Molecular analysis of endobronchial ultrasound needle aspirates in patients with non-small cell lung cancer: Results from the SCOPE database.

OBJECTIVE: Molecular subtyping of non-small cell lung cancer (NSCLC) is critical in the diagnostic evaluation of patients with advanced disease. This study aimed to examine whether samples from endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) of intrathoracic lymph nodes and/or lung lesions are adequate for molecular analysis across various institutions. METHODS: We retrospectively reviewed all cases of linear EBUS-TBNA with a final bronchoscopic diagnosis of NSCLC entered in the Stather Canadian Outcomes registry for chest ProcEdures database. The primary outcome was specimen inadequacy rate for each molecular target, as defined by the local laboratory or pathologist. RESULTS: A total of 866 EBUS-TBNA procedures for NSCLC were identified. Specimen inadequacy rates were 3.8% for EGFR, 2.5% for ALK-1 and 3.5% for PD-L1. Largest target size was not different between adequate and inadequate specimens, and rapid onsite evaluation did not increase specimen adequacy rates. One centre using next-generation sequencing for EGFR had lower adequacy rates than 2 others using matrix-assisted laser desorption/ionization time-of-flight mass spectrophotometry. CONCLUSION: EBUS-TBNA specimens have a very low-specimen inadequacy rate for molecular subtyping of non-small cell lung cancer.

LOGGIC/FIREFLY-2: a phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating RAF alteration.

BACKGROUND: Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1 study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use. METHODS: LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m2 (not to exceed 600 mg), or investigator's choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate. DISCUSSION: The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022.

Patient perspectives on the use of indwelling pleural catheters in malignant pleural effusions.

BACKGROUND: Indwelling pleural catheters are an effective treatment option for patients with malignant pleural effusions. Despite their popularity, there remains a paucity of data on the patient experience and key patient-centred outcomes. OBJECTIVE: To investigate the experience of patients receiving an indwelling pleural catheter to better inform and identify potential areas for improvement in care. METHODS: This was a multicentre survey study at three academic, tertiary-care centres in Canada. Patients with a diagnosis of malignant pleural effusion who had an indwelling pleural catheter inserted were included. An adapted questionnaire specific to indwelling pleural catheters was used with responses recorded on a 4-point Likert scale. Patients completed the questionnaire in-person or by phone at 2-week and 3-month follow-up appointments. RESULTS: A total of 105 patients were enrolled in the study with 84 patients included in the final analysis. At the 2-week follow-up, patient-reported improvements in dyspnoea and quality of life from indwelling pleural catheter were high at 93% and 87%, respectively. The predominant issues identified were discomfort at time of insertion (58%), itching (49%), difficulty with sleeping (39%), discomfort with home drainage (36%) and the pleural catheter reminding patients of their disease (63%). Avoiding hospitalisation for the management of dyspnoea was important to 95% of patients. Findings were similar at 3 months. CONCLUSIONS: Indwelling pleural catheters are an effective intervention to directly improve dyspnoea and quality of life but have important disadvantages for some; clinicians and patients should be aware of these when making an informed decision regarding treatment.

Combination Tissue Plasminogen Activator and DNase for Loculated Malignant Pleural Effusions: A Single-center Retrospective Review.

BACKGROUND: Indwelling pleural catheters (IPCs) are frequently used for the management of malignant pleural effusions (MPEs), but drainage can be impaired by pleural loculations. We aimed to evaluate the safety and effectiveness of intrapleural tissue plasminogen activator (tPA) versus combination tPA-deoxyribonuclease (DNase) in the treatment of loculated MPE. METHODS: We performed a retrospective review of patients with confirmed or presumed MPEs requiring IPC insertion. We compared the efficacy of intrapleural tPA, tPA-DNase, and procedural intervention on pleural fluid drainage. Secondary endpoints included the need for future pleural procedures (eg, thoracentesis, IPC reinsertion, chest tube insertion, or surgical intervention), IPC removal due to spontaneous pleurodesis, and IPC-related complications. RESULTS: Among 437 patients with MPEs, loculations developed in 81 (19%) patients. Twenty-four (30%) received intrapleural tPA, 46 (57%) received intrapleural tPA-DNase, 4 (5%) underwent a procedural intervention, and 7 (9%) received ongoing medical management. tPA improved pleural drainage in 83% of patients, and tPA-DNase improved pleural drainage in 80% of patients. tPA alone may be associated with increased rates of spontaneous pleurodesis compared with tPA-DNase. There was no difference in complications when comparing tPA, combination tPA-DNase, procedural intervention, and no therapy. CONCLUSION: Both intrapleural tPA and combination tPA-DNase appear to be safe and effective in improving pleural fluid drainage in selected patients with loculated MPE, although further studies are needed.

Effect of chemotherapy, immunotherapy, and targeted therapies on removal of indwelling pleural catheters in non-small cell lung cancer patients with malignant pleural effusions.

BACKGROUND: Indwelling pleural catheters (IPCs) are a mainstay therapy for malignant pleural effusions (MPEs). Many patients treated with IPCs achieve pleurodesis. We aimed to identify the effect of systemic therapies for non-small cell lung cancer (NSCLC) on IPC removal in patients with associated MPEs. METHODS: We completed a retrospective cohort study of adult IPC recipients with metastatic NSCLC at the pleural effusion clinic at the Royal Alexandra Hospital from 2009 to 2020. We used logistic regression to assess the rates of IPC removal and Cox regression to assess the time to IPC removal. RESULTS: 232 patients met inclusion criteria with 248 IPCs reviewed. The overall pleurodesis rate was 42.7% with a median time to pleurodesis of 68 (IQR 38-140) days. In univariate analysis, chemotherapy (OR 1.86, CI 0.99-3.49) and epidermal growth factor receptor (EGFR) targeted therapy (OR 3.81, CI 1.86-7.79) were associated with higher rates of pleurodesis. In multivariate analysis, increased rates of pleurodesis were associated with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≤2 (OR 4.82, CI 2.24-10.37) and EGFR targeted therapy (OR 3.87, CI 1.80-8.32). Earlier IPC removal was associated with EGFR targeted therapy in both univariate (HR 1.84, CI 1.20-2.83) and multivariate analysis (HR 1.86, CI 1.19-2.92). CONCLUSIONS: Treatment with EGFR targeted therapy is associated with increased rates and earlier removal of IPC in patients with NSCLC in our cohort. Further large cohort studies are required to determine if this relationship persists.

Outcomes for Malignant Pleural Effusions Because of Melanoma Treated With Indwelling Pleural Catheters.

BACKGROUND: Indwelling pleural catheters (IPCs) reduce dyspnea and improve quality of life in patients with malignant pleural effusions (MPEs). Data on outcomes of MPEs secondary to metastatic melanoma managed with IPCs are scarce. We aimed to evaluate outcomes of patients receiving IPCs for MPEs secondary to melanoma compared with other malignancies. METHODS: We identified patients from our prospectively collected database of all patients who had an IPC insertion for MPEs at our tertiary care center for melanoma between May 2006 and November 2018 and for nonmelanoma between May 2006 and June 2013. Chart reviews were conducted to obtain patient demographics, catheter complications, time of IPC removal or death, x-ray imaging, and pleural fluid characteristics. RESULTS: We identified 27 MPEs because of melanoma and 1114 because of nonmelanoma malignancies treated with IPC. The most frequent complication was pleural fluid loculation requiring fibrinolytics which was significantly higher in the melanoma (14.8%) compared with the nonmelanoma group (3.8%; P =0.02). Cumulative incidence functions for catheter removal ( P =0.8) or death with catheter in situ ( P =0.3) were not significant between melanoma and nonmelanoma groups in competing risk analysis. Baseline radiographic pleural effusion scores were similar, but became significantly higher (increased pleural opacity) in the melanoma group at time points following IPC insertion ( P <0.05). CONCLUSION: MPEs because of melanoma had a higher rate of loculations requiring fibrinolytics and less radiographic improvement after IPC insertion suggesting this patient subgroup has a more complicated pleural space which may be less responsive to drainage.

Protocol for the Stather Canadian Outcomes Registry for Chest ProcedurEs (SCOPE).

INTRODUCTION: The Stather Canadian Outcomes registry for chest ProcedurEs (SCOPE registry) is a Canadian multicentre registry of chest procedures. METHODS AND ANALYSIS: The SCOPE registry is designed as a multicentre prospective database of specific bronchoscopic or other pulmonary procedures. Each procedure of interest will be associated with a registry module, and data capture designed to evaluate effectiveness of procedures on relevant patient outcomes. Participating physicians will be asked to enter data for all procedures performed in a given module. The anonymised dataset will be housed in a web-based electronic secure database. Specific modules included will be based on participating physician suggestions, capacity and consensus of the steering committee and relevance of hypotheses/research potential. ETHICS AND DISSEMINATION: The central registry is under approval from the Conjoint Health Research Ethics Board at the University of Calgary. We aim for registry data to lead to publication of manuscripts in international medical journals as the primary mode of dissemination. Data may also be used by local investigators for personal and/or institutional quality control purposes as well as to inform health policies. Data requests from non-participating investigators for use under ethics approved research protocols can be considered.

Clinical Predictors of Successful and Earlier Removal of Indwelling Pleural Catheters in Benign Pleural Effusions.

BACKGROUND: Indwelling pleural catheters (IPCs) are an emerging therapy for persistent benign pleural effusions. IPCs may achieve pleurodesis and be removed. OBJECTIVES: We aimed to identify factors associated with higher pleurodesis rates and earlier IPC removal in benign pleural effusions. METHODS: We reviewed a database of IPCs inserted for nonmalignant pleural effusions in the period August 2007 to June 2017 in patients who underwent medical thoracoscopy (MT). Clinical, radiologic, and pleural fluid data were recorded. Logistic regression and Cox proportional hazards were used to assess the rate of and time to pleurodesis. RESULTS: 304 IPCs were reviewed. 52 were excluded from the pleurodesis analysis due to removal for another reason, or because of an eventual diagnosis of malignant disease. The overall pleurodesis rate was 74%, and median time to pleurodesis was 42 (IQR 18-93) days. Variables with increased pleurodesis rates in multivariate analysis include Eastern Cooperative Oncology Group performance status score of ≤2 (odds ratio [OR] 4.22, 95% confidence interval [CI] 1.75-10.16) and MT (OR 5.27, 95% CI 2.74-10.11). No variables were associated with reduced pleurodesis rates in multivariate analysis. Variables that predicted earlier removal in multivariate analysis included secondary pleural infection (hazard ratio [HR] 14.19, 95% CI 4.11-48.91), % eosinophils (HR 1.03, 95% CI 1.01-1.05), and connective tissue disease (HR 2.59, 95% CI 1.20-5.57). Variables that predicted delayed removal include pleural effusion above the hilum (HR 0.54, 95% CI 0.34-0.85), liver failure (HR 0.31, 95% CI 0.16-0.60), and heart failure (HR 0.32, 95% CI 0.20-0.52). CONCLUSIONS: IPCs are safe in benign effusions. Clinicians should consider numerous factors when predicting the rate of and time to pleurodesis.

Catheter Tract Metastasis in Mesothelioma Patients with Indwelling Pleural Catheters: A Retrospective Cohort Study.

BACKGROUND: Use of indwelling pleural catheters (IPCs) for the management of symptomatic pleural effusions in patients with mesothelioma has increased in popularity. An important concern with this approach is the potential for the development of catheter tract metastasis (CTM). OBJECTIVES: To determine the incidence of IPC-related CTM in patients with malignant pleural mesothelioma (MPM). METHODS: In this single-center retrospective cohort study, patients with biopsy-confirmed MPM who had an IPC inserted between May 2006 and July 2017 were identified from a prospectively collected database. Thoracic CT scans following IPC insertion were reviewed to assess for evidence of CTM. Patients were followed until death or last documented patient encounter with a minimum of 6-month follow-up. RESULTS: A total of 90 patients were included in the cohort. CTM was identified in 23 of 90 patients (26%). Median time from IPC insertion to CTM was 408 days (interquartile range 196-721 days). Medical thoracoscopy at the time of IPC insertion did not lead to a significantly increased odds of CTM (OR 2.30; 95% CI 0.66-7.94; p = 0.19). Incidence of CTM was not different between mesothelioma subtypes (p = 0.09). Patient-reported dyspnea scores were improved following IPC insertion in 80% of patients. CONCLUSIONS: CTM was identified in over a quarter of MPM patients when follow-up imaging was reviewed. Treating physicians should be cognizant of the possibility of CTM at the site of prior IPC.

Effect of Chemotherapy on Removal of Indwelling Pleural Catheters in Breast Cancer Patients with Malignant Pleural Effusions.

BACKGROUND: Indwelling pleural catheters (IPC) are commonly used in the management of malignant pleural effusions (MPE). The effect of systemic chemotherapy on IPC removal has not been reported previously. OBJECTIVES: The purpose of this study is to identify the effect of chemotherapy on the removal of IPCs in breast cancer patients with MPEs. METHODS: In this retrospective cohort study at an academic tertiary-care center, patients with breast cancer and MPE who received an IPC between 2006 and 2016 were identified from a prospectively collected database. Patient chemotherapy data were obtained, as well estrogen receptor (ER) and human epidermal growth factor receptor-2 status at the time of diagnosis. Patients receiving chemotherapy while their IPC was in situ were compared to those who did not. The primary outcome was time to IPC removal. All patients were followed until IPC removal or death. RESULTS: A total of 207 patients and 216 IPCs were included in the analysis. There was no difference in time to IPC removal between the chemotherapy and no-chemotherapy groups (HR 0.73, 95% CI 0.50-1.07, p = 0.10) or rate of IPC removal (OR 1.16, 95% CI 0.68-1.98, p = 0.59). The risk of IPC infection was not different between patients who received chemotherapy and those who did not (RR 0.57, 95% CI 0.06-5.39, p = 0.48). CONCLUSIONS: Treatment with chemotherapy with an IPC in situ was not associated with a reduced time to IPC removal in our breast cancer population. IPC insertion in patients receiving chemotherapy is safe and not associated with an increased risk of infection.

Clinical predictors of successful and earlier pleurodesis with a tunnelled pleural catheter in malignant pleural effusion: a cohort study.

BACKGROUND: Tunnelled pleural catheters used to treat malignant pleural effusions may achieve pleurodesis. We aimed to identify factors associated with higher pleurodesis rates and earlier catheter removal. METHODS: We retrospectively reviewed a prospective database of tunnelled pleural catheters inserted consecutively between May 2006 and June 2013 for confirmed malignant pleural effusion. The cohort included patients who underwent medical thoracoscopy. Clinical, radiologic and pleural fluid data were recorded. We used logistic regression and Cox regression to assess rates of and days to pleurodesis, respectively. RESULTS: We analyzed data for 1071 tunnelled pleural catheters in 956 patients. Increased rates of pleurodesis were associated with lymphoma (odds ratio [OR] 3.49, 95% confidence interval [CI] 1.93-6.33), ovarian cancer (OR 2.93, 95% CI 1.68-5.11), Eastern Cooperative Oncology Group Scale of Performance Status grade 2 or less (OR 2.79, 95% CI 1.79-4.34), medical thoracoscopy (OR 2.21, 95% CI 1.28-3.85), protein level (OR 1.03, 95% CI 1.01-1.06), albumin level (OR 1.07, 95% CI 1.03-1.12) and percent eosinophils (OR 1.04, 95% CI 1.00-1.07). Reduced rates of pleurodesis were associated with gastrointestinal cancers (OR 0.41, 95% CI 0.19-0.87), hydropneumothorax on the postdrainage chest radiograph (OR 0.62, 95% CI 0.41-0.94) and percent other cells on cell count (OR 0.98, 95% CI 0.97-0.99). Earlier pleurodesis was associated with ovarian cancer (hazard ratio [HR] 1.48, 95% CI 1.06-2.08), medical thoracoscopy (HR 1.45, 95% CI 1.10-1.92), protein level (HR 1.03, 95% CI 1.01-1.04) and percent eosinophils (HR 1.02, 95% CI 1.00-1.04). Delayed pleurodesis was associated with breast cancer (HR 0.61, 95% CI 0.46-0.81), hydropneumothorax with 80% or less lung expansion (HR 0.55, 95% CI 0.38-0.80) and percent other cells (HR 0.99, 95% CI 0.98-1.00). INTERPRETATION: Clinicians should consider numerous factors to predict the probability of and timing to pleurodesis with tunnelled pleural catheters.

Pigment epithelium-derived factor short peptides facilitate full-thickness cutaneous wound healing by promoting epithelial basal cell and hair follicle stem cell proliferation.

A previous study by our group showed that a 44-amino-acid fragment of pigment epithelium-derived factor (PEDF) facilitated corneal epithelial wound healing. In the present study this fragment was shortened to obtain peptides of 18, 20 and 29 amino acids in length, and their promoting effects on the healing of full-thickness skin wounds were assessed. Peptides were delivered periodically by topical application to punch wounds of mice. The wound healing speed was evaluated by measuring the reduction of wound areas at 4 and 7 days after injury. Histological analysis with Masson's trichrome staining was used to confirm epithelialization and dermal collagen deposition. Proliferation of epithelial basal cells was documented by 5-bromo-2'-deoxyuridine incorporation. Hair follicle stem cells were identified by immunostaining for leucine-rich repeat-containing G protein-coupled receptor 6. The results indicated that the 20- and 29-amino-acid short peptides significantly reduced the time required for wound healing compared to the vehicle. Histological analysis confirmed faster epithelial cell coverage of open wounds. Treatment with the PEDF peptide fragments also contributed to granulation, tissue formation by increasing the fibroblast population and enhancing collagen deposition in the dermis. Wounds treated with PEDF peptide fragments contained more basal cells proliferated in the epithelium. Moreover, hair follicle stem cells were also stimulated to proliferate by peptide exposure. In conclusion, the present study reported the identification of two short peptides that can enhance the healing of full-thickness skin wounds following topical application. The underlying mechanisms may involve activation of basal cell proliferation and mobilization of hair follicle stem cells.

Safety and Performance Characteristics of Outpatient Medical Thoracoscopy and Indwelling Pleural Catheter Insertion for Evaluation and Diagnosis of Pleural Disease at a Tertiary Center in Canada.

BACKGROUND: Many centers performing medical thoracoscopy (MT) to diagnose pleural disease will insert a chest tube and admit patients to hospital after the procedure, which is inconvenient for patients and contributes to healthcare costs. We report the data on the safety, outcomes, and performance characteristics of outpatient MT with indwelling pleural catheter (IPC) insertion in a large Canadian cohort. METHODS: This retrospective cohort study reviewed patients who underwent outpatient MT and IPC insertion under conscious sedation. Patients without complications were discharged the same day. We report the data on safety, outcomes, and performance characteristics of our program. RESULTS: Outpatient MT and IPC insertion was performed on 218 patients. 99.1% of patients were safely discharged the same day. There was no procedure associated mortality. Pleural malignancy (59.6%) and nonspecific pleuritis (29.4%) were the most common pathologies. Pleural nodularity detected endoscopically was excellent at predicting malignancy with a positive predictive value of 92.5% and is more frequently detected endoscopically when compared to CT scan (p < 0.001). CONCLUSIONS: In the setting of a comprehensive pleural disease program, outpatient MT can be safely performed and is an alternative to an inpatient surgical approach for undiagnosed pleural effusions.

Early Bronchus-Associated Lymphoid Tissue Lymphoma Diagnosed with Immunoglobulin Heavy Chain Molecular Testing.

When extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT), a low grade B-cell lymphoma, arises in the lung it is referred to as bronchus-associated lymphoid tissue (BALT) lymphoma. We describe a patient with a history of Sjögren's syndrome and rheumatoid arthritis with dyspnea and imaging consistent with lymphoid interstitial pneumonia (LIP). However, while histology and immunohistochemistry lacked definitive features of a lymphoma, immunoglobulin heavy chain (IgH) polymerase chain reaction testing demonstrated B-cell monoclonality, consistent with an early BALT lymphoma.

Prevalence of osteopenia and osteoporosis in patients with moderate to severe asthma in Western Canada.

PURPOSE: Steroids, inhaled and systemic, are used to treat airway inflammation in patients with asthma; however, steroids are recognized to cause a number of side effects, including osteoporosis. We evaluated the prevalence of osteopenia/osteoporosis in patients with moderate-severe asthma managed through the Edmonton Regional Severe Asthma Centre. METHODS: We performed a retrospective chart review and analyzed 57 charts on patients with moderate-severe asthma followed through the specialty clinic, and recorded their bone mineral density (BMD). Steroid use was reviewed and the frequency of osteopenia/osteoporosis was compared in patients requiring continuous systemic steroids (Group 1, n=15), intermittent systemic steroids (Group 2, n=15) or inhaled steroids only (Group 3, n=27). RESULTS: The mean age (mean±SD) was 50±14.8 years. Cumulative systemic steroid dose of prednisone equivalent was higher in Group 1 (12.5 mg/day) than Group 2 (3.2 mg/day) (p=0.002). The frequency of osteopenia / osteoporosis was not significantly different between patients in Group 1(67%) and Group 2 (53%, p=0.46) but was significantly greater in patients from Group 1 in comparison with Group 3 (33%, p=0.038). CONCLUSION: Patients with moderate-severe asthma have a high prevalence of reduced bone density. Many patients treated with intermittent systemic steroids for exacerbations, or who were stable on inhaled steroids, had either osteopenia or osteoporosis before the age of 50. National and international osteoporosis guidelines should emphasize earlier screening for asthma patients; and increase awareness of the detrimental effects of short-term systemic steroids and inhaled steroids on BMD, especially when started at an early age and in northern climates.

Radar-raingauge data combination techniques: a revision and analysis of their suitability for urban hydrology.

The applicability of the operational radar and raingauge networks for urban hydrology is insufficient. Radar rainfall estimates provide a good description of the spatiotemporal variability of rainfall; however, their accuracy is in general insufficient. It is therefore necessary to adjust radar measurements using raingauge data, which provide accurate point rainfall information. Several gauge-based radar rainfall adjustment techniques have been developed and mainly applied at coarser spatial and temporal scales; however, their suitability for small-scale urban hydrology is seldom explored. In this paper a review of gauge-based adjustment techniques is first provided. After that, two techniques, respectively based upon the ideas of mean bias reduction and error variance minimisation, were selected and tested using as case study an urban catchment (∼8.65 km(2)) in North-East London. The radar rainfall estimates of four historical events (2010-2012) were adjusted using in situ raingauge estimates and the adjusted rainfall fields were applied to the hydraulic model of the study area. The results show that both techniques can effectively reduce mean bias; however, the technique based upon error variance minimisation can in general better reproduce the spatial and temporal variability of rainfall, which proved to have a significant impact on the subsequent hydraulic outputs. This suggests that error variance minimisation based methods may be more appropriate for urban-scale hydrological applications.

A spatial-temporal rainfall generator for urban drainage design.

The work presented here is a contribution to the Thames Water project of improving the Counters Creek catchment sewerage system in London. An increase in the number of floods affecting basements in the area has indicated the need for improvements to the system. The cost of such improvements could be very high, and as such it is important to determine whether the traditional approach of applying 30-year spatially uniform design storms results in substantial overestimation. The first step in this is to generate simulations of spatially distributed rainfall events, from which 30-year storms can be extracted. Storms are modelled as clusters of Gaussian rainfall cells, extending the earlier Willems method to radar rainfall data. The parameters describing the cells and their motion are sampled from probability distributions derived from parameter estimates gained from 45 historical storm events within the catchment for the period 2000-2011. This spatial-temporal stochastic rainfall generator produces a two-dimensional time series of simulated storm events, from which events of given return period can be identified.

DDB2 is a novel AR interacting protein and mediates AR ubiquitination/degradation.

Damaged DNA-binding protein 2 (DDB2), a protein that binds damaged DNA, is a DDB1 and CUL4-associated factor. This study is the first to demonstrate that DDB2 is a novel androgen receptor (AR)-interacting protein; and mediating contact with AR and CUL4A-DDB1 complex for AR ubiquitination/degradation. DNA damage induces both p53 and DDB2 gene expression those two can inhibit AR expression. The former reduces AR via transcription regulation but the latter via proteosome degradation. Thereby DDB2 can inhibit cell growth rate in AR-expressing cells (LNCaP) but not in AR-null cells (PC3). Hence DDB2 may be a potential regimen for prostate cancer treatment, especially in androgen-refractory patients harboring high amount of AR who cannot be cured by androgen ablation.