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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.

We address the problem of learning how compatible two products are. Assessing compatibility is challenging because the meaning of compatibility changes depending on product categories. In this study, we leverage domain experts’ knowledge to generate labels and datasets. Next, we engineer 58 different features from product titles and product descriptions. We experiment with both tree-based and deep learning classifiers using different sets of features to capture compatibility patterns across four product categories. Although the performance does not show consistent pattern across all categories, the precision and recall of the best algorithm from most categories are above 90%. In addition, we find that the performance of classifiers are in general satisfactory. Based on human validation, few best-performing classifiers demonstrate better performance than labels generated from domain experts.

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.

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.To evaluate the clinical effectiveness of BT for solitary urinary bladder tumours in terms of survival, local recurrence (LR) rates, and adverse events.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.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%.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.

Introduction The pre-hospital environment provides significant challenges to clinicians who wish to rapidly administer warmed blood products and fluids to patients with haemorrhagic shock. Large-bore circulatory access is required with the use of devices that will successfully warm cold blood with minimal impact on flow rates. Until now, no information has been available that defines UK Helicopter Emergency Medical Services’ (HEMS) use of circulatory access and fluid warming devices, nor the recent adoption of pre-hospital blood product transfusion. Methods A survey was sent to all 22 UK HEMS asking which circulatory access devices crews have available, whether blood products are being transfused and if fluid warming devices are used as part of their resuscitations. Results All services responded. All UK HEMS use peripheral intravenous cannulae and intraosseous access. In addition, seven use central venous catheters and three use large-bore peripheral access (the Arrow Rapid Infusion Catheter®). Three services use landmark technique alone to gain central venous access, whereas four use a combination of landmark and ultrasound-guided techniques. Different sites for central venous access are used: subclavian (seven services), internal jugular (four) and femoral (four). Fourteen services carry pre-hospital blood products of which six transfuse packed red blood cells; four transfuse packed red blood cells and fresh frozen plasma; four transfuse packed red blood cells and lyophilised plasma. Eight services carry no pre-hospital blood products. Seventeen HEMS use fluid warmers; 13 use the Belmont® buddy lite™ and four use the QinFlow Warrior. Conclusion The use of a variety of policies and range of equipment has evolved across UK HEMS, demonstrating a lack of consensus on best practice. This is the first study to record a complete picture of current UK HEMS practice with regard to the use of circulatory access devices, fluid warmers and blood product administration.

Immune checkpoint inhibitors (ICIs) are active in metastatic urothelial carcinoma (MUC). They have joined chemotherapy (CT) as a standard of care. Here, we investigate the activity of CT after progression on ICIs. Two cohorts of sequential patients with MUC were described ( n =28). Cohort A received first-line ICIs followed by CT after progression. Cohort B received CT after failure of first-line platinum-based CT followed by ICIs. Response rate (RR) to CT was assessed using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) by a designated radiologist. Best RR for cohort A was 64%. Two patients experienced clinical progression and died before the first radiographic assessment. RR for cohort B was 21%, which was significantly lower than that for cohort A. Progression of disease occurred in 43% of cohort B patients by the end of CT. These data suggest a lack of cross resistance between CT and ICIs in MUC. Therefore, the sequencing of these drugs is likely to be important to maximise outcomes. This is particularly true after first-line ICIs as subsequent CT has significant activity. Patient summary In this report, we studied the effect of chemotherapy in metastatic bladder cancer, which relapsed after immune checkpoint inhibitors. We found that the activity of chemotherapy was maintained despite previous exposure to immune therapy. This underlines the importance of sequencing these agents to maximise outcomes.

A saltern associated with salt production was excavated at Pyde Drove, near Woolavington. The large assemblage of briquetage recovered has allowed for some novel interpretations of the function of the different component types within the hearth structures. The saltern comprised a mound of waste material adjacent to 12 brine-settling tank pits and two salt water channels. A further settling tank was revealed beneath the mound. The pottery indicates that activity on the site dates to the later Romano-British period.

This article describes several approaches to assessing student understanding using written explanations that students generate as part of a multiple-document inquiry activity on a scientific topic (global warming). The current work attempts to capture the causal structure of student explanations as a way to detect the quality of the students’ mental models and understanding of the topic by combining approaches from Cognitive Science and Artificial Intelligence, and applying them to Education. First, several attributes of the explanations are explored by hand coding and leveraging existing technologies (LSA and Coh-Metrix). Then, we describe an approach for inferring the quality of the explanations using a novel, two-phase machine-learning approach for detecting causal relations and the causal chains that are present within student essays. The results demonstrate the benefits of using a machine-learning approach for detecting content, but also highlight the promise of hybrid methods that combine ML, LSA and Coh-Metrix approaches for detecting student understanding. Opportunities to use automated approaches as part of Intelligent Tutoring Systems that provide feedback toward improving student explanations and understanding are discussed.