Co-crystallisation and humanisation of an anti-HER2 single-domain antibody as a theranostic tool.

Human epidermal growth factor receptor-2 (HER2) is a well-recognised biomarker associated with 25% of breast cancers. In most cases, early detection and/or treatment correlates with an increased chance of survival. This study, has identified and characterised a highly specific anti-HER2 single-domain antibody (sdAb), NM-02, as a potential theranostic tool. Complete structural description by X-ray crystallography has revealed a non-overlapping epitope with current anti-HER2 antibodies. To reduce the immunogenicity risk, NM-02 underwent a humanisation process and retained wild type-like binding properties. To further de-risk the progression towards chemistry, manufacturing and control (CMC) we performed full developability profiling revealing favourable thermal and physical biochemical 'drug-like' properties. Finally, the application of the lead humanised NM-02 candidate (variant K) for HER2-specific imaging purposes was demonstrated using breast cancer HER2+/BT474 xenograft mice.

Nanobody inhibitors of Plexin-B1 identify allostery in plexin-semaphorin interactions and signaling.

Plexin-B1 is a receptor for the cell surface semaphorin, Sema4D. This signaling system has been implicated in a variety of human diseases, including cancer, multiple sclerosis and osteoporosis. While inhibitors of the Plexin-B1:Sema4D interaction have been previously reported, understanding their mechanism has been hindered by an incomplete structural view of Plexin-B1. In this study, we have raised and characterized a pair of nanobodies that are specific for mouse Plexin-B1 and which inhibit the binding of Sema4D to mouse Plexin-B1 and its biological activity. Structural studies of these nanobodies reveal that they inhibit the binding of Sema4D in an allosteric manner, binding to epitopes not previously reported. In addition, we report the first unbound structure of human Plexin-B1, which reveals that Plexin-B1 undergoes a conformational change on Sema4D binding. These changes mirror those seen upon binding of allosteric peptide modulators, which suggests a new model for understanding Plexin-B1 signaling and provides a potential innovative route for therapeutic modulation of Plexin-B1.

Identifying unmet needs and challenges in the definition of a plaque in mycosis fungoides: An EORTC-CLTG/ISCL survey.

BACKGROUND: Consensus about the definition and classification of 'plaque' in mycosis fungoides is lacking. OBJECTIVES: To delineate a comprehensive view on how the 'plaque' entity is defined and managed in clinical practice; to evaluate whether the current positioning of plaques in the TNMB classification is adequate. METHODS: A 12-item survey was circulated within a selected panel of 22 experts (pathologists, dermatologists, haematologists and oncologists), members of the EORTC and International Society for Cutaneous Lymphoma. The questionnaire discussed clinical and histopathological definitions of plaques and its relationship with staging and treatment. RESULTS: Total consensus and very high agreement rates were reached in 33.3% of questions, as all panellists regularly check for the presence of plaques, agree to evaluate the presence of plaques as a potential separate T class, and concur on the important distinction between plaque and patch for the management of early-stage MF. High agreement was reached in 41.7% of questions, since more than 50% of the responders use Olsen's definition of plaque, recommend the distinction between thin/thick plaques, and agree on performing a biopsy on the most infiltrated/indurated lesion. High divergence rates (25%) were reported regarding the possibility of a clinically based distinction between thin and thick plaques and the role of histopathology to plaque definition. CONCLUSIONS: The definition of 'plaque' is commonly perceived as a clinical entity and its integration with histopathological features is generally reserved to specific cases. To date, no consensus is achieved as for the exact definition of thin and thick plaques and current positioning of plaques within the TNMB system is considered clinically inadequate. Prospective studies evaluating the role of histopathological parameters and other biomarkers, as well as promising diagnostic tools, such as US/RM imaging and high-throughput blood sequencing, are much needed to fully integrate current clinical definitions with more objective parameters.

Real-Life Barriers to Diagnosis of Early Mycosis Fungoides: An International Expert Panel Discussion.

Mycosis fungoides (MF) is a rare, primary cutaneous T-cell lymphoma that is challenging to diagnose due to its heterogeneous clinical presentation and complex histology. The subtlety of the initial clinical appearance of MF can result in diagnostic delays and hesitancy to refer suspected cases to specialist clinics. An unmet need remains for greater awareness and education. Therefore, an international expert panel of dermatologists, oncologists, hematologists, and dermatopathologists convened to discuss and identify barriers to early and accurate MF diagnosis that could guide clinicians toward making a correct diagnosis. Confirmation of MF requires accurate assessment of symptoms and clinical signs, and subsequent correlation with dermatopathological findings. This review summarizes the expert panel's guidance, based on the literature and real-life experience, for dermatologists to help include MF in their list of differential diagnoses, along with simple clinical and histopathologic checklists that may help clinicians to suspect and identify potential MF lesions and reduce diagnostic delays.

Identification, binding, and structural characterization of single domain anti-PD-L1 antibodies inhibitory of immune regulatory proteins PD-1 and CD80.

Programmed death-ligand 1 (PD-L1) is a key immune regulatory protein that interacts with programmed cell death protein 1 (PD-1), leading to T-cell suppression. Whilst this interaction is key in self-tolerance, cancer cells evade the immune system by overexpressing PD-L1. Inhibition of the PD-1/PD-L1 pathway with standard monoclonal antibodies has proven a highly effective cancer treatment; however, single domain antibodies (VHH) may offer numerous potential benefits. Here, we report the identification and characterization of a diverse panel of 16 novel VHHs specific to PD-L1. The panel of VHHs demonstrate affinities of 0.7 nM to 5.1 µM and were able to completely inhibit PD-1 binding to PD-L1. The binding site for each VHH on PD-L1 was determined using NMR chemical shift perturbation mapping and revealed a common binding surface encompassing the PD-1-binding site. Additionally, we solved crystal structures of two representative VHHs in complex with PD-L1, which revealed unique binding modes. Similar NMR experiments were used to identify the binding site of CD80 on PD-L1, which is another immune response regulatory element and interacts with PD-L1 localized on the same cell surface. CD80 and PD-1 were revealed to share a highly overlapping binding site on PD-L1, with the panel of VHHs identified expected to inhibit CD80 binding. Comparison of the CD80 and PD-1 binding sites on PD-L1 enabled the identification of a potential antibody binding region able to confer specificity for the inhibition of PD-1 binding only, which may offer therapeutic benefits to counteract cancer cell evasion of the immune system.

Cutaneous T-cell lymphoma: diagnosing subtypes and the challenges.

Cutaneous T-cell lymphoma is a rare type of extranodal non-Hodgkin's lymphoma that primarily affects the skin. The uncertain pathogenesis and variable clinical presentation make the diagnosis and management of cutaneous T-cell lymphoma a challenge. Cutaneous T-cell lymphoma is a chronic, relapsing illness with treatment aimed at symptomatic relief and improving patient related quality of life. Early-stage cutaneous T-cell lymphoma typically follows an indolent course, often being mistaken for benign dermatological conditions which can lead to a diagnostic delay. Advanced stage cutaneous T-cell lymphoma has a poor prognosis with significant morbidity. Accurate diagnosis and early involvement of a specialist team is paramount to ensure correct management and improved patient outcomes. Promising advances are being made to develop novel agents which could improve prognosis and quality of life. This article provides an overview of the two main subtypes of cutaneous T-cell lymphoma: mycosis fungoides and Sézary syndrome. Clinical presentation, histopathological correlation and diagnostic challenges are reviewed alongside example case studies.

PD-L1 testing and immunotherapy selection - early laboratory experience and its potential role in head and neck cancer management.

Anti-programmed cell death protein-1 (PD-1) therapy has been relatively recently approved in a defined context by NICE in adults in the management of recurrent and metastatic head and neck squamous cell carcinomas (HNSCC). In this context, companion diagnostic programmed cell death ligand-1 (PD-L1) testing, previously established at our center for lung and bladder tumors, was undertaken in a few head and neck cancer cases. The scope of this study was to audit the relevant PD-L1 data and integrate the findings in our current clinical practice, with a view to promote improved routine laboratory biomarkers in HNSCC. Histopathology reports documenting tumor type, PD-L1 result and type of clone/assay were included in this study. Over a 5-year period, PD-L1 testing was undertaken in 199 cancer cases, including 3 with head and neck squamous carcinoma with low focal positive staining. Immunotherapy treatment in HNSCC demonstrates a discreet but still significant improvement in the overall survival of PD-L1 positive subjects.

The UK's contribution to cancer control in low-income and middle-income countries.

Cancer mortality rates in low-income and middle-income countries (LMICs) are unacceptably high, requiring both collaborative global effort and in-country solutions. Experience has shown that working together in policy, clinical practice, education, training, and research leads to bidirectional benefit for LMICs and high-income countries. For over 60 years, the UK National Health Service has benefited from recruitment from LMICs, providing the UK with a rich diaspora of trained health-care professionals with links to LMICs. A grassroots drive to engage with partners in LMICs within the UK has grown from the National Health Service, UK academia, and other organisations. This drive has generated a model that rests on two structures: London Global Cancer Week and the UK Global Cancer Network, providing a high-value foundation for international discussion and collaboration. Starting with a historical perspective, this Series paper describes the UK landscape and offers a potential plan for the future UK's contribution to global cancer control. We also discuss the opportunities and challenges facing UK partnerships with LMICs in cancer control. The UK should harness the skills, insights, and political will from all partners to make real progress.

Quality of Life Effect of the Anti-CCR4 Monoclonal Antibody Mogamulizumab Versus Vorinostat in Patients With Cutaneous T-cell Lymphoma.

BACKGROUND: Sézary syndrome (SS) and mycosis fungoides (MF), 2 types of cutaneous T-cell lymphoma, cause significant morbidity and adversely affect patients' quality of life (QoL). The present study assessed the QoL measurement changes in patients receiving mogamulizumab versus vorinostat. PATIENTS AND METHODS: A multicenter phase III trial was conducted of patients with stage IB-IV MF/SS with ≥ 1 failed systemic therapy. The QoL measures included Skindex-29 and the Functional Assessment of Cancer Therapy-General. The symptoms, function, and QoL subdomains were longitudinally modeled using mixed models with prespecified covariates. Meaningful change thresholds (MCTs) were defined using distribution-based methods. The categorical changes by group over time and the time to clinically meaningful worsening were analyzed. RESULTS: Of the 372 randomized patients, mogamulizumab demonstrated improvement in Skindex-29 symptoms (cycles 3, 5, and 7; P < .05) and functional (cycles 3 and 5; P < .05) scales. A significantly greater proportion of mogamulizumab-treated patients improved by MCTs or more from baseline in the Skindex-29 symptoms domain (cycles 3, 5, 7, and 11) and functioning domain (cycle 5). Significant differences in the Functional Assessment of Cancer Therapy-General physical well-being (cycles 1, 3, and 5; P < .05) were observed in favor of mogamulizumab and a greater proportion of patients had declined by MCTs or more at cycles 1, 3, 5, and 7 with vorinostat treatment. The median time to symptom worsening using Skindex-29 was 27.4 months for mogamulizumab versus 6.6 months for vorinostat. In the patients with SS, the time to worsening favored mogamulizumab (P < .005) for all Skindex-29 domains. The time to worsening was similar for the 2 MF treatment arms. CONCLUSION: The symptoms, function, and overall QoL of patients with MF/SS favored mogamulizumab over vorinostat across all time points. Patients with the greatest symptom burden and functional impairment derived the most QoL benefit from mogamulizumab.

Allosteric activation of MALT1 by its ubiquitin-binding Ig3 domain.

The catalytic activity of the protease MALT1 is required for adaptive immune responses and regulatory T (Treg)-cell development, while dysregulated MALT1 activity can lead to lymphoma. MALT1 activation requires its monoubiquitination on lysine 644 (K644) within the Ig3 domain, localized adjacent to the protease domain. The molecular requirements for MALT1 monoubiquitination and the mechanism by which monoubiquitination activates MALT1 had remained elusive. Here, we show that the Ig3 domain interacts directly with ubiquitin and that an intact Ig3-ubiquitin interaction surface is required for the conjugation of ubiquitin to K644. Moreover, by generating constitutively active MALT1 mutants that overcome the need for monoubiquitination, we reveal an allosteric communication between the ubiquitination site K644, the Ig3-protease interaction surface, and the active site of the protease domain. Finally, we show that MALT1 mutants that alter the Ig3-ubiquitin interface impact the biological response of T cells. Thus, ubiquitin binding by the Ig3 domain promotes MALT1 activation by an allosteric mechanism that is essential for its biological function.

BA08: An open-label, single-arm, non-randomised, phase 2 trial of cisplatin, methotrexate and vinblastine (CMV) for pure squamous cell cancer of the urinary tract.

BACKGROUND: Pure squamous cell carcinoma (SCC) of the urinary tract is rare in the UK and has a poor prognosis compared with transitional cell carcinoma (TCC). Cisplatin based chemotherapy has been shown to be effective in TCC. METHODS: Patients with T3-T4, pelvic relapsed, nodal or metastatic SCC of the urinary tract were recruited into an open-label, single-arm, non-randomised, phase 2 trial evaluating the activity and safety of cisplatin, methotrexate and vinblastine (CMV) chemotherapy. CMV was given as three 21-day cycles of methotrexate 30mg/m2 (day 1 & 8), vinblastine 4mg/m2 (day 1 & 8) and cisplatin 100mg/m2 (day 2). RESULTS: 38 patients were recruited. Overall response was 39% (95% CI 24%, 55%)-13% CR and 26% PR. Median OS was 7.8 months (95% CI 3.4, 12.6) with 39% 1-year survival. Toxicity was acceptable. CONCLUSION: CMV is well tolerated and active in patients with pure SCC of the urinary tract.

The acceptability and feasibility of lay-health led interventions for the prevention and early detection of cancer.

BACKGROUND: US-based evidence suggests that lay-health worker (LHW) interventions can increase awareness around cancer risk-related lifestyles, symptom recognition, and screening programme uptake. The suitability of LHW interventions in the UK and the potential barriers and facilitators for implementation is currently unknown. This study explored the acceptability and feasibility of developing LHW interventions for cancer prevention, screening, and early diagnosis. METHODS: Purposive sampling recruited 5 separate lay groups: (1) completed cancer treatment; (2) friends/family of cancer patients; (3) cancer hospital volunteers; (4) cancer charity volunteers; and (5) members of the public. Audio-recorded focus groups and semi-structured interviews were transcribed for thematic analysis using framework matrices. RESULTS: Forty-one people (66% female, aged 23-84 years) participated. Three main themes are reported: (1) scope of LHW roles, with a clear remit embedded within communities or primary care practices; (2) defining LHW tasks, with a focus on supporting people overcome barriers including lack of cancer symptom knowledge and non-attendance at screening; and (3) clear boundaries, with LHW training and on-going support from healthcare staff seen as key for intervention success. All groups were uncomfortable about having lifestyle-related risk conversations and potentially inflicting guilt. The post-treatment group expressed less concern about the possible emotional impact of discussing cancer symptoms, compared with the other groups. CONCLUSIONS: LHW interventions to promote early diagnosis or screening were generally considered acceptable in a UK context. LHW interventions focussing on reducing cancer risk may be less feasible.

A phase III study of lenalidomide maintenance after debulking therapy in patients with advanced cutaneous T-cell lymphoma - EORTC 21081 (NCT01098656): results and lessons learned for future trial designs.

EORTC 21081 was a randomized phase III study of observation alone versus lenalidomide maintenance (25 mg po for 21 days) after debulking therapy in patients with advanced-stage cutaneous T-cell lymphomas (CTCLs). The aim was to investigate whether maintenance treatment with lenalidomide prolonged response after debulking in patients who had not been previously treated with intravenous chemotherapy. A total of 26 centres from 10 different European countries registered 30 patients with advanced CTCL. Twenty-one patients were randomized (20% of the 105 patients initially deemed necessary for the study; the study was terminated early following withdrawal of funding support from Celgene). Of 30 registered patients, nine failed to be randomized, 12 were randomized to observation alone, and nine to lenalidomide maintenance. Median progression-free survival was 5.3 months (95% CI: 1.87-22.54) in the maintenance lenalidomide group and two months (95% CI: 0.92-7.82) in the observation alone group. Although statistical comparison in the study was severely underpowered and would not be meaningful, this study provides useful information, revealing rapid disease progression within four weeks in a third of patients, highlighting the need for maintenance therapy.

Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model.

PURPOSE: Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. PATIENTS AND METHODS: Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). RESULTS: Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). CONCLUSION: To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients.

Impact of Radiotherapy When Added to Androgen-Deprivation Therapy for Locally Advanced Prostate Cancer: Long-Term Quality-of-Life Outcomes From the NCIC CTG PR3/MRC PR07 Randomized Trial.

PURPOSE: The NCIC CTG PR3/MRC PR07 randomized phase III trial compared androgen-deprivation therapy (ADT) alone versus ADT with radiotherapy (RT) for patients with locally advanced prostate cancer. This article reports the health-related quality-of-life (HRQOL) outcomes of this trial. PATIENTS AND METHODS: A total of 1,205 patients were randomly allocated to either ADT alone or ADT with RT. HRQOL was assessed at baseline and every 6 months thereafter using the European Organisation for Research and Treatment of Cancer Core Questionnaire and a prostate cancer-specific checklist or the Functional Assessment of Cancer Therapy-Prostate questionnaire. Mean changes from baseline scores for five function domains and nine symptom domains were analyzed as those most relevant to ADT and RT. The proportions of patients with improved, stable, or worsened HRQOL scores according to instrument-specific minimal important differences were calculated. RESULTS: Baseline questionnaires were completed by 1,028 patients (88%). At 6 months, RT had a statistically significant impact on mean score for bowel symptoms (P = .02), diarrhea (P < .001), urinary function (P = .003), and erectile dysfunction (P = .008); by 3 years, however, there were no significant between-group differences in any domain. Generalized linear mixed modeling revealed no significant between-arm differences in any of the function scales but showed significant deterioration in both arms over time for Functional Assessment of Cancer Therapy-Prostate total score, treatment outcome index, and physical and functional well-being. CONCLUSION: The addition of RT to ADT for patients with locally advanced prostate cancer significantly improved overall survival and had only modest and transient negative impact on relevant domains of HRQOL.

Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer.

PURPOSE: We have previously reported that radiotherapy (RT) added to androgen-deprivation therapy (ADT) improves survival in men with locally advanced prostate cancer. Here, we report the prespecified final analysis of this randomized trial. PATIENTS AND METHODS: NCIC Clinical Trials Group PR.3/Medical Research Council PR07/Intergroup T94-0110 was a randomized controlled trial of patients with locally advanced prostate cancer. Patients with T3-4, N0/Nx, M0 prostate cancer or T1-2 disease with either prostate-specific antigen (PSA) of more than 40 µg/L or PSA of 20 to 40 µg/L plus Gleason score of 8 to 10 were randomly assigned to lifelong ADT alone or to ADT+RT. The RT dose was 64 to 69 Gy in 35 to 39 fractions to the prostate and pelvis or prostate alone. Overall survival was compared using a log-rank test stratified for prespecified variables. RESULTS: One thousand two hundred five patients were randomly assigned between 1995 and 2005, 602 to ADT alone and 603 to ADT+RT. At a median follow-up time of 8 years, 465 patients had died, including 199 patients from prostate cancer. Overall survival was significantly improved in the patients allocated to ADT+RT (hazard ratio [HR], 0.70; 95% CI, 0.57 to 0.85; P < .001). Deaths from prostate cancer were significantly reduced by the addition of RT to ADT (HR, 0.46; 95% CI, 0.34 to 0.61; P < .001). Patients on ADT+RT reported a higher frequency of adverse events related to bowel toxicity, but only two of 589 patients had grade 3 or greater diarrhea at 24 months after RT. CONCLUSION: This analysis demonstrates that the previously reported benefit in survival is maintained at a median follow-up of 8 years and firmly establishes the role of RT in the treatment of men with locally advanced prostate cancer.

Escalated-dose versus control-dose conformal radiotherapy for prostate cancer: long-term results from the MRC RT01 randomised controlled trial.

BACKGROUND: The aim of this trial was to compare dose-escalated conformal radiotherapy with control-dose conformal radiotherapy in patients with localised prostate cancer. Preliminary findings reported after 5 years of follow-up showed that escalated-dose conformal radiotherapy improved biochemical progression-free survival. Based on the sample size calculation, we planned to analyse overall survival when 190 deaths occurred; this target has now been reached, after a median 10 years of follow-up. METHODS: RT01 was a phase 3, open-label, international, randomised controlled trial enrolling men with histologically confirmed T1b-T3a, N0, M0 prostate cancer with prostate specific antigen of less than 50 ng/mL. Patients were randomly assigned centrally in a 1:1 ratio, using a computer-based minimisation algorithm stratifying by risk of seminal vesicle invasion and centre to either the control group (64 Gy in 32 fractions, the standard dose at the time the trial was designed) or the escalated-dose group (74 Gy in 37 fractions). Neither patients nor investigators were masked to assignment. All patients received neoadjuvant androgen deprivation therapy for 3-6 months before the start of conformal radiotherapy, which continued until the end of conformal radiotherapy. The coprimary outcome measures were biochemical progression-free survival and overall survival. All analyses were done on an intention-to-treat basis. Treatment-related side-effects have been reported previously. This trial is registered, number ISRCTN47772397. FINDINGS: Between Jan 7, 1998, and Dec 20, 2001, 862 men were registered and 843 subsequently randomly assigned: 422 to the escalated-dose group and 421 to the control group. As of Aug 2, 2011, 236 deaths had occurred: 118 in each group. Median follow-up was 10·0 years (IQR 9·1-10·8). Overall survival at 10 years was 71% (95% CI 66-75) in each group (hazard ratio [HR] 0·99, 95% CI 0·77-1·28; p=0·96). Biochemical progression or progressive disease occurred in 391 patients (221 [57%] in the control group and 170 [43%] in the escalated-dose group). At 10 years, biochemical progression-free survival was 43% (95% CI 38-48) in the control group and 55% (50-61) in the escalated-dose group (HR 0·69, 95% CI 0·56-0·84; p=0·0003). INTERPRETATION: At a median follow-up of 10 years, escalated-dose conformal radiotherapy with neoadjuvant androgen deprivation therapy showed an advantage in biochemical progression-free survival, but this advantage did not translate into an improvement in overall survival. These efficacy data for escalated-dose treatment must be weighed against the increase in acute and late toxicities associated with the escalated dose and emphasise the importance of use of appropriate modern radiotherapy methods to reduce side-effects. FUNDING: UK Medical Research Council.

Dynamic contrast-enhanced MRI in patients with muscle-invasive transitional cell carcinoma of the bladder can distinguish between residual tumour and post-chemotherapy effect.

INTRODUCTION: Treatment of muscle-invasive bladder cancer with chemotherapy results in haemorrhagic inflammation, mimicking residual tumour on conventional MR images and making interpretation difficult. The aim of this study was to use dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to estimate descriptive and tracer kinetic parameters post-neoadjuvant chemotherapy and to investigate whether parameters differed in areas of residual tumour and chemotherapy-induced haemorrhagic inflammation (treatment effect, Tr-Eff). METHODS AND MATERIALS: Twenty-one patients underwent DCE-MRI scans with 2.5s temporal resolution before and following neoadjuvant chemotherapy. Regions-of-interest (ROIs) were defined in areas suspicious of residual tumour on T2-weighted MRI scans. Data were analysed semi-quantitatively and with a two-compartment exchange model to obtain parameters including relative signal intensity (rSI80s) and plasma perfusion (Fp) respectively. The bladder was subsequently examined histologically after cystectomy for evidence of residual tumour and/or Tr-Eff. Differences in parameters measured in areas of residual tumour and Tr-Eff were examined using Student's t-test. RESULTS: Twenty-four abnormal sites were defined after neoadjuvant chemotherapy. On pathology, 10 and 14 areas were identified as residual tumour and Tr-Eff respectively. Median rSI80s and Fp were significantly higher in areas of residual tumour than Tr-Eff (rSI80s = 2.9 vs 1.7, p < 0.001; Fp = 20.7 vs 9.1 ml/100ml/min, p = 0.03). The sensitivity and specificity for differentiating residual tumour from Tr-Eff were 70% and 100% (rSI80s), 60% and 86% (Fp), and 75% and 100% when combined. CONCLUSION: DCE-MRI parameters obtained post-treatment are capable of distinguishing between residual tumour and treatment effect in patients treated for bladder cancer with neoadjuvant chemotherapy.