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PURPOSE: Hypofractionated radiation therapy can be used to treat patients with muscle-invasive bladder cancer unable to have radical therapy. Toxicity is a key concern, but adaptive plan-of the day (POD) image-guided radiation therapy delivery could improve outcomes by minimizing the volume of normal tissue irradiated. The HYBRID trial assessed the multicenter implementation, safety, and efficacy of this strategy.METHODS: HYBRID is a Phase II randomized trial that was conducted at 14 UK hospitals. Patients with T2-T4aN0M0 muscle-invasive bladder cancer unsuitable for radical therapy received 36 Gy in 6 weekly fractions, randomized (1:1) to standard planning (SP) or adaptive planning (AP) using a minimization algorithm. For AP, a pretreatment cone beam computed tomography (CT) was used to select the POD from 3 plans (small, medium, and large). Follow-up included standard cystoscopic, radiologic, and clinical assessments. The primary endpoint was nongenitourinary Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 (≥G3) toxicity within 3 months of radiation therapy. A noncomparative single stage design aimed to exclude ≥30% toxicity rate in each planning group in patients who received ≥1 fraction of radiation therapy. Local control at 3-months (both groups combined) was a key secondary endpoint.RESULTS: Between April 15, 2014, and August 10, 2016, 65 patients were enrolled (SP, n = 32; AP, n = 33). The median follow-up time was 38.8 months (interquartile range [IQR], 36.8-51.3). The median age was 85 years (IQR, 81-89); 68% of participants (44 of 65) were male; and 98% of participants had grade 3 urothelial cancer. In 63 evaluable participants, CTCAE ≥G3 nongenitourinary toxicity rates were 6% (2 of 33; 95% confidence interval [CI], 0.7%-20.2%) for the AP group and 13% (4 of 30; 95% CI, 3.8%-30.7%) for the SP group. Disease was present in 9/48 participants assessed at 3 months, giving a local control rate of 81.3% (95% CI, 67.4%-91.1%).CONCLUSIONS: POD adaptive radiation therapy was successfully implemented across multiple centers. Weekly ultrahypofractionated 36 Gy/6 fraction radiation therapy is safe and provides good local control rates in this older patient population.

Introduction: Neoadjuvant chemotherapy followed by radical cystectomy (RC) and pelvic lymph node dissection is the standard radical management for muscle‐invasive bladder cancer (MIBC). However, major pelvic surgery is not suitable for all patients and combined modality therapy (CMT) offers an alternative for patients who want to retain their bladder. Brachytherapy (BT), as part of CMT, has been offered in selective cases of bladder cancer. Objectives: To evaluate the clinical effectiveness of BT for solitary urinary bladder tumours in terms of survival, local recurrence (LR) rates, and adverse events. Methods: A systematic review was conducted using defined search terms using online databases. Articles that discussed the use of BT as part of multi‐modality treatments for MIBC were included. Results: Searches returned 112 articles of which 20 were deemed suitable for analysis. In all, 15 of the 20 articles reported overall survival (OS) at 5 years, 2747 patients were at risk and 1670 were alive after 5 years (60%): seven studies reported OS at 10 years, with 817 patients at risk and 350 alive at 10 years (42%). Disease‐specific survival at 5 years was reported in four studies, with 371 patients at risk and 279 alive (75%) at 5 years. LR rates were reported across all 20 studies and ranged from 0% to 32%. Conclusion: Brachytherapy as part of CMT for MIBC is not a standard technique. It is an effective treatment in experienced centres for a selected patient population who wish to preserve their bladder. In such patients, CMT‐BT is well tolerated with an acceptable safety profile.

BACKGROUND: The literature on total en bloc spondylectomy (TES) of bone tumors of the lumbar spine is sparse and heterogeneous. Therefore, the aim was to systematically pool the data from the published studies to quantitatively summarize the morbidity and mortality and to identify factors associated with favorable outcomes and complications. METHOD: A systematic literature search for studies with individual patient-level data was conducted using specific medical subject heading(MeSH) terms. The outcome measures assessed included complications, tumor recurrence, survival, and function. Individual patient data were pooled from all the studies and quantitatively analyzed to assess the association of different factors with outcomes and complications. RESULTS: Twelve studies were included in this review with a total of 145 TES cases. Of all patients, 50% had at least 1 reported complication post surgery and this was associated with advancing age (OR 1.04, P < 0.001), metastatic disease (OR 5.61, P < 0.001), and adjuvant chemo and/or radiotherapy (OR 20.3, P = 0.001). Intralesional excision (OR 5.2, P = 0.01) and primary malignant tumors (OR 3.3, P = 0.02) were associated with a high recurrence rate. However, the surgical approach was not associated with differences in survival (P = 0.874) or recurrence (P = 0.525) rates. L5 tumor resection was associated with excessive bleeding. Postoperatively, there was an overall improvement in the Frankel grades in most patients. CONCLUSION: TES is associated with high rates of complications especially in association with primary malignant and metastatic diseases. However, the number of publications on this topic remain scarce and heterogeneous. Hence, there is a need for standardization in the reporting of the outcomes and complications to help with decision-making and consenting for this procedure.

Background Hepatic burden is a significant confounder in the assessment of impact of primary tumour resection in metastatic small bowel neuroendocrine tumours (SI-NET). For SI-NET metastatic hepatic burden >10% disease replacement or > 5 hepatic metastases are known prognostic markers, though nomograms and scores do not adequately account for this. Most trials do not adequately account for hepatic burden when assessing the survival difference between SI-NET primary tumour resection and no resection. We propose a sampling methodology to more accurately assess metastatic liver burden in SI-NET and correlate with delayed resection vs. upfront primary tumour resection at a specialist NET surgical unit. Methods Patients referred for metastatic SI-NET between January 2003 and February 2020 were identified from a prospective dataset. The earliest CT scan after diagnosis was used. The axial, coronal and sagittal slice position limits of the whole liver were recorded. These limits allowed equitable slice position of the liver, with 8 equally distributed axial, 4 equally distributed coronal and 4 equally distributed sagittal slices. Each slice was used to define the liver and metastatic area as assessed using liver CT windows. Liver burden was estimated as percentage total metastatic area summed from all 8 axial, 4 coronal and 4 sagittal slices. Results 157 total patients were on the collated data base and 46 patients were identified with an appropriate CT. Liver burden was positively skewed. Liver burden was significantly higher for delayed resection vs. upfront resection in all planes of assessment (axial: 11.61% vs. 0.14%, p = 0.003; coronal: 13.46% vs. 0.33%, p = 0.006; sagittal: 10.46% vs. 0.16%, p = 0.008). All planar assessments correlated well with one another (all Kendall’s tau ≥0.851, all p Conclusions Hepatic burden differs between resection groups in a small sample at our centre, highlighting the unmeasured confounders favouring primary tumour resection via positive bias. Therefore, hepatic burden needs quantifying in prospective studies that assess primary tumour resection in SI-NET. This is to ensure comparable groups after randomisation. Our method provides an assessment of this metastatic SI-NET liver burden.

INTRODUCTION AND OBJECTIVE:Robotic radical prostatectomy (RARP) is a standalone therapeutic modality, with the need for salvage radiotherapy often treated as an unpredictable setback. In fact it’s ...

Users' clicks on Web search results are one of the key signals for evaluating and improving web search quality and have been widely used as part of current state-of-the-art Learning-To-Rank(LTR) models. With a large volume of search logs available for major search engines, effective models of searcher click behavior have emerged to evaluate and train LTR models. However, when modeling the users' click behavior, considering the bias of the behavior is imperative. In particular, when a search result is not clicked, it is not necessarily chosen as not relevant by the user, but instead could have been simply missed, especially for lower-ranked results. These kinds of biases in the click log data can be incorporated into the click models, propagating the errors to the resulting LTR ranking models or evaluation metrics. In this paper, we propose the De-biased Reinforcement Learning Click model (DRLC). The DRLC model relaxes previously made assumptions about the users' examination behavior and resulting latent states. To implement the DRLC model, convolutional neural networks are used as the value networks for reinforcement learning, trained to learn a policy to reduce bias in the click logs. To demonstrate the effectiveness of the DRLC model, we first compare performance with the previous state-of-art approaches using established click prediction metrics, including log-likelihood and perplexity. We further show that DRLC also leads to improvements in ranking performance. Our experiments demonstrate the effectiveness of the DRLC model in learning to reduce bias in click logs, leading to improved modeling performance and showing the potential for using DRLC for improving Web search quality., Comment: SIGIR 2021 Short Paper

Query categorization is an essential part of query intent understanding in e-commerce search. A common query categorization task is to select the relevant fine-grained product categories in a product taxonomy. For frequent queries, rich customer behavior (e.g., click-through data) can be used to infer the relevant product categories. However, for more rare queries, which cover a large volume of search traffic, relying solely on customer behavior may not suffice due to the lack of this signal. To improve categorization of rare queries, we adapt the Pseudo-Relevance Feedback (PRF) approach to utilize the latent knowledge embedded in semantically or lexically similar product documents to enrich the representation of the more rare queries. To this end, we propose a novel deep neural model named Attentive Pseudo Relevance Feedback Network (APRF-Net) to enhance the representation of rare queries for query categorization. To demonstrate the effectiveness of our approach, we collect search queries from a large commercial search engine, and compare APRF-Net to state-of-the-art deep learning models for text classification. Our results show that the APRF-Net significantly improves query categorization by 5.9% on F1@1 score over the baselines, which increases to 8.2% improvement for the rare (tail) queries. The findings of this paper can be leveraged for further improvements in search query representation and understanding.

Intradural disc herniation is a rare entity reported at 0.04–1.1% that occurs most commonly in the lumbar spine particularly at L4–L5 region. There is a paucity of literature due to the rarity of this condition. Intradural disc herniations must be considered in the differential diagnosis of prolapsed intervertebral disc disease especially with recent worsening of symptoms and mismatch of unenhanced magnetic resonance induction (MRI) findings. The confirmation is made with intraoperative findings. An intradural disc herniation is most often diagnosed intraoperatively. Contrast enhanced MRI scan is mandatory for pre-operative diagnosis. We report on two cases presenting to our unit in the form of recurrent intradural disc disease following previous lumbar surgery occurring within 3 months of the index procedure in both cases.

Neuroendocrine neoplasms are known to have heterogeneous biological behavior. G3 neuroendocrine tumours (NET G3) are characterized by well-differentiated morphology and Ki67 > 20%. The prognosis of this disease is understood to be intermediate between NET G2 and neuroendocrine carcinoma (NEC). Clinical management of NET G3 is challenging due to limited data to inform treatment strategies. We describe clinical characteristics, treatment, and outcomes in a large single centre cohort of patients with gastroenteropancreatic NET G3. Data was reviewed from 26 cases managed at Queen Elizabeth Hospital, Birmingham, UK, from 2012 to 2019. Most commonly the site of the primary tumour was unknown and majority of cases with identifiable primaries originated in the GI tract. Majority of cases demonstrated somatostatin receptor avidity. Median Ki67 was 30%, and most cases had stage IV disease at diagnosis. Treatment options included surgery, somatostatin analogs (SSA), and chemotherapy with either platinum-based or temozolomide-based regimens. Estimated progression free survival was 4 months following initiation of SSA and 3 months following initiation of chemotherapy. Disease control was observed following treatment in 5/11 patients treated with chemotherapy. Estimated median survival was 19 months; estimated 1 year survival was 60% and estimated 2 year survival was 13%. NET G3 is a heterogeneous group of tumours and patients which commonly have advanced disease at presentation. Prognosis is typically poor, though select cases may respond to treatment with SSA and/or chemotherapy. Further study is needed to compare efficacy of different treatment strategies for this disease.

Background Bladder cancer (BC) is the 9th most common cancer worldwide, but little progress has been made in improving patient outcomes over the last 25 years. The King’s Health Partners (KHP) BC biobank was established to study unanswered, clinically relevant BC research questions. Donors are recruited from the Urology or Oncology departments of Guy’s Hospital (UK) and can be approached for consent at any point during their treatment pathway. At present, patients with bladder cancer are approached to provide their consent to provide blood, urine and bladder tissue. They also give access to medical records and linkage of relevant clinical and pathological data across the course of their disease. Between June 2017 and June 2019, 531 out of 997 BC patients (53.3%) gave consent to donate samples and data to the Biobank. During this period, the Biobank collected fresh frozen tumour samples from 90/178 surgical procedures (of which 73 were biopsies) and had access to fixed, paraffin embedded samples from all patients who gave consent. Blood and urine samples have been collected from 38 patients, all of which were processed into component derivatives within 1 to 2 h of collection. This equates to 193 peripheral blood mononuclear cell vials; 238 plasma vials, 224 serum vials, 414 urine supernatant vials and 104 urine cell pellets. This biobank population is demographically and clinically representative of the KHP catchment area. Conclusion The King’s Health Partners BC Biobank has assembled a rich data and tissue repository which is clinically and demographically representative of the local South East London BC population, making it a valuable resource for future BC research.

IntroductionGiven the need for more bladder cancer research and the recently observed advantages of introducing the trials within cohort (TwiCs) design, the set-up of the Graham Roberts Study (Roberts Study) will provide valuable infrastructure to answer a wide variety of research questions of a clinical, mechanistic, as well as supportive care nature in the area of bladder cancer.MethodsUsing the TwiCs design, we will recruit patients aged 18 or older who are willing and able to provide signed informed consent and have a diagnosis of new or recurrent bladder cancer into this prospective cohort study. All patients must have a basic understanding of the English language. The following questionnaires will be collected at baseline and every 12 months subsequently: Functional Assessment of Chronic Illness Therapy for Bladder Cancer, the Functional Assessment of Chronic Illness Therapy-Fatigue, the Patient Heath Questionnaire-9, the standardised instrument for a generic health status (EQ-5D-5L), a Short Questionnaire to Assess Health-Enhancing Physical Activity and the Hertfordshire Short Questionnaire to Assess Diet Quality.Ethics and disseminationDue to the nature of this study, we obtained full ethical clearance from the London—Fulham Research Ethics Committee (17/LO1975). All participants must provide full informed consent before recruitment onto the study. The results of this study will be published in peer-reviewed journals and data collected as part of the study will be made available to potential collaborators on an application basis.

Consensus in Bladder Cancer Research Priorities Between Patients and Healthcare Professionals Using a Four-stage Modified Delphi Method

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication of T-lymphocyte deplete allogeneic hematopoietic stem cell transplantation (allo-HSCT). For patients with PTLD refractory to Rituximab, donor lymphocyte infusion (DLI) is established as a successful option for salvage therapy. However, although in vivo lymphocyte expansion has been correlated with good clinical outcome following DLI, the specificity and functional characteristics of EBV-specific T-cell responses remain poorly characterized. Here we describe two patients with Rituximab-refractory PTLD complicating T-cell deplete allo-HSCT, both of whom were successfully rescued with 1 × 106/Kg unselected stem cell donor-derived DLI. Prospective analyses revealed that complete clinical and radiological responses were associated with in vivo expansion of T and NK cells. Furthermore, EBV MHC tetramer, and interferon gamma analyses revealed a marked increase in EBV-specific T-cell frequency from 4 weeks after DLI. Reactivity was demonstrated against a range of EBV latent and lytic antigens, including those detected in tumor biopsy material. The immunodominant EBV-specific T cell response expanding in vivo following infusion matched the dominant response present in the DLI preparations prior to administration. Furthermore, differences in the repertoire of subdominant antigen-specific T-cells were also detected, suggesting that antigen-encounter in vivo can shape the immune response. These results demonstrate the value of prospectively studying in vivo T-cell responses, by facilitating the identification of important specificities required for clinical efficacy. Applying this approach on a larger scale promises to yield data which may be essential for the optimization of future adoptive immunotherapeutic strategies for PTLD.

Purpose To determine the impact on clinical management of patients with high-risk (HR) prostate cancer at diagnosis and patients with biochemical recurrence (BCR) using a new kit form of 68Ga-prostate-specific membrane antigen (PSMA), namely tris(hydroxypyridinone) (THP)-PSMA, with positron emission tomography-computed tomography (PET-CT). Methods One hundred eighteen consecutive patients (50 HR, 68 BCR) had management plans documented at a multidisciplinary meeting before 68Ga-THP-PSMA PET-CT. Patients underwent PET-CT scans 60-min post-injection of 68Ga-THP-PSMA (mean 159 ± 21.2 MBq). Post-scan management plans, Gleason score, prostate-specific antigen (PSA) and PSA doubling time (PSAdt) were recorded. Results HR group: 12/50 (24%) patients had management changed (9 inter-modality, 3 intra-modality). Patients with PSA < 20 μg/L had more frequent management changes (9/26, 34.6%) compared with PSA > 20 μg/L (3/24, 12.5%). Gleason scores > 8 were associated with detection of more nodal (4/16, 25% vs 5/31, 16.1%) and bone (2/16, 12.5% vs 2/31, 6.5%) metastases. BCR group: Clinical management changed in 23/68 (34%) patients (17 inter-modality, 6 intra-modality). Forty out of 68 (59%) scans were positive. Positivity rate increased with PSA level (PSA < 0.5 μg/L, 0%; PSA 0.5–1.0 μg/L, 35%; PSA 1.0–5.0 μg/L, 69%; PSA 5.0–10.0 μg/L, 91%), PSAdt of < 6 months (56% vs 45.7%) and Gleason score > 8 (78.9% vs 51.2%). Conclusions 68Ga-THP-PSMA PET-CT influences clinical management in significant numbers of patient with HR prostate cancer pre-radical treatment and is associated with PSA. Management change also occurs in patients with BCR and is associated with PSA and Gleason score, despite lower scan positivity rates at low PSA levels < 0.5 μg/L.

Total en bloc spondylectomy (TES) is a surgical technique that is indicated for primary malignant bone tumours, aggressive benign tumours and infrequently solitary metastatic lesions. Primary bone tumours in the axial skeleton are rare. It’s estimated they comprise 11% of all primary bone tumours and only 4% of all tumours found in the spine (1,2). Conversely metastatic spine disease is a significant health burden.

Background: Although comorbidities are identified in routine oncology practice, intervention plans for the coexisting needs of older people receiving chemotherapy are rarely made. This study evaluates the impact of geriatrician-delivered comprehensive geriatric assessment (CGA) interventions on chemotherapy toxicity and tolerance for older people with cancer.Methods: Comparative study of two cohorts of older patients (aged 70+ years) undergoing chemotherapy in a London Hospital. The observational control group (N=70, October 2010–July 2012) received standard oncology care. The intervention group (N=65, September 2011–February 2013) underwent risk stratification using a patient-completed screening questionnaire and high-risk patients received CGA. Impact of CGA interventions on chemotherapy tolerance outcomes and grade 3+ toxicity rate were evaluated. Outcomes were adjusted for age, comorbidity, metastatic disease and initial dose reductions.Results: Intervention participants undergoing CGA received mean of 6.2±2.6 (range 0–15) CGA intervention plans each. They were more likely to complete cancer treatment as planned (odds ratio (OR) 4.14 (95% CI: 1.50–11.42), P=0.006) and fewer required treatment modifications (OR 0.34 (95% CI: 0.16–0.73), P=0.006). Overall grade 3+ toxicity rate was 43.8% in the intervention group and 52.9% in the control (P=0.292).Conclusions: Geriatrician-led CGA interventions were associated with improved chemotherapy tolerance. Standard oncology care should shift towards modifying coexisting conditions to optimise chemotherapy outcomes for older people.Keywords: comprehensive geriatric assessment; elderly; geriatric oncology; chemotherapy tolerance; toxicity; interventions

Schematic maps are an important component of assistance for navigating transport networks worldwide. By showing routes as simple straight lines, they reduce the cognitive load of journey planning, and by revealing the underlying structure of networks, they make their key features easier to identify and learn. However, although there are many suggestions for optimizing schematic maps so as to maximize these benefits, to date these have not been directly supported by published usability studies or psychological theory. In this paper, we suggest that there are circumstances in which conventional schematic maps fail to yield benefits, and we compare journey planning using the current official RATP Paris Metro map with an all-curves design which replaces straight lines and corners with gentle curves. Three separate usability studies with slightly different methodologies showed that the journey planning time for the all-curves map was better than the RATP version, with effect sizes ranging from 0.48 to 1.12. Subjective usability ratings were derived from questionnaires, and user preferences, but neither were correlated with objective usability measures. We conclude that (1) in terms of designing schematics, there is no evidence to suggest that any rule-set can be claimed to be a gold-standard, and it is important to match the design rules to the properties of the network, (2) in some circumstances, radical departures from traditional ideas can yield usability benefits, and (3) map usability appears to be distinct from map engagement, although the latter is undoubtedly important in encouraging people fully to make use of navigation aides.

The present study explored different approaches for automatically scoring student essays that were written on the basis of multiple texts. Specifically, these approaches were developed to classify whether or not important elements of the texts were present in the essays. The first was a simple pattern-matching approach called "multi-word" that allowed for flexible matching of words and phrases in the sentences. The second technique was latent semantic analysis (LSA), which was used to compare student sentences to original source sentences using its high-dimensional vector-based representation. Finally, the third was a machine-learning technique, support vector machines, which learned a classification scheme from the corpus. The results of the study suggested that the LSA-based system was superior for detecting the presence of explicit content from the texts, but the multi-word pattern-matching approach was better for detecting inferences outside or across texts. These results suggest that the best approach for analyzing essays of this nature should draw upon multiple natural language processing approaches.

Introduction Tenascin-C (TNC) is a large extracellular matrix glycoprotein that shows prominent stromal expression in many solid tumours. The profile of isoforms expressed differs between cancers and normal breast, with the two additional domains AD1 and AD2 considered to be tumour associated. The aim of the present study was to investigate expression of AD1 and AD2 in normal, benign and malignant breast tissue to determine their relationship with tumour characteristics and to perform in vitro functional assays to investigate the role of AD1 in tumour cell invasion and growth. Methods Expression of AD1 and AD2 was related to hypoxanthine phosphoribosyltransferase 1 as a housekeeping gene in breast tissue using quantitative RT-PCR, and the results were related to clinicopathological features of the tumours. Constructs overexpressing an AD1-containing isoform (TNC-14/AD1/16) were transiently transfected into breast carcinoma cell lines (MCF-7, T-47 D, ZR-75-1, MDA-MB-231 and GI-101) to assess the effect in vitro on invasion and growth. Statistical analysis was performed using a nonparametric Mann-Whitney test for comparison of clinicopathological features with levels of TNC expression and using Jonckheere-Terpstra trend analysis for association of expression with tumour grade. Results Quantitative RT-PCR detected AD1 and AD2 mRNA expression in 34.9% and 23.1% of 134 invasive breast carcinomas, respectively. AD1 mRNA was localised by in situ hybridisation to tumour epithelial cells, and more predominantly to myoepithelium around associated normal breast ducts. Although not tumour specific, AD1 and AD2 expression was significantly more frequent in carcinomas in younger women (age ≤40 years; P < 0.001) and AD1 expression was also associated with oestrogen receptor-negative and grade 3 tumours (P < 0.05). AD1 was found to be incorporated into a tumour-specific isoform, not detected in normal tissues. Overexpression of the TNC-14/AD1/16 isoform significantly enhanced tumour cell invasion (P < 0.01) and growth (P < 0.01) over base levels. Conclusions Together these data suggest a highly significant association between AD-containing TNC isoforms and breast cancers in younger women (age ≤40 years), which may have important functional significance in vivo.

Analysis of the chicken genome has shown that the chicken has a different repertoire of chemokines and chemokine receptors to those of mammals and other species. In this study, we report the sequencing and analysis of a bacterial artificial chromosome containing the entire chicken MIP family CC chemokine cluster. The gene duplication and divergence events that have taken place in mammals do not appear to have occurred as extensively in the avian lineage, as chickens possess fewer MIP family chemokine genes than humans or mice. We previously proposed that the four chicken MIP family members be named chicken (ch) CCLi1-4, according to their position on chicken chromosome 19, until such time as further analysis could determine if any of them were direct orthologues of mammalian MIP family members. Our analysis herein, combined with that of others, suggests that chCCLi4 is the orthologue of mammalian CCL5, and that chCCLi3 (K203) may be an orthologue of human CCL16. The other two chemokines do not have obvious orthologues, and thus we propose that they should still be called chCCLi1 and chCCLi2, until their biological function is further characterised. A similar pattern applies to the MIP family chemokine receptors, with only three receptor genes present at the relevant locus in the chicken genome, compared to four in man and mouse (CCR1, CCR2, CCR3 and CCR5). Of the three chicken receptor genes, only two look likely to be receptors for the MIP family chemokines, the third grouping with human, mouse and chicken CCR8 in phylogenetic analysis. The two chicken MIP CC receptors (CCRs) are not direct orthologues of the mammalian MIP CCRs.

Purpose To report toxicity and early survival data for IDEAL-CRT, a trial of dose-escalated concurrent chemoradiotherapy (CRT) for non-small cell lung cancer. Patients and Methods Patients received tumor doses of 63 to 73 Gy in 30 once-daily fractions over 6 weeks with 2 concurrent cycles of cisplatin and vinorelbine. They were assigned to 1 of 2 groups according to esophageal dose. In group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose, which was escalated following a 6 + 6 design from 65 Gy through 68 Gy to 71 Gy, allowing an esophageal maximum tolerated dose to be determined from early and late toxicities. Tumor doses for group 2 patients were determined by other tissue constraints, often lung. Overall survival, progression-free survival, tumor response, and toxicity were evaluated for both groups combined. Results Eight centers recruited 84 patients: 13, 12, and 10, respectively, in the 65-Gy, 68-Gy, and 71-Gy cohorts of group 1; and 49 in group 2. The mean prescribed tumor dose was 67.7 Gy. Five grade 3 esophagitis and 3 grade 3 pneumonitis events were observed across both groups. After 1 fatal esophageal perforation in the 71-Gy cohort, 68 Gy was declared the esophageal maximum tolerated dose. With a median follow-up of 35 months, median overall survival was 36.9 months, and overall survival and progression-free survival were 87.8% and 72.0%, respectively, at 1 year and 68.0% and 48.5% at 2 years. Conclusions IDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal maximum tolerated dose to be identified from relatively few patients.

Background Melanotic neuroectodermal tumor of infancy (MNTI) is exceptionally rare and occurs predominantly in the head and neck (92.8 % cases). The patient reported here is only the eighth case of MNTI presenting in an extremity, and the first reported in the fibula. Case presentation A 2-month-old female presented with a mass arising in the fibula. Exhaustive genomic, transcriptomic, epigenetic and pathological characterization was performed on the excised primary tumor and a derived cell line. Whole-exome analysis of genomic DNA from both the tumor and blood indicated no somatic, non-synonymous coding mutations within the tumor, but a heterozygous, unique germline, loss of function mutation in CDKN2A (p16INK4A, D74A). SNP-array CGH on DNA samples revealed the tumor to be euploid, with no detectable gene copy number variants. Multiple chromosomal translocations were identified by RNA-Seq, and fusion genes included RPLP1-C19MC, potentially deregulating the C19MC cluster, an imprinted locus containing microRNA genes reactivated by gene fusion in embryonal tumors with multilayered rosettes. Since the presumed cell of origin of MNTI is from the neural crest, we also compared gene expression with a dataset from human neural crest cells and identified 185 genes with significantly different expression. Consistent with the melanotic phenotype of the tumor, elevated expression of tyrosinase was observed. Other highly expressed genes encoded muscle proteins and modulators of the extracellular matrix. A derived MNTI cell line was sensitive to inhibitors of lysine demethylase, but not to compounds targeting other epigenetic regulators. Conclusions In the absence of somatic copy number variations or mutations, the fully transformed phenotype of the MNTI may have arisen in infancy because of the combined effects of a germline CDKN2A mutation, tumor promoting somatic fusion genes and epigenetic deregulation. Very little is known about the etiology of MNTI and this report advances knowledge of these rare tumors by providing the first comprehensive genomic, transcriptomic and epigenetic characterization of a case. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2669-3) contains supplementary material, which is available to authorized users.

Background Incidence and mortality from traumatic intra-cranial haemorrhage (ICH) is increased in patients on warfarin [1]. Prothrombin Complex Concentrates (PCC) rapidly reverse warfarin anti-coagulation and have been shown to reduce haematoma expansion and mortality in warfarinised patients sustaining ICH [2]. We aimed to determine the feasibility of pre-hospital use of PCCs by physicians and their clinical effectiveness in warfarinised patients sustaining traumatic ICH.

The recently devised National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) appears superior to the revised IPI (R-IPI) in delineating outcome in diffuse large B-cell lymphoma. We examined the outcome of a population-based cohort of 223 consecutive patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) or R-CHOP-like immuno-chemotherapy between January 2005 and December 2011 by both the NCCN-IPI and R-IPI, and further stratified outcome by the achievement of both computerized tomography (CT) and positron emission tomography (PET)-CT complete remission (CR), with the latter reassessed using blinded central review by an independent nuclear medicine and radiology specialist. The NCCN-IPI was superior to the R-IPI in identifying patients at very high risk of systemic and/or central nervous system relapse. Notably, both the NCCN-IPI and the R-IPI remained strongly predictive of relapse irrespective of CT or PET-defined remission status following R-CHOP. Patients with high-risk NCCN-IPI scores (≥6) have a dismal outcome following R-CHOP therapy regardless of PET-defined response to R-CHOP. Moreover, such patients appear refractory to salvage chemotherapy and thus require alternative therapeutic approaches, although age and performance status may, for many patients, preclude the safe delivery of a primary intensified regimen. By contrast, patients with NCCN-IPI 1-5 who achieve PET-CR following R-CHOP have excellent outcomes and may merit reduced follow up frequency.

EBV-driven relapse of peripheral T-cell lymphoma, masquerading as a post transplant lymphoproliferative disorder following allo-SCT

Summary Androgen administration can cause prostate cancer progression, and androgen deprivation therapy is a commonly used therapeutic modality in the treatment of prostate cancer. In trying to answer the posed clinical question, this article reviews the risks and benefits of testosterone replacement therapy in this setting and the published data from clinical series. Recommendations are made based on the available evidence.

In the US in particular, there is an increasing emphasis on the importance of science in education. To better understand a scientific topic, students need to compile information from multiple sources and determine the principal causal factors involved. We describe an approach for automatically inferring the quality and completeness of causal reasoning in essays on two separate scientific topics using a novel, two-phase machine learning approach for detecting causal relations. For each core essay concept, we initially trained a window-based tagging model to predict which individual words belonged to that concept. Using the predictions from this first set of models, we then trained a second stacked model on all the predicted word tags present in a sentence to predict inferences between essay concepts. The results indicate we could use such a system to provide explicit feedback to students to improve reasoning and essay writing skills.

Background: Significant toxicity in chemotherapy trials is usually defined as grade greater than or equal to3. In clinical practice, however, multiple lower grade toxicities are often considered meaningful. The purpose of this observational cohort study was to identify which level of toxicity triggers treatment modification and early discontinuation of chemotherapy in older people.Methods: Patients aged 65+ were recruited in a central London hospital. A total of 108 patients were recruited at the start of new chemotherapy treatment between October 2010 and July 2012.Results: Mean age was 72.1±5 years, median 72 and range 65–86 years. Of the patients, 50.9% (55) were male with gastrointestinal (49), gynaecological (18), lung (15) and other cancers (26). Chemotherapy was palliative in 59.3% (64/108), curative/ neoadjuvant/adjuvant in the others. Mean number of cycles completed was 4.2±3. Treatment modifications due to toxicity occurred in 60 (55.6%) patients, 35% (21/60) of whom had no greater than grade 2 toxicity. Early treatment discontinuation because of toxicity occurred in 23 patients (21.3%), 39.1% (9/23) of whom had no greater than grade 2 toxicity.Conclusions: Many older patients did not complete treatment as planned. Treatment was modified/discontinued even for one or two low-grade toxicities. Further work is required to clarify whether low-grade toxicity has a greater clinical impact in older people, or whether clinicians have a lower threshold for modifying/discontinuing treatment in older people.

With an increasing focus on science and technology in education comes an awareness that students must be able to understand and integrate scientific explanations from multiple sources. As part of a larger project aimed at deepening our understanding of student processes for integrating multiple sources of information, we are developing machine learning and natural language processing techniques for evaluating students' argumentative essays. In previous work, we have focused on identifying conceptual elements of the essays. In this paper, we present a method for inferring the causal structure of student essays. We used a standard parser to derive grammatical dependencies of the essay and converted them to logic statements. Then a simple inference mechanism was used to identify concepts linked to syntactic connectors by these dependencies. The results suggest that we will soon be able to provide explicit feedback that enables teachers and students to improve comprehension.

Oncology services do not routinely assess broader needs of older people with cancer. This study evaluates a comprehensive geriatric assessment and comorbidity screening questionnaire (CGA-GOLD) covering evidence-based domains and quality of life (EORTC-QLQ-C30). Patients aged 65+ attending oncology services were recruited into (1) Observational cohort (completed CGA-GOLD, received standard oncology care), (2) Intervention cohort (responses categorised ‘low-risk’, ‘high-risk’, ‘possible need’ by geriatricians). N = 417 observational patients (1002 invited by post, 418 consented, age 73.9 ± 5.4) completed CGA-GOLD in 11.7 ± 7.9 min, 86.3% required no assistance, 3.1% overall missing responses. Multiple problems reported: hypertension (18.1%), diabetes (16.9%), dyspnoea on flat surfaces (27.6%), polypharmacy (46%), difficulty walking (14.9%), fatigue (40.5%), living alone (30.9%), social isolation (11.2%), recent functional dependence (27.8%), urinary incontinence (21.4%), falls (13.3%). 237/239 intervention patients completed CGA-GOLD and consecutive subsets examined. The doctor and nurse specialist independently identified same need level in 87.3% (high inter-rater reliability kappa = 0.80), taking 1–2 min per questionnaire. Need level remained unchanged following hospital notes review against responses in 90% (75/83). ‘Possible need’ patients were telephoned with change in 29% (16/55) to low-risk and none to high-risk, confirming high need was not being missed. CGA-GOLD screening questionnaire was acceptable to older patients, feasibly administered in NHS cancer services, described comorbidities, CGA and QOL needs, and reliably identified higher risk patients requiring further input for optimal cancer treatment.

Historical data for older men with high-risk nonmetastatic prostate cancer treated with radiotherapy alone have demonstrated a 10-year prostate-cancer-specific mortality of around 30%. The development of dose escalation, using techniques such as intensity-modulated radiotherapy, has enabled more targeted delivery of treatment with improved efficacy and a reduction in the risk of toxicity compared with conventional radiotherapy. The combination of radiotherapy and androgen-deprivation therapy (ADT) has been shown to improve overall survival compared with radiotherapy or ADT alone without a significant increase in toxicity in patients with minimal comorbidities. There is evidence that patient age has only a marginal effect on genitourinary and gastrointestinal toxicities following radiotherapy. Further research has shown that although age does have an effect on the likelihood of sexual dysfunction after radiation therapy, there is no significant difference in the proportion of men aged ≥75 years who feel that sexual dysfunction is a moderate or serious problem before or 24 months after diagnosis. Radical radiotherapy is effective and well tolerated in senior men with high-risk prostate cancer and should be offered in combination with long-term ADT to patients with minimal comorbidities. In case of significant comorbid conditions, shorter durations of ADT may be considered.

INTRODUCTIONPCR-based whole-genome amplification (WGA) has the goal of generating microgram quantities of genome-representative DNA from picogram or nanogram amounts of starting material. This amplification should introduce little, or ideally no, representational bias. In contrast to other techniques for WGA, PCR-based methods are generally less affected by DNA quality and are more applicable to DNA extracted from various sources (fixed and fresh tissues). Primer extension preamplification PCR (PEP-PCR), in contrast to degenerate oligonucleotide primed PCR (DOP-PCR), uses totally degenerate 15-mer PCR primers. An additional difference is that in PEP-PCR, the number of potential priming sites is orders of magnitude larger. The effectiveness of PEP-PCR has been increased by several alterations. The improved PEP (I-PEP) PCR approach, described in this protocol, uses a DNA polymerase cocktail that includes Taq DNA polymerase (to carry out the primer extension as in a traditional PCR) and a proofreading DNA polymerase (to provide 3′-to-5′-exonuclease activity, excising misincorporated nucleotides that slow the progression of Taq DNA polymerase). The result is far more efficient WGA, with increased fidelity due to the removal of the misincorporated nucleotides. Similar to DOP-PCR, PEP-PCR generates a smear of DNA fragments that are visible on an agarose gel.