to 16.2) and 12.0 (95% CI, 10.5 to 14.9) months, respectively (hazard ratio, 0.96; 95% CI, 0.70 to 1.31; P = .80). Discontinuation due to adverse events were similar in both arms (6% lapatinib and 5% placebo). The rate of grade 3 to 4 adverse events for lapatinib and placebo was 8.6% versus 8.1% ( P = .82). Preplanned subset analysis of patients strongly positive for HER1/HER2 (3+ on immunohistochemistry; n = 111), patients positive for only HER1 (n = 102), and patients positive for only HER2 (n = 42) showed no significant benefit with lapatinib in terms of PFS and overall survival ( P > .05 for each). Conclusion This trial did not find significant improvements in outcome by the addition of maintenance lapatinib to standard of care.
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http://dx.doi.org/10.1200/JCO.2015.66.3468DOI Listing
January 2017

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

BMC Med 2016 11 14;14(1):185. Epub 2016 Nov 14.

Centre for Evolution and Cancer, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK.

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.
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http://dx.doi.org/10.1186/s12916-016-0729-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108081PMC
November 2016

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

Support Care Cancer 2017 03 8;25(3):739-748. Epub 2016 Nov 8.

Centre for Psychiatry, Wolfson Institute of Preventive Medicine, Queen Mary University of London,, London, UK.

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.
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http://dx.doi.org/10.1007/s00520-016-3454-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5269457PMC
March 2017

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

Pharm Stat 2016 11 2;15(6):507-516. Epub 2016 Sep 2.

Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London, London, UK.

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.
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http://dx.doi.org/10.1002/pst.1773DOI Listing
November 2016

Safety and Efficacy of Pazopanib Therapy Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer.

JAMA Oncol 2016 Oct;2(10):1303-1309

Cancer Sciences Unit, University of Southampton, Southampton, England.

Importance: The role of cytoreductive nephrectomy in patients with metastatic renal cancer in the era of targeted therapy is uncertain.

Objective: To establish the safety and efficacy of upfront pazopanib therapy prior to cytoreductive nephrectomy in previously untreated patients with metastatic clear cell renal cancer.

Design, Setting, And Participants: Single-arm phase 2 study of 104 previously untreated patients with metastatic clear cell renal cancer recruited between June 2008 and October 2012 at cancer treatment centers with access to nephrectomy services. The minimum follow-up was 30 months.

Interventions: Patients received 12 to 14 weeks of preoperative pazopanib therapy prior to planned cytoreductive nephrectomy and continued pazopanib therapy after surgery. Treatment was stopped at disease progression.

Main Outcomes And Measures: The primary end point was clinical benefit (using Response Evaluation Criteria in Solid Tumors, version 1.1) prior to surgery (at 12-14 weeks). Secondary end points included surgical complications, progression-free survival (PFS), overall survival (OS), and biomarker analysis.

Results: Of 104 patients recruited, 100 patients were assessable for clinical benefit prior to planned nephrectomy; 80 of 104 (76.9%) were men; median [interquartile range] age, 64 [56-71] years). Overall, 84 of 100 (84% [95% CI, 75%-91%]) gained clinical benefit before planned nephrectomy. The median reduction in the size of the primary tumor was 14.4% (interquartile range, 1.4%-21.1%). No patients were unable to undergo surgery as a result of local progression of disease. Nephrectomy was performed in 63 (61%) of patients; 14 (22%) reported surgical complications. The 2 most common reasons for not undergoing surgery were progression of disease (n = 13) and patient choice (n = 9). There was 1 postoperative surgical death. The median PFS and OS for the whole cohort were 7.1 (95% CI, 6.0-9.2) and 22.7 (95% CI, 14.3-not estimable) months, respectively. Patients with MSKCC poor-risk disease or progressive disease prior to surgery had a poor outcome (median OS, 5.7 [95% CI, 2.6-10.8] and 3.9 [95% CI, 0.5-9.1] months, respectively). Surgical complications were observed in 14 (22%) of the nephrectomies. Biomarker analysis from sequential tissue samples revealed a decrease in CD8 expression (20.00 vs 13.75; P = .05) and significant reduction in expression of von Hippel-Lindau tumor suppressor (100 vs 40; P < .001) and C-MET (300 vs 100; P < .001) and increased programmed cell death ligand 1 expression (0 vs 1.5; P < .001) in the immune component. No on-treatment biomarker correlated with response.

Conclusions And Relevance: Nephrectomy after upfront pazopanib therapy could be performed safely and was associated with good outcomes in patients with intermediate-risk metastatic clear cell renal cancer.
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http://dx.doi.org/10.1001/jamaoncol.2016.1197DOI Listing
October 2016

Phase II Randomized Preoperative Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole Compared With Anastrozole Alone in Patients With Estrogen Receptor-Positive Breast Cancer.

J Clin Oncol 2016 06 14;34(17):1987-94. Epub 2016 Mar 14.

Peter Schmid, Alice Shia, Shah-Jalal Sarker, and Louise Lim, Queen Mary University London; Sarah E. Pinder, Patrycja Gazinska, Natalie Woodman, Peter Parker, and Arnie Purushotham, Kings College London; Robert Price, Kings College Hospital; Jennifer Hu, Barts Health National Health Service (NHS) Trust, London; Duncan Wheatley, Royal Cornwall Hospital, Truro; Jane Macaskill, Ninewells Hospital Dundee, Dundee; Charles Zammit, Hannah Butler, and Gemma Earl, Brighton & Sussex University Hospitals NHS Trust, Brighton; Nigel Bundred, University Hospital of South Manchester, Manchester; Sirwan Hadad, Royal Hallamshire Sheffield, Sheffield; Darren Korbie and Matt Trau, Australian Institute for Bioengineering and Nanotechnology, and Matt Trau, University of Queensland; Paul Mainwaring, Mater Research Centre; Brisbane, Australia; Steven Gendreau, Mark R. Lackner, Mika Derynck, and Timothy R. Wilson, Genentech, South San Francisco, CA; and Alastair Thompson, MD Anderson Cancer Centre, Houston, TX.

Purpose: Preclinical data support a key role for the PI3K pathway in estrogen receptor-positive breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. This preoperative window study assessed whether adding the PI3K inhibitor pictilisib (GDC-0941) can increase the antitumor effects of anastrozole in primary breast cancer and aimed to identify the most appropriate patient population for combination therapy.

Patients And Methods: In this randomized, open-label phase II trial, postmenopausal women with newly diagnosed operable estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers were recruited. Participants were randomly allocated (2:1, favoring the combination) to 2 weeks of preoperative treatment with anastrozole 1 mg once per day (n = 26) or the combination of anastrozole 1 mg with pictilisib 260 mg once per day (n = 49). The primary end point was inhibition of tumor cell proliferation as measured by change in Ki-67 protein expression between tumor samples taken before and at the end of treatment.

Results: There was significantly greater geometric mean Ki-67 suppression of 83.8% (one-sided 95% CI, ≥ 79.0%) for the combination and 66.0% (95% CI, ≤ 75.4%) for anastrozole (geometric mean ratio [combination:anastrozole], 0.48; 95% CI, ≤ 0.72; P = .004). PIK3CA mutations were not predictive of response to pictilisib, but there was significant interaction between response to treatment and molecular subtype (P = .03); for patients with luminal B tumors, the combination:anastrozole geometric mean ratio of Ki-67 suppression was 0.37 (95% CI, ≤ 0.67; P = .008), whereas no significant Ki-67 response was observed for pictilisib in luminal A tumors (1.01; P = .98). Multivariable analysis confirmed Ki-67 response to the combination treatment of patients with luminal B tumors irrespective of progesterone receptor status or baseline Ki-67 expression.

Conclusion: Adding pictilisib to anastrozole significantly increases suppression of tumor cell proliferation in luminal B primary breast cancer.
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http://dx.doi.org/10.1200/JCO.2015.63.9179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075966PMC
June 2016

A Randomised Phase 2 Study of AZD2014 Versus Everolimus in Patients with VEGF-Refractory Metastatic Clear Cell Renal Cancer.

Eur Urol 2016 Mar 11;69(3):450-6. Epub 2015 Sep 11.

St. James's University Hospital, University of Leeds, Leeds, UK.

Background: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor used in vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma (mRCC). It acts on only part of the mTOR complex (TORC1 alone). In vitro data support the use of mTOR inhibitors with broader activity (TORC1 and TORC2).

Objective: The purpose of this study was to determine whether combined TORC1 and TORC2 inhibition with AZD2014 has superior activity to everolimus in VEGF-refractory clear cell mRCC.

Design, Setting, And Participants: Patients with measurable mRCC and VEGF-refractory disease were eligible for this trial.

Intervention: Starting in February 2013, patients were randomised (1:1) to AZD2014 (50 mg twice daily) or everolimus (10 mg once daily) until progression of disease at 10 centres across the United Kingdom.

Outcome Measurements And Statistical Analysis: Progression-free survival (PFS) was the primary end point and was compared using the stratified log-rank test. Secondary end points included tolerability, response rates, overall survival (OS), and pharmacokinetics (PK) analysis. The study was planned to recruit 120 patients.

Results And Limitations: Recruitment into the trial was stopped early (June 2014) due to lack of efficacy of AZD2014. At that point, 49 patients were randomised (26 to AZD2014 and 23 to everolimus). The PFS for AZD2014 and everolimus was 1.8 and 4.6 mo, respectively (hazard ratio: 2.8 [95% confidence interval (CI), 1.2-6.5]; p=0.01). Progression of disease as the best response to therapy was 69% for AZD2014 and 13% for everolimus (p<0.001). Grade 3-4 adverse events (AEs) occurred in 35% of AZD2014 and 48% of everolimus patients (p=0.3). Only 4% of patients stopped AZD2014 due to AEs. PK analysis suggested concentrations of AZD2014 were compatible with the therapeutic range. Final stratified OS hazard ratio at the time of trial closure (January 2015) was 3.1 (95% CI, 1.1-8.4; p<0.02).

Conclusions: The PFS and OS of AZD2014 were inferior to everolimus in this setting despite acceptable AE and PK profiles.

Patient Summary: There is a strong rationale for testing mTOR inhibitors with a broader spectrum of activity than everolimus in metastatic clear cell renal cell carcinoma. AZD2014 is such an agent, but in this study, it was inferior to everolimus despite its attractive toxicity profile.
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http://dx.doi.org/10.1016/j.eururo.2015.08.035DOI Listing
March 2016

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.

J Clin Microbiol 2015 Jul 22;53(7):2103-8. Epub 2015 Apr 22.

Blizard Institute of Cell and Molecular Science, Queen Mary University of London, London, United Kingdom Department of Haemato-Oncology, St. Bartholomew's Hospital, London, United Kingdom

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.
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http://dx.doi.org/10.1128/JCM.00110-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4473207PMC
July 2015

Insufficient demonstration of long-term stability of Aspergillus galactomannan.

J Clin Microbiol 2014 Nov;52(11):4118

Blizard Institute of Cell and Molecular Science, Queen Mary University of London, London, United Kingdom Department of Haemato-Oncology, St. Bartholomew's Hospital, London, United Kingdom

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http://dx.doi.org/10.1128/JCM.02342-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313258PMC
November 2014

Repeatability of quantitative FDG-PET/CT and contrast-enhanced CT in recurrent ovarian carcinoma: test-retest measurements for tumor FDG uptake, diameter, and volume.

Clin Cancer Res 2014 May 26;20(10):2751-60. Epub 2014 Feb 26.

Authors' Affiliations: Department of Radiology, St. Bartholomew's Hospital/Barts Health NHS Trust; Department of Medical Oncology, St Bartholomew's Hospital/Barts Health NHS Trust; Department of Nuclear Medicine, Barts Cancer Institute; Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London; Departments of Oncology and Radiology, Cambridge University Hospitals Foundation Trust; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre; NIHR Cambridge Biomedical Research Centre; and Cambridge Experimental Cancer Medicine Centre, Cambridge, United Kingdom; Merck and Co, Whitehouse Station; Sanofi, Bridgewater, New Jersey; and Merck Imaging, West Point, PennsylvaniaAuthors' Affiliations: Department of Radiology, St. Bartholomew's Hospital/Barts Health NHS Trust; Department of Medical Oncology, St Bartholomew's Hospital/Barts Health NHS Trust; Department of Nuclear Medicine, Barts Cancer Institute; Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London; Departments of Oncology and Radiology, Cambridge University Hospitals Foundation Trust; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre; NIHR Cambridge Biomedical Research Centre; and Cambridge Experimental Cancer Medicine Centre, Cambridge, United Kingdom; Merck and Co, Whitehouse Station; Sanofi, Bridgewater, New Jersey; and Merck Imaging, West Point, PennsylvaniaAuthors' Affiliations: Department of Radiology, St. Bartholomew's Hospital/Barts Health NHS Trust; Department of Medical Oncology, St Bartholomew's Hospital/Barts Health NHS Trust; Department of Nuclear Medicine, Barts Cancer Institute; Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University of London; Departments of Oncology and Radiology, Cambridge University Hospitals Foundation Trust; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre; NIHR Cambridge

Purpose: Repeatability of baseline FDG-PET/CT measurements has not been tested in ovarian cancer. This dual-center, prospective study assessed variation in tumor 2[18F]fluoro-2-deoxy-D-glucose (FDG) uptake, tumor diameter, and tumor volume from sequential FDG-PET/CT and contrast-enhanced computed tomography (CECT) in patients with recurrent platinum-sensitive ovarian cancer.

Experimental Design: Patients underwent two pretreatment baseline FDG-PET/CT (n = 21) and CECT (n = 20) at two clinical sites with different PET/CT instruments. Patients were included if they had at least one target lesion in the abdomen with a standardized uptake value (SUV) maximum (SUVmax) of ≥ 2.5 and a long axis diameter of ≥ 15 mm. Two independent reading methods were used to evaluate repeatability of tumor diameter and SUV uptake: on site and at an imaging clinical research organization (CRO). Tumor volume reads were only performed by CRO. In each reading set, target lesions were independently measured on sequential imaging.

Results: Median time between FDG-PET/CT was two days (range 1-7). For site reads, concordance correlation coefficients (CCC) for SUVmean, SUVmax, and tumor diameter were 0.95, 0.94, and 0.99, respectively. Repeatability coefficients were 16.3%, 17.3%, and 8.8% for SUVmean, SUVmax, and tumor diameter, respectively. Similar results were observed for CRO reads. Tumor volume CCC was 0.99 with a repeatability coefficient of 28.1%.

Conclusions: There was excellent test-retest repeatability for FDG-PET/CT quantitative measurements across two sites and two independent reading methods. Cutoff values for determining change in SUVmean, SUVmax, and tumor volume establish limits to determine metabolic and/or volumetric response to treatment in platinum-sensitive relapsed ovarian cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-2634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5152730PMC
May 2014

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

Br J Haematol 2014 Mar 23;164(6):790-803. Epub 2013 Dec 23.

Centre for Psychiatry, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK.

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.
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http://dx.doi.org/10.1111/bjh.12698DOI Listing
March 2014

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.

Br J Haematol 2014 Feb 15;164(4):526-35. Epub 2013 Nov 15.

Centre for Haemato-Oncology, Barts Cancer Institute, Barts and The London Medical School, Queen Mary University of London, London, UK.

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.
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http://dx.doi.org/10.1111/bjh.12651DOI Listing
February 2014

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

Int J Mol Sci 2013 Jun 24;14(7):12970-7. Epub 2013 Jun 24.

Blizard Institute of Cell and Molecular Science, Queen Mary University of London, London E1 2AT, UK.

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.
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http://dx.doi.org/10.3390/ijms140712970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742168PMC
June 2013

A C++ program to calculate sample sizes for cost-effectiveness trials in a Bayesian framework.

Comput Methods Programs Biomed 2013 Jun 8;110(3):471-89. Epub 2013 Feb 8.

Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary, University of London, UK.

Cost-Effectiveness Analysis (CEA) has become an increasingly important component of clinical trials. However, formal sample size calculations for such studies are not common. One of the reasons for this might be due to the absence of readily available computer software to perform complex calculations, particularly in a Bayesian setting. In this paper, a C++ program (using NAG library functions/subroutines) is presented to estimate the sample sizes for cost-effectiveness clinical trials in a Bayesian framework. The program can equally be used to calculate sample sizes for efficacy trials. The Bayesian approach to sample size calculation is based on that of O'Hagan and Stevens (A. O'Hagan, J.W. Stevens, Bayesian assessment of sample size for clinical trials of cost-effectiveness, Medical Decision Making 21 (2001) 219-230). With this program, the user can calculate sample sizes for various thresholds of willingness to pay and under various assumptions of the correlations between cost and effects. Under some prior, the program produces frequentist sample size as well. The program runs under windows environment and running time is very short.
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http://dx.doi.org/10.1016/j.cmpb.2013.01.008DOI Listing
June 2013

Objective assessment of skills acquisition during laparoscopic surgery courses.

Surg Innov 2013 Oct 14;20(5):530-8. Epub 2012 Dec 14.

1Queen Mary University of London, London, UK.

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.
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http://dx.doi.org/10.1177/1553350612468960DOI Listing
October 2013

Accuracy of FAST scan in blunt abdominal trauma in a major London trauma centre.

Int J Surg 2012 30;10(9):470-4. Epub 2012 May 30.

Barts and the London NHS Trust, Whitechapel, London E1 1BB, UK.

Introduction: Blunt abdominal trauma (BAT) is a leading cause of morbidity and mortality. Rapid diagnosis and treatment with the Advanced Trauma Life Support guidelines are vital, leading to the development of Focused Assessment with Sonography in Trauma (FAST).

Methods: A retrospective study carried out from January 2007-2008 on all patients who presented with BAT and underwent FAST scan. All patients subsequently had a CT scan within 2 h of admission or a laparotomy within two days. The presence of intra-peritoneal free fluid was interpreted as positive.

Results: 100 patients with BAT presented; 71 had complete data. The accuracy of FAST in BAT was 59.2%; in these 31 (43.7%) were confirmed by CT and 11 (15%) by laparotomy. There were 29 (40.8%) inaccurate FAST scans, all confirmed by CT. FAST had a specificity of 94.7% (95% CI: 0.75-0.99) and sensitivity of 46.2% (95% CI: 0.33-0.60). Positive Predictive Value of 0.96 (0.81-0.99) and Negative Predictive Value of 0.39 (0.26-0.54). Fisher's exact test shows positive FAST is significantly associated with Intra-abdominal pathology (p=0.001). Cohen's chance corrected agreement was 0.3. 21 out of 28 who underwent laparotomies had positive FAST results indicating accuracy of 75% (95% CI: 57%-87%).

Conclusion: Patients with false negative scans, requiring therapeutic laparotomy is concerning. In unstable patients FAST may help in triaging and identifying those requiring laparotomy. Negative FAST scans do not exclude abdominal injury. Further randomised control trials are recommended if the role of FAST is to be better understood.
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http://dx.doi.org/10.1016/j.ijsu.2012.05.011DOI Listing
June 2013

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).

Stroke 2012 May 29;43(5):1362-9. Epub 2012 Mar 29.

King's College, London, UK.

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.
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http://dx.doi.org/10.1161/STROKEAHA.111.645234DOI Listing
May 2012
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