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AIMS: The Malthus Programme predicts national and local radiotherapy demand by combining cancer incidence data with decision trees detailing the indications, and appropriate dose fractionation, for radiotherapy. Since the last model update in 2017, technological advancements and the COVID-19 pandemic have led to increasing hypofractionation of radiotherapy schedules. Indications for radiotherapy have also evolved, particularly in the context of oligometastatic disease. Here we present a brief update on the model for 2021. We have updated the decision trees for breast, prostate, lung and head and neck cancers, and incorporated recent cancer incidence data into our model, generating a current estimate of fraction demand for these four cancer sites across England.MATERIALS AND METHODS: The decision tree update was based on evidence from practice-changing randomised controlled trials, published guidelines, audit data and expert opinion. Site- and stage-specific incidence data were taken from the National Disease Registration Service. We used the updated model to estimate the proportion of patients who would receive radiotherapy (appropriate rate of radiotherapy) and the fraction demand per million population at a national and Clinical Commissioning Group level in 2021.RESULTS: The total predicted fraction demand has decreased by 11.4% across all four cancer sites in our new model, compared with the 2017 version. This reduction can be explained primarily by greater use of hypofractionated treatments (including stereotactic ablative radiotherapy) and a shift towards earlier stage presentation. The only large change in appropriate rate of radiotherapy was an absolute decrease of 3% for lung cancer.CONCLUSIONS: Compared with our previous model, the current version predicts a reduction in fraction demand across England. This is driven principally by hypofractionation of radiotherapy regimens, using technology that requires increasingly complex planning. Treatment complexity and local service factors need to be taken into account when translating fraction burden into linear accelerator demand or throughput.

Image-based data mining (IBDM) and voxel-based analysis (VBA) have shown great promise in the retrospective analysis of routine clinical data, offering a way to analyze a patient population without selection. In radiation therapy, IBDM analyzes whole dose distributions for their effect on a given outcome with no prior assumptions. Recent extensions in IBDM methodologies include per voxel survival analyses, allowing the generation of more robust and testable hypotheses. An essential aspect to produce solid conclusions includes applying the correct statistical techniques to account for multiple testing. There is a growing interest in applying IBDM/VBA techniques in radiation therapy, which is a relatively new area with limited examples in the literature. We present this editorial to discuss guidelines for best practice. In doing so, we highlight 3 recently published papers applying IBDM techniques to radiation therapy data 1 , 2 , 3 and suggest alternative, more robust analysis methods.

Triple negative breast cancer (TNBC) is the most lethal breast cancer subtype. Extended periods of lactation protect against breast cancer development, but the mechanisms underlying this protection are unknown. We examined the effects of the milk protein alpha-casein over expression in the triple negative MDA-MB-231 breast cancer cell line. The effects of recombinant alpha-casein added exogenously to MDA-MB-231 breast cancer cells, and immortalised human fibroblasts were also investigated. We used transcriptional reporters to understand the signalling pathways downstream of alpha-casein in breast cancer cells and these fibroblasts that were activated by breast cancer cells. To extend our findings to the clinical setting, we analysed public gene expression datasets to further understand the relevance of these signalling pathways in triple negative breast cancer cells and patient samples. Finally, we used small molecular inhibitors to target relevant pathways and highlight these as potential candidates for the treatment of TN breast cancer. High levels of alpha-casein gene expression were predictive of good prognosis across 263 TNBC patient tumour samples. Alpha-casein over expression or exogenous addition reduces cancer stem cell (CSC) activity. HIF-1alpha was identified to be a key downstream target of alpha-casein, in both breast cancer cells and activated fibroblasts, and STAT transcription factors to be upstream of HIF-1alpha. Interestingly, HIF-1alpha is regulated by STAT3 in breast cancer cells, but STAT1 is the regulator of HIF-1alpha in activated fibroblasts. In analysis of 573 TNBC patient samples, alpha-casein expression, inversely correlated to HIF-1alpha, STAT3 and STAT1. STAT1 and STAT3 inhibitors target HIF-1alpha signalling in activated fibroblasts and MDA-MB-231 breast cancer cells respectively, and also abrogate CSC activities. Our findings provide an explanation for the protective effects of lactation in TNBC. Clinical data correlates high alpha-casein expression with increased recurrence-free survival in TNBC patients. Mechanistically, alpha-casein reduces breast cancer stem cell activity in vitro, and STAT3 and STAT1 were identified as regulators of pro-tumorigenic HIF-1alpha signalling in breast cancer cells and fibroblasts respectively.

After radiation exposure, one of the critical processes for cellular survival is the repair of DNA double strand breaks. The pathways involved in this response are complex in nature and involve many individual steps that act across different time scales, all of which combine to produce an overall behaviour. It is therefore experimentally challenging to unambiguously determine the mechanisms involved and how they interact whilst maintaining strict control of all confounding variables. In silico methods can provide further insight into results produced by focused experimental investigations through testing of the hypotheses generated. Such computational testing can asses competing hypotheses by investigating their effects across all time scales concurrently, highlighting areas where further experimental work can have the most significance. We describe the construction of a mechanistic model by combination of several hypothesised mechanisms reported in the literature and supported by experiment. Compatibility of these mechanisms was tested by fitting simulation to results reported in the literature. To avoid over-fitting, we used an approach of sequentially testing individual mechanisms within this pathway. We demonstrate that using this approach the model is capable of reproducing published protein kinetics and overall repair trends. This provides evidence supporting the feasibility of the proposed mechanisms and revealed how they interact to produce an overall behaviour. Furthermore, we show that the assumed motion of individual double strand break ends plays a crucial role in determining overall system behaviour.

Background and Purpose:Assessment of dosimetric accuracy of radiosurgery on different treatment platforms.Material and Methods:Thirty-three single fraction treatment plans were assessed at thirty centres using an anthropomorphic head phantom with target and brainstem structures. The target being a single irregular shaped target, ~8cc, 10 mm from the brainstem. The phantom was “immobilised”, scanned, planned and treated following the local protocols. EBT-XD films and alanine pellets were used to measure absolute dose, inside both the target and the brainstem, and compared with TPS predicted dose distributions.Results:PTV alanine measurements from gantry-based linacs showed a median percentage difference to the TPS of 0.65%. Cyberknife (CK) had the highest median difference of 2.3% in comparison to the other platforms. Gamma Knife (GK) showed the smallest median of 0.3%. Similar trends were observed in the OAR with alanine measurements showing median percentage differences of 1.1%, 2.0% and 0.4%, for gantry-based linacs, CK and GK respectively. All platforms showed comparable gamma passing rates between axial and sagittal films.Conclusions:This comparison has highlighted the dosimetric variation between measured and TPS calculated dose for each delivery platform. The results suggest that clinically acceptable agreement with the predicted dose distributions is achievable by all treatment delivery systems.

AIM: Pseudomyxoma peritonei (PMP) is a rare neoplasm of the appendix, which if untreated disseminates throughout the abdominal cavity and generates considerable morbidity. Since 2002 in the UK, patients with PMP have been managed via two nationally commissioned centres. We evaluated referrals and treatment pathways over time at the Manchester centre.METHOD: Data from all patients referred with suspected PMP were prospectively collected (2002-2015). Definitive treatment was cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy (HIPEC). Disease burden was quantified using the Peritoneal Cancer Index (PCI: score 0-39) and complete cytoreduction (CC) defined by scores of 0/1. Novel treatment algorithms were developed for patients with low-grade appendiceal mucinous neoplasm (LAMN) localised to the peri-appendiceal tissue.RESULTS: 817 patients with confirmed PMP were referred increasing from 11 in 2002 to 103 in 2015. Disease burden was high with mean PCI of 31 in the first quartile (Q1), levelling-off to 15,15,17 thereafter (p = 0.002). The proportion of CC0/1 increased from 67% in Q1 to 77% Q2 and 74% Q3/4. Where complete cytoreduction was achieved, 5 and 10-year overall survival was 77% and 66%. The proportion of patients referred with localised LAMN increased over time reaching 25% each year since 2010 (Ptrend CONCLUSION: The establishment of a national treatment centre was associated with an initial presentation of patients with advanced disease. The programme has demonstrated a clear trend over time towards earlier referral and adoption of minimal invasive techniques for localised disease. This article is protected by copyright. All rights reserved.

AIM: Six Phase III randomized trials have determined the effectiveness of chemoradiotherapy as primary treatment for anal squamous cell carcinoma (ASCC), but outcomes reported in these trials varied widely, hindering evidence synthesis. To improve reporting in all future trials, we aim to develop a core outcomes set (COS). As the first stage of COS development, we undertook a systematic review to summarize the outcomes reported in studies evaluating chemoradiotherapy for ASCC.METHOD: Systematic literature searches identified studies evaluating radiotherapy or chemoradiotherapy for ASCC. Outcomes and accompanying definitions were extracted verbatim and categorized into domains.RESULTS: From 5170 abstracts, we identified 95 eligible studies, reporting 1192 outcomes and 533 unique terms. We collapsed these terms into 86 standardized outcomes and five domains: survival; disease activity; life impact [including quality of life (QoL)]; delivery of care; and toxicity. The most commonly reported domains were survival and disease activity, reported in 74 (86%) and 54 (62%) studies, respectively. No outcome was reported in every publication. Over half (43/86) of the standardized outcome terms were reported in fewer than five studies, and 21 (25%) were reported in a single study only. There was wide variation in definitions of disease-free survival, colostomy-free survival and progression-free survival (PFS). Anal continence was reported in only 35 (41%) studies.CONCLUSION: Outcomes reported in studies evaluating chemoradiotherapy for ASCC were heterogenous and definitions varied widely. Outcomes likely to be important to patients, such as ano-rectal function, toxicity and QoL, have been neglected. A COS for future trials will address these issues.

Despite the effectiveness of endocrine therapies to treat estrogen receptor-positive (ER+) breast tumours, two thirds of patients will eventually relapse due to de novo or acquired resistance to these agents. Cancer Stem-like Cells (CSCs), a rare cell population within the tumour, accumulate after anti-estrogen treatments and are likely to contribute to their failure. Here we studied the role of p21-activated kinase 4 (PAK4) as a promising target to overcome endocrine resistance and disease progression in ER+ breast cancers. PAK4 predicts for resistance to tamoxifen and poor prognosis in 2 independent cohorts of ER+ tumours. We observed that PAK4 strongly correlates with CSC activity in metastatic patient-derived samples irrespective of breast cancer subtype. However, PAK4-driven mammosphere-forming CSC activity increases alongside progression only in ER+ metastatic samples. PAK4 activity increases in ER+ models during acquired resistance to endocrine therapies. Targeting PAK4 with either CRT PAKi, a small molecule inhibitor of PAK4, or with specific siRNAs abrogates CSC activity/self-renewal in clinical samples and endocrine-resistant cells. Together, our findings establish that PAK4 regulates stemness during disease progression and that its inhibition reverses endocrine resistance in ER+ breast cancers.

Complementary structural and dynamical information on drug-DNA interplay has been achieved at a molecular level, for Pt/Pd-drugs, allowing a better understanding of their pharmacodynamic profile which is crucial for the development of improved chemotherapeutic agents. The interaction of two cisplatin-like dinuclear Pt(ii) and Pd(ii) complexes with DNA was studied through a multidisciplinary experimental approach, using quasi-elastic neutron scattering (QENS) techniques coupled with synchrotron-based extended X-ray absorption fine structure (SR-EXAFS) and Fourier-Transform Infrared Spectroscopy-Attenuated Total Reflectance (SR-FTIR-ATR). DNA extracted from drug-exposed human triple negative breast cancer cells (MDA-MB-231) was used, with a view to evaluate the effect of the unconventional antineoplastic agents on this low prognosis type of cancer. The drug impact on DNA's dynamical profile, via its hydration layer, was provided by QENS, a drug-triggered enhanced mobility having been revealed. Additionally, an onset of anharmonicity was detected for dehydrated DNA, at room temperature. Far- A nd mid-infrared measurements allowed the first simultaneous detection of the drugs and their primary pharmacological target, as well as the drug-prompted changes in DNA's conformation that mediate cytotoxicity. The local environment of the absorbing Pd(ii) and Pt(ii) centers in the drugs' adducts with adenine, guanine and glutathione was attained by EXAFS.

Background Docetaxel chemotherapy is a standard of care for metastatic castrate-resistant prostate cancer (mCRPC): 40–50% of patients achieve a biochemical response. However, there is a lack of response predictive biomarkers. Objective To assess lactate dehydrogenase (LDH) as a docetaxel response biomarker in mCRPC and to examine the association of LDH with genomic alterations in primary diagnostic biopsies. Design, setting, and participants Clinical and associated primary tumour-targeted next-generation sequencing data from matched training (n = 150) and test (n = 120) cohorts of progressive mCRPC patients receiving docetaxel therapy were analysed. Data were correlated with large-scale prostate cancer genomic datasets. Outcome measurements and statistical analysis Prostate-specific antigen (PSA) response, radiographic response, biochemical progression-free survival (PFS), overall survival (OS), genomic analysis of primary biopsies, and genomic datasets (Memorial Sloan Kettering Cancer Center [MSKCC] and SU2C/PCF). Results and limitations Serum LDH ≥450 U/l is a reliable prognostic biomarker (area under the curve: 0.757 [standard deviation 0.054, 95% confidence interval [CI] 0.650–0.864, p < 0.001]) in progressive mCRPC, predicting PFS at 3 mo. Patients with LDH ≥450 U/l were poorer PSA responders, with shorter PFS (213 vs 372 d, hazard ratio [HR] 1.876, 95% CI 1.289–2.7300) and OS (362 vs 563 d, HR 1.630, 95% CI 1.127–2.357). High LDH is an independent surrogate marker for survival following docetaxel and predicts a poor radiological response (p = 0.043). Of the 14 patients with LDH ≥450 U/l available for next-generation sequencing, nine (64.3%) were more likely to have DNA repair gene mutation(s) (BRCA1/2, ATM, CHEK2, Fanconi anaemia gene) in their primary biopsy. Cross correlation with MSKCC and SU2C/PCF databases revealed a positive correlation between LDHA, PARP1 (r = 0.667, p < 0.01), and other DNA repair genes. Conclusions Genomic abnormalities of LDHA and DNA repair in primary biopsies link to high pretreatment LDH and poor response to docetaxel in mCRPC. Patient summary The presence of mutations of the lactate dehydrogenase and DNA repair pathways are associated with aggressive prostate cancer and poor response to chemotherapy later in the disease.

Background: Improving cancer survival in the UK, despite recent significant gains, remains a huge challenge. This can beattributed to, at least in part, patient and diagnostic delays, when patients are unaware they are suffering from a cancerous symptomand therefore do not visit a general practitioner promptly and/or when general practitioners fail to investigate the symptom orrefer promptly. To raise awareness of symptoms that may potentially be indicative of underlying cancer among members of thepublic a symptom-based risk assessment model (developed for medical practitioner use and currently only used by some UKgeneral practitioners) was utilized to develop a risk assessment tool to be offered to the public in community settings. Such a toolcould help individuals recognize a symptom, which may potentially indicate cancer, faster and reduce the time taken to visit totheir general practitioner. In this paper we report results about the design and development of the REACT (Risk Estimation forAdditional Cancer Testing) website, a tool to be used in a community setting allowing users to complete an online questionnaireand obtain personalized cancer symptom-based risk estimation.Objective: The objectives of this study are to evaluate (1) the acceptability of REACT among the public and health carepractitioners, (2) the usability of the REACT website, (3) the presentation of personalized cancer risk on the website, and (4)potential approaches to adopt REACT into community health care services in the UK.Methods: Our research consisted of multiple stages involving members of the public (n=39) and health care practitioners (n=20)in the UK. Data were collected between June 2017 and January 2018. User views were collected by (1) the “think-aloud” approachwhen participants using the website were asked to talk about their perceptions and feelings in relation to the website, and (2)self-reporting of website experiences through open-ended questionnaires. Data collection and data analysis continued simultaneously,allowing for website iterations between different points of data collection.Results: The results demonstrate the need for such a tool. Participants suggest the best way to offer REACT is through a guidedapproach, with a health care practitioner (eg, pharmacist or National Health Service Health Check nurse) present during theprocess of risk evaluation. User feedback, which was generally consistent across members of public and health care practitioners,has been used to inform the development of the website. The most important aspects were: simplicity, ability to evaluate multiplecancers, content emphasizing an inviting community “feel,” use (when possible) of layperson language in the symptom screeningquestionnaire, and a robust and positive approach to cancer communication relying on visual risk representation both with affectedindividuals and the entire population at risk.Conclusions: This study illustrates the benefits of involving public and stakeholders in developing and implementing a simplecancer symptom check tool within community. It also offers insights and design suggestions for user-friendly interfaces of similarhealth care Web-based services, especially those involving personalized risk estimation.

Meta-iodobenzylguanidine (mIBG) has been radiolabelled at the no-carrier-added level with [124I] for a proof of concept study to assess the diagnostic accuracy of [124I]mIBG PET/CT in detecting metastatic deposits in patients diagnosed with metastatic neuroblastoma. Radiolabelling of mIBG was achieved via the iododesilylation reaction between [124I]sodium iodide and meta-trimethylsilylbenzylguanidine. [124I]mIBG was produced in 62–70 % radioiodide incorporation yield from [124I]sodium iodide. The average amount of formulated [124I]mIBG was 359 MBq (range 344–389 MBq) with an average specific radioactivity of 4.1 TBq μmol−1 (range 1.8–5.9 TBq μmol−1) at end of synthesis.

Infrared spectral histopathology has shown great promise as an important diagnostic tool, with the potential to complement current pathological methods. While promising, clinical translation has been hindered by the impracticalities of using infrared transmissive substrates which are both fragile and prohibitively very expensive. Recently, glass has been proposed as a potential replacement which, although largely opaque in the infrared, allows unrestricted access to the high wavenumber region (2500–3800 cm−1). Recent studies using unstained tissue on glass have shown that despite utilising only the amide A band, good discrimination between histological classes could be achieved, and suggest the potential of discriminating between normal and malignant tissue. However unstained tissue on glass has the potential to disrupt the pathologist workflow, since it needs to be stained following infrared chemical imaging. In light of this, we report on the very first infrared Spectral Histopathology SHP study utilising coverslipped H&E stained tissue on glass using samples as received from the pathologist. In this paper we present a rigorous study using results obtained from an extended patient sample set consisting of 182 prostate tissue cores obtained from 100 different patients, on 18 separate H&E slides. Utilising a Random Forest classification model we demonstrate that we can rapidly classify four classes of histology of an independent test set with a high degree of accuracy (>90%). We investigate different degrees of staining using nine separate prostate serial sections, and demonstrate that we discriminate on biomarkers rather than the presence of the stain. Finally, using a four-class model we show that we can discriminate normal epithelium, malignant epithelium, normal stroma and cancer associated stroma with classification accuracies over 95%.

Context The androgen receptor (AR) gene exon 1 CAG repeat length has been proposed to be a determinant of between-individual variations in androgen action in target tissues, which might regulate phenotypic differences of human ageing. However, findings on its phenotypic effects are inconclusive. Objective To assess whether the AR CAG repeat length is associated with longitudinal changes in endpoints that are influenced by testosterone (T) levels in middle-aged and elderly European men. Design Multinational European observational prospective cohort study. Participants A total of 1887 men (mean ± s.d. age: 63 ± 11 years; median follow up: 4.3 years) from centres of eight European countries comprised the analysis sample after exclusion of those with diagnosed diseases of the hypothalamic–pituitary–testicular (HPT) axis. Main outcome measures Longitudinal associations between the AR CAG repeat and changes in androgen-sensitive endpoints (ASEs) and medical conditions were assessed using regression analysis adjusting for age and centre. The AR CAG repeat length was treated as both a continuous and a categorical (6–20; 21–23; 24–39 repeats) predictor. Additional analysis investigated whether results were independent of baseline T or oestradiol (E2) levels. Results The AR CAG repeat, when used as a continuous or a categorical predictor, was not associated with longitudinal changes in ASEs or medical conditions after adjustments. These results were independent of T and E2 levels. Conclusion Within a 4-year time frame, variations in the AR CAG repeat do not contribute to the rate of phenotypic ageing, over and above, which might be associated with the age-related decline in T levels.

P002: Introduction. Results of standard treatment for older patients (pts) withclassical Hodgkin lymphoma (cHL) are sub-optimal and alternativeapproaches are required. Brentuximab vedotin (BV) is a CD30 targetedantibody-drug conjugate which in the pivotal* phase 2 trial inrelapsed/refractory cHL produced an objective response rate of 75%,complete remission rate of 34% and manageable toxicity. BREVITY isa study of efficacy/tolerability of BV in older, frail or comorbid pts withpreviously untreated cHL. Methods. This was a phase II, Simon 2-stage,single arm study requiring 30 evaluable pts. Primary outcome was completemetabolic response rate (CMR, Deauville Score 1-3) by centrallyreviewed PET-CT after 4 cycles of BV. Secondary outcomes includedPFS, OS, toxicity and comorbidity assessment (CIRS-G). Inclusion criteriawere previously untreated cHL stage 2 (with B symptoms and/ormediastinal bulk) or stages 3/4 with cardiac/respiratory compromise(at any age) or an ECOG score 1-3 and considered unfit for standardchemotherapy (in pts ≥60 yrs). BV dose was 1.8 mg/kg every 3 weeks,reduced to 1.2 mg/kg for toxicity. Pts in CMR/PMR after 4 doses BVcontinued to a total of 16 cycles if CT and/or PET-CT every 4 cyclesconfirmed ongoing response. PFS/OS data is not mature. Results. 38 ptswere recruited Feb 2014-Oct 2015 at 12 UK centres; demographics areshown in Table 1.Table 1.35 pts were treated and evaluable for toxicity, 31 are evaluable forresponse. Median follow-up for alive pts is 11.6(range 0.9, 21.4) months.A median of 4 cycles were given per pt (range 1, 16). 28(12%) cycles in14 pts were modified due to toxicity and 11 pts stopped treatment dueto adverse events (AEs). 695 AEs were reported of which 601(86%)were grade 1/2. 26(74%) pts had at least 1 AE ≥grade 3, most commonlyinfection, myelosuppression or neuropathy. CMR rate at PET4 was25.8%(95% CI 13.7, 43.2) and combined CMR/PMR rate was83.7(95%CI: 67.4, 92.9). To date 21(67.7%) pts have progressed. Discussion.In this study BV monotherapy produced a high objectiveresponse rate although the CMR rate after 4 cycles did not meet thepre-specified 40% level. Toxicity was greater than in the pivotal* studywhere pts were younger/fitter and led to treatment termination in somepts. Nevertheless BV is effective in this older comorbid population. Afollow-on study incorporating BV at lower dose in combination withother agents and growth factor support aimed at improving the CMRrate is in development.

The EuroScience Open Forum 2016 (ESOF16) was held this year in Manchester. While hundreds of seminars, workshops and debates on the latest scientific and technological topics took place in the conference venue, an inspiring science festival of activities and events was developed to bring science alive in the city and engage the whole community. The key themes of the ‘Science in the City’ festival were “Science Feast”, “Science of Me”, “History of Science”, “Building Something Impossible”, “Big Science Stage” and “Tiny Science”.In this context, we were invited to take part in a public engagement event funded by the research programme initiative ‘Marie Skłodowska-Curie Actions (MSCA)’ of the European Commission. The idea was to create a special two-day event for children and their families named ‘Science is a Revolution’ on the weekend preceding ESOF16 at the Museum of Science and Industry in Manchester. Amongst the 8 topics of the event, we contributed to 3 workshops, namely ‘nanomedicine’, ‘graphene’ and ‘microscopy’.

Introduction: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin’s lymphoma (NHL) comprising 3 molecular subtypes: germinal center B-cell (GCB), activated B-cell (ABC) and class III. ABC patients (pts) have a poor prognosis. The immunomodulatory drug lenalidomide (Len) produces durable responses in pts with aggressive NHL (Witzig 2011), with preferential activity reported in non-GCB DLBCL (Hernandez-Ilizaliturri 2011). Methods: This randomized, multicenter, open-label, phase 2/3 study was conducted to determine the efficacy and safety of single-agent Len vs single-agent investigator’s choice (IC) in relapsed/refractory DLBCL pts who received ≥2 prior therapies, or were ineligible for stem cell transplantation or further combination chemotherapy. DLBCL subtype (GCB vs non-GCB) was determined by a central pathology lab using immunohistochemistry (IHC) per the Hans method (Hans 2004). Pts were stratified by subtype, then randomized 1:1 to receive Len (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin) until progressive disease (PD), unacceptable toxicity, or voluntary withdrawal. In the event of radiologically confirmed PD, pts in the IC arm were allowed to cross over to Len. The primary endpoint for Stage 1 was overall response rate (ORR), as determined by an Independent Response Assessment Committee. Progression-free survival (PFS), overall survival (OS) and subtype analysis using gene expression profiling (GEP) were exploratory endpoints. Concordance of GEP and IHC was evaluated from 3 separate laboratories. Results: IHC subtyping agreement rate among the 3 laboratories ranged from 87.5%-97.9%, and sensitivity of IHC to detect ABC or GCB subtypes vs GEP ranged from 92.3%-100.0%. By IHC, 102 DLBCL pts (GCB, n=48; non-GCB, n=54) were treated with ≥1 dose of Len or IC (modified intent-to-treat population) in Stage 1. In this heavily pretreated population, >90.0% of pts received ≥2 prior systemic chemotherapies; 25 pts in Len and 32 pts in IC received ≥3 prior systemic chemotherapy regimens. Median age was 65 y in the IC arm vs 69 y in the Len arm. Twenty-nine pts crossed over from IC to Len after confirmed PD. All pts, regardless of subtype or therapy group, experienced ≥1 treatment-emergent adverse event, with neutropenia, anemia, and thrombocytopenia being the most common. Efficacy data are presented in the Table. Pts with GCB or non-GCB DLBCL (per IHC) treated with Len had similar ORR, but the data suggested greater improvements in PFS and OS with Len vs IC in the non-GCB pts. In an exploratory analysis of pts subtyped by GEP, ABC pts treated with Len vs IC-treated showed greater improvements in ORR, PFS, and OS compared with GCB pts. Prespecified criterion to advance to Stage 2 was a 2-sided 15% significance level in ORR in favor of Len based on IHC-defined subtype. The data did not fulfill this requirement, and Stage 2 was not opened. Conclusion: Len monotherapy showed clinical activity in heavily pretreated pts with DLBCL. The data suggest improved ORR, PFS, and OS with Len vs IC in the non-GCB population as defined by IHC, and the difference appears to be more pronounced in the ABC population as defined by GEP. Subtyping by GEP is warranted in further studies of Len in DLBCL.

Exposure to ionizing radiation is ubiquitous, and it is well established that moderate and high doses cause ill-health and can be lethal. The health effects of low doses or low dose-rates of ionizing radiation are not so clear. This paper describes a project which sets out to summarize, as a restatement, the natural science evidence base concerning the human health effects of exposure to low-level ionizing radiation. A novel feature, compared to other reviews, is that a series of statements are listed and categorized according to the nature and strength of the evidence that underpins them. The purpose of this restatement is to provide a concise entrée into this vibrant field, pointing the interested reader deeper into the literature when more detail is needed. It is not our purpose to reach conclusions on whether the legal limits on radiation exposures are too high, too low or just right. Our aim is to provide an introduction so that non-specialist individuals in this area (be they policy-makers, disputers of policy, health professionals or students) have a straightforward place to start. The summary restatement of the evidence and an extensively annotated bibliography are provided as appendices in the electronic supplementary material.